Sixth Edition

Jubb, Kennedy, and Palmer’s

Pathology of
DOMESTIC
ANIMALS
Volume 3
This page intentionally left blank
Sixth Edition

Jubb, Kennedy, and Palmer’s

Pathology of
DOMESTIC
ANIMALS
Volume 3

EDITED BY:

M. GRANT MAXIE, DVM, PHD, DIPLOMATE ACVP

Co-Executive Director, Laboratory Service Division
Director, Animal Health Laboratory
University of Guelph
Guelph, Ontario
Canada
3251 Riverport Lane
St. Louis, Missouri 63043

JUBB, KENNEDY, AND PALMER’S PATHOLOGY ISBN: 978-0-7020-5322-1 (3 VOLUME SET)

OF DOMESTIC ANIMALS, SIXTH EDITION 978-0-7020-5317-7 (VOLUME 1)
978-0-7020-5318-4 (VOLUME 2)
978-0-7020-5319-1 (VOLUME 3)

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Library of Congress Cataloging-in-Publication Data

Jubb, Kennedy, and Palmer’s pathology of domestic animals / edited by M. Grant Maxie.—Sixth
edition.
   p. ; cm.
  title: Pathology of domestic animals
  Includes bibliographical references and index.
  ISBN 978-0-7020-5322-1 (3 vol. set : alk. paper)—ISBN 978-0-7020-5317-7 (v. 1 : alk. paper)—
ISBN 978-0-7020-5318-4 (v. 2 : alk. paper)—ISBN 978-0-7020-5319-1 (v. 3 : alk. paper)
  I.  Maxie, M. Grant, editor.  II.  Title: Pathology of domestic animals.
  [DNLM:  1.  Pathology, Veterinary.  2.  Animals, Domestic.  SF 769]
  SF769.P345 2016
  636.089’607—dc23
2015009121
Vice President and Publisher: Loren Wilson Publishing Services Managers: Anne Altepeter and
Content Strategy Director: Penny Rudolph Patricia Tannian
Content Development Manager: Jolynn Gower Senior Project Manager: Sharon Corell
Content Development Specialist: Brandi Graham Project Manager: Louise King
Content Coordinator: Kayla Mugle Designer: Brian Salisbury

Printed in China

Last digit is the print number:  9  8  7  6  5  4  3  2  1 

Contributors

Dorothee Bienzle, DVM, PhD, Barry J. Cooper, BVSc, PhD,

Diplomate ACVP Diplomate ACVP
Professor Professor Emeritus of Pathology
Department of Pathobiology Department of Biomedical Sciences
Ontario Veterinary College Cornell University
University of Guelph Ithaca, New York
Pathobiology USA
University of Guelph Muscle and tendon
Guelph, Ontario
Canada
Hematopoietic system Linden E. Craig, DVM, PhD,
Diplomate ACVP
Department of Biomedical and
Carlo Cantile, DVM, PhD Diagnostic Sciences
Professor of Veterinary Pathology University of Tennessee College of
Department of Veterinary Science Veterinary Medicine
University of Pisa Knoxville, Tennessee
Pisa, Italy USA
Nervous system Bones and joints

John M. Cullen, VMD, PhD,

Diplomate ACVP
Jeff L. Caswell, DVM, DVSc, PhD, Professor
Diplomate ACVP Department of Population Health and
Professor Pathobiology
Department of Pathobiology College of Veterinary Medicine
Ontario Veterinary College North Carolina State University
University of Guelph Raleigh, North Carolina
Guelph, Ontario USA
Canada Liver and biliary system
Respiratory system

Keren E. Dittmer, BVSc, PhD,

Rachel E. Cianciolo, VMD, PhD, Diplomate ACVP
Diplomate ACVP Institute of Veterinary, Animal, and
Assistant Professor Biomedical Sciences
Co-Director, International Veterinary Massey University
Renal Pathology Service Palmerston North, Manawatu
Department of Veterinary Biosciences New Zealand
College of Veterinary Medicine Bones and joints
The Ohio State University
Columbus, Ohio
USA
Urinary system

v
vi Contributors

Robert A. Foster, BVSc, PhD, Elizabeth A. Mauldin, DVM,

MACVSc, Diplomate ACVP Diplomate ACVP, Diplomate ACVD
Professor Associate Professor
Department of Pathobiology Department of Pathobiology
Ontario Veterinary College School of Veterinary Medicine
University of Guelph University of Pennsylvania
Guelph, Ontario Philadelphia, Pennsylvania
Canada USA
Female genital system Integumentary system
Male genital system

M. Grant Maxie, DVM, PhD,

Andrea Gröne, DVM, PhD, Diplomate ACVP
Diplomate ACVP, Diplomate ECVP Co-Executive Director, Laboratory
Professor Service Division
Faculty of Veterinary Medicine Director, Animal Health Laboratory
Department of Pathobiology University of Guelph
Utrecht University Guelph, Ontario
Utrecht, The Netherlands Canada
Endocrine glands Introduction to the diagnostic process

Jesse M. Hostetter, DVM, PhD, Margaret A. Miller, DVM, PhD,

Diplomate ACVP Diplomate ACVP
Associate Professor Professor
Department of Veterinary Pathology Department of Comparative
College of Veterinary Medicine Pathobiology
Iowa State University Purdue University
Ames, Iowa West Lafayette, Indiana
USA USA
Alimentary system Introduction to the diagnostic process

Kenneth V. F. Jubb† F. Charles Mohr, DVM, PhD,

Emeritus Professor
Faculty of Veterinary and Agricultural
Sciences
University of Melbourne
Melbourne, Victoria, Australia
Pancreas
Matti Kiupel, Dr med vet habil, PhD,
Diplomate ACVP
Professor
Department of Pathobiology and
Diagnostic Investigation
College of Veterinary Medicine
Michigan State University
East Lansing, Michigan
USA
Hematopoietic system
Diplomate ACVP
Professor of Clinical Anatomic
Pathology
Department of Veterinary Pathology,
Microbiology, and Immunology
School of Veterinary Medicine
University of California
Davis, California
USA
Urinary system
Bradley L. Njaa, DVM, MVSc,
Diplomate ACVP
Anatomic Pathologist III
IDEXX Laboratories, Inc.
Professor (Adjunct)
Department of Veterinary Pathobiology
Oklahoma State University
Stillwater, Oklahoma
USA
Special senses

†
Deceased.
 Contributors vii

Jeanine Peters-Kennedy, DVM, Donald H. Schlafer, DVM, PhD,

Diplomate ACVP, Diplomate ACVD
Assistant Clinical Professor
Department of Biomedical Sciences
College of Veterinary Medicine
Cornell University
Ithaca, New York
USA
Integumentary system
Diplomate ACVP/ACVM/ACT
Emeritus Professor
Department of Biomedical Sciences
College of Veterinary Medicine
Cornell University
Ithaca, New York
USA
Female genital system

Brandon L. Plattner, DVM, PhD, Margaret J. Stalker, DVM, PhD,

Diplomate ACVP Diplomate ACVP
Assistant Professor Animal Health Laboratory
Department of Pathobiology Laboratory Services Division
Ontario Veterinary College University of Guelph
University of Guelph Guelph, Ontario
Guelph, Ontario Canada
Canada Liver and biliary system
Alimentary system

Andrew W. Stent, BVSc,

Nicholas A. Robinson, BVSc (Hons), MANZCVS, PhD
PhD, MACVSc, Diplomate ACVP Faculty of Veterinary and Agricultural
Professor Sciences
College of Veterinary Medicine University of Melbourne
University of Minnesota Melbourne, Victoria
St. Paul, Minnesota Australia
USA Pancreas
Cardiovascular system

Keith G. Thompson, BVSc, PhD,

Wayne F. Robinson, BVSc, MVSc, Diplomate ACVP
PhD, MACVSc, Diplomate ACVP Emeritus Professor
Emeritus Professor Pathobiology Section
Federation University Australia Institute of Veterinary, Animal, and
Victoria, Australia Biomedical Sciences
Cardiovascular system Massey University
Palmerston North, Manawatu
New Zealand
Bones and joints

Thomas J. Rosol, DVM, PhD,

Diplomate ACVP Francisco A. Uzal, DVM, FRVC, PhD,
Professor Diplomate ACVP
Department of Veterinary Biosciences California Animal Health and Food
Senior Advisor, Life Sciences, Safety Laboratory
Technology Commercialization University of California
Office San Bernardino, California
College of Veterinary Medicine USA
The Ohio State University Alimentary system
Columbus, Ohio
USA
Endocrine glands
viii Contributors

Beth A. Valentine, DVM, PhD, Kurt J. Williams, DVM, PhD,

Diplomate ACVP Diplomate ACVP
Professor Department of Pathobiology and
Department of Biomedical Sciences Diagnostic Investigation
College of Veterinary Medicine College of Veterinary Medicine
Oregon State University Michigan State University
Corvallis, Oregon East Lansing, Michigan
USA USA
Muscle and tendon Respiratory system

V.E.O. (Ted) Valli, DVM, PhD, R. Darren Wood, DVM, DVSc,

Diplomate ACVP
Professor Emeritus
Department of Pathobiology
College of Veterinary Medicine
University of Illinois at
Urbana-Champaign
Champaign, Illinois
USA
Hematopoietic system
Diplomate ACVP
Associate Professor
Department of Pathobiology
Ontario Veterinary College
University of Guelph
Guelph, Ontario
Canada
Hematopoietic system

Sameh Youssef, BVSc, PhD, DVSc,

Brian P. Wilcock, DVM, PhD Diplomate ACVP
Histovet Surgical Pathology Professor
Guelph, Ontario Department of Pathology
Canada Alexandria Veterinary College
Special senses Alexandria University
Alexandria, Egypt
Nervous system
Preface
In this sixth edition of Pathology of Domestic Animals, we
continue the long tradition of surveying the literature and
updating the information in this reference textbook in light
of our own practical experience in the pathology of the major
domestic mammals. True to the spirit of the first edition, this
text is designed to explain the pathogenesis of common and
not-so-common diseases, define the distinguishing features of
these various conditions, and put them in a context relevant
to both students and working pathologists. Knowledge has
been generated incrementally since the publication of the fifth
edition, particularly with respect to improved understanding
of pathogenesis at the molecular level, as well as through the
use of improved diagnostic tools, including the frontier of
whole genome sequencing. My thanks to the contributors to
this edition for their rigorous perusal of the literature in their
areas of interest, for their addition of insightful information
to their chapters, and for their inclusion of many new figures.
NEW TO THE SIXTH EDITION
The most noticeable, and I think very welcome, change in the
sixth edition is the addition of full-color figures throughout
the text. Nearly all of the images from prior editions have
been replaced. These new images clearly depict the diagnostic
features of hundreds of conditions.
We have also added a new chapter, “Introduction to the
Diagnostic Process,” to the usual lineup of chapters in these 3
volumes. The goal of this new chapter is to illustrate the
whole-animal perspective and detail the approaches to sys-
temic, multi-system, and polymicrobial disease.
The complete index is again printed in each volume as an
aid to readers. “Further reading” lists have been pruned in the
print book to save space. All references are available on any
electronic version of the text as well as on the companion
website that accompanies the purchase of any print book.
These online references link to abstracts on PubMed.com.
COMPANION WEBSITE
In addition to updating the graphic design of these volumes,
the print version of Pathology of Domestic Animals now has a
companion website, accessible at:
PathologyofDomesticAnimals.com
Included on the companion website are:
• A complete image collection, including 325 bonus, elec-
tronic-only figures that have been called out in the text.
These figures are identified in the printed version as “eFigs.”
• An expanded list of useful references, each linked to the
original abstract on PubMed.com.
I hope that we have captured significant changes and
have synthesized this new knowledge to provide a balanced
overview of all topics covered. Keeping pace with evolving
agents and their changing impacts is a never-ending challenge.
We have used current anatomical and microbial terminology,
based on internationally accepted reference sources, such as
the Universal Virus Database of the International Committee
on Taxonomy of Viruses (http://www.ncbi.nlm.nih.gov/
ICTVdb/index.htm). Microbial taxonomy is, of course, con-
tinually evolving, and classifications and names of organisms
can be expected to be updated as newer phylogenetic analyses
are reported. Debate continues, for example, over the
taxonomy of Chlamydophila/Chlamydia spp. And change will
continue.
We have attempted to contact all contributors of figures
from previous editions and from various archives and apolo-
gize to any whom we were unable to contact or who were
overlooked. If any individual recognizes an image as one of
his/her own or as belonging to a colleague, we would be happy
to correct the attribution in a future printing.
Acknowledgments
My thanks to Elsevier for their help and support throughout
this project, beginning in the United Kingdom with Robert
Edwards and Carole McMurray, and more recently in the
United States, with Penny Rudolph, content strategy director;
Brandi Graham, content development specialist; Sharon
Corell, senior project manager; Louise King, project manager,
and the entire behind-the-scenes production team.
Grant Maxie
Guelph, Ontario, 2015
ix
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 These volumes are dedicated to Drs. Kenneth V.F. Jubb (1928-2013)1,
Peter C. Kennedy (1923-2006)2, and Nigel C. Palmer,
and to my family—Laura, Kevin, and Andrea.

Drs. Palmer, Jubb, and Kennedy while working on the third edition in Melbourne, 1983. (Courtesy,
University of Melbourne.)

1
http://www.vet.unimelb.edu.au/news/2013/memorial.html
2
http://senate.universityofcalifornia.edu/inmemoriam/peterckennedy.htm
This page intentionally left blank
Contents

VOLUME ONE 3 Pancreas  353

1 Introduction to the Diagnostic Process  1
M. Grant Maxie, Margaret A. Miller
2 Bones and Joints  16
Linden E. Craig, Keren E. Dittmer, Keith G. Thompson
3 Muscle and Tendon  164
Barry J. Cooper, Beth A. Valentine
4 Nervous System  250
Carlo Cantile, Sameh Youssef
5 Special Senses  407
Brian P. Wilcock, Bradley L. Njaa
6 Integumentary System  509
Elizabeth A. Mauldin, Jeanine Peters-Kennedy
VOLUME TWO
1 Alimentary System  1
Francisco A. Uzal, Brandon L. Plattner,
Jesse M. Hostetter
2 Liver and Biliary System  258
John M. Cullen, Margaret J. Stalker
Kenneth V.F. Jubb†, Andrew W. Stent
4 Urinary System  376
Rachel E. Cianciolo, F. Charles Mohr
5 Respiratory System  465
Jeff L. Caswell, Kurt J. Williams
VOLUME THREE
1 Cardiovascular System  1
Wayne F. Robinson, Nicholas A. Robinson
2 Hematopoietic System  102
V.E.O. (Ted) Valli, Matti Kiupel,
Dorothee Bienzle (with R. Darren Wood)
3 Endocrine Glands  269
Thomas J. Rosol, Andrea Gröne
4 Female Genital System  358
Donald H. Schlafer, Robert A. Foster
5 Male Genital System  465
Robert A. Foster

†
Deceased

xiii
This page intentionally left blank
CHAP TER 1 
Cardiovascular System
Wayne F. Robinson  •  Nicholas A. Robinson
DISEASES OF THE HEART 2
GENERAL CONSIDERATIONS 2
Normal structure and function 2
Morphologic patterns of heart disease 4
The mural and valvular endocardium and the heart
valves proper 4
The myocardium 4
The pericardium 5
Pathophysiologic patterns of heart disease 5
Disturbances of impulse formation or impulse conduction 5
Depressed myocardial contractile strength 5
Impeded blood flow 5
Regurgitant blood flow 5
Abnormal pattern of blood flow (shunted blood flow) 6
Restricted atrial/ventricular filling 6
HEART FAILURE 6
Intrinsic cardiac responses in heart failure 7
Cardiac dilation 7
Cardiac hypertrophy 7
Systemic responses in heart failure 9
Syndromes of circulatory failure 10
Cardiac syncope 10
Peripheral circulatory failure 10
Congestive heart failure 10
EXAMINATION OF THE HEART 12
CONGENITAL ABNORMALITIES OF THE HEART AND
LARGE VESSELS 14
Malformations causing systemic to pulmonary
(left-to-right) shunting 16
Atrial septal defect 16
Atrioventricular (AV) septal defect 17
Ventricular septal defect 17
Patent ductus arteriosus 17
Malformation of semilunar or atrioventricular valves 19
Pulmonic stenosis 19
Tetralogy of Fallot 20
Aortic and subaortic stenosis 20
Dysplasia of the right atrioventricular valve 21
Left atrioventricular valvular insufficiency or stenosis 22
Transposition complexes 22
Miscellaneous cardiac anomalies 22
Vascular anomalies 23
PERICARDIAL DISEASE 24
Noninflammatory lesions of the pericardium 24
Hydropericardium 24
Hemopericardium 25
Serous atrophy of pericardial fat 25
Pericarditis 25
ENDOCARDIAL DISEASE 27
Degenerative lesions 27
Myxomatous valvular degeneration (“endocardiosis”) in dogs 27
Valvular cysts 30
Subendocardial fibrosis 30
Subendocardial mineralization 30
Endocarditis 30
MYOCARDIAL DISEASE 33
Hemorrhage of the heart and its membranes 33
Myocardial degeneration 34
Myocardial necrosis 34
Fluoroacetate poisoning 37
Gousiekte 38
Avocado poisoning 38
Taurine deficiency in cats 38
Myocardial necrosis secondary to neural injury 39
Doxorubicin (Adriamycin) cardiotoxicity 39
Porcine stress syndrome (pale, soft, and exudative [PSE] pork) 39
Mulberry heart disease of swine 39
Myocarditis 41
Encephalomyocarditis virus infection 43
Parasitic myocarditis 43
Cardiomyopathies 44
Feline cardiomyopathies 46
Canine cardiomyopathies 48
Bovine cardiomyopathies 50
DISEASES OF THE CONDUCTION SYSTEM 51
NEOPLASMS OF THE HEART 52
DISEASES OF THE VASCULAR SYSTEM 54
GENERAL CONSIDERATIONS 54
ARTERIES 56
Congenital anomalies 56
Degeneration of arteries 56
Arteriosclerosis 56
Atherosclerosis 57
Arteriolosclerosis 59
Mineralization 60
Arterial rupture, aneurysms 62
Arterial thrombosis and embolism 63
Aortic-iliac thrombosis in horses 64
Disseminated intravascular coagulation 64
Arterial hypertrophy 66
“High-altitude disease” of cattle 66
Congenital and acquired cardiac disease and pulmonary
arterial hypertension 66
Medial hypertrophy of the pulmonary arteries of cats 67
Vasculitis 67
Polyarteritis nodosa (panarteritis or periarteritis nodosa) 71
Viral vasculitides 71
Rickettsial vasculitides 80
Verminous arteritis 83
VEINS 88
Phlebothrombosis and thrombophlebitis 89
Parasitic thrombophlebitis 91
Schistosomiasis (bilharziasis) 91
LYMPHATICS 94
Congenital anomalies 94
Dilation and rupture of lymphatics 95
Lymphangitis 96
Ulcerative lymphangitis 97
Epizootic lymphangitis 97
Parasitic lymphangitis 98
VASCULAR NEOPLASMS 98
Angioma 99
Angiosarcoma 99
1
2 CHAPTER 1  •  Cardiovascular System
ACKNOWLEDGMENTS
This update of the Cardiovascular System chapter is based on
previous editions by Drs. Ken Jubb, Peter Kennedy, Nigel Palmer,
Wayne Robinson, and Grant Maxie, and their contributions are
gratefully acknowledged.
DISEASES OF THE HEART
GENERAL CONSIDERATIONS
The heart is structured and functions to fulfill a singular role,
which is to move sufficient volumes of blood to all organs in
the body to meet the varying metabolic needs of the organism.
For this purpose, the heart can be described as an in-series,
2-stage, rate-variable, one-way pump. From this characteriza-
tion, the heart must provide sufficient force to eject the blood
it receives, respond to the host’s needs by varying the amount
of blood ejected per unit time, and finally, ensure one-way
flow without impediment of forward flow as well as prevent
backflow. As befits a biological pump, the heart is a physically
active organ that rhythmically contracts and relaxes which,
over an average 10-year lifetime of a dog, beats in the vicinity
of 400 million times and receives and ejects ten million  and ventricular walls.
liters of blood—by any measure, a remarkable and sustained
performance.
If the structure or function of any of the components of
the pump are compromised or fail, it will result in either
diminution, or at worst, complete cessation of function. Addi-
tionally, if each component of the heart as a pump is examined
and understood, it then facilitates the understanding and cat-
egorization of the causes and effects of component dysfunc-
tion. We are concerned predominantly with the diseases that
interfere with the heart’s rate and rhythm, its strength of con-
traction, and the flow of blood through the heart. Heart disease
may be clinically detectable and, when sufficiently severe,  base of the aorta. The left coronary artery gives rise to the left
may give rise to heart failure, or may be only evident on  descending and the left circumflex coronary arteries. The epi-
postmortem (eFig. 1-1).
Under the anatomic units of the pericardium, endocardium,
and myocardium, we will first consider the normal form and
function of the heart, the morphologic patterns of disease, its
pathophysiology, and finally, its reaction to injury and its spe-
cific diseases.
Normal structure and function
Located within the mediastinum, the heart is enclosed in the
fibroserous pericardial sac, which is lined by a serosal mem-
brane and contains several milliliters of clear serous fluid that
acts as a lubricant.
The heart consists of a right and left side; each side consists
of an atrium and a ventricle. The ventricles function as 2
pumps in series. Venous blood from the body enters the right
atrium, passes into the right ventricle, and is pumped through
the pulmonary artery into the lungs to be oxygenated and to
give up its carbon dioxide. Oxygenated blood returns via the
pulmonary veins to the left atrium, enters the left ventricle,
and is then pumped to the body via the aorta. Heart weight
varies with species, age, sex, nutritional status, and fitness level
of the animal; averages about 1% of body weight in newborns;
and decreases to 0.3-0.8% in juveniles and adults.
Ventricular thickness varies greatly. Left ventricular free
wall and interventricular septum are normally 2-4 times
thicker than the right ventricular free wall. An increase in
General Considerations
myocardial mass is termed hypertrophy; an increase in chamber
volume is termed dilation. An overall increase in the external
dimensions of the heart is termed cardiomegaly.
The 4 cardiac valves are structured to allow unimpeded
unidirectional blood flow, to prevent backflow, and to withstand
pressure, especially those of the left side of the heart. The atrio-
ventricular (AV) valves, supported by tendinous cords
(chordae tendineae) and papillary muscles of the ventricles,
allow flow from the atria into the ventricles and prevent
backflow into the atria. The right AV (RAV, tricuspid) valve
has 3 valve cusps (2 cusps in the dog). The left AV (LAV,
bicuspid, mitral) valve in most species consists of 2 cusps. The
pulmonic and aortic semilunar (crescent moon-shaped) valves
each have 3 cusps, and they allow flow into the pulmonary
artery and aorta, respectively, and prevent backflow into the
ventricles. The nodules (nodules of Arantius) in the center of
the free edges of the semilunar valve cusps are normal struc-
tures. Valve cusps are normally thin and translucent. The free
edges of the valve cusps (coaptation region) normally overlap
during closure, and therefore fenestrations of the valve edges
are usually insignificant. Normal valve function depends on
coordinated actions of the respective annulus and leaflets, and
in the case of AV valves, the tendinous cords, papillary muscles,
The cardiac muscle and valves are supported at the base
of the heart by the cardiac skeleton, which consists of 4 fibrous
rings, the fibrous triangle, and the fibrous or membranous part of
the ventricular septum. The fibrous triangle fills the space
between the AV openings and the base of the aorta; it consists
of dense fibrous connective tissue in pigs and cats, fibrocarti-
lage in dogs, hyaline cartilage in horses, and bone (os cordis)
in large ruminants.
The blood supply to the heart is primarily via 2 major coro-
nary arteries. The left and right coronary arteries arise, respec-
tively, behind the left and right cusps of the aortic valve at the
cardial coronary arteries give rise to the intramural arteries that
penetrate the myocardium. Most coronary arterial blood flow
occurs during ventricular diastole, when the coronary microcir-
culation is not compressed by myocardial contraction.
The myocardial conduction system consists of modified
cardiac myocytes that initiate and conduct an electrical
impulse (Fig. 1-1). The sinus node (sinoatrial node, SA node)
is located subepicardially at the junction of the cranial vena
cava and the right auricle. Because cells in the sinus node are
not capable of remaining in a depolarized state, after each
repolarization, their membranes permit leakage of sodium and
potassium until they reach a stage of depolarization (the criti-
cal threshold), when they rapidly depolarize. The impulse
from this pacemaker (the dominant pacemaker) in turn causes
atrial depolarization and contraction, and travels through
internodal bundles to the AV node located in the interatrial
septum just cranial to the coronary sinus. The impulse slows
while traversing the AV node before traveling via the AV
bundle (bundle of His) to the left and right bundle branches,
or crura, through the Purkinje fibers. These modified myocar-
dial cells ramify within the myocardium and transmit the
depolarizing impulse to ventricular myocytes.
Although each component of the conduction system has
different rates of diastolic depolarization, the sinus node has
the most frequent rate and is therefore dominant. The fre-
quency of depolarization of the sinus node is in turn modified
 2.e1

Clinically detectable
No clinical disease,
disease (murmur,
lesion detected
arrhythmia) but no
at autopsy
evidence of failure

Heart disease

May give
rise to

Heart failure

Congestive heart failure Acute heart failure

(fluid accumulation, edema) (collapse, weakness)

Both may be present

eFigure 1-1  Relationship between heart disease and heart

failure. Heart disease may be present without attendant clinical
signs or may give rise to either acute or congestive heart failure.
(Modified from Robinson WF, Huxtable CRR, eds. Clinicopatho-
logic Principles for Veterinary Medicine. Cambridge, UK: 
Cambridge University Press, 1988. Reprinted with permission.)
Diseases of the Heart
Cranial vena cava
SA node
RA
LA AV node
Internodal Left bundle
pathways branch
AV trunk
(bundle of His)
LV
Right bundle RV
branch
Cardiac
conducting fibers
Figure 1-1  The myocardial conduction system. Major species
differences include ramification of the cardiac conduction fibers,
which can reach the subepicardium in some species (not shown).
AV, atrioventricular; LA, left atrium; RA, right atrium; LV, left
ventricle; RV, right ventricle; SA, sinoatrial. (Modified from
Robinson WF, Huxtable CRR, eds. Clinicopathologic Principles
for Veterinary Medicine. Cambridge, UK: Cambridge University
Press, 1988. Reprinted with permission.)
by the autonomic nervous system. Atrial and ventricular myo-
cytes do not normally exhibit the property of automaticity.
However, when atrial or ventricular myocytes are injured,
they may repeatedly depolarize independent of a stimulus
from the conduction system and may become dominant pace-
makers. There are diseases that specifically affect the conduc-
tion system producing dysrhythmias (abnormalities of rate and
rhythm), but it is the dysrhythmias resulting from disease
injuring the atrial and ventricular myocytes that are most
common. The cardiac wall has 3 layers:
1. The epicardium, the outermost layer
2. The myocardium, the thick muscular middle layer
3. The endocardium, the innermost layer, which is continu-
ous with the tunica intima of the great vessels entering and
leaving the heart
The epicardium, or visceral pericardium, consists of a thin
layer of mesothelium resting on elastic fiber-rich connective
tissue that merges with that of the myocardium. The epicar-
dium is continuous with the parietal pericardium, which con-
sists of an inner mesothelial layer and a thick layer of collagen
and elastic fibers. The cavity between the visceral and parietal
pericardium contains serous fluid that lubricates the surfaces
and reduces friction between the epicardium and pericardium
during cardiac motion. Although the pericardial sac is not a
vital organ, its proper function includes prevention of sudden
cardiac dilation, assurance of equal end-diastolic transmural
pressures throughout the ventricles, limitation of right ven-
tricular stroke work, hydrostatic compensation for gravita-
tional or inertial forces, reduction of friction, and maintenance
of cardiac alignment and streamlined cardiac flow.
General Considerations 3
The myocardium, the generator of the force required to
eject blood from the atria and ventricles, consists of striated
muscle cells—cardiac myocytes—embedded in a well-
vascularized connective tissue framework. Individual myo-
cytes, which account for about 2 3 of the myocardial volume,
are intimately joined at intercalated discs to function as a unit.
Each cardiac myocyte consists of a single, central nucleus;
mitochondria; abundant contractile elements (myofibrils),
predominantly composed of actin, myosin, tropomyosin, and
troponin; sarcoplasmic reticulum that stores calcium needed
for the initiation of contraction; and the cell membrane (sar-
colemma) and T tubules needed for impulse conduction.
Myocytes may be binucleate in some species, for instance,
dogs, and are commonly multinucleate in pigs (4-16 nuclei
per cell). The actin and myosin filaments comprise contractile
units called sarcomeres, which are demarcated by Z lines.
Mitochondria occupy about 20-30% of the volume of cardiac
myocytes versus 2% in skeletal muscle, reflective of the great
dependence of cardiac muscle on aerobic metabolism. Sarco-
mere length varies from 1.6-2.2 µm; ventricular dilation
increases sarcomere length, which enhances contractility (Frank-
Starling relationship). Atrial cardiac myocytes are typically
smaller than ventricular cardiac myocytes, predominantly
because they operate in a low-pressure system where less
force is required to eject blood. There are consequently many
fewer myofibrils and mitochondria per cell, but they contain
specific granules encasing the hormone atrial natriuretic factor
(ANF) which is released on dilation or stretching of the atria.
The cardiac interstitium contains blood vessels and fibro-
blasts in a diverse extracellular matrix that consists of colla-
gens, proteoglycans, noncollagenous glycoproteins, growth
factors and cytokines, and extracellular proteases. The collagen
network of the heart is arranged into 3 interconnected regions:
the collagenous weave of the endomysium around individual
fibers, the perimysium around groups of fibers, and the epimy-
sium around the whole muscle. This fibrillar collagenous
network of the myocardium prevents overstretching of myo-
fibers, transmits myofiber-generated force to the chamber, and
provides tensile strength and stiffness to the chamber. The
collagenous struts that connect adjacent myofibers provide
proper alignment during contraction. Struts that connect
myocytes to capillaries help to maintain capillary patency
during high intraventricular pressure.
The endocardium lines the heart and consists of a mono-
layer of endothelium on a continuous basement membrane,
covering the inner subendothelial layer of dense collagen, and
the outer subendothelial layer composed of collagen, elastin,
and blood and lymph vessels. The atrioventricular (AV) valves
are endocardial infoldings with a layer rich in elastin on the
atrial side (atrialis); a central layer (fibrosa) of dense irregular
connective tissue covered by layers of elastic fibers; and, on
the ventricular side, loose connective tissue (spongiosa). The
central collagen of the AV valves is continuous with the dense
collagen of the chordae tendineae, which are attached to the
ventricular papillary muscles. The aortic and pulmonic semi-
lunar valves consist of a ventricularis layer of collagen and
radially aligned elastin on the ventricular side, a central spon-
giosa layer of water and glycosaminoglycans, and a fibrosa layer
of collagen and elastin arranged in a circumferential direction
on the great vessel side of the valves to resist back-pressure of
blood. Valve cusps are predominantly avascular.
The coronary arteries feed a dense capillary network that
supplies the myocardium, endocardium, epicardium, cardiac
4 CHAPTER 1  •  Cardiovascular System
skeleton, and bases of the cardiac valves. Blood collected by
venules and veins is drained into the right atrium via the coro-
nary sinus. Lymphatic capillaries draining the cardiac connec-
tive tissue are continuous with larger lymph vessels in the
endocardium and epicardium. Sympathetic and parasympa-
thetic innervation is extensive in the atria, and particularly
around the SA and AV nodes.
Morphologic patterns of heart disease
The 3 broad anatomic divisions of the heart—the mural and
valvular endocardium, the myocardium, and the pericardium—
exhibit differing features in the face of disease. It is not that
the usual suspects that affect all organs are not in play. Inher-
ited disease, infectious agents, toxins, nutritional deficiencies,
and neoplasia all affect the heart, but it is the combination of
the structure of the heart, the biological characteristics of the
cells comprising the heart, and their response to injury, in
concert with the host’s general response to injury, that results
in the display of the particular features of heart disease. It
should be remembered that the heart may also show evidence
of disease as an integral part of diseases of another organ
system or systemic disease.
The mural and valvular endocardium and
the heart valves proper
Valvular abnormality from any cause can lead to disturbances
of blood flow through the heart either by altering the normal
unidirectional pattern of flow, or by impeding blood flow into
or out of the chambers. Alterations in hemodynamics reflect
changes in systolic workloads characterized by changed pres-
sure loading during contraction (afterload), or changed volume
loading during diastole (preload). Most valvular disorders
impose only a single preload or afterload on the heart. This
encompasses those valvular disorders that cause either insuf-
ficiency (failure to close) or stenosis (narrowing, failure to open).
Some of the congenital heart abnormalities, such as patent
ductus arteriosus and tetralogy of Fallot, have multiple preload
and afterload effects. The general rules are (eFig. 1-2):
1. Valvular insufficiency increases the preload on the
ventricle.
2. Semilunar valvular stenosis, outflow tract stenosis, and
hypertension increase the afterload on the ventricle.
3. AV valvular stenoses and pericardial disorders decrease the
preload on the ventricles.
Subendocardial hemorrhage is a frequent accompaniment
to a myriad of diseases of the heart, but more particularly,
with systemic disease, where the heart is just another surface
where hemorrhage can be observed. Subendocardial mineral-
ization occurs as either a dystrophic or metastatic phenome-
non. Additions to valves and/or the mural endocardium result
from disturbances to the health of the endothelial lining of
the mural and valvular endocardium, and because of the loca-
tion, can have wide-ranging consequences. The most severe
and extensive occurs with microorganisms, particularly bacte-
ria, that arrive via the systemic circulation that adhere to
endothelium and/or subendocardium after the endothelium
has been damaged or eroded. The cascade of events that
follow, especially the incitement of thrombosis, results in a
mass of platelets, fibrin, and inflammatory cells (vegetations)
accumulating on the exposed surfaces, impeding blood flow
through the heart and predisposing to thrombotic emboli
lodging in end-arteries in organs throughout the host. Although
healing may occur, the healed valve is rarely returned to its
General Considerations
original state and is often left thickened, shrunken, and dis-
torted. Affected valves may be either insufficient or stenotic
or both, but one or the other usually predominates. Distor-
tions of the structure of heart valves in the absence of vegeta-
tions and with an intact valvular endothelium are commonly
encountered. Valves can be effaced, displaced, shrunken,
thickened, or, in the case of the AV valves, no longer firmly
anchored to the papillary muscles. All result, to a greater or
lesser extent, in a diminution of effective unidirectional blood
flow. Probably the best examples of distortions in architecture
are those seen in congenital heart disease, such as valvular
aortic and pulmonic stenosis, left and right AV valvular steno-
sis or insufficiency. Similar lesions can be seen in acute or
healed valvular endocarditis and degenerative diseases of the
AV valves, such as endocardiosis in dogs. Abnormal chamber
or great vessel communication is of special interest because
of the altered hemodynamics that ensue in the transition from
fetal to postnatal life. Predominantly congenital in origin, it is
often the result of incomplete closure of fetal communications
between the atria, ventricles, and great vessels following birth.
Acquired arteriovenous communication can also occur.
The myocardium
The myocardium may be primarily and specifically affected
by a particular disease, but it may also be just another organ
involved in systemic disease. The morphologic manifestations
of myocardial disease reflect some of the characteristics of the
myocardium, such as the predominance of contractile proteins
in each cardiac myocyte; the exquisite compartmentalization
of calcium required for regular and orderly contraction; its
high requirement for energy for regular contraction; its end-
arterial blood supply, predisposing the myocardium to infarc-
tion; and the very limited capacity of cardiac myocytes for
regeneration. Cardiac myocytes, however, have a remarkable
capacity to increase in mass (hypertrophy) in response to an
increase in either physiologic or pathologic workload.
As do all tissues, the myocardium has a limited set of reac-
tions to injury, but the pattern and distribution of lesions may
aid in arriving at a morphologic and etiologic diagnosis. The
stage of irreversible damage to a myocyte, at least in ischemia,
is determined by structural and functional changes in the
mitochondria. Irreversible damage occurs after only 30
minutes of ischemia, whether or not flow is restored.
Shortly after birth, most cardiac myocytes lose their ability
to regenerate. Once the neonatal period passes and a particular
myocyte or group of myocytes is lost, there is usually no
replacement. There is, however, recent evidence to show that
there is a low level of cardiac myocyte turnover throughout
life. On the death of myocytes, there is progressive scavenging
of the necrotic or apoptotic remnants of the myocytes and
replacement by fibrosis. Remaining myocytes do have the
capacity for compensatory hypertrophy.
Myocardial injury may be functionally manifest as either
irregularities in the rate or rhythm of impulse formation and
conduction (dysrhythmias), or as depression in the force of
myocardial contraction. Dysrhythmias are usually associated
with acute, nonlethal, often focal injury to cardiac myocytes.
Contractility disturbances occur when there are either insuf-
ficient numbers of ventricular myocytes for effective contrac-
tion, as occurs in massive ischemic necrosis of ventricular
myocytes following blockage of a major coronary artery, or
when there is generalized ineffective contraction of normal
numbers of myocytes. Generalized, ineffective myocardial
 4.e1

Semilunar Stenoses
Supra/subvalvular and
valvular stenosis
Increased ventricular
afterload
Concentric hypertrophy

Hemodynamic
effects of
valvular
abnormalities

Insufficiencies AV stenoses
[Both AV and SL valves] Decreased ventricular
Increased ventricular preload
preload Increased atrial afterload
Eccentric hypertrophy

eFigure 1-2  Hemodynamic effects of valvular abnormalities. AV, atrioventricular; SL, semilunar.
(Courtesy Vasileios Psychas.)
Diseases of the Heart
contraction is most commonly seen as a feature of dilated
cardiomyopathies. The basis of generalized ineffective con-
traction is complex and reflects the many contributing factors
to the normal functioning of cardiac myocytes. For example,
with the cardiomyopathies, there are a number of disorders
that have as their origin inherited defects in either contractile
proteins, cytoskeletal proteins, or mitochondrial proteins, all
leading to a lowering of the effectiveness of contraction.
A number of grossly observable permutations and combi-
nations assist in arriving at a diagnosis that involves the myo-
cardium. An increase in ventricular wall thickness or mass
should lead the investigator to search for a cause of increased
workload performed by the heart, such as a stenotic valve, or
a shunt between chambers or great vessels, which produce an
increased afterload on the heart. If no obvious cause for the
increased mass can be discerned, a primary myocardial disease,
such as hypertrophic cardiomyopathy, should be considered.
A dilated ventricular lumen accompanied by a normal to thin
ventricular wall leads toward consideration of an increased
preload on the heart, such as AV or semilunar valvular insuf-
ficiency or a vascular shunt. In the absence of an inciting cause,
dilated cardiomyopathy should be considered. Focal pale
areas in an otherwise normally appearing myocardium suggest
destruction of cardiac myocytes alone, cellular infiltration
alone, or a combination of the two. The most common causes
include bacterial and viral infections as well as nutritional
deficiencies and toxins that induce necrosis of cardiac  cardiac output. Disturbances of both impulse formation and
myocytes. Metastatic neoplasms should also be considered.
Although rare in domestic animals, a special type of focal,
well-circumscribed area of paleness with a reddened periph-
ery is indicative of a recent infarct following thrombosis of a
coronary artery. Focal scarring/fibrosis of the ventricular wall
is characteristic of a healed infarct or replacement fibrosis of
necrotic cardiac myocytes. Discrete nodules in the chamber
walls, especially of the ventricles, are typical of bacterial/
fungal/parasitic infections. Frank abscessation is more typical
of bacterial infection, whereas nodules with caseous centers
ringed by well-demarcated fibrous tissue suggest intermediate
stage parasitic infection.
The pericardium
The inability of the pericardium to stretch rapidly to accom-
modate additional fluid in the pericardial sac leads to clinically
significant disease. Fluid accumulation prevents adequate
filling of the chambers during diastole, lowering stroke volume
and cardiac output. This is also central feature of a resolving
or resolved pericarditis.
• Blood, often clotted blood, within the pericardial sac is
often the result of a ruptured atrium, ventricle, great vessel,
or coronary artery. Unclotted blood in the pericardial sac,
of unknown cause, occurs in dogs.
• Clear fluid in the pericardial sac should lead to an inves-
tigation of causes of hypoproteinemia and as part of a
number of infectious diseases.
• Fibrinous/purulent exudates in the pericardial sac usually
indicate acute bacterial/mycoplasmal infection. The pres-
ence of pericardial and epicardial fibrosis often indicates a
prolonged and ineffective attempt at repairing acute fibrin-
ous and purulent pericarditis.
Pathophysiologic patterns of heart disease
When the heart is diseased, there is a restricted array of altera-
tions in function that can be categorized as follows.
General Considerations 5
Disturbances of impulse formation or
impulse conduction
Diseases affecting the sinus node of the heart’s specialized
conduction system can lead to an increase, decrease, or absence
of impulse formation. Any disease affecting the conducting
fibers—the intra-atrial conduction pathways, the AV node, the
common bundle, right and left bundle branches, or Purkinje
fibers—can result in a decrease or an absence of impulse con-
duction. These are manifest as various forms of bradyarrhyth-
mias (heart block), such as sinoatrial arrest; first-, second-,
and third-degree heart block; and left and right bundle 
branch block.
By far and away the most significant and most common
disturbances of impulse formation are those that arise from
injury to atrial and ventricular myocytes. Common causes
include electrolyte disturbances, coronary arterial thrombosis
or embolism, nutritional deficiencies, bacterial and viral infec-
tions, and toxins, especially plant toxins. The predominant
alterations in heart rate and rhythm are an increased rate and
an erratic rhythm (tachyarrhythmias). It should be noted that
arrhythmias arise from the inappropriate depolarization of
injured components of the conduction system or cardiac myo-
cytes (ectopic pacemakers) that are often in close proximity
to necrotic/apoptotic myocytes. The major pathophysiologic
effect of disturbances of the heart’s rate rhythm or conduction
is erratic filling and contraction, leading to a depression in
impulse conduction can be readily classified through the use
of electrocardiography.
Depressed myocardial contractile strength
This category is essentially one of either a decrease in ventricu-
lar myocardial contractile critical mass, such as in massive myo-
cardial necrosis, or, in a heart that has sufficient ventricular
myocardial mass, but where there is a disturbance in the effec-
tiveness of contraction. The latter occurs in a number of dilated
cardiomyopathies, especially in dogs and cats.
Impeded blood flow
This occurs with stenosis (narrowing) of the AV or semilunar
valves, resulting in either a restriction of blood flow from one
chamber to another (atrium to ventricle), or from a ventricle
to the major arteries. This places an increased systolic work-
load (afterload) on the affected chamber. The lesion is not
invariably pure in nature. Stenotic valves can also be mildly
regurgitant, but it is the stenosis that predominates. Stenosis
can either be congenital or acquired. More common forms of
acquired impedance of blood flow include acute valvular
endocarditis with thrombosis or healed endocarditis with
resultant distorting fibrosis of the valves.
Regurgitant blood flow
This is associated with lesions of the AV and semilunar valves
in which the valve structure is so effaced that it becomes
insufficient and cannot prevent backflow of blood from ven-
tricle to atrium or from a great vessel back to its ventricle.
With regurgitation, the heart responds by increasing its stroke
volume, which places an increased diastolic load (preload) on
the heart. The lesion can be congenital, such as congenital
mitral insufficiency, or acquired, such as healed endocarditis
or the degenerative AV valvular condition endocardiosis, in
dogs. Again, some primarily insufficient valves can be mildly
stenotic, but in these cases, the insufficiency predominates.
6 CHAPTER 1  •  Cardiovascular System
Abnormal pattern of blood flow
(shunted blood flow)
Although these can be acquired, they are much more com-
monly congenital in origin. They can be simple communica-
tions between the great vessels (patent ductus arteriosus), the
atria (patent foramen ovale/atrial septal defect), or the ven-
tricles (ventricular septal defect). The pathophysiology can be
complicated where the defect results in increases in both
preload and afterload on particular chambers. A special case
of shunted blood flow occurs with the transposition of the
great vessels.
Restricted atrial/ventricular filling
Pericardial disease, either acute or chronic, can restrict chamber
filling during diastole, as can some of the hypertrophic cardio-
myopathies. In essence, the compliance of either the pericar-
dium or the myocardium is reduced, which prevents full
diastolic relaxation of the ventricles. The major pathologic
effect is one of increased central venous pressure leading to
congestive heart failure, which can be predominantly right-
sided or left-sided, depending on which chamber is most
affected.
Further reading
Bergmann O, et al. Evidence for cardiomyocytes renewal in humans.
Science 2009;324:98-102.
Bonow RO, et al., editors. Braunwald’s Heart Disease. A Textbook of
Cardiovascular Medicine. 9th ed. Philadelphia: Elsevier Saunders;
2012.
Ettinger SJ, Feldman EC, editors. Textbook of Internal Veterinary Med-
icine: Diseases of the Dog and Cat. 7th ed. Philadelphia: Saunders
Elsevier; 2010.
Hurst JW, et al. The Heart. 13th ed. New York: McGraw-Hill; 2011.
Miller LM, et al. Cardiovascular System and Lymphatics. In: Zachary JF,
McGavin MD, editors. Pathologic Basis of Veterinary Disease.
5th ed. St Louis: Elsevier; 2012.
Orton EC. The Heart. In: Bojrab MJ, Monnet E, editors. Mechanisms of
Disease in Small Animal Surgery. Boca Raton, Fla: CRC Press; 2010.
Plendl J. Cardiovascular System. In: Eurell JO, Frappier BL, editors. Dell-
man’s Textbook of Veterinary Histology. 6th ed. Ames, Iowa: Wiley
Blackwell; 2007. p. 117-133.
Schoen FJ, Mitchell RN. The heart. In: Kumar V, et al., editors. Robbins
and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia:
Saunders; 2010. p. 529-587.
HEART FAILURE
Heart failure is the end point of a number of causes, rather than
a specific disease, and denotes a situation in which all compen-
satory mechanisms have been exhausted, and the heart is
unable to meet the demands of the animal. The syndrome is
characterized by diminished cardiac output (“forward failure”),
or damming back of blood in the venous system (“backward
failure”), or both. The heart can fail because of impaired pump
function or because of increased cardiac work demands; both
mechanisms may be operative in some cases. The heart can
fail as a pump because of
1. Decreased myocardial contractility, or loss or replacement
of myofibers, or
2. Decreased distensibility (compliance), or
3. Dysrhythmia (abnormal heart rate and/or rhythm)
Heart Failure
Increased cardiac work demands on one or both ventricles
result from disturbed hemodynamics, in the form of sustained
pressure overload (e.g., obstructed flow in aortic valvular
stenosis) or volume overload (e.g., regurgitant flow in mitral
valvular regurgitation).
Congestive heart failure is characterized by vascular conges-
tion and edema fluid within the interstitium of tissues and body
cavities. Not all cases of heart failure are of the congestive type.
Although in congestive heart failure the clinical manifesta-
tions are more or less constant, in acute heart failure, there
may be intermittent weakness and syncope caused by a sub-
stantial change in heart rate or rhythm, resulting in a precipi-
tous drop in cardiac output. The effect of acute heart failure
is often sudden unexpected death, often with minimal lesions.
Circulatory failure, or shock, denotes a state of inadequate
peripheral vascular perfusion and is used to describe a state that
may or may not be the result of heart failure. It is character-
ized by a drop in effective circulating blood volume. Common
causes are acute internal or external hemorrhage, dehydration,
or endotoxic shock. Shock can of course lead to acute heart
failure.
Based on clinical manifestations, heart failure may be pre-
dominantly either left-sided failure or right-sided failure. Left-
sided failure results in left atrial dilation, pulmonary congestion
and edema, and clinical signs of dyspnea and cough. A promi-
nent feature of chronic left-sided heart failure is the presence
of hemosiderin-laden macrophages (“heart failure cells”) in
pulmonary alveoli, the result of diapedesis of red cells into 
the alveoli. Right-sided failure results in excessive right atrial
pressure and systemic venous congestion, expressed as jugular
distension, hepatic and splenic enlargement, ascites, and
peripheral edema. Cor pulmonale is defined as right heart
failure secondary to pulmonary disease, such as chronic obstruc-
tive pulmonary disease, dirofilariasis, or pulmonary thrombo-
embolism. Because the cardiovascular system is closed, failure
of one ventricle will ultimately lead to failure of the other,
culminating in global or biventricular failure.
Although there are many causes that lead to intermittent
or permanent lowering of effective cardiac output, there is a
limited set of responses to this by the animal. The major
compensatory mechanisms include the intrinsic cardiac
responses of dilation and hypertrophy, and the systemic
responses, which include increased heart rate and peripheral
resistance, redistribution of blood flow, venular constriction, and
increased blood volume. In each case, the compensatory
responses are at least temporarily beneficial and are directed
toward increasing cardiac output to meet the metabolic needs
of the animal. The range within which the compensatory
mechanisms result in an increase in cardiac output is wide.
Indeed, the increase may be up to 5 times the basal rate. As
cardiac output falls below the requirements of the animal,
signs of congestive heart failure appear. These may be inter-
mittent or prolonged, depending on the nature of the defect.
An untoward side effect of the systemic responses is
increased capillary hydrostatic pressure that leads to the accu-
mulation of edema fluid. This can involve the systemic or
pulmonary veins. Right-sided lesions, such as right atrioven-
tricular (AV) valvular insufficiency, pulmonic stenosis, or pul-
monary hypertension, result in peripheral-dependent edema
(e.g., submandibular edema [“bottle-jaw”], brisket edema),
ascites, hydrothorax, and hydropericardium. Left-sided defects,
such as left AV or aortic valvular insufficiency, cause pulmo-
nary edema as the predominant finding.
 6.e1

Further reading
Borg TK, et al. The cell biology of the cardiac interstitium. Trends Car-
diovasc Med 1996;6:65-70.
Darke PGG, et al. Color Atlas of Veterinary Cardiology. London: Mosby-
Wolfe; 1996.
Fox PR, et al. Textbook of Canine and Feline Cardiology. Principles and
Clinical Practice. 2nd ed. Philadelphia: WB Saunders; 1999.
Robinson TF, et al. Skeletal framework of mammalian heart muscle.
Arrangement of inter- and pericellular connective tissue structures.
Lab Invest 1983;49:482-498.
Tilley LP, Goodwin J-K. Manual of Canine and Feline Cardiology.
Philadelphia: WB Saunders; 2001.
Ware WA. Cardiovascular Disease in Small Animal Medicine. London:
Manson Publishing; 2011.
Diseases of the Heart
Figure 1-2  Cardiac dilation in a lamb. Left ventricular dilation
with effacement of papillary muscles and severe subendocardial
fibrosis. (Courtesy Vasileios Psychas.)
Intrinsic cardiac responses in heart failure
Cardiac dilation
Dilation is a response to an increased workload in both physio-
logic and pathologic states. Increasing the end-diastolic volume,
and hence stretching the myofibers, can increase the contrac-
tile force of the heart and increase the stroke volume and
cardiac output. This is known as the Frank-Starling relation-
ship, or heterometric autoregulation. Transient cardiac dila-
tion is an acute response to increased demands, for instance,
increased exercise. Continued stretch increases contractile
force to a limit, after which increased stretch will result in a
decrease in tension developed. The limit of stretch in most
species appears to be a sarcomere length of 2.2-2.4 µm.
Chronic dilation of a ventricle can occur through addition of
sarcomeres and hence lengthening of myocytes.
Various disease conditions can cause an increased diastolic
workload (preload) and hence dilation of the heart, such as
arteriovenous shunts, and AV and semilunar valvular insuffi-
ciencies (Fig. 1-2). Acute volume overload of a chamber is
expected to lead to dilation, whereas chronic volume overload is
one stimulus to the development of cardiac hypertrophy.
Cardiac hypertrophy
Cardiac hypertrophy is a reversible increase in the mass and a
minimal increase in the number of myocardial cells, and is a
compensatory response to an increase in mechanical work or to
trophic signals. In general, chronic pressure overload leads to
myocardial hypertrophy, whereas chronic volume overload
leads to combined ventricular dilation and hypertrophy. Hyper-
plasia, or increase in the number of cells, has recently been
shown to occur in response to workload, although the capacity
of the myocyte to divide decreases rapidly prior to birth, and
little mitotic activity is observed after the first few weeks  chondria, altered protein synthesis and degradation, and cyto-
of life.
At this juncture, it is important to distinguish between hyper-
trophy that is physiologic and hypertrophy that is pathologic in
nature. Physiologic hypertrophy is a response to exercise or
pregnancy and results in a mild increase in heart weight, not
>10-20% normalized to body weight. It is an extension of the
normal growth process, is without deleterious effect and
occurs without the induction of the molecular stress fetal gene
program that is associated with the development of pathologic
Heart Failure 7
hypertrophy. Physiologic hypertrophy is initiated by ligands
that include thyroid hormone, insulin, insulin growth factor
1, and growth hormone. Additionally, cardiac function is
maintained or enhanced and is reversible. On the other hand,
with pathologic hypertrophy, there may be up to a 4-fold
increase in mass, depressed cardiac function, and the induction
of a molecular fetal stress cardiac gene program. Of particular
note is the initiation of hypertrophy by mechanical work
through the activation of stretch-sensing transducing proteins
located in the plasma membrane, within the cardiac Z line, or
by adhesion complexes. The following discussion will be con-
cerned only with the process of hypertrophy following a
defined change in workload or stimulation. The presence of
hypertrophy in the absence of an observable increase in work-
load will be considered to be primary and is discussed under
the cardiomyopathies.
In pathologic hypertrophy, the mass and size of the heart
are increased through a restricted number of hypertrophic
stimuli resulting in the activation of a limited number of
intracellular signal transduction pathways that alter gene
expression. The initiating actions include mechanical stimuli
(stretch) or trophic stimuli (polypeptide growth factors; vaso-
active agents, such as angiotensin II and α-adrenergic agonists),
all of which increase the rate of protein synthesis; the amount
of protein, especially contractile proteins; the size of myo-
cytes; and the number of sarcomeres and mitochondria. The
hypertrophic response is accompanied by selective upregula-
tion of several immediate early-response genes and embryonic
forms of contractile and other proteins. The phenotype of the
hypertrophic myocyte may be changed by this expression of
embryonic genes, for instance, induction of atrial natriuretic
factor occurs in ventricular myocytes, and late response genes,
such as β-myosin heavy chain and skeletal α-actin, may be
expressed (a switch from adult to fetal/neonatal forms). Other
genes are also activated and selectively regulated in hypertro-
phy, including immediate early genes or proto-oncogenes 
that encode early regulatory factors (c-jun, c-fos, egr-1),
growth factors (transforming growth factor-β, insulin-like
growth factor, fibroblast growth factor), vasoactive agents
(α-adrenergic agonists, endothelin-1, angiotensin II), and com-
ponents involved in receptor-mediated signaling pathways,
such as protein kinase C.
In pathologic states, hypertrophy is an adaptive response of
limited benefit, where myocytes have impaired intrinsic con-
tractility, impaired ventricular relaxation, and decreased 
compliance, which cause increased end-diastolic pressure and
limited exercise performance. Once further muscle mass
cannot meet the demands posed by increased workload, heart
failure ensues. Degenerative changes occur in myofibers,
including loss of myocardial contractile elements. Limitations
to continued hypertrophy and the reasons for eventual myo-
cardial failure include inadequacy of the vascular supply to
the enlarged fibers, diminished oxidative capacity of mito-
skeletal alterations. The capillary density in hypertrophic
myocardium typically does not keep pace with myofiber size,
intercapillary distances increase, and fibrous tissue is deposited
in the interstitium (“reactive interstitial fibrosis”). Also, the
altered isoforms of proteins produced by expression of fetal
genes may be less functional than adult forms. Myocyte hyper-
trophy occurs only if increased protein synthesis exceeds the
rate of degradation. Similarly, hypertrophy of the ventricle
occurs only if growth of individual myocytes exceeds the
8 CHAPTER 1  •  Cardiovascular System Heart Failure

apoptotic loss of myocytes; excessive apoptosis can contribute
to failure of a hypertrophic heart. This postulate is supported
by experimental work with receptor-mediated Gαq signaling
of cultured rat cardiac myocytes (Gαq is the α subunit of the
Gq family of G proteins, guanine nucleotide–binding proteins,
which transduce signals); moderate levels of Gq signaling
stimulate cardiac hypertrophy, whereas high-level Gq activa-
tion results in cardiac myocyte apoptosis.
There are distinctive anatomic patterns of hypertrophy that
accompany the increase in workload. Concentric cardiac
hypertrophy, that is, an increase in mass of the ventricle without
accompanying increase in end-diastolic volume, characterizes
increased systolic loads (increased afterloads), such as aortic
stenosis, pulmonic stenosis, and pulmonary hypertension in
patent ductus arteriosus. There is often a decrease in the
volume of the ventricular lumen (Fig. 1-3). An increase in
diastolic load (increased preload), typically produced by AV or
semilunar valvular insufficiencies or by arteriovenous shunts,
results in eccentric cardiac hypertrophy, which is an increase
in myocardial mass accompanied by increased end-diastolic
volume (dilated chamber). Because of dilation, the thickness of
the involved ventricular wall is usually no more than normal
and may be less (Fig. 1-4).
In relation to altered hemodynamic loads placed on the
heart, AV valvular stenosis or pericardial fibrosis restrict ven-
tricular filling, leading to a decrease of the load on the myo-
cardium (Fig. 1-5).
The gross appearance of the hypertrophic heart depends
on the chamber affected and the nature of the insult. In
general, hypertrophy of the right side of the heart makes the
heart broader at its base; hypertrophy of the left side increases
the organ length; bilateral hypertrophy produces a more
rounded shape than normal.
In concentric hypertrophy, there is increased thickness of the
wall of the affected chamber, and a marked increase in the
size of the papillary muscles and the trabeculae carneae (Fig.
1-6). Although the hypertrophy may emphasize one or other
chamber, the whole heart is involved. When the right ventricle
is involved, the moderator band (trabecula septomarginalis)
may be much thickened. Extreme hypertrophy of one chamber
Increased ventricular afterload (Pressure overload)
Increased
ventricular
systolic
Increased resistance pressure
to ventricular ejection
Ventricle undergoes
compensatory
hypertrophy
(concentric)
Figure 1-3  Increased ventricular afterload. The involved ventri-
cle undergoes concentric hypertrophy following increased resis-
tance to ventricular ejection. End-diastolic volume may be
reduced. The shaded area shows the outline of a normal ventricle.
(Modified from Robinson WF, Huxtable CRR, eds. Clinicopatho-
logic Principles for Veterinary Medicine. Cambridge, UK: 
Cambridge University Press, 1988. Reprinted with permission.)

Increased ventricular preload (volume overload)

Increased venous
return from AV
shunt such as PDA

Either bidirectional flow or

increased volume of
blood received by ventricle

Increased end
diastolic volume

Ventricle undergoes
Increased ventricular compensatory
contractility following hypertrophy (eccentric)
stretching of myofibers
Figure 1-4  Increased ventricular preload. Increased ventricular preload may result from (1) bidi-
rectional flow from insufficient atrioventricular (AV) or semilunar valves, or (2) increased volume
of blood from intracardiac or extracardiac arteriovenous shunts. The ventricle dilates and under-
goes eccentric hypertrophy. The shaded area shows the outline of a normal ventricle. PDA, patent
ductus arteriosus. (Modified from Robinson WF, Huxtable CRR, eds. Clinicopathologic Principles
for Veterinary Medicine. Cambridge, UK: Cambridge University Press, 1988. Reprinted with
permission.)
Diseases of the Heart Heart Failure 9

Decreased preload

AV valve
stenosis or
pericardial
disease

Decreased
cardiac output

Decreased end
diastolic volume
Restriction of blood flow
into the ventricle
Figure 1-5  Decreased ventricular preload. Decreased ventricular
preload follows atrioventricular (AV) valvular stenosis or myocar-
dial restriction, such as pericardial fibrosis. End-diastolic volume
decreases because of restricted inflow. (Modified from Robinson
WF, Huxtable CRR, eds. Clinicopathologic Principles for Veteri-
nary Medicine. Cambridge, UK: Cambridge University Press,
1988. Reprinted with permission.)
Figure 1-6  Concentric left ventricular hypertrophy. The ven-
tricular free wall and interventricular septum are thickened, and
the lumen of the ventricle is reduced, in this cross-section of
ventricles from a dog.
may encroach on the diastolic capacity of its opposite number.
Microscopically, the myocytes are enlarged, but the increase
in the size of fibers is not uniform and is not always easy to
discern on routine microscopy.
In eccentric hypertrophy and dilation, the heart tends to be
globose, and even though the mass is increased, the wall is
usually thin. The papillary muscles may also be attenuated
(Fig. 1-7).
Figure 1-7  Eccentric left ventricular hypertrophy in dilated car-
diomyopathy in a dog. The lumen of the left ventricle is increased
relative to the thickness of the walls of the ventricle.
In both types of hypertrophy, the endocardium may be
diffusely opaque as a result of subendocardial fibrosis, and 
this alteration may be the best indication of dilation in the
atria, in which dilation and hypertrophy can be difficult 
to assess.
An example of concentric cardiac hypertrophy occurs 
in cats with hyperthyroidism (thyrotoxicosis), a condition
usually resulting from the presence of thyroid hyperplasia or
adenoma. The thyroid glands in these cases are unilaterally or
bilaterally enlarged, nodular, pink to dark brown, and may
contain cysts. Microscopically, the thyroids usually exhibit a
mixture of hyperplastic areas, adenomatous nodules, and
normal follicles (see also disorders of the thyroid gland in Vol.
3, Endocrine glands). The pathogenesis of ventricular hyper-
trophy in this disease is not clear, but may involve the direct
action of thyroid hormones on myocardium, enhanced myo-
cardial adrenergic receptor number or affinity, peripheral 
vasodilation, and work hypertrophy in response to increased
peripheral tissue demands for oxygen and dissipation of heat.
The hearts in most cases are symmetrically hypertrophied;
however, some exhibit asymmetric hypertrophy. The left 
ventricular lumen is usually reduced in size. Affected myofi-
bers are enlarged, but are not in disarray in the great 
majority of cases. The hypertrophy is reversible on return 
to euthyroidism.
Systemic responses in heart failure
The extracardiac features of heart failure stem from 2 basic
pathophysiologic changes: fluid accumulation and tissue or
organ ischemia. Depending on the cause of the heart failure,
both effects may be present, but it is more usual for one to
predominate.
Fluid accumulation results from the retention of sodium
and water, which primarily involves the kidneys, and also
involves atrial natriuretic factor released from the heart (eFig.
1-3A). The influence of the failing heart on the kidneys stems
from its inability to supply them with an adequate flow of
blood. Blood flow through different parts of the kidneys
depends on the vasomotor tone of blood vessels within the
 9.e1

Depression in
cardiac output

Redistributed/decreased
Increased ADH
renal blood flow

Increased retention
of water
Increased filtration fraction:
Increased renin/
Proportionally more sodium
angiotensin/aldosterone
delivered to tubules
Increase in
blood volume

Increased retention
of sodium
A
Pathologic features of CHF

Left-sided failure Right-sided failure

Gross features Gross features

Pulmonary edema [heavy, wet Subcutaneous edema, ascites,
lungs exude fluid on pressure. hydrothorax, hydropericardium.
White froth in airways] Enlarged congested liver

Histopathology Histopathology
Pulmonary venous congestion; Dilated congested hepatic sinusiods;
alveolar edema; alveolar macrophages parenchymal atrophy
contain RBCs/hemosiderin
B
eFigure 1-3  Congestive heart failure. A. Pathogenesis of heart failure. This involves sodium and
water retention by the kidney following reduced blood flow/redistribution of blood flow to the
kidney. Increased antidiuretic hormone (ADH) activity also contributes to the retention of water.
All lead to an increase in blood volume. (Modified from Robinson WF, Huxtable CRR, eds. Clini-
copathologic Principles for Veterinary Medicine. Cambridge, UK: Cambridge University Press,
1988. Reprinted with permission.) B. Pathologic features of congestive heart failure (CHF).
RBCs, red blood cells.
10 CHAPTER 1  •  Cardiovascular System
parenchyma. It is considered that many, if not all, of the intra-
renal blood flow changes in heart failure follow increased
activity of the sympathetic nervous system.
The kidneys receive approximately 20% of the output of
the left ventricle, almost all of which flows through the renal
cortices. One of the earliest changes following a drop in
cardiac output is redistribution of blood flow within the
kidney. There is reduced flow through the outer renal cortex
and increased flow within the outer renal medulla. This results
in readjustment of the filtration fraction, which is the ratio of
glomerular filtration rate (GFR) to renal blood flow. Contrary
to expectations, there is a less than proportionate drop in GFR
compared with renal blood flow, resulting in an increased
filtration fraction. As a consequence, proportionally more
sodium moves through the glomerular filter, leading to pro-
portionally more sodium being delivered into the proximal
convoluted tubule. Because the rate of sodium resorption
remains constant, a greater number of sodium ions are
resorbed. Also, because of the increased filtration fraction,
local plasma osmotic pressure in the efferent arteriole increases,
causing greater resorption of sodium and water.
The alteration in renal blood flow in heart failure also
increases the activity of the renin-angiotensin-aldosterone
system, producing more sodium resorption from the distal
convoluted tubule. There is also increased water-retaining
activity by antidiuretic hormone.
A mechanism within the heart also regulates blood volume,
blunting the activity of aldosterone and the renin-angiotensin
system. Atrial natriuretic factor (ANF), with natriuretic and
diuretic properties, is present in granules in some of the atrial
myocytes. If the atrial pressure is elevated or the atria are
distended, ANF is released and causes natriuresis, vasodilation,
suppression of the renin-angiotensin-aldosterone axis, and
decreased arterial blood pressure. In terms of homeostasis, ANF
has effects opposite to those of aldosterone, thus providing a
balance to fluid regulation. Although plasma ANF is signifi-
cantly increased in dogs with chronic left AV valvular insuf-
ficiency, it is not clear whether the metabolic effects of
aldosterone or ANF predominate, but it would appear that
the effects of aldosterone over-ride those of ANF.
It should be noted that none of the hormones mentioned
produce the edema of congestive heart failure if administered
alone. In addition, once a new steady state has been reached,
the hormonal state returns to relatively normal limits. Last,
the mechanisms that are brought into play are not exclusive to
the syndrome of heart failure. Any situation that leads to a
drop in effective circulating blood volume will activate the
sodium- and water-retaining mechanism. The fundamental
difference between these states and congestive heart failure is
that the total blood volume in heart failure is already more
than adequate, but the effective blood volume is much dimin-
ished because of the poor cardiac output. The volume
changes in heart failure should be viewed as an integrated
response by the body to compensate for the inability of the
heart to respond to the normal hemodynamic needs of  the lungs and the diminution in cardiac output. The pulmo-
the body.
The expansion of blood volume has both a beneficial and
a detrimental effect. By increasing blood volume, venous
return is enhanced and, in turn, cardiac output and tissue
perfusion are improved. However, this is to the detriment of
the balance between capillary hydrostatic pressure and plasma
osmotic pressure. This leads to an increase in the amount of
fluid in the interstitial spaces and body cavities.
Heart Failure
Syndromes of circulatory failure
Circulatory failure, the term implying severe systemic conse-
quences, falls into 3 general categories: cardiac syncope, periph-
eral circulatory failure, and congestive heart failure.
Cardiac syncope
Cardiac syncope is characterized clinically by profound
changes in blood pressure and heart rate with bradycardia or
tachycardia, either of which may result in inadequate output
of blood. Both may occur in the presence or absence of organic
heart disease.
In one form of cardiac syncope, hypersensitive or hyperac-
tive reflexes, for which the vagus nerve is the efferent limb,
may result in reflex inhibition of the heart rate, manifest as
extreme bradycardia or as asystole. The sudden deaths that
result from acute pleural irritation or the tracheal irritation of
aspirated vomitus fall into this group, and obviously there may
be no organic heart lesion.
In a second form of cardiac syncope, the heart rate is
extremely rapid, and the cardiac output severely reduced.
Such may occur in paroxysmal tachycardia, atrial flutter or
fibrillation, and ventricular fibrillation.
Third, in organic heart disease with complete obstruction
of impulse conduction from the atrium to the ventricle 
(complete heart block), syncope may occur if there is suffi-
cient delay before the ventricle assumes an independent
rhythm.
Finally, cardiac syncope may terminate a syndrome of con-
gestive cardiac failure when the cardiac reserve is depleted
and the heart cannot increase its output sufficiently to meet
sudden increases in peripheral needs.
Peripheral circulatory failure
Peripheral circulatory failure is characterized by reduction in
the effective circulating blood volume with insufficient venous
return and reduced cardiac output. Acute hemorrhage and
shock are examples of this form of circulatory failure.
Congestive heart failure
The combination of compensatory mechanisms, brought into
play to maintain cardiac output, is in general successful.
However, there is also the planting of the seeds of destruction.
Both the local increase in venous hydrostatic pressure and the
increased sodium and water retention by the kidneys tend to
promote the development of interstitial edema. Depending on
the inciting abnormality, it is usual for one side of the heart
to fail before the other, but it must be remembered that the
cardiovascular system is a closed circuit and that failure of one
side will eventually embarrass the other (eFig. 1-3B).
Left-sided heart failure is ushered in by progressive dilation
of the left ventricle and atrium, although this progression may
be marked by exacerbations and remissions if hypertrophy is
given time to develop. The major extracardiac manifestations
of left-sided failure arise from the damming back of blood in
nary venous congestion is transmitted back to the capillaries of
the alveolar wall, and edema fluid accumulates in the inter-
stitial tissue and the alveolar spaces. The consequent reduction
in pulmonary vital capacity and impaired gaseous exchange
of cardiogenic pulmonary edema result in hypoxic stimulation
of the carotid sinus and medullary respiratory centers so that
reflex dyspnea occurs. A wheezing bronchial cough is common
and is presumed to be due to irritation of the respiratory
Diseases of the Heart Heart Failure 11

A B

C
Figure 1-8  Congestive heart failure. A. Left-sided congestive heart failure in a dog. Pulmonary
alveolar capillaries are congested, and there is hemorrhage into alveoli that contain hemosiderin-
laden macrophages (“heart-failure cells”). H&E. B. Same section as (A) stained with Prussian blue
to highlight the abundance of iron derived from hemosiderin in alveolar macrophages. C. Chronic
passive congestion of the liver, leading to zonal hepatocyte atrophy, in right-sided congestive heart
failure in a dog. H&E.

mucosae by the edema fluid. Cyanosis may be present but is
more often the rule in right ventricular failure.
At postmortem, the lungs are usually of normal color, but
may be light brown, and are heavy and wet. Stable, white froth
is present in the airways, and fluid exudes from the cut surface.
Because of its low protein content, there is little evidence of
the abundant fluid on microscopic examination. The alveoli
contain erythrocytes and a scattering of macrophages, some of
which contain hemosiderin. It may be necessary to use a dif-
ferential stain for iron to confirm the presence of these
so-called “heart-failure cells” or siderophages (Fig. 1-8A, B).
They are more numerous in chronic disease, and hemosiderin
within their cytoplasm may be sufficient to produce tawny
discoloration of the lungs.
In right-sided heart failure, the major extracardiac mani-
festations depend on increased hydrostatic pressure in the
systemic and portal venous systems, and the reduction of flow
from the lungs to the left ventricle. Renal complications occur
more frequently in right-sided than in left-sided heart failure,
leading to increased blood volume, peripheral edema, and
more marked azotemia.
There is some species difference in the distribution of
edema in congestive heart failure. In ruminants and horses,
dependent subcutaneous edema is expected; in the other species,
excess subcutaneous fluid is scant or absent. In dogs, the pre-
dominant accumulation of fluid is in the peritoneal cavity. In
cats, it is in the thorax.
Grossly, the liver is enlarged and congested and has a
“nutmeg” appearance on section because of chronic passive
congestion (Fig. 1-8C). Microscopically, the sinusoids are
dilated, with atrophy of the parenchyma about the central
veins. In more severe or acute cases, the parenchyma in this
location may undergo degeneration or necrosis. It is excep-
tional for an animal with congestive failure to live long enough
for severe fibrosis and nodularity to occur. Impaired hepatic
function is not usually a significant part of the clinical course,
although jaundice may be observed.
Congestion of the stomach and intestines is evident, and
this may impair their function, which is manifest usually as
diarrhea. In horses, the subserosal lymphatics, particularly of
the large bowel, are often readily discernible, dilated, and filled
with edema fluid. The systemic and portal veins are distended,
12 CHAPTER 1  •  Cardiovascular System Examination of the Heart

and the spleen is enlarged and congested. However, this latter
finding is masked if the animal in question has been eutha-
nized using barbiturates.
EXAMINATION OF THE HEART
In a gross postmortem examination of the heart, it is impor-
tant to examine 4 major areas: pericardium, myocardium,
mural and valvular endocardium, and the great vessels. A
useful system is to follow the route of blood flow through the
heart, that is, an inflow-outflow method of dissection (Fig.
1-9A, eFig. 1-4). This technique may require modification in
the case of cardiac anomalies. Examination of the heart in the
planes used for echocardiographic examination could be
beneficial.
• The initial examination of the heart and great vessels is
best made with the organs in situ to assess abnormalities
of size and position.

i ii iii iv

A v vi vii viii
Caudal
AV node vena cava 1 Sinus
node
2
Septum

Coronary sinus
AV node
AV bundle RV
Bundle branches free wall

3 Ventricular septum
B
Figure 1-9  Examination of the heart. A. Gross examination. (i) Heart oriented to show right
atrium/ventricle facing. (ii) Incision made transversely from caudal vena cava to right auricular
appendage. (iii) Incision commenced in right atrium into junction between right ventricle and
interventricular septum. (iv) Right ventricle opened to display right atrioventricular valve. (v)
Incision continued to display right ventricular outflow tract and pulmonic valve. (vi) Heart oriented
to display left atrium (transversely incised from pulmonary vein to left auricular appendage) and
left ventricular free wall. (vii) Left ventricle free wall incised from base to apex displaying the left
atrioventricular valve. (viii) Left ventricular outflow tract and aortic valve displayed by incision
through left atrioventricular valve. Goat. B. Microscopic examination of the heart. The cardiac
conduction system can be assessed via block 1, in which the sinus node is located subepicardially
in the terminal groove at the junction of the cranial vena cava and right auricular appendage, and
block 2, in which the atrioventricular (AV) node is located subendocardially on the right side of
the interatrial septum, just cranial to the coronary sinus: Serial sections through this block will
reveal the AV node, the common bundle, and the origins of the bundle branches. A block through
the left ventricular free wall, including papillary muscle, or block 3, through the ventricular septum,
is the minimal representative sample to take from a grossly normal heart. RV, right ventricle.
 12.e1

1 Amputate apex 2 Open right atrium 3 Open right side

of right ventricle

4 Open left side of right 5 Right ventricle opened

ventricle and pulmonary trunk

6 Open left atrium 7 Open right side 8 Left ventricle open,

of left ventricle may open aorta (arrow)
eFigure 1-4  Gross examination of the heart (see text for details).
(1) Transect apex of heart and examine ventricular walls. (2)
Open right atrium from caudal vena cava to the tip of the right
atrial appendage. (3) Follow blood flow through right ventricle.
(4) Cut right ventricular free wall adjacent to septum and out
pulmonic valve. (5) Right ventricle and pulmonary trunk opened;
moderator band transected. (6) Open left atrium. (7) Open left
ventricle toward the apex. (8) Left ventricle opened and left
atrioventricular valve exposed; aorta may be opened as indicated
by arrow.
Diseases of the Heart Examination of the Heart 13

• Incise the pericardial sac and examine the pericardial fluid

before the thoracic viscera are removed; note the volume
Table • 1-1 
and color of the fluid, the presence of fibrin, and so forth.
• Remove the thoracic viscera and examine the external
Heart weight:body weight (HW/BW) ratios and
surfaces of pericardium, epicardium, and great vessels. left ventricular free wall plus septum:right
• Open the abdominal aorta in situ to the iliac bifurcation ventricular free wall [(LV + S)/RV] ratios in
and examine for such abnormalities as thrombi and ver- postmortem accessions of cattle without
minous arteritis; remove the aorta with the abdominal significant cardiovascular disease
viscera in a horse to better examine the cranial mesenteric
Age HW/BW (%) (n) (LV + S)/RV (n)
artery and its branches.
• The heart may be detached from the lungs if anomalies are <7 days 0.91 (5) 1.69 (5)
absent, but it is usually better left attached to allow careful 7-30 days 0.90 (6) 2.13 (6)
examination of vessels, for instance, pulmonary artery for
30-365 days 0.48 (9) 2.78 (10)
thrombi.
• Examine the atria, ventricles, and coronary arteries exter- >1 year 0.48 (11) 2.78 (15)
nally, and confirm normal relationships.
• When opening the heart, always inspect structures before
cutting, and try to preserve a stenotic or dilated valve or vessel. Table • 1-2 
• Open the right atrium, from the caudal vena cava to the
tip of the auricular appendage. Note any thrombus, and Reference values for heart weight:body weight
check the right AV valve and the foramen ovale/fossa (HW/BW) ratio and ventricular ratio [(LV + S)/
ovalis. Leave the cranial vena cava unopened, as a block of RV] in normal mature animals at postmortem
tissue to include the sinus node may be taken at the junc-
tion of the cranial vena cava and the right auricle. Examine Species N HW/BW (%) (LV + S)/RV
the right AV valve before cutting.
• Open the lateral side of the right ventricle adjacent to the X X ± 2 SD X X ± 2 SD
ventricular septum. Examine the right AV valve and Dog 21 0.71 0.43-0.99 3.26 2.39-5.12
chordae tendineae. The septal leaflet of the right AV valve
Horse 12 0.69 0.41-0.97 3.12 2.43-4.34
is normally thicker than the free leaflets. Transect the mod-
erator band (trabecula septomarginalis). Cat 9 0.58 0.28-0.88 3.45 2.94-4.17
• Cut through the rostral wall of the right ventricle, and open Cow 15 0.48 0.30-0.66 2.78 2.43-4.00
the pulmonic valve if there is no stenosis. Check the pul- Goat 11 0.46 0.26-0.66 3.12 2.50-4.17
monary arteries for thrombi, especially in animals with Sheep 8 0.41 0.17-0.65 3.33 2.63-4.54
indwelling jugular catheters. Note the patency or closure
Pig 8 0.40 0.32-0.48 2.94 2.38-3.84
of the ductus arteriosus (bear to the right when opening
the pulmonary artery in neonates to avoid cutting through BW, body weight; HW, heart weight; LV + S, left ventricular free wall
a patent ductus arteriosus and creating a false anomaly). + septum; RV, right ventricular free wall; x , mean; SD, standard devia-
tion; x, mean.
• Open the left atrium by cutting into the auricular append-
age and then parallel to the ventricular groove. Examine
the interatrial septum, foramen ovale/fossa ovalis, and the weigh the whole heart, right ventricular free wall, and left
left AV valve. ventricular free wall plus septum.
• Open the left ventricle by cutting longitudinally through the • The ratio of normal heart weight to body weight (HW : BW)
free wall (from base to apex), examining the left AV valve is 0.5-1.0%, depending on age and species (Tables 1-1, 1-2).
before cutting it. Chordae tendineae should be carefully • The HW : BW ratio is higher in neonates than in adults, the
examined before cutting the left AV valve to ensure that more athletic species (horses, dogs) have higher HW : BW
pre-existing ruptures of the chordae are detected. ratios, HW : BW ratio is increased by training or exercise,
• Continue to follow the blood flow by cutting through the and males typically have greater HW : BW ratios than do
left ventricular outflow tract and into the aorta. Note that females of the same species.
the pulmonary artery will be transected by this action. • The ratio of the weight of the left ventricle plus septum
• The circumference of the 4 cardiac valves may be mea- divided by the weight of right ventricular free wall [(LV 
sured at this time with a flexible ruler or string. Normal + S)/RV] is 2.8-4.0 in mature animals; (LV + S)/RV >4.0
right AV/left AV valve circumference ratio for dogs is 2:1. indicates left ventricular hypertrophy; (LV + S)/RV <2.8 is
The right ventricle is responsible for systemic circulation consistent with right ventricular hypertrophy.
in the fetus. Hence, in neonatal hearts, the wall thickness of The usual tissue block taken for routine histology is of left
the left and right ventricles is approximately equal; it is not ventricular papillary muscle, as this area is one of the most
until a month or more after birth that the mature proportions susceptible to damage and most representative in cases of
are attained. Ventricular wall thickness is poorly correlated generalized disease. Detailed examination of the heart, includ-
with ventricular mass, and heart weights provide more valid ing the conduction system, requires collection of tissue blocks
information about ventricular hypertrophy than do thickness (Fig. 1-9B) from the junction of the cranial vena cava and right
measurements, especially in cases of dilation and eccentric auricle (sinus node), both atria, the interatrial septum/dorsum
hypertrophy. To accurately assess cardiac mass, the heart should of the ventricular septum at the base of the heart just cranial
be weighed and the weight compared to body weight. After to the coronary sinus (atrioventricular node), right ventricular
removing the pericardial sac and postmortem blood clots, free wall and AV valve, ventricular septum, left ventricular
14 CHAPTER 1  •  Cardiovascular System
free wall/papillary muscle and AV valve, great vessels, plus any
grossly evident lesions.
The selection of sections to study the specialized conduc-
tion system should include the sinus node, the AV node, the
common bundle (bundle of His), left and right crura (bundle
branches), and conducting fibers. The sinus node lies subepi-
cardially in the terminal groove (sulcus terminalis) at the
junction of the cranial vena cava and the right atrium. Sections
should include either side of that site, to incorporate tissue in
the sulcus terminalis region. The AV node is obtained by
removing a block of tissue from the coronary sinus to the
cranial edge of the septal leaflet of the right AV valve. The
block includes interatrial septum and dorsal ventricular
septum, and will then contain the AV node, which is located
subendocardially on the right side of the interatrial septum,
the common bundle, and the left and right crura. The speci-
men should be serially sectioned into samples 3 mm thick,
and all samples should be processed.
In routine cases, there are no special requirements for fixa-
tion. Stains of particular use are hematoxylin and eosin,
Masson trichrome, phosphotungstic acid hematoxylin, Luxol
fast blue, and Gomori aldehyde fuchsin.
Note that rigor mortis begins earlier in myocardial than in
skeletal musculature, and reaches greater development in the
more powerful left ventricle. Rigor should completely express
the blood from the left ventricle; rigor of the right ventricle
is less efficient, and emptying is incomplete. The presence of
some clotted blood in the right ventricle is normal, whereas
if present in the left ventricle, it is indicative of incomplete
rigor and therefore perhaps of severe myocardial degenera-
tion. The presence of unclotted blood in the left ventricle
some hours after death is more difficult to interpret. Unclot-
ted blood, the result of fibrinolysis, may flow back into the
ventricle when rigor passes.
Blood usually clots slowly after death and permits eryth-
rocytes to sediment. Where blood is present in volume, as in
the heart and arterial trunks, sedimentation and subsequent
clotting leads to the formation of “currant jelly” and “chicken
fat” clots, the former containing erythrocytes, and the latter
largely devoid of them. Chicken fat clots are to be expected
in horses, which normally have a rapid erythrocyte sedimenta-
tion rate, and are in relative excess in anemia. Postmortem
clots are to be distinguished from thrombi; clots are not
attached to the endocardium.
Biopsy of the heart in not commonly undertaken in vivo,
but is possible via transvenous endomyocardial biopsy. Mul-
tiple biopsy samples of the right ventricular myocardium may
be obtained by this means, and may be used, for example, to
monitor the cardiotoxic effects of anthracycline therapy.
Further reading
Abel ED, Doenst T. Mitochondrial adaptations to physiological versus
pathological hypertrophy. Cardiovasc Res 2011;90:234-242.
Bernardo B, et al. Molecular distinction between physiological and
pathological cardiac hypertrophy: experimental findings and thera-
peutic strategies. Pharmacol Ther 2010;128:191-227.
Bourlaug BA, Redfield MM. Are systolic and diastolic heart failure
overlapping or distinct phenotypes within the heart failure spec-
trum? Circulation 2011;123:2006-2014.
Falk T, et al. Associations between cardiac pathology and clinical, echo-
cardiographic and electrocardiographic findings in dogs with con-
gestive heart failure. Vet J 2010;185:68-74.
Congenital Abnormalities of the Heart and Large Vessels
Jacob M, Wilson Tang WH. Pathophysiology of congestive heart failure.
In: Griffen BP, et al., editors. The Cleveland Clinic Cardiology
Board Review. Philadelphia: Lippincott Williams & Wilkins.; 2013.
p. 155-163.
Kemp CD, Conte JV. The pathophysiology of heart failure. Cardiovasc
Pathol 2012;21:365-371.
King JM, et al. The Necropsy Book. Gurnee, Ill: CL Davis DVM Founda-
tion; 1999.
Lymperopoulos A, et al. Adrenergic nervous system in heart failure:
pathophysiology and therapy. Circ Res 2013;113:739-753.
Maillet M, et al. Molecular basis of physiologic heart growth: funda-
mental concepts and new players. Nature Rev Mol Cell Biol
2013;14:38-48.
Schoning P, et al. Body weight, heart weight, and heart-to-body weight
ratio in greyhounds. Am J Vet Res 1995;56:420-422.
Souders CA, et al. Pressure overload induces early morphological
changes in the heart. Am J Pathol 2012;181:1226-1235.
Towbin JA. Molecular genetic basis of sudden cardiac death. Cardio-
vasc Pathol 2001;10:283-295.
CONGENITAL ABNORMALITIES OF
THE HEART AND LARGE VESSELS
In the transition from fetal to neonatal life, substantial adjust-
ments occur within the cardiovascular system. There are altera-
tions in the pressures in cardiac chambers and great vessels, the
pattern of blood flow, and the volume of blood flow. Because
of these changes, the retention postnatally of fetal vascular
communications, such as the ductus arteriosus, may place an
excessive load on the heart in the postnatal period and beyond.
There are also congenital heart defects, such as pulmonic ste-
nosis, which compromise the fetus, the newborn, and the adult.
It is typically only those defects that allow adequate in utero
development and a reasonably successful perinatal life that are
recognized; anomalies sufficiently severe to cause death in
utero, or in the neonatal period, often are not.
As with most diseases, there is a spectrum of change. The
variation in severity of a particular lesion may be wide and will
necessarily influence whether clinical signs are observed. As such,
there is a higher incidence of congenital heart disease than is
recognized clinically. There is also a group of congenital heart
diseases that do not produce clinical signs of heart failure, but
which are manifested by upper alimentary dysfunction.
Although little is known of the causes of many cardiac mal-
formations in domestic mammals, there is no doubt that,
especially in dogs, some are genetically determined. The dem-
onstration that some congenital heart diseases are genetically
determined arose from the observation that the incidence of
defects was higher in purebred populations. It has been
thought that both patent ductus arteriosus (PDA) and
conotruncal defects have a polygenic inheritance pattern,
where the full expression of these diseases depends on the
inheritance of a number of genes from different loci. However,
studies on Keeshonds with conotruncal defects indicate that
the inheritance pattern is most compatible with a single auto-
somal locus. The data suggest the presence of a mutant allele
that is partially penetrant in heterozygotes and fully penetrant
in homozygotes. Congenital subaortic stenosis in the New-
foundland dog is also genetically determined; it may either be
polygenic or a single dominant gene that is variably expressed.
Table 1-3 outlines the breed-specific predisposition to con-
genital heart disease in the dog.
 14.e1

Further reading
Adams JW, et al. Enhanced Gαq signaling: a common pathway medi-
ates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad
Sci U S A 1998;95:10140-10145.
Brand T, et al. Expression of nuclear proto-oncogenes in isoproterenol-
induced cardiac hypertrophy. J Mol Cell Cardiol 1993;25:1325-
1337.
Edwards WD. Cardiovascular system. In: Ludwig J, editor. Handbook
of Autopsy Practice. 3rd ed. New Jersey: Humana Press; 2002.
p. 21-43.
Gerdes AM, Capasso JM. Structural remodeling and mechanical dys-
function of cardiac myocytes in heart failure. J Mol Cell Cardiol
1995;27:849-856.
Hardt SE, Sadoshima J. Negative regulators of cardiac hypertrophy.
Cardiovasc Res 2004;63:500-509.
Hill JA, Olson EN. Cardiac plasticity. N Engl J Med 2008;358:1370-
1380.
Horban A, et al. Correlation between function and proto-oncogene
expression in isolated working rat hearts under various overload
conditions. J Mol Cell Cardiol 1997;29:2903-2914.
Keene BW, et al. Modified transvenous endomyocardial biopsy tech-
nique in dogs. Am J Vet Res 1990;51:1769-1772.
Matsuo T, et al. Mechanisms of cardiac hypertrophy in canine volume
overload. Am J Physiol 1998;275:H65-H74.
McMullen JR, et al. Phosphoinositide 3-kinase (p110α) plays a critical
role for the induction of physiological, but not pathological, cardiac
hypertrophy. Proc Natl Acad Sci U S A 2003;100:12355-12360.
Miller PJ, Holmes JR. Observations on structure and functions of the
equine mitral valve. Equine Vet J 1984;16:457-460.
Parmley WW. Neuroendocrine changes in heart failure and their clinical
relevance. Clin Cardiol 1995;18:440-445.
Sheaff MT, Hopster DJ. Post Mortem Technique Handbook. London:
Springer; 2001. p. 87-116.
Sugden PH, Clerk A. Cellular mechanisms of cardiac hypertrophy. J Mol
Med 1998;76:725-746.
Takemura N, et al. Atrial natriuretic peptide in the dog with mitral
regurgitation. Res Vet Sci 1991;50:86-88.
Tamamori M, et al. Endotheün-3 induces hypertrophy of cardiomyo-
cytes by the endogenous endothelin-1-mediated mechanism. J Clin
Invest 1996;97:366-372.
Woeber KA. Thyrotoxicosis and the heart. N Engl J Med 1992;327:94-
98.
Yamazaki T, et al. Molecular mechanism of cardiac cellular hypertrophy
by mechanical stress. J Mol Cell Cardiol 1995;27:133-140.
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels 15

Table • 1-3 
Breed-specific predispositions to congenital heart disease in dogs
Defect Breed

Patent ductus arteriosus
Pulmonic stenosis
Subaortic stenosis
Persistent right aortic arch
Tetralogy of Fallot
Atrial septal defect
Ventricular septal defect
Tricuspid insufficiency or dysplasia
Mitral insufficiency or dysplasia
Bichon Frise, Chihuahua, Cocker Spaniel, Collie, English Springer Spaniel, German Shepherd, Keeshond,
Kerry Blue Terrier, Maltese Terrier, Pomeranian, Poodle, Shetland Sheepdog, Yorkshire Terrier
Airedale Terrier, Beagle, Chihuahua, English Bulldog, Fox Terrier, Mastiff, Miniature Schnauzer,
Samoyed, Scottish Terrier, West Highland White Terrier
Boxer, English Bulldog, German Shepherd, German Shorthaired Pointer, Golden Retriever, Great
Dane, Newfoundland, Rottweiler, Samoyed
German Shepherd, Great Dane, Irish Setter
English Bulldog, Keeshond
Doberman Pinscher, Samoyed
English Bulldog
German Shepherd, Golden Retriever, Great Dane, Labrador Retriever, Weimaraner
Bull Terrier English Bulldog, Chihuahua, German Shepherd, Great Dane

Table • 1-4 
Proportions (%) of canine congenital cardiac anomalies in 4 surveys
Patterson Mulvihill, Priester Hunt et al. Tidholm
Anomaly* (1953-1965), n = 248 (1964-1971), n = 700 (1977-1989), n = 100 (1989-1996), n = 151

Patent ductus arteriosus 30 36 34 11

Atrioventricular valve dysplasia 4 9 18 15
Pulmonic stenosis 21 11 18 20
Aortic stenosis 15 6 10 35
Persistent right aortic arch 8 12 7 —
Ventricular septal defect 7 10† 7 12
Tetralogy of Fallot 4 — 3 0.6
Atrial septal defect 4 3 0 3
Other 7 13 3 3
Total (%) 100 100 100 100
*~7-9% of dogs had more than one anomaly.
†
Includes tetralogy of Fallot.

In humans, increasing attention has been focused on muta-
tions in transcription modulators, signal transduction, and
structural protein genes as causes of inherited congenital  and subaortic stenosis are common (Table 1-4). In cattle, atrial
heart disease. This includes the transcription factors Nkx2-5,
GATA4, and TBX-5, and the NOTCH pathway genes
JAGGED1, NOTCH1, and NOTCH2. The NOTCH pathway
genes have been associated with valvular defects and tetralogy
of Fallot. Further insights into the normal and abnormal devel-
opment of the heart and great vessels have come from the
effects of targeted gene mutations and deletions using the
zebrafish, Danio rerio, as an experimental model.
There may be other as yet undefined factors that contrib-
ute to the development of congenital heart disease in domestic
animals. In humans, cardiac and vascular anomalies are
common features of several syndromes produced by chromo-
somal abnormalities and viral infections such as rubella. There
is little evidence to suggest the presence of similar abnormali-
ties or infections associated with congenital heart disease in
domestic animals.
The pattern and incidence of congenital cardiac disease varies
with the species examined. In dogs, PDA, pulmonic stenosis,
and ventricular septal defects (VSDs) and transpositions of
the main vessels are most frequently diagnosed. Subaortic
stenosis and endocardial cushion defects are the most frequent
anomalies in pigs. In cats, endocardial cushion defects and
congenital left AV valve insufficiency appear to be common.
Congenital cardiovascular disease is quite uncommon in
horses.
In cases of suspected cardiac abnormality, it is essential to
examine the heart and large vessels in situ because relations
are difficult to trace once the organ is removed. Some animals
are born with hearts that, although of normal arrangement,
are very small. In the majority of cases of cardiac abnormality,
the anomaly is reflected in gross enlargement of the organ and
in alteration of the size or disposition of the large vessels.
Cardiac malformations are extremely variable, and their analy-
sis can be perplexing if it is not remembered that they do
16 CHAPTER 1  •  Cardiovascular System Congenital Abnormalities of the Heart and Large Vessels

follow fairly simple basic patterns. The recognition of the The consequence of an ASD in the neonate is excessive flow
primary abnormality is an essential first step. This then assists from the left to right atrium, with resultant volume overload on
in the recognition of secondary abnormalities, which develop the right ventricle and elevated central venous pressure (Figs.
as adjustments to allow blood to circulate through the heart. 1-10, 1-11). In some cases, following the development of
An understanding of the mechanics of abnormal development pulmonary hypertension, the flow through the defect is
is necessarily based on an understanding of the normal devel- reversed, leading to cyanosis.
opment of the organ, for which reference should be made to
a standard text of embryology. Aorta
There is no completely satisfactory system for classifying
congenital heart defects, as they may be complex or may
Cranial vena cava PA
overlap as part of a spectrum. Based on a combination of ana-
tomic defects and functional effects, they may be classified as
PV
• Malformations causing systemic to pulmonary (left-to-
right) shunting PV
• Malformations of cardiac valves RA
• Transposition complexes LA
• Miscellaneous cardiac anomalies
• Vascular anomalies Caudal
vena cava
Malformations causing systemic to pulmonary
(left-to-right) shunting
In the development of the heart, there are 3 major arteriove-
nous communications: between the atria, the ventricles, and RV
LV
the great vessels. These connections are necessary for shunting
of blood in the fetus. The atrial and ventricular septa close in
utero; the foramen ovale and the ductus arteriosus close early
in the neonatal period. Failure of closure results in atrial septal
defect (ASD), VSD, or PDA, 3 of the more common congenital
cardiac defects in domestic animals. Less common defects in Figure 1-10  Atrial septal defect (ASD). An ASD usually results
this group include AV septal defect, persistent truncus arteriosus, in increased blood flow from the left (LA) to the right (RA)
aorticopulmonary window, and anomalous pulmonary venous atrium. The right ventricle (RV) dilates under this increased
return. volume load. Also, a mild increase in afterload develops from the
increased volume load within the right ventricle. LV, left ventricle;
Atrial septal defect PA, pulmonary artery; PV, pulmonary vein. (Modified from Rob-
In the fetus, separation of the left and right atria commences inson WF, Huxtable CRR, eds. Clinicopathologic Principles for
with the downgrowth of the septum primum, which grows Veterinary Medicine. Cambridge, UK: Cambridge University
toward the AV junction, where the developing endocardial Press, 1988. Reprinted with permission.)
cushions begin to form the AV valves and separate the ven-
tricles. The septum fuses with the endocardial cushions, oblit-
erating the ostium primum, and then begins to fenestrate in its
middle. The fenestration is destined to become the ostium
secundum. A second septum (septum secundum) develops
downward and to the right of the septum primum. With its
semilunar edge, the septum secundum and the remains of the
septum primum form the foramen ovale. Within the left
atrium, the septum primum forms the flap valve of the
foramen ovale that allows blood flow from right atrium to left
atrium in the fetus. In the majority of animals, anatomic
closure of the foramen ovale follows functional closure post-
natally. A probe-patent foramen ovale postnatally is not an ASD, *
for although the foramen ovale may not be anatomically
closed, it is functionally closed (valvular competent) because
left atrial pressure exceeds right atrial pressure.
An ASD can result from
• Defects of the septum between the right upper pulmonary
veins and the cranial vena cava (sinus venosus defect)
• Failure of fusion of septum primum with the endocardial
cushions (ostium primum defect, low in the atrial septum
adjacent to the AV valves, a form of AV septal defect)
• An excessively large ostium secundum or inadequate
development of the septum secundum (ostium secundum Figure 1-11  Atrial septal defect (arrow) in a 3-week-old lamb. A
defect, in mid-septum at the site of the fossa ovalis, the high ventricular septal defect is also evident (asterisk). (Courtesy
most common type) M.J.M. Sula.)
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels 17

A B
Figure 1-12  Ventricular septal defect. A. High ventricular septal defect (arrow) in a dog, involving
the pars membranacea. The chamber of the left ventricle is enlarged (volume overload) and is
accompanied by mild subendocardial fibrosis following chronic dilation. (Courtesy D. Hayden.)
B. Large ventricular septal defect of the muscular part of the interventricular septum in a calf.

Atrioventricular (AV) septal defect
Also known as endocardial cushion defects or AV canal defects,
these malformations arise from deficiency of the AV septum
that separates the left ventricular inlet from the right atrium.
The atrial septum primum must fuse with the endocardial
cushions, which in turn contribute to the development of the
atrial and ventricular septa, and to the medial leaflets of the
left and right AV valves. Anomalous development may result
in a range of anatomic defects, including ostium primum defect
(partial AV canal), VSD with a cleft in the right AV valve, or
common AV canal. The common or complete AV septal defect
consists of an ostium primum defect, a VSD, and a common
AV orifice.
Defects of the AV canal are among the most common defects
in the pig. In the largest series examined, 40% of pigs with
congenital heart disease had this defect. It is also a frequent
finding in cats.
Ventricular septal defect
Ventricular septal defect is one of the most common defects
encountered in domestic animals. The separation of the left and
right ventricles is completed by 3 parts of the embryonic
heart: the muscular portion of the septum, the downward
growth of the conotruncal ridges, and the membranous portion
of the septum derived from the endocardial cushions. Defects
can be related to defective development of any of the 3 parts.
VSDs are usually single but may be multiple, and most com-
monly involve the membranous septum (Fig. 1-12A). This type
of VSD is termed paramembranous or perimembranous, as they
exceed the bounds of the membranous septum and involve a
muscular defect at their periphery; they may also be referred
to as subaortic or infracristal. Less common sites of VSD are
subpulmonary (infundibular, conal, supracristal), below the
septal leaflet of the right AV valve, or in the muscular portion of
the ventricular septum toward the apex of the heart (Fig.
1-12B). Although occurring most commonly as an isolated
defect, VSD is also seen as part of a number of other defects,
such as tetralogy of Fallot or persistent truncus arteriosus.
There appears to be a high incidence of spontaneous postnatal
closure of small VSDs in humans, and a similar phenomenon
has been reported in dogs.
The presence of a VSD has no deleterious effect on the
fetus because left and right ventricular pressures are equal,
and there is therefore little flow across the defect. Postnatally,
the effects of VSDs are related to the size of the defect and the
level of pulmonic vascular resistance relative to the systemic resis-
tance. Pulmonary vascular resistance normally drops postna-
tally, leading to a left-to-right shunt. Left ventricular output is
maintained by an increase in end-diastolic volume and aug-
mentation of contractility by the Frank-Starling mechanism.
Because right ventricular pressure equals left ventricular pres-
sure, the right ventricle is confronted with a large systolic and
diastolic load. Both ventricles undergo hypertrophy, the left
being more obviously eccentric in nature (Fig. 1-13).
Eventually, pulmonary hypertension can lead to shunt
reversal (right-to-left), cyanosis, and death. The term Eisen-
menger complex is applied to VSD cases in which, instead
of the usual left-to-right shunt, flow has been reversed to a
right-to-left shunt through the VSD as a consequence of
severe pulmonary hypertension that is, in turn, due to high
pulmonary vascular resistance. The more general term 
of Eisenmenger syndrome is applied to any anomalous
circulatory communication (e.g., ASD, VSD, PDA) that leads
to obliterative pulmonary vascular disease, with resulting
reversal of the left-to-right shunt across the pulmonary-
systemic communication.
Patent ductus arteriosus
Patent ductus arteriosus (PDA) is one of the more common
defects, and it is recorded in all species (Fig. 1-14). In the dog
18 CHAPTER 1  •  Cardiovascular System
Aorta
Cranial vena cava
PA
PV
PV
RA
LA
Caudal
vena cava
LV
RV
Figure 1-13  Ventricular septal defect (VSD). Blood flow in a
VSD is usually left to right, creating both an increased preload
and afterload on the right ventricle. The increased volume of
blood returning through the pulmonary circuit places an
increased preload on the left atrium and ventricle, which can
cause left ventricular dilation and hypertrophy. For abbreviations,
see Figure 1-10. (Modified from Robinson WF, Huxtable CRR,
eds. Clinicopathologic Principles for Veterinary Medicine.  the left ventricle and pressure overload of the right ventricle,
Cambridge, UK: Cambridge University Press, 1988. Reprinted
with permission.)
Figure 1-14  Patent ductus arteriosus (PDA) in a pig, with a
probe through the PDA connecting pulmonary artery (bottom)
with aorta. (Courtesy A. Rovira.)
it has a polygenic inheritance pattern, and PDA may result
from hypoplasia or asymmetry of ductal smooth muscle plus
aorta-like elastic tissue in the ductus wall. The ductus devel-
ops from the sixth left branchial arch, and functions in the
fetus to divert a major portion of blood from the pulmonary
Congenital Abnormalities of the Heart and Large Vessels
artery to the aorta. The flow from venous to arterial side is a
consequence of the presence of the high vascular resistance
of the fetal pulmonary bed. The structure of the normal
ductus differs from the adjacent pulmonary artery or aorta. In
contrast to the large elastic arteries, the media of the ductus
has a dense layer of smooth muscle, which is responsive to a
number of compounds. Among the most powerful are epi-
nephrine, norepinephrine, and angiotensin; less effective ones
include oxygen, acetylcholine, bradykinin, and indomethacin,
a prostaglandin inhibitor. Prostaglandin E2 keeps the ductus in
a dilated state. Of the compounds mentioned, oxygen and
acetylcholine are probably the most important in vivo in
causing constriction.
With contraction of the medial smooth muscle, the ductus
becomes functionally closed in the first few hours after birth.
There are exceptions. The ductus in some foals may remain
patent for up to 5 days, and a continuous murmur is detect-
able up to that time. A ductus arteriosus that remains patent
beyond this time is considered to be abnormal. They are
minimally responsive, or nonresponsive, to oxygen and other
compounds that constrict the normal ductus.
Continued patency results in a number of sequelae that are
dependent on the size of the PDA and the relationship
between the pulmonary and systemic vascular resistance. In
uncomplicated cases, the blood flow is from the aorta to the
pulmonary artery (left-to-right shunt) during both systole and
diastole. Depending upon the ensuing rise of pulmonary arte-
rial pressure, there may be left-to-right flow only during
systole. In severe cases, the shunt is reversed and flow from
the pulmonary artery to the aorta (right-to-left shunt) occurs.
If the ductus is of sufficient size, there is volume overload of
resulting in compensatory hypertrophy of both ventricles.
There is also left atrial dilation resulting from increased 
pulmonary blood flow (Fig. 1-15). The ascending aorta and
pulmonary artery are dilated, probably resulting from a com-
bination of turbulent flow and altered pressure relationships.
The development of congestive heart failure with a large PDA
is not only related to pulmonary vascular resistance, but also
to the ability of the left ventricle to handle volume overload.
In dogs where aorticopulmonary shunts were created experi-
mentally, a communication of 3 mm or less in diameter may
lead to the slow development of left ventricular hypertrophy,
but it is otherwise well tolerated. A window of 5 mm in
diameter may lead to pulmonary hypertension, with degen-
erative changes in pulmonary vessels and congestive heart
failure.
As a consequence of turbulent flow, a PDA is predisposed
to thrombosis, which is referred to as endocarditis of the
ductus. The anatomic appearance of the PDA ranges from a
ductus diverticulum, which is a blind funnel-shaped out-
pouching of the aorta at the site of the ductus, to a ductus
that approaches the diameter of the aorta. The length of the
patent ductus may also vary. In some cases, there is virtually
no ductus, but, instead, an opening between the aorta and
pulmonary artery, which are closely approximated. Hypopla-
sia and asymmetry of ductus-specific smooth muscle and the
presence of aorta-like elastic tissue in the ductus wall, as 
has been observed in some cases, may cause patency. In 
dogs, as the number of genes that determine its presence
increases, the histologic appearance of the PDA more closely
resembles the aorta, and the clinical severity of the defect
increases.
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels 19

Aorta

PDA
Cranial vena cava

PV

PV

RA
PA LA Left atrial
dilation
Caudal
vena cava

Increased RV
afterload LV Figure 1-16  Pulmonic stenosis in a dog. The pulmonary artery
has been opened showing the poststenotic dilation and the thick-
ened, distorted pulmonary valves fixed in a closed position.
(Courtesy A. G. Armien.)

Increased
preload
Aorta
Figure 1-15  Patent ductus arteriosus (PDA). In most cases,
blood flow through a PDA occurs during both systole and diastole
from the aorta into the pulmonary artery. The right ventricle Cranial vena cava PA
hypertrophies concentrically because of the increased afterload
(pulmonary arterial hypertension). The left atrium and ventricle PV
hypertrophy eccentrically because of the increased preload
(increased volume of blood returning from the pulmonary circuit). PV
For abbreviations, see Figure 1-10. (Modified from Robinson WF,
RA
Huxtable CRR, eds. Clinicopathologic Principles for Veterinary LA
Medicine. Cambridge, UK: Cambridge University Press, 1988.
Reprinted with permission.) Caudal
vena cava

Malformation of semilunar or
atrioventricular valves
Failure of adequate development of the semilunar valves
RV
usually results in valvular or subvalvular stenosis. Anomalous LV
AV valves may be insufficient or stenotic or both.

Pulmonic stenosis
Pulmonic stenosis is a relatively common congenital anomaly in
dogs, but an unusual finding in other domestic species. It is
inherited in Beagles, and is suspected to be so in English Bull-
dogs, Bull Mastiffs, Chihuahuas, and terrier types. The term
pulmonic stenosis encompasses 3 anatomic variations: supraval-
vular, valvular, and subvalvular or infundibular stenosis. Valvu-
lar stenosis, the most common form in dogs, is probably due
to disordered fusion of the valve cushions and their failure to
hollow out properly. The valve, which is then more or less
dome shaped with an irregular central perforation, is sur-
rounded by 3 recognizable sinuses of Valsalva that are small
and irregular in form (Fig. 1-16). Subvalvular or infundibular
stenosis is produced by a ring of connective tissue that encir-
cles the upper portion of the outflow tract of the right ven-
tricle, or by hypertrophy of the crista supraventricularis
muscle ridge. With each form, the pulmonary trunk is dilated
and thin walled. This is probably due to a combination of
turbulent flow and a drop in pressure, creating a venturi  be malformation of the left aortic sinus of Valsalva and inver-
effect in the pulmonary artery. Concentric right ventricular
Figure 1-17  Pulmonic stenosis is usually valvular and places an
increased afterload on the right ventricle which undergoes con-
centric hypertrophy. There is poststenotic dilation of the pulmo-
nary artery. For abbreviations, see Figure 1-10. (Modified from
Robinson WF, Huxtable CRR, eds. Clinicopathologic Principles
for Veterinary Medicine. Cambridge, UK: Cambridge University
Press, 1988. Reprinted with permission.)
hypertrophy is always present because of the increased afterload
placed on the right ventricle (Fig. 1-17).
In English Bulldogs, the breed most commonly affected by
pulmonic stenosis, the stenosis is frequently caused by a cir-
cumpulmonary left coronary artery that originates from a single
right coronary artery. The cause of this syndrome appears to
sion of the proximal segment of the left main coronary artery.
20 CHAPTER 1  •  Cardiovascular System Congenital Abnormalities of the Heart and Large Vessels

Aorta
PA
Aorta

RV
tal
LV ep
l a rs
t
icu ec
e ntr def
V
A

B
Aorta PA

LV

RV

C
Figure 1-18  Tetralogy of Fallot. A. Over-riding aorta and right ventricular hypertrophy can be
seen. B. High ventricular septal defect and over-riding aorta evident. C. Pulmonic stenosis and
right ventricular hypertrophy are evident. (Arrows—red for left side and blue for right side—on
white plastic tubes show direction of blood flow). LV, left ventricle; PA, pulmonary artery;
RV, right ventricle. (Courtesy V. Psychas.)

Tetralogy of Fallot
The primary lesion in tetralogy of Fallot is obstruction to right
ventricular outflow, either through pulmonic stenosis or infun-
dibular stenosis that results from abnormal conotruncal par-
titioning. The other lesions in the tetrad are ventricular septal
defect (VSD), overriding aorta, and secondary right ventricular
hypertrophy (Fig. 1-18A-C). Tetralogy is one of the congenital
heart diseases that invariably results in clinical signs. Affected
animals fatigue easily and are usually cyanotic and polycythemic.
The latter is a response to hypoxia. Growth rate is usually
retarded. At least in Keeshonds, the condition is inherited as a
defect at a single autosomal locus, in which there is partial
penetrance in heterozygotes and complete penetrance in
homozygotes. Analysis of affected Keeshonds has revealed
various grades of malformation. The spectrum of anomalies
included subclinical defects of the crista supraventricularis,
VSD, pulmonic stenosis with abnormal nonpatent interven-
tricular septum, and tetralogy of Fallot. Closure of the inter-
ventricular septum is contributed to by the conotruncal
septum. The flow of blood from the right ventricle into the
dextroposed aorta does not depend on the degree of overrid-
ing, but on the severity of the pulmonic stenosis (Fig. 1-19).
Aortic and subaortic stenosis
Isolated congenital aortic valvular stenosis is distinctly uncom-
mon. Subvalvular aortic (subaortic) stenosis is, in contrast, a
common defect in pigs and often occurs in conjunction with
what has been termed endocardiosis of the left AV valve. In one
study of 321 pigs that had left AV valvular abnormalities
(endocardiosis), 258 had accompanying subaortic stenosis.
Subaortic stenosis is among the more frequently encountered
anomalies in dogs, and often occurs in association with left
AV valvular disease. Dog breeds commonly affected include
the German Shepherd dog, Weimaraner, Golden Retriever,
German Shorthaired Pointer, Saint Bernard, Newfoundland,
Dogue de Bordeaux, and English Bull Terrier.
The anatomic appearance of the subvalvular lesion ranges
from a number of small fibrous plaques on the endocardial
surface of the left ventricular outflow tract on the interven-
tricular septal aspect, to a completely encircling fibrous band
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels
Aorta
PA
Cranial vena cava
PV
PV
RA
LA
Caudal
vena cava
RV
LV
Figure 1-19  Tetralogy of Fallot. The severity of the pulmonic
stenosis determines the predominant direction of flow. If severe
pulmonic stenosis is present, the flow is into the aorta via the
ventricular septal defect. The right ventricle hypertrophies con-
centrically because of the increased afterload placed on it. For
abbreviations see Figure 1-10. (Modified from Robinson WF,
Huxtable CRR, eds. Clinicopathologic Principles for Veterinary
Medicine. Cambridge, UK: Cambridge University Press, 1988.
Reprinted with permission.)
Figure 1-20  Aortic and subaortic stenosis. Note thickened aortic
valves and ridge of fibrous tissue in the aortic outflow tract. Dog.
(Courtesy A. Wuenschmann.)
just below the aortic valve (Fig. 1-20). There may also be
involvement of the aortic valve. The subendocardial thicken-
ings are composed of connective tissue in irregular arrange-
ments, intermixed with abundant mucinous ground substance.
The change is sometimes fibrocartilaginous in nature. Where
there is an accompanying left AV valvular defect, it is com-
posed of a thickened, ridged, and larger cranial leaflet, which
21
Aorta
PA
Cranial vena cava
PV
PV
RA
LA
Caudal
vena cava
RV LV
Figure 1-21  Aortic and subaortic stenosis place an increased
afterload on the left ventricle, which hypertrophies concentrically.
There is poststenotic dilation of the aorta. For abbreviations 
see Figure 1-10. (Modified from Robinson WF, Huxtable CRR,
eds. Clinicopathologic Principles for Veterinary Medicine. 
Cambridge, UK: Cambridge University Press, 1988. Reprinted
with permission.)
forms part of the left ventricular outflow tract. The cranial
leaflet forms about 13 of the cylinder that is the left ventricu-
lar outflow tract and, when abnormal, completes the stenosing
subaortic ring.
As with pulmonary outflow tract obstruction, increased
afterload on the left ventricle and turbulent poststenotic flow
produce compensatory concentric hypertrophy of the involved ven-
tricle and poststenotic dilation of the aorta (Fig. 1-21). Intimal
proliferation of collagen and deposition of glycosaminoglycans
in the intramural coronary arteries is common. This may well
explain the presence of multifocal myocardial necrosis and
fibrosis, and the relatively common clinical finding of sudden
death, presumably resulting from the generation of ventricular
dysrhythmias following myocardial necrosis.
The heritability of this anomaly in dogs is either polygenic
or involves a major dominant gene with modifiers. There is
some question as to whether it is a true congenital lesion. In
one experimental study, no dog exhibited the typical lesion
before 25 days of age. There is also some evidence that the
severity of the condition increases with age.
Dysplasia of the right atrioventricular valve
Dysplasia of the right AV valve appears to be one of the more
common defects observed in the cat, but is uncommon in other
domestic species. Affected dog breeds include Dogue de 
Bordeaux and Labrador Retriever. The anatomic characteris-
tics of right AV dysplasia are focal or diffuse thickening of the
leaflets, some of which may be absent, or short chordae ten-
dineae and papillary muscles, and direct fusion of portions of
22 CHAPTER 1  •  Cardiovascular System
the affected valve with the ventricular wall. In right AV dys-
plasia, the valve is insufficient, the right atrium is enlarged, and
the right ventricle is eccentrically hypertrophied. The anomaly
may be associated with malformation of the left AV valve
complex or VSD. In Ebstein’s anomaly of the right AV valve,
there is downward displacement of the basal portions of the
valve into the right ventricle. The morphologically similar
canine right AV valve malformation has been mapped to a
susceptibility locus on chromosome 9 in several kindreds of
purebred Labrador Retriever dogs. Right AV atresia—absence
of the right AV orifice—is accompanied by an interatrial com-
munication, right ventricular hypoplasia, and usually a VSD.
Left atrioventricular valvular insufficiency or stenosis
A mixed-frequency holosystolic murmur, with its point of
maximum intensity on the left caudal sternal border, is indica-
tive of left AV valve insufficiency. Commonly heard in old
dogs with endocardiosis, it may also be associated with moder-
ate to severe left-sided failure in young dogs and cats. Malfor-
mation of the left AV valve complex is probably the most common
congenital cardiac anomaly in the cat. The lesion has a relatively
wide spectrum of severity, and may result in either an insuffi-
cient or a stenotic valve. Anatomically, there is an enlarged
annulus, short thick leaflets, short thickened chordae tendin-
eae, upward malposition of atrophic or hypertrophic papillary
muscles, and enlargement of the left atrium and ventricle.
There is also diffuse endocardial fibrosis. In dogs, the lesion
has been most commonly seen in Cavalier King Charles  tissue, and Purkinje cells. False tendons are of debatable sig-
Spaniels, Great Danes, English Bull Terriers, and, to a lesser
extent, German Shepherd dogs.
Transposition complexes
Some of the more severe cardiac anomalies are a combination
of defects of the aorta and pulmonary artery. Malposition or
transposition of arterial trunks is a condition in which the
aorta lies in relation to the pulmonary artery such that it
receives blood from the right ventricle, the basic defect being
dextroposition of the aorta. There are 4 degrees, or types, of this
anomaly:
• Overriding aorta—(the most common type), the aorta
straddles the interventricular septum, which is defective,
and receives blood from both ventricles, and the pulmo-
nary artery leaves the right ventricle;
• Partial transposition—both vessels leave the right ventricle;
• Overriding pulmonary artery—the pulmonary artery strad-
dles a defective ventricular septum and the aorta emerges
from the right ventricle;
• Complete transposition—the aorta emerges from the right
ventricle and the pulmonary artery emerges from the left
(eFig. 1-5).
It is usual in these transposition complexes for either the
pulmonary artery or the aorta to be hypoplastic.
Miscellaneous cardiac anomalies
Congenital hematomas (hemocysts) on the margins of the AV
valves are common, especially in calves, but appear to be of little
consequence. These are usually blood-filled cysts lined by
endothelium; they originate in the clefts normally present in
the substance of the valves in intrauterine life. The cysts may
measure up to 1.0 cm in diameter and be multiple. There is
some question as to whether the cysts involute within a few
months of birth, or whether they persist for a year or more,
by which time the content is changed to serous fluid. A similar
Congenital Abnormalities of the Heart and Large Vessels
process, termed valvular telangiectasis in the septal cusp of the
right AV valve in Beagles, has been reported to progress from
telangiectasis through scarring and osseous metaplasia.
Primary endocardial fibroelastosis is characterized by
diffuse endocardial thickening by collagen and elastic fibers,
and left ventricular hypertrophy and dilation in the absence
of any associated cardiac malformation. The fact that diffuse
endocardial thickening occurs when any chamber of the heart
remains dilated for a prolonged period has probably led to the
confusion that exists about endocardial fibroelastosis. There
have been reports in the literature describing the existence of
this condition in a number of species, but the primary disease
has only been well documented in cats and, to a lesser extent,
dogs. The disease in affected Burmese kittens commences with
localized endocardial lymphedema. This is detectable micro-
scopically, but not grossly, at 1 day of age. Progressive deposi-
tion of endocardial collagen and elastin follows and allows
macroscopic detection from 20 days of age. The left atrium is
dilated, and the left ventricle is hypertrophied and dilated.
The endocardial fibrosis progressively involves cardiac con-
ducting fibers, which exhibit some degenerative change.
Although not definitely established, there appears to be little
doubt of the inherited nature of the disease.
False tendons are thin, often branching, structures that
traverse the cavity of the left ventricle and are not connected
to the valve cusps; they are common in domestic mammals.
They are composed of cardiac muscle, blood vessels, fibrous
nificance, but may play a role in innocent murmurs and 
cardiac dysrhythmia.
Cor triatriatum (triple atria) is a rare lesion in cats and dogs
resulting from failure of incorporation of the common pulmo-
nary vein into the left atrium. A membrane separates the left
atrium into 2 compartments, which can impede pulmonary
drainage and lead to pulmonary edema. Cor triatriatum dexter
(right atrium) can cause ascites.
Epithelial inclusions are found occasionally in ventricular
myocardium in well-defined areas of discoloration or spongi-
ness. The inclusions are present as acinar or ductular structures
lined by a simple layer of cuboidal epithelial cells on a base-
ment membrane. The inclusions are possibly of endodermal
origin from the foregut and represent displacements arising
very early in embryogenesis, when the heart rudiment is adja-
cent to the developing foregut.
Myocardial bridges are anatomic variants that are superfi-
cial myocardial bands that run across short segments of a
coronary artery located epicardially in the dog, cat, goat,
sheep, and human. The bridges appear to be of little functional
significance.
Congenital absence of the pericardium occurs in dogs.
Affected animals are usually asymptomatic.
Double-chambered right ventricle is a rare cardiac anomaly
in cats and dogs.
Variations in the position of the heart are not cardiac mal-
formations but, instead, malformations of adjacent structures:
• In ectopia cordis, the heart may lie in extrathoracic, prester-
nal, or intra-abdominal positions (Fig. 1-22). Dislocations
within the thorax are the result of asymmetrical pressure,
as for example, in congenital diaphragmatic hernia or
pleural effusion.
• In peritoneopericardial diaphragmatic hernia, which
occurs in dogs and cats, intestine and/or liver are present
in the pericardial sac.
 22.e1

eFigure 1-5  Complete transposition of aorta and pulmonary

artery in a foal. Coronary arteries arise from a common trunk
(arrowhead).
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels
Figure 1-22  Ectopia cordis in a calf. Extrathoracic ventral loca-
tion of the heart through a sternal and skin defect. (Courtesy 
R.W. Cook.)
Figure 1-23  The persistent right aortic arch traverses the esopha-
gus and the trachea, resulting in marked dilation of the esophagus
cranial to the persistent arch. (Courtesy P. Nation.)
• Dextrocardia is a rare condition in dogs in which the apex
of the heart, which normally points to the left (levocardia),
points to the right. Dextrocardia may be part of situs inver-
sus, in which the heart and other internal organs are trans-
posed in a mirror-image fashion. Kartagener’s syndrome, a
rare condition in dogs, includes dextrocardia, sinusitis, and
bronchiectasis, the last 2 features as a result of ciliary
dyskinesia.
Vascular anomalies
Persistence of the right aortic arch is a well-known anomaly
in dogs and has been observed in cattle. It is due to persistence
of the right fourth aortic arch instead of, as is normal, the left
fourth aortic arch. A right aorta descends to the right of the
midline, arches over the origin of the right bronchus, and
descends either to the left or right of the vertebral column.
With the aorta in this position, the ductus arteriosus (ligamen-
tum arteriosum), passing from the aorta to the pulmonary
artery, encloses the esophagus and compresses it against the
trachea. Obstruction of the esophagus at this point leads to
dysphagia and, shortly, to dilation of the cervical portion of
the esophagus (Fig. 1-23).
A double aortic arch is a variation of the foregoing in
which the left arch persists as well as the right. Both arches arise
23
Figure 1-24  Aortic coarctation (hypoplasia) with right atrioven-
tricular (AV) stenosis in a dog. Hypoplastic aorta (arrowhead),
pulmonary artery (arrow), right AV valvular stenosis (asterisk).
(Courtesy A. G. Armien.)
from the ascending aorta. The right arch, which is usually the
larger of the 2, follows the course given above. It is joined
above the esophagus by the small left arch. The significant end
result is constriction of the esophagus.
Aorticopulmonary septal defect, or window, is a rare defect
in dogs that results from incomplete division of the truncus
arteriosus. Pulmonary hypertension develops, leading to right-
to-left shunting of blood.
Coarctation of the aorta is another rare defect in dogs, and
is seen as narrowing of the aorta adjacent to the ductus
arteriosus/ligamentum arteriosum. Left ventricular pressure
overload can result in left heart failure. Additional malforma-
tions of the aorta reported in dogs include interruption of the
aorta and tubular hypoplasia of the ascending aorta (Fig. 1-24).
Congenital aneurysm of the aorta or of the pulmonary
artery, involves, for either vessel, the trunk and arch, but may
not extend beyond the insertion of the ligamentum arterio-
sum. Aortic aneurysm may be associated with aneurysm of
one or more of the aortic sinuses of Valsalva.
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24 CHAPTER 1  •  Cardiovascular System
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PERICARDIAL DISEASE
Primary disease confined to the pericardium is rare, but the
close anatomic relationship of the pericardium to the heart,
lungs, and pleura sometimes results in the extension of disease
processes from the latter organs to the pericardium. It is also
often a site for the location of infectious agents as part of
systemic infections, particularly in the neonate. Somewhat
paradoxically, the pericardium is not needed for normal  rupture and result in a bloodstained effusion. Neoplastic
life, but pericardial disease can be life threatening. The peri-
cardial sac may be removed surgically for relief of pericardial
constriction.
The pericardial cavity may communicate with the perito-
neal cavity through clefts in the diaphragm; hence herniated
intestine may be found surrounding the heart as a result of
congenital peritoneopericardial diaphragmatic hernia. Partial or
complete congenital absence of the pericardial sac is without
clinical effect. Pericardial cysts are rare congenital anomalies
that occur in one of the costophrenic angles.
Epicardial fibrous fronds occur on the atria of Beagle dogs
as an occasional incidental finding at postmortem.
Noninflammatory lesions of the pericardium
Hydropericardium
The pericardial sac normally contains a very small quantity of
clear, serous fluid. Any excess in the volume of clear fluid is
referred to as hydropericardium. A small increase in volume
occurs by transudation after death, and it is soon reddened by
postmortem hemolysis.
Hydropericardium is often part of generalized anasarca and
is thus seen in many cachectic illnesses, perhaps as the result
of hypoalbuminemia, and in congestive heart failure (Fig. 1-25).
It may also be the product of local events such as implanted
metastases of neoplasms on the pericardium, and lymphoma-
tous infiltrations of the myocardium; primary tumors about
Pericardial Disease
Figure 1-25  Hydropericardium in a cat as the result of hypopro-
teinemia associated with the cachexia of neoplasia. The outline
of the heart is just visible through the fluid-filled pericardial sac.
the base of the heart and in the cranial mediastinum are rather
common causes of hydropericardium. Hydropericardium may
also accompany congenital and acquired peritoneopericardial
hernias and uremia. Infectious processes of the pleura, especially
granulomatous inflammations, may cause irritation of the peri-
cardium sufficient to provoke a sterile serous effusion; the
infection may eventually extend to the pericardial sac. If drain-
age of the thoracic duct is disrupted, for example, by a cardiac
neoplasm, then the fluid may be chylous (chylopericardium).
In hydropericardium, the serosal surfaces remain smooth
and glistening, but if the fluid persists for a long time, it may
produce slight fibrous thickening and opacity of the pericar-
dial and epicardial surfaces. It is usually about the base of the
ventricles, and small villus proliferations of the serosa may
involvement of the pericardium characteristically has this
result.
The pericardial fluid is clear or light yellow, without floc-
cules, and with low content of protein. Fluid rich in protein,
including fibrinogen, is often found in acute toxemias of clos-
tridial (gas gangrene group) origin. Clotting occurs soon after
exposure to air. In such cases, exudation is due to direct injury
to the endothelium by circulating toxins. Fluid that is copious
and gels on exposure also is characteristic of African horse
sickness and of heartwater. In pigs with edema disease or
mulberry heart disease, fibrin is often formed antemortem.
The presence of protein, especially fibrin, in pericardial fluid
is only an index of the degree of endothelial injury and
increased permeability and is not a precise point of distinction
between an exudate and a transudate. Inflammatory exudates
can be differentiated from transudates on the basis of the
higher content of protein and cells in exudates and histologic
evidence of inflammation involving the pericardium and
epicardium.
The volume of fluid that accumulates is quite variable and
of lesser significance than the rate at which it accumulates.
When fluid accumulates rapidly, the pericardium is put under
tension, the heart is compressed, and venous blood pools in
the splanchnic and systemic circulations because of impaired
atrial and ventricular filling (cardiac tamponade). When the
fluid accumulates slowly, there is time for stretching and adap-
tation of the pericardium so that very large amounts of fluid
Diseases of the Heart
Figure 1-26  Acute, severe, hemopericardium in a dog, following
rupture of a right atrial hemangiosarcoma. (Courtesy A. G.
Armien.)
can accumulate before there is significant impairment of dia-
stolic filling of the heart.
Hemopericardium
The term hemopericardium is limited to accumulations of pure
blood in the pericardial cavity, and should not apply to mix-
tures of blood and serous fluid. If the blood is clotted, it can
be assumed that the process is a true hemopericardium. Death
usually supervenes rapidly. It is an unusual lesion, except fol-
lowing cardiac rupture, puncture or other direct trauma. It is
seen in horses in which rupture of the intrapericardial aorta
or atria occurs. In dogs, hemopericardium occurs in atrial
rupture in endocardiosis, hemorrhage from atrial hemangio-
sarcoma, in ulcerative atrial endocarditis of renal failure, and
rarely, following rupture of a coronary artery or from hemor-
rhage from a heart base thymic remnant (Fig. 1-26). In young,
growing swine, rupture of the heart, particularly of an atrium,
a coronary artery, or the aorta occurs on rare occasions. These
deaths have not been examined specifically with deficiency of
copper in mind, but attention is drawn to the remarkable
cardiovascular lesions of experimental deficiency, which is
discussed with diseases of the arteries.
Idiopathic pericardial hemorrhagic effusion occurs pre-
dominantly in large-breed dogs, and is characterized by the
presence of both clotted and unclotted blood in the pericar-
dial sac without obvious cause. The clinical presentation is
that of slowly developing right-sided heart failure, with some
having accompanying left-sided heart failure. The heart sounds
are muffled or inaudible on initial presentation, with no evi-
dence of dysrhythmias. However, some subsequently develop
atrial fibrillation. The clinical course can be prolonged. The
slow onset of clinical signs suggests either slow or intermittent
bleeding, allowing distension without tamponade. Indeed,
some dogs may make a full clinical recovery following aspira-
tion of the pericardial fluid.
Serous atrophy of pericardial fat
In cachexia of any cause, and paralleling fairly closely the
reduction in body weight, there is progressive mobilization of
depot fat, including that beneath the epicardium. As the lipid
vacuoles are reduced in size, they are replaced by protein-
aceous fluid, and with a concomitant increase in interstitial
Pericardial Disease 25
Figure 1-27  Serous atrophy of epicardial fat, which is gelatinous
and translucent around the coronary groove in a cachectic alpaca.
fluid, the depots are converted to gray, gelatinous masses that
may be flecked by small white foci of fat necrosis (Fig. 1-27).
Further reading
Alleman AR. Abdominal, thoracic, and pericardial effusions. Vet Clin
North Am Small Anim Pract 2003;33:89-118.
Aronson LR, Gregory CR. Infectious pericardial effusion in five dogs.
Vet Surg 1995;24:402-407.
Dempsey SM, et al. A review of the pathophysiology, classification, and
analysis of canine and feline cavitary effusions. J Am Anim Hosp
Assoc 2011;47:1-11.
Hall DJ, et al. Pericardial effusion in cats: a retrospective study of
clinical findings and outcome in 146 cats. J Vet Intern Med
2007;21:1002-1007.
Vogtli T, et al. Hemorrhagic pericardial effusion in dogs. A retrospective
study of 10 cases (1989-1994) with a review of the literature.
Schweiz Arch Tierheilkd 1997;139:217-224.
Pericarditis
It is seldom possible by examination of the lesion itself to
decide the cause of pericardial inflammation, although 
a decision on the cause is often possible when the total 
pathologic picture in the cadaver is noted. For this reason and
for descriptive purposes, we use a morphologic classification
of pericarditis.
Fibrinous pericarditis is usually the result of hematogenous
microbial infections, but it may arise by lymphatic permeation
from an inflammatory process in adjacent tissue. In cattle,
fibrinous pericarditis, with or without some hemorrhage, is
commonly part of pasteurellosis, blackleg, sporadic bovine
encephalomyelitis, contagious bovine pleuropneumonia, clos-
tridial hemoglobinuria, and some of the neonatal coliform
infections that enter via the umbilicus. In swine, it is frequently
part of the morbid picture of Glasser’s disease and past­
eurellosis, is a common complication of porcine enzootic
 25.e1

Further reading
Aronsohn MG, Carpenter JL. Surgical treatment of idiopathic pericar-
dial effusion in the dog: 25 cases (1978-1993). J Am Anim Hosp
Assoc 1999;35:521-525.
Bouvy BM, Bjorling DE. Pericardial effusion in dogs and cats: 1. Normal
pericardium and cause and pathophysiology of pericardial effusion.
Compend Contin Educ Pract Vet 1991;13:417-424.
Bradley GA, et al. Hemopericardium in a dog due to hemorrhage
originating in a heart base thymic remnant. J Vet Diagn Invest
1992;4:211-212.
Gwatkin R, Moynihan W. Valvular lesion in swine: rupture of heart in
two cases. Can J Comp Med Vet Sci 1942;6:213-214.
Mansfield CS, et al. Intra-atrial rhabdomyoma causing chylopericar-
dium and right-sided congestive heart failure in a dog. Vet Rec
2000;147:264-267.
Mesfin GM. Spontaneous epicardial fibrous fronds on the atria of
Beagle dogs. Vet Pathol 1990;27:458-461.
Petrus DJ, Henik RA. Pericardial effusion and cardiac tamponade sec-
ondary to brodifacoum toxicosis in a dog. J Am Vet Med Assoc
1999;215:647-648.
26 CHAPTER 1  •  Cardiovascular System
pneumonia (infection with Mycoplasma hyopneumoniae and
other agents), and is occasionally observed in salmonellosis
and in streptococcal infection of piglets. Fibrinous pericarditis
in adult sheep is usually part of pasteurellosis; in lambs, it is
usually part of pasteurellosis or caused by streptococci. In
horses, Mycoplasma felis causes pericarditis and pleuritis; strep-
tococcal pericarditis may coexist with polyarthritis. Fibrinous
pericarditis in horses may also be associated with the mare
reproductive loss syndrome. Pericarditis is rare in cats, but it
is seen as part of feline infectious peritonitis.
In fibrinous pericarditis, there is seldom significant exuda-
tion of fluid, so distension of the pericardial sac is not to be
expected. The exudation of fibrin usually begins about the
base of the heart and extends from there to cover, more or
less completely, both the pericardium and epicardium. The
fibrin is gray-white, but it may be flecked with blood, or
yellow if a large number of leukocytes are added to the
exudate. Except for small pools of serum or serous exudate,
the pericardium and epicardium are in apposition. When the
leaves are drawn apart, the exudate is drawn out into villus-
like projections to give an appearance responsible for the
names “cor villosum,” “shaggy heart,” and “bread-and-butter
pericarditis” (Fig. 1-28).
The completeness of resolution depends upon how quickly
the fibrinous exudate can be removed, which is a function of
the amount of fibrin, and how quickly the mesothelium can
be regenerated, which is a function of the amount of meso-
thelium that has been destroyed. Restorative processes compete
with the processes of organization. Within a week or so, there
will be well-formed fibrous tissue in the deepest parts. Imme-
diately superficial to this, there will be young granulation
tissue and then a stratum of fibroblasts mixed with leukocytes,
and on the surface, there remains the fibrin clot infiltrated
with numerous leukocytes. If the course is prolonged,
Figure 1-28  Fibrinous pericarditis in a foal. Greatly thickened
pericardial sac and extensive fibrinous exudate loosely attached
to the epicardium, accompanied by epicardial hemorrhage.
Pericardial Disease
organization and scarring will result in focal or diffuse fibrous
adhesions between the pericardial surfaces, with partial or
complete obliteration of the sac.
The residual lesions of fibrinous pericarditis occur as more
or less distinct variants. Focal, patchy thickenings of the epi-
cardium without adhesions form minimal residue and are
usually more distinct on the ventricles than on the atria, where
they may be obscured by normal fat. The original scar tissue
may undergo fatty metaplasia or be edematous. (The same
lesion also occurs covering healed foci of superficial myocar-
ditis.) Focal or diffuse adhesive pericarditis varies in extent
from a few “violin strings” across the sac to complete oblitera-
tion of the sac. Inclusion cysts lined by mesothelium are often
present in fibrous adhesions, and there tends to be excess fluid
present in non-obliterated portions of the sac. The pericar-
dium is separable from the epicardium by blunt dissection. As
the connective tissue is not dense, there is usually no embar-
rassment of cardiac function.
Purulent pericarditis almost invariably denotes the presence
of pyogenic bacteria, either as primary pathogens or as oppor-
tunists in fibrinous pericarditis. It occurs almost solely in cattle
as a result of traumatic perforation by a foreign body originat-
ing in the reticulum, but it is observed in cats and horses in
association with empyema (pyothorax). Migrating grass awns
(“foxtail,” Hordeum glaucum, and H. leparinum) have been
identified as causes of suppurative pericarditis in dogs in the
western United States.
The suppurative pericardial fluid may appear as thin,
cloudy exudate; as frank, creamy pus; or as a mixture of pus
and masses of fibrin. The color depends on the organisms
present, but usually varies from yellow to green, being irregu-
larly dirty gray when putrefactive bacteria are present. The
exudate is usually foul smelling. The volume of exudate varies
from a thin layer on the serosal surface to 4 L or more. In the
early stages, it can be wiped or washed off to reveal the vas-
cular injection and granularity of the membranes. Soon, the
whole of the epicardium is covered with coagulum; the pari-
etal layer of the pericardium is less severely affected, and
separation of the 2 reveals a shaggy appearance of the heart
(cor villosum).
Microscopically, the subjacent tissues are densely infiltrated
with leukocytes, the reaction extending more deeply than in
fibrinous pericarditis, the formation of new blood vessels and
connective tissue is prominent, and the overlying coagulated
exudate is densely infiltrated with leukocytes.
Resolution probably never occurs. Because of the severity of
the inflammatory reaction, healing is by organization, as is
characteristic of all suppurative inflammations. Although the
course of suppurative pericarditis may be prolonged, the per-
sistence of the inciting agent, or more usually agents, prevents
complete organization.
Constrictive pericarditis resulting from progressive organi-
zation can be so severe and diffuse that it leads to impaired
diastolic filling and the development of right-sided heart
failure (Fig. 1-29). The adhesions cannot be broken down by
blunt dissection and may be mineralized. They obliterate the
pericardial cavity, but they may also extend beyond it to
involve the mediastinum. The heart, which is confined by scar
tissue, may be smaller than normal, or it may be greatly
enlarged and hypertrophic, especially when there are also
extrapericardial adhesions present. There is always severe
cardiac dysfunction, and death occurs from congestive heart
failure.
Diseases of the Heart
Figure 1-29  Chronic constrictive pericarditis in a cow, typical of
traumatic reticulopericarditis. Note the wide band of fibrosis on
the surface of the epicardium (arrow). (Courtesy A. P. Loretti.)
Further reading
Bolin DC, et al. Microbiologic and pathologic findings in an epidemic
of equine pericarditis. J Vet Diagn Invest 2005;17:38-44.
Braun U. Traumatic pericarditis in cattle: clinical, radiographic and
ultrasonographic findings. Vet J 2009;182:176-186.
Perkins SL, et al. Pericarditis and pleuritis caused by Corynebacterium
pseudotuberculosis in a horse. J Am Vet Med Assoc 2004;224:1133-
1138.
Shubitz LF, et al. Constrictive pericarditis secondary to Coccidioides
immitis infection in a dog. J Am Vet Med Assoc 2001;218:
537-540.
Veloso GF, et al. Septic pericarditis and myocardial abscess in an English
Springer spaniel. J Vet Cardiol 2014;16:39-44.
ENDOCARDIAL DISEASE
The most clinically significant endocardial lesions affect the
heart valves rather than the mural endocardium. Lesions may
cause valvular stenosis, or valvular insufficiency, or both. Ste-
nosis of a valve, or failure to open completely, impedes the forward
flow of blood. Valvular insufficiency, alternatively termed regur-
gitation, or incompetence results in reversed flow of blood. Valvu-
lar dysfunction may produce abnormal heart sounds that are
detectable clinically as murmurs. The consequences of valvular
disease depend upon the rapidity of onset, type, and duration
of the lesion, and may be ameliorated by cardiac compensa-
tory mechanisms.
The propensity of thrombi to form on the free margins of
valves is well known, but the factors leading to it are not. It
may be related to the continual movement and the resulting
apposition of the surfaces of the free margins of the valves.
There are also ill-defined factors, such as intercurrent disease
or increased workload, which promote the development of
thrombi. The lack of an internal blood supply to the valve may
also be a contributing factor, and in common with other vas-
cular structures, injured endothelial cells release inflammatory
mediators, such as prostaglandins, and other substances, such
as adenosine diphosphate, which are potent stimulators of
platelet aggregation. Once the endothelium is removed, the
exposed collagen also stimulates the aggregation of platelets.
The presence of the initial thrombus leads to further clotting.
In contrast to cardiac myocytes, endothelial cells have a great
capacity for regeneration and for covering any breach in their
Endocardial Disease 27
continuity. If the original insult is removed, which without
appropriate treatment is not often, the valve heals by fibrosis,
but a shrunken, distorted, insufficient, or stenotic valve may
remain.
Little is known of the process leading to the abnormal
development of valves in the embryo, or the progressive accu-
mulation of glycosaminoglycans in the degenerative disease
endocardiosis. The various theories are discussed under the
appropriate heading. However, both lead to deficiencies of
valve function.
Acute rupture of chordae tendineae can occur spontane-
ously or in association with chronic valvular degeneration or
valvular endocarditis. As well, acute rupture of chordae ten-
dineae or papillary muscles, and resultant acute valvular insuf-
ficiency and heart failure, can also be caused by blunt trauma
to the chest.
Degenerative lesions
Myxomatous valvular degeneration
(“endocardiosis”) in dogs
Myxomatous valvular degeneration, commonly termed endo-
cardiosis, is the most common cardiovascular lesion in dogs. It is
a significant cause of clinically apparent left-sided heart failure,
but is also frequently encountered as an incidental finding at
postmortem. Advanced endocardiosis of the left atrioventricu-
lar (AV) (mitral) valve leads to mitral insufficiency and regur-
gitant flow into the left atrium, noted clinically as a systolic
murmur, and culminates in left-sided heart failure. The
shrunken, distorted AV valves are seen with greatest frequency
in toy, small, and medium breeds of dogs, especially in 
males of breeds such as the Poodle, Pomeranian, Schnauzer,
Chihuahua, Doberman Pinscher, Whippet, Fox Terrier, Boston
Terrier, Cavalier King Charles Spaniel, Dachshund, and the
English Cocker Spaniel. There are significant negative associa-
tions for the Labrador Retriever and the German Shepherd
dog. The prevalence of the disease increases with age, from 5%
at <1 year of age to >75% at 16 years of age. Endocardiosis is
also reported in the left AV valves of normal market-weight
pigs, but appears to be clinically inconsequential.
Endocardiosis affects chiefly the left AV valve (Fig. 1-30A-C).
The right AV valve is less severely and less frequently affected.
The aortic and pulmonic semilunar cusps are only occasionally
involved. Grossly, the affected AV cusps are shortened and
thickened. The thickening of the leaflet may be more or less
uniform with a rounded edge, or with prominent nodular
thickenings on the free margin. The valves are opaque and
white, but the surface is smooth and glistening, without any evi-
dence of inflammation. The chordae tendineae may also be
thickened and occasionally are ruptured, allowing eversion of
the leaflet into the atrium and leading to acute ventricular
failure. The left AV valvular annulus may be enlarged.
The least severe gross change consists of a few small, dis-
crete nodules at the line of closure of the valve. These progress
to multiple larger nodules that tend to coalesce in the area of
contact. There may be irregular areas of opacity in the proxi-
mal portions of the leaflet. The nodules may coalesce to form
plaque-like deformities in the area of cusp contact. The
chordae tendineae are thickened at their points of insertion
into the valve, and there are clearly defined areas of opacity
on the basal portions of the leaflet. The most severe change is
characterized by a gross distortion of the valve by gray-white
nodules and elevated plaques. The cusps are contracted,
 27.e1

Further reading
Buttenschon J, et al. Microbiology and pathology of fibrinous pericar-
ditis in Danish slaughter pigs. J Vet Med A 1997;44:271-280.
Day MJ, Martin MW. Immunohistochemical characterisation of the
lesions of canine idiopathic pericarditis. J Small Anim Pract
2002;43:382-387.
Seahorn JL, et al. Case-control study of factors associated with fibrin-
ous pericarditis among horses in central Kentucky during spring
2001. J Am Vet Med Assoc 2003;223:832-838.
Stafford Johnson JM, et al. Septic fibrinous pericarditis in a cocker
spaniel. J Small Anim Pract 2003;44:117-120.
Wood JLN, Chanter N. Mycoplasma infections in horses: a fresh look
using modern methods may reveal an elusive “virus.” Equine Vet J
1996;28:177-179.
Worth LT, Reef VB. Pericarditis in horses: 18 cases (1986-1995). J Am
Vet Med Assoc 1998;212:248-253.
28 CHAPTER 1  •  Cardiovascular System Endocardial Disease

C
Figure 1-30  Endocardiosis in a dog. A. Smooth, glistening, nodular thickening of the left atrio-
ventricular (AV) valve. The left atrium also shows the presence of “jet lesions,” which are irregular
raised areas of subendocardial fibrosis. B. Close-up endocardiosis left AV valve. Cusps are thickened
and shrunken. (Courtesy E. Olson.) C. Dilated left atrium resulting from volume overload of the
atrium. There are also tears of the atrial wall, which led to hemopericardium.

thickened, and irregular. There may also be fixed upward
displacement of the free margin of the valve. Enlargement and
redundancy of the valve may be seen as doming or hooding
of the body of the valve toward the atrium; this prolapse of
the body of the redundant left AV valve into the atrium
(“mitral valve prolapse”) may be seen both echocardiographi-
cally and at postmortem. Chordae tendineae may be ruptured,
in which case the free edge of the valve may prolapse as a flail
leaflet. Care should be taken in the assessment of the valves,
because both the left and right AV valve leaflets thicken with
increasing age, and the free margin of the septal leaflet of the
right AV valve is normally distinctly thicker than the free
leaflets.
Changes secondary to AV valvular insufficiency are dilation
of the atria, particularly the left atrium, and dilation of the
ventricles. The ventricles may be eccentrically hypertrophied.
The left atrial and ventricular subendocardium may be
diffusely thickened by fibrosis following prolonged dilation.
There may also be evidence of regurgitation in the form of
focal elevated streaks and plaques of subendocardial fibrosis
in the atria (“jet lesions”). Left atrial tears may also be seen in
advanced cases, and these tears may rupture and lead to hemo-
pericardium. Mural thrombi can form in the dilated left
atrium; dislodgement of the thrombi can result in thrombo-
embolism, for instance, of coronary arteries leading to myo-
cardial infarction.
Microscopically, the earliest changes are present on the
atrial side of the valves. There is proliferation of the endothe-
lium, increased numbers of subendothelial fibroblasts and
macrophages, and splitting and separation of elastic fibers
between the atrialis and spongiosa. However, it is the thickening
of the spongiosa and degeneration of the fibrosa that are the most
prominent features of endocardiosis. The spongiosa is greatly
thickened by the proliferation of loose fibroblastic tissue and
Diseases of the Heart Endocardial Disease 29

A B

C
Figure 1-31  Microscopy of endocardiosis in a dog. A. Normal valve leaflet. H&E. (Courtesy C.
Foutz.) B. Affected leaflet. Myxomatous degeneration of the stratum spongiosum of the atrioven-
tricular valve. H&E. C. The increase in glycosaminoglycans in the affected valve leaflet is high-
lighted by staining with Alcian blue.

the deposition of the proteoglycans, hyaluronic acid, and
chondroitin sulfate (Fig. 1-31A-C). In a few cases, amyloid
may be deposited. There is no increase in collagen or elastic
tissue in the spongiosa. The changes in the fibrosa are also
marked. Collagen bundles become swollen and hyalinized,
fragment, and disappear. In advanced cases, only scattered
remnants of the fibrosa remain. Similar changes are seen in
chordae tendineae. Intramural coronary arteriosclerosis and
focal myocardial necrosis and fibrosis are commonly seen in
the left ventricular myocardium, especially the papillary
muscle, if the ventricle is hypertrophic.
The cause of endocardiosis is not known, but there is clearly
a genetically influenced degeneration of connective tissue at its
center. This suggestion is supported by the observation that the
most frequently affected breeds are of the chondrodystro-
phoid type. Endocardiosis is inherited in Dachshunds and
Cavalier King Charles Spaniels; a polygenic mode of inheri-
tance is suggested.
Recent research suggests that alteration in tensile strain on
the valves is involved in the initial phases of the disease. Given
the genetic nature in some breeds and the familial nature  intolerance, poor performance, or congestive heart failure
in others, the origin of the increased tensile strain on the  result. Dilation of the pulmonary artery may also ensue, indi-
valves may be the result of abnormal architecture of the AV
valvular complex and possibly abnormal conformation of the
ventricles themselves. This increased tensile strain leads to
increased serotonin levels in the valve itself, in turn activating
the transforming growth factor-β (TGF-β) group of pro-
teins. TGF-β proteins in turn promote the activation of
myofibroblasts/mesenchymal cell phenotypes. Whether the
increased production of proteoglycans is initiated by the same
mechanism remains to be seen. Activation of matrix metal-
loproteinases also appears to contribute to the destruction of
collagen and other fibrillar proteins in the valve.
There is a striking similarity of endocardiosis to the pro-
lapsed mitral valve syndrome of humans, in which there is
deposition of glycosaminoglycans in the spongiosa secondary
to an as yet undefined abnormality of collagen metabolism.
Mitral valve prolapse also occurs in humans in association
with connective-tissue disorders, such as Marfan syndrome,
Ehlers-Danlos syndrome, osteogenesis imperfecta, and a
variety of muscular dystrophies.
Mitral insufficiency in the horse can result from endocardio-
sis, endocarditis, flail valve leaflets, rupture of chordae tendin-
eae, and left AV valve prolapse. Clinical signs of exercise
cating pulmonary hypertension, and may presage pulmonary
artery rupture.
30 CHAPTER 1  •  Cardiovascular System Endocardial Disease

Valvular cysts
Congenital hematomas (hemocysts) on the margins of the AV
valves are common, especially in calves (see previously, Mis-
cellaneous cardiac anomalies). Blood cysts and serous cysts have
been reported in the AV valves in 11% of the hearts in a series
of 30,000 slaughter cattle, with a higher incidence in cows
than calves. Blood-filled cysts were often present on both AV
valves, whereas serous cysts occurred more frequently on the
left AV valve. This suggests that cysts do not regress with age;
indeed their incidence and size may increase with age. The
endothelium lining the blood-filled cysts was positive for
factor VIII–related antigen. The cysts may represent ectasias
of blood vessels and lymphatics.

Subendocardial fibrosis
Subendocardial fibrosis may be diffuse or focal, congenital, or
acquired. The congenital lesions are discussed under Congeni-
tal abnormalities of the heart and large vessels. Diffuse suben-
docardial fibrosis is seen whenever a ventricle or atrium is dilated
for a prolonged period. It is probably best exemplified by the
dilated cardiomyopathy of large-breed dogs.
Subendocardial fibrosis in localized areas is observed
chiefly in the atria and is regarded as a reaction of the endo- Figure 1-32  Extensive subendocardial mineralization in the left
cardium to abnormal jets of blood or to turbulence following atrium and ventricle of a horse following ingestion of Solanum
congenital or acquired valvular disorders (see Fig. 1-30A). glaucophyllum (vitamin D analogue toxicosis). (Courtesy A. P.
They are loosely termed jet lesions, but are probably areas Loretti.)
subject to increased static pressure in turbulent flow.

Subendocardial mineralization
Subendocardial mineralization is associated with a variety of
disorders. It occurs commonly in opaque plaques or as small
grains in the left atrium, and occasionally in the trunk of the
aorta in dogs that have recovered from ulcerative endocarditis
of renal insufficiency (see Mineralization, later). Prominent
white plaques of mineralization also occur beneath the endo-
cardium of the right ventricle in nutritional myopathy of lambs.
Subendocardial mineralization in the atria and left ventricle
may accompany endocardial fibrosis when these cavities are
acutely dilated, either as congenital or acquired defects, and
in a variety of prolonged debilitating diseases in cattle (Fig. 1-32).
Calcium and phosphorus are deposited in degenerate suben-
docardial muscle, but more commonly in fibroelastic tissue.
The fibroelastic tissue is modified either by chronic disease  primary on the valves, from which there may be some encroach-
or elevated serum levels of calcium and phosphorus, as in
vitamin D intoxication, or following the ingestion of plants
containing vitamin D analogues (see Vol. 3, Endocrine glands).
Proprietary rodenticides based on calciferols cause this lesion
in dogs.
Further reading
Aupperle H, et al. N-linked glycans of proteins from mitral valves of
normal pigs and pigs affected by endocardiosis. Eur J Biochem
2000;267:1299-1306.
Aupperle H, et al. Immunohistochemical characterization of the extra-
cellular matrix in normal mitral valves and in chronic valve disease
(endocardiosis) in dogs. Res Vet Sci 2009;87:277-283.
Disatian S, Orton EC. Autocrine serotonin and transforming growth
factor beta 1 signaling mediates spontaneous myxomatous mitral
valve disease. J Heart Valve Dis 2009;18:44-51.
Fox PR. Pathology of myxomatous mitral valve disease in the dog. J Vet
Cardiol. 2012;14:103-126.
Lacerda CM, et al. Static and cyclic tensile strain induce myxomatous
effector proteins and serotonin in canine mitral valves. J Vet Cardiol.
2012;14:223-230.
Marcato PS, et al. Blood and serous cysts in the atrioventricular valves
of the bovine heart. Vet Pathol 1996;33:14-21.
Orton EC, et al. Signaling pathways in mitral valve degeneration. J Vet
Cardiol 2012;14:7-17.
Endocarditis
Endocarditis is one of the more significant of the endocardial
alterations. It is usually bacterial in cause, the exceptions being
occasional parasitic or mycotic lesions. Any portion of the
endocardium may become inflamed, but the lesions are usually
ment on the adjacent mural endocardium (Fig. 1-33A, B). The
left AV valve is most commonly affected in most species, fol-
lowed by aortic, right AV valve, and pulmonic, except in cattle,
in which the right AV valve is more commonly affected.
Many bacterial species are capable of causing acute valvu-
lar endocarditis, and the larger the number of cases examined,
the wider the variety of pathogens recognized. In cattle, True-
perella pyogenes is probably the most common pathogen, and
a primary focus of infection can often be found in some other
site, such as a traumatic peritoneal abscess, hepatic abscess,
metritis, or mastitis. Streptococci of enteric origin are also of
some importance in cattle, although the manner of their sys-
temic invasion is not clear. Erysipelothrix rhusiopathiae causes
endocarditis in a variety of animals, most commonly in the
pig; however, streptococci are more commonly isolated from
cases of acute bacterial endocarditis of swine. Mature horses
seldom develop bacterial endocarditis, but the lesion has been
observed in association with Streptococcus equi, Actinobacillus
equuli, Escherichia coli, Pseudomonas aeruginosa, and Candida
parapsilosis. A number of cases in horses have originated from
 30.e1

Further reading
Aupperle H, et al. Expression of transforming growth factor-beta1,
-beta2 and -beta3 in normal and diseased canine mitral valves.
J Comp Pathol 2008;139:97-107.
Castagnaro M, et al. Morphological and biochemical investigations of
mitral valve endocardiosis in pigs. Res Vet Sci 1997;62:121-125.
Corcoran BM, et al. Identification of surface morphologic changes in
the mitral valve leaflets and chordae tendineae of dogs with myxo-
matous degeneration. Am J Vet Res 2004;65:198-206.
Gagna C, et al. Pathology of mitral valve in regularly slaughtered pigs:
an abattoir survey on the occurrence of myxoid degeneration
(endocardiosis), fibrosis and valvulitis. Zentralbl Veterinarmed A
1998;45:383-395.
Lester WM. Myxomatous mitral valve disease and related entities: the
role of matrix in valvular heart disease. Cardiovasc Pathol
1995;4:257-264.
McCarthy KP, et al. Anatomy of the mitral valve: understanding the
mitral valve complex in mitral regurgitation. Eur J Echocardiogr
2010;11:13-19.
Olsen LH, et al. Epidemiology and inheritance of mitral valve prolapse
in Dachshunds. J Vet Intern Med 1999;13:448-456.
Reef VB, et al. Severe mitral regurgitation in horses: clinical, echocar-
diographic, and pathological findings. Equine Vet J 1998;30:18-27.
Seki Y, et al. Transmural myocardial infarction caused by thromboem-
bolism associated with mitral insufficiency in a dog. J Vet Med Sci
1998;60:741-743.
Diseases of the Heart Endocardial Disease 31

A B
Figure 1-33  Endocarditis. A. Vegetative endocarditis of the right atrioventricular valve of a cow,
caused by Trueperella pyogenes. (Courtesy J. Schefers.) B. Ulcerative, destructive endocarditis of
the aortic valve of a dog. (Courtesy M. Bouljihad.)

septic jugular vein thrombophlebitis. Minor outbreaks of

endocarditis occur in lambs and are usually caused by Strep-
tococcus spp., particularly enterococci; there may be associated
polyarthritis. Endocarditis is seldom observed in dogs, but can
be associated with a variety of organisms, especially Streptococ-
cus spp., Staphylococcus aureus, and Escherichia coli, and less
frequently with Bartonella spp., Erysipelothrix rhusiopathiae,
Erysipelothrix tonsillarum, Pseudomonas aeruginosa, Pasteurella
multocida, or various Aspergillus spp. (Fig. 1-34A, B). Endocar-
ditis is unusual in cats, but has been caused by Bartonella spp.
and Streptococcus spp. In general, neonatal animals are more
prone to develop endocarditis in association with septicemias
of bacterial origin. The major features of endocarditis are
shown in eFigure 1-6.
The manner by which bacteria localize on a valve is not A
clear, and there is seldom detectable evidence of some sepa-
rate underlying disease of the leaflet. In active thrombotic
valvular endocarditis, bacteria are invariably present in the
lesion. Two factors that must be included in any concept of
pathogenesis are
1. The tendency for lesions to occur at the lines of apposition
of the valve surfaces exposed to the forward flow of blood
2. The necessity for sustained or recurrent bacteremia
It is possible that simple debilitation of endothelial cells in
recurrent bacteremia and aggravated locally on the valves by
the trauma of apposition may alter the adhesiveness of the
leaflet endothelium sufficiently for bacterial adhesion to occur.
It is of significance that valvular endocarditis can be produced
in normal animals by a single intravenous injection of bacteria
of suitable type and virulence; the incidence of endocarditis
is increased if the hearts of such animals are subjected to
increased workloads or the valves are traumatized during the
experiments. There is also the possibility that bacterial endo-
carditis can begin within the valve during septicemia, as has
been demonstrated by isolation of bacteria from the spongiosa
of pig valves.
Particular strains of Erysipelothrix rhusiopathiae can selec- B
tively adhere to the valvular endothelium of porcine heart
valves in vitro, with greatest numbers at the base of chordae Figure 1-34  Vegetative endocarditis in a dog. A. The valve leaflet
tendineae. The phenomenon of selective adherence has been is expanded by fibrin, inflammatory cells, and numerous bacterial
demonstrated for pathogens associated with other organ colonies. H&E. B. Gram’s stain highlighting numerous colonies in
system disease, notably staphylococci and streptococci in the vegetation (Erysipelothrix rhusiopathiae).
 31.e1

Begins at Valvular vegetations

lines of mostly composed
apposition of fibrin, few platelets
of valves and neutrophils

Some bacteria Bacterial colonies

selctively adhere embedded in the thrombi.
to valvular These may detach
endothelium to produce emboli

Infectious in origin
Valvular
Sustained or intermittent Healing of the
endocarditis
lesion occurs from
Bacteremia/fungemia the base by fibrosis
Parasitic [rarely]

eFigure 1-6  Major features of endocarditis.

32 CHAPTER 1  •  Cardiovascular System
mastitis and enterotoxigenic coliforms in colibacillosis. There
is also an immunologic cross-reaction between E. rhusiopath-
iae antigens and valvular and myocardial antigens. Various
Streptococcus spp. have been shown to adhere to exposed base-
ment membrane of porcine valves.
The lesion of acute bacterial endocarditis is usually
observed as irregular vegetations on the affected valve. It is
quite exceptional to find the earliest lesion, which consists of
irregular ulcerations on the swollen leaflet. The composition of
vegetations is similar to that of thrombi with, however, few
platelets. Numerous bacterial colonies are present in the vegeta-
tions, almost always in pure populations. It is wise to make
preliminary identification of the organisms by smears, because
although they persist in colonies buried in the vegetations,
they may not be cultivable. With the current techniques of
molecular biology, such as PCR, it should be possible to iden-
tify at least the genus of the noncultivable organisms embed-
ded in the thrombus. The bacteria that initiate the lesion are
enmeshed in the early layers of thrombi and are buried deeply
as new layers are formed on the surface. With continued
multiplication, many microscopic colonies are formed, and
without appropriate antimicrobial treatment, it is their per-
sistence in the protected environment that is the reason
healed bacterial endocarditis is seldom seen. Even though the
bacteria in the thrombi may lose their vitality, as indicated by
lack of cultivability, they are persistently antigenic.
Grossly, the vegetations are yellow-red or yellow-gray and
usually covered by a thin clot of blood, which can be easily
peeled off. The surface of the vegetation is friable, and small
vegetations can be easily removed to leave a granular, eroded
surface on the valve. The ulcerations are especially common
in the commissures and at the free margins of the valves,
imparting to them a rough, serrated appearance. The primary
valvular lesion frequently extends to the adjacent mural endo-
cardium and, in the cases of aortic valvular endocarditis, to
the adjacent aortic intima in the sinuses of Valsalva, which
may involve an orifice of a coronary artery, predisposing to
myocardial embolism. Endocarditis of the AV valves tends to
spread along the chordae tendineae, causing some of them  sion of aortic valvulitis into the right coronary artery and fis-
to rupture. Acute swelling and inflammatory change take
place in the substance of the valve itself, often with necrosis,
which obscures the line of partition between the valve and its
surface vegetation.
Organization of the thrombus proceeds from the base  fistula between the left ventricular outflow tract and the left
by the usual process of granulation, which is likely to be
impeded or destroyed by bacterial growth. Early scarification
in the deepest layers separates the thrombus from the  One of the more common forms of mural endocarditis
underlying myocardium and is frequently accompanied  occurs in renal failure in dogs. The lesion is confined, within
by mineralization.
Valvular endocarditis is commonly fatal, although resolution
may be complete if lesions are only minor. Clinical signs in
animals with endocarditis may only be detected late in the
disease, with the most common being pyrexia, lameness, and
cardiac murmurs. The frequency with which clinical signs are
observed is dependent on the husbandry conditions under
which the animal is kept. Other sequelae are those resulting
from valvular damage or embolism. Portions of the vegetations
may become detached and carried as emboli, to become
impacted in the vessels of other organs. Such emboli may be
either bland, that is, consist of thrombotic material only, or
septic, consisting of thrombotic material together with the enmeshed
infectious agent. Emboli arising in the right heart may produce
pulmonary abscesses or pulmonary thrombosis. These latter
Endocardial Disease
do not produce pulmonary infarcts in the absence of pre-
existing pulmonary congestion. Emboli arising in the left heart
produce their most obvious effects in the kidney and spleen
as septic or aseptic infarcts and embolic glomerulitis, and in
the myocardium as myocardial abscesses or interstitial myo-
carditis. Arthritis is commonly observed in association with
endocarditis in the dog. Cerebral embolism is rare in animals.
Unless the valvular lesions are very slight, there is, with
healing, some degree of permanent damage, especially if the
inflammation is recurrent. Shrinkage or adhesion of leaflets
may cause narrowing of the orifice (stenosis), or insufficiency
as a result of failure of the distorted valves to close the orifice.
Stenosis and insufficiency may coexist. The usual outcome is
congestive heart failure.
Mural endocarditis may be merely an extension to the
walls of the cardiac chambers of a process originating on the
valves. This is almost invariably true of endocarditis caused by
Trueperella pyogenes. Small foci of mural endocarditis may be
found adjacent to foci of myocarditis, especially myocardial
abscesses. Right or biventricular thrombosis in alpacas has
been associated with mural endocarditis and inconsistent iso-
lation of a causative agent. This suggests the possibility of a
fastidious organism as the cause, such as Bartonella spp. or the
possibility of an underlying cardiomyopathy.
Parasitic endocarditis caused by the larvae of Strongylus
vulgaris occurs in horses acutely in the form of vegetative
valvular endocarditis and chronically as caseous and calcare-
ous nodules attached to the endocardium at various sites,
including the apex of the left ventricle and protruding into
the cavity. There is, in the same cases, parasitic aortitis of the
bulb. With the advent of effective anthelmintics, parasitic
endocarditis in horses is rare.
An acute form of ulcerative mural endocarditis occurs in
cattle dying from blackleg, as red thrombotic masses attached
to the free wall of the right ventricle and, less often and less
extensively, on the right atrial and valvular endocardium.
Various unique intracardiac fistulae or shunts have been
reported as sequelae to endocarditis in dogs, including exten-
tulation into the right atrium; perforation of the membranous
interventricular septum, leading to a left ventricular outflow
tract–right atrial shunt (Gerbode defect) in a dog with severe
mural endocarditis caused by a Bordetella-like organism; and a
atrium adjacent to the mitral valve annulus in a dog with
Staphylococcus intermedius endocarditis.
the heart, to the left atrium, but similar lesions occur in the
large elastic arteries, being more frequent in the pulmonary
and aortic trunks immediately proximal to the valves, and less
frequently in the descending aorta and its major branches.
(The vascular lesions associated with renal failure are dis-
cussed under Diseases of the vascular system.) The endocar-
dial and major-arterial lesions are more common in acute 
than in chronic renal failure, insofar as these syndromes are
distinguishable.
The ulcerative atrial lesion, which is identical to the arterial
lesion, begins as a swelling of the interstitial spaces of the
subendocardium or intima of the arteries, with deposition of
glycosaminoglycans. Initially, the endothelium is intact and,
when viewed grossly in this stage, the endothelial surface is
seen to be raised slightly, finely wrinkled, and slightly opaque
Diseases of the Heart
Figure 1-35  Ulcerative atrial mural endocarditis of uremia in a
dog. (Courtesy Vasileios Psychas.)
but still shiny. The lesion may not progress farther than this
but, instead, heals with some fibrosis, which leaves areas of
uneven opacity. More usually, however, there is progression to
necrosis involving the cellular elements as well as collagen,
elastic, and reticulin fibers. The necrotic tissue ulcerates, and
the margin is densely infiltrated by leukocytes (Fig. 1-35). The
ulcerations may perforate the wall of the atrium. Thrombi, in
greater or lesser amounts, form on the ulcerated surface.
Heavy deposits of calcium salts often form in the degenerate
tissue. If renal sufficiency is re-established, the endocardial
lesion may heal leaving irregular patches of fibrosis with an
intact endothelium, often covering persistent white plaques
of mineralization. Other extrarenal lesions of uremia are con-
sidered in Vol. 2, Urinary system.
Further reading
Erol E, et al. Bartonella bovis isolated from a cow with endocarditis.
J Vet Diagn Invest 2013;25:288-290.
Firshman AM, et al. Thrombotic endocarditis in 10 alpacas. J Vet Intern
Med 2008;22:456-461.
Jarplid B, et al. Observations of apparent early valvular endocarditis in
swine. J Vet Diagn Invest 1997;9:449-451.
Malik R, et al. Vegetative endocarditis in six cats. J Feline Med Surg
1999;1:171-180.
Ohad DG, et al. Molecular detection of Bartonella henselae and Bar-
tonella koehlerae from aortic valves of Boxer dogs with infective
endocarditis. Vet Microbiol 2010;141:182-185.
Porter SR, et al. Vegetative endocarditis in equids (1994-2006). J Vet
Intern Med 2008;22:1411-1416.
Sykes JE, et al. Evaluation of the relationship between causative organ-
isms and clinical characteristics of infective endocarditis in dogs: 71
cases (1992-2005). J Am Vet Med Assoc 2006;228:1723-1734.
MYOCARDIAL DISEASE
Myocardial dysfunction can be the product of a wide variety
of agents and conditions (Table 1-5). This section deals with
the range of myocardial disease, from the more-or-less specific
myocardial conditions of degeneration, necrosis, hemorrhage,
Myocardial Disease 33
Table • 1-5 
Causes of myocardial dysfunction in
domestic animals
Infectious Viruses, chlamydiae, rickettsiae, bacteria, fungi,
protozoa, helminths
Toxic Ionophores (monensin, salinomycin,
maduramicin), catecholamines, antineoplastics
(cyclophosphamide, doxorubicin,
daunorubicin), doxycycline, gossypol,
saccharated iron, thallium, toxic plants
(many), insects (blister beetle [Epicauta])
Metabolic Hyperthyroidism, hypocalcemia
Nutritional Vitamin E-selenium, taurine (cats), copper,
deficiency thiamine
Genetic Porcine stress syndrome
Neuromuscular Muscular dystrophy
Storage Glycogen storage disease, amyloidosis
disorders,
other
depositions
Infiltrative Neoplasia (lymphoma, hemangiosarcoma)
Idiopathic Cardiomyopathy
and myocarditis, through idiopathic myocardial disease (cardio-
myopathy). The reaction of myocardium to insults is limited, and
includes the usual expressions of degeneration, necrosis,
inflammation, and healing. Acute changes, such as necrosis and
hemorrhage, will be discussed first. Given time to adapt to an
insult, a diseased myocardium may grossly take one of 2 con-
formations: dilated or hypertrophic. This classification is useful
conceptually, but is somewhat arbitrary, and individual cases
will often have features of more than one form, for instance,
the heart in a cat with hyperthyroidism will hypertrophy, but
it may eventually dilate and fail.
Hemorrhage of the heart and its membranes
Petechial and larger subepicardial hemorrhages are so common
in horses that die naturally that they are almost to be regarded
as normal. The incidence of hemorrhages in sheep and cattle
is somewhat lower; they are seldom seen in dogs and cats.
Subepicardial hemorrhages are common in instances of asphyxia
or death in anoxia, and in many acute infectious fevers. Larger
ecchymotic hemorrhages that may involve most of the epicar-
dium occur in the hemorrhagic diatheses.
Subendocardial hemorrhages have the same pathogenesis
but are considerably less common. Ecchymotic hemorrhages
beneath the endocardium of the left ventricle occur in
instances of acute cerebral injury and are useful as a diagnostic
indication of clostridial enterotoxemia in lambs and calves,
being present in a considerable proportion of cases.
Small interstitial capillary hemorrhages within the myocar-
dium accompany those within the subserosa. Deep myocardial
hemorrhages that do not extend to the serosa are commonly
present in pigs that die of asphyxia; they are distributed in the
wall of the right ventricle in the vicinity of the descending
coronary grooves. A remarkable degree of myocardial hemor-
rhage occurs in mulberry heart disease of swine (see Mulberry
heart disease of swine, later).
 33.e1

Further reading
Allen BL, et al. Streptococcus anginosus adheres to vascular endothe-
lium basement membrane and purified extracellular matrix pro-
teins. Microb Pathog 2002;32:191-204.
Bennett D, Taylor DJ. Bacterial endocarditis and inflammatory joint
disease in the dog. J Small Anim Pract 1987;29:347-365.
Bratberg AM. Immunological cross reactions of antigens of E. rhusio-
pathiae and heart tissue from swine. Acta Vet Scand 1981;22:46-
54.
Chomel BB, et al. Fatal case of endocarditis associated with Bartonella
henselae type I infection in a domestic cat. J Clin Microbiol
2003;41:5337-5339.
MacDonald KA, et al. A prospective study of canine infective endocar-
ditis in northern California (1999-2001): emergence of Bartonella
as a prevalent etiologic agent. J Vet Intern Med 2004;18:56-64.
Maxson AD, Reef VB. Bacterial endocarditis in horses: ten cases (1984-
1995). Equine Vet J 1997;29:394-399.
Pesavento PA, et al. Pathology of Bartonella endocarditis in six dogs.
Vet Pathol 2005;42:370-373.
Ramirez GA, et al. Left ventricular outflow tract-right atrial communi-
cation (Gerbode type defect) associated with bacterial endocarditis
in a dog. Vet Pathol 2003;40:579-582.
Smith AN, et al. Left ventricular outflow tract to left atrial fistula asso-
ciated with endocarditis in a dog. J Am Anim Hosp Assoc
2000;36:133-136.
Takahasi T, et al. Taxonomic evidence that serovar 7 of Erysipelothrix
strains isolated from dogs with endocarditis are Erysipelothrix ton-
sillarum. J Vet Med B Infect Dis Vet Public Health 2000;47:311-313.
Vasconcelos D, et al. Lesions caused by natural infection with Strepto-
coccus suis type 9 in weaned pigs. J Vet Diagn Invest 1994;6:
335-341.
34 CHAPTER 1  •  Cardiovascular System
Myocardial degeneration
Cardiac muscle is structurally similar to skeletal muscle and
is subject to the same anatomic types of degeneration. There
is, however, a greater liability for cardiac muscle to undergo
degeneration as a response to many nonspecific causes, prob-
ably related to its continuous activity. Diffuse nonspecific myo-
cardial degeneration occurs secondarily in a variety of systemic
diseases, especially infectious fevers, anemia, and toxemia.
Hydropic change, or vacuolar degeneration, of the myocar-
dium is characterized grossly by a dull gray appearance and
increased friability so that the myocardium is easily torn. On
cut surface, the muscle is smoother than normal, the outlines
of individual muscle bundles obscured.
Fatty change—the appearance of lipid vacuoles in myocyte
cytoplasm—is a more severe event than hydropic change, and
may be recognized grossly as uneven patches of pale yellow
myocardium. The process of fatty change is not uniform, and
it is sometimes possible to recognize, beneath the endocar-
dium, alternating bundles of fibers or strips of myocardium
more yellow than the remainder (“thrush-breast heart”). Both
hydropic change and fatty change are reversible forms of cel-
lular injury.
Atrophy of the heart occurs in chronic wasting diseases and
malnutrition. In some cases, the atrophy is accompanied by
dark pigmentation, and it is then called “brown atrophy.” It
should be recognized, however, that atrophy can occur without
pigmentation, and pigmentation can occur without atrophy.
Ruminants are principally affected by atrophy, brown or not,
and rarely does the atrophic heart produce clinical distur-
bance. The epicardial fat may be gelatinous, the endocardium
wrinkled, and myocardium brown and friable. Histologically,
the muscle fibers are thin, the nuclei small and dark, and
masses of brown pigment granules are present within second-
ary lysosomes at the nuclear poles. The pigment is lipofuscin
(“wear-and-tear pigment”), an oxidation product of unsatu-
rated lipids.
Xanthosis (xanthomatosis) refers to the abnormal lipofuscin
pigmentation of the myocardium and skeletal muscles seen in
cattle, particularly mature Ayrshire cows (see Vol. 1, Muscle
and tendon). Microscopically, lipofuscin is commonly seen at
the nuclear poles of cardiac myocytes in aged dogs and cats.
Mineralization occurs quite commonly in the myocardium,
and is to be expected whenever there is necrosis of fibers.
Calcium salts are selectively deposited in the Purkinje network
in organomercurial poisoning in cattle, in which the mineral-
ization is preceded by hyaline necrosis of the Purkinje fibers
and is followed by surrounding fibrosis.
Osteocartilaginous metaplasia of the right atrial myocar-
dium in sheep is a common incidental finding in adults, and
has been reported at a prevalence of ~10%. The foci of meta-
plasia are often palpable grossly, but may only be detectable
by radiography or microscopy. Histologically, the myocardium
of the atrial free wall contains trabeculae of lamellar bone that
are bordered by cartilage and chondroid matrix (Fig. 1-36).
The metaplastic regions are not associated with the os cordis
at the heart base.
Myocardial necrosis*
Focal to massive myocardial necrosis, or residual scars thereof,
is a common lesion in postmortem material. The causes are
*Contribution to the Myocardial necrosis section by Dr. R. McKenzie
is gratefully acknowledged.
Myocardial Disease
Figure 1-36  Osteocartilaginous metaplasia of the right atrium in
a sheep. The central aspect of the atrial free wall contains large
areas of mature lamellar bone and cartilage. H&E.
quite varied and part of a number of disease syndromes
described elsewhere in these volumes.
In infectious disease, the distinction between myocardial
necrosis and myocarditis with myofiber necrosis is somewhat
arbitrary—inflammatory cells will invade necrotic myocar-
dium; in acute myocarditis, inflammatory cells should be inti-
mately associated with necrotic myocardial cells, and adjacent
myocytes may appear normal. Necrosis predominates in
highly fatal foot-and-mouth disease in neonatal lambs, piglets,
and calves, whereas the residual lesions in older cattle qualify
as myocarditis with a significant inflammatory response. Ful-
minating infection by canine distemper virus in young puppies
is purely degenerative, whereas parvoviral and herpesviral
infections in the same age group contain elements of an
inflammatory response. Of the bacterial diseases, and except-
ing blackleg, Histophilus somni appears to be responsible for a
residual syndrome of sudden death in cattle with myocardial
necrosis or infarction, although in some cases myocardial
abscesses may be present.
Severe, often fatal, myocardial necrosis is typically part of
the important vitamin E and selenium-responsive syndromes
of nutritional myopathy of lambs, calves (Fig. 1-37A, B),
swine, and horses, and in mulberry heart disease of swine. 
It may also be seen as part of equine rhabdomyolysis and 
of capture myopathy and other exertional syndromes (see 
Vol. 1, Muscle and tendon).
Deficiency disease, additional to those that respond to
vitamin E and selenium, may include myocardial necrosis. It
occurs, although not invariably, in thiamine deficiency in car-
nivores, always as a single acute episode. Falling disease of
cattle in Australia and Florida is a syndrome of sudden death
believed to result from prolonged copper deficiency. Myocar-
dial scars accompany acute lesions, suggesting repetitive epi-
sodes and resembling the lesions of fluoroacetate poisoning in
cattle eating the gidgee plant, Acacia georginae, which is to be
distinguished from the nontoxic Acacia cambadgei (gidyea,
gidgee). In cats, taurine deficiency causes myocardial failure.
Toxic myocardial degeneration is common, and although
some examples are accompanied by degeneration of skeletal
muscle, they are described here. Injectable saccharated iron
compounds, by virtue of the capacity of iron to generate free
radicals in ferric/ferrous translations, cause fatal myocardial
Diseases of the Heart Myocardial Disease 35

B
A
Figure 1-37  Nutritional myopathy. A. Pale areas of myocardial necrosis in a lamb. (Courtesy
Vasileios Psychas.) B. Myocardial necrosis and mineralization of necrotic myocytes in a calf. H&E.

necrosis in piglets. Monensin, an ionophore that is widely used

as a coccidiostat and growth promotant in ruminants, may
contaminate compounded feeds for simple-stomached animals
and is cardiotoxic for horses and pigs (see Vol. 1, Muscle and
tendon for details of poisoning in other species). Also, rumi-
nants fed dried poultry litter containing the ionophores 
maduramicin or salinomycin develop severe cardiac myocyte
atrophy and interstitial fibrosis sufficient to result in clinical
signs of congestive heart failure. Myocardial necrosis occurs in
dogs ingesting rodenticides that contain thallium; these have
been widely replaced by warfarin analogues and calciferols.
Galenia africana (yellow bush or kraalbos) is a bushy
plant that is toxic to sheep and goats in South Africa, causing
a syndrome known as waterpens or waterbelly as ascites is a
prominent feature of this toxicosis. The toxin has not been
identified. Hepatotoxicosis appears to develop first, advancing
from dilation of central veins and sinusoids to centrilobular
and bridging fibrosis, with areas of coagulative necrosis. Myo-
cardial changes begin with myocyte hypertrophy and progress Figure 1-38  Extensive subendocardial hemorrhage in left ven-
to patchy degeneration and necrosis of myofibers and light tricle in oleander poisoning in a horse. (Courtesy S. Diab.)
fibrosis.
Plants that contain cardiac glycosides of both the bufadi- the observed clinical syndrome, and the presence of recogniz-
enolide and cardenolide types are of worldwide distribution. able plant parts in the ingesta. The cardiac glycosides are
Poisoning by bufadienolide cardiac glycoside–containing inhibitors of the sodium-potassium ATPase pump, which is
plants is the most important plant-associated poisoning of responsible for maintaining membrane ion concentrations and
livestock in southern Africa, and may be acute or chronic. the membrane potential of cardiac muscle fibers.
Acute poisoning is caused by plants of the family Iridaceae Chronic cardiac glycoside poisoning (“krimpsiekte”) is a
(“tulip”), for instance, Homeria pallida (the cape tulip), H. botulism-like, paretic condition of small stock that is caused by
miniata, Moraea polystachya, M. bipartita; family Liliaceae members of the family Crassulaceae (“plakkies”) that contain
(“slangkop”), for instance, Urginea sanguinea; and family San- cumulative bufadienolides, for instance, Tylecodon wallichii, T.
talaceae, for instance, Thesium lineatum (“witstorm”). As well, ventricosus, Cotyledon orbiculata, Kalanchoe lanceolata.
several species of Bryophyllum (synonym Kalanchoe) that Cardenolide cardiac glycoside—containing plants, for
occur in Madagascar and have been introduced to southern instance, Nerium oleander (common pink oleander), Cascabela
and eastern Africa, and Australia, for instance, B. tubiflorum thevetia (Thevetia peruviana, yellow oleander), of the family
and B. pinnatum, contain bufadienolides (bryotoxins A, B, C, Apocynaceae, are seldom eaten by livestock and are usually of
or bryophyllins). little veterinary importance. However, when ingested, typi-
In acute poisoning, death occurs within a few hours of cally as plant clippings mixed with other garden waste, their
ingesting the plant. Affected animals have cardiovascular positive inotropic effects on the heart can cause tachycardia,
(tachycardia, arrhythmia, heart block), gastrointestinal, respi- arrhythmias, and sudden death. Long-term exposure to olean-
ratory, and neuromuscular signs. Some cases may live for a few der can result in degeneration, fibrosis, and mononuclear cell
days and have scattered foci of myocardial necrosis, but usually infiltration of the myocardium (Fig. 1-38). Oleandrin, the
a diagnosis must be based on demonstrated access to the plant, responsible cardenolide, can be detected in blood or urine by
36 CHAPTER 1  •  Cardiovascular System
thin-layer chromatography or by high-performance liquid
chromatography/mass spectrometry (LC/MS). Summer
pheasant’s eye (Adonis aestivalis or Adonis microcarpa), which
contains cardenolides similar to oleander and foxglove (Digi-
talis spp.), causes endocardial and epicardial hemorrhage and
mild multifocal myocardial necrosis; strophanthidin, the agly-
cone of several cardenolides in Adonis, can be detected by LC/
MS in gastrointestinal contents from affected horses.
Not all acute cardiotoxicoses of botanical origin can be
ascribed to glycosides. Whereas chronic Phalaris spp. toxicosis
does produce interesting changes in the central nervous
system, the acute toxicosis is of much greater economic
importance as the cause of quick death in animals first exposed
to grazing on this pasture species. The acute toxicant in
Phalaris appears to be a tryptamine alkaloid, which may inter-
fere with the metabolism and action of serotonin and other
catecholamines. In sheep and cattle, Lantana camara causes
myocardial necrosis that might have an entirely different
pathogenesis, possibly dependent on reduced myocardial per-
fusion as a result of chronic reduction in circulating blood
volume. Poisoning by Cassia spp., including Cassia occiden-
talis (coffee senna), Karwinskia humboldtiana (coyotillo),
and Cicuta douglasii (western water hemlock), causes mus-
cular and myocardial necrosis in livestock. Vicia villosa (hairy
vetch) and V. benghalensis poisoning involves many organs,
including the heart. The lesions are unusual for a poisoning in
that there is a substantial chronic eosinophilic granulomatous
inflammatory response associated with the necrosis. Young
ruminants (before the rumen has developed), pigs, and dogs
are susceptible to the cardiotoxic effects of gossypol, a toxic
alcohol, when cottonseed meal is incorporated in their feed
as a protein supplement. Eupatorium rugosum (white snake-
root) causes myocardial and skeletal muscle damage through
the action of tremetol, another toxic alcohol. High erucic acid
rapeseed oil can cause myocardial degeneration and necrosis
in a variety of species; this effect has been mitigated by the
development of canola, which has low erucic acid content.
Acute selenium toxicosis resulting from the ingestion
of various selenium-accumulating plants, including certain
species of locoweed (Astragalus and Oxytropis), and western
aster (Symphyotrichum ascendens, formerly Aster ascendens),
occurs in horses, cattle, sheep, and pigs in China and western
North America. Cattle dying acutely had severe myocardial
necrosis, with some survivors developing severe myocardial
fibrosis and congestive heart failure. Selenium toxicity is
covered in detail in Vol.1 Integumentary system.
Cantharidin, the toxic principle in blister beetles (Epicauta
spp.), is thought to be the cause of gastric lesions, hemorrhagic
cystitis, enterocolitis, and myocardial necrosis in horses that
ingest the beetles in baled alfalfa hay.
Focal myocardial necrosis is also frequently observed as an
incidental finding on microscopic examination in many dis-
eases, and its immediate pathogenesis can seldom be ascer-
tained, but the lesions are thought to have an ischemic basis.
Ischemic myocardial necrosis occurs in thrombotic disease,
such as disseminated intravascular coagulation in the micro-
angiopathy of vitamin E/selenium deficiency, and in inflam-
matory vascular disease, such as periarteritis nodosa. Poor
myocardial perfusion may be the cause of the multifocal myo-
cardial necrosis seen occasionally in hypocalcemic parturient
dairy cows. The subendocardial necrosis seen following  Figure 1-39  Locally extensive infarct (pale areas) in apex of left
acute brain injury (“brain-heart syndrome”) may result from
coronary arterial spasm and/or catecholamine excess. Another
Myocardial Disease
example of catecholamine-induced myocardial necrosis is
that seen in cases of functional pheochromocytoma. The exact
mechanism(s) of catecholamine toxicosis is unknown, but
may involve a direct toxic effect, such as free radical damage
of myocyte membranes.
Coronary embolism is a relatively common cause of focal
myocardial necrosis, the emboli originating from vegetations
of left-sided endocarditis; septic emboli may result in myocar-
dial abscesses. In granulocytopenic diseases, bacterial embo-
lism may result in multiple minute myocardial infarcts, the
best examples being seen worldwide in bracken fern (Pterid-
ium spp.) poisoning in cattle. Myocardial infarction may occur
in polyarteritis (periarteritis nodosa and allied lesions).
Arteriosclerosis, although common in animals, is very
seldom severe enough to be responsible for ischemia of the
myocardium. In aged dogs, some degree of hyalinosis of the
intramural coronary arteries is frequently seen and may be
associated with, and presumably the cause of, myocardial
infarcts. This condition is called multifocal intramural myocar-
dial infarction (discussed later with Arteriolosclerosis). Hearts
that are dilated or hypertrophic are susceptible to focal necro-
sis of apparently random distribution, although larger lesions
are more obvious in the subendocardium of the left ventricle
and papillary muscles.
The gross and microscopic appearance of myocardial
necrosis is dependent on the interval between the initial insult
and death. Gross changes of necrosis are not readily apparent
until 12 hours after injury. By 18 to 24 hours, the affected
area, in which calcium salts may be deposited, is paler and
gray-brown (Fig. 1-39). The overlying serous membrane is
usually normal. Myocardial degeneration, mineralization, and
necrosis are most common in the subendocardial myocardium.
This area undergoes the greatest intramyocardial tension
during systole and is the most likely to be ischemic. However,
proliferative or thrombotic lesions completely occluding
vessels in these areas are rarely observed even with careful
technique. The common small foci of myocardial necrosis may
not be visible from the serous surface, and perhaps may be
recognizable only microscopically. The necrosis resulting 
from infarction will, if sufficiently large, involve the serosal
surfaces and produce fibrinohemorrhagic thickening of the
pericardium that may neatly overlie and indicate the infarcted
ventricle of a dog. (Courtesy University of Minnesota Veterinary
Diagnostic Laboratory.)
Diseases of the Heart
area. In cases dying within 24 hours, the pericardial reaction
may be the only indication grossly of infarction, the necrotic
muscle at this stage not being clearly altered or merely pale.
The necrotic area becomes more sharply defined by hyper-
emia by the second to fourth days. By the tenth day, there is
beginning replacement of the necrotic zone by fibrous
ingrowth. Replacement fibrosis is well established by the end
of the sixth week. A substantial, often transmural loss of myo-
cardium and replacement by fibrous tissue may lead to the
development of aneurysms of the ventricular wall.
Microscopically, lesions are not usually detectable for the
first 6-12 hours. However, ultrastructural changes are observed
within 1 hour. Recognition as early as 2 hours may be possible
using special stains, such as hematoxylin-basic fuchsin-picric
acid. Necrosis becomes apparent by routine stains after 12
hours (Figs. 1-40, 1-41). Subsequently, neutrophils infiltrate
Figure 1-40  Myocardial necrosis in a calf. Focal necrosis of
cardiac myocytes showing eosinophilia, loss of cross striations, and
absence of nuclei (arrowhead). Extensively mineralized necrotic
cardiac myocytes (arrow). Some normal cardiac myocytes remain
in lower portion. H&E.
Figure 1-41  Myocardial necrosis in a calf. Phosphotungstic acid
hematoxylin (PTAH) stain emphasizes the contraction bands
(collapsed sarcomeres) in the necrotic cardiac myocytes (arrow).
Normal cardiac myocytes (above and below arrow) have fine cross
striations of normal sarcomeres.
Myocardial Disease 37
the affected area, and the nuclei of the myocytes become
pyknotic. At this stage, macrophages are evident. Granulation
tissue appears at the periphery of the lesion toward the end
of the first week and usually predominates by the end of the
sixth week.
There are variations in the microscopic appearance of
myocyte necrosis, and some attempt has been made to associ-
ate the differing microscopic patterns with particular causes,
but these associations are not definitive. The first variant is
coagulative necrosis characterized by cellular swelling, nuclear
hyperchromasia, early loss of striations, and a “granular”
appearance of the myocyte. This type of change is observed
primarily in ischemic states. Coagulative myocytolysis is typi-
fied by the presence of thick, irregular, eosinophilic bands,
with an accompanying loss of striations and lightly staining
granular areas in myocytes. The bands are hypercontracted
sarcomeres (“contraction bands”) (see Fig. 1-41) and the light
granular areas are mitochondria. Evidence from experimental
models suggests that the alteration is the result of the excessive
release of endogenous catecholamines. However, this change
may be observed in normal myocardium if it is fixed imme-
diately after death. Colliquative myocytolysis appears as a loss
of striations, and homogeneous, weakly eosinophilic cyto-
plasm. The ultrastructural appearance is characterized by
intracellular edema, with disintegration of fibrils and other
organelles. Waviness of myocardial fibers is claimed by some to
be one of the earliest changes observed in myocardial infarc-
tion in humans. The affected fibers are not necrotic, but are
thinner and undulating in appearance. It is thought that the
waviness is due to irreversible stretching followed by compres-
sion of ischemic fibers by the surrounding viable myocardium.
Attenuated wavy fibers (<6 µm diameter, wavy appearance)
have been noted to be common in the myocardium of dogs
with dilated cardiomyopathy.
Anichkov (Anitschkow) cells, also known as “caterpillar
cells,” have been observed in myocarditis and a variety of natu-
rally occurring and experimentally induced myocardial necro-
ses. They are also seen in rheumatic fever in humans in
association with Aschoff bodies. Anichkov cells appear as large
mononuclear cells in which the nuclear chromatin is present
in an undulating wavy ribbon with slender processes radiating
from it (Fig. 1-42). The origin of these cells is in dispute. Sug-
gestions include a fibroblastic, pericytic, endothelial, or myo-
cytic origin. Depending on the theory accepted, the function
is either that of a macrophage or an abortive attempt at
cardiac myocyte regeneration.
A few of the more interesting examples of myocardial
degeneration and necrosis follow.
Fluoroacetate poisoning
Sodium fluoroacetate (compound 1080) is used extensively
in some parts of the world as a vertebrate pesticide, and espe-
cially as a rodenticide. It is also highly toxic for most domestic
mammals. The median lethal dose for most species is ~0.25-
1.00 mg/kg of body weight. Fluoroacetate is not directly toxic,
but becomes so when converted to fluoroacetyl–coenzyme A.
This compound is then combined with oxaloacetic acid to
form fluorocitrate. The citric acid cycle enzymes cis-aconitase
and succinic dehydrogenase are inhibited by fluorocitrate,
effectively inhibiting the production of adequate amounts of
adenosine triphosphate (ATP). Accidental poisoning by fluo-
roacetate occurs either by direct ingestion of the poison, or
indirectly, as when dogs eat poisoned rabbits.
38 CHAPTER 1  •  Cardiovascular System
Figure 1-42  Focal myocarditis (Aschoff body) characterised by
multinucleated giant cells (long arrow), lymphocytes, and some
cells with caterpillar nuclei (Anichkov cells, short arrow) in a dog.
H&E.
Fluoroacetate of plant origin is responsible for sometimes
devastatingly large episodes of poisoning of ruminants. Plants
known to accumulate fluoroacetate in lethal quantities for
ruminants are Gastrolobium spp. and Acacia georginae in
Australia, Dichapetalum spp. (gibflaar) in Africa, and Pali-
courea marcgravii in Brazil. Whether fluoroacetate has any role
in the physiologic economy of the plants is not known, but in
the case of A. georginae, there are differences in the develop-
ment of toxicity in the species. In D. cymosum, there are
seasonal differences, toxicity being greater in spring and
autumn, and especially in young leaves. Young leaves, includ-
ing sucker growth, and pods and seeds are more toxic than
the mature leaves of A. georginae.
The syndromes of intoxication vary with the species
affected but are either chiefly neurologic, as in dogs, which
become extremely excited and convulsive, or chiefly cardiac,
as in ruminants. Sheep may collapse suddenly and die within
a few minutes. Those less severely affected may develop car-
diorespiratory distress and weakness if driven, with death
supervening shortly thereafter. Some showing these signs, if
left undisturbed, may recover to appear normal until again
forced to exercise. The syndrome in cattle is the same as in
sheep, death occurring with cardiac failure, fibrillation, cyano-
sis, dyspnea, and terminal convulsions. Exercise, excitement,
or a large drink of water may precipitate clinical signs.
The postmortem findings in ruminants are referable to
myocardial injury. This may or may not be conspicuous,
depending on the size of the dose and the opportunity for
repeated episodes of poisoning. The concentration of fluoro-
acetate in D. cymosum is large, and histologic evidence of acute
myocardial injury is seen. In A. georginae poisoning, both acute
and chronic myocardial changes may be seen. There is some
flabbiness of the myocardium, with prominent hemorrhages
beneath the cardiac serosa. In acute cases, there are irregular
areas of myocardial pallor and mottling sometimes associated
with older scars. There is multifocal myocytolysis or hyaline
degeneration of the myocardial fibers, with intense infiltration
of mononuclear cells. Loss of sarcoplasm leaves an open mesh-
work of reticulum and vessels, which eventually condenses
and scars.
Myocardial Disease
Gousiekte
Gousiekte (“quick” disease) is a plant poisoning of ruminants in
southern Africa that is of great economic importance in that
region. The disease is characterized by acute heart failure 5-8
weeks after the ingestion of certain plants in the family Rubia-
ceae. Clinical signs are seldom seen in natural cases; animals
are usually found dead. A number of plants can cause the
disease, including Pachystigma pygmaeum, P. thamnus, P. latifo-
lium, Fadogia homblei, Pavetta harborii, and Pavetta schuman-
niana. Pavetamine is the water-soluble, heat-stable toxin
responsible for causing gousiekte.
Gross pathologic changes include generalized congestion,
ascites, hydropericardium, hydrothorax, and pulmonary edema.
Ventricular dilation is an inconsistent feature. However, the
ventricular walls are thinner and have a tough consistency. In
a small proportion of cases, the heart is macroscopically
normal. Microscopically, there is focal-to-extensive myofiber loss
with replacement fibrosis. The surviving myofibers may be atro-
phied, and groups of lymphocytes and macrophages may be
present in areas of fibrosis.
Avocado poisoning
Sheep and goats may die following the ingestion of fresh leaves
from some varieties of the avocado tree (Persea americana);
the active principle “persin” is a monoglyceride that has struc-
tural affinities with polyether ionophore antibiotics. Animals
may die suddenly after ingesting comparatively few leaves,
whereas others may show few ill effects. In those that die,
lesions consist of endocardial hemorrhage, especially of the
papillary muscles; hydropericardium; pale, flabby heart;
ascites; hepatic degeneration; and pale kidneys. Cardiac lesions
are those of cardiac myocyte necrosis and congestion and hem-
orrhage of variable severity. Although horses can be poisoned
following the ingestion of avocado leaves, it is not usually fatal.
Consumption of avocado leaves also results in depression
of milk production in lactating goats. The affected mammary
glands are edematous and reddened with clots in the large
ducts. The Guatemalan, but not the Mexican, variety of
avocado induces these changes in the mammary gland.
Taurine deficiency in cats
Taurine-deficiency myocardial failure (TDMF) in cats is a
primary systolic myocardial disorder associated with taurine defi-
ciency; many cases of feline dilated cardiomyopathy are actu-
ally examples of TDMF. Decreased systolic function results in
signs associated with decreased cardiac output giving rise to
bilateral congestive heart failure. End-diastolic ventricular
volume and pressure are increased, as are atrial volume and
pressure.
Taurine (2-aminoethane sulfonic acid), an essential amino
acid for cats, is abundant in fresh meat, but must be supple-
mented in commercial feline diets to prevent the develop-
ment of TDMF, central retinal degeneration, and developmental
abnormalities in kittens. Taurine is required in myocardium
for the modulation of tissue calcium influx through cardiac
calcium channels. Taurine supplementation will restore myo-
cardial function to normal in most cats with low plasma
taurine levels and echocardiographic evidence of cardiac
chamber dilation and myocardial failure. Cats, and other
mammals, have an obligatory need to conjugate bile acids with
taurine or glycine; cats not only have a limited capacity to
synthesize taurine, but are unable to use glycine for bile acid
conjugation.
Diseases of the Heart
As the syndrome is now well recognized, cats are  myocardial muscle. The development of PSS is intimately
unlikely to die of TDMF. In cats that do die, gross and histo-
logic cardiac lesions are as described later for feline dilated
cardiomyopathy.
Myocardial necrosis secondary to neural injury
The effect of the central nervous system on the myocardium
is mediated by the autonomic nervous system and, in particu-
lar, the sympathetic nervous system. The heart is richly inner-
vated with autonomic fibers, and myocytes, particularly
ventricular myocytes, have high concentrations of β receptors.
Both the rate and inotropic state of the heart are stimulated
by catecholamines. In a number of species, the continuous
administration of norepinephrine for 1-2 weeks results in focal
myocardial necrosis. Multifocal myocardial necrosis may
develop in dogs with paroxysmal tachycardia resulting from
functional pheochromocytomas. Also, experimentally induced
intracranial hemorrhage produces focal myocardial necrosis,
which can be prevented by prior administration of either
reserpine, a catecholamine-depleting drug, or propanolol,
which blocks β receptors.
Multifocal myocardial necrosis occurs in dogs, horses, cows,
sheep, pigs, goats, and wildlife in association with neurologic
disease of diverse origin (“brain-heart syndrome”), from exter-
nal trauma to infectious disease. The primary lesion may
involve the head, central nervous system, or major nerve plex-
uses. The microscopic appearance of the myocardial lesions is
dependent on the time elapsed between insult and death. It
varies from acute myocardial degeneration and necrosis to
almost complete resolution by fibrosis. There are, no doubt, a
number of cases with no gross or microscopic lesions where
insufficient time elapsed between the onset of clinical signs
and death. The findings of multifocal myocardial necrosis on
autopsy in any species should alert the pathologist to examine the
central nervous system for abnormality. Secondary multifocal
myocardial necrosis also occurs in dogs with gastric torsion,
and in dogs and cats with acute necrotizing pancreatitis and
septic peritonitis.
Doxorubicin (Adriamycin) cardiotoxicosis
Doxorubicin, an antineoplastic agent of the anthracycline
antibiotic group, is used in the treatment of lymphoma and
other neoplasia in dogs; cardiotoxicosis is the major factor limit-
ing its use. Acute cardiotoxicosis appears to be mediated by
peroxidative injury or expression of cytokines. As well, binding
of doxorubicin to nuclear and mitochondrial DNA causes
blockage of DNA, RNA, and protein synthesis. Chronic doxo-
rubicin cardiotoxicosis, which may be due to decreased protein
synthesis as well as altered divalent cation concentration,
occurs in dogs given cumulative doses. Congestive heart
failure occurs in such dogs; microscopic myocardial changes
consist of myocytic vacuolar degeneration (“adria cells”), myo-
cytolysis, myofibril atrophy, and fibrosis. The cardiotoxicity of
doxorubicin is reduced when administered as a pegylated
liposomal form.
Porcine stress syndrome (pale, soft, and exudative
[PSE] pork)
Porcine stress syndrome (PSS) is primarily a disease of skeletal
muscle (see Vol. 1, Muscle and tendon). A single nucleotide
mutation, HAL-1843, in the ryanodine receptor 1 increases the
susceptibility 4-fold to PSS, but pigs without the mutation can
also develop the disease. The mutation is not expressed in
Myocardial Disease 39
associated with stocking density, transportation time, and
other antemortem stressors. Death from PSS may occur as a
result of peracute heart failure secondary to the metabolic and
hormonal sequelae of PSS, namely, acidosis, hyperkalemia,
hyperthermia, and hypercatecholemia. The latter may produce
myocardial necrosis. Sudden death caused by cardiac failure
also occurs in sows, both with and without association with
the PSS gene mutation.
Clinically, affected pigs exhibit muscular tremor, dyspnea,
hyperthermia, and cutaneous blanching and erythema. Death
quickly ensues. Typical autopsy findings include the rapid
development of rigor, pulmonary edema, hydropericardium,
and splanchnic congestion. In some, there is epicardial and
endocardial hemorrhage with irregular areas of pallor in the
left ventricular myocardium. The presence or absence of myo-
cardial necrosis in PSS is a major difference between the
European and North American descriptions of the disease.
Myocardial necrosis is a common finding in European cases.
When present, the necrotic areas are prominent in the inner
third of the wall and papillary muscles. The microscopic
appearance of the necrotic fibers is characterized by loss of
the normal striation pattern, the presence of contraction
bands, and fine granulation of the sarcoplasm.
A variant of PSS associated with a mutation in the dystro-
phin gene, and markedly decreased expression of dystrophin in
both cardiac and skeletal myocytes has been recently described.
Mulberry heart disease of swine
The name “mulberry heart” is vaguely suggested by the exten-
sive hemorrhages on the surface of the heart, and its major fea-
tures are depicted in eFigure 1-7. The disease occurs in pigs
only, chiefly those 2-4 months of age and in excellent condi-
tion, but it has been observed in animals from 3 weeks to 4
years of age. Among old pigs, the incidence is sporadic, but in
young pigs, it occurs in short, snappy outbreaks. In most cases,
typically affected animals are found dead. The circumstances
of sudden death combined with the gross and microscopic
lesions strongly suggest that the affected animals die of acute
heart failure following the development of ventricular dys-
rhythmias (Figs. 1-43, 1-44). Despite the associated gross and
microscopic findings, mulberry heart disease is generally a
diagnosis of exclusion; this is particularly the case today when
Figure 1-43  Severe epicardial hemorrhage with excess pericar-
dial fluid containing fibrin strands in mulberry heart disease in a
pig. (Courtesy R.W. Cook.)
 39.e1

MULBERRY HEART DISEASE

Most probable cause-increased
metabolic demand for vitamin E

Gross Pathology Clinical Presentation

Hydrothorax, hydropericardium Most commonly occurs as short
Epicardial hemorrhage[mulberry heart] outbreaks in pigs 2-4 months of age
Myocardial necrosis[sometimes] Can occur sporadically in pigs of any age
Leukoencephalomalacia in some survivors

Histopathology
Myocardial necrosis
Widespread fibrinoid necrosis of arteriolar walls
Hyaline thrombi, disruption of endothelium
Leukoencephalomalacia

eFigure 1-7  Major features of mulberry heart disease.

40 CHAPTER 1  •  Cardiovascular System
Figure 1-44  Extensive necrosis of myocardium (pale areas) with
hemorrhage in mulberry heart disease. (Courtesy M. Culhane.)
extensive arrays of molecular diagnostic tests are often
available.
Raising weanling piglets on a diet deficient in selenium and
vitamin E can regularly reproduce the disease. Such animals may
develop disease within 2 weeks. As discussed with diseases of
muscle (in Vol. 1, Muscle and tendon), selenium is an integral
part of the membrane enzyme glutathione peroxidase, which
reduces toxic lipid peroxides to hydroxy acids. Vitamin E is
an antioxidant and acts synergistically with selenium to protect
membranes from high concentrations of lipoperoxides. Field
studies, particularly from the Scandinavian countries, have
shown that although dietary selenium supplementation mark-
edly reduces the incidence of hepatosis dietetica and nutri-
tional myopathy, the prevalence of mulberry heart disease
remains the same. It is also evident that tissue levels of sele-
nium, particularly those in the heart and liver, are within the
normal range. It is now considered that vitamin E deficiency
plays a central role in the development of mulberry heart disease.
However, there is not universal agreement on this. Although
some studies show lower tissue levels of vitamin E in affected
pigs, others show no difference. Additionally, it has been sug-
gested that the disease is the result of altered vitamin E
metabolism and not a consequence of inadequate dietary
vitamin E levels. It may be that mulberry heart disease is
precipitated following a lack of bioavailability of vitamin E in
tissues, or possibly a greater requirement for vitamin E under
certain dietary circumstances, such as diets containing large
amounts of unsaturated fat.
Animals dying of mulberry heart disease are always in
excellent body condition. There may be slight cyanosis of the
ears and ventral abdomen, and exophthalmos, the latter result-
ing from orbital and palpebral edema. The intermuscular con-
nective tissues are usually wet, and there may be obvious
edema, especially in the axillary and inguinal regions and near
the xiphoid process. The skeletal muscles are normal.
The principal gross lesions occur in the thorax. Some 50 mL
or more of heavy, straw-colored fluid that clots on exposure
to air is invariably present in the pleural cavity. The lungs are
edematous and slightly or severely congested, but not severely
enough to account for the degree of edema. The pericardium
is edematous and opaque and is always acutely distended with
fluid transudate. Either heavy strands or a lace of fibrin float
Myocardial Disease
Figure 1-45  Focal cerebrocortical leukomalacia (arrows) in mul-
berry heart disease. (Courtesy R.W. Cook.)
in the fluid. The fibrin is not fixed to the serous surface and,
from where it is in contact with the epicardium, it can easily
be lifted off to reveal a clean, glistening, serous membrane.
Hemorrhages, linear and ecchymotic, are present beneath the
epicardium. They may be few, or they may be extensive and
involve the epicardium of all chambers, the myocardium, and
beneath the endocardium of the papillary muscles and septum.
In some, multiple pale streaks and patches of necrosis extend
from the epicardial surface into the myocardium. There may
be similar lesions visible from the endocardial surface.
The abdominal cavity contains a small volume of clear
transudate and some fine unattached strands of fibrin on the
intestine. The stomach usually contains a mass of dry feed, 
and its fundic mucosa is diffusely congested. The small intes-
tine is empty and dry, with serosal vessels congested. The liver
is congested, sometimes markedly so, with edema of the 
wall of the gallbladder. In some animals that survive 24 
hours or more, there is bilaterally symmetrical softening of the
white matter forming the cores of the cerebral gyri. The soften-
ings are visible grossly as gray, translucent, depressed areas
studded with tiny hemorrhages that are sometimes confluent
(Fig. 1-45).
Microscopically in acute deaths, degeneration of myofibers
may be minimal or absent. In these cases, there is merely
subserosal edema, with some plugging of lymphatics by fibrin,
and interstitial hemorrhage. In others, which are probably less
acute cases, there are substantial areas of myocardial necrosis
(Fig. 1-46). The extent of mineralization of the necrotic fibers
varies, but never appears to be as severe as that seen in lambs
or calves with nutritional myopathy.
The second prominent lesion, which is most probably unrelated
to the myocardial necrosis, is observed in arterioles of many
organs. The change is seen in the heart, kidneys, liver, stomach,
intestine, mesentery, skeletal muscle, and skin. There appears
to be gradation in the severity of change, from endothelial
swelling with increased permeability, to necrosis of smooth
muscle cells of the media. The basic appearance includes the
accumulation of fibrinoid in arteriolar walls, formation of hyaline
thrombi, disruption of endothelium, and necrosis of smooth muscle
cells. Periodic acid–Schiff (PAS) staining of affected arterioles
emphasizes the accumulation of fibrinoid. The lungs show
congestion and edema only. There is congestion and edema of
Diseases of the Heart
Figure 1-46  Myocardial hemorrhage with necrosis and mineral-
ization of myocardiocytes in mulberry heart disease. H&E.
the liver, associated in some cases with central necrosis in the
lobules. Proteinaceous fluid produces focal detachments of the
retina and intercapillary edema of the glomerular tufts.
The development of the cerebral lesions can be correlated
roughly with the duration of the clinical illness. In the majority
of cases, where death occurs suddenly, there is no microscopic
change in the brain, or merely some slight venous congestion
and edema of the cortical white matter. In pigs that live for
some hours, there is edematous separation of the fiber tracts
of the white matter of the frontal cortex, with acute swelling
and fragmentation of oligodendroglia. The overlying gray
matter is edematous. In animals that survive for 24 hours or
more, it is usual to find severe lysis of the white matter in the
cerebrum, which is more or less extensive but usually avoids
the internal capsule, corpus medullare, and association fibers.
The cores of the gyri of the frontal lobes are most consistently
and severely involved, but in some cases, all portions of the
cerebrum are involved, and in these, there may be similar
lesions in the thalamus and brainstem. The vessels, venules
especially, in the degenerate areas are severely injured and may
be totally necrotic, although more frequently, there is only
endothelial and adventitial swelling and proliferation. Hyaline
thrombi are formed in many vessels, and droplets of similar
character form in the perivascular spaces. The overlying gray
matter is edematous. The vessels are hypertrophic and cuffed
by adventitial cells and a few eosinophils. In a few cases,
degenerate foci are also present in the cerebellum; these
involve the molecular layer with foci of softening or narrow
sheets of hemorrhage.
The lesions in mulberry heart disease depend on the length
of time pigs survive after the initial damage occurs. Most pigs
die from ventricular dysrhythmia, and those that die immedi-
ately no doubt have substantial areas of myofiber death, but
there has been insufficient time for the morphologic manifes-
tations of the necrosis to appear. A period of 6-12 hours must
elapse before myofiber necrosis can be reliably recognized.
After that, the lesions become increasingly evident and prog-
ress through stages to replacement fibrosis of the necrotic
areas if the pig survives.
In the experimentally induced disease, serum enzyme
levels indicative of myocardial damage may be raised for up
to 21 days before death. The extent of cardiac damage is
related to the length of time the serum enzymes are raised or,
Myocardial Disease 41
alternatively, to a large increase over a shorter period. The
microangiopathy prominent in this disease probably occurs inde-
pendently of the myofiber necrosis. It is also nonspecific, as the
same change is seen in many porcine viral infections and
bacterial toxemias. It is, however, a useful indicator of the
presence of mulberry heart disease.
Further reading
Barbut S, et al. Progress in reducing the pale, soft and exudative (PSE)
problem in pork and poultry meat. Meat Sci 2008;79:46-63.
Baroldi G, et al. Myocardial contraction bands. Definition, quantifica-
tion and significance in forensic pathology. Int J Legal Med
2001;115:142-151.
Burrows GW, Tyrl RL. Toxic Plants of North America. 2nd ed. Ames,
Iowa: Wiley-Blackwell; 2013.
Caloni F, et al. Plant poisoning in domestic animals: epidemiological
data from an Italian survey (2000-2011). Vet Rec 2013;172:580-
583.
Davis TZ, et al. Toxicokinetics and pathology of plant-associated acute
selenium toxicosis in steers. J Vet Diagn Invest 2012;24:319-327.
Galey FD, et al. Diagnosis of oleander poisoning in livestock. J Vet
Diagn Invest 1996;8:358-364.
Ganote CE. Contraction band necrosis and irreversible myocardial
injury. J Mol Cell Cardiol 1983;15:67-73.
Guardia MD, et al. Risk assessment of PSE condition due to pre-
slaughter conditions and RYR1 gene in pigs. Meat Sci 2004;67:471-
478.
Kellerman TS, et al. Plant Poisonings and Mycotoxicoses of Livestock
in Southern Africa. 2nd ed. Cape Town: Oxford University Press;
2005.
McKenzie RA. Australia’s Poisonous Plants, Fungi and Cyanobacteria:
A Guide to Species of Medical and Veterinary Importance.
Collingwood. Victoria, Australia: CSIRO Publishing; 2012.
Nonneman DJ, et al. A defect in dystrophin causes a novel porcine
stress syndrome. BMC Genomics 2012;13:233.
Panciera RJ, et al. Hairy vetch (Vicia villosa Roth) poisoning in cattle:
update and experimental induction of disease. J Vet Diagn Invest
1992;4:318-325.
Reiner AC, et al. Oleander toxicosis in equids: 30 cases (1995-2010).
J Am Vet Med Assoc 2013;242:540-549.
Shen H, et al. Vitamin E and selenium levels are within normal range
in pigs diagnosed with mulberry heart disease and evidence for viral
involvement in the syndrome is lacking. Transbound Emerg Dis
2011;58:483-491.
Shen H, et al. Vitamin E and selenium levels are within normal range
in pigs diagnosed with mulberry heart disease and evidence for viral
involvement in the syndrome is lacking. Transbound Emerg Dis
2011;58:483-491.
Sula MJM, et al. Characterization of cardiac lesions in calves after
ingestion of Japanese yew (Taxus cuspidata). J Vet Diagn Invest
2013;25:522-526.
Wrogemann K, Pena SDJ. Mitochondrial calcium overload: a general
mechanism for cell necrosis in muscle diseases. Lancet 1976;
1:672-673.
Myocarditis
Myocarditis, or inflammation of the myocardium, is a common
lesion found in a wide variety of systemic diseases (Table 1-6),
but it is rarely primary. It occurs hematogenously in many
infectious diseases, and also by direct extension from inflam-
matory lesions of the endocardium and pericardium. A

Further reading
Basaraba RJ, et al. Toxicosis in cattle from concurrent feeding of
monensin and dried distiller’s grains contaminated with macrolide
antibiotics. J Vet Diagn Invest 1999;11:79-86.
Bastianello SS, et al. A chronic cardiomyopathy in feedlot cattle attrib-
uted to toxic levels of salinomycin in the feed. J S Afr Vet Assoc
1996;67:38-41.
Bradley GA. Myocardial necrosis in a Pug dog with necrotizing menin-
goencephalitis. Vet Pathol 1991;28:91-93.
Bradley R, Duffell SJ. Sudden death and myocardial necrosis in cattle.
J Pathol 1981;135:19-38.
Bradley R, Duffell SJ. The pathology of the skeletal and cardiac muscles
of cattle with xanthosis. J Comp Pathol 1982;92:85-97.
Burroughs GW, et al. Suspected hybrid vetch (Vicia villosa crossed with
Vicia dyscarpa) poisoning of cattle in the Republic of South Africa.
J S Afr Vet Assoc 1983;54:75-79.
Combs AB, Acosta D. Toxic mechanisms of the heart. A review. Toxicol
Pathol 1990;18:583-596.
Cranley JJ, McCullagh KO. Ischaemic myocardial fibrosis and aortic
strongylosis in the horse. Equine Vet J 1981;13:35-42.
Davies RL, Whyte PBD. Adonis microcarpa (pheasant’s eye) toxicity in
pigs fed field pea screenings. Aust Vet J 1989;66:141-143.
Flory W, et al. The toxicologic investigation of a feed grain contami-
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42 CHAPTER 1  •  Cardiovascular System Myocardial Disease

Table • 1-6 
Causes of myocarditis in domestic animals
Viruses Canine herpesvirus, canine parvovirus 2,
encephalomyocarditis virus, equid herpesvirus 1,
foot-and-mouth disease virus, murid herpesvirus
(murine cytomegalovirus), porcine circovirus 2
and/or porcine parvovirus (in postweaning
multisystemic wasting syndrome [PMWS]),
pseudorabies virus, West Nile virus
Bacteria Actinobacillus equuli, Actinobacillus suis,
Bartonella vinsonii, Borrelia burgdorferi (Lyme
disease), Clostridium chauvoei, Histophilus
somni, Leptospira spp., Streptococcus suis,
Neorickettsia (Ehrlichia) risticii
Protozoa Neospora caninum, Sarcocystis, Toxoplasma
gondii, Trypanosoma spp.
Helminths Trichinella spiralis A

number of specific parasitic infestations also produce myocar-

ditis. Effectors of the immune and inflammatory responses in
myocarditis can have numerous deleterious effects on the
myocardium: cytolytic T lymphocytes can produce focal
cardiac myocyte necrosis; activated lymphocytes and macro-
phages can release a host of inflammatory cytokines that can
lead to altered cardiac myocyte metabolism, decreased con-
tractility, and dysrhythmias, and to increased matrix and myo-
cardial fibrosis. Death resulting from myocarditis may occur
acutely because of dysrhythmia where inflammation is often
focal and can be missed grossly. Nonfatal cases of myocarditis
may progress to congestive heart failure, subsequent to exten-
sive cardiac myocyte loss and fibrosis.
Pyogenic bacteria, which may originate from any other sup- B
purative focus in the body or, as in the case of Listeria mono-
Figure 1-47  Myocarditis. A. Myocardial blackleg (Clostridium
cytogenes and Actinobacillus equuli, produce foci of acute
chauvoei) with myocardial necrosis and hemorrhage in right ven-
suppurative myocarditis that may develop into abscesses with
tricular free wall, in an ox. (Courtesy S. Diab.) B. Multifocal to
inevitable destruction of the involved tissue (eFig. 1-8). In
coalescing myocarditis in ventricle wall, caused by Blastomyces
these, it is often possible to demonstrate bacterial emboli.
dermatitidis in a dog. (Courtesy M. Bouljihad.)
Clostridium chauvoei may produce necrotizing myocarditis
similar to the typical lesion in skeletal muscle (Fig. 1-47A).
Tuberculous myocarditis is rare, and when present, the granu-
lomatous reaction is typical of the species. Occasionally, fungal fibers vary widely in extent and in the severity of degeneration.
organisms can cause multifocal pyogranulomatous lesions (Fig. The cause may sometimes be apparent in the histologic nature
1-47B). Bartonella henselae is being increasingly recognized as of the lesion, as, for example, in malignant catarrhal fever of
a cause of both pyogranulomatous myocarditis and endocar- cattle, in which inflammation is centered on the blood vessels.
ditis in cats. An additional feature of this disease is myositis In toxoplasmosis, the degeneration of myocytes predominates
involving muscles of the diaphragm. over the inflammatory reaction and the organism is identifi-
Necrobacillary myocarditis occurs in cattle secondary to able. In most cases of interstitial myocarditis, however, diagnosis
extensive necrobacillosis in other tissues; the necrosuppura- of the cause can only be made by reference to the total pathologic
tive reaction is typical for the organism. Other bacterial causes picture. Only infrequently can death be attributed to the myo-
of suppurative myocarditis include Clostridium piliforme cardial lesions, and then only when considerable degeneration/
(Bacillus piliformis) and Citrobacter koseri. There is also exten- necrosis of the myocardial fibers has occurred, as in foot and
sive myocarditis in some systemic mycoses, such as Aspergillus mouth disease of young animals. Some other viral infections,
terreus in dogs, particularly the German Shepherd dog. such as canine parvovirus infection and encephalomyocarditis
Less specific interstitial myocarditis occurs in many infectious virus infection, are exceptions to this general principle.
diseases and is not detectable grossly. The basic pattern is usually Myocarditis is seen in systemic viral infections, such as
the same, the reaction being centered on the interstitial and canine distemper, canine herpesviral infection, and pseudora-
perivascular connective tissues, with edema and infiltration of bies in piglets and dogs. The myocarditis caused by canine
lymphocytes, plasma cells, macrophages, and some eosino- parvovirus 2 infection (Fig. 1-48) is discussed in Vol. 2, Ali-
phils. Neutrophils are few. The changes in the myocardial mentary system and peritoneum.
 42.e1

eFigure 1-8  Embolic suppurative myocarditis, caused by Trueper-

ella pyogenes, in a lamb. Multiple abscesses, one of which has
encroached upon and caused thrombosis in a coronary artery
(arrow).
Diseases of the Heart
Figure 1-48  Unusually severe parvoviral myocarditis (pale areas)
in a dog. (Courtesy D. Hayden.)
Myocarditis is part of a number of important and wide-
ranging clinical and pathologic syndromes in porcine fetuses,
stillborn piglets, and young piglets. These include postweaning
multisystemic wasting syndrome (PMWS), porcine dermatitis
and nephropathy syndrome (PDNS), and reproductive failure
caused by porcine circovirus 2; porcine reproductive and
respiratory syndrome (PRRS) caused by the PRRS arterivirus;
and porcine myocarditis syndrome (PMC) caused by the
novel Bungowannah pestivirus (see Vol. 3, Female genital
system).
“Eosinophilic myocarditis” is so called because the reaction
to sarcocysts is predominantly by eosinophils, which produce
the typical, small, green to gray-green foci observed occasion-
ally in cattle at routine meat inspection. This syndrome is not
to be confused with the eosinophilic myocarditis present in
cases of poisoning by ingestion of hairy vetch (Vicia villosa).
Atrial myocarditis is an infrequently reported entity of
undetermined cause in dogs that manifests clinically as an
arrhythmia (sinoatrial arrest, supraventricular tachyarrhyth-
mias). Lesions are confined to the atria and can vary from  organs, with the myocardium exhibiting the highest titer of
a lymphocyte predominant infiltration to extensive fibrosis
(Fig. 1-49).
Encephalomyocarditis virus infection
There are 3 members of the genus Cardiovirus in the family
Picornaviridae, and the type species is Encephalomyocarditis
virus (EMCV). All species are antigenically related and by
most tests are indistinguishable from each other. EMCV can
infect humans and other mammals, principally swine and sub-
human primates. Rodents, in which it appears to be clinically
inapparent and behaves as an enterovirus, may act as reservoir
hosts, but infection in laboratory rodents commonly produces
fatal encephalitis or myocarditis. The source of infection in
outbreaks of myocarditis in swine is thought to be through
consumption of feed or water contaminated with virus from
rats or other rodents. Ingestion of diseased rodent carcasses is
also a likely source of infection. Experimental transmission of
disease to swine has been accomplished by feeding the virus,
Myocardial Disease 43
Figure 1-49  Focally extensive myocarditis of the right atrium in
a dog.
but susceptible pigs kept in close contact with infected pigs
did not develop disease.
Sudden death or death following a brief period of excita-
tion and collapse characterizes the clinical disease in the per-
acute form in swine. In less severe cases, there may be fever,
anorexia, and progressive paralysis. The mortality rate is vari-
able. At autopsy, there is hydrothorax, hydropericardium,
ascites, and pulmonary congestion and edema. In severe cases,
there is extreme pallor of the ventricles, with yellow-to-white
foci 2-10 mm in diameter throughout the myocardium. In less
severe cases, gross lesions are minimal to absent. Microscopi-
cally, the dominant lesions are focal-to-diffuse myocardial
necrosis. Patchy mineralization of necrotic areas is evident,
accompanied by a mononuclear inflammatory reaction that
varies greatly in intensity. Survival allows fibrous scarring to
develop. There is little evidence of encephalomyelitis. EMCV
infection has also been associated with reproductive failure
characterized by mummified fetuses and stillbirth, as well as
failure of conception and early embryonic deaths. Fetuses that
die toward the end of gestation have multifocal myocardial
necrosis.
Experimentally infected swine may die between 2 and 11
days postinoculation. Virus is present in the feces for 7-9 days
following oral administration and may be isolated from all
virus. The virus titer falls rapidly and may not be found in
cases that have been infected for 11 days or more. Experimen-
tal inoculation of mice regularly produces both encephalitis
and myocarditis. Strains of EMCV may be adapted to produce
either encephalitis or myocarditis.
Parasitic myocarditis
The parasites that tend to localize in the myocardium are the
same as those that have an affinity for skeletal muscle. Parasites
without such affinity may also be found in the myocardium
in the course of their wanderings, especially if they are migrat-
ing in an abnormal host or in unusually large numbers in the
normal host.
Of those parasites with an affinity for cardiac and skeletal
muscle, the ubiquitous sarcocysts are the most common (see
Vol. 1, Muscle and tendon). The finding of myocardial sarcocysts
is very common in ruminants. This increases with the age of
the animal and implies a previous acute sarcocystosis in which
44 CHAPTER 1  •  Cardiovascular System
schizonts are formed in endothelial cells, usually with little
effect. The sarcocysts may be found in the cardiac conducting
fibers as well as myocardial fibers and normally appear to be
harmless. The multifocal eosinophilic granulomatous reaction to
degenerating Sarcocystis cruzi cysts may occur alone or in
association with similar lesions of eosinophilic myositis in
skeletal muscles. Degenerate cysts are occasionally visible
within foci of myocarditis. The cyst content is highly toxic,
but whether degeneration or rupture of the cyst is primary or
is secondary to some other cause of focal myocardial degen-
eration is unknown.
A rather severe myocarditis in dogs caused by the protozoal
parasite Neospora caninum is seen in association with myositis
and encephalomyelitis. Affected dogs vary in age from 2 days
to 7 years and may be presented with hindlimb paresis or
ataxia, skeletal muscle atrophy, and in some cases, sudden
collapse attributable to dysrhythmias induced by the myocar-
ditis. The differentiation of Neospora caninum from Toxo-
plasma gondii in paraffin-embedded tissue is best accomplished
by the use of immunohistochemistry. Additionally, Neospora
caninum is commonly associated with bovine abortion.
The various cysticerci of Taenia ovis, T. saginata, T. solium,
and hydatid cysts are frequently found in the myocardium,
which is one of their sites of predilection (eFig. 1-9). These
parasites are described with parasitic diseases of the intestine
(see Vol. 2, Alimentary system and peritoneum), which is the
habitat of their definitive stage.
Trichinella spiralis is described with diseases of muscle in
Vol. 1, Muscle and tendon. However, it is worth noting here
that the larvae of this parasite invade the myocardium,  Pathol 2003;129:161-168.
but are seldom found there, either because they continue  Rosa FA, et al. Cardiac lesions in 30 dogs naturally infected with Leish-
their migration or are destroyed. The myocardial reaction is a
severe interstitial myocarditis, with basophilic degeneration
and necrosis of fibers in the areas of inflammation.
The pyogranulomatous myocarditis caused by Trypano-
soma cruzi (Fig. 1-50) is described in Vol. 3, Hematopoietic
system. Leishmania infantum chagasi also causes a lympho-
plasmacytic and less commonly a granulomatous myocarditis
in dogs. In Africa, myocarditis can occur in dogs infected with
Trypanosoma brucei, and in cattle infected with T. congolense
or T. vivax.
Figure 1-50  Lymphoplasmacytic myocarditis (Chagas disease)
caused by Trypanosoma cruzi in a dog. Note the amastigote-
containing pseudocyst in a cardiac myocyte. H&E. (Courtesy B. F.
Porter.)
Myocardial Disease
Further reading
Allan GM, Ellis JA. Porcine circoviruses: a review. J Vet Diagn Invest
2000;12:3-14.
Chand RJ, et al. Pathogenesis of porcine reproductive and respiratory
syndrome virus. Curr Opin Virol 2012;2:256-263.
Cruz-Chan JV, et al. Immunopathology of natural infection with Try-
panosoma cruzi in dogs. Vet Parastiol 2009;162:151-155.
Finlaison DS, et al. Field and laboratory evidence that Bungowannah
virus, a recently recognized pestivirus, is the causative agent of the
porcine myocarditis syndrome (PMC). Vet Microbiol 2009;136:259-
265.
Finlaison DS, et al. Experimental infection of the porcine foetus with
Bungowannah virus, a novel pestivirus. Vet Microbiol 2010;144:
32-40.
Guedes PM, et al. Development of chronic cardiomyopathy in canine
Chagas disease correlates with high IFN-gamma, TNF-alpha, and
low IL-10 production during acute phase infection. Vet Immunol
Immunopathol 2009;130:43-52.
Haines DM, et al. Immunohistochemical study of Hemophilus somnus,
Mycoplasma bovis, Mannheimia haemolytica, and bovine viral diar-
rhea virus in death losses due to myocarditis in feedlot cattle. Can
Vet J 2004;45:231-234.
MacInnes JI, Desrosiers R. Agents of the “suis-ide diseases” of swine:
Actinobacillus suis, Haemophilus parasuis, and Streptococcus suis.
Can J Vet Res 1999;63:83-89.
Papaioannou N, et al. Pathogenesis of encephalomyocarditis virus
(EMCV) infection in piglets during the viraemia phase: a histo-
pathological, immunohistochemical and virological study. J Comp
mania infantum chagasi. Vet Pathol 2014;51:603-606.
Segales J. Porcine circovirus type 2 (PCV2) infections: clinical signs,
pathology and laboratory diagnosis. Virus Res 2012;164:10-19.
Snijder EJ, et al. Arterivirus molecular biology and pathogenesis. J Gen
Virol 2013;94:2141-2163.
Varanat M, et al. Identification of Bartonella henselae in 2 cats with
pyogranulomatous myocarditis and diaphragmatic myositis. Vet
Pathol 2012;49:608-611.
Warman S, et al. Dilatation of the right atrium in a dog with polymyo-
sitis and myocarditis. J Sm Anim Pract 2008;49:302-305.
Woolley R, et al. Atrial myocarditis as a cause of sinus arrest in a dog.
J Small Anim Pract 2007;48:455-457.
Cardiomyopathies
The term cardiomyopathy was originally coined for a group
of human myocardial diseases in that were of unknown or
obscure cause. Cardiomyopathies are now well-defined clini-
copathologic entities that have been increasingly shown to be
either genetically determined abnormalities of myocardial
contractile, cytoskeletal or mitochondrial proteins, or respon-
sive to substances such as taurine and carnitine. Initially, a
diagnosis of cardiomyopathy was arrived at by the absence of
common causes of heart failure and the presence of abnor-
malities not readily explained. In humans, where cardiomy-
opathies were first recognized, there must be absence of
significant coronary arterial disease; vascular disease or anomaly;
systemic hypertension, past or present; and vascular shunts inside
or outside the heart. Features usually present include cardio-
megaly, either as dilation or hypertrophy; mural thrombosis,
usually in the left ventricle; and, fibrosis or other lesions indicative
of generalized myocardial involvement.
 44.e1

eFigure 1-9  Parasitic myocarditis. Mineralized foci of degenerate

Cysticercus ovis in a lamb.
44.e2

Further reading
Agungpriyono DR, et al. Subacute massive necrotizing myocarditis by
canine parvovirus type 2 infection with diffuse leukoencephaloma-
lacia in a puppy. Vet Pathol 1999;36:77-80.
Appel MJG. Lyme disease in dogs and cats. Compend Contin Educ
Pract Vet 1990;12:617-626.
Barber JS, Trees AJ. Clinical aspects of 27 cases of neosporosis in dogs.
Vet Rec 1996;139:439-443.
Bolt DM, et al. Non-suppurative myocarditis in piglets associated with
porcine parvovirus infection. J Comp Pathol 1997;117:107-118.
Breitschwerdt EB, et al. Bartonella vinsonii subsp. berkhoffii and related
members of the alpha subdivision of the Proteobacteria in dogs
with cardiac arrhythmias, endocarditis, or myocarditis. J Clin Micro-
biol 1999;37:3618-3626.
Cassidy JP, et al. Myocarditis in sibling boxer puppies associated with
Citrobacter koseri infection. Vet Pathol 2002;39:393-395.
Deem DA, Fregin GF. Atrial fibrillation in horses: a review of 106 clini-
cal cases, and consideration of prevalence, clinical signs, and prog-
nosis. J Am Vet Med Assoc 1982;180:261-265.
Dubey JP, Lindsay DS. A review of Neospora caninum and neosporosis.
Vet Parasitol 1996;67:1-59.
Ellis J, et al. Reproduction of lesions of postweaning multisystemic
wasting syndrome in gnotobiotic piglets. J Vet Diagn Invest
1999;11:3-14.
Gajadhar AA, Marquardt WC. Ultrastructural and transmission evi-
dence of Sarcocystis cruzi associated with eosinophilic myositis in
cattle. Can J Vet Res 1992;56:41-46.
Hattel AL, et al. Neosporosis-associated bovine abortion in Pennsylva-
nia. Vet Parasitol 1998;74:307-313.
Hervas J, et al. Myocarditis associated with Theileria spp. in calves.
Zentralbl Veterinarmed B 1998;45:401-405.
Kimeto BA, et al. Haemorrhagic pancarditis in cattle infected with
Trypanosoma vivax. Vet Parasitol 1990;34:295-301.
Lange LG, Schreiner GF. Immune mechanisms of cardiac disease. N Engl
J Med 1994;330:1129-1135.
Lees W, et al. Outbreak of Cysticercus bovis (Taenia saginata) in feedlot
cattle in Alberta. Can Vet J 2002;43:227-228.
Machado EM, et al. A study of experimental reinfection by Trypano-
soma cruzi in dogs. Am J Trop Med Hyg 2001;65:958-965.
Machida N, et al. Cardio-histopathological observations on aborted
equine fetuses infected with equid herpesvirus 1 (EHV-1). J Comp
Pathol 1997;116:379-385.
Ndung’u JM, et al. Cardiac damage in dogs infected with T. brucei;
clinical and electrocardiographic features. J Small Anim Pract
1991;32:579-584.
Nho WG, et al. Detection of canine parvovirus in naturally infected
dogs with enteritis and myocarditis by in situ hybridization. J Vet
Diagn Invest 1997;9:255-260.
Reams RY, et al. Streptococcus suis infection in swine: a retrospective
study of 256 cases: II. Clinical signs, gross and microscopic lesions,
and coexisting microorganisms. J Vet Diagn Invest 1994;6:326-334.
Segales J, et al. Porcine circovirus diseases. Anim Health Res Rev
2005;6:119-142.
Thurmond MC, et al. Predictive values of fetal histopathology and
immunoperoxidase staining in diagnosing bovine abortion caused
by Neospora caninum in a dairy herd. J Vet Diagn Invest 1999;11:90-
94.
Uzal FA, et al. Outbreak of clostridial myocarditis in calves. Vet Rec
2003;152:134-136.
Van Rensburg IBJ. The differential diagnoses of myocarditis and myo-
cardial necrosis in puppies. J S Afr Vet Assoc 1988;59:107.
Young JK, et al. Naturally occurring Tyzzer’s disease in a puppy. Vet
Pathol 1995;32:63-65.
Diseases of the Heart
Of the features described for humans that must be  teins. There is massive loss of myocytes with fatty infiltration
absent, coronary arterial disease and systemic hypertension
may be disregarded in domestic animals because of their com-
parative rarity. In domestic animals, the diagnosis of a cardio-
myopathy rests on the absence of significant congenital or
acquired valvular or vascular abnormality, the presence of dila-
tion or hypertrophy of one or both ventricles and possibly all 4
chambers, and accompanied in some cases by diffuse fibrosis.
An additional exclusion, at least for cats, should be that of
hyperthyroidism.
Since the original definition, the term cardiomyopathy has
been used loosely to describe any abnormality of the myocar-
dium for which an etiology cannot be defined. There has also
been some attempt to classify cardiomyopathies into primary
(obscure etiology) and secondary (known systemic or etiologic
abnormalities) categories. A classification of similar style cat-
egorizes cardiomyopathies as either intrinsic or extrinsic in
cause. Under this classification, intrinsic causes are demonstra-
bly genetic or suspected to be so, whereas extrinsic cardiomy-
opathies include those of infectious, nutritional, or toxic
origin. At this stage, we prefer the categorization of cardiomyopa-
thies as either primary (of genetic or suspected genetic origin) or
secondary (of known cause other than genetic).
Great progress has been made in the understanding of
primary cardiomyopathies. Mutations in a number of genes
coding for proteins associated with cardiac contraction lead to
the development of hypertrophic cardiomyopathy in people
and gene abnormalities associated with cytoskeletal proteins or
mitochondrial enzymes lead to the development of dilated car-
diomyopathies. There is also evidence that one of the cardio-
myopathies in dogs, and a familial dilated cardiomyopathy in
people, results from a mutation in a carnitine transporter gene
causing an absolute or metabolic deficiency of carnitine and so
can be classified as primary. If the understanding of the etiology
and pathogenesis of the cardiomyopathies continues to prog-
ress, then the term cardiomyopathy may become obsolete.
Cardiomyopathies generally fall into 3 pathologic forms: (1)
dilated (congestive), (2) hypertrophic, and (3) restrictive
forms. As the clinical and pathologic patterns of the cardio-
myopathies were first described in people, a brief discussion
of the essential features in this species is warranted.
Dilated (congestive) cardiomyopathy (DCM) is a
common form in humans. The genetic basis of dilated cardio-
myopathies includes abnormalities in genes associated with
cytoskeletal proteins (such as desmin, lamin A and B) and mito-
chondrial genes, the latter leading to defects in oxidative
phosphorylation.
DCM is characterized by dysfunction of the systolic phase of
the cardiac cycle, where there is lowered force of contraction
and increased ventricular end-diastolic volume. There is
enlargement and dilation of both atria and ventricles. The
ventricles are hypertrophied, but, because of the dilation, the
hypertrophy is not as apparent as in the hypertrophic form of
the disease. Microscopically, there is variation in myocyte size,
myocyte degeneration and necrosis, and variably severe fibro-
sis. These changes are however, from a pathologist’s viewpoint,
disappointingly nonspecific.
A variant of DCM is that of arrhythmogenic right ventricular
cardiomyopathy (ARVC). ARVC is an inherited disease of
cardiac myocytes in humans that is characterized by right
ventricular failure and severe disturbances of cardiac rhythm,
including ventricular tachycardia or fibrillation. The molecular
basis of ARVC revolves around defects in desmosomal pro-
Myocardial Disease 45
and fibrosis. ARVC also occurs in dogs, especially Boxer dogs;
in cats; and in Hereford cattle.
Hypertrophic cardiomyopathy (HCM) is a diastolic rather
than a systolic ventricular disorder. The hypertrophic ventricle
is abnormally stiff (less compliant), resulting in impaired ven-
tricular filling. It is most commonly inherited as an autosomal
dominant characteristic within which there is a high preva-
lence of subclinical disease. Sudden unexpected death is often
the first manifestation of HCM. There is left, and sometimes
right, ventricular hypertrophy, reduced size of the ventricular
lumen, and dilation and often hypertrophy of the atria. The
pattern and extent of the ventricular hypertrophy varies from
localized hypertrophy of the ventricular septum (asymmetrical
septal hypertrophy), to the hypertrophy being symmetrical or
even apical in nature. Microscopically, the myocytes are hyper-
trophied, with many arranged in a whorled or disorganized
pattern. Although the disordered myocyte arrangement is not
unique to HCM, it is more severe. Fibrosis of variable severity
accompanies the hypertrophic process.
Mutations in genes that code for proteins associated with the
process of cardiac contraction have been identified in cases of
HCM. Understanding of the molecular nature of HCM in
people has progressed rapidly, providing insight into cardio-
myopathies in domestic species. Genes involved in HCM
include the cardiac troponin T gene (cTnT), the myosin heavy
chain gene (MyHC), and the cardiac myosin-binding protein C
gene (MyBPC3). The mutations in each gene appear not to be
singular in nature; for example, many mutations have been
identified in the MyBPC3 gene alone. The inherited form of
HCM is therefore a genetically diverse disease, which presents
as a common clinical and pathologic syndrome. Interestingly,
mutations of the cTnT gene can cause both DCM and HCM,
and mutation in the same codon in the cardiac troponin I
(cTnI) gene causes both HCM and RCM.
Restrictive cardiomyopathy (RCM) is characterized by
impaired ventricular filling because of reduced ventricular compli-
ance, with unimpaired systolic function. The ventricles are
usually of normal size, but both atria are usually dilated.
Reduced compliance of one or both ventricles may occur
because of interstitial or endomyocardial fibrosis with or
without eosinophilia of the ventricles. Restrictive cardiomy-
opathy may also result from the deposition of amyloid
or occur in association with the disease sarcoidosis. These
infiltrative cardiomyopathies are, strictly speaking, secondary
cardiomyopathies.
The endomyocardial form of human RCM is subdivided
into 2 major forms: Loeffler endomyocarditis occurs predomi-
nantly in temperate climates; endomyocardial fibrosis is most
common in equatorial Africa. Although the end-stage of both
forms is pathologically indistinguishable, the natural history
and clinical patterns are quite separable. The Loeffler (hypere-
osinophilic) variant principally affects males and is associated
with hypereosinophilia, thromboembolism, and arteritis. In
endomyocardial fibrosis, there is no male predominance, and
it occurs in younger patients with no accompanying eosino-
philia. At least for the Loeffler variant, endomyocardial fibrosis
results from release of granules from infiltrating eosinophils in
the earlier phase of the disease.
The major features of the primary cardiomyopathies are
depicted in eFigure 1-10. Cardiomyopathies occurring in
domestic animals have been similarly classified and have been
documented in cats, dogs, cattle, and pigs.
 45.e1

Classification of primary cardiomyopathies

Hypertrophic cardiomyopathy Dilated [congestive] Restrictive [infiltrative]

Hypertrophic ventricle
Diastolic disorder-reduced compliance
Restricted ventricular filling
Many have genetic basis associated with
mutations in contractile proteins-myosin/
cardiac troponin T/cardiac myosin binding protein
cardiomyopathy
Dilated ventricle
Systolic dysfunction-decreased contractility
Many have a genetic basis
Mutations in genes associated with
cytoskeletal proteins and mitochondria
Cardiomyopathy
Diastolic disorder
Restriction of ventricular filling
Severe endomyocardial fibrosis

eFigure 1-10  Major features of primary cardiomyopathies.

46 CHAPTER 1  •  Cardiovascular System
Further reading
Amat di San Filippo C, et al. Cardiomyopathy and carnitine deficiency.
Mol Genet Metab 2008;94:162-166.
Gomes AV, Potter JD. Molecular and cellular aspects of troponin car-
diomyopathies. Ann N Y Acad Sci 2004;1015:214-224.
Hare JM. The dilated, restrictive and infiltrative cardiomyopathies. In:
Bonow RO, et al., editors. Braunwald’s Heart Disease: A Textbook
of Cardiovascular Medicine. 9th ed. Philadelphia: Elsevier Saunders;
2012. p. 1561-1581.
Maron BJ. Hypertrophic cardiomyopathy. In: Bonow RO, et al., editors.
Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine.
9th ed. Philadelphia: Elsevier Saunders; 2012. p. 1582-1594.
Nout YS, et al. Cardiac amyloidosis in a horse. J Vet Intern Med
2003;17:588-592.
Schoen FJ, Mitchell RN. The heart. In: Kumar VK, et al., editors. Robbins
and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia:
Saunders Elsevier; 2010. p. 529-587.
Feline cardiomyopathies
Feline cardiomyopathies constitute a well-recognized, but diverse,
group of morphologic and functional disorders (eFig. 1-11).
Echocardiography is the definitive test used clinically to dif-
ferentiate and classify feline cardiomyopathies. Hypertrophic
cardiomyopathy is most commonly encountered (58%), fol-
lowed by restrictive (21%), dilated (10%), unclassified (10%),
and excessive left ventricular moderator band (<1%) cardio-
myopathies. Although feline cardiomyopathy was only recog-
nized as an entity in the relatively recent past, a common
consequence of cardiomyopathy, iliac thromboembolism, was
originally described >70 years ago. There is a wide range in
the age of onset of clinical signs, from 7 months to 24 years
of age. Presenting clinical signs include lethargy, anorexia,
dyspnea, tachypnea, and occasionally abdominal distension.
Murmurs, most often associated with mitral or tricuspid insuf-
ficiency, gallop rhythms, and dysrhythmias of various types are
frequently encountered. Approximately 13 of cats with car-
diomyopathy develop unilateral or bilateral thromboembolic
hindlimb ischemia. The causes of feline cardiomyopathy
include genetic and nutritional origins, and a possible role for
viral infection following the detection by PCR of feline pan-
leukopenia virus genome in cats with idiopathic hypertrophic,
dilated, and restrictive cardiomyopathies and myocarditis.
Hypertrophic cardiomyopathy, the most common form of
cardiomyopathy in cats, is a diastolic disorder, resulting from
ventricular myocardial hypertrophy in the absence of an
obvious cause. There is normal or near-normal systolic myo-
cardial function, but diminished capacity to accept diastolic
flow from the left atrium. Left ventricular volume is normal
or decreased, and the papillary muscles are usually greatly
enlarged in relation to the volume of the ventricle. The left
atrium is usually dilated.
It is inherited as an autosomal dominant trait in Maine
Coon and Ragdoll cats, the basis of which appear to be muta-
tions in the gene coding for myosin binding protein C3, a
defect also described in hypertrophic cardiomyopathy in
people. Similar and additional mutations in genes coding for
contractile genes are likely in other breeds, including the Sibe-
rian, Sphynx, Bengal, Chartreux, and Norwegian Forest cats.
The gross pathologic features of feline HCM include an
enlarged heart, with comparatively massive symmetrical con-
centric hypertrophy of both ventricles in the majority of cases,
Myocardial Disease
but especially notable for the left ventricle (Fig. 1-51A). The
left ventricular lumen is often slit-like. Some cases have asym-
metrical hypertrophy of the left ventricle, with the ventricular
septum thicker than the left ventricular free wall. Findings of
lesser frequency include atrial thrombi, focal areas of ventricu-
lar fibrosis, and fibrosis of the endocardium in the region of
the left ventricular outflow tract.
Microscopically, myofibers are hypertrophied and contain
vesicular nuclei. Myofiber disarray, characterized by inter-
weaving of myofibers in the left ventricular free wall and
ventricular septum, may be observed (Fig. 1-51B). This may
also be present in the right ventricle. Extensive interstitial fibro-
sis is also a consistent feature (Fig. 1-51C), especially in the
inner 2 3 of the left ventricular free wall. Scattered focal areas
of dense replacement fibrosis are seen in a minority of cats.
As indicated by increased plasma cTnI concentrations, cats
with moderate to severe HCM have ongoing myocardial
damage, which may be the stimulus for replacement fibrosis.
Focal endocardial thickening by fibrosis also occurs commonly.
Intramyocardial arteries may have medial hypertrophy, and
scattered perivascular accumulations of lymphocytes and
monocytes may be present.
Ultrastructurally, the hypertrophied myofibers have large
pleomorphic nuclei with undulating surfaces and prominent
nucleoli. Dense accumulations of Z-band material are also
evident in myocytes, as is the presence of lipofuscin granules.
Although these changes are seen in normal cat myocytes, the
intensity of the changes is greater in cardiomyopathic cases. 
A concentrically hypertrophied heart also occurs in cats 
with hyperthyroidism, and this should not be confused with
hypertrophic cardiomyopathy (see Cardiac hypertrophy,
previously).
Restrictive cardiomyopathy is a less common and less well-
defined form of feline cardiomyopathy and is characterized by
impaired diastolic ventricular filling, which may be due to
severe endomyocardial fibrosis. Systolic function is usually
normal. Feline RCM has also been termed “left ventricular
endocardial fibrosis” (LVEF). Endomyocarditis may be an ante-
cedent to LVEF. Feline RCM occurs predominantly in older
cats with clinical signs of left-sided or bilateral heart failure.
Cardiac murmurs and dysrhythmias are common. Pathologic
features include severe endocardial thickening with mural
thrombosis. Left atrial enlargement is marked, the result of the
restriction of ventricular filling. The left ventricle is thickened,
and the lumen volume may be significantly diminished.
Microscopically, the myocardium and endocardium may be
replaced by granulation tissue of various ages; adjacent myo-
cardium may be infiltrated by histiocytes, lymphocytes, and
plasma cells. Bartonella infection has been suggested as a pos-
sible cause of feline endomyocarditis. RCM has also been
reported in cats with hypereosinophilic syndrome.
Dilated cardiomyopathy has decreased markedly in pre­
valence since the discovery of taurine-deficiency myocardial
failure in cats. On postmortem, all chambers of the heart are
enlarged, and the ventricles are dilated and flabby with thinned
walls (Fig. 1-52). The endocardium may be pale and slightly
thickened by subendocardial fibrosis. The papillary muscles
and trabeculae may be atrophied and appear small in relation
to the ventricular volume. Often only minor lesions are found
on microscopy. Myocardial fibers are moderately hypertro-
phied, accompanied by mild diffuse interstitial fibrosis. There
may also be focal areas of myofiber loss with replacement
fibrosis. In some cases, there may be extensive areas of 
 46.e1

Further reading
Anan R, et al. Patients with familial hypertrophic cardiomyopathy
caused by a Phe110Ile missense mutation in the cardiac troponin T
gene have variable cardiac morphologies and a favorable prognosis.
Circulation 1998;98:391-397.
Dai KS, et al. Intramural coronary arterial disease in swine with natu-
rally occurring hypertrophic cardiomyopathy. J Submicrosc Cytol
Pathol 1997;29:511-519.
Hughes SE. The pathology of hypertrophic cardiomyopathy. Histopa-
thology 2004;44:412-427.
Kushwaha SS, et al. Restrictive cardiomyopathy. N Engl J Med
1997;336:267-276.
Liu SK, et al. Comparison of morphologic findings in spontaneously
occurring hypertrophic cardiomyopathy in humans, cats and dogs.
Am J Cardiol 1993;72:944-951.
Marian AJ, Roberts R. Molecular genetics of hypertrophic cardiomy-
opathy. Annu Rev Med 1995;46:213-222.
Moolman-Smook JC, et al. Identification of a new missense mutation
in MyBP-C associated with hypertrophic cardiomyopathy. J Med
Genet 1998;35:253-254.
Sauramura A, et al. Taurine modulates ion influx through cardiac
calcium channels. Cell Calcium 1990;11:251-259.
Sisson DD, Thomas WP. Myocardial diseases. In: Ettinger SJ, Feldman
EC, editors. Textbook of Veterinary Internal Medicine: Diseases of
the Dog and Cat. 7th ed. Philadelphia: WB Saunders; 1995.
p. 995-1031.
Yu B, et al. Molecular pathology of familial hypertrophic cardiomyopa-
thy caused by mutations in the cardiac myosin binding protein C
gene. J Med Genet 1998;35:205-210.
46.e2

Dilated
Taurine deficiency*
Systolic Dysfunction
Depressed contractility
Ventricles flabby/dilated.

Hypertrophic
Diastolic disorder-
decreased compliance
Concentric hypertrophy Restrictive
Autosomal dominant Feline Severe endomyocardial
in some breeds Cardiomyopathies fibrosis
Mutations in myosin Impaired diastolic filling
binding protein C
Myofiber disarray,
interstitial fibrosis

Excessive moderator
bands
Moderator bands enlarged
Probably a congential
defect rather than
a true primary
cardiomyopathy

eFigure 1-11  Major features of feline cardiomyopathies. Dilation resulting from taurine deficiency
is not technically a cardiomyopathy because of the known etiology.*
Diseases of the Heart
A bers. Ultrastructural examination contributes little to the
B a congenital defect that is only manifest later in life. Affected cats
C may be found. Microscopically, the abnormal moderator bands
Figure 1-51  Feline hypertrophic cardiomyopathy. A. Symmetri-
cal hypertrophic cardiomyopathy with increased thickness of the
left ventricular free wall and interventricular septum. (Courtesy
I. Matise.) B. Focal area of cardiac myofiber disarray. C. Extensive
replacement fibrosis (blue) of cardiac myocytes (red). Masson
trichrome.
Myocardial Disease 47
Figure 1-52  Feline dilated cardiomyopathy. Chamber of left
ventricle markedly increased in volume accompanied by thinned
ventricular walls. (Courtesy A. Wuenschmann.)
myocardial fibrosis. There is no significant disarray of myofi-
understanding of the pathologic picture.
An ARVC-like syndrome occurs in cats, where prominent
clinical features include supraventricular and ventricular
arrhythmias, marked enlargement of the right ventricle and
atrium, and right-sided congestive heart failure, Gross lesions
include right ventricular luminal dilation, wall thinning, and
apical aneurysm. Microscopically, the ventricles, especially the
right ventricle, have myocarditis, myocyte necrosis, myocyte
atrophy, fibrosis, and fatty replacement.
Excessive moderator bands (false tendons) in the left ven-
tricle bridging the ventricular septum and free wall and entan-
gling the papillary muscles are associated with heart failure
and death in cats. Although not strictly a cardiomyopathy, it
is considered under the heading of cardiomyopathies as the
clinical syndrome occurs in mature cats. In all probability, it is
exhibit a range of clinical signs that are mostly referable to
left-sided heart failure. They include lethargy, dyspnea,
anorexia, pale mucous membranes, and cardiac murmurs.
Radiographic findings include cardiomegaly, hydrothorax, 
and pulmonary edema. Various conduction disturbances also
occur.
Gross changes are dominated by the presence of numerous
pink-white bands spanning the left ventricular lumen and
papillary muscles. Most commonly, the bands connect the
cranial and caudal papillary muscles to the ventricular septum.
In others, the bands insert between the ventricular septum
and the left ventricular free wall. The left ventricle may be
dilated or show increased wall thickness. In neither case is the
heart weight significantly different from that of normal cats.
The left atrium is enlarged, and pulmonary edema, pleural
effusion, hepatic congestion, and aortic thromboembolism
consist of Purkinje cells and dense, mature collagen covered
by endothelium. Loose fibrous connective tissue is present
between the endothelium and the dense collagen, with the
variation in size of the moderator bands the result of more or
less mature collagen. Ventricular alterations include myocyte
atrophy or hypertrophy, focal fibrosis, and intramural coronary
arterial luminal narrowing, intimal thickening, medial hyper-
plasia, and perivascular fibrosis.
48 CHAPTER 1  •  Cardiovascular System Myocardial Disease

Canine DCM has the clinical features of a short history of

Further reading
Ferasin L, et al. Feline idiopathic cardiomyopathy: a retrospective study
of 106 cats (1994-2001). J Feline Med Surg 2003;5:151-159.
Fox PR, et al. Spontaneously occurring arrhythmogenic right ventricular
cardiomyopathy in the domestic cat: a new animal model similar
to the human disease. Circulation 2000;102:1863-1870.
Godiksen MT, et al. Hypertrophic cardiomyopathy in young Maine
Coon cats caused by the p.A31P cMyBP-C mutation—the clinical
significance of having the mutation. Acta Vet Scand 2011;9:
53-57.
Kershaw O, et al. Diagnostic value of morphometry in feline hypertro-
phic cardiomyopathy. J Comp Pathol 2012;147:73-83.
Longeri M, et al. Myosin-binding protein C DNA variants in domestic
cats (A31P, A74T, R820W) and their association with hypertrophic
cardiomyopathy. J Vet Intern Med 2013;27:275-285.
Payne JR, et al. Prognostic indicators in cats with hypertrophic cardio-
myopathy. J Vet Intern Med 2013;27:1427-1436.
Ripoll VT, et al. The R820W mutation in the MYBPC3 gene, associated
with hypertrophic cardiomyopathy in cats, causes hypertrophic car-
diomyopathy and left ventricular non-compaction in humans. Int J
Cardiol 2010;145:405-407.
Trehiou-Sechi E, et al. Comparative echocardiographic and clinical fea-
tures of hypertrophic cardiomyopathy in 5 breeds of cats: a retro-
spective analysis of 344 cases (2001-2011). J Vet Intern Med
2012;26:532-541.
cough, depression, dyspnea, weight loss, syncope, and polydip-
sia, or may occur without premonitory signs as sudden death.
Clinical signs are often referable to left-sided congestive heart
failure and hence pulmonary edema, or may be due to biven-
tricular failure and include ascites. Soft systolic murmurs,
indicative of left atrioventricular (LAV) or right atrioventricu-
lar (RAV) valvular insufficiency, may be heard on auscultation.
Atrial fibrillation is the most common electrocardiographic
abnormality; ventricular tachycardia and ventricular prema-
ture contractions are common in most Doberman Pinschers
with DCM. Echocardiographically, there is cardiomegaly, with
increased end-diastolic volume and poor contractile function.
The prognosis is poor, with mean survival times of 6-12 months
after the onset of treatment.
Autopsy findings in typically affected cases are those of
congestive heart failure. All chambers, particularly the left ven-
tricle, are markedly dilated and may be hypertrophied. The
AV rings are dilated (Fig. 1-53A), the endocardium may be
opaque due to subendocardial fibrosis, and there may be atrial
thrombosis. There may also be some evidence of infarction in

Canine cardiomyopathies
The most commonly recognized is dilated cardiomyopathy
(DCM), especially in young to middle-aged giant and large-
breed dogs, such as the St. Bernard, Irish Wolfhound, Estrela
Mountain dogs, and Great Dane, but also afflicting an ever-
growing list of other breeds, including Airedale Terriers,
Boxers, Doberman Pinschers, English Cocker Spaniels, 
Newfoundlands, Portuguese Water dogs, Presa Canario dogs,
Standard Poodles, and Toy Manchester Terriers. The major
features of the disease are depicted in eFigure 1-12.
Although the causes of canine DCM are still mostly unknown,
it is increasingly apparent that most have a genetic basis, but as
yet, no abnormalities in myocardial cytoskeletal genes have been
identified as they have been in human dilated cardiomyopathy. A
There is a familial tendency in the Doberman Pinscher, English
Cocker Spaniel, Boxer, Great Dane, Irish Wolfhound, and
Newfoundland; DCM may be an X-linked recessive trait in
Great Danes. Infantile dilated cardiomyopathy is inherited in
Portuguese Water dogs as an autosomal recessive trait. There
is a strong association between the presence of cardiomyopa-
thy and a particular complement C4 phenotype (C4:4) in the
English Cocker Spaniel. This is not suggested to be causal, but
to indicate a genotype that is predisposed to the development
of the disease. A singular finding is that of a deficiency in the
mitochondrial respiratory chain in affected Doberman Pin-
schers, which has its origin in a 16-bp deletion in the pyruvate
dehydrogenase kinase 4 (PDK4) gene on chromosome 14.
Carnitine deficiency may play a role in some subtypes of
cardiomyopathy, although the evidence is not strong. Low
blood taurine concentrations have also been found in dogs B
with DCM that had been fed certain lamb-rice commercial
diets. The DCM in Portuguese Water dogs can be reversed in Figure 1-53  Canine dilated cardiomyopathy. A. Dilated left ven-
some pups by oral taurine supplementation. Hypothyroidism tricular lumen accompanied by thinning of the left ventricular
has been noted as a reversible cause of myocardial failure in free wall and interventricular septum. B. Thin, wavy cardiac myo-
2 Great Danes. cytes often seen in dilated cardiomyopathies. (Courtesy E. Olson.)
 48.e1

Further reading
Baty CJ, et al. Natural history of hypertrophic cardiomyopathy and
aortic thromboembolism in a family of domestic shorthair cats.
J Vet Intern Med 2001;15:595-599.
Bond BR, et al. Echocardiographic findings in 103 cats with hyperthy-
roidism. J Am Vet Med Assoc 1988;192:1546-1549.
Fox PR, et al. Echocardiographic assessment of spontaneously occur-
ring feline hypertrophic cardiomyopathy. An animal model of
human disease. Circulation 1995;92:2645-2651.
Herndon WE, et al. Cardiac troponin I in feline hypertrophic cardiomy-
opathy. J Vet Intern Med 2002;16:558-564.
Liu SK, et al. Excessive moderator bands in the left ventricle of 21 cats.
J Am Vet Med Assoc 1982;180:1215-1219.
Liu SK, et al. Hypertrophic cardiomyopathy and hyperthyroidism in the
cat. J Am Vet Med Assoc 1984;185:52-57.
Meurs KM, et al. Molecular screening by polymerase chain reaction
detects panleukopenia virus DNA in formalin-fixed hearts from cats
with idiopathic cardiomyopathy and myocarditis. Cardiovasc Pathol
2000;9:119-126.
Nakagawa K, et al. Hypertrophic cardiomyopathy in a mixed breed cat
family. J Vet Med Sci 2002;64:619-621.
Pion PD, et al. Myocardial failure in cats associated with low plasma
taurine: a reversible cardiomyopathy. Science 1987;237:764-768.
Saxon B, et al. Restrictive cardiomyopathy in a cat with hypereosino-
philic syndrome. Can Vet J 1991;32:367-369.
Stalis IH, et al. Feline endomyocarditis and left ventricular endocardial
fibrosis. Vet Pathol 1995;32:122-126.
Taugner FM. Stimulation of the renin-angiotensin system in cats with
hypertrophic cardiomyopathy. J Comp Pathol 2001;125:122-129.
Van Vleet JF, et al. Pathologic alterations in hypertrophic and conges-
tive cardiomyopathy of cats. Am J Vet Res 1980;41:2037-2048.
48.e2

Breed association/inheritance Histopathology

Giant breeds and Airdale, Boxer, Two major types
Doberman, Standard Poodle 1. Fatty infiltration/degenerative type
Autosomal recessive in 2. Attenuated wavy fiber type
Portugese water dogs May see both forms in the one breed

Boxer cardiomyopathy
Arrhythmogenic Right Ventricular
Cardiomyopathy (AVRC)
Autosomal dominant [incomplete
penetrance]: 8bp deletion in striatin
gene on chromosome 17
Striatin colocates with 3
desmosomal proteins
Doberman cardiomyopathy
16bp deletion in pyruvate
Canine dilated dehydrogenase kinase
cardiomyopathies 4[PDK4]gene on chromosome
14 leading to mitochondral abnormalities
and lipofuscin accumulation

eFigure 1-12  Types of cardiomyopathies in dogs.

Diseases of the Heart
distant organs. The finding, in some cases, of multifocal myo-
cardial degeneration, necrosis, or fibrosis is expected, but  dogs is encouraging. Striatin co-localizes in the region of the
unrewarding, with regard to possible causes. Ultrastructural
examination of myocardium from cases of dilated cardiomy-
opathy shows increases in intermyofibrillar spaces, lipofuscin
granules, fat droplets and myelin figures, mitochondrial hyper-
plasia, disruption of myofibrils, and Z-band thickening. These
ultrastructural changes are not specific for cardiomyopathy,
but are more severe than seen with other causes of congestive
heart failure.
There appear to be 2 histologically distinct forms of DCM:
(1) the “fatty infiltration–degenerative” type seen, for example,
in Boxers and Doberman Pinschers, and (2) the “attenuated
wavy fiber” type seen in many giant-, large-, and medium-sized
breeds, including some Boxers and Doberman Pinschers (Fig.
1-53B). This histologic classification of canine DCM may be
superior to classification by breed-specific syndromes, because
both forms may affect some breeds, such as Boxers and  humans, affected and carrier dogs develop Duchenne cardio-
Doberman Pinschers. This postmortem classification does not
however assist antemortem etiologic diagnosis of DCM.
A variant of DCM is arrhythmogenic right ventricular
cardiomyopathy (ARVC), a primary familial myocardial
disease in humans and in Boxer dogs that is associated with
cardiovascular morbidity and risk of sudden death. It is trans-
mitted as an autosomal dominant trait in humans and Boxers.
ARVC in Boxers is characterized by various events, alone or
in combination, including ventricular arrhythmias of sus-
pected right ventricular (RV) origin, syncope, heart failure,
and/or sudden death. Right ventricular dilation or aneurysms
are common. Histopathologic findings include severe myocyte
loss in the RV, with replacement by adipose or fibroadipose
tissue (Fig. 1-54). Focal fibroadipose lesions may also be
present in both atria and in the left ventricle (LV). Myocarditis
may be present in the RV and LV in dogs that have died sud-
denly and may be the source of arrhythmias.
ARVC is an ion channel defect in humans, with mutations
in genes coding for protein constituents of the special junc-
tions and some nondesmosomal proteins. Mutations identified
include those coding for desmocollin-2, desmoplakin and pla-
kophilin, ryanodine receptor 2, desmin, lamins A and C, titin,
and striatin. The recent discovery of an 8-bp deletion in the
Figure 1-54  Arrhythmogenic right ventricular cardiomyopathy
in a Boxer dog. Note the extensive, cardiac myocyte replacement
by adipose tissue. (Courtesy E. Olson.)
Myocardial Disease 49
striatin gene located on chromosome 17 in affected Boxer
intercalated disc with 3 desmosomal proteins. Recent evi-
dence also shows that dysfunction in the Wnt/β-catenin
pathway is involved where there is mislocalization of 
β-catenin and striatin and an increase in the total amount of
β-catenin in Boxer dogs with ARVC.
Hypertrophic cardiomyopathy is much less common than
the dilated form. Associated clinical syndromes include sudden
death, death during anesthesia, and congestive heart failure.
Disproportionate thickening of the ventricular septum may
cause the ratio of the interventricular wall thickness to left
ventricular free wall thickness to exceed 1.2:1, and there may
be histologic evidence of myofiber disarray in the ventricular
septum.
In canine X-linked muscular dystrophy in Golden Retriev-
ers, an animal model for Duchenne muscular dystrophy in
myopathy characterized by myocardial interstitial, especially
subepicardial, fibrosis, leading to cardiac insufficiency.
Further reading
Bélanger MC, et al. Taurine-deficient dilated cardiomyopathy in a
family of golden retrievers. J Am Anim Hosp Assoc 2005;41:284-
291.
Delmar M, et al. The cardiac desmosome and arrhythmogenic
cardiomyopathies: from gene to disease. Circ Res 2010;107:
700-714.
Everett RM, et al. Dilated cardiomyopathy of Doberman pinschers:
retrospective histomorphologic evaluation of heart from 32 cases.
Vet Pathol 1999;36:221-227.
Legge CH, et al. Histological characterization of dilated cardiomyopa-
thy in the juvenile toy Manchester terrier. Vet Pathol 2013;50:1043-
1052.
Lobo L, et al. Histologic characterization of dilated cardiomyopathy in
Estrela Mountain Dogs. Vet Pathol 2010;47:637-642.
Meurs KM, et al. A splice site mutation in a gene encoding for PDK4,
a mitochondrial protein, is associated with the development of
dilated cardiomyopathy in the Doberman pinscher. Hum Genet
2012;131:1319-1325.
Muers KM, et al. Association of dilated cardiomyopathy with striatin
mutation genotype in Boxer dogs. J Vet Intern Med 2013;27:1437-
1440.
O’Sullivan ML, et al. Evaluation of 10 genes encoding cardiac proteins
in Doberman Pinschers with dilated cardiomyopathy. Am J Vet Res
2011;72:932-939.
Oxford EM, et al. Change in β-catenin localization suggests involve-
ment of the canonical Wnt pathway in Boxer dogs with arrhyth-
mogenic right ventricular cardiomyopathy. J Vet Intern Med
2014;28:92-101.
Ricklet S, Pieperhoff S. Mutations with pathogenic potential in proteins
located in or at the composite junctions of the intercalated disk
connecting mammalian cardiomyocytes: a reference thesaurus for
arrhythmogenic cardiomyopathies and for Naxos and Carvajal dis-
eases. Cell Tissue Res 2012;348:325-333.
Vollmar A, et al. Dilated cardiomyopathy in juvenile doberman pin-
schers. J Vet Cardiol. 2003;5:23-27.
Werner P, et al. A novel locus for dilated cardiomyopathy maps to
canine chromosome 8. Genomics 2008;91:517-521.
Wiersma AC, et al. Evaluation of 15 candidate genes for dilated car-
diomyopathy in the Newfoundland dog. J Hered 2008;99:73-80.
 49.e1

Tidholm A, et al. Canine idiopathic dilated cardiomyopathy: I. Aetiol-

Further reading ogy, clinical characteristics, epidemiology and pathology. Vet J
Alroy J, et al. Inherited infantile dilated cardiomyopathy in dogs: 2001;162:92-107.
genetic, clinical, biochemical, and morphologic findings. Am J Med Tidholm A, Jonsson L. Histologic characteristics of canine dilated car-
Genet 2000;95:57-66. diomyopathy. Vet Path 2005;42:1-8.
Basso C, et al. Arrhythmogenic right ventricular cardiomyopathy Thomas RE. Congestive cardiac failure in young Cocker Spaniels (a form
causing sudden cardiac death in boxer dogs: a new animal model of cardiomyopathy?): details of eight cases. J Small Anim Pract
of human disease. Circulation 2004;109:1180-1185. 1987;28:265-279.
Biesiadecki BJ, et al. Cardiac troponin T variants produced by aberrant Vollmar AC. The prevalence of cardiomyopathy in the Irish wolfhound:
splicing of multiple exons in animals with high instances of dilated a clinical study of 500 dogs. J Am Anim Hosp Assoc 2000;36:
cardiomyopathy. J Biol Chem 2002;277:50275-50285. 125-132.
Bishop L. Ultrastructural investigations of cardiomyopathy in the dog.
J Comp Pathol 1986;96:685-698.
Borgarelli M, et al. Canine idiopathic dilated cardiomyopathy: II. Patho-
physiology and therapy. Vet J 2001;162:182-195.
Calvert CA. Dilated congestive cardiomyopathy in Doberman pinschers.
Compend Contin Educ Pract Vet 1986;8:417-430.
Day MJ. Inheritance of serum autoantibody, reduced serum IgA and
autoimmune disease in a canine breeding colony. Vet Immunol
Immunopathol 1996;53:207-219.
Fascetti AJ, et al. Taurine deficiency in dogs with dilated cardiomyopa-
thy: 12 cases (1997-2001). J Am Vet Med Assoc 2003;223:1137-
1141.
Fernandez del Palacio MJ, et al. Arrhythmogenic right ventricular
dysplasia/cardiomyopathy in a Siberian husky. J Small Anim Pract
2001;42:137-142.
Gilbert SJ, et al. Increased expression of promatrix metalloproteinase-9
and neutrophil elastase in canine dilated cardiomyopathy. Cardio-
vasc Res 1997;34:377-383.
Gooding JP, et al. Echocardiographic characterization of dilated cardio-
myopathy in the English cocker spaniel. Am J Vet Res 1986;47:1978-
1983.
Keene BL, et al. Myocardial L-carnitine deficiency in a family of dogs
with dilated cardiomyopathy. J Am Vet Med Assoc 1991;98:647-
650.
Liu SK, et al. Hypertrophic cardiomyopathy in the dog. Am J Pathol
1979;94:497-508.
McCutcheon LJ, et al. Respiratory chain defect of myocardial mito-
chondria in idiopathic dilated cardiomyopathy of Doberman pin-
scher dogs. Can J Physiol Pharmacol 1992;70:1529-1533.
Meurs KM, et al. Clinical features of dilated cardiomyopathy in Great
Danes and results of a pedigree analysis: 17 cases (1990-2000).
J Am Vet Med Assoc 2001;218:729-732.
Meurs KM, et al. Genome-wide association identifies a deletion in the
3′ untranslated region of striatin in a canine model of arrhythmo-
genic right ventricular cardiomyopathy. Hum Genet 2010;128:315-
324.
Moise NS, et al. Duchenne’s cardiomyopathy in a canine model: elec-
trocardiographic and echocardiographic studies. J Am Coll Cardiol
1991;17:812-820.
Morales M, et al. Dilated cardiomyopathy in Presa canario dogs: ECG
findings. J Vet Med A Physiol Pathol Clin Med 2001;48:577-580.
Oxford EM, et al. Ultrastructural changes in cardiac myocytes from
Boxer dogs with arrhythmogenic right ventricular cardiomyopathy.
J Vet Cardiol 2011;13:101-113.
Phillips DE, Harkin KR. Hypothyroidism and myocardial failure in two
Great Danes. J Am Anim Hosp Assoc 2003;39:133-137.
Sandusky GE Jr, et al. Histological and ultrastructural evaluation of
cardiac lesions in idiopathic cardiomyopathy in dogs. Can J Comp
Med 1984;48:81-86.
Sleeper MM, et al. Dilated cardiomyopathy in juvenile Portuguese
water dogs. J Vet Intern Med 2002;16:52-62.
50 CHAPTER 1  •  Cardiovascular System Myocardial Disease

Bovine cardiomyopathies†
Several syndromes of cardiomyopathy are recorded in cattle.
Dilated cardiomyopathy occurs in Holsteins in many countries,
including Canada, Australia, and Japan, and in Simmental-Red
Holstein crossbreds in Switzerland. Many of the cases emanate
from common sires, and an autosomal recessive mode of
inheritance has been suggested. A nonsense mutation in the
optic atrophy 3 (OPA3) gene on chromosome 18 is present
in affected Red Holstein cattle. OPA3 is located on the mito-
chondrial membrane, and mutations lead to disruption of
mitochondrial morphology, and presumably, mitochondrial
dysfunction. OPA3 mutations are also involved in the devel-
opment of optic atrophy, cataracts, and neurologic disorders.
The cardiomyopathy occurs in young adult to mature animals, A
with the clinical signs particularly referable to right-sided
heart failure, including dependent subcutaneous edema,
hydrothorax, ascites, and severe hepatic congestion. There is
no indication of the presence of electrocardiographic abnor-
malities. The heart is enlarged with dilation of both ventricles.
Microscopically, there is a mixture of atrophied and hypertro-
phied myofibers with vacuolation, and there are islands of
interstitial and replacement fibrosis, fatty replacement, and
ongoing myofiber necrosis.
Dilated cardiomyopathy in Japanese black calves is con-
sidered to be inherited as an autosomal recessive trait. Sudden
death or death after a short period of severe dyspnea occurs
in calves younger than 30 days. Lesions found at autopsy
include marked cardiac enlargement with left ventricular 
dilation, hydropericardium, hydrothorax, ascites, pulmonary
edema, and hepatic and splenic congestion. Extensive myo- B
cardial degeneration and necrosis with fibrosis are present in
the left ventricle, particularly affecting the papillary muscles.
The right ventricle is similarly but less often involved. The
clinical and pathologic pattern is reminiscent of that seen in
Hereford calves with cardiomyopathy.
A cardiomyopathy associated with a tightly curled
(“woolly”) haircoat in polled and horned Herefords has also
been described. This cardiocutaneous syndrome is inherited
as an autosomal recessive trait and is now known to be caused
by a 7-bp duplication in the NF kappaB interacting protein 1
gene on chromosome 18. In contrast, similar human cardio-
cutaneous diseases, such as Naxos disease and Carvajal syn-
drome, are caused by mutations in genes encoding proteins
associated with composite intercellular junctions.
Affected animals are identifiable at birth by their distinc- C
tive haircoat and signs of cardiac dysfunction, including Figure 1-55  Cardiomyopathy and woolly haircoat syndrome in
arrhythmias. Some calves develop bilateral ocular keratitis Hereford calves. A. Extensive subepicardial fibrosis of the right
immediately after birth. Most calves are found dead at <12 ventricle in a 7-day-old calf. B. Severe myocardial necrosis, min-
weeks of age. Occasionally, calves are seen to collapse and die eralization, and fibrosis of both ventricles in a 5-day-old calf. 
following exertion. Even in some calves that die at 1 week of C. Extensive subepicardial myocyte loss with replacement fibrosis
age, there are severe lesions in the ventricles consisting of in a 17-day-old calf. Masson trichrome. (Courtesy R.W. Cook.)
necrosis, mineralization, and fibrosis of the myocardium, and
are detectable at birth, an indication of their in utero onset
(Fig. 1-55A-C). heart failure, and in these, the heart is eccentrically
Hypertrophic cardiomyopathy has been reported in hypertrophied.
Holsteins.
Bovine generalized glycogenosis type II (Pompe’s disease),
although not a primary cardiomyopathy, deserves mention. Further reading
Most affected animals have generalized muscle weakness. Furuoka H, et al. Hereditary dilated cardiomyopathy in Holstein-Friesian
Occasional cases, however, exhibit clinical signs of left-sided cattle in Japan: association with hereditary myopathy of the dia-
phragmatic muscles. J Comp Pathol 2001;125:159-165.
†
Contribution to this section by Dr. R. Cook is gratefully Nart P, et al. Morphometry of bovine dilated cardiomyopathy. J Comp
acknowledged. Pathol 2004;130:235-245.
 50.e1

Further reading
Bradley R, et al. Cardiomyopathy in adult Holstein Friesian cattle in
Britain. J Comp Pathol 1991;104:101-112.
Dolf G, et al. Evidence for autosomal recessive inheritance of a major
gene for bovine dilated cardiomyopathy. J Anim Sci 1998;76:1824-
1829.
Machida N, et al. Two necropsy cases of hypertrophic cardiomyopathy
in Holstein cattle. J Vet Med Sci 1996;58:929-932.
Storie GJ, et al. Cardiomyopathy and wooly haircoat syndrome of
Hereford cattle. Aust Vet J 1991;68:119.
Watanabe S, et al. Evidence for a new lethal gene causing cardiomy-
opathy in Japanese black calves. J Heredity 1979;70:255-258.
Weekes J, et al. Bovine dilated cardiomyopathy: proteomic analysis of
an animal model of human dilated cardiomyopathy. Electrophoresis
1999;20:898-906.
Diseases of the Heart
Owczarek-Lipska M, et al. A nonsense mutation in the optic atrophy
3 gene (OPA3) causes dilated cardiomyopathy in Red Holstein
cattle. Genomics 2011;97:51-57.
Simpson MA, et al. A mutation in NFkappaB interacting protein 1
causes cardiomyopathy and woolly haircoat syndrome of Poll Her-
eford cattle. Anim Genet 2009;40:42-46.
DISEASES OF THE CONDUCTION SYSTEM
The clinical and electrocardiographic features of primary con-
duction system disturbances are well documented, but com-
paratively rare. The clinical signs are primarily intermittent
collapse, and sometimes sudden death. Electrocardiography
may show a variety of abnormalities, such as sinoatrial  persistent atrial standstill, which occurs in dogs (most com-
arrest, second- or third-degree atrioventricular (AV) block,  monly in English Springer Spaniels) and has been described in
AV dissociation, left or right bundle branch block, Wolff-
Parkinson-White syndrome (rarely), and ventricular tachycar-
dia. It should not be forgotten that many if not most
dysrhythmias are secondary to more or less extensive myocardial
degeneration, necrosis, inflammation, or neoplasia, particularly
when in close proximity to the conduction system.
In contrast, reports on the gross and microscopic examination
of cases of primary conduction system disturbances are remark-
ably sparse. This may be due in part to negative pathologic
findings in some cases, or to time and effort required to ade-
quately examine the conduction system. When an abnormal-
ity of the conduction system is suspected, tissue samples from
the appropriate regions should be collected as part of the
postmortem (see Examination of the heart, previously). The
use of special stains such as Masson trichrome and phospho-
tungstic acid hematoxylin (PTAH) assist in highlighting the
presence of excessive fibrosis and the relative paucity of con-
tractile elements in the cells of the conduction system, respec-
tively. For purposes of comparison, it is advisable to have a
reference set of blocks of the conduction system from normal
animals.
Sudden unexpected death, sudden episodes of viciousness
or seizures have been associated with AV nodal, or common
bundle degeneration, particularly in the Doberman Pinscher.
Note that the presence of mineralized cartilage or osseous
metaplasia in the central fibrous body in close proximity to
conduction tissue is a normal finding in large-breed dogs at all
ages. The common bundle is fibrotic, degenerate, and in some
cases replaced by fat. In most cases, there is myointimal 
proliferation in arterioles in this region, possibly leading to
ischemia of the common bundle. A similar phenomenon  Fonfara S, et al. English Springer Spaniels with significant
has been observed in other breeds, including the German
Shepherd dog.
There is also a syndrome of sudden death in outwardly
healthy, nonsyncopal young German Shepherd dogs that is sus-
pected to be hereditary in nature. Affected animals die unex-
pectedly during sleep or during rest following exercise.
Ventricular tachycardia is the most common arrhythmia, the
frequency of which increases during rest when the heart rate
is slowest, and ends in ventricular fibrillation. The underlying
defect is suggested to be regional paucity of sympathetic
nerves in ventricular myocardium.
Hereditary stenosis of the common bundle has been
observed in cases of syncope and sudden death in Pug dogs.
Electrocardiographically, such dogs have intermittent sinus
arrest and paroxysmal second-degree AV block. The sinus
node, the AV node, and the bundle branches are normal. The
Diseases of the Conduction System 51
paroxysmal AV block could be related to the lesion in the
common bundle, but the sinus pauses are probably the result
of excessive parasympathetic activity. Affected dogs are abnor-
mally sensitive to small amounts of acetylcholine.
Deafness in the Dalmatian dog is associated with an abnor-
mal blotchy coat color, and such animals may die suddenly. A
proportion of affected dogs exhibit episodes of sinus pauses.
In one case, the right atrium was fibrotic and atrophied. This
was accompanied by marked narrowing of the coronary arter-
ies, including those of the sinus node. These clinical and patho-
logic findings are similar to those seen in congenital deafness
in humans.
The presence of an atrophic and fibrotic atrium in the
previous case is the outstanding feature of the syndrome of
Siamese cats. The atrium is grossly dilated, and the walls are
thin, transparent, and pink. Microscopically, there is myocyte
atrophy and fibrosis, with a variable mononuclear cell pres-
ence. In some cases, atrophy of skeletal musculature is also
evident. Given the nature of the end-stage lesions, the ante-
cedent may be an active myocarditis (see Fig. 1-49). The
syndrome is similar in many respects to a form of muscular
dystrophy in people termed Emery-Dreifuss disease.
Sick sinus syndrome occurs in Miniature Schnauzers, West
Highland White Terriers, and Dachshunds, and it is familial in
Miniature Schnauzers. Prolonged sinus pauses cause syncope.
Defects of the conduction system of Alaskan sled dogs
that died suddenly during the Iditarod race included marked
fibrosis or fatty infiltration of the sinus node, AV node, AV
bundle, and bundle branches, and focal scarring of the left
ventricle. These pathologic changes may have led to fatal
dysrhythmias.
Equine grass sickness (equine dysautonomia) is suspected
to be a clinical form of botulism. The neurodegenerative
changes noted in terminal parasympathetic ganglionic neurons
in the heart, which include chromatolysis and vacuolation,
may account for the tachycardia noted in this disease.
Ventricular pre-excitation, a rare cause of weakness,
syncope, or congestive heart failure in dogs and cats, can result
when sinus node impulses bypass the normal conduction
system via accessory pathways (bundle of Kent, James fibers,
Mahaim fibers, or intranodal tract) to cause premature ven-
tricular activation.
Further reading
bradyarrhythmias-presentation, troponin I and follow up after pace-
maker implantation. J Small Anim Pract 2010;51:155-161.
Kaneshige T, et al. Complete atrioventricular block associated with
lymphocytic myocarditis of the atrioventricular node in two young
adult dogs. J Comp Pathol 2007;137:146-150.
Park DS, Fishman GI. The cardiac conduction system. Circulation
2011;123:904-915.
Perkins JD, et al. Functional and histopathological evidence of cardiac
parasympathetic dysautonomia in equine grass sickness. Vet Rec
2000;146:246-250.
Sosunov EA, et al. Mechanisms of alpha-adrenergic potentiation of
ventricular arrhythmias in dogs with inherited arrhythmic sudden
death. Cardiovasc Res 2004;61:715-723.
Woolley R, et al. Atrial myocarditis as a cause of sinus arrest in a dog.
J Small Anim Pract 2007;48:455-457.
 51.e1

Further reading
Beckett SD, et al. Syncopal attacks and sudden death in dogs: mecha-
nisms and etiologies. J Am Anim Hosp Assoc 1978;14:378-386.
Bharati S, et al. The conduction system in sudden death in Alaskan sled
dogs during the Iditarod race and/or during training. Pacing Clin
Electrophysiol 1997;20(3 Pt 1):654-663.
Brain CM, et al. Sudden and unexpected death in horses and ponies:
an analysis of 200 cases. Equine Vet J 1988;20:99-103.
Gavaghan BJ, et al. Persistent atrial standstill in a cat. Aust Vet J
1999;77:574-579.
Hill BL, Tilley LP. Ventricular preexcitation in seven dogs and nine cats.
J Am Vet Med Assoc 1985;187:1026-1031.
James TN. Congenital deafness and cardiac arrhythmias. Am J Cardiol
1967;19:627-643.
James TN, et al. Hereditary stenosis of the His bundle in pug dogs.
Circulation 1975;52:1152-1160.
James TN, Drake EH. Sudden death in Doberman pinschers. Ann Intern
Med 1968;68:821-829.
Kiryu K, et al. Pathologic and electrocardiographic findings in sudden
cardiac death in racehorses. J Vet Med Sci 1999;61:921-928.
Liu SK, et al. Lesions of the conduction system in the cat with cardio-
myopathy. Recent Adv Cardiac Struct Metab 1975;10:681-693.
Meierhenry EF, Liu SK. Atrioventricular bundle degeneration associated
with sudden death in the dog. J Am Vet Med Assoc 1978;172:1418-
1422.
Moise NS. Inherited arrhythmias in the dog: potential experimental
models of cardiac disease. Cardiovasc Res 1999;44:37-46.
Robinson WF, et al. Sinoatrial arrest associated with primary atrial
myocarditis in a dog. J Small Anim Pract 1981;22:99-107.
Sandusky GE Jr, et al. Morphologic variations and aging in the atrio-
ventricular conduction system of large breed dogs. Anat Rec
1979;193:883-902.
52 CHAPTER 1  •  Cardiovascular System
Figure 1-56  Aortic body tumor in a dog. (Courtesy R. Kovi,
C. Foutz.)
NEOPLASMS OF THE HEART
Primary neoplastic disease of the heart in all domestic species is
rare, with the possible exception of hemangiosarcoma in the
right atrium of dogs (see Vascular neoplasms). In contrast,
metastasis to the myocardium from primary tumors of other
organs is relatively common. Primary tumors of the aortic body
(chemodectomas) and of ectopic thyroid and parathyroid may
arise at the base of the heart in dogs (Fig. 1-56) (see Vol. 3,
Endocrine glands).
Hemangiosarcoma, a tumor of high-grade malignancy, may
either arise as a primary in the myocardium, or metastasize to
the myocardium, most commonly from the spleen or the skin.
Characteristics of the tumor are described under Vascular
neoplasms.
Other primary cardiac tumors are rare, and include  reported in the dog, cat, and cattle. They are believed to arise
rhabdomyoma; rhabdomyosarcoma; angioleiomyoma; myxoma;
myxosarcoma; chondrosarcoma; osteosarcoma; granular cell
tumor; peripheral nerve sheath tumors, including neurofibroma;
fibroma; fibrosarcoma; leiomyoma; lipomas; pericardial mesothe-
lioma; and undifferentiated sarcoma.
Rhabdomyomas are anomalous formations (hamartomas) of
myocardial fibers seen as one or more circumscribed but non-
encapsulated nodules within the myocardium. It has been sug-
gested that swine cardiac rhabdomyomas are not hamartomas
but may represent congenital dysplasia of the perinatal cardiac
myocytes with myofibrillar degeneration. However, recent
evidence suggests that, at least in pigs, some rhabdomyomas
are of Purkinje cell origin. This is based on the fact that the
cells in question stain specifically for protein gene product 9.5,
a marker for neuronal tissue and Purkinje fiber cell origin.
Rhabdomyomas are rare in animals, but are most common in
pigs, and have been observed in cattle, sheep, and dogs; a breed
predisposition has been noted in red wattle pigs. Grossly, the
nodules are gray and may be found anywhere in the heart.
Those projecting into a chamber are very susceptible to hem-
orrhage and necrosis, and may become cystic (Fig. 1-57).  tumors are rare in animals but have been reported to occur in
Neoplasms of the Heart
Figure 1-57  Rhabdomyoma in a sheep. (Courtesy Massey Uni-
versity, Department of Pathobiology.)
Histologically, the cell type is predominantly mature myocar-
diocyte in type in a variant of rhabdomyoma, but cells in
rhabdomyomas are more typically large, vacuolated, glycogen
rich, with scant myofibrils, and resemble Purkinje cells; cells
with fine cytoplasmic strands extending from the nucleus to
the peripheral cytoplasm are referred to as “spider cells.”
Fibrosis can be extensive, and the connective tissues may be
impregnated with iron and calcium salts.
Angioleiomyomas have been recently recognized in
cattle (10-129 months of age) in Japan. These tumors were
previously diagnosed as schwannomas (neurofibroma), hem-
angiomas, leiomyosarcomas, or rhabdomyosarcomas. Angi-
oleiomyomas are characteristically located subendocardially 
in the right or left ventricle, involve the valve complex 
(valves, chordae tendineae, papillary muscles), are well cir-
cumscribed and project into the ventricular lumen. Two his-
tologic patterns coexist in each tumor to varying extents. The
first pattern is of interlacing fascicles of spindle-shaped cells,
the second of uniformly sized vascular channels. Giant cells,
positive for factor VIII–related antigen, are also a feature in
all tumors.
Myxomas are the most common cardiac tumor in adult
humans, but are rare in domestic animals; they have been
from multipotent vasoformative cells. They may originate
from the endocardium of any of the 4 cardiac chambers 
or from the heart valves. Gross appearance is often multilobu-
lar, soft, and gelatinous. Histologically, myxomas are covered
by endothelium on their surface, and are hypocellular, consist-
ing of stellate or globular cells, blood vessels, and smooth
muscle cells within an abundant myxoid matrix. Blood flow
may be interrupted by these intracavitary space-occupying
masses, and although they do not metastasize, they may gener-
ate emboli.
Primary cardiac chondrosarcoma occurs rarely and most
probably arises from cartilaginous or similar tissue that is
present in the cardiac skeleton. Of the few that have been
described, one arose in the right atrium, with the others arising
in the atrioventricular valves. As the tumors produce little
cartilaginous matrix, a positive reaction to the presence of
S100 protein is required to confirm the chondrocytic origin
of the neoplastic cells.
A granular cell tumor or granular cell myoblastoma has
been described in the right atrium of a dog. Granular cell
Diseases of the Heart Neoplasms of the Heart 53

Figure 1-58  Neurofibroma in an ox. (Courtesy Noah’s Arkive.)

A
a variety of organs, including the lung, brain, meninges, and
tongue. The tumor has a distinctive light and electron micro-
scopic appearance consisting of spindle-shaped to large polyg-
onal cells containing prominent cytoplasmic granules within
lysosomes. The cells are considered to be of neural origin as
nerve-specific S100 protein is present within the cytoplasmic
granules.
Neurofibromas (schwannomas) are either isolated or mul-
tiple benign neoplasms of peripheral nerves (Fig. 1-58, eFig.
1-13). Cattle are most frequently affected, with the most
common sites being peripheral nerves, brachial plexus, auto-
nomic ganglia, intercostal nerves, and cardiac nerves. The
disease is usually detected only at slaughter. When the heart
is involved, the tumors are single or multiple, round or nodular
masses, either on the epicardial surface or within the myocar-
dium. The microscopic appearance is of interwoven bundles
or whorls of elongated cells. There may be palisading of nuclei B
and variable amounts of collagen present. The principal cell is
Figure 1-59  Metastatic lymphoma in a dog. A. Lymphoma in all
probably of Schwann or perineural origin.
chambers of the heart. B. Opened atria showing lymphoma pro-
Lymphoma (lymphosarcoma) is the most common meta-
truding into atrioventricular lumen. (Courtesy A. G. Armien.)
static neoplasm involving the heart (Fig. 1-59A, B), and occurs
most commonly in the cow and the dog. It may be nodular
or diffuse, although the distinction is arbitrary because there
is overlap of the 2 forms. In the nodular form, there are foci,
primarily in the atria (particularly the right atrium), which
may be up to 5 cm or more in diameter. The nodules are Further reading
covered by endothelium and are therefore smooth. When Akkoc A, et al. Cardiac metastasing rhabdomyosarcoma in a great
beneath the epicardium, they may be difficult to distinguish dane. Vet Rec 2006;158:803-804.
from epicardial fat. They are prone to central necrosis, and this Aupperle H, et al. Primary and secondary heart tumours in dogs and
resembles necrotic adipose tissue. On section, the wall of the cats. J Comp Pathol 2007;136:18-26.
atrium is more diffusely thickened, is moderately soft to cut, Castleman WL, et al. Rhabdomyosarcoma in 8 horses. Vet Pathol
and has a pale appearance. If squeezed, milky fluid exudes 2011;48:1144-1150.
from the cut surface. Globular masses like those beneath the Jacobsen B, et al. Proposing the term purkinjeoma: protein gene
epicardium are also found under the endocardium projecting product 9.5 expression in 2 porcine cardiac rhabdomyomas indi-
into the cardiac cavities. In the diffuse or infiltrating form, the cates possible purkinje fiber cell origin. Vet Pathol 2010;47:738-
myocardium appears irregularly thickened and gray-white, 740.
with the ventricular walls being especially involved. These foci Misdorp W. Congenital and hereditary tumours in domestic animals:
or areas of infiltration blend with normal myocardium and 2. Pigs. A review. Vet Q 2003;25:17-30.
hence are difficult to distinguish from foci of myocardial Pavarini SP, et al. Malignant peripheral nerve sheath tumor as a cause
degeneration or myocarditis. If they cause some thickening of of chronic cardiac insufficiency in cattle. Acta Vet Scand 2013;55:
the myocardium, such lesions are to be first regarded as lym- 7-13.
phoma and indicate the need for careful search for primary Soilleux EJ, Davies DR. Epithelial cyst of the cardiac papillary muscle:
lesions elsewhere in the body. Lymphoid neoplasms are con- case report and review of the literature. J Clin Pathol 2006;59:1203-
sidered in detail in Vol. 3, Hematopoietic system. 1205.
 53.e1

eFigure 1-13  Neurofibroma, bovine. Section through a nodular

enlargement of an epicardial nerve.
53.e2

Further reading
Albers TM, et al. Histochemical and ultrastructural characterization of
primary cardiac chondrosarcoma. Vet Pathol 1997;34:150-151.
Balli A, et al. Cardiac tamponade due to pericardial mesothelioma in
an 11-year-old dog: diagnosis, medical and interventional treat-
ments. Schweiz Arch Tierheilkd 2003;145:82-87.
Bradley R, et al. Ovine and porcine so-called cardiac rhabdomyoma
(hamartoma). J Comp Pathol 1980;90:551-558.
Campbell MD, Gelberg HB. Endocardial ossifying myxoma of the right
atrium in a cat. Vet Pathol 2000;37:460-462.
Colbourne CM, et al. Mesothelioma in horses. Aust Vet J 1992;69:275-
278.
Foale RD, et al. Left ventricular myxosarcoma in a dog. J Small Anim
Pract 2003;44:503-507.
Girard C, et al. Intrapericardial neoplasia in dogs. J Vet Diagn Invest
1999;11:73-78.
Machida N, et al. Cardiac myxoma of the tricuspid valve in a dog.
J Comp Pathol 2003;129:320-324.
Machida N, et al. Primary malignant mixed mesenchymal tumour of
the heart in a dog. J Comp Pathol 2003;128:71-74.
Machida N, et al. Myocardial hamartoma of the right atrium in a dog.
J Comp Pathol 2002;127:297-300.
Merlo M, et al. Primary right atrium haemangiosarcoma in a cat.
J Feline Med Surg 2002;4:61-64.
Omi K, et al. An immunohistochemical study of peripheral neuro­
blastoma, ganglioneuroblastoma, anaplastic ganglioglioma,
schwannoma and neurofibroma in cattle. J Comp Pathol 1994;111:
1-14.
Perez J, et al. Right-sided heart failure in a dog with primary cardiac
rhabdomyosarcoma. J Am Anim Hosp Assoc 1998;34:208-211.
Sanford SE, et al. Primary cardiac granular cell tumor in a dog. Vet
Pathol 1984;21:489-494.
Swartant MS, et al. Intracardiac tumors in two dogs. J Am Anim Hosp
Assoc 1987;23:533-538.
Tanimoto T, Ohtsuki Y. The pathogenesis of so-called cardiac rhabdo-
myoma in swine: a histological, immunohistochemical and ultra-
structural study. Virchows Arch 1995;427(2):213-221. Erratum in:
Virchows Arch 1996;428:69.
Taylor DP, et al. Primary cardiac rhabdomyosarcoma in a steer. Aust Vet
J 2002;80:571-572.
Uno K, et al. Extraskeletal mesenchymal chondrosarcoma in a cow.
J Comp Pathol 1989;101:31-38.
Venco L, et al. Primary cardiac rhabdomyosarcoma in a cat. J Am Anim
Hosp Assoc 2001;37:159-163.
Ware WA, Hopper DL. Cardiac tumors in dogs: 1982-1995. J Vet Intern
Med 1999;13:95-103.
54 CHAPTER 1  •  Cardiovascular System
Tursi M, et al. Myocardial adenomatoid tumor in eight cattle: evidence
for mesothelial origin of bovine myocardial epithelial inclusions. Vet
Pathol 2009;46:897-903.
Une Y, et al. Cardiac angioleiomyoma in 44 cattle in Japan (1982-
2009). Vet Pathol 2010;47:923-930.
DISEASES OF THE VASCULAR SYSTEM
GENERAL CONSIDERATIONS
The vascular system may be arbitrarily divided into a delivery
system (the arterial system), an exchange network (the microcir-
culation), and a removal system (the venous and lymphatic
systems). Impaired function of the vascular system can be
generalized, as occurs in shock, or may be localized when the
supply of oxygenated arterial blood to tissue is decreased,
causing ischemia. Impaired venous drainage causes congestion,
and decreased lymphatic drainage of tissue fluids causes
lymphedema.
The arterial system is subdivided into large elastic arteries,
medium and small muscular arteries, and arterioles, with gradual
transitions between these divisions. Arterial vessels are char-
acterized histologically by walls composed of 3 layers: the
internal, middle, and external tunics; or tunica interna (intima),
tunica media (media), and tunica externa (adventitia).
The intima consists of endothelium; subendothelial con-
nective tissue, which contains collagen, elastin, proteoglycan
(ground substance), fibroblasts and smooth muscle cells; and
the internal elastic membrane, which is the outer limit of the
intima. The thickness of the intima decreases as the vessel size
decreases, until the subendothelial layer eventually disappears.
The internal elastic membrane is not readily distinguishable
in elastic arteries because of its continuity with medial elastic
tissue, but is very prominent in muscular arteries, and disap-
pears at the level of the smaller arterioles.
The media consists of concentric layers of smooth muscle
cells and elastic fibers, and the external elastic membrane.  there are large openings between the endothelial cells and a
In elastic arteries, the media consists of fenestrated elastic
laminae, with smooth muscle cells lying between laminae.
Intercellular ground substance is especially prominent in the
tunica media of elastic arteries in the horse. The elastic laminae
diminish and smooth muscle predominates as vessels become
more distant from the heart. The media of muscular arteries is
up to 40 muscle cells thick, whereas the media of arterioles
is 1-3 cells thick. Definitions of the upper limit of arteriolar
diameter range from 300 µm if tissues are fixed by perfusion
to 100 µm if allowed to contract, but there are no sharp dis-
tinctions between small arteries and large arterioles. The thick-
ness of the media as seen in routine material is greatest in
relation to the luminal diameter in small arteries and arteri-
oles, and it is these vessels, particularly arterioles, which par-
ticipate actively in blood pressure regulation and also bear the
consequences of hypertension. Contraction of muscular arter-
ies and arterioles upon an animal’s death forces blood from
the lumina, and causes longitudinal folding that appears as
scalloping of the internal elastic membrane when seen in
cross-section. The external elastic membrane is best defined
in the large elastic arteries, and becomes indistinct in muscular
arteries.
The adventitia consists of a feltwork of elastic and collagen
fibers continuous with the surrounding connective tissue. The
interlacing network of collagen fibers in the adventitia limits
General Considerations
expansion of the elastic arteries. Elastic fibers decrease in the
adventitia with decreasing vessel size. Vasa vasorum and nervi
vasorum supply the adventitia and the outer half of the media.
The intima and inner half of the media are avascular and depen-
dent upon diffusion from the vascular lumen, and are thus
more subject to degenerative changes than the outer media.
The microcirculation is the exchange system in which gases,
nutrients, and waste products are transferred between the blood
and the extravascular tissues. The microcirculation consists of
vessels of <100 µm in diameter: namely, arterioles, terminal
arterioles (metarterioles, precapillary sphincter areas), capillaries,
postcapillary venules, and venules. This classification overlaps
microcirculation and macrocirculation (arteries and veins),
but is useful conceptually as will be seen in disorders such as
disseminated intravascular coagulation, which affect primarily
the microcirculation. Arterioles open through precapillary
sphincters or through metarterioles into capillaries in most
tissues, or into sinusoids in the liver. Capillaries are low-
pressure tubules, of ~8 µm in diameter, composed of endo-
thelial cells surrounded by a basal lamina; the endothelial cells
are connected by tight junctions that allow rapid passage of
small molecules such as glucose. The basal lamina is a molecu-
lar sieve that prevents passage of larger protein molecules.
Capillary endothelial cells possess few endoplasmic organelles,
but often contain pinocytotic vesicles. Capillaries may be con-
tinuous, the most common type; fenestrated (60-80 µm fenes-
trae closed by thin diaphragms), as in the gastrointestinal tract
and endocrine glands; or porous (without diaphragms closing
the pores), as in renal glomeruli. Fenestration of the endothe-
lial cells allows increased permeability. During tissue healing,
cords of endothelial cells grow into the tissues by mitosis,
develop lumina, and become functional capillaries. Undiffer-
entiated perivascular cells, or pericytes, are ensheathed by gly-
cocalyx that is continuous with the capillary basal lamina.
Mitosis of pericytes is easily stimulated, and they may be
transformed into fibroblasts or smooth muscle cells. Sinusoids
are less uniform than capillaries and more permeable because
discontinuous basal lamina.
Veins are termed small, medium, or large or, alternatively,
venules, collecting veins, and great veins; all have large lumina
in relation to their wall thickness. Classification of veins by
wall characteristics is difficult because the layers in their walls
may be absent or difficult to distinguish. Venules of >30 µm
in diameter have an incomplete muscular media and thin
adventitia. Venular endothelium is normally more permeable
than that of capillaries and is also more sensitive to vasoactive
amines, the action of which can cause leakage. In the lymph
node paracortex, postcapillary venules, which are nonmuscular
venules with prominent endothelium, are important sites of
lymphocytic traffic. The media is of increasing thickness in
medium and large veins, and the internal elastic lamina
becomes more prominent. However, the adventitia is the thick-
est layer in veins, whereas the media predominates in arteries.
Backflow of blood in veins is prevented by the presence of
semilunar valves, which are invaginations of the intima into
the venous lumen. Venous valves are not present in venae
cavae or hepatic portal vein. Paucity of valves in veins of the
head and face may contribute to incidental venous congestion
in these areas.
Lymphatic capillaries originate in loose connective tissue,
and consist of very permeable walls and endothelial cells that
may lack, or have a discontinuous, basal lamina. In larger
Diseases of the Vascular System
lymphatics, valves are present, the basal lamina is continuous,
and walls consist of 3 ill-defined layers; an internal elastic
lamina is usually absent. The thin-walled veins and lymphatics
are more susceptible to compression and occlusion, are more
often involved by inflammation in adjacent tissue, and are
more liable to neoplastic invasion than are the thicker-walled
arteries.
Endothelium and smooth muscle, the main components of
vessel walls, play important roles in all types of vascular disease.
A wealth of information is accumulating about the important
properties and reactive capabilities of these seemingly simple
cells. For example, in addition to maintaining a permeability
barrier between blood and tissues, the endothelium is recognized
as the largest paracrine organ in the body. It produces antico-
agulants, procoagulants, fibrinolytic agents, prostanoids, con-
nective tissue components, adenosine, and a host of other
substances. Vascular homeostasis is maintained by complex
interactions among endothelial cells, leukocytes, and platelets,
each of which produce vasodilators and vasoconstrictors and
can interact to inhibit or promote thrombosis.
Vascular endothelial cells, as well as forming the throm­
boresistant monolayer lining of the vascular system,  activates the intrinsic pathway of coagulation. Fibronectin, or
mechanically insulate the circulating blood from the highly
thrombogenic subendothelial materials. The thromboresis-
tance of the endothelium is normally maintained by a balance
between antithrombotic and thrombotic factors; stimulation
of excessive prothrombosis can lead to clotting and thrombo-
sis, whereas excessive antithrombosis can lead to ineffective
hemostasis and bleeding (eFig. 1-14).
Antithrombosis is normally accomplished through
• Binding and inhibition of thrombin via activation by
thrombomodulin of protein C and protein S, via accentua-
tion of antithrombin activity by heparin-like molecules,
and via the presence of α2-macroglobulin
• Inhibition of platelet aggregation through elaboration of
prostacyclin (PGI2), a potent inhibitor of platelet aggrega-
tion and a vasodilator, and by adenosine diphosphatase
(ADPase)-mediated conversion of pro-aggregating ADP to
adenine nucleotide platelet inhibitors
• Promotion of fibrinolysis by synthesis of tissue plasminogen
activators
Procoagulant activities include:
• The presence of minute amounts of tissue factor (tissue
thromboplastin) in endothelial cells, further production of
which can be stimulated by endotoxin and by cytokines
such as interleukin-1 (IL-1) and tumor necrosis factor
• Synthesis and secretion of von Willebrand factor, needed
for adherence of platelets to subendothelial components,
and secretion of platelet activating factor, an activator and
aggregator of platelets
• Inhibition of fibrinolysis through release of plasminogen
activator inhibitors
In addition to their role in hemostasis, endothelial cells
participate in modulation of blood flow and vascular reactivity
by production of endothelium-derived relaxing factor (nitric
oxide); endothelin, a vasoconstrictor; angiotensin converting
enzyme, which converts angiotensin I to angiotensin II; and
prostacyclin. Endothelial cells modulate the actions of various
vasoconstrictors (catecholamines, serotonin, arginine, vaso-
pressin) and vasodilators (histamine, leukotrienes, adenine
nucleotides), and in concert with the endothelium-derived
factors can thereby allow blood vessels to rapidly adapt to
changes in hemodynamic conditions.
General Considerations 55
Endothelial cells aid in the regulation of inflammation and
immunity through production of IL-1 and various adhesion
molecules, which moderate adhesion and hence emigration of
leukocytes. The most important adhesion molecule pairs are
the selectins, the immunoglobulins intercellular adhesion 
molecule 1 (ICAM-1) and vascular cell adhesion molecule 1
(VCAM-1), and the β2 and β1 integrins. Endothelial cells also
aid in regulation of cell growth by production of growth stimula-
tors (platelet-derived growth factor, colony-stimulating factor,
and fibroblast growth factor), and production of growth inhib-
itors (heparin, transforming growth factor-β). Endothelial cells
produce basement membrane, and are capable of contraction.
The endothelium is a semipermeable membrane that can 
also transport metabolites, including proteins through the
cytoplasm via pinocytotic vesicles. Weibel-Palade bodies,
rod-shaped cytoplasmic organelles that store von Willebrand
factor, serve as ultrastructural markers of endothelial cells.
Subendothelial connective tissues consist of various types of
collagen, elastin, proteoglycans, fibronectin, laminin, and
thrombospondin. Of these, fibrillar collagen is the most potent
stimulus for platelet adhesion and activation; collagen also
“molecular glue,” normally functions to stabilize cell-to-cell
and cell-to-substrate attachments, but also becomes cross-
linked to fibrin and helps to anchor hemostatic plugs.
Mild endothelial injury, as occurs in the course of inflam-
mation, may be apparent histologically as hypertrophy of
endothelial cells (“reactive” cells). As well, increased vascular
permeability may lead to insudation of plasma proteins,
including fibrinogen, into the subendothelial area, and hence
contribute to vascular hyalinosis. Because the intima and inner
media depend upon diffusion of metabolites from the vascular
lumen for their nutrition, such subendothelial deposits may
impair the viability of smooth muscle cells and contribute to
degeneration, or fibrinoid necrosis, of vessel walls. Thus the
endothelial barrier must be preserved to maintain a normal envi-
ronment for medial smooth muscle cells. Necrosis of endothe-
lium, which may be caused by a wide variety of agents, leads
to exposure of subendothelial collagen, a potent inducer of
coagulation and platelet aggregation, and hence thrombosis.
Endothelial cells at the edges of denuded areas will proliferate
and migrate to repair the endothelial defect or to form an
endothelial covering over (endothelialize) a mural thrombus.
Severe microvascular damage, as occurs because of lipoperoxi-
dation of endothelial membranes in vitamin E/selenium defi-
ciency in pigs, can result in hemorrhage and organ failure.
Vascular smooth muscle cells are important both as effec-
tors of vasoconstriction and dilation, and as cells capable of
synthesizing basement membrane, collagen, elastin, and pro-
teoglycans of the extracellular space. In response to growth
factors derived from platelets and monocyte/macrophages,
smooth muscle cells of the media migrate through fenestrae
of the internal elastic lamina to the subendothelial area where,
as “myointimal” cells, they proliferate and are responsible for
organization or collagenization of deposits, including thrombi.
Examples of endoarterial organization and arterio-occlusive
disease are discussed later in this chapter. In common with
other muscle cells, medial smooth muscle cells respond to an
increased workload by hypertrophy. Medial hypertrophy is a
prominent consequence, as well as a cause, of pulmonary
hypertension. Sustained vasoconstriction, as is induced by
ergot (Claviceps purpurea) or fescue grass (Festuca arundina-
cea, Festuca eliator) poisoning, can lead to gangrene of the
 55.e1

The balance between thrombosis

and antithrombosis

Thrombosis
Release of tissue factor
from subendothelium after
endothelial cell injury.
Antithrombosis
Binding and inhibition of thrombin
via thrombomodulin activation
of protein C & S
Heparin-like molecules
-2 macroglobulin

Synthesis and secretion Inhibition of

of von Willebrand factor fibrinolysis via
Inhibition of platelet
Platelet aggregating factor plasminogen
aggregation by prostacyclins
activator inhibitors
ADPase-mediated ADP breakdown
Promotion of fibrinolysis via tissue
plasminogen activators

eFigure 1-14  Balance between thrombotic and antithrombotic factors. ADP, adenosine
diphosphate.
56 CHAPTER 1  •  Cardiovascular System
extremities; fescue toxicosis in cattle (summer syndrome) is
caused by infestation of the grass by the endophyte Neotypho-
dium (Acremonium) coenophialum, which produces the ergo-
peptide alkaloids, ergovaline, ergosine, and ergonine. Along
with the other components of the vessel wall, smooth muscle
cells may be involved in degenerative and inflammatory
changes, as described later, and contribute to fibrinoid necrosis
of the wall.
Normal aging changes of vessels include intimal thickening
resulting from proliferation of myointimal cells and accumula-
tion of their products, deterioration of medial elastic fibers,
medial fibrosis and loss of medial smooth muscle, and accu-
mulation of ground substance in the media. These slowly
progressive changes are usually of little consequence given the
large functional reserve of the vascular system, but do lead to
loss of resilience of the vessel walls and may cause vessel wall
thinning, stretching, and hence increased tortuosity.
Further reading
Bajema IM, Bruijn JA. What stuff is this! A historical perspective on
fibrinoid necrosis. J Pathol 2000;191:235-238.
Botha CJ, et al. Gangrenous ergotism in cattle grazing fescue (Festuca
elatior L.) in South Africa. J S Afr Vet Assoc 2004;75:45-48.
Galley HF, Webster NR. Physiology of the endothelium. Br J Anaesth
2004;93:105-113.
Miller LM, et al. Cardiovascular system and lymphatic vessels. In:
Zachary JF, McGavin MD, editors. Pathologoc Basis of Veterinary
Disease. 5th ed. St Louis: Elsevier; 2012. p. 539-588.
Mitchell RN, Schoen FJ. Blood vessels. In: Kumar V, et al., editors.
Robbins and Cotran Pathologic Basis of Disease. 8th ed.
Philadelphia: Saunders-Elsevier; 2010. p. 487-528.
Plendl J. Cardiovascular system. In: Eurell JO, Frappier BL, editors. Dell-
man’s Textbook of Veterinary Histology. 6th ed. Ames, Iowa: Wiley
Blackwell; 2007. p. 117-133.
ARTERIES
Congenital anomalies
Minor variations occur in the course and distribution of arter-
ies among individuals of a species, but these are of little sig-
nificance except possibly in surgical procedures.
Arteriovenous fistula, the communication of an artery and
vein that bypasses the capillary system, is a defect that may
arise developmentally or be acquired subsequent to physical
trauma, inflammatory necrosis involving adjacent vessels, neo-
plastic infiltration, or rupture of an arterial aneurysm into a
vein. Fistulas occur in dogs, cats, horses, and cattle, but are
uncommon. Clinically, fistulas most commonly occur in the
extremities and appear as a pulsating, fluctuant swelling in
which there is a palpable thrill and a machinery-like bruit on
auscultation. In general, arteriovenous fistulas cause decreased
peripheral resistance and increased venous return to the right
heart. When 20-50% of the cardiac output is shunted through
the fistula, high-output cardiac failure can occur. The veins
involved are usually thick-walled (“arterialized”), may be
dilated and extremely tortuous, and may have intimal sclero-
sis. Hepatic arteriovenous fistula (congenital hamartoma)
occurs in dogs and cats, and can cause portal hypertension,
portocaval shunts, and ascites (see Vol. 3, Liver and biliary
system).
Thebesian veins connect the cardiac chambers, between
the trabeculae carneae, with the myocardial sinusoids and
Arteries
capillaries. They may also connect with coronary arterioles to
form direct connections between the coronary arterioles and
the cardiac chambers. Areas of myocardium in which the
Thebesian vein system is richly persistent are randomly dis-
tributed, and the true nature of the defect may be overlooked
because of the tortuous aneurysmal dilation of the affected
coronary artery. Injection studies are necessary to demonstrate
the extent of the anastomosis.
Further reading
Hosgood G. Arteriovenous fistulas: pathophysiology, diagnosis, and
treatment. Compend Contin Educ Pract Vet 1989;11:625-636.
Koide K, et al. Congenital hepatic arteriovenous fistula with intrahe-
patic portosystemic shunt and aortic stenosis in a dog. J Vet Med
Sci 2004;66:299-302.
Nakata TM, et al. Transarterial coil embolization of an abdominal aor-
tocaval fistula in a dog. J Vet Intern Med 2014;28:656-660.
Degeneration of arteries
Arteriosclerosis
Arteriosclerosis literally means “hardening of the arteries,” and
is more fully defined as chronic arterial change consisting of
hardening, loss of elasticity, and luminal narrowing resulting
usually from proliferative and degenerative, rather than inflam-
matory, changes of the media and intima. The term athero­
sclerosis is applied to lesions of arteriosclerosis in which
degenerative fatty changes also occur. Atherosclerosis is the most
common and important type of arteriosclerosis in humans, and
the terms can thus be used interchangeably with little loss of
meaning when discussing this species. In domestic animals,
arteriosclerosis is common, but of little clinical importance, and
atherosclerosis is rare.
Arteriosclerosis develops slowly in animals, its extent and
incidence being greater in older animals. The disease may
become so widespread in individual animals that microscopi-
cally normal vessels may be difficult to find. The sclerotic
vessels are usually not accompanied by significant distur-
bances of blood flow, although ischemic change, especially of
brain and heart, may be seen. Well-developed lesions may be
good sites for thrombus formation in animals when thrombo-
genic circumstances prevail.
Arteriosclerosis uncomplicated by focal degeneration in the
sclerotic plaques and with no or minimal lipid deposition is the
lesion usually found in older horses, ruminants, and carnivores.
There is a predilection for the abdominal aorta and points of
arterial branching, but it is also seen in peripheral and pulmo-
nary arteries and in the thoracic aorta. The extensiveness of
the lesions is very variable, so that there is no clear differentia-
tion between a permissible aging change and a pathologic
process. The nature of the insult (or insults) to the vessel walls
that result in sclerosis is not known, although there are numer-
ous possibilities. Hemodynamic factors probably contribute,
especially to development of plaques about the orifices of
arterial branches.
Arteriosclerotic plaques produce a slight thickening and
wrinkling of the intima and are white, well delineated, and
oval to linear in shape. They can be found microscopically in
many animals in which they are not visible to the naked eye.
Their presence in peripheral, including coronary and cerebral
vessels, can be correlated with arteriosclerosis of the abdomi-
nal aorta.
 56.e1

Further reading
Adams JC, Lawler J. The thrombospondins. Int J Biochem Cell Biol
2004;36:961-968.
Bassenge E. Endothelial function in different organs. Prog Cardiovasc
Dis 1996;39:209-228.
Blodgett DJ. Fescue toxicosis. Vet Clin North Am Equine Pract
2001;17:567-577.
Carvalho D, Savage C. Cytokines, adhesion molecules, antiendothelial
cell autoantibodies and vascular disease. Cardiovasc Pathol
1997;6:61-78.
Cotran RS, Mayadas-Norton T. Endothelial adhesion molecules in
health and disease. Pathol Biol (Paris) 1998;46:164-170.
Fagrell B, Intaglietta M. Microcirculation: its significance in clinical and
molecular medicine. J Intern Med 1997;241:349-362.
Gwathmey JK, Paige JA. Endothelin and vasoactive peptides: new
cardiovascular mediators. J Vet Pharmacol Ther 1994;17:420-425.
Hirschi KK, D’Amore PA. Pericytes in the microvasculature. Cardiovasc
Res 1996;32:687-698.
Ju H, Dixon IM. Extracellular matrix and cardiovascular diseases. Can J
Cardiol 1996;12:1259-1267.
Michel CC. Capillaries, caveolae, calcium and cyclic nucleotides: a new
look at microvascular permeability. J Mol Cell Cardiol 1998;30:2541-
2546.
Schiffrin EL, Touyz RM. Vascular biology of endothelin. J Cardiovasc
Pharmacol 1998;32(Suppl. 3):S2-S13.
Turk JR. Physiologic and pathophysiologic effects of endothelin: impli-
cations in cardiopulmonary disease. J Am Vet Med Assoc
1998;212:265-270.
56.e2

Further reading
Bouayad H, et al. Peripheral acquired arteriovenous fistula: a report of
four cases and literature review. J Am Anim Hosp Assoc
1987;23:205-211.
Lamb CR, Naylor JM. Arteriovenous fistula in the orbit of a calf. Can
Vet J 1985;26:105-107.
Parks AH, et al. Lameness in a mare with signs of arteriovenous fistula.
J Am Vet Med Assoc 1989;194:379-380.
Diseases of the Vascular System
The initiating lesion(s) and the evolution of plaque forma-
tion are not fully elucidated. Microthrombi composed chiefly
of platelets are deposited at natural sites of turbulence or of
endothelial denudation, and may initiate the lesion. Platelets
secrete platelet-derived growth factor (PDGF), epidermal
growth factor, transforming growth factor-β, and other mito-
gens; PDGF stimulates migration and proliferation of smooth
muscle cells. Alternatively, the initial change in the vessel wall
may occur as the result of a nondenuding insult to the endo-
thelium; endothelial cells themselves produce several mito-
gens, including PDGF.
Histologically, the internal elastic lamina shows an early
distinctive change, becoming irregular in outline, partially
duplicated, and fragmented or discontinuous. Smooth muscle
cells migrate into the intima from the media to function as do
fibroblasts outside of arteries; these intimal smooth muscle
cells produce most of the connective tissue matrix of the
intimal plaque, including collagen, elastic tissue, and proteo-
glycans. In young plaques, or the deeper portions of older ones,
the smooth muscle cells (“myointimal cells”) are numerous and
intimately mixed with collagen, elastic fibrils, basement mem-
brane, and proteoglycans as the so-called musculoelastic layer.
In large and older plaques, a more superficial elastic hyper-
plastic layer may be recognized by a more compact arrange-
ment of collagen and elastica with relatively few cells. This
lamination of plaques is not always clearly evident, and its
development may depend on the age of the lesion as well as
on the segment of vessel involved, whether chiefly muscular
or chiefly elastic.
Further reading
Falk T, et al. Arteriosclerotic changes in the myocardium, lung, and
kidney in dogs with chronic congestive heart failure and myxoma-
tous mitral valve disease. Cardiovasc Pathol 2006;15:185-193.
Fishbein GA, Fishbein MC. Arteriosclerosis: rethinking the current clas-
sification. Arch Pathol Lab Med 2009;133:1309-1316.
Williams KJ. Coronary arteriosclerosis with myocardial atrophy in a
13-year-old dog. Vet Pathol 2003;40:695-697.
Atherosclerosis
Atherosclerosis is of little practical importance in domestic
animals, but is primarily of interest for the development of
animal models of the human disease. The atherosclerotic  and iliac arteries, as in man, and the plaques may cause con-
susceptibility of animals varies; rabbits, chickens, and pigs are
atherosensitive, whereas dogs, cats, cattle, goats, and rats are
atheroresistant. Swine and nonhuman primates are usually
considered to be the best large-animal models of human ath-
erosclerosis, and genetically modified mice are proving to be
valuable in the elucidation of the contribution of single factors
to the pathogenesis of the disease.
In humans, atherosclerosis and its complications of myocar-
dial infarction, stroke, and peripheral vascular disease are major
causes of morbidity and mortality in the developed world. Ath-
erosclerosis affects the large elastic arteries (aorta, iliac) and
the large and medium caliber muscular arteries (carotid, coro-
nary, femoral). The essential lesion is the atheroma or fibrofatty
plaque, which is a focal, raised, intimal plaque with a core of
lipid (predominantly cholesterol and its esters) covered by a
fibrous cap. Complications of plaques include mineralization,
ulceration, superimposed thrombosis, intraplaque hemorrhage,
and aneurysmal dilation. Fatty streaks, another type of fatty
Arteries 57
intimal lesion, are common in the aorta and large arteries of
domestic animals, especially ruminants and swine, and humans.
The streaks, which are soft, smooth, nonelevated lesions
ranging from pinpoint size up to several square centimeters,
are rarely visible grossly unless the aorta is stained with a fat
stain such as Sudan IV, which stains the lesions bright orange.
Streaks and plaques may coexist in the same area, but fatty
streaks also occur in areas in which plaques do not occur; thus,
the role of fatty streaks in the genesis of atherosclerosis is
unresolved. The major features of atherosclerosis are shown
in eFig. 1-15.
Multiple pathogenetic influences can contribute to the develop-
ment of plaques. The various events and theories of develop-
ment of atherosclerosis have been unified in the “response to
injury” hypothesis. Endothelial injury or dysfunction can occur
as the result of hyperlipidemia, with the cholesterol present
in low-density (LDL) and very-low-density lipoproteins
(VLDL) seen as a primary culprit. Additional risk factors in
humans are genetics, hypertension, smoking, obesity, inactiv-
ity, and diabetes mellitus. Immunologic mechanisms, toxins,
and viruses may also damage endothelium. Infectious agents,
such as Chlamydia pneumoniae, have been proposed as con-
tributing to the pathogenesis of atherosclerosis in humans, but
there is no evidence to date of a similar link in dogs or cats.
Endothelial injury leads to platelet adhesion, monocyte
adhesion and infiltration, and smooth muscle migration and
proliferation, as discussed above under Arteriosclerosis. The
involvement of various proinflammatory cytokines and che-
mokines are also considered to influence the development of
the atheromatous plaque. The feature added in atherosclerosis
is insudation of lipid, which is seen as extracellular lipid, often
with acicular clefts or as intracellular lipid in “foam cells.” The
lipid-laden foam cells that are characteristic of both fatty
streaks and atheromatous plaques may be either activated
macrophages or smooth muscle cells; macrophages predomi-
nate in streaks, whereas smooth muscle cells predominate in
the fibrous cap of plaques. Endothelial cell dysfunction is
emerging as an endocrinopathy that may contribute to the
effects of atherosclerosis through impaired ability of endothe-
lial cells to produce endothelial-derived relaxing factor and
through increased production of endothelin.
Atherosclerosis develops commonly only in the pig among
domestic species. Fatty streaks and atheromatous plaques
develop in the aorta, extramural coronary arteries, cerebral
siderable stenosis of vessels in swine 8-12 years of age. The
extent of lipid deposition can be influenced by feeding
extraordinary diets containing much lipid, including choles-
terol, but the atheromas rarely reach the degree of develop-
ment seen in humans, and they do not lead to occlusive
thrombus formation, which usually requires softening and
ulceration of the atheromatous plaque. The initial deposition
of lipid occurs in the proliferated smooth muscle cells, which
show signs of degeneration and which may become foam cells.
Macrophages also appear, containing lipid. Fat may be demon-
strable extracellularly, presumably released by degenerate
cells. Deposits of cholesterol and mineral, not extensive, may
be associated with softening of larger atheromatous plaques.
However, except in pigs fed high-fat diets, lipid is usually a
minor component of the predominantly fibromuscular
plaques.
Of the domestic animals, the deposition of cholesterol and
other lipids in the arteries in more than trace amounts occurs
 57.e1

Further reading
Fankhauser R, et al. Cerebrovascular disease in various animal species.
Ann N Y Acad Sci 1965;127:817-859.
Luginbuhl H. Vascular diseases in animals: comparative aspects of
cerebrovascular anatomy and pathology in different species. In:
Millikan CH, Siekert RG, et al., editors. Cerebral Vascular Diseases.
New York: Grune and Stratton; 1966. p. 3-27.
Maher ER Jr, Rush JE. Cardiovascular changes in the geriatric dog.
Compend Contin Educ Pract Vet 1990;12:921-931.
Marcus LC, Ross JR. Microscopic lesions in the hearts of aged horses
and mules. Pathol Vet 1967;4:162-185.
Nanda BS, Getty R. Age related histomorphological changes in the
cerebral arteries of domestic pig. Exp Gerontol 1971;6:453-460.
Prasad MC, et al. Caprine arterial diseases: I. Spontaneous aortic
lesions. Exp Mol Pathol 1972;17:14-28.
Schaub RG, et al. Platelet adhesion and myointimal proliferation in
canine pulmonary arteries. Am J Pathol 1981;104:13-22.
Whitney JC. Some aspects of the pathogenesis of canine arteriosclero-
sis. J Small Anim Pract 1976;17:87-97.
57.e2

Location
Large elastic arteries
and large/medium
muscular arteries

Atherosclerosis Complications
Essential lesion
Common in Mineralization/
Sub-intimal humans ulceration/
atheroma-fibrofatty
Uncommon in thrombosis of
plaque
domestic animals the plaque

Plaque
composition
Lipids especially
cholesterol both
intra and
extracellular

eFigure 1-15  Diagram of essential features of atherosclerosis.

58 CHAPTER 1  •  Cardiovascular System
Figure 1-60  Atherosclerosis of coronary arteries with irregular
thickening of vessels in a dog. (Courtesy J. Schefers.)
Figure 1-61  Atherosclerosis of meningeal arteries in a dog.
(Courtesy J. Schefers.)
only in dogs (Figs. 1-60 to 1-62), and then almost always in
association with hypothyroidism or diabetes mellitus. In dogs,
hypercholesterolemia is chiefly related to hypothyroidism, but
even in thyroidectomized, cholesterol-fed, hypercholesterol-
emic experimental dogs, only occasional dogs classed as
“hyper-responders” developed atherosclerosis, perhaps as a
result of an increased proportion of cholesterol-rich VLDL. A
breed predisposition to atherosclerosis in Miniature Schnau-
zers may be the result of idiopathic hyperlipoproteinemia.
The deposition of lipids in dogs begins in the middle and outer
layers of the media and occurs more extensively perhaps in the
small muscular arteries than in the large elastic ones; if present,
aortic lesions occur as intimal plaques. The veins are normal.
The vascular changes can be severe enough to be seen on gross
inspection. The vessels are enlarged, less pliable than normal,
and their walls are thickened and ill-defined because a hyper-
plastic adventitia merges irregularly with surrounding tissues.
Projecting into the lumens of the vessels on cross-section are
tiny yellow-brown nodules. In vessels large enough to be
opened longitudinally, there are numerous small yellow flat
elevations that may be confluent.
The media may be greatly increased in thickness by the
accumulation of lipid, most of which is in foam cells, but some
Arteries
Figure 1-62  Subintimal streaks and plaques of atherosclerosis in
the abdominal aorta in a dog. (Courtesy N. Kirchhof.)
is present in identifiable smooth muscle cells of the media or
free in the interstitium as droplets or crystals. The deposition
of lipid in the internal layers of the media leads to disruption
of the internal elastic lamina and involvement of the intima.
Substantial deposits of lipid may lead to eccentric enlarge-
ment of the vessel. Associated with the lipidosis, and possibly
as a response to it, there is progressive proliferation of fibrous
connective tissue. Beginning with the formation of fine fibrils
in and about the areas of lipid deposition, the fibrosis is pro-
gressive and may eventually completely transform the struc-
ture of the wall. The connective tissues become hyalinized and
relatively acellular and may be heavily impregnated with salts
of calcium and iron, present as granules, large aggregates, or
crystalline plaques.
Atheromatosis of the degree described above in dogs is rare.
Clinical consequences of severe atherosclerosis appear to be
infrequent in dogs, even though the vessels most severely
involved are those of the heart, brain, and kidney. Occasion-
ally, however, as in humans, rupture of the atheromatous area
into the lumen with thrombosis or even widespread lipid
embolism has been observed.
The morphology of atherosclerosis differs in dogs and in
humans; in dogs lipid is present in the intima, but is primarily
located in the media and adventitia of atherosclerotic arteries,
however, in humans, lipid is present primarily in the intima (Fig.
1-63A, B). The term “xanthomatosis” has been applied to the
canine condition in the past, but its use is inadvisable as it
may cause confusion with the human condition of primary
xanthomatosis (type II hyperlipoproteinemia), in which there
is premature atherosclerotic coronary artery disease, but also
xanthomatous infiltration of the myocardium, dermis, and
other organs with an associated granulomatous reaction. A
similar condition in other animal species is referred to as
xanthomatosis, and is characterized by the presence of lipid-
laden foam cells in subcutaneous or intracutaneous accumula-
tions known as xanthomas. A familial hyperlipoproteinemia
occurs in lipoprotein lipase deficient cats, and results in the
formation of xanthomata in a variety of organs; atherosclerosis
is not a feature of this condition.
Further reading
Furie MB, et al. Plaque attack—one hundred years of atherosclerosis
in the American Journal of Pathology. Am J Pathol 2012;180:2184-
2187.
 58.e1

Further reading
Armstrong ML, Heistad DD. Animal models of atherosclerosis. Athero-
sclerosis 1990;85:15-23.
Chastain CB, Graham CL. Xanthomatosis secondary to diabetes mel-
litus in a dog. J Am Vet Med Assoc 1978;172:1209-1211.
DeBowes LJ. Lipid metabolism and hyperlipoproteinemia in dogs.
Compend Contin Educ Pract Vet 1987;9:727-734.
Johnstone AC, et al. The pathology of an inherited hyperlipoprotein-
aemia of cats. J Comp Pathol 1990;102:125-137.
Maher ER Jr, Rush JE. Cardiovascular changes in the geriatric dog.
Compend Contin Educ Pract Vet 1990;12:921-931.
Ross R. Atherosclerosis-an inflammatory disease. N Eng J Med
1999;340:115-126.
Vanhoutte PM. Endothelial dysfunction: the first step toward coronary
arteriosclerosis. Circ J 2009;73:595-601.
Diseases of the Vascular System
A blood pressure, is an important disease of humans, and occurs
B lesion is a primary or a secondary event is difficult. Primary
Figure 1-63  Atherosclerosis. A. Extensive subintimal and medial
infiltration with lipid macrophages (“foam cells”) accompanied by
perivascular lymphocytic infiltration in a dog. B. Large complex
fibrofatty plaque within the subintima of a coronary artery of a
human. Note the severe vascular luminal compromise. (Courtesy
S. Mackey-Bojack.)
Galkina E, Ley K. Immune and inflammatory mechanisms of athero-
sclerosis. Annu Rev Immunol 2009;27:165-197.
Getz GS, Reardon CA. Animal models of atherosclerosis. Arterioscler
Thromb Vas Biol 2012;32:1104-1115.
Ginzinger DG, et al. Diet-induced atheroscelrosis in the domestic cat.
Lab Invest 1997;77:409-419.
Hamamdzic D, Wilensky RL. Porcine models of accelerated coronary
atherosclerosis: role of diabetes mellitus and hypercholesterolemia.
J Diabetes Res 2013;2013:761415.
Li X, et al. Animal models for the atherosclerosis research: a review.
Protein Cell 2011;2:189-201.
Libby P, et al. Progress and challenges in translating the biology of
atherosclerosis. Nature 2011;473:317-325.
Mizuno Y, et al. Inflammation and the development of atherosclerosis—
effects of lipid lowering therapy. J Atheroscler Thromb 2011;18:351-
358.
Soltaric-Quckermann IC, et al. Chlamydia in canine or feline coronary
arteriosclerotic lesions. BMC Res Notes 2011;4:350.
Arteries 59
Arteriolosclerosis
Arteriolosclerosis describes a heterogeneous group of arteriolar
lesions that may be predominantly hyaline or predominantly
hyperplastic. The major cause of these changes in vessels in
humans is hypertension, but the pathogenesis of the lesions
in domestic animals is often not determined. Endothelial
damage is likely the primary event in these conditions. Hyaline
degeneration—the microscopic appearance of amorphous,
brightly eosinophilic material in vessel walls—can occur as the
result of increased vascular permeability that allows insuda-
tion of various plasma components; it includes the amyloid
deposits of renal glomeruli and elsewhere, and the fibrin and
necrotic smooth muscle of “fibrinoid necrosis.” Fibrinoid necro-
sis may predate and initiate inflammatory cellular infiltration,
after which the reaction would be termed arteritis. Thickening
of the arteriolar wall may cause luminal narrowing and hence
ischemia of the region supplied.
Systemic hypertension, or persistently elevated systemic
as either primary (essential) hypertension or secondary hyperten-
sion. Both forms of hypertension are typically prolonged in
their clinical course, but accelerated or malignant hypertension
develops in about 5% of affected individuals. Both primary
and secondary hypertensions have been reported in dogs and
cats; the primary form is rare, and the secondary form is more
common. Hypertension may often go unrecognized as the
routine measurement of blood pressure in domestic animals
is problematic and as such is not part of the routine physical
examination. The diagnosis of hypertension could well become
more frequent as noninvasive techniques for measurement of
blood pressure come into common use.
Renal disease, likely the most common cause of hypertension
in dogs and cats, may be either a cause or an effect of hyper-
tension, thus determining whether a hypertensive vascular
hypertensive lesions can lead to decreased renal perfusion,
activation of the renin-angiotensin-aldosterone system, and
hence more hypertension. On the other hand, primary chronic
renal disease can lead to inadequate excretion of sodium and
water, blood volume expansion, and hence secondary hyper-
tension. In either case, hypertension is self-perpetuating as
medial hypertrophy and hyalinization of renal arteries 
lead to more nephrosclerosis, further hypertension, and more
pressure-induced vascular damage.
Secondary hypertension is reported to occur in >60% of
dogs with chronic renal disease, and may also occur in associa-
tion with endocardiosis, pheochromocytoma, hyperadreno-
corticism, hypothyroidism and hyperthyroidism, and diabetes
mellitus. In cats, hypertension occurs in association with
chronic renal disease, hyperthyroidism, and chronic anemia.
Systemic and local hypertensions reportedly accompany acute
and chronic laminitis in horses; hypertension is suggested to
occur in acute and chronic laminitis in cattle. The hyperten-
sion of feline hyperthyroidism is reversible on resolution of
the primary condition. The presenting sign in canine and feline
hypertension may be blindness due to hypertensive retinopathy;
ocular lesions include retinal vascular tortuosity, intraocular
hemorrhage, and retinal detachment, the results of retinal
arterial degeneration. In the face of hypertension, retinal and
choroidal arterioles constrict; sustained vasoconstriction may
lead to ischemic necrosis of the arteriolar smooth muscle,
increased vascular permeability, hyalinization, edema, and
hemorrhage. Left ventricular hypertrophy commonly occurs
60 CHAPTER 1  •  Cardiovascular System Arteries

in hypertension in response to increased demand for cardiac

output plus increased peripheral vascular resistance (increased
afterload).
Pulmonary hypertension—persistent elevation of pulmonary
arterial blood pressure—can occur both as the cause and as the
result of pulmonary arterial disease (see Vol. 2, Respiratory
system); and, in this chapter, Arterial hypertrophy, and Diro-
filariasis (heartworm disease).
Widespread arterial degeneration commonly occurs in dogs
with uremia, and is most frequently noted in small muscular
arteries and arterioles of the gastric submucosa, tongue, colon,
gallbladder, urinary bladder, and kidneys. Less frequently
affected are arteries of the small intestine, myocardium, and
other organs. The arterial and arteriolar lesions, in concert with
degenerative capillary lesions, produce ischemic injury, and
contribute to grossly observed lesions of uremia, such as
uremic gastric infarction.
The arterial lesions of acute renal insufficiency consist of
subendothelial deposition of fibrin, disruption of the internal
elastic lamina, necrosis of medial smooth muscle, mineraliza- Figure 1-64  Arteriolar hyalinosis. The tunica media of the small
tion, and sometimes, neutrophilic infiltration. These lesions caliber coronary artery is partially replaced by eosinophilic amor-
may be segmental or circumferential in the vessel wall. This phous material (arrow) in a dog. H&E.
arterial reaction is primarily degenerative rather than inflam-
matory, and is similar to hyaline arteriolosclerosis of benign
nephrosclerosis (patchy ischemic atrophy) in humans. In Arteriolar hyaline degeneration is seen in swine as part of
chronic renal insufficiency, medial hypertrophy and adventitial the pathologic picture in meninges in organomercurial poison-
fibrosis produce thickening and whorling of renal interlobular ing, in various organs in edema disease, and chiefly in the heart
and intralobular arteries and afferent arterioles. These changes in hepatosis dietetica and mulberry heart disease. The progres-
are similar to hyperplastic arteriolosclerosis of humans, which sion of arterial lesions in edema disease is from mural edema,
is characterized by concentric fibrosis and smooth muscle to hyaline degeneration, to medial necrosis and intramural and
proliferation in the intima (onion-skinning); these hyperplastic perivascular hemorrhage, at which stage acute severe hyper-
changes, in combination with fibrinoid necrosis of the media tension develops, likely as a result of increased vascular resis-
of arterioles, are features of malignant hypertension. tance, and hypertension in turn exacerbates vascular damage;
Hyalinosis is commonly observed in the splenic arterioles adventitial proliferation follows in survivors. Certain strains 
of dogs and pigs, affecting most frequently those of the lym- of Escherichia coli produce edema disease toxin (Shiga-like
phatic nodules. This change is more severe in dogs with a toxin-II variant, SLT-IIv), which preferentially targets vessels
variety of diseases, including diabetes mellitus and chronic of the gastric and colonic submucosa and the cerebellar folia,
renal disease, and thus may be of hypertensive origin. A hyper- perhaps because of concentration of a toxin receptor, such as
trophic hyalinization is regularly observed in the uterine  globotetraosylceramide, at these sites.
and ovarian arteries in pregnant and postpartum animals;  Cerebrospinal angiopathy in swine is characterized by
the elastic tissue is increased in amount, the intima is mark- lesions in arterioles, primarily in the brainstem, which include
edly thickened and hyaline, and the muscularis may be subendothelial hyaline deposits, degeneration or fibrinoid
atrophic. necrosis of the media, and perivascular eosinophilic droplets.
Hypertrophic hyalinization, or hyalinosis, is observed in old The vascular lesions cause demyelination and malacia, and
dogs, affecting principally the intramural coronary arteries (Fig. hence nervous signs, and are probably manifestations of sub-
1-64) and small meningeal and cerebral vessels. The hyaliniza- clinical edema disease.
tion is not clearly of clinical significance in the brain but may
cause multifocal intramural myocardial infarction (MIMI) and,
in concert with valvular endocardiosis, lead to congestive heart Further reading
failure. The hyaline deposits consist predominantly of fibrin Kellihan HB, Stepien RL. Pulmonary hypertension in dogs: diagnosis
or glycosaminoglycans or, less commonly, amyloid. Other and therapy. Vet Clin North Am Small Anim Pract 2010;40:623-
lesions encountered in the intramyocardial arteries include 641.
musculoelastic intimal thickenings, intimal cushions, and Reusch CE, et al. Endocrine hypertension in small animals. Vet Clin
microthrombi; these lesions occur at sites of turbulent blood North Am Small Anim Pract 2010;40:335-352.
flow, namely, bifurcations and branchings. Stepien RL. Feline systemic hypertension: diagnosis and management.
Sclerosis of intramural coronary arteries, predominantly of J Fel Med Surg 2011;13:35-43.
the left ventricle, occurs in dogs with congenital subaortic Zabka TS, et al. Pulmonary arteriopathy and idiopathic pulmonary arte-
stenosis and occurs in the right ventricle of dogs with pul- rial hypertension in six dogs. Vet Pathol 2006;43:510-522.
monic stenosis. Intimal thickening resulting from fibroelastic
and smooth muscle proliferation can result in myocardial
infarction and scarring. The intimal proliferation may occur in Mineralization
response to decreased coronary perfusion pressure and Mineralization (calcification) occurs quite frequently in the
increased intramural tension during systole. arteries of animals, either as a dystrophic or metastatic process.
 60.e1

Further reading
Andersson L, Bergman A. Pathology of bovine laminitis especially as
regards vascular lesions. Acta Vet Scand 1980;21:559-566.
Cheville NF. Uremic gastropathy in the dog. Vet Pathol 1979;16:292-
309.
Davies TS, et al. The pathology of subacute methylmercurialism in
swine. Cornell Vet 1976;66:32-55.
Dimski DS, Hawkins EC. Canine systemic hypertension. Compend
Contin Educ Pract Vet 1988;10:1152-1158.
Kamiya S, Daigo M. Relationship between glycosaminoglycans and
pregnancy-induced sclerosis in bovine uterine arteries. Jpn J Vet Sci
1988;50:1055-1059.
Kobayashi DL, et al. Hypertension in cats with chronic renal failure or
hyperthyroidism. J Vet Internal Med 1990;4:58-62.
MacLeod DL, et al. Reproduction of edema disease of swine with puri-
fied Shiga-like toxin-II variant. Vet Pathol 1991;28:66-73.
Nakamura K, et al. Perivascular eosinophilic droplets in swine brain
induced by Escherichia coli toxin. Can J Vet Res 1986;50:438-440.
Nielsen NO. Edema disease. In: Leman AD, et al., editors. Diseases of
Swine. 6th ed. Ames, Iowa: Iowa State University Press; 1986.
p. 528-540.
Paulsen ME, et al. Arterial hypertension in two canine siblings: ocular
and systemic manifestations. J Am Anim Hosp Assoc 1989;25:287-
295.
Perry LA, et al. Pulmonary hypertension. Compend Contin Educ Pract
Vet 1991;13:226-233.
Rau L. Hypertension, endothelium, and cardiovascular risk factors. Am
J Med 1991;90(Suppl. 2A):13S-18S.
Van Vleet JF, et al. Ultrastructural alterations in nutritional cardiomy-
opathy of selenium-vitamin E deficient swine: II. Vascular lesions.
Lab Invest 1977;37:201-211.
Diseases of the Vascular System
Figure 1-65  Extensive mineralization of the aorta in Solanum
glaucophyllum (S. malacoxylon) poisoning (vitamin D analogue
toxicosis) in a horse. (Courtesy E. Odriozola, F. Gianitti.)
Dystrophic mineralization, or mineralization of dying or dead
tissue, occurs in areas of inflammation, degeneration, and
thrombosis, and not necessarily in association with pre-existing
arteriosclerosis. Metastatic mineralization occurs as the result
of hypercalcemia and/or hyperphosphatemia. The distinction
between dystrophic and metastatic mineralization may be
artificial. In vitamin D toxicosis, for example, some maintain
that degeneration occurs prior to mineralization as a result of
direct vitamin D toxicity, and that hypercalcemia and miner-
alization are secondary events. Although the cardiovascular
system is particularly susceptible to mineralization, mineral-
ization of other soft tissues, such as the renal tubular and
pulmonary alveolar basement membranes, endocardium and
myocardium, and gastric mucosa, usually occurs concomi-
tantly with vascular mineralization.
Vitamin D poisoning occurs in a variety of circumstances,
and leads to mineralization of vessels and other tissues in
association with hypercalcemia and/or hyperphosphatemia (Fig.
1-65). The disease can be endemic in herbivores, cattle  and sites of predilection include the globus pallidus and inter-
most often, that have consumed plants (such as Solanum
glaucophyllum [formerly Solanum malacoxylon], S. torvum,
Trisetum flavescens, Cestrum diurnum) that contain 1,25-
dihydroxycholecalciferol or a related compound. Horses and
pigs are occasionally poisoned by inadvertent overdoses of
vitamin D in feed. Accidental poisoning of dogs and cats with
a cholecalciferol (vitamin D3) rodenticide is common.
Mineralization occurs in dogs with hypercalcemia resulting
from pseudohyperparathyroidism, in some dogs in association
with chronic renal insufficiency, and in hypomagnesemic
cattle. Mineralization also occurs spontaneously in animals of
advanced age and, in cattle especially, in a variety of chronic
debilitating diseases, such as Johne’s disease. In sporadic cases,
the causes of mineralization are generally unknown and may
be nonspecific.
Calcium and phosphorus are deposited in association with
extracellular vesicles adjacent to elastic fibers and, in the
smaller vessels, may produce a complete, concentric ring of
medial mineralization; this is the domestic animal equivalent
of Monckeberg’s arteriosclerosis (medial calcific sclerosis) of
humans. Mineralized lesions in the aorta and pulmonary artery
are usually in the form of flat plaques and are often very strik-
ing grossly; complete encirclement is seldom seen. The
Arteries 61
Figure 1-66  Intimal bodies (arrow) in a horse.
button-like protuberances that are seen in the aorta about the
orifices of smaller branches are not primarily aortic but,
instead, concentric lesions in the small efferents that project
when the opened vessel undergoes elastic recoil. The plaques
in the large vessels are brittle, and the smaller arteries are
transformed into rigid tubes that can be fractured easily.
Osseous metaplasia may also occur.
Intimal bodies occur commonly in small arteries and arteri-
oles of horses, particularly in the submucosa of the intestine,
but in other organs as well. Intimal bodies appear in section
as multiple irregular mineralized masses covered by endothe-
lium and usually protruding into the arterial lumen (Fig.
1-66). They occur in horses of all ages, are not associated with
strongyle infection, and have no apparent functional signifi-
cance. These bodies apparently arise from degeneration and
mineralization of subendothelial smooth muscle cells and
intercellular material.
The deposition of iron salts with calcium (siderocalcinosis)
is observed commonly in horses, the incidence and severity of
the change increasing with age. Vessels of all types are involved
nal capsule in the brain. Mostly, the deposits are without
notable consequence, but secondary malacia may occur. It is
also possible that malacia of other cause may exacerbate the
cerebrovascular siderosis.
The mineralized nodules in the intima of the aorta in the horse
are probably all healed lesions of verminous arteritis (Strongy-
lus vulgaris migration).
Further reading
Eason C, et al. Toxicity of cholecalciferol to rats in a multi-species bait.
N Z J Ecol 2010;34:233-236.
Falk T, et al. Arteriosclerotic changes in the myocardium, lung, and
kidney in dogs with chronic congestive heart failure and myxoma-
tous mitral valve disease. Cardiovasc Pathol 2006;15:185-193.
Murphy MJ, Talcott PA. Anticoagulant rodenticides. In: Peterson ME,
Talcott PA, editors. Small Animal Toxicology. 3rd ed. St Louis:
Elsevier; 2013. p. 435-446.
Schenck PA, Chew DJ. Hypercalcemia: a quick reference. Vet Clin North
Am Small Anim Pract 2008;38:449-453.
Schwarz T, et al. Aortic and cardiac mineralization in the dog. Vet
Radiol Ultrasound 2002;43:419-427.
 61.e1

Further reading
Bjotvedt G. Spontaneous renal arteriosclerosis in greyhounds. Canine
Pract 1986;13:26-30.
Bundza A, Stevenson DA. Arteriosclerosis in seven cattle. Can Vet J
1987;28:49-51.
De Oliveira AC, et al. Intimal asteroid bodies in horses: light and elec-
tron microscopic observations. Vet Pathol 1985;22:226-231.
Drazner FH. Hypercalcemia in the dog and cat. J Am Vet Med Assoc
1981;178:1252-1256.
Haggard DL, et al. Tetany associated with magnesium deficiency in
suckling beef calves. J Am Vet Med Assoc 1978;172:495-497.
Imaizumi K, et al. Morphological changes of the aorta and pulmonary
artery in thoroughbred racehorses. J Comp Pathol 1989;101:1-9.
Morris KML. Plant induced calcinosis: a review. Vet Human Toxicol
1982;24:34-48.
Rosol TJ, Capen CC. Pathogenesis of humoral hypercalcemia of malig-
nancy. Domestic Anim Endocrinol 1988;5:1-21.
Thomas JB, et al. Cholecalciferol rodenticide toxicity in a domestic cat.
Aust Vet J 1990;67:274-275.
62 CHAPTER 1  •  Cardiovascular System Arteries

Arterial rupture, aneurysms

Rupture of arteries as a result of physical trauma is common;
spontaneous ruptures are not. The aortic lesions produced by
Spirocerca lupi in dogs occasionally lead to rupture. Rupture of
a uterine artery is a cause of fatal hemorrhage in aged mares
at parturition and is associated with low serum copper levels.
Mycotic infection in the guttural pouch in horses may lead to
focal destruction of the wall of the internal carotid or maxil-
lary artery and can lead to fatal hemorrhage.
Rupture of the aorta is well known, but certainly uncommon,
in the horse. The ruptures occur during periods of excitement
and activity, such as racing or in stallions while breeding, and
are probably related to increased intra-aortic pressure. A pre-
disposing aortic lesion has not been definitely identified, but
fragmentation, degeneration, and mineralization of elastic A
fibers may contribute to weakening of the wall. “Cystic medial
necrosis,” the presence of pools of ground substance within
the elastic media, has been suggested to be an underlying
cause, but this change is present in the aortas of many normal
horses. Intimal thickening and medial fibrosis of vasa vasora
may predispose to aortic medial necrosis and rupture. Tears
occur in the ascending aorta at any level from the aortic val-
vular annulus to the level of the brachiocephalic trunk (Fig.
1-67A), and range from 0.5-1 cm tears in the right coronary
sinus to large transverse or 3-cornered tears in the cranial wall
of the aorta. Hemorrhage may occur into a number of differ-
ent sites. Hemopericardium, the most common sequel to aortic
rupture, leads to sudden death; hemorrhage into, and disrup-
tion of, the atrioventricular node or bundle of His also leads
to sudden death; dissection through the ventricular septum
and into the right ventricle (aortocardiac fistula) causes pro-
gressive right heart failure; dissection of blood along the aortic B
wall may lead to formation of an aneurysm, which may in turn Figure 1-67  A. Aortic rupture (arrow) in a horse. (Courtesy E.
rupture. Olson.) B. Rupture and linear tears in the root of the pulmonary
Spontaneous rupture of the pulmonary artery also occurs artery (arrows) in a horse (Courtesy M. Chalkley.)
in horses, but is even less frequent than aortic rupture 
(Fig. 1-67B).
Rupture of the aorta, pulmonary artery, or coronary artery
occurs experimentally, although not as a natural event, in greyhounds, possibly as a result of arteriosclerosis and hemo-
copper-deficient swine, and has been extensively investigated dynamic stresses, and can rupture with fatal consequences.
because of similarities with Marfan syndrome, an inherited Dissecting aneurysms may be of consequence by causing ste-
disorder in the fibrillin 1 (FBN1) gene in man and cattle in nosis of the aortic lumen, as well as by rupturing. True aneu-
which dissecting aortic aneurysms occur. Degeneration of elas- rysms are composed of all, or most, of the layers of the vessel wall.
tica appears to be the basis of the vascular lesions of copper Dilation of the cranial mesenteric artery may occur in the
deficiency, and is due to a deficiency of a copper-containing course of verminous arteritis in horses; the arterial wall is often
enzyme, lysyl oxidase, which is responsible for cross-linking of greatly thickened, but the dilation could be termed an inflam-
collagen and elastin. Similarly, feeding β-aminoproprionitrile matory rather than a true aneurysm. False aneurysms result
to pigs, rats or turkeys causes dissecting aortic aneurysms and from rupture of an artery or aneurysm and are essentially
skeletal changes, an experimental model known as lathyrism, hematomas communicating with an arterial lumen; their walls
but is due to inhibition, rather than deficiency, of lysyl oxidase. are formed by the surrounding fibrous tissue.
An aneurysm is a localized abnormal dilation of any vessel.
Aneurysms are of most importance when they affect the aorta;
they occur most commonly in humans as a complication of Further reading
atherosclerosis, but are infrequent occurrences in domestic Gershenson RT, et al. Abdominal aortic aneurysm associated with sys-
animals other than turkeys. On the basis of their gross appear- temic fungal infection in a German Shepherd dog. J Am Anim Hosp
ance, aneurysms may be classified as berry, saccular, fusiform, Assoc 2011;47:45-49.
or dissecting. In a dissecting aneurysm, blood enters the wall Hirano T, et al. Identification of an FBN1 mutation in bovine Marfan
of an artery through an intimal tear, dissects between medial syndrome-like disease. Anim Genet 2012;43:11-17.
layers, and creates a cavity within the arterial wall. A dissecting Lepage OM, et al. The mystery of fungal infection in the guttural
aortic aneurysm (dissecting hematoma, or acute aortic dissec- pouches. Vet J 2004;168:60-64.
tion) is one manifestation of aortic rupture in horses, and  Ploeg M, et al. Aortic rupture and aorto-pulmonary fistulation in the
may precede fatal aortic rupture. Dissecting aneurysms occur Friesian horse: characterization of the clinical and gross post-
in the coronary and renal arteries of young, male, racing  mortem findings in 24 cases. Equine Vet J 2013;45:101-106.
 62.e1

Further reading
Chetboul V, et al. Familial aortic aneurysm in Leonberg dogs. J Am Vet
Med Assoc 2003;223:1159-1162.
Coulson WF, et al. Lathyrism in swine. Arch Pathol 1969;87:411-417.
Marr CM, et al. Aorto-cardiac fistulas in seven horses. Vet Radiol Ultra-
sound 1998;39:22-31.
Potter KA, Besser TE. Cardiovascular lesions in bovine Marfan syn-
drome. Vet Pathol 1994;31:501-509.
Rings DM, et al. False carotid aneurysm in a sheep. J Am Vet Med Assoc
1986;189:799-801.
Robinson PN, Booms P. The molecular pathogenesis of the Marfan
syndrome. Cell Mol Life Sci 2001;58:1698-1707.
Simpson CF, et al. Similarity of aortic pathology in Marfan’s syndrome,
copper deficiency in chicks, and B-aminopropionitrile toxicity in
turkeys. Exp Mol Pathol 1980;32:81-90.
Stowe HD. Effects of age and impending parturition upon serum
copper of thoroughbred mares. J Nutr 1968;95:179-183.
van der Linde-Sipman JS, et al. Necrosis and rupture of the aorta and
pulmonary trunk in four horses. Vet Pathol 1985;22:51-53.
Diseases of the Vascular System
Figure 1-68  Organizing thrombus in the pulmonary artery of a
dog. H&E. (Courtesy E. Olson.)
Sleeper MM, et al. Aortic root disease in four horses. J Am Vet Med
Assoc 2001;219:491-496.
Waldrop JE, et al. Aortic dissection associated with aortic aneurysms
and posterior paresis in a dog. J Vet Intern Med 2003;17:
223-229.
Arterial thrombosis and embolism
The 3 major predispositions to thrombosis are
1. Injury to endothelium, for instance, via infectious, toxic, or
immunologic mechanisms
2. Altered blood flow, as occurs with stasis or turbulence
3. Hypercoagulability of the blood, which may result from
increased concentrations of activated procoagulants,
increased numbers or stickiness of platelets, or decreased
concentrations of inhibitors such as antithrombin in the
nephrotic syndrome.
The relative contribution of each of the above 3 features
(Virchow’s triad) may vary. Endothelial injury, by itself, is the
major cause of thrombosis, especially in the heart and arteries.
Stasis must usually be combined with endothelial damage
and/or hypercoagulability to induce thrombosis.
Thrombi are of importance because they occlude the vessel
at the site involved (Fig. 1-68), and because pieces of the
thrombus break off giving rise to emboli that may occlude
vessels distal to the site of thrombosis. Arterial occlusion is of
significance in organs with an end-arterial blood supply, such
as the kidney, because of the absence of collateral circulation
and the development of infarction. Simultaneous occlusion of
a large number of pulmonary arterioles or arteries by thrombi
can lead to right heart failure (cor pulmonale) and death. Even
in areas with extensive collateral circulation, blood flow in
vessels that are not thrombosed may be compromised by the
release of vasoactive substances, such as serotonin and/or pros-
taglandins from the thrombus.
Specific causes and examples of thrombosis abound. As
discussed later, thrombosis is a common complication of arte-
ritis. Specific examples of thrombosis, namely, aortic-iliac
thrombosis in horses and disseminated intravascular coagula-
tion, are discussed later.
Thromboembolism occurs in a variety of conditions and
species (eFig. 1-16). In verminous arteritis in horses, emboli
Arteries 63
Figure 1-69  Iliac thromboembolism in a cat.
arise from thrombi in the cranial mesenteric artery and cause
intestinal ischemia, and possibly infarction. Saddle thromboem-
boli of the aortic trifurcation in cats (Fig. 1-69) arise from
thrombi in the dilated left atrium in cases of cardiomyopathy
and cause paraparesis of acute onset; the clinical signs of aortic
trifurcation obstruction, referred to as the 5 p’s, are pain, paresis,
pulselessness, poikilothermy, and pallor. Arterial thromboembo-
lism occasionally occurs as a result of congenital cardiac
defects and the formation of intracardiac thrombi. Emboli
commonly arise from the cardiac valves in cases of vegetative
bacterial endocarditis. Thrombi that develop in animals under-
going extended anesthesia can result in fatal pulmonary
microthromboembolism, a common occurrence in humans,
but a condition that is seldom recognized in domestic animals.
Pulmonary thromboembolism may well complicate a variety
of conditions, such as cardiac or renal disease, physical 
trauma, disseminated intravascular coagulation, hyperadreno-
corticism, and neoplasia, but be underdiagnosed as a cause of
morbidity.
Thrombosis is by far the most common antecedent to
embolism, but emboli other than thromboemboli occasionally
occur. Venous air embolism is a rare complication of pneumo-
cystography, laparoscopy, or cryosurgery; an air trap develops
in the right ventricle and may cause fatal blockage of circula-
tion. Foreign bodies, such as pellets or bullets, may be embolic
and occlude major vessels such as the aorta. Larval and adult
parasites, such as strongyles and heartworms, may be embolic
in the arterial system, especially if killed by therapy, and may
cause arterial occlusion plus a granulomatous response. Emboli
of neoplastic cells can result in distant metastases. Fibrocarti-
laginous embolism can result in necrotizing myelopathy in
dogs, pigs, and humans (Fig. 1-70). Fractures of bones, espe-
cially of those of the pelvis, and trauma of soft tissues can
result in fat embolism; death may occur because of emboliza-
tion of the central nervous system. Embolic fat may also
originate from rupture of fat-laden hepatocytes.
Further reading
Carr AP, et al. Prognostic factors for mortality and thromboembolism
in canine immune-mediated hemolytic anemia: a retrospective
study of 72 dogs. J Vet Intern Med 2002;16:504-509.
de Laforcade AM. Diseases associated with thrombosis. Top Comp
Anim Med 2012;27:59-64.
Gandini G, et al. Fibrocartilaginous embolism in 75 dogs: clinical find-
ings and factors influencing the recovery rate. J Small Anim Pract
2003;44:76-80.
 63.e1

eFigure 1-16  Laminations in an arterial thrombus, with organi-

zation from the intima and markedly reduced eccentric lumen, in
aortic-iliac thrombosis in a calf.
63.e2

Further reading
Anderson WI, et al. Infarction of the pons and medulla oblongata
caused by arteriolar thrombosis in a horse. Cornell Vet 1990;80:285-
289.
Boswood A, et al. Aortic and iliac thrombosis in six dogs. J Small Anim
Pract 2000;41:109-114.
Du Preez ER, et al. Aortic thromboembolism associated with traumatic
reticuloperitonitis in a downer cow. J S Afr Vet Assoc 1995;66:254-
255.
Forrest LJ, et al. Digital arterial thrombosis in a septicemic foal. J Vet
Intern Med 1999;13:382-385.
Gilroy BA, Anson LW. Fatal air embolism during anesthesia for laparos-
copy in a dog. J Am Vet Med Assoc 1987;190:552-554.
Green RA. Pathophysiology of antithrombin III deficiency. Vet Clin
North Am Small Anim Pract 1988;18:95-104.
Jones RS, et al. Pulmonary micro-embolism following orthopaedic
surgery in a thoroughbred gelding. Equine Vet J 1988;20:382-384.
LaRue MJ, Murtaugh RJ. Pulmonary thromboembolism in dogs: 47
cases (1986-1987). J Am Vet Med Assoc 1990;197:1368-1372.
Meschter CL. Disseminated sweat gland adenocarcinoma with acrone-
crosis in a cat. Cornell Vet 1991;81:195-203.
Rudmann DG, Stevenson GW. Aortic-iliac thromboembolism as an
uncommon sequel to Staphylococcus aureus valvular endocarditis
in a calf. J Vet Diagn Invest 1993;5:288-290.
Schermerhorn T, et al. Pulmonary thromboembolism in cats. J Vet
Intern Med 2004;18:533-535.
Stuart BP, et al. Ischemic myopathy associated with systemic dirofila-
riasis. J Am Anim Hosp Assoc 1978;14:36-39.
Swanwick RA, Williams OJ. Fatal myocardial infarct in a greyhound.
J Small Anim Pract 1982;23:451-455.
Whigham HM, et al. Aortic foreign body resulting in ischemic neuro-
myopathy and development of collateral circulation in a cat. J Am
Vet Med Assoc 1998;213:829-832.
64 CHAPTER 1  •  Cardiovascular System
Figure 1-70  Fibrocartilaginous emboli in the meningeal and
spinal cord veins of a dog. H&E. (Courtesy A. Allen, coordinator,
Western Conference of Veterinary Diagnostic Pathologists.)
Figure 1-71  Large organized thrombus in the terminal aorta and
the internal and external iliac arteries in a horse with aortic-iliac
thrombosis. (Courtesy University of Guelph.)
Kuzi S, et al. Plasma antithrombin activity as a diagnostic and prognos-
tic indicator in dogs: a retrospective study of 149 dogs. J Vet Int
Med 2012;24:587-596.
Smith SA, Tobias AH. Feline arterial thromboembolism: an update. Vet
Clin North Am Small Anim Pract 2004;34:1245-1271.
Terrell SP, et al. Fatal intraoperative pulmonary fat embolism during
cemented total hip arthroplasty in a dog. J Am Anim Hosp Assoc
2004;40:345-348.
Whiteman T, Hassouna HI. Hypercoagulable states. Hematol Oncol Clin
North Am 2000;14:355-377.
Aortic-iliac thrombosis in horses
Aortic-iliac thrombosis causes exercise intolerance and hindleg
lameness (intermittent claudication) in affected horses. The
condition is seen most frequently in racing Thoroughbreds and
Standardbreds, especially young males. The oldest lesions are
located at the aortic quadrifurcation and in the distal portions
of the femoral and internal iliac arteries (Fig. 1-71, eFigs. 1-17,
1-18), and consist of partially or completely occlusive masses
Arteries
of well-organized and well-vascularized fibrous tissue, occa-
sionally containing hemorrhagic or degenerate areas. Proximal
to these organized masses, large unorganized thrombi are
often present. The tunica intima is obliterated by the occlusive
masses, except for the internal elastic lamina, which usually
remains intact. The tunica media is largely unaffected, except
for ischemic necrosis of the media in greatly distended arteries
or under thick plaques. The pathogenesis of the lesions is
unknown. The lesions may result from organization of
strongyle-related thromboemboli, or from progressive enlarge-
ment and organization of spontaneously developing fibrous
intimal plaques.
Further reading
Oyamada T, et al. Pathology of aortic-iliac thrombosis in two horses.
J Equine Sci 2007;18:59-65.
Swanson TD. Aortic-iliac thrombosis in horses. Compend Contin Ed
Pract Vet 2011;33:E1-E3.
Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) is a common and
important intermediary mechanism of disease, but is not a disease
in itself. It may be defined as a pathologic activation of the
coagulation system that leads to generalized intravascular clot-
ting involving, in particular, arterioles and capillaries. The
process may be acute, subacute, or chronic, and may be localized
or generalized. Macrothrombosis does not usually develop in
this disorder. The terms “consumption coagulopathy,” “defibrina-
tion syndrome,” and “consumptive thrombohemorrhagic disorder”
are also used because of the massive consumption of coagula-
tion factors that occurs and that may be sufficiently severe for
hemorrhagic diathesis to result.
A wide array of agents and conditions will initiate coagulation
(Box 1-1), either by
• Causing widespread endothelial damage and thus exposing
thrombogenic subendothelial collagen, or
• Directly activating the coagulation cascade via the intrinsic
or extrinsic pathway.
Exposure of monocytes, macrophages, and endothelial cells
to disease agents or mediators will cause expression of tissue
factor (tissue thromboplastin) on the cell surfaces and activation
of the extrinsic pathway of coagulation, and is likely a pre-
dominant pathway of DIC. As well as leading to expression
of intravascular tissue factor, inflammation promotes coagula-
tion by eliciting the expression of leukocyte adhesion molecules
on intravascular cell surfaces, and by downregulating the fibri-
nolytic and protein C anticoagulant pathways. Thrombin can
in turn promote inflammatory responses, leading to further
vascular injury. Stasis of blood flow and plasma hyperviscosity
are other factors that may contribute to DIC.
Many of the agents listed in Box 1-1 may initiate DIC by
more than one route. For example, gram-negative bacterial
endotoxin can cause
• Endothelial damage (either directly or via mediators such
as interleukin-1 and tumor necrosis factor), which exposes
subendothelial collagen and leads to activation of platelets
and Hageman factor
• Activation of the complement cascade and hence platelet
activation
• Direct activation of Hageman factor and hence the intrin-
sic pathway
 64.e1

eFigure 1-17  Organized thrombi partially occluding external

iliac and popliteal arteries in a horse with aortic-iliac thrombosis.
(Courtesy University of Guelph.)

a b c d

e f g

eFigure 1-18  Aortic-iliac thrombosis in a horse. Sections of left

external iliac-femoral-popliteal artery. (a) Peripheral organization
of partially occlusive thrombotic mass. (a-c, e-g) various degrees
of arterial occlusion by mature fibrous tissue. (d) unaffected artery
distal to lesion. Masson trichrome. (From Maxie MG, Physick-
Sheard PW. Aortic-iliac thrombosis in horses. Vet Pathol
1985;22:238-49.)
64.e2

Further reading
Brama PA, et al. Thrombosis of the aorta and the caudal arteries in the
horse; additional diagnostics and a new surgical treatment. Vet Q
1996;18(Suppl. 2):S85-S89.
Maxie MG, Physick-Sheard PW. Aortic-iliac thrombosis in horses. Vet
Pathol 1985;22:238-249.
Moore LA, et al. Aorto-iliac thrombosis in a foal. Vet Rec 1998;142:
459-462.
Diseases of the Vascular System Arteries 65

kallikrein-kinin system; generation of kinins contributes to

BOX • 1-1  increased vascular permeability, hypotension, and shock.
When coagulation is initiated, activated Hageman factor
Agents or conditions known to induce
simultaneously converts plasminogen to plasmin. Plasmin
disseminated intravascular coagulation cleaves fibrinogen/fibrin to produce fibrinogen/fibrin degrada-
in animals tion products that inhibit thrombin activity, fibrin polymeriza-
tion, and platelet aggregation. A negative feedback system
Bacteria normally exists between thrombosis (coagulation) and fibri-
• Gram-negative (endotoxin)
nolysis (anticoagulation) in which thrombin helps convert
• Gram-positive
plasminogen to plasmin to cause fibrinolysis and hence limit
• Rickettsia rickettsii (Rocky Mountain spotted fever)
thrombosis. In addition, a dynamic equilibrium exists between
production of tissue plasminogen activator and production of
Helminths plasminogen activator inhibitors by endothelial cells.
• Angiostrongylus vasorum
The clinical manifestations of DIC are protean and vary with
• Dirofilaria immitis
the organ(s) in which thrombosis predominates and the severity
of a hemorrhagic diathesis. Clinical presentations include shock,
Protozoa organ failure, hemorrhage, or hemolysis depending upon the
• Babesia spp.
relative activation of thrombin and plasmin and hence the
• Sarcocystis spp.
dominance of thrombosis or hemorrhage. Hemorrhage is
• Theileria spp.
usually only seen in animals that survive acute episodes with
• Trypanosoma spp.
thrombosis and shock, or in those reacting to a moderate
procoagulatory stimulus. Perhaps the most common result of
Viruses acute DIC is shock, which is due to reduced venous return to
• African swine fever virus
the right heart, plus systemic and pulmonary arterial hyper-
• Aleutian mink disease virus
tension resulting from thrombosis. Specific examples of DIC
• Bluetongue virus
include
• Canine adenovirus 1 (infectious canine hepatitis)
• The generalized Shwartzman-like reaction (GSR) (bilat-
• Classical swine fever virus
eral hemorrhagic renal cortical necrosis, induced experi-
• Epizootic hemorrhagic disease virus of deer
mentally by timed injections of endotoxin), which is seen
• Feline infectious peritonitis virus
as a cause of oliguric renal failure in septicemic or endo-
toxemic postpartum cows
Neoplasia • Hemorrhagic adrenal necrosis (Waterhouse-Friderichsen
• Carcinoma
syndrome) seen in septicemic calves
• Hemangiosarcoma
• Microangiopathic hemolytic anemia (MHA) (an intravas-
• Leukemia
cular fragmentation anemia) seen in septicemic calves
• Acrocyanosis and gangrene seen in the extremities of
Other calves recovering from septicemia
• Aflatoxicosis
• The hemolytic-uremic syndrome (HUS), in which coagula-
• Antigen-antibody complexes—incompatible blood
tion is combined with microangiopathic hemolytic anemia
transfusion
and acute renal failure; a similar syndrome is seen in Grey-
• Gastric dilation-volvulus
hound dogs with idiopathic cutaneous and renal glomeru-
• Heat stroke
lar vasculopathy (“Alabama rot”).
• Hyperlipemia in ponies
Animals that die with DIC may have petechial to ecchy-
• Hyperosmolality
motic hemorrhages on mucosae and serosae and in the skin,
• Immunologic endothelial injury
and may have variable thrombotic or hemorrhagic involve-
• Ingestion of red maple leaves
ment of internal organs. Histologically, microthrombi may be
• Nephrotic syndrome
associated with congestion, edema, hemorrhage, and necrosis.
• Proteolytic enzymes—pancreatitis, snakebite
Microthrombi are most easily detected microscopically in capil-
• Shock, vascular stasis, prolonged anesthesia, acidosis
laries of brain, renal glomeruli, adrenals, lungs, and myocardium,
• Tissue necrosis—hepatic, pneumonia, postsurgery, burns
but may occur in any organ. They consist primarily of fibrin
(hyaline thrombi), platelets (granular thrombi), or of fibrin
degradation products (hyaline globules or “shock bodies”); pul-
monary alveolar hyaline membranes are also said to be a form
• Leukocyte damage, which results in tissue factor (tissue of hyaline microthrombi. Because fibrinolysis is an ongoing
thromboplastin) release process that continues after death, most microthrombi are lysed
Viral infections are postulated to induce DIC by viral- or within 3 hours of death and may not be found if postmortem
antiplatelet antibody–mediated platelet aggregation, by examination is delayed. With routine hematoxylin and eosin
causing endothelial damage, and by causing Hageman factor staining, microthrombi appear as homogeneous pink masses
activation by immune complexes. Also, in feline infectious in dilated small blood vessels. Identification of microthrombi
peritonitis for example, hepatic necrosis impairs macrophage is aided by the use of special stains such as Martius-scarlet-
clearance of activated clotting factors and may potentiate the blue, which stains fibrin red, or phosphotungstic acid 
coagulation defect. Another important pathophysiologic event hematoxylin (PTAH), which stains fibrin purple. Even with
that accompanies activation of coagulation is activation of the special stains, incompletely polymerized fibrin is difficult 
66 CHAPTER 1  •  Cardiovascular System
to demonstrate. Red cells that impinge on fibrin strands in the
microcirculation may fragment; these red cell fragments
(schistocytes) may be detected within blood vessels in histo-
logic sections as well as blood smears, thus serving as indica-
tors of DIC.
Further reading
Bensaude E, et al. Classical swine fever virus induces proinflammatory
cytokines and tissue factor expression and inhibits apoptosis and
interferon synthesis during the establishment of long-term infection
of porcine vascular endothelial cells. J Gen Virol 2004;85:1029-
1037.
Chantrey J, et al. Haemolytic-uraemic syndrome in a dog. J Vet Med A
Physiol Pathol Clin Med 2002;49:470-472.
Dallap BL. Coagulopathy in the equine critical care patient. Vet Clin
North Am Equine Pract 2004;20:231-251.
De Laforcade AM, et al. Serial evaluation of protein C and antithrom-
bin in dogs with sepsis. J Vet Int Med 2008;22:26-30.
Dolente BA, et al. Clinicopathologic evidence of disseminated intravas-
cular coagulation in horses with acute colitis. J Am Vet Med Assoc
2002;220:1034-1038.
Gao H, et al. Bench-to-bedside review: sepsis, severe sepsis and septic
shock—does the nature of the infecting organism matter. Critical
Care 2008;12:212-217.
Gasser AM, et al. Canine Rocky Mountain spotted fever: a retrospec-
tive study of 30 cases. J Am Anim Hosp Assoc 2001;37:41-48.
Hardaway RM. A review of septic shock. Am Surg 2000;66:22-29.
Monreal L, et al. Hypercoagulation and hypofibrinolysis in horses with
colic and DIC. Equine Vet J Suppl 2000;32:19-25.
Putsche JC, Kohn B. Primary immune-mediated thrombocytopenia in
30 dogs (1997-2003). J Am Anim Hosp Assoc 2008;44:250-257.
Vallee I, et al. African swine fever virus infection of porcine aortic
endothelial cells leads to inhibition of inflammatory responses,
activation of the thrombotic state, and apoptosis. J Virol
2001;75:10372-10382.
Arterial hypertrophy
Hypertrophy of arteries may affect one or all components of
the arterial wall. High-altitude disease of cattle, described later,
is a result of hypoxia-induced pulmonary arterial constriction
and subsequent hypertrophy that lead to pulmonary hyper-
tension and eventual right heart failure (cor pulmonale).
Various cardiac anomalies cause pulmonary arterial hyperten-
sion and hyperperfusion, which result in pulmonary arterial
hypertrophy and additional pulmonary hypertension. Arterial
hypertrophy occurs in collateral vessels in response to the extra
load they carry after occlusion of the artery that usually sup-
plies an area. A specific form of hypertrophy occurs in the
pulmonary arteries of cats and is described later. Systemic arte-
rial involvement in the hypertension associated with chronic
renal disease is described previously.
“High-altitude disease” of cattle
This disease is caused by pulmonary hypertension that results in
dilation and hypertrophy of the right ventricle with the ultimate
development of cardiac decompensation and right-sided congestive
cardiac failure. Edematous swelling of the venter, as is typical
of congestive heart failure in cattle, is responsible for the
synonym “brisket disease.” The syndrome in cattle resembles,
in many respects, the chronic mountain sickness of humans
residing at high altitude, and represents failure of the
Arteries
cardiorespiratory system to adjust to the hypoxia of higher
altitudes. There are species differences in the hypertensive
response to hypoxia; sheep and dogs are hyporesponders,
humans are intermediate, whereas cattle and pigs are hyper-
responders and are prone to develop hypertensive heart failure
at altitudes of ~2,500 meters and above. There are also varia-
tions within species, and some cattle react dramatically to
degrees of hypoxia that only mildly inconvenience others.
Young cattle are more susceptible than adults, and the mor-
bidity rate is highest in animals exposed to high altitudes for
the first time. In animals imported from low altitudes to about
3,500 meters, the incidence of severe pulmonary hypertension
approaches 50%, whereas in herds maintained at such alti-
tudes for many generations, high-altitude disease may not
affect >2%. The different morbidity rates are probably attrib-
utable to natural selection in the resident population.
Cattle exposed to critical altitudes, or experimentally to
comparable degrees of hypoxic stimulation, develop a several-
fold increase in pulmonary arterial pressure and pulmonary
vascular resistance that may gradually be reduced to near-
normotensive levels when the animals are returned to low
altitudes. A distinctive feature of the pulmonary vasculature
in cattle is the inherently well-developed muscular media of
the arteries and veins with diameters as small as 20 µm, which
implies an unusual potential for vasomotor activity. Hypoxia-
induced vasoconstriction leads to work-induced hypertrophy of
the muscular media of pulmonary arteries and arterioles, and
hence hypertension, and may be compounded by reaction
hypertrophy that occurs in response to increased arterial pres-
sure. In cattle affected with high-altitude disease, there is
uniformly prominent hypertrophy of the muscular media of
pulmonary arteries and arterioles, and usually adventitial pro-
liferation around pulmonary arteries of all sizes. The activation
of platelet-derived growth factor-β receptor-JNK1 signaling
may initiate this proliferation. The hypertension may also
cause endothelial damage, thrombosis, intimal proliferation,
and medial mineralization, especially in elastic pulmonary
arteries.
Further reading
Newman JH, et al. High altitude pulmonary hypertension in cattle
(brisket disease): candidate genes and gene expression profiling of
peripheral blood mononuclear cells. Pulm Circ 2011;1:462-469.
Panzhinskiy E, et al. Hypoxia induces a unique proliferative response in
adventitial fibroblasts by activating PDGF( receptor-JNK1 signalling.
Cardiovasc Res 2012;95:356-365.
Congenital and acquired cardiac disease and
pulmonary arterial hypertension
Congenital heart diseases that feature increased pulmonary
arterial pressure (hypertension) and increased blood flow
(hyperperfusion) often occur with left-to-right shunting of
blood, such as a large ventricular septal defect or patent
ductus arteriosus. Pulmonary arterial hypertension, which
may even lead to reversal of the shunt and cyanosis (Eisen-
menger’s syndrome), produces pulmonary arterial constriction
and hypertrophy, increased pulmonary vascular resistance, and
sustained pulmonary hypertension by means of a number of
arterial responses. These responses range from persistence of
the normal thick muscular wall configuration of fetal life, to
acquired lesions that are the response to hypertension. These
 66.e1

Further reading
Amano H, et al. Effects on endotoxin pathogenicity in pigs with acute
septicemia of Haemophilus parasuis infection. J Vet Med Sci
1997;59:451-455.
Asakura H, et al. Pathophysiology of disseminated intravascular coag-
ulation (DIC) progresses at a different rate in tissue factor-induced
and lipopolysaccharide-induced DIC models in rats. Blood Coagul
Fibrinolysis 2003;14:221-228.
Boudreaux MK, et al. Evaluation of antithrombin-III activity as a coin-
dicator of disseminated intravascular coagulation in cats with
induced feline infectious peritonitis virus infection. Am J Vet Res
1989;50:1910-1913.
Cowell AK, et al. Severe systemic reactions to Hymenoptera stings in
three dogs. J Am Vet Med Assoc 1991;198:1014-1016.
Esmon CT, et al. Inflammation, sepsis, and coagulation. Haematologica
1999;84:254-259.
Grindem CB, et al. Thrombocytopenia associated with neoplasia in
dogs. J Vet Intern Med 1994;8:400-405.
Hargis AM, Feldman BF. Evaluation of hemostatic defects secondary to
vascular tumors in dogs: 11 cases (1983-1988). J Am Vet Med
Assoc 1991;198:891-894.
Hertzke DM, et al. Glomerular ultrastructural lesions of idiopathic cuta-
neous and renal glomerular vasculopathy of greyhounds. Vet Pathol
1995;32:451-459.
Hoffmann R. Adrenal lesions in calves dying from endotoxin shock,
with special reference to the Waterhouse-Friderichsen syndrome.
J Comp Pathol 1977;87:231-239.
Kraje AC, et al. Unusual metastatic behavior and clinicopathologic
findings in eight cats with cutaneous or visceral hemangiosarcoma.
J Am Vet Med Assoc 1999;214:670-672.
Long PH, Payne JW. Red maple-associated pulmonary thrombosis in a
horse. J Am Vet Med Assoc 1984;184:977-978.
Machida N, et al. Myocardial infarction secondary to a disseminated
coagulopathy in a cow. Cornell Vet 1991;81:129-135.
Maxie MG, et al. A comparative study of the disease in cattle caused
by Theileria parva or T. lawrencei: II. Hematology, clinical chemistry,
coagulation studies and complement. Vet Parasitol 1982;10:1-19.
Millis DL, et al. Abnormal hemostatic profiles and gastric necrosis in
canine gastric dilatation-volvulus. Vet Surg 1993;22:93-97.
Momotani E, et al. Histopathological evaluation of disseminated intra-
vascular coagulation in Haemophilus somnus infection in cattle.
J Comp Pathol 1985;95:15-23.
Morris CF, et al. Hemolytic uremic-like syndrome in two horses. J Am
Vet Med Assoc 1987;191:1453-1454.
Norris CR, et al. Pulmonary thromboembolism in cats: 29 cases (1987-
1997). J Am Vet Med Assoc 1999;215:1650-1654.
Semeraro N, Colucci M. Changes in the coagulation-fibrinolysis balance
of endothelial cells and mononuclear phagocytes: role in dissemi-
nated intravascular coagulation associated with infectious diseases.
Int J Clin Lab Res 1992;21:214-220.
Strickland KN. Canine and feline caval syndrome. Clin Tech Small Anim
Pract 1998;13:88-95.
Teige J Jr, Gamlem H. The generalized Shwartzman reaction in asso-
ciation with E. coli enterotoxemia in a pig. Acta Vet Scand
1977;18:316-322.
Valladares JE, et al. Study of haemostatic disorders in experimentally
induced leishmaniasis in beagle dogs. Res Vet Sci 1998;64:195-198.
Wellde BT, et al. Trypanosoma vivax: disseminated intravascular coagu-
lation in cattle. Ann Trop Med Parasitol 1989;83(Suppl. 1):177-183.
Yeruham I, et al. Clinical, clinico-pathological and serological studies
of Babesia ovis in experimentally infected sheep. Zentralbl Veteri-
narmed B 1998;45:385-394.
66.e2

Further reading
Bisgard GE. Pulmonary hypertension in cattle. Adv Vet Sci Comp Med
1977;21:151-172.
Tucker A, Rhodes J. Role of vascular smooth muscle in the development
of high altitude pulmonary hypertension: an interspecies evalua-
tion. High Alt Med Biol 2001;2:173-189.
Diseases of the Vascular System Arteries 67

acquired lesions include prominent medial hypertrophy, intimal

proliferations that may be obliterative, disruption of elastic
laminae, adventitial fibrosis, and plexiform lesions (vascular
occlusion by myointimal proliferations containing irregular
vascular channels). These changes may be mediated by
increased expression of various mediators, such as matrix
metalloproteinases and endothelin-1. In the early, cellular,
phase of the lesion, migration of medial smooth muscle cells
through the internal elastic lamina and into the intima, pos-
sibly in response to a chemical attractant, such as endothelial
cell–derived growth factor, is followed by their conversion to
myofibroblasts and production of ground substance, collagen,
and elastin, which produce marked intimal thickening. Aged
mature lesions become less cellular, myofibroblasts revert to
smooth muscle cells, and thin elastotic septa separate wide
vascular channels; these channels may be thrombosed. As the
pulmonary vascular lesions progress, the arteries may dilate
and their walls undergo fibrinoid degeneration. Together, these Figure 1-72  Medial hyperplasia/hypertrophy of pulmonary arte-
lesions constitute “plexogenic pulmonary arteriopathy,” which riole in a cat (normal variation in cats). H&E.
in its more severe manifestations is an end-stage irreversible
arterial condition that is associated with a poor prognosis, 
even if the underlying cardiac anomaly can be corrected
surgically.
Of the acquired heart diseases, there is increasing evidence
that valvular lesions of the left heart, such as canine LAV
valvular endocardiosis, can lead to pulmonary hypertension
and right-sided congestive heart failure. With this in mind, it
should not be surprising to expect recognition of pulmonary
hypertension in other species accompanying acquired chronic
left heart valvular disease.

Further reading
Connolly DJ, et al. Right-to-left shunting patent ductus arteriosus with
pulmonary hypertension in a cat. J Small Anim Pract 2003;44:184-
188. erratum in J Small Anim Pract 2003;44:226.
Glaus TM, et al. Clinical and pathological characterisation of primary
pulmonary hypertension in a dog. Vet Rec 2004;154:786-789.
Kellihan HB, Stephien RL. Pulmonary hypertension in dogs: diagnosis
and therapy. Vet Clin North Am Small Anim Pract 2010;40:623-
641.
Matsui K, et al. Immunohistochemical study of endothelin-1 and matrix
metalloproteinases in plexogenic pulmonary arteriopathy. Pathol
Res Pract 2002;198:403-412.
Medial hypertrophy of the pulmonary
arteries of cats
Pulmonary medial hypertrophy and hyperplasia commonly occur
in cats, but are of no clinical significance even when very severe
and generalized. The change is seen with equal frequency in
specific-pathogen-free and conventional cats; displays no age,
sex, or breed predilection; and appears to be normal anatomic
variation in cats. Pulmonary hypertension does not result from
the vascular change, right ventricular pressure does not
increase, nor does the right ventricle hypertrophy. The most
severely affected vessels may be grossly visible on the cut
surface of the lung and through the pleura when the lungs are
collapsed, and are even palpable in some cases. The histologic
spectrum of arterial changes ranges from mild sporadic (Fig.
1-72) or generalized hypertrophy of the tunica media, to
marked medial hypertrophy and hyperplasia with concomi-
tant intimal proliferation and severe luminal encroachment.
Figure 1-73  Medial hyperplasia/hypertrophy with mild periar-
teritis in dirofilariasis in a cat. H&E. (Courtesy A. Allen, coordina-
tor, Western Conference of Veterinary Diagnostic Pathologists.)
Thrombosis has not been observed, but adhesion of endothe-
lial surfaces across the lumen occurs, providing sinuous 
channels and an appearance similar to that of an organized,
recanalized thrombus. Frequently, the arterial hypertrophy is
accompanied by fibromuscular hyperplasia in the pulmonary
parenchyma and around alveolar ducts.
Similar pulmonary arterial lesions have been described in
cats infected with the parasites Aelurostrongylus abstrusus and
Dirofilaria immitis (Fig. 1-73).
Further reading
Browne LE, et al. Pulmonary arterial disease in cats seropositive to
Dirofilaria immitis but lacking adult heartworms in the heart and
lungs. Am J Vet Res 2005;66:1544-1549.
Vasculitis
Vasculitis, or inflammation of a vessel, is characterized by the
presence of inflammatory cells within and around the blood vessel
wall with concomitant vessel wall damage as indicated by fibrin
deposition, collagen degeneration, and necrosis of endothelial and
 67.e1

Further reading
Dorfmuller P, et al. Pathology and aspects of pathogenesis in pulmo-
nary arterial hypertension. Sarcoidosis Vasc Diffuse Lung Dis
2003;20:9-19.
Fishman AP. Changing concepts of the pulmonary plexiform lesion.
Physiol Res 2000;49:485-492.
Kolm US, et al. Plexogenic pulmonary arteriopathy in a Pembroke
Welsh corgi. J Small Anim Pract 2004;45:461-466.
Turk JR, et al. Plexogenic pulmonary arteriopathy in a dog with ven-
tricular septal defect and pulmonary hypertension. J Am Anim Hosp
Assoc 1982;18:608-612.
67.e2

Further reading
Lister AL, Atwell RB. Feline heartworm disease: a clinical review. J Feline
Surg Med 2008;10:137-144.
Rawlings CA, et al. Response of the feline heart to Aelurostrongylus
abstrusus. J Am Anim Hosp Assoc 1980;16:573-578.
Rogers WA, et al. Pulmonary artery medial hypertrophy and hyperplasia
in conventional and specific-pathogen-free cats. Am J Vet Res
1971;32:767-774.
68 CHAPTER 1  •  Cardiovascular System Arteries

smooth muscle cells. The fibrillary, homogeneous, or granular
eosinophilic material observed by light microscopy and
referred to as “fibrinoid” consists of fibrin, immunoglobulins,
complement, and platelets. Degenerate collagen and smooth
muscle also contribute to increased eosinophilia of the vascu-
lar wall. Thrombosis may occur because of endothelial injury
and initiation of coagulation. The above changes in the blood
vessel wall distinguish vasculitis from perivascular infiltration
with inflammatory cells. Neutrophils, lymphocytes, or macro-
phages may predominate in vasculitis, and the predominant
cell type may be used to classify the vasculitis. Neutrophilic
vasculitis may be further subdivided into leukocytoclastic, in
which fragmented neutrophil nuclei or “nuclear dust” are
present, and nonleukocytoclastic, in which there is little
nuclear dust. The predominant cell type may vary over the
course of the vasculitis, as the condition becomes chronic or
resolves (eFig. 1-19).
Vasculitis is an important component of a wide variety of
inflammatory diseases, both infectious and noninfectious (Box
1-2), although its origin remains undetermined in many cases.
Vascular degeneration that lacks a significant inflammatory cell
component occurs in a number of toxic and metabolic conditions,
such as mercury poisoning and mulberry heart disease, and
has been excluded from this classification. The terms vasculitis
and angiitis are used interchangeably and may be used in
preference to the more specific term arteritis, because arteries,
capillaries, and veins may be involved simultaneously in some
conditions. Also, the wall of the vessel may be obscured or
obliterated by inflammatory changes, precluding definitive
classification. The consequences of vasculitis depend upon the
size, numbers, and types of vessels affected, and upon the
degree of obstruction caused, as noted under Arterial throm-
bosis and embolism. Vasculitis in general and specific forms of
arteritis will be discussed in this section; phlebitis and lymphan-
gitis are discussed in the sections Veins and Lymphatics,
respectively.
Vasculitides may be classified according to the size of the
blood vessels involved (large, medium, small), the histologic

BOX • 1-2 
Causes of vasculitis in domestic animals

Infectious • Histoplasma farciminosum (lymphangitis)

• Viral • Mucor spp.
• African horse sickness virus • Sporotrichum schenkii (lymphangitis)
• African swine fever virus • Protozoal
• Bluetongue virus • Besnoitia besnoiti
• Border disease virus • Hepatozoon americanum
• Bovine adenovirus • Helminths
• Bovine ephemeral fever virus • Medium to large vessels, usually endovasculitis
• Bovine viral diarrhea virus • Aelurostrongylus abstrusus
• Classical swine fever virus (hog cholera) • Angiostrongylus vasorum
• Equid herpesvirus 1 • Brugia spp. (lymphangitis)
• Equine arteritis virus • Dirofilaria immitis
• Equine infectious anemia virus • Elaeophora spp.
• Feline infectious peritonitis virus • Onchocerca spp.
• Ovine herpesvirus 2 (sheep-associated malignant • Schistosoma spp. (phlebitis)
catarrhal fever) • Spirocerca lupi
• Porcine reproductive and respiratory syndrome virus • Strongylus vulgaris
• Visna/maedi virus (ovine progressive pneumonia)
• Chlamydial Noninfectious
• Chlamydophila abortus (Chlamydia psittaci) • Immune mediated
• Chlamydophila pecorum (sporadic bovine • Anaphylactoid purpura
encephalomyelitis) • Food hypersensitivity
• Bacterial • Foreign proteins (serum sickness)
• Actinobacillus pleuropneumoniae, A. suis • Paraneoplastic, for instance, lymphoma
• Corynebacterium pseudotuberculosis (lymphangitis) • Polyarteritis nodosa
• Coxiella burnetii • Purpura hemorrhagica
• Ehrlichia (Cowdria) ruminantium (heartwater) • Rheumatoid arthritis
• Ehrlichia canis, E. equi • Rabies vaccine reaction
• Erysipelothrix rhusiopathiae • Staphylococcal hypersensitivity
• Haemophilus parasuis • Systemic lupus erythematosus
• Histophilus somni • Nonimmune mediated
• Rickettsia rickettsii (Rocky Mountain spotted fever) • Drug reaction, for example, itraconazole, ivermectin,
• Salmonella spp. trimethoprim-sulfadiazine/sulfamethoxazole
• Streptococcus suis • Uremia
• Mycotic
• Aspergillus fumigatus, A. niger
• Encephalitozoon cuniculi
 68.e1

Primary area
affected
(Endotheluim,
media, adventitia)

Morphology
Etiologies
Fibrinoid change
in wall of vessel Infectious [bacteria,
viruses], immune-
Cell type present
mediated [type III
[neutrophils,
and Type IV],
lymphocytes,
toxins, drugs
macrophages] Vasculitis
(Angiitis)

Type and size Sequelae

of vessel affected Thrombosis/
Artery, vein, ischemia/
lymphatic large, infarction
medium, small DIC

eFigure 1-19  Common types of vasculitis and their major features. DIC, disseminated intravas-
cular coagulation.
Diseases of the Vascular System
characteristics of the lesion, or clinical effects. However, many
cases overlap in their morphologic and clinical manifestations,
and are simply termed “systemic necrotizing vasculitis.”
Improvement in the classification of necrotizing vasculitides
will require further characterization of causes and of the spec-
trum of immune-mediated changes in vessels. Until such time,
the use of accurate morphologic descriptions of vascular
lesions is preferable to placing vasculitides, especially those of
known cause, in such ill-defined categories as “polyarteritis
nodosa.” The wide range of lesions observed probably reflects
the variety of antigens or other agents involved, the intensity
and chronicity of antigenic exposure, the relative contribu-
tions of immune-complex versus delayed-hypersensitivity
reactions, the genetic variation among individuals, and the
stage of development at which the lesion is observed.
Vasculitis may be of considerable significance in the pathogen-
esis of a condition, usually because of the occurrence of thrombo-
sis, ischemia, and infarction (Fig. 1-74). As well as having local
effects resulting from thrombosis and infarction, arteritis may
affect distant organs, as occurs when obliterative pulmonary
endoarteritis leads to congestive heart failure in dogs infected
with Dirofilaria immitis. (The term endoarteritis is used in
preference to endarteritis to avoid implying that end arteries
are primarily affected.)
Arteritis of hematogenous origin occurs in the course of
conditions such as septicemias and bacterial endocarditis. The
primary injury may be to the endothelium and intima or it
may, when the organisms localize in the vasa vasorum, affect
first the adventitia and outer lamellae. The arteritis in pigs
with septicemic salmonellosis, erysipelas, or classical swine
fever is conspicuously expressed cutaneously as erythematous
areas of purple discoloration on the ears, perineum, snout, and
venter, which, if the animal survives, may become necrotic and
slough. Lesions with this basis may also occur in other organs,
and indeed are often seen as infarcts in the spleen in erysipelas
and classical swine fever. In affected portions of vessels, the
endothelium swells and proliferates, and vessel walls undergo
acute fibrinoid necrosis. The formation of thrombi in these
areas in turn gives rise to infarcts and necrosis.
Vasculitis arising by extension of inflammation and infection
from adjacent tissues may occur, especially if the original
inflammatory process is suppurative or necrotizing. It is
Figure 1-74  Necrotizing vasculitis of arteriole in malignant
catarrhal fever in an ox. H&E. (Courtesy J. Schefers.)
Arteries 69
encountered most often in bacterial pneumonias, adjacent to
abscesses, in purulent meningitis, in local lesions of aspergil-
losis and mucormycosis, and in acute metritis, especially if
complicated by necrobacillosis. Fungi of the family Mucorales
have a distinct affinity for arteries and produce necrotizing,
thrombotic arteritis.
Vasculitis may also develop from within the vessel as a result
of endothelial injury by infectious agents and/or immune reac-
tions. Endothelial damage and exposure of subendothelial
collagen leads to activation of Hageman factor, and hence
activation of complement, kinin, and plasmin systems, and to
increased vascular permeability and inflammation. Infectious
agents may cause endothelial damage either directly or
through the actions of various toxic products, such as endo-
toxins of gram-negative bacteria, or exotoxins of bacteria such
as Corynebacterium pseudotuberculosis. Mannheimia haemolyt-
ica endotoxin (lipopolysaccharide [LPS]) can directly damage
endothelial cells; such damage may be reduced or increased
by the activity of neutrophils, depending on the concentration
of LPS present. The mechanism of LPS-mediated damage may
involve prostaglandins or production of oxygen radicals by
endothelial cells. In the absence of LPS, M. haemolytica leu-
kotoxin may contribute to endothelial damage. In the case of
Actinobacillus pleuropneumoniae, rather than endotoxin causing
endothelial damage, cytotoxicity is apparently caused by a
104 kDa hemolysin. Histophilus somni lipo-oligosaccharide
has been shown to cause cytotoxicity and apoptosis of bovine
endothelial cells through the generation of reactive oxygen
and nitrogen intermediates. Many viruses are endotheliotro-
pic, for example, the viruses of equine arteritis, infectious
canine hepatitis, canine distemper, Hendra virus, African swine
fever, and classical swine fever (see Box 1-2).
Immune reactions are primary causes of vasculitis
in domestic animals, but appear to be less important than 
in man.
Type III hypersensitivity reactions, or Arthus reactions, cause
necrotizing vasculitis by the deposition of immune complexes
in vessel walls, usually in association with the endothelial
basement membrane. The complexes fix complement, and
complement fragments attract neutrophils that release lyso-
somal enzymes and oxygen radicals (superoxide anion, hydro-
gen peroxide, hydroxyl radical, hypochlorous acid) in the
process of phagocytosing immune complexes, and hence cause
necrosis. As the Arthus reaction matures, neutrophils diminish
and mononuclear cells, including plasma cells, predominate.
The morphology of immune-complex–mediated vasculitis can
be modified by the relative concentrations of immune reac-
tants or secondary mediators; increases in antibody or comple-
ment concentrations can change an Arthus-like reaction to a
Shwartzman-like reaction. Immune complexes can be found
in vessel walls in a variety of immune-mediated conditions,
including systemic lupus erythematosus, Aleutian disease of
mink, feline infectious peritonitis, and systemic coronavirus-
associated disease in ferrets. However, even though immuno-
globulins or immune complexes are found in the walls of
affected vessels, this is not definitive proof that the immune
reaction caused the vasculitis. Conversely, the absence of
immune complexes from a vessel wall lesion does not rule out
immune-complex vasculitis, because immune reactants can
disappear rapidly. The underlying lesion in porcine dermatitis
and nephropathy syndrome (PDNS) is necrotizing systemic
vasculitis, which has a predilection for skin and kidney, and 
is thought to have an immune-complex origin; porcine
70 CHAPTER 1  •  Cardiovascular System
circovirus 2 antibody titers were excessively high in PDNS
pigs in a case-control study.
Cell-mediated type IV, or delayed hypersensitivity, reactions
may be involved in some types of vasculitis in which there is
lymphocytic predominance, such as the arteritis of malignant
catarrhal fever and of Border disease. In malignant catarrhal
fever, the vasculitis is characterized by accumulations of prin-
cipally lymphocytes and fewer macrophages in the adventitia
and intima of affected small and medium arteries and veins
of the alimentary tract, eye, kidney, liver, lung, and brain;
neutrophils and plasma cells are rare. Lymphocytes may later
invade the media, although adventitial infiltration continues
to predominate, and there may be medial myocyte necrosis
with variable amounts of fibrinoid degeneration and endothe-
lial hyperplasia; thrombosis may be seen in advanced cases.
There is a possibility of, but little direct evidence for, direct
viral cytolysis in malignant catarrhal fever.
Vasculitis in humans has been associated with a variety  inflammatory immune response in placental tissues. J Comp Pathol
of drugs (see Hypersensitivity vasculitis). Examples of
hypersensitivities in dogs include itraconazole, ivermectin,
allergy immunotherapy (hyposensitization) injections, and
ibuprofen.
Genetic predisposition to vasculitis occurs in a number of
dog breeds, for instance, Beagle (“Beagle pain syndrome”),
Greyhound, Chinese Shar-Pei (“Shar-Pei fever”), German
Shepherd dog, Bernese Mountain dog. Vasculitis may be pre-
cipitated by vaccination or infection, but is more often of
obscure cause. Arteritis may be found as an incidental “back-
ground” lesion in clinically normal animals. For example, mild
idiopathic arteritis and intimal thickening occurs in extramu-
ral coronary arteries in 5-10% of young Beagle and mixed-
breed dogs, which can complicate the interpretation of lesions
in dogs used in arterial toxicity studies.
A more severe, febrile syndrome, variously named Beagle
pain syndrome, canine juvenile polyarteritis syndrome, or idio-
pathic canine polyarteritis, occurs in Beagles and other breeds.
In this syndrome, necrotizing arteritis affects the coronary,
mediastinal and cervical spinal arteries, resulting in thrombo-
sis, infarction, and hemorrhage as well as progressive atrophy
of temporal and cervical muscles; amyloidosis occurs in  454.
some chronically affected dogs (Fig. 1-75). The syndrome
appears to be immune mediated; some affected dogs have
Figure 1-75  Lymphoplasmacytic vasculitis in the leptomeninges
in Beagle pain syndrome. H&E.
Arteries
antineutrophil cytoplasmic antibodies (ANCA) and other
immunologic irregularities similar to Kawasaki disease in
humans.
An idiopathic vasculopathy occurs in kenneled and racing
Greyhound dogs (Alabama rot), involving skin and occasionally
kidneys. Deep, slowly healing cutaneous ulcers occur as the
result of fibrinoid arteritis, thrombosis, and hemorrhagic
infarction. Renal lesions include acute necrosis of glomeruli
and of afferent arterioles, glomerular capillary thrombosis, and
acute tubular necrosis. The pathogenesis of the condition is
thought to be the result of the effects of Shiga toxin from E.
coli O157:H7 producing a variant of the hemolytic-uremic
syndrome.
Further reading
Buxton D, et al. Ovine chlamydial abortion: characterization of the
2002;127:133-141.
Caswell JL, Nykamp SG. Intradural vasculitis and hemorrhage in full
sibling Welsh springer spaniels. Can Vet J 2003;44:137-139.
Eaton BT, Broder CC. Hendra and Nipah viruses: different and danger-
ous. Nat Rev Microbiol 2006;4:23-35.
Font A, et al. Acute paraplegia associated with vasculitis in a dog with
leishmaniasis. J Small Anim Pract 2004;45:199-201.
Garner MM. Clinicopathologic features of a systemic coronavirus-
associated disease resembling feline infectious peritonitis in the
domestic ferret (Mustela putorius). Vet Pathol 2008;45:236-246.
Hansen S, et al. Coxiella burnetii associated placental lesions and infec-
tion level in parturient cows. Vet J 2011;190:e135-e139.
Hooper P, et al. Comparative pathology of the diseases caused by
Hendra and Nipah viruses. Microbes Infect 2001;3:315-322.
Innerå M. Cutaneous vasculitis in small animals. Vet Clin North Amer
Sm Anim Pract 2013;43:113-134.
Kipar A, et al. Morphologic features and development of granuloma-
tous vasculitis in feline infectious peritonitis. Vet Pathol 2005;42:321-
330.
Maratea KA, et al. Vascular lesions in nine Gottingen minipigs with
thrombocytopenic purpura syndrome. Vet Pathol 2006;43:447-
McClenahan D, et al. Effects of lipopolysaccharide and Mannheimia
haemolytica leukotoxin on bovine lung microvascular endothelial
cells and alveolar epithelial cells. Clin Vaccine Immunol 2008;15:338-
347.
Opriessnig T, Langolir I. Current state of knowledge of porcine circovi-
rus type 2-associated lesions. Vet Pathol 2013;50:23-38.
Paessler S, Walker DH. Pathogenesis of viral hemorrhagic fevers. Ann
Rev Pathol 2013;8:411-440.
Richards A, Kavanagh D. Pathogenesis of thrombotic microangiopathy:
insights from animal models. Nephron Exp Nephrol 2009;113:97-
103.
Russell GC, et al. Malignant catarrhal fever: a review. Vet J 2009;
179:324-335.
Snyder PW, et al. Pathologic features of naturally occurring juvenile
polyarteritis in Beagle dogs. Vet Pathol 1995;32:337-345.
Wellenberg GJ, et al. Excessive porcine circovirus type 2 antibody titres
may trigger the development of porcine dermatitis and nephropa-
thy syndrome: a case-control study. Vet Microbiol 2004;99:203-
214.
Wong KT, Tan CT. Clinical and pathological manifestations of human
henipavirus infection. Curr Top Microbiol Immunol 2012;359:
95-104.
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Shilton CM, et al. Adenoviral infection in captive moose (Alces alces)

Further reading in Canada. J Zoo Wildl Med 2002;33:73-79.
Ackermann MR, et al. Ventral dermatitis and vasculitis in a calf with Simon S, et al. The vascular lesions of a cow and bison with sheep-
bovine leukocyte adhesion deficiency. J Am Vet Med Assoc associated malignant catarrhal fever contain ovine herpesvirus
1993;202:413-415. 2-infected CD8+ T lymphocytes. J Gen Virol 2003;84(Pt 8):2009-
Anderson TD, et al. Pathogenesis of placentitis in the goat inoculated 2013.
with Brucella abortus: II. Ultrastructural studies. Vet Pathol Son WC. Idiopathic canine polyarteritis in control beagle dogs from
1986;23:227-239. toxicity studies. J Vet Sci 2004;5:147-150.
Andrew SE. Feline infectious peritonitis. Vet Clin North Am Small Anim Svensson C, Bergsten C. Laminitis in young dairy calves fed a high
Pract 2000;30:987-1000. starch diet and with a history of bovine viral diarrhoea virus infec-
Arteritis and arterial drug toxicity in the safety assessment of drugs. tion. Vet Rec 1997;140:574-577.
Toxicol Pathol 1989;17:65-231 (17 papers). Sylte MJ, et al. Reactive oxygen and nitrogen intermediates contribute
Bratberg B. Acute vasculitis in pigs: a porcine counterpart to malignant to Haemophilus somnus lipooligosaccharide-mediated apoptosis of
catarrhal fever. Proc Int Pig Vet Soc Congress, Copenhagen, bovine endothelial cells. Vet Immunol Immunopathol 2004;97:207-
Denmark, Am Assoc Swine Pract 1980;353. 217.
Breider MA, et al. Interaction of bovine neutrophils in Pasteurella hae- Szeredi L, et al. Detection of equine herpesvirus-1 in the fetal mem-
molytica mediated damage to pulmonary endothelial cells. Vet branes of aborted equine fetuses by immunohistochemical and
Immunol Immunopathol 1991;27:337-350. in-situ hybridization techniques. J Comp Pathol 2003;129:147-153.
Cowan LA, et al. Clinical and clinicopathological abnormalities in grey- Thomson JR, et al. Porcine dermatitis and nephropathy syndrome.
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Darbes J, et al. Histopathological findings in pigs of various ages suf- Van Dellen AF, et al. Light and electron microscopical studies on canine
fering from spontaneous infection with the porcine reproductive encephalitozoonosis: cerebral vasculitis. Onderstepoort J Vet Res
and respiratory syndrome virus (PRRSV). Zentralbl Veterinarmed A 1978;45:165-186.
1996;43:353-363. van Moll P, et al. Immunocytochemical demonstration of Coxiella bur-
Fondati A, et al. Familial cutaneous vasculopathy and demodicosis in netii antigen in the fetal placenta of naturally infected sheep and
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Gavaghan BJ, et al. Acute onset of pulmonary necrotising arteritis in a Vincent-Johnson NA. American canine hepatozoonosis. Vet Clin North
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1998;76:786-791. Wilkins PA, et al. Listeria monocytogenes septicemia in a thoroughbred
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Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997;337:1512-
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Kemi M, et al. Histopathology of spontaneous panarteritis in beagle
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Liggitt HD, DeMartini JC. The pathomorphology of malignant catarrhal
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Malik R, et al. Acute febrile neutrophilic vasculitis of the skin of young
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Mathieson PW, et al. Animal models of systemic vasculitis. J Autoim-
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Morris DD. Cutaneous vasculitis in horses: 19 cases (1978-1985). J Am
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Morris DO, Beale KM. Cutaneous vasculitis and vasculopathy. Vet Clin
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Nichols PR, et al. A retrospective study of canine and feline cutaneous
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O’Toole D, et al. Chronic generalized obliterative arteriopathy in cattle:
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Reams RY, et al. Streptococcus suis infection in swine: a retrospective
study of 256 cases: II. Clinical signs, gross and microscopic lesions,
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Rotermund A, et al. Cutaneous and renal glomerular vasculopathy in
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Diseases of the Vascular System
Polyarteritis nodosa (panarteritis,
or periarteritis nodosa)
The term “polyarteritis nodosa” has been applied to a hetero-
geneous group of arteritides, which occur sporadically in all
species of domestic animals, on the basis of similarities with
classic polyarteritis nodosa in humans, in which small and
medium-sized arteries undergo severe necrotizing inflammation,
often in a sharply segmental (nodose) pattern, and with a predi-
lection for branching points. As all layers of the arterial wall
are involved, the lesion is also referred to as “panarteritis.”
Arterioles, capillaries, and venules are not involved, and glo-
merulonephritis is not present.
The only agent thus far associated with the condition in
man is hepatitis B antigen, which is found in 25-40% of indi-
viduals with necrotizing vasculitis. High mortality occurred in
the human disease before the advent of corticosteroid and
cyclophosphamide therapy. Polyarteritis nodosa has been
reported in dogs having rheumatoid arthritis and systemic
lupus erythematosus; separation of the vasculitis component
from disease syndromes is of problematic value. Also, as noted
previously in the section Vasculitis, a more appropriate term
for idiopathic vasculitides is probably systemic necrotizing
vasculitis rather than polyarteritis nodosa, which has tended
to become a catchall term.
A wide variety of clinical and pathologic manifestations
occur in polyarteritis nodosa as described in man and domestic
animals. Although occasionally associated with the death of
an animal, lesions are also noted in otherwise normal animals
at slaughter. Renal, coronary, hepatic, and gastrointestinal
vessels are perhaps most commonly involved (Fig. 1-76). Arte-
rial lesions at all stages of development, namely, acute, healing,
and healed, may occur simultaneously in one individual and even
within the same vessel.
The acute lesions are often typical of immune-complex–
induced arteritis, and inflammation and necrosis of the arte-
rial wall may be segmental or circumferential. Thrombosis
may occur and lead to infarction and hemorrhage. As the
reaction progresses, neutrophils are replaced in the media by
mononuclear cells, and fibroplasia may result in grossly visible
fibrous thickening of the wall. The vascular lumen may be
obliterated by organization of a thrombus plus intimal prolif-
eration. The term “periarteritis” has been used in the past
Figure 1-76  Chronic fibrosing vasculitis in renal artery (polyar-
teritis nodosa) in a goat. H&E. (Courtesy E. Olson.)
Arteries 71
to describe a stage in the vascular reaction in which mono-
nuclear cells surround the vessel, but the term is now 
little used.
Microscopic polyangiitis (hypersensitivity vasculitis, micro-
scopic polyarteritis, leukocytoclastic vasculitis) affects smaller
vessels in humans, namely, arterioles, capillaries, and venules in
skin, mucous membranes, lungs, brain, heart, gastrointestinal
tract, kidneys, and muscle. Suspected causes include many
common drugs such as penicillin, microbes such as strepto-
cocci, heterologous proteins, and tumor antigens. The reaction
often occurs 7-10 days after exposure to the stimulus; remis-
sion usually follows removal of the agent. Lesions typical of
leukocytoclastic vasculitis are seen. Because larger arteries are
spared, macroscopic infarcts are uncommon. Hypersensitivity
vasculitis appears to be the basis of some cases of hemorrhagic
purpura in horses; other causes of subcutaneous edema and
mucosal hemorrhages, such as equine viral arteritis, equine
infectious anemia, and equine ehrlichiosis, must also be 
considered. Trimethoprim-sulfadiazine and trimethoprim-
sulfamethoxazole have caused hypersensitivity vasculitis
in dogs.
Further reading
Clemo FA, et al. Differentiating spontaneous from drug-induced vas-
cular injury in the dog. Toxicol Pathol 2003;31(Suppl.):25-31.
Eleftheriou D, et al. Systemic polyarteritis nodosa in the young: a single
centre experience over 32 years. Arthritis Rheum 2013;65:2476-
2485.
Ferreras MC, et al. Pathologic features of systemic necrotizing vasculi-
tis (polyarteritis nodosa) in sheep. J Comp Pathol 2013;149:74-81.
Hughes LB, Bridges SL Jr. Polyarteritis nodosa and microscopic polyan-
giitis: etiologic and diagnostic considerations. Curr Rheumatol Rep
2002;4:75-82.
Son WC. Idiopathic canine polyarteritis in control beagle dogs from
toxicity studies. J Vet Sci 2004;5:147-150.
Viral vasculitides
Equine viral arteritis.  This disease is caused by species
Equine arteritis virus (EAV), an RNA virus of the family
Arteriviridae, genus Arterivirus, which is pathogenic only for
horses and is cytopathic in equine kidney culture. Although
serologic surveys indicate that infection with EAV is common
in North America and Europe, clinical disease is uncommon.
Most strains of EAV are avirulent, and mortality is rare in
natural outbreaks. Long-lasting immunity follows recovery.
Transmission of virus occurs primarily by respiratory and vene-
real routes during the acute phase of infection; venereally
infected mares can infect nonimmune mares by aerosol trans-
mission. Long-term carrier stallions play an important role in
perpetuation and dissemination of the virus; a carrier state has
not been demonstrated in mares or foals. There is some evi-
dence for resistance/susceptibility to the severity of the disease
based on the host’s permissiveness of infection of CD3+ lym-
phocytes. The major features of the disease are shown in
eFigure 1-20.
The clinical disease is characterized by fever; variable
anorexia and depression; leukopenia; edema of the ventral
body wall and limbs, especially the hindlimbs; skin rash, most
commonly on the neck; serous, later mucopurulent, oculona-
sal discharge with rhinitis and conjunctivitis; and periorbital/
supraorbital edema. Dyspnea, coughing, ataxia, and diarrhea
 71.e1

Further reading
Carpenter JL, et al. Polyarteritis nodosa and rheumatic heart disease in
a dog. J Am Vet Med Assoc 1988;192:929-932.
Curtis R, et al. Polyarteritis in a cat. Vet Rec 1979;105:354.
Elling F. Nutritionally induced necrotizing glomerulonephritis and poly-
arteritis nodosa in pigs. Acta Path Microbiol Scand A 1979;87A:387-
392.
Gardiner AC, et al. Periarteritis in experimental border disease of
sheep: III. Immunopathological observations. J Comp Pathol
1980;90:469-474.
Jansen JH, Nordstoga K. Renal lesions in Norwegian slaughter pigs.
Macroscopic and light microscopic studies. Zentralbl Veterinarmed
A 1992;39:582-592.
Rae CA. Lymphocytic enteritis and systemic vasculitis in sheep. Can Vet
J 1994;35:622-625.
Werner LL, et al. Acute necrotizing vasculitis and thrombocytopenia in
a horse. J Am Vet Med Assoc 1984;185:87-90.
71.e2

Arterivirus
[RNA virus]
Virulence varies
Most strains avirulent
Transmission aerosol
and venereal

Clinical signs Pathogenesis

Fever; anorexia, Panvasculitis
depression; ventral
edema; leukopenia; Initial infection of
oculonasal discharge; macrophages followed
diarrhea; abortion by endothelial cells
Equine
viral arteritis

Gross lesions Histopathology

Widespread Hyaline to fibrinoid
hemorrhages necrosis of media
and edema; fluid of small muscular
in all serous cavities; arterioles
pulmonary edema; Thrombosis [sometimes]
enteritis [hemorrhagic
diphtheritic] Necrosis in
lymph nodes

eFigure 1-20  Major features of equine viral arteritis.

72 CHAPTER 1  •  Cardiovascular System
are less frequent. Pregnant mares often abort during or shortly
after the febrile period, probably resulting from myometritis
and decreased progesterone production by a hypoxic pla-
centa. Specific lesions are present occasionally in aborted
fetuses, and include necrotizing vasculitis, and inflammatory
foci in various organs. Newborn foals may succumb to inter-
stitial pneumonia. There is also a necrotizing vasculitis in the
placenta.
The virus is pathogenic to endothelial cells and causes pan-
vasculitis, that is, inflammation of veins, lymphatics, and arteries.
Following initial replication of the virus in macrophages, endo-
thelial cells are invaded beginning 3 days after experimental
aerosol infection. As inflammation progresses and neutrophils
damage the internal elastic lamina, medial cells are invaded.
The most severe edema occurs at days 6 and 7 when phlebitis,
lymphangitis, and capillary damage are most pronounced.
Arterial necrosis peaks at day 10, when edema has largely
disappeared. The vascular lesions will resolve if the horse
survives. Antibody appears to play little role in the pathogen-
esis of the disease, in contrast to the immune-complex com-
ponent of some other viral vasculitides.
The gross lesions of the disease, in addition to the changes
observed clinically, consist principally of hemorrhages and
edema. Petechial hemorrhages are found on all serous mem-
branes, in the substance of the lungs, and in the gastric mucosa.
Larger hemorrhages may be present in the adrenals. There is
excessive fluid that contains much protein and some strands
of fibrin in all serous cavities. As much as 10 L may be present
in the pleural and peritoneal cavities. The connective tissues
and mesenteries of the body cavities are saturated with edema
fluid, and the wall of the gut may be thickened by edema.
Enteritis, hemorrhagic, or diphtheritic in character, usually
more severe in the large than in the small intestine, is regularly
present. The lungs are more-or-less severely edematous.
Characteristic microscopic lesions occur focally or segmen-
tally in the media of small muscular arteries (Fig. 1-77). The
smooth muscle cells undergo necrosis and are replaced by
hyaline or fibrinoid material. There is edema of the wall and
adventitia and infiltration of leukocytes, chiefly lymphocytes,
the nuclei of which undergo fragmentation with necrosis. The
endothelium and intima may have been repaired so that
thrombosis is unusual; thrombosis may, however, occur in the
Figure 1-77  Multifocal vasculitis with fibrosing perivascular and
perineural inflammation in equine viral arteritis. (From an Armed
Force Institute of Pathology Wednesday Slide Conference, 2000.)
Arteries
intestine and lungs. The arterial lesions occur in many organs
but are perhaps most consistently present in the gut and adrenals.
Infarction is most common in the intestines, particularly in
the cecum and colon. Massive necrosis of lymph nodes also
occurs. Extensive necrosis of the adrenals may result from
direct viral injury and infarction.
Diagnosis is made through detection of seroconversion or
more commonly, identification of the virus in the presence of
compatible lesions. Differential diagnoses for EVA include dis-
eases caused by other viruses (equid herpesvirus 1, equine
adenovirus, influenza A virus, equine infectious anemia virus,
African horse sickness virus, Hendra virus, Getah virus), plus
purpura hemorrhagica, septic shock, and poisoning by the
toxic plant hoary alyssum (Berteroa incana).
Further reading
Del Piero F. Equine viral arteritis. Vet Pathol 2000;37:287-296.
Go YY, et al. Assessment of correlation between in vitro CD3+ T cell
susceptibility to EAV infection and clinical outcome following exper-
imental infection. Vet Microbiol 2012;157:220-225.
Miszczak F, et al. Emergence of novel equine arteritis virus (EAV)
variants during persistent infection in the stallion: origin of the
2007 French EAV outbreak was linked to an EAV strain present
in the semen of a persistently infected carrier stallion. Virol
2012;423:165-174.
African horse sickness.  African horse sickness (AHS) is a
vector-borne disease of solipeds, and occasionally of dogs 
and camels, caused by species African horse sickness virus
(AHSV), family Reoviridae, genus Orbivirus, that is closely
related to bluetongue virus. The disease is endemic in sub-
Saharan Africa, from where it spreads to southern Africa and
occasionally northern Africa. It has also extended on occasion
through the Middle East as far as India, and apparently with
climate change, the vector has become established in southern
Europe. Its importance lies in the extreme lethal potential of the
infection in susceptible horses and the very wide distribution of
the competent insect vectors.
The vectors of AHSV are primarily Culicoides biting
midges, particularly Culicoides imicola. Transmission by mos-
quitoes or ticks is of minor importance. AHSV requires an
ambient temperature of ≥15° C to replicate and be transmit-
ted by Culicoides. Historically, in enzootic areas south of the
Sahara, outbreaks of disease occurred in seasons when noctur-
nal biting insects were active, outbreaks subsiding shortly after
the first frosts. It is possible that, in climatically suitable areas,
transmission might occur throughout the year. Annual recru-
descence poses the question of reservoirs for over-winter per-
sistence; the natural reservoir remains unknown, although the
zebra is most likely. Even in districts where AHS occurs annu-
ally, the distribution tends to be limited to low-lying areas
such as valleys, swamps, and areas of summer rain.
African horse sickness is primarily a disease of the horse and
its close relatives, but a wide range of species is susceptible to
the virus experimentally, including goats, guinea pigs, mice,
ferrets, and rats. The major features of the disease are shown
in eFig. 1-21. The horse is the most susceptible to infection
and to illness; the mortality rate in susceptible populations of
horses may be as high as 95%. The mortality rate in mules
(~80%) is less than that in horses, but greater than that in the
 72.e1

Further reading
Cho HJ, et al. Detection of antibodies to equine arteritis virus by a
monoclonal antibody-based blocking ELISA. Can J Vet Res
2000;64:38-43.
Del Piero F. Diagnosis of equine arteritis virus infection in two horses
by using monoclonal antibody immunoperoxidase histochemistry
on skin biopsies. Vet Pathol 2000;37:486-487.
Hullinger PJ, et al. Seroprevalence of antibodies against equine arteritis
virus in horses residing in the United States and imported horses.
J Am Vet Med Assoc 2001;219:946-949.
Szeredi L, et al. Equine viral arteritis in a newborn foal: parallel detec-
tion of the virus by immunohistochemistry, polymerase chain reac-
tion and virus isolation. J Vet Med B Infect Dis Vet Public Health
2003;50:270-274.
72.e2

Orbivirus
Closely related to bluetongue
virus
Nine major antigenic types
Infects solipeds; sometimes
camels and dogs
insect tramsmitted

Clinical signs
Four clinical syndromes:
Peracute/pulmonary form [fever,
respiratory distress]; Pathogenesis not well
understood
Subacute/cardiac form [fever, severe
subcutaneous edema, petechial Virus in many tissues
hemorrhages] No obvious endothelial invasion
Mixture of pulmonary /cardiac form
Mild form - AHS fever
[remittent fever] African
horse sickness

Gross features
Depends on clinical form Histopathology
Hydrothrax; Pulmonary edema; Diffuse severe
petechial /ecchymotic hemorrhages;
Alveolar edema; Widespread
swollen and edematous lymph nodes'
hemorrhage;
subcutaneous edema;
hydropericardium

eFigure 1-21  Major features of African horse sickness (AHS).

Diseases of the Vascular System
Egyptian donkey. The South African donkey and the zebra are
resistant. The role of dogs, and other scavenging carnivores, in
the disease cycle is not known. The disease is not contagious
by contact, but dogs may acquire it from eating infected
horseflesh. Infection, detected by viral isolation/detection or
serologically, can be common in dogs in some circumstances,
but vector transmission from dogs is unlikely.
In many parts of Africa, the use of the horse, mule, and
donkey is dependent on the control of AHS, but this control
has been difficult to attain. The primary obstacle has been the
multiplicity of antigenic types of AHSV of which there are at
present 9 major antigenic types. These types have a basic anti-
genic relationship that may be demonstrated in the horse, but
the relationship is not sufficiently close to provide solid immu-
nity amongst types. Indeed, although all strains investigated
can be fitted into one of the major types, the antigenic diver-
sity of strains within a single type is such that very few strains
are identical. This is certainly the situation in enzootic areas
where a large number of different strains may be isolated
during an outbreak. On the other hand, there has been close
antigenic relationship between the viruses recovered during
the epizootic outbreaks that occurred outside the reservoir-
host range where the transmission was from horse to horse.
This suggests that, although the AHSV is extremely mutable,
mutations do not readily occur when the disease is transmitted
from horse to horse. Recovered horses are immune to homolo-
gous challenge, and possess some immunity to heterologous
challenge. Vaccines are currently available to either prevent or
to lower the severity of the disease.
Four clinical forms of AHS are described: pulmonary (per-
acute), mixed (acute), cardiac (subacute), and AHS fever (mild)
forms, from most to least severe. Most cases are of the mixed
form, perhaps reflecting variations in the susceptibility of the
host, the virulence of the virus, or the tropism of virus for
different parts of the vascular system.
The peracute or pulmonary form of the disease, the most
common form in epizootics, has an incubation period of 3-5
days. Fever occurs suddenly and is of short duration, followed
by the acute onset of respiratory distress. Death may occur in
a few hours from pulmonary edema, and frothy fluid fills the
respiratory tract and may flow from the nostrils.
The subacute or cardiac form is usually associated with
infections that are not fully virulent or are encountered in
animals in which infection by heterologous strains has stimu-
lated some immunity. The incubation period is 7-14 days with
clinical signs of fever lasting 3-6 days. As the fever subsides,
edematous swellings appear in the temporal or supraorbital
fossae and the eyelids. The swellings extend to the lips, cheeks,
tongue, intermandibular space, and throat. Swelling from sub-
cutaneous fluid may affect the upper neck and sometimes the
chest and shoulders. Terminally, petechial hemorrhages usually
occur on the conjunctiva and ventral surface of the tongue.
The mortality rate may be as high as 50%, and is attributed
to cardiac failure and pulmonary edema.
As observed above, many cases are mixtures of the pulmo-
nary and cardiac form. Initial pulmonary signs of relatively
mild degree may be followed by characteristic swelling of the
head and death from cardiac failure, or the cardiac form may
be followed by sudden onset of dyspnea and pulmonary edema.
The mild clinical form of the disease, AHS fever, may not
be noticed in outbreaks. It is characterized by remittent fever
lasting for a week or so. This is the form of the disease to be
expected in animals with immunity to heterologous strains
Arteries 73
and in resistant species such as donkey and zebra. The mortal-
ity rate is ~70%.
The pathogenesis of the signs and lesions is related to sites
of viral replication. Virus is found early and develops to
highest titer in spleen, lymph nodes, lung, and the large 
intestine; the titer in myocardium is low. Viral infection 
causes degeneration and loss of endothelium in myocardial
and pulmonary capillaries, with resulting increased vascular
permeability, edema, hemorrhage, and microthrombosis. 
Vascular permeability of pulmonary capillaries may be
increased through the action of inflammatory mediators
released by activated intravascular macrophages.
Gross lesions observed at autopsy depend largely on the
clinical form of disease. In the pulmonary form, the most char-
acteristic changes are edema of the lungs and hydrothorax
(Fig. 1-78A). In very acute cases, edema and mottled hyper-
emia of the lungs are seen, whereas in cases with a somewhat
more protracted course extensive interstitial and subpleural
edema are also present, but hyperemia is less evident. Other
lesions commonly observed are periaortic and peritracheal
edematous infiltration, diffuse or patchy hyperemia of the
glandular fundus of the stomach, hyperemia and petechial
hemorrhages in the mucosa and serosa of the small and large
intestines, subcapsular hemorrhages in the spleen, and conges-
tion of the renal cortex. All the lymph nodes are enlarged and
edematous, especially those in the thoracic and abdominal
cavities. The pericardial sac may contain variable amounts of
fluid, and numerous petechial hemorrhages occur in the peri-
cardium. Cardiac lesions are usually not conspicuous, but
epicardial and endocardial petechial hemorrhages may some-
times be evident.
In the cardiac form, the most characteristic lesions are the
edematous infiltration of the subcutaneous, subfascial, subse-
rous, and intermuscular tissues. Only the head and neck may
be involved, but in more severe cases, the edema also involves
lower parts of the neck, brisket, and shoulders (Fig. 1-78B).
Hydropericardium is a constant finding, the pericardial sac
often containing 2 L or more of fluid (Fig. 1-78C). The epi-
cardium and endocardium show numerous, almost confluent
ecchymotic hemorrhages. The lungs are usually normal or only
slightly engorged, and the thoracic cavity rarely contains an
excess of fluid. The lesions in the gastrointestinal tract are
generally similar to those found in the pulmonary form,
except that submucosal edema tends to be far more pro-
nounced. Ascites is unusual.
In the mixed form, the lesions are a combination of those
observed in the pulmonary and cardiac forms. In fact, most of
the fatal cases of AHS can be considered to be of the mixed form,
with lesions typical of either the pulmonary or the cardiac
form predominating.
The infective dose of AHS virus for dogs is large, and high
infective titers are not known to be gained except by ingestion
of infected horseflesh. The course of the disease in dogs is
similar to the pulmonary form in horses with fever and severe
respiratory distress. The mortality in dogs showing respiratory
signs is very high. At autopsy, the lungs are edematous and
may have some superimposed bronchopneumonia. There is
much froth in the airways, copious hydrothorax in which the
fluid gels on exposure, and saturation of mediastinal tissues.
Histologic changes are not helpful in diagnosis or understand-
ing of pathogenesis.
The clinical signs of AHS are usually characteristic, 
although AHS might be confused with equine encephalosis,
74 CHAPTER 1  •  Cardiovascular System
A
Figure 1-78  African horse sickness in a horse. A. Severe, acute pulmonary edema. B. Subcutane-
ous edema of a hindlimb. C. Excess blood-tinged fluid in the pericardial sac. (Courtesy Foreign
Animal Diseases Diagnostic Laboratory, National Veterinary Services Laboratories.)
anthrax, equine infectious anemia, equine babesiosis, purpura
hemorrhagica, equine viral arteritis, equine viral rhinopneu-
monitis, or trypanosomiasis.
Diagnosis requires virus isolation, virus identification, or
serology.
Further reading
Carrasco L, et al. The role of pulmonary intravascular macrophages in
the pathogenesis of African horse sickness. J Comp Pathol
1999;121:25-38.
Gomez-Villamandos JC, et al. Pathogenesis of African horse sickness:
ultrastructural study of the capillaries in experimental infection.
J Comp Pathol 1999;121:101-116.
Stern AW. African horse sickness. Compend Contin Educ Vet
2011;33:E1-E5.
African swine fever.  African swine fever (ASF) is an acute-
to-chronic, febrile, viral disease of swine, characterized by high
fever, cutaneous hyperemia, abortions, edema, and hemorrhage in
internal organs, particularly lymph nodes. Species African swine
fever virus (ASFV) infects only members of the Suidae family
and is a harmless companion of the warthog (Phacochoerus
aethiopicus) and the bush pig (Potamochoerus porcus). However,
Arteries
B
C
the virus is a constant and major threat to domestic pigs.
Originally limited to sub-Saharan Africa, the disease has
appeared in southern and western Europe, most recently in
Georgia in the Caucasus, the Caribbean, Brazil, Madagascar,
and Mauritius. International spread of ASF is primarily through
infected pork products in garbage fed to pigs. Once a focus of
infection is established, spread is most likely to occur by direct
or indirect contact. In Africa, the transmission of the virus
from wild Suidae to domestic pigs is primarily by the argasid
tick Ornithodoros moubata, a true biological vector and a
reservoir of the virus in nature. Additional arthropod vectors
exist.
The causative agent, ASFV, is an enveloped DNA virus,
family Asfarviridae, genus Asfivirus. It is a relatively resistant
virus that may survive in the environment or in uncooked
pork products for prolonged periods. There are several anti-
genically different strains of ASFV. Viral virulence is classified
as high, moderate, and mild. In an area free of the disease, ASF
is typically seen as a peracute or acute disease with high mor-
bidity and mortality, but as virulence diminishes with time,
subacute, chronic, and inapparent forms become increasingly
evident. Survivors remain persistently infected.
The immunologic response of swine to strains of ASFV is
unusual and is incompletely understood. Susceptible animals
infected with African field strains develop precipitating and
 74.e1

Further reading
Brown CC, et al. Presence of African horse sickness virus in equine
tissues, as determined by in situ hybridization. Vet Pathol
1994;31:689-694.
Mellor PS, Hamblin C. African horse sickness. Vet Res 2004;35:
445-466.
Diseases of the Vascular System Arteries 75

complement-fixing, but rarely neutralizing or protective, anti- contains ingesta, but the mucosa is apt to be inflamed and
bodies. The animals remain viremic and usually die within eroded. Changes in the small intestine may be absent or
7-10 days. Pigs that recover are resistant to infection with the consist of segmental areas of congestion and mucosal pete-
homologous virus. In the case of infection with highly virulent chiation. More severe intestinal changes may be found in the
ASFV, even though 10 days may have elapsed since infection, large intestine; these may include large areas of hemorrhage,
pigs typically die before development of anti-ASF immuno- severe congestion, and ulceration. Lesions suggesting “button
globulin, probably because of the demise of antigen-presenting ulcer” are very rare in this disease, presumably because few
cells in lymph nodes, spleen, and liver. animals survive long enough for their development.
There is no cross-protection conferred by infections by The postmortem appearance of subacute and chronic cases
classical swine fever virus (CSFV) and ASFV. of ASF varies considerably. In the subacute cases that die after
The ASFV replicates in and activates monocytes and mac- 3-4 weeks of illness, there may be lymph node and renal
rophages of various lymphoid tissues and organs, resulting in hemorrhage, an enlarged but not congested spleen, lobular
release of cytokines, such as interleukin-1 and tumor necrosis consolidation of cranial lung lobes, and intestinal mucosal
factor-α, and hence causes widespread cell death through hemorrhage (Fig. 1-79A, B). Prominent features of the chronic
apoptosis of T and B lymphocytes in lymphoid tissue and of form include fibrinous pericarditis and pleuritis; splenic and
endothelial cells in arterioles and capillaries, accounting for lymph node enlargement; lobular consolidation of the lungs,
the lesions of the acute disease. Activation of pulmonary intra- which may progress to necrosis and mineralization of an entire
vascular macrophages and release of cytokines incites pulmo- lobe; skin lesions ranging from raised hyperemic plaques to
nary edema, neutrophil sequestration, and formation of necrotic areas; swollen joints; and arthritis. The meningoen-
microthrombi in septal capillaries. It also appears that the cephalomyelitis and periportal hepatitis observed in the acute
virus modulates signaling pathways in macrophages, hence disease persist in the chronic disease. Lesions in aborted fetuses
interfering with the expression of host immunomodulatory are inconsistent but include petechiation of placentas, skin,
genes; this evasion of host defenses allows infections to be and myocardium, mottled lungs and liver, and anasarca.
persistent. The major features of the disease are shown in 
eFig. 1-22.
The peracute form of ASF is a severe acute viral hemorrhagic
fever characterized by a 1-3 day course of pyrexia, hyperpnea,
and cutaneous hyperemia, with morbidity and mortality
approaching 100%. However, the usual clinical course of ASF
is acute. Following an incubation period of 4-10 days, there is
a reduction in appetite, pyrexia, marked cutaneous reddening,
dyspnea, and severe leukopenia. Pregnant sows may abort. The
clinical signs in the less severe forms of the disease are variable.
The signs may be a mild expression of those seen in the acute
disease and may be confused easily with other diseases. There
are recurring periods of pyrexia, dyspnea, growth retardation,
and emaciation. Death may occur during one of the periods
of pyrexia. It is important to realize that the clinical signs of
chronic ASF may be indistinguishable from those seen in classical
swine fever (CSF).
The ASFV tends to affect the same organs and tissues as A
does the CSFV. The anatomic differences tend to be quantita-
tive and dependent on the more fulminating nature of ASF;
only splenomegaly and hematoma-like visceral lymph nodes are
particularly characteristic of ASF. The vascular lesions that can
develop rapidly, namely, hemorrhage and edema, are apt to be
more severe in ASF than in CSF, whereas the lesions that
develop more slowly, such as infarction, tend to be absent.
The pig dead from acute ASF shows few or no signs of
recent wasting. Gastrosplenic and renal lymph nodes are
usually intensely hemorrhagic, and ecchymotic hemorrhages
may be present on the serous membranes. The spleen is
usually enlarged and may be markedly enlarged and friable;
infarction cannot usually be recognized grossly. Pulmonary
edema, not common in CSF, is present frequently in pigs with
ASF. The pulmonary septa are thickened by a yellow gelati-
nous infiltrate. Pulmonary hemorrhage is also common. The B
gallbladder is often edematous, and the vessels of the wall are
engorged and conspicuous. Both petechiae and ecchymoses Figure 1-79  African swine fever. A. Enlarged hemorrhagic renal
are present on the serosal and mucosal surfaces. In some out- and sublumbar lymph nodes. B. Incised, enlarged and hemor-
breaks of the disease, there are extensive pancreatic hemor- rhagic, presternal lymph nodes. (Courtesy Foreign Animal Dis-
rhages and necrosis. The renal changes are similar to those of eases Diagnostic Laboratory, National Veterinary Services
CSF and consist of subcapsular petechiae. The stomach often Laboratories.)
 75.e1

African swine fever

Only Suidae infected
ASF virus an Asfivirus [enveloped DNA virus]
Several strains of virus of varying virulence

Gross lesions Clinical signs

Lymph nodes enlarged and A number of clinical forms which vary
intensely hemorrhagic mostly in the duration of the illness
Spleen enlarged, pulmonary High morbidiity and mortality
edema and hemorrahge in the peracute form. Clinical
Intestinal hemorrhage signs of a hemorrhagic fever
Petechiae and ecchymoses on Acute and subacute forms less
serosal and mucosal surafces severe and of longer duration
Subcapsular renal petechiae

Pathogenesis
ASFV replicates in cells of monocyte/
macrophage lineage and lymphoid tissues.
HISTOPATHOLOGY Subacute and chronic Leads to a massive release of cytokines
Extensive apoptosis/necrosis cases of ASF have from activated, dying and dead cells
of cells of the monocyte/ lymph node, renal
macrophage system hemorrhage, fibrinous
pericarditis and pleuritis
Extensive lymphoid
apoptosis/necrosis
Degeneration of
vascular endothelium,
fibrinoid change
and thrombosis

eFigure 1-22  Major features of African swine fever (ASF). ASFV, African swine fever virus.
76 CHAPTER 1  •  Cardiovascular System Arteries

A B

C D
Figure 1-80  African swine fever in a pig. A. Extensive hemorrhage and necrosis in lymph node.
B. Necrosis/apoptosis, especially of lymphocytes in tonsil. C. Extensive thrombosis in renal vessels.
D. Necrotizing vasculitis in renal arterioles. H&E. (Courtesy Armed Forces Institute of Pathology
[archive].)

Histologically, infection by a highly virulent strain of ASFV
causes extensive necrosis of cells of the mononuclear phago-
cyte system, whereas infection with a moderately virulent
strain causes little necrosis (Fig. 1-80A, B). The histologic find-
ings in acute ASF are very similar to those of CSF, but there are
important differences. A major difference is that ASFV does not
infect epithelium. Necrosis with karyorrhexis in lymphoid
tissue everywhere is often very obvious in ASF; frank necrosis
is quite rare in CSF, although mature lymphocytes are apt to
be absent in lymphoid tissue. Renal tubular degeneration with
amorphous casts in the medulla is frequent in ASF, but rare
in CSF. In ASF, necrosis of periportal hepatocytes and infiltrat-
ing lymphocytes is common, whereas microscopic hepatic
lesions are usually absent in CSF. The vascular cuffs in the
brain in ASF contain much more necrotic debris than do the
lesions in CSF. The degeneration of vascular endothelium and
the fibrinoid arterial changes are identical (Fig. 1-80C, D). Vas-
cular endothelial damage in the lung may cause thrombosis
of vessels and thickening of alveolar walls. Pigs dead of acute
ASF may have glomerular capillary thrombosis; surviving pigs
may develop focal segmental glomerulonephritis.
Because there is no treatment or effective vaccine against
ASF, rapid diagnosis is critical to disease control. A diagnosis
of ASF is confirmed by detection of ASFV antigen in tissues
by direct immunofluorescence, detection of ASF antibody by
indirect immunofluorescence or ELISA, detection of virus
genome by PCR, and virus isolation. Differential diagnoses
include classical swine fever (from which ASF cannot be dif-
ferentiated by clinical or postmortem examination), erysipe-
las, salmonellosis, pasteurellosis, and other septicemias.
Further reading
Blome S, et al. Pathogenesis of African swine fever in domestic pigs
and European wild boar. Virus Res 2013;173:122-130.
Costard S, et al. African swine fever: how can global spread be pre-
vented? Philos Trans R Soc Lond B Biol Sci 2009;364:2683-2696.
Gomez-Villamandos JC, et al. African swine fever and classical swine
fever: a review of the pathogenesis. Dtsch Tierarztl Wochenschr
2003;110:165-169.
Mozos E, et al. Cutaneous lesions in experimental acute and subacute
African swine fever: an immunohistopathological and ultrastruc-
tural study. Dtsch Tierarztl Wochenschr 2003;110:150-154.
Penrith ML. African swine fever. Onderstepoort J Vet Res 2009;76:
91-95.
Sanchez-Vizcaino JM, Mur L. African swine fever diagnosis update. Dev
Biol (Basel) 2013;135:159-165.
 76.e1

Further reading
Angulo A, et al. Virus-host interactions in African swine fever: the
attachment to cellular receptors. Arch Virol Suppl 1993;7:169-183.
Carrasco L, et al. African swine fever: expression of interleukin-1 alpha
and tumour necrosis factor-alpha by pulmonary intravascular mac-
rophages. J Comp Pathol 2002;126:194-201.
Dixon LK, et al. African swine fever virus proteins involved in evading
host defence systems. Vet Immunol Immunopathol 2004;100:117-
134.
Edwards JF, et al. Mechanism of thrombocytopenia in African swine
fever. Am J Vet Res 1985;46:2058-2063.
Gomez-Villamandos JC, et al. African swine fever virus infection of
bone marrow: lesions and pathogenesis. Vet Pathol 1997;34:97-
107.
Hervas J, et al. The lesional changes and pathogenesis in the kidney in
African swine fever. Vet Res Commun 1996;20:285-299.
Kleiboeker SB, Scoles GA. Pathogenesis of African swine fever virus in
Ornithodoros ticks. Anim Health Res Rev 2001;2:121-128.
Vallee I, et al. African swine fever virus infection of porcine aortic
endothelial cells leads to inhibition of inflammatory responses, acti-
vation of the thrombotic state, and apoptosis. J Virol 2001;75:
10372-10382.
Diseases of the Vascular System
Classical swine fever (hog cholera).  Classical swine fever
(CSF) is a highly contagious viral disease of swine; it may occur
as acute, subacute, chronic, or inapparent syndromes. Acute CSF
is a disease of high morbidity and mortality caused by a viru-
lent strain of the virus; low-virulence virus may cause inap-
parent disease. Classical swine fever is said to have developed
de novo in Ohio, United States, in the early 1800s. It subse-
quently spread to almost all countries and is also known as
swine fever, Schweinepest, peste du porc, and peste svina. Species
Classical swine fever virus (CSFV) produces disease only in
swine. The disease has been eradicated from Australia, Canada,
the United Kingdom, and the United States, but it remains a
problem in Central and South America and several European
countries.
CSF is caused by a Pestivirus, a member of the family Fla-
viviridae. Other members of the genus include bovine viral
diarrhea virus (BVDV), Bungowannah virus and border
disease virus (BDV). CSFV and BVDV are closely related
antigenically, and although pestiviruses other than CSFV are
thought to be harmless to pigs, natural BVDV infection can
cause clinical signs and postmortem lesions indistinguishable from
those of chronic CSF. Under appropriate circumstances, CSFV,
BVDV, Bungowannah virus, and BDV may produce transpla-
cental infection, and hence persistent infections and congeni-
tal anomalies. The CSFV is an enveloped, single-stranded
RNA virus that replicates intracytoplasmically. Most strains do
not produce a cytopathic effect in porcine cell cultures. The
enveloped nature of the virus makes it sensitive to lipid sol-
vents and to desiccation. However, the virus may persist for
prolonged periods in uncooked pork products.
Antigenic variation exists among strains of CSFV, and field
strains vary widely in virulence. The interaction of a particular
strain of virus and the host provides a range of disease syn-
dromes. Strains of CSFV are usually classified as being of high,
moderate, or low virulence, or as being avirulent. Highly virulent
strains produce the features of the classic acute disease in pigs
of all ages; the morbidity may reach 100%, with a mortality
rate of up to 90%. Strains of moderate virulence induce sub-
acute or chronic disease, and pigs may subsequently die or
recover. In pigs infected postnatally, strains of low virulence
produce few or no signs of disease and induce immunity, but
may cause fetal abnormalities. Artificially attenuated strains
used as vaccines are avirulent, even for fetuses. Virulence of
CSFV may be unstable; virulence can increase by one passage
through pigs.
Transmission of the disease is usually by direct contact of
infected pigs or wild boar with susceptible pigs; CSF is
endemic in wild boar in parts of Europe. The virus is present
in urine, feces, and lacrimal and oronasal secretions of infected
pigs, as well as semen of infected boars. Even with the less
virulent strains, the virus may be excreted in the urine for
periods up to 3 months. The major mechanism of spread of
virus of low virulence occurs from continuous virus shedding
by chronic or persistently infected asymptomatic pigs. Minor
modes of transmission include fomites and arthropods.
Clinically, classical swine fever is characteristically an acute
disease of high morbidity and mortality, most animals surviving
only to 14 days after showing the first signs of illness, namely,
anorexia, depression, fever, and leukopenia. Persistent infec-
tion (i.e., survival of >30 days) is caused by CSFV strains of
moderate or low virulence and may arbitrarily be divided into
chronic and late-onset types. In chronic CSF, typical acute
disease is followed by clinical improvement, the result of
Arteries 77
specific antibody formation, but later by immune exhaustion
and chronic disease in which the pig is viremic and more
susceptible to secondary bacterial infection. Late-onset CSF
occurs in pigs that are persistently viremic and immunotoler-
ant to CSFV as a result of fetal infection by CSFV of low viru-
lence. The latest date for the development of a persistent
infection of the fetus appears to be about day 70 of gestation;
by day 85 viral antigen may be detected in a few fetuses, but
virus cannot be isolated. Signs that develop in viremic, but
previously asymptomatic, pigs include anorexia, depression,
leukopenia, conjunctivitis, dermatitis, diarrhea, runting, and
paraparesis. The late-onset form of CSF is the porcine equivalent
of mucosal disease in cattle, in which BVDV infection of fetal
calves results in persistently viremic, immunotolerant animals.
The major clinical features of CSF are shown in eFig. 1-23.
The pathogenesis of CSF is not fully understood, but
involves the effects of the virus on the immune system (lym-
phoreticular cells and macrophages), the vascular endothelium,
and epithelial cells. The effect of the monocytotropic CSFV on
the immune system varies with the stage of differentiation;
mature cells degenerate, whereas undifferentiated cells
respond by proliferation. CSFV replicates in macrophages in
lymph nodes and lymphoid tissues and can cause depletion of
lymphocytes indirectly through expression of apoptotic cyto-
kines, such as tumor necrosis factor-α. Similarly, intestinal
epithelial cell necrosis appears be the product of release of
chemical mediators from activated macrophages, rather than
direct viral infection. Endothelial changes are primarily degen-
erative but some proliferative changes occur. Damage to endo-
thelial and other cells leads to thrombocytopenia, consumption
coagulopathy, and in turn disseminated intravascular coagula-
tion and hemorrhage.
The classic or acute form of the disease, which affects pigs
of all ages, commences by entry of the virus through the
mucous membranes with initial replication in the tonsillar
epithelium. This is followed by spread to the cervical lymph
nodes with viremia within 16 hours of infection. The virus has
a propensity to replicate in cells of the immune system, par-
ticularly in lymph nodes, bone marrow, and other lymphoid
aggregates, such as the spleen and Peyer’s patches. After 3-4
days, the virus invades endothelial cells and epithelial cells,
including those of the pharyngeal mucosa, gastrointestinal
tract, gallbladder, pancreas, salivary gland, uterus, adrenal, and
thyroid. The clinical signs are not specific and do not provide
good correlation with pathologic changes, although, in the
acute disease, they may be sufficient for presumptive diagnosis
where the disease is endemic.
Superficially, the eyelids are frequently adherent and sticky,
and the carcass is dehydrated and soiled by terminal diarrhea.
The irregular erythema that can be seen in the animal when
alive is less obvious, but hemorrhages, particularly in unpig-
mented areas of skin, may be seen. If present, they are most
numerous on the abdomen and the inner aspects of the thighs.
Diagnostic lesions may be sparse in CSF, especially if per-
acute, and it may be impossible to establish the diagnosis on
the basis of the gross lesions in a single animal. The lesions most
commonly present are hemorrhages in the periphery of the lymph
nodes and renal petechiae (Fig. 1-81A). The renal hemorrhages
may be very few, and in all cases the kidney capsule should
be removed and the surface examined in good light. Hemor-
rhages in the lymph nodes are more obvious; characteristically,
only the periphery of the node is involved. In acute cases, this
produces a distinctive bright red halo; if the case is more
 77.e1

Classical swine fever

Pestivirus
(Variation in strain virulence)

Transplacental infection Acute, chronic to

(70 days gestation) persistent infection
leads to immune in immunocompetent animals
tolerance of infection

Clinical syndromes vary

Fetal abnormalities
Abortion, stillbirth,
mummification, congenital
abnormalities-heart and CNS
from acute, subacute, chronic,
inapparent infection
Late onset runting
syndrome
Low virulence virus
Anorexia, depression,
conjunctivitis, runting,
paraparesis

eFigure 1-23  Major clinical syndromes of classical swine fever. CNS, central nervous system.
78 CHAPTER 1  •  Cardiovascular System
B outlined circular areas of hemorrhage and necrosis. The central
Figure 1-81  Classical swine fever (hog cholera). A. Cortical
surface of kidney with multiple petechial hemorrhages (turkey
egg kidney). B. Splenic infarct (arrow). (Courtesy Foreign Animal
Diseases Diagnostic Laboratory, National Veterinary Services
Laboratories.)
chronic, the halo may be the dirty brown of partially degraded
hemoglobin. Less frequently, the hemorrhage in the node is
diffuse. The nodal changes are generalized, but nodes most apt
to show severe changes are the mandibular, colonic, hepatic,
and iliac; changes in the renal lymph nodes are not useful in
this context.
Splenic infarction is almost pathognomonic of acute CSF.
Unfortunately, the tendency for infarcts to develop in the
disease varies with the strain of the virus, with reports of
incidence of 1-87%. When present, infarcts occur as single or
multiple, dark red, pyramidal blebs 0.5-2 cm in diameter,
usually along free edges but occasionally on the flat surface
(Fig. 1-81B). The spleen in CSF is not enlarged, as it is in
septicemias, and is red-brown so that the infarcts contrast
quite sharply with the meaty parenchyma. In addition to the
hemorrhages of the kidney, petechiae are common in the
urinary bladder (eFig. 1-24), the larynx (eFig. 1-25), the gastric
mucosa, the lung, and the epicardium, in about that decreas-
ing order of frequency. There is usually a small amount of
straw-colored fluid in the pericardial sac. There may be hem-
orrhagic lobular pneumonia.
Irregular, but sharply outlined areas of necrosis develop in
the tonsils and posterior fauces. The stomach of an animal
Arteries
Figure 1-82  Classical swine fever. Mild lymphoplasmacytic vas-
culitis with hypertrophied endothelial cells in the brain of a pig.
H&E. (From Joint Pathology Center Veterinary Systemic Pathol-
ogy Online database.)
dead of CSF is empty except for a small amount of watery
mucus and ingesta. The fundic mucosa is congested, and mild
or severe erosions may be present. Specific lesions do not
occur in the small intestine, but the mesentery is usually con-
gested. It is in the colon and cecum that the virus combines
with the intestinal flora to produce craterous mucosal defects,
“button ulcers,” which are characteristic of the subacute or
chronic stage of the disease. These lesions begin as sharply
area is yellow and dry. As the lesion ages, the rim, which is
composed of necrotic epithelium, bacteria, and detritus, is
raised above the surrounding mucous membrane, and concen-
tric rings form as if growth were cyclic. The center of lesions
sinks giving a slight diskoid shape. If this necrotic tissue and
debris is removed, a deep ulcer is revealed. Growth arrest lines
may be seen in the ribs of chronically sick pigs. Gross lesions
are not usually present in the brain, but the brain should be
removed because it is there that the histologic changes can be
best appreciated. The major features of the gross postmortem
findings are shown in eFigure 1-26.
Microscopically, all areas within the brain may be affected,
but the lesions are usually most conspicuous in the medulla,
pons, mid-brain, and thalamus. The response is largely con-
fined to the vessels and their supporting mesoderm. Many of
the venules have eccentric cuffs, which are formed in part by
transmural migration of monocytes. Mitotic figures and nuclear
chromatin of necrotic cells are frequently present together in
the cuff, as proliferation and necrosis are coexistent. Swelling
and degeneration of the endothelial cells occur in the walls of
the smaller vessels (Fig. 1-82). All changes from slight thicken-
ing to necrosis of the wall may be seen. The lumen is often
compromised by these reactions. The response of the neural
parenchyma appears to be entirely secondary to the vascular
lesions; often it is nonexistent or confined to minimal neuronal
degeneration, or it may consist of glial nodules formed about
obstructed or destroyed capillaries. If severe cerebral edema
develops, there may be widespread damage to the oligoden-
droglia. The vessels of the eyes, choroid plexuses, and the
leptomeninges are similarly involved.
 78.e1

eFigure 1-25  Laryngeal hemorrhages in acute classical swine

fever.

eFigure 1-24  Hemorrhages in mucosa of urinary bladder in acute

classical swine fever.

Classical swine fever

gross lesions

Hemorrhage, infarction, Petechiae

necrosis, (apoptosis)

Hemorrhage periphery Splenic infarction Necrosis, ulceration Renal cortical surface,

of lymph nodes [Not always present] Tonsils, button ulcers bladder, larynx, lung,
in colon and cecum epicardium, gastric mucosa

eFigure 1-26  Major gross postmortem findings in classical swine fever.

Diseases of the Vascular System
Vascular lesions usually are most severe in lymphoid tissue
but may occur anywhere. The lesions vary from slight thickening
of the capillary wall to fibrinoid necrosis of arterioles. As these
changes develop, there is a tendency for extravasations to
occur and for microthrombi to form.
Microscopic areas of infarction are common in the lymph
nodes and skin, but only in the spleen, tonsil, gallbladder, and
large intestine are these areas usually large enough to be
grossly visible. In some cases, swelling and paleness of the
capillary wall is obvious. The nuclei of endothelia in these
vessels are enlarged and the nuclear chromatin is dispersed as
fine dust. Less often, the endothelial proliferation is so marked
as to be the most conspicuous change. In general, in acute
cases the degenerative changes are most prominent, whereas
in chronic ones proliferative changes are more obvious.
In the periphery of lymph nodes (the equivalent of the
medulla in other species), lesions vary from slight edema and
proliferation of the reticuloendothelial elements to extensive
hemorrhage. It is the intermediate stages that are the most
common and in which the nature of the lesion is best visual-
ized; in these, there is necrosis of the small vessels and second-
ary hemorrhages and parenchymal necrosis.
In the spleen, the most pronounced lesions are in the fol-
licular arteries, particularly those at the apex of the pyramidal
infarcts. The swelling and hyalinization of these vessels may
be so severe as to occlude the lumen. Survival of tissue within
the infarcted area will depend on how long the infarction
preceded death. Even if the spleen is free of gross and microscopic
infarction, vascular changes of the type seen elsewhere can usually
be found. They are often associated with perivascular hemor-
rhage. In addition, there is reticuloendothelial hyperplasia and
absence of mature lymphocytes.
The kidney tubules often show nonspecific degenerative
changes. The subcapsular hemorrhages seen grossly are the
result of increased vascular permeability and erythrodiapede-
sis. Immune-complex–mediated mesangioproliferative glo-
merulonephritis occurs with deposition of IgM, IgG, and C1q
in mesangial, subepithelial, and subendothelial sites; infiltra-
tion of the mesangium by macrophages and later neutrophils;
and ultrastructurally, the fusion of foot processes and the  Middle East, Asia, and Australia. In temperate climates, BEF
presence of viral particles in glomerular endothelial cells  is a disease of summer and autumn, and ceases abruptly at the
and podocytes. The major histologic features are shown in  first frost; the host/reservoir for overwintering or between
eFigure 1-27.
In utero infections can result in a variety of effects, includ-
ing abortion, mummified fetuses, and stillborn piglets. Fetal
abnormalities, such as ascites, petechiation of skin and other
organs, hepatic nodularity, pulmonary hypoplasia, microceph-
alus, hydrocephalus, cerebellar hypoplasia, and hypomyelino-
genesis, may also be observed. Persistently infected pigs that
survive may be runts and die 2-11 months after birth. These
piglets have severe thymic atrophy and pale swollen lymph
nodes; some may have focal colonic mucosal necrosis.
Serologic diagnosis of CSF is difficult. Antibodies to CSFV
and BVDV cross-react in many assays; they may be differenti-
ated by specific virus neutralization tests. The prescribed tests
in the World Organization for Animal Health (OIE) Manual
are the neutralization peroxidase-linked assay, fluorescent
antibody virus neutralization, and ELISA. CSFV antigen can
be detected in live pigs by real-time (RT)-PCR, and in
formalin-fixed tissue by semi-nested RT-PCR or by in situ
hybridization.
Differential diagnoses for CSF include African swine fever
(clinicopathologically indistinguishable), BVDV infection,
Arteries 79
porcine reproductive and respiratory syndrome (PRRS), post-
weaning multisystemic wasting syndrome (PMWS), porcine
dermatitis and nephropathy syndrome (PDNS), salmonellosis,
erysipelas, acute pasteurellosis, other viral encephalomyeliti-
des, streptococcosis, leptospirosis, and coumarin poisoning.
Further reading
Calderon NL, et al. Ultrastructural glomerular changes in experimental
infection with the classical swine fever virus. Vet Res 2000;31:447-
453.
Elbers AR, et al. Assessment of the use of gross lesions at post-mortem
to detect outbreaks of classical swine fever. Vet Microbiol
2003;96:345-356.
Gogin A, et al. African swine fever in the North Caucasus region and
the Russian Federation in years 2007-2012. Virus Res 2013;173:198-
203.
Gomez-Villamandos JC, et al. African swine fever and classical swine
fever: a review of the pathogenesis. Dtsch Tierarztl Wochenschr
2003;110:165-169.
Paton DJ, Greiser-Wilke I. Classical swine fever: an update. Res Vet Sci
2003;75:169-178.
Sanchez-Cordon PJ, et al. A histopathologic, immunohistochemical,
and ultrastructural study of the intestine in pigs inoculated with
classical swine fever virus. Vet Pathol 2003;40:254-262.
Tao J, et al. Bovine viral diarrhea virus (BVDV) infections in pigs. Vet
Microbiol 2013;165:185-189.
Bovine ephemeral fever.  Bovine ephemeral fever (BEF), a
noncontagious vector-borne viral disease of cattle and water
buffalo, is characterized by sudden onset of fever, stiffness, and
lameness, usually with high morbidity and low mortality, and
with rapid recovery within 3-4 days of the onset of clinical signs.
The cause is species Bovine ephemeral fever virus (BEFV),
genus Ephemerovirus, family Rhabdoviridae. The disease is
endemic in tropical regions of Africa and Asia and occurs as
epidemics in subtropical and temperate regions of Africa, the
epizootics is probably in wild ruminants. Infection usually
confers lifelong immunity. The likely vectors are various
species of Culicoides and mosquitoes.
Clinical disease ranges from almost imperceptible clinical
signs to death, with considerable individual variation in an
outbreak. Mild disease may be exacerbated by environmental
stress, for instance, exposure causing dehydration. Disease is
milder in young than in mature animals, in lean than in fat
animals, in light steers and cows than in bulls, and in dry cows
than in those in heavy lactation. The incubation period is
usually 2-4 days. The fever may be biphasic, triphasic, or
multiphasic; clinical signs are milder in early than in later
phases of fever. Mildly affected animals may have fever, be
lame, or be stiff for 1-2 days, and then recover completely.
Neutrophilia with a left shift and concurrent lymphopenia,
hyperfibrinogenemia, and hypocalcemia occur early in the
course of disease. More severely affected animals are anorectic,
have oculonasal discharge, and may have muscle tremors, stiff-
ness, lameness, and patchy edema of the face or jaw. Rumen
motility ceases, and the animal may be constipated. Animals
in lateral recumbency are usually still able to rise. Lactation
 79.e1

Classical swine fever

Hemorrhage
Necrosis
Apoptosis
Proliferation

Immune system Vascular endothelium Epithelial cells

Degeneration/necrosis/ Combination of degeneration/ Necrosis/apoptosis-possibly
apoptosis of mature cells. necrosis/apoptosis and proliferation secondary to macrophage cytokines
Proliferation of immature cells Also thrombosis, infarction, DIC

Hemorrhage, necrosis/ Brain Sharply outlined areas of

apoptosis of lymphoid (medulla, pons, mid brain, thalamus) hemorrhage and necrosis
elements. Fibrinoid necrosis Monocytic perivascular cuffing
of arteriolar walls both proliferation and necrosis/apoptosis
kidney-glomerulonephritis

eFigure 1-27  Major histopathologic findings in classical swine fever. DIC, disseminated intravas-
cular coagulation.
79.e2

Further reading
Carrasco CP, et al. Interaction of classical swine fever virus with den-
dritic cells. J Gen Virol 2004;85:1633-1641.
Choi C, et al. Classical swine fever virus induces tumor necrosis factor-
alpha and lymphocyte apoptosis. Arch Virol 2004;149:875-889.
Floegel-Niesmann G, et al. Virulence of recent and former classical
swine fever virus isolates evaluated by their clinical and pathologi-
cal signs. J Vet Med B Infect Dis Vet Public Health 2003;50:214-220.
Ha SK, et al. Development of an optimized protocol for the detection
of classical swine fever virus in formalin-fixed, paraffin-embedded
tissues by semi-nested reverse transcription-polymerase chain reac-
tion and comparison with in situ hybridization. Res Vet Sci
2004;77:163-169.
Handel K, et al. Comparison of reverse transcriptase-polymerase chain
reaction, virus isolation, and immunoperoxidase assays for detect-
ing pigs infected with low, moderate, and high virulent strains of
classical swine fever virus. J Vet Diagn Invest 2004;16:132-138.
Kleiboeker SB. Swine fever: classical swine fever and African swine
fever. Vet Clin North Am Food Anim Pract 2002;18:431-451.
Moennig V, et al. Clinical signs and epidemiology of classical swine
fever: a review of new knowledge. Vet J 2003;165:11-20.
Ruiz-Villamor E, et al. Classical swine fever: pathogenesis of glomeru-
lar damage and immunocharacterization of immunocomplex
deposits. J Comp Pathol 2001;124:246-254.
Terpstra C, Wensvoort G. Natural infections of pigs with bovine viral
diarrhoea virus associated with signs resembling swine fever. Res
Vet Sci 1988;45:137-142.
80 CHAPTER 1  •  Cardiovascular System
falls by an average of 50%, and does not usually recover to
normal during that lactation. Cows in late pregnancy may
abort. In very severe cases, there may be temporary or perma-
nent paralysis of all limbs, inability to swallow, and drooling;
in 1-4 days, loss of reflexes, coma, and death follow.
Whether the disease is mild or severe, recovery commences
quite suddenly and is complete in 95-97% of uncomplicated cases,
giving rise to the name “ephemeral fever.” Although mortality is
usually <1%, the most productive mature animals are often
lost, plus there are losses of milk production, abortion losses,
and temporary infertility in bulls. Other sequelae include fatal
pulmonary emphysema, pneumonia, mastitis, and locomotor
disturbances. The total economic loss in an outbreak can be
severe.
The essential gross feature of BEF is serofibrinous polyserosi-
tis, which variously affects the synovial, pericardial, thoracic,
and peritoneal cavities, and is the result of increased vascular
permeability. The serosal membranes themselves are often
edematous and may be hemorrhagic; the edema fluid in cavi-
ties often contains fibrin clots. Severely affected joints may be
surrounded by brown or yellow gelatinous periarticular fluid
that also extends along tendon sheaths and fascial planes.
There may be patchy pulmonary edema, visceral and parietal
pleuritis, epicarditis at the base of the heart, edematous lymph
nodes in the febrile stages, and necrosis in some skeletal
muscles; myonecrosis is likely the result of recumbency.
Histologically, affected tissues are edematous and infil-
trated by neutrophils, and may also be hyperemic and hemor-
rhagic. Vascular changes include endothelial swelling and
hyperplasia, hyperplasia of pericytes, fibrinoid necrosis of arte-
rioles, perivascular fibroplasia, and thrombosis of occasional
vessels in muscles. Wallerian degeneration has been reported
in the upper cervical spinal cord in cases with chronic paraly-
sis, but may be secondary to trauma.
The pathogenesis of BEF is poorly understood, but is likely
mediated through cytokines. BEFV α1 protein is expressed in
infected cells and has the properties of a viroporin, which may
facilitate virus replication. Neutrophils appear to play a
central, but undefined, role in pathogenesis; cattle in which
neutrophils are experimentally depleted develop viremia but
not clinical disease. Interferon-α, interleukin 1, and tissue
necrosis factor circulate in high titer during the acute phase
of BEF.
The clinical signs observed in an epizootic are usually diag-
nostic. The diagnosis can be confirmed by virus detection/
isolation. Serologic diagnosis may be complicated by cross-
reaction with antibody to Kimberley virus, an arbovirus that
induces production of low levels of serum neutralizing anti-
body to BEFV but does not protect against BEFV.
Further reading
Aziz-Boaron O, et al. Circulation of bovine ephemeral fever in the
Middle East—strong evidence for transmission by winds and animal
transport. Vet Microbiol 2012;158:300-307.
Blasdell KR, et al. A reverse-transcription PCR method for detecting all
known ephemeroviruses in clinical samples. J Virol Methods
2013;191:128-135.
Joubert DA, et al. Bovine ephemeral fever rhabdovirus α1 protein has
viroporin-like properties and binds importin β1 and importin 7. J
Virol 2014;88:1591-1603.
Kirkland PD. Akabane and bovine ephemeral fever virus infections. Vet
Clin North Am Food Anim Pract 2002;18:501-514.
Arteries
Rickettsial vasculitides
Heartwater (cowdriosis).  Heartwater is a tick-borne rickett-
siosis of ruminants that is endemic in sub-Saharan Africa and
has been identified in several Caribbean islands. The common
name, heartwater, is derived from the pericardial effusion that
is typically present in small ruminants, but sometimes absent
in infected cattle. Heartwater is a major vector-borne disease
of ruminants in Africa, third in importance only to East Coast
fever and trypanosomiasis, but has a wider distribution than
either of these. Mortalities caused by heartwater are estimated
to be 3 times greater than those caused by babesiosis and
anaplasmosis. The causative agent is Ehrlichia (Cowdria)
ruminantium, order Rickettsiales. Isolates of E. ruminantium
cross-react strongly with Ehrlichia equi and to a lesser extent
with E. canis, in indirect fluorescent antibody tests. The vectors
are 3 host ticks of the Amblyomma genus, principally A. var-
iegatum, A. hebraeum, and A. pomposum. Amblyomma macu-
latum and A. cajennense are suitable vectors present on the
American mainland. Trans-stadial transmission occurs in
vector ticks; transovarian transmission is infrequent. When a
tick feeds on an infected host, organisms apparently first infect
and develop within gut cells. Subsequent stages of the organ-
ism continue their development in hemolymph and salivary
gland, and are transferred to the vertebrate host during tick
feeding.
The various strains of Ehrlichia ruminantium are antigeni-
cally similar, but differ considerably in their virulence. The
various domestic hosts also differ in their susceptibility.
Imported breeds of cattle, sheep, and goats are as a rule much
more susceptible than indigenous breeds. There is also an
important age difference in susceptibility. Calves and lambs
<3 weeks of age are highly resistant to heartwater. This is a
true age resistance, and it is independent of maternal immu-
nity. Ruminants are most susceptible at about the stage of
early maturity, and in the absence of treatment, mortality is
expected to be ~60% in cattle and close to 100% in European
breeds of sheep, although this will depend on the virulence of
the infecting strain.
There also appear to be differences in susceptibility among
the African antelopes. The blesbok and black wildebeest are
known to be susceptible to infection without showing signs
of illness. Wildlife may act as reservoirs of infection, although
this is not necessary as the tick itself is a reservoir; infection
survives in adult ticks for >15 months. Domestic ruminants
that have recovered from the disease seldom remain as carriers
of the circulating organism for >3 weeks after recovery, but it
is not clear whether the agent remains in a masked form in
tissues. Immunity of variable duration follows recovery, often as
premunity; sterile immunity may persist for a year or more
after disappearance of the organism. Immunity in natural
infections is expected to be reinforced by reinfections.
The early development of the parasite is not completely
understood, but probably takes place in reticulum cells and
macrophages of lymph nodes and spleen in which initial bodies
are demonstrable at about the fourth day of infection. Organ-
isms are then released into the blood and parasitize vascular
endothelial cells. The organism is demonstrable in capillary
endothelium of brain 1-3 days after it is demonstrable in
lymph nodes. Ehrlichia ruminantium parasitizes endothelial
cells but is also present in the blood; the infection is readily
transmissible by inoculation of blood collected during the
febrile stage or shortly thereafter. The colonies (groups,
clusters, morulae) of microorganisms in endothelial cells lie
 80.e1

Further reading
Losos GJ. Infectious Tropical Diseases of Domestic Animals. Harlow, UK:
Longman Scientific and Technical.; 1986. p. 452-477.
St George TD. Bovine ephemeral fever: a review. Trop Anim Health
Prod 1988;20:194-202.
Uren MF, et al. Studies on the pathogenesis of bovine ephemeral fever
in experimental cattle: III. Virological and biochemical data. Vet
Microbiol 1992;30:297-307.
Wang FI, et al. Bovine ephemeral fever in Taiwan. J Vet Diagn Invest
2001;13:462-467.
Young PL, Spradbrow PB. Demonstration of vascular permeability
changes in cattle infected with bovine ephemeral fever virus.
J Comp Pathol 1990;102:55-62.
Diseases of the Vascular System Arteries 81

characteristically in membrane-bound vacuoles in the cytoplasm

at the poles of the endothelial cell nuclei. Colonies and organisms
are pleomorphic; colonies are formed by binary fission of
organisms. Organisms range in size from 0.2 to >2.5 µm and
are termed small, medium, or large; each is surrounded by a
double membrane, and based on their internal morphology,
they may be termed elementary (electron-dense), intermediate,
or reticulate bodies; usually only organisms of the same form
are found within a vacuole. They can be found in sections and
are present in all organs and in vessels of all calibers, but are
best sought in the capillaries of the cerebral cortex in squash-
smear preparations or in imprints from the endothelium of a
large vessel, such as the jugular vein. Giemsa is the preferred
method of staining.
The natural incubation period of heartwater is 2-3 weeks
but varies considerably. In the peracute form of the disease,
death occurs rapidly in convulsions without warning. The
usual clinical syndrome in susceptible animals is acute, with a Figure 1-83  Hydrothorax in heartwater. (Courtesy Foreign
course of up to 6 days. There is high fever and its attendant Animal Diseases Diagnostic Laboratory, National Veterinary Ser-
signs, and dyspnea. As the course advances, nervous signs vices Laboratories.)
develop. These are especially prominent in cattle and consist
of chewing movements, protrusion of the tongue, twitching
of eyelids and blinking, unsteadiness of gait, circling, and a
terminal convulsive phase in which there is prominent cutane-
ous hyperesthesia. Diarrhea is common in cattle but less
common in sheep. Mild progressive anemia may develop, as
may leukopenia (neutropenia, eosinopenia, and lymphocyto-
sis) and hypoalbuminemia. In the subacute syndrome, the
course is prolonged and leads either to slow recovery or to
collapse and death. Animals with high natural resistance or
partial immunity may show transient fever only.
The pathogenesis of the increased capillary permeability
seen in heartwater is unclear; the severity of edema is often
thought to be out of proportion to the numbers of infecting
organisms. Production of a toxin has been suggested, but not
proven; Ehrlichia stains negatively with Gram’s stain, has a cell
wall similar to that of gram-negative bacteria, and has been
suggested to produce endotoxin. Complement and the prod-
ucts of arachidonic acid metabolism may play a role in the Figure 1-84  Hydropericardium in heartwater. (Courtesy Foreign
generation of vasoactive substances. Animal Diseases Diagnostic Laboratory, National Veterinary Ser-
The gross anatomic changes in heartwater are the same in vices Laboratories.)
each ruminant species but generally are less prominent in
cattle than in sheep or goats; lesions may be inconspicuous or
absent in treated animals. The disease does not alter the hyperemia with submucosal edema in the lower alimentary
general condition of the animal appreciably. Typical gross tract, but it is most pronounced in the abomasum. Petechial
lesions include effusion in body cavities, hydropericardium, hemorrhages are present in the endocardium, mucosa of
edema of lungs, brain, mediastinum, and associated lymph stomach and gut, tracheobronchial mucosa, and lymph nodes.
nodes, and splenomegaly, although all of the lesions rarely Lesions in the brain are common and account for the
occur simultaneously (Fig. 1-83). The name of the disease is nervous signs that characterize the disease, especially in cattle,
derived from the hydropericardium, but this is sometimes and for the failure of animals to recover with chemotherapy.
absent. The effusion, which is serous with some fibrinous Gross changes are inconstant on inspection of the surface of
strands, is more constant and copious in sheep than in cattle the brain. Petechial hemorrhages may be present over the
(Fig. 1-84). The other serous cavities also contain excess serous cerebellum, and the choroid plexus may be dull and thick-
fluid; there may be several liters in the pleural and peritoneal ened. On slicing, petechial, ecchymotic, and larger hemor-
cavities of cattle and up to half a liter in sheep and goats. rhages may be numerous in all parts of the brain.
When exudation is copious, the mediastinum and retroperi- The microscopic lesions in the brain are reflections of para-
toneal tissues are also edematous. The membranes remain sitism and injury to small vessels, especially capillaries and
clear and glistening. The lungs are severely edematous, espe- venules. Either histologic sections or impression smears will
cially in the peracute form. The lymph nodes of the head, show colonies of E. ruminantium visible in endothelial cyto-
neck, and cranial mediastinum especially are swollen and plasm of untreated cases (Fig. 1-85). There is acute inflamma-
edematous. The spleen is almost invariably much enlarged in tion of the choroid plexus with fibrinous exudate in the
sheep and goats, being sometimes up to 6 times its normal stroma, congestion, hemorrhage, and accumulation of inflam-
size, but splenomegaly in cattle is only moderate. There is matory cells about the vessels. Within the brain, vascular
82 CHAPTER 1  •  Cardiovascular System
Figure 1-85  Heartwater in an ox. Impression smear showing
intracellular Ehrlichia ruminantium organisms. (Courtesy M.
Domingo Alvarez.)
injury leads to perivascular or larger hemorrhages and accu-
mulation of protein droplets in the perivascular space. Focal
or larger areas of malacia surround the vessels and are in
various stages of development from edematous disruption of
white matter with glial activation to microcavitation.
The diagnosis of heartwater depends largely on the dem-
onstration of organisms in endothelial cells in brain either in
smears or section; brain biopsy can be used to establish the
diagnosis in the living animal. The pCS20 PCR assay is the
most reliable and specific assay for the detection of E. rumi-
nantium in ruminants and Amblyomma ticks. Various antibody
detection assays are available, including indirect fluorescent
antibody, polyclonal competitive ELISA, major antigenic
protein (MAP-1) ELISA, and Western blot, but often lack
specificity because of cross-reactivity with closely related
ehrlichiae.
Further reading
Allsopp BA. Natural history of Ehrlichia ruminantium. Vet Parastiol
2010;167:123-135.
Brown CC, Skowronek AJ. Histologic and immunochemical study of
the pathogenesis of heartwater (Cowdria ruminantium infection) in
goats and mice. Am J Vet Res 1990;51:1476-1480.
Mebus CA, Logan LL. Heartwater disease of domestic and wild rumi-
nants. J Am Vet Med Assoc 1988;192:950-952.
Vacheiry N, et al. Differential strain-specific diagnosis of the heart­
water agent: Ehrlichia ruminantium. Infect Genet Evolution
2008;8:459-466.
Rocky Mountain spotted fever.  Rocky Mountain spotted
fever (RMSF), a febrile exanthema caused by Rickettsia rick-
ettsii, is an important rickettsiosis of dogs and humans; R.
rickettsii or antigenically similar organisms infect a wide variety
of mammals and birds. RMSF occurs in dogs throughout the
Americas (and is known by various other names, for instance,
Brazilian spotted fever, BSF), with most cases in North
America occurring during the tick season (April to Septem-
ber). Canine monocytic ehrlichiosis (CME), a very similar
acute nonspecific febrile illness, is caused by Ehrlichia canis in
Brazil; BSF must be differentiated from CME.
Arteries
The ticks most commonly responsible for the transmission
of RMSF are Dermacentor variabilis and D. andersoni; these
ticks serve as vectors, reservoirs, and natural hosts for R. rick-
ettsii. The rickettsiae are maintained in nature in a primary
sylvan cycle, involving mostly small rodents. Dogs can develop
a high and persistent rickettsemia, and are a potential public
health danger; humans can be infected during tick removal by
contact with hemolymph of engorged ticks or with tick
excreta. Tetracycline therapy is effective, and dogs are immune
after recovery.
Dogs are usually infected via the bite of infected ticks. The
rickettsiae invade and replicate within endothelial cells of small
blood vessels; endothelial damage is probably mediated by
phospholipase A and a trypsin-like protease, of either rickett-
sial or host origin. There is little evidence for production of
endotoxin or exotoxin by R. rickettsii. Endothelial damage
leads to platelet activation and activation of coagulation and
fibrinolytic systems; thrombosis in RMSF is thought to arise in
reaction to endothelial damage.
Vasculitis in RMSF is a product of endothelial swelling and
necrosis with secondary contributions from the immune and
phagocytic host responses mounted by lymphocytes and 
macrophages, but is not primarily caused by immune- 
complex formation or by cell-mediated mechanisms. The
action of various mediators, such as those of the kallikrein-
kinin system, in addition to direct endothelial necrosis, leads
to increased vascular permeability and hence edema and mul-
tifocal hemorrhage.
Dogs <2 years of age are predominantly affected. Purebred
dogs, especially German Shepherd dogs, appear to be more
susceptible than are crossbreds. Following an incubation
period of a few days, clinical findings in affected dogs include,
in decreasing order of frequency, listlessness and depression,
high fever, history or actual presence of ticks, anorexia,
myalgia/arthralgia, lymphadenomegaly, vestibular deficits,
dyspnea, conjunctivitis, paralumbar hyperesthesia, edema of
face and extremities, petechiae or hemorrhagic diathesis, and
vomiting and diarrhea. Vasculitis may be visible by means of
ophthalmoscopic examination of retinal vessels.
Laboratory findings include anemia, leukopenia followed
by leukocytosis, thrombocytopenia, prolongation of acti-
vated partial thromboplastin time, hyperfibrinogenemia, and
increased concentrations of fibrin/fibrinogen degradation
products. The thrombocytopenia is at least partly due to the
development of antiplatelet antibodies. Serum biochemistry
usually reveals hypoalbuminemia, increased alkaline phospha-
tase activity, and hypercholesterolemia. Increased concentra-
tions of aldosterone and antidiuretic hormone may contribute
to expansion of plasma and extracellular fluid volumes and
hence edema. Edema of the medulla oblongata may contrib-
ute to cardiorespiratory depression. Death may occur in the
acute stages of disease as the result of peripheral vascular col-
lapse, hemorrhagic diathesis, and thrombosis, although fully
developed disseminated intravascular coagulation (DIC) is an
unusual event in RMSF in dogs. Necrosis of extremities 
may occur. Damage to the cardiovascular system, brain, or
kidneys may cause death or permanent organ dysfunction;
severely affected dogs may die with rapidly progressive
meningoencephalitis.
Gross lesions include edema of ears and muzzle; ulcerative
glossitis; scrotal dermatitis; petechiation of mucous mem-
branes, caudal abdominal skin, pleura, and gastric wall; hemor-
rhagic colitis; and hemorrhagic lymphadenopathy.
 82.e1

Further reading
Du Plessis JL. Electron microscopy of Cowdria-infected macrophages
suggests that in the absence of binary fission a mosaic of organisms
develops from an amorphous electron dense matrix. Onderstepoort
J Vet Res 1999;66:39-46.
Mwangi DM, et al. Cellular immune responses of cattle to Cowdria
ruminantium. Dev Biol Stand 1998;92:309-315.
Simbi BH, et al. Comparing the detection of exposure to Ehrlichia
ruminantium infection on a heartwater-endemic farm by the pCS20
polymerase chain reaction assay and an indirect MAP1-B enzyme
linked immunosorbent assay. Onderstepoort J Vet Res 2003;70:231-
235.
van Halderen A, et al. Abortion in a heifer associated with the intra-
uterine transmission of Cowdria ruminantium-like organisms fol-
lowing heartwater vaccination. J S Afr Vet Assoc 1996;67:158-160.
Van Heerden H, et al. Characterization of the pCS20 region of different
Ehrlichia ruminantium isolates. Vet Microbiol 2004;101:279-291.
Diseases of the Vascular System
The prominent histologic lesion of RMSF is necrotizing vas-
culitis of small veins, capillaries, and arterioles, with perivascular
accumulations predominantly of lymphocytes and macro-
phages. This lesion is seen most commonly in skin, testes,
alimentary tract, pancreas, kidneys, urinary bladder, myocar-
dium, meninges, retina, and skeletal muscle. Acute meningo-
encephalitis may be present. There may also be acute splenitis,
acute interstitial pneumonia, and multifocal necrosis of myo-
cardium, adrenals, and liver. A moderate degree of glomerulo-
nephritis may be present.
The most reliable serologic test for RMSF is the species-
specific microimmunofluorescent method. High antibody
titers develop to R. rickettsii, but usually decline after 3-5
months. Direct fluorescent antibody staining of a skin biopsy
is positive in up to 80% of infected dogs; coccobacillary organ-
isms are present in endothelial cells and vessel walls. Infection
may also be confirmed by PCR detection of the agent in
peripheral blood.
Further reading
Elchos BN, Goddard J. Implications of presumptive fatal Rocky Moun-
tain spotted fever in two dogs and their owner. J Am Vet Med Assoc
2003;223:1450-1452, 1433.
Gasser AM, et al. Canine Rocky Mountain spotted fever: a retrospec-
tive study of 30 cases. J Am Anim Hosp Assoc 2001;37:41-48.
Labruna MB, et al. Rocky Mountain spotted fever in dogs, Brazil. Emerg
Infect Dis 2009;15:458-460.
Piranda EM, et al. Experimental infection of dogs with a Brazilian strain
of Rickettsia rickettsii: clinical and laboratory findings. Mem Inst
Oswaldo Cruz 2008;103:696-701.
Verminous arteritis
Here we are concerned with those parasites whose natural
habitat is the lumen or the wall of arteries. Parasites that,
accidentally or as part of their life cycle, migrate in tissues
may, depending on the route they take, cause vasculitis in
various organs. The chief offenders in this regard are the larvae
of the genera Strongylus and Ascaris; the vascular lesions of
Ascaris infestations are described under diseases of the intes-
tine (see Vol. 2, Alimentary system and peritoneum). Angio-
strongylus vasorum, which inhabits the pulmonary arteries of
dogs, is described with the lungworms. Spirocerca lupi, which
passes part of its history in the adventitia of the thoracic aorta,
is described in its final habitat, the esophagus.
Dirofilariasis (heartworm disease).  The dog is the only
mammal commonly infected by Dirofilaria immitis (heart-
worm), and is the only significant reservoir of infection. In areas
where heartworm infection is enzootic in dogs, a number of
other mammals may become infected, including domestic cats
and wild felids, wild canids (coyotes, foxes, wolves), ferrets,
sea lions, muskrats, horses, and rarely humans. If D. immitis
develops to maturity in hosts other than the dog, microfilare-
mia is usually low or absent, and heart failure is rare. Pulmo-
nary dirofilariasis is of considerable importance in humans
because the spherical, subpleural granulomas produced may
be mistaken radiographically for primary or metastatic lung
tumors, leading to thoracotomy and excisional biopsy for diag-
nosis. Dirofilaria immitis is genetically heterogeneous and has a
tropical and subtropical distribution in southern Europe, Asia,
Australia, and North and South America, although its range
has extended into more northern temperate zones in North
Arteries 83
America and southern temperate zones in Australia. As with
most, if not all filarid worms, D. immitis contains the bacterial
endosymbiont, Wolbachia, which is essential for the normal
development of the parasite, and also contributes to the
pathogenesis of the disease.
There are 40 recognized species of Dirofilaria, 6 of which
have been shown to infect humans as accidental dead-end
hosts. Diagnostic tests based on genomics are being increas-
ingly used to differentiate among the Dirofilaria species infect-
ing the host. Adults of D. repens occur in subcutaneous
connective tissues of dogs and other carnivores (and rarely
humans). Similarly, D. tenuis is found in the subcutaneous
connective tissue of the raccoon in the southern United States.
None of these 3 filarids usually develops to maturity in
humans, but they may be found in cysts in various parts of
the body, especially in the lungs. D. striata, a parasite of
bobcats (Lynx rufus), has been reported in dogs in Florida. A
species of Dirofilaria found in both dogs and humans in Hong
Kong with a 94-95% homology with D. immitis and D. repens
has been tentatively named D. hongkongensis.
Adult D. immitis worms live in the pulmonary arteries and
right heart, but they can develop in various other arteries and
veins, and have been reported from a variety of unusual sites,
including the eye and brain. Adult males are 12-20 cm long
by 0.7-0.9 mm in diameter; females are 25-31 cm by
1.0-1.3 mm. The adult female worms are viviparous, and
release microfilariae into the bloodstream; mosquitoes obtain
microfilariae in blood meals. The first, second, and early third
larval stages of D. immitis are obligate parasites of mosquitoes,
predominantly of the genera Aedes, Culex, or Anopheles.
Larvae develop to the infective stage in about 13 days in the
malpighian tubules. They then migrate to the cephalic spaces
of the head or to the proboscis of the mosquito and escape
into a new host when the mosquito feeds. The infective larvae
are about 1.2 mm long when they enter the host, and are
about 5 cm long when they reach the right ventricle 3-4
months later. In the meantime, the parasites have wandered
and grown in the connective tissue, chiefly those of the sub-
cutis and muscles, finally leaving these to migrate to the heart
via the veins. They mature in a further 3 months. Thus the
prepatent period is 6-8 months. Adults may live for several
years and microfilariae can survive in a dog for as long as 2.5
years. Adult heartworms may be found in cutaneous nodules
occasionally in dogs, and rarely in cats.
The clinical diagnosis of dirofilariasis in dogs depends upon
the detection of microfilariae in the blood, preferably by the
microscopic examination of centrifuged sediment of lysed
blood (modified Knott’s test), or by a filter technique. Microfi-
lariae of D. immitis (290-315 µm long, straight body and tail,
tapered head) must be differentiated from those of Dipetalo-
nema reconditum (270-290 µm, curved body, blunt head,
most have a buttonhook tail), the adults of which are non-
pathogenic and are commonly found in the subcutaneous
connective tissue of dogs; these microfilariae can also be dif-
ferentiated by PCR or histochemical means. The average
number of circulating microfilariae per adult female D. immitis
decreases as the number of adult worms increases. Hence the
numbers of circulating microfilariae indicate neither the numbers
of adult worms present nor the severity of heartworm disease in
an individual dog. Although microfilariae are present in the
blood more or less continuously, there is a tendency to peri-
odicity, with maximum numbers occurring in the evening 
and in the summer, coincident with maximal activity of 
 83.e1

Further reading
Davidson MG, et al. Vascular permeability and coagulation during Rick-
ettsia rickettsii infection in dogs. Am J Vet Res 1990;51:165-170.
Grindem CB, et al. Platelet-associated immunoglobulin (antiplatelet
antibody) in canine Rocky Mountain spotted fever and ehrlichiosis.
J Am Anim Hosp Assoc 1999;35:56-61.
Paddock CD, et al. Short report: concurrent Rocky Mountain spotted
fever in a dog and its owner. Am J Trop Med Hyg 2002;66:197-199.
Procop GW, et al. Immunoperoxidase and immunofluorescent staining
of Rickettsia rickettsii in skin biopsies. A comparative study. Arch
Pathol Lab Med 1997;121:894-899.
84 CHAPTER 1  •  Cardiovascular System
mosquitoes. Microfilariae are pooled in internal organs, espe-
cially the lungs, in the daytime. Fetal pups may be infected by
microfilariae from the bitch and have microfilaremia, but the
pups do not harbor adult worms. Cats infected with D. immitis
are typically amicrofilaremic, given low numbers of adult
female worms or male-only infections, hence antigen- or
antibody-detection tests are required for diagnosis.
Occult dirofilariasis, that is, heartworm infection without
microfilaremia, occurs in 10-67% of infected dogs, primarily as
a result of destruction of microfilariae by immune mecha-
nisms (“immune-mediated occult disease”), but also as the
result of prepatent infections, single-sex infections, and drug-
induced sterility of adult heartworms. Clinical diagnosis of
occult dirofilariasis then rests on the findings of the indirect
fluorescent antibody test, antigen detection tests, and cardio-
pulmonary imaging. Circulating antibodies are usually detect-
able only in dogs without microfilaremia.
The clinical signs of canine dirofilariasis are usually those
of cardiovascular dysfunction, such as cough and tiring on
exercise, which may progress to congestive heart failure.
Heartworm disease is usually seen in dogs that are older than
5 years and have had continuous or multiple infections. There
is a rough correlation between the numbers of worms present
and the severity of the disturbance, but there are exceptional
cases, and severe signs may appear in dogs with only a few
worms. Clinically normal dogs may harbor up to about 30
worms, and clinically affected dogs 50 or more. Dirofilariasis
in cats usually causes cough and dyspnea, but may as well
cause vomiting, neurologic signs, and malaise; sudden death is
another possible outcome.
Adult heartworms are normally found in the pulmonary arter-
ies and right ventricle (Fig. 1-86), but may be found in the right
atrium and venae cavae in heavy infestations. Young adult
worms usually develop first in small pulmonary arteries, and
progressively involve more proximal arteries as they grow.
Adult worms may be found in the right ventricle if more than
about 25 are present, and in the right atrium and venae cavae
if there are 50 or more worms. The caudal lobar pulmonary
arteries are usually the most heavily infested vessels. Right
heart failure develops as a consequence of pulmonary hyperten-
sion, which in turn is the result of pulmonary vascular sclerosis.
Of secondary importance is mechanical interference of the
Figure 1-86  Dirofilaria immitis (heartworm) in pulmonary
artery and right ventricle of a dog.
Arteries
worms with cardiac blood flow and valve function. Pulmonary
sclerosis and hypertension slowly regress following removal of
the adult worms.
Heartworm disease is primarily a pulmonary vascular disease,
and is characterized by myointimal proliferations in small
peripheral arteries initially, and later in the large lobar arteries,
especially the right caudal lobar artery (Fig. 1-87A, B). The
fibromuscular intimal proliferations in the larger vessels produce
a grossly visible shaggy or roughened appearance, a change
pathognomonic of heartworm disease. The vascular reaction is
to both the immature and mature adult worms, and begins as
an endoarteritis with infiltration of leukocytes, primarily
eosinophils. Neutrophils are also present in the arterial wall,
partly in response to the intracellular bacteria Wolbachia har-
bored by D. immitis. The leukocytic response subsides and is
replaced by myointimal proliferation that produces irregular
rugose to villus projections enmeshing the worms; the myo-
intimal proliferation occurs at sites of direct contact with
worms, is likely due to mechanical irritation and endothelial
damage, and is possibly mediated by platelet-derived growth
factor.
Thrombosis may be associated with either live or dead
worms, and thromboembolism, especially following adulti-
cide therapy, may further exacerbate pulmonary hyperten-
sion; the presence of dead parasites initiates a granulomatous 
A
B
Figure 1-87  Heartworm infection in a dog. A. Pulmonary artery
with severe extensive vasculitis and heartworms in lumen. H&E.
B. Higher power of (A) showing subintimal myofibrosis and
villous projections into the pulmonary arterial lumen. H&E.
(Courtesy R. Kovi.)
Diseases of the Vascular System
reaction in the vessel wall, which may extend into the  cava and hepatic veins are similar to the reactions usually seen
pulmonary parenchyma. Thrombi may be organized and
recanalized. Pulmonary infarction is an uncommon sequel to
thromboembolism.
Pulmonary parenchymal changes that accompany the above
vascular changes include periarterial granulomatous inflam-
mation, hemosiderosis, diffuse interalveolar fibrosis, prolifera-
tion of alveolar epithelium, and fibrous pleural thickenings.
Dead worms commonly incite pulmonary granuloma forma-
tion. Adulticide therapy causes embolization of worms and
resulting thrombosis and granulomatous inflammation; resolu-
tion of these lesions is underway by 6 weeks post-treatment.
Proliferative intimal lesions will progressively resolve after
surgical removal of adult worms; resolution of advanced,
fibrotic, obstructive arterial lesions is unlikely. Severe pulmo-
nary arterial disease often results in chronic or low-grade DIC,
and hence thrombocytopenia and hemoglobinuria. Microfi-
lariae entrapped in the lung in a state of antibody excess are
surrounded by neutrophils and eosinophils, producing eosino-
philic pneumonitis. This allergic pneumonitis may be the
precursor of pulmonary eosinophilic granulomatosis, which is
characterized by 1-8 cm diameter nodules composed of eosin-
ophils, lymphocytes, plasma cells, and macrophages, and
devoid of microfilariae, plus peripheral blood eosinophilia.
Additional lesions of heartworm disease include those of
right heart failure, such as chronic passive congestion of the
liver, and occasionally ascites. Membranoproliferative glomeru-
lonephritis occurs primarily because of glomerular deposition
of immune complexes, either formed in circulating blood in
a state of antigen excess, or formed in situ in the glomeruli.
The intensity of the immune-complex deposition varies
directly with the intensity and duration of infection and the
antibody response; the immune response may be toward
immature heartworms, microfilariae, or adult heartworms.
Physical damage to glomerular endothelium has been attrib-
uted to microfilariae. The result of glomerular disease in diro-
filariasis is proteinuria, which is usually mild to moderate in
severity. Renal failure and uremia are uncommon. Microfi-
lariae are usually of little consequence to the dog, but when
they die, they may incite formation of microgranulomas in
various organs, such as the lung, liver, and kidney.
Aberrant migration of adult heartworms into the systemic
arterial circulation, a rare event, results in thromboembolism
and hence signs such as hindlimb lameness and interdigital
ischemic necrosis.
The vena caval syndrome (venae cavae syndrome, liver
failure syndrome) is a variant of heartworm disease seen
usually in young dogs in which large numbers of adult worms
(100+) fill the right atrium and venae cavae, likely as the result
of retrograde migration from the pulmonary arteries. The  in or on the intima of arterioles and arteries, being constrained
syndrome is characterized by sudden onset of weakness, anor­
exia, bilirubinuria, hemoglobinuria, and anemia. Shock occurs
because of obstruction and decreased venous return. The mass
of worms may also interfere with valve function, causing tri-
cuspid regurgitation, which, together with pulmonary hyper-
tension, results in decreased left ventricular preload and
congestive right ventricular failure. Hepatic congestion is very
severe, hepatic lymphatics may be distended, and ascites may
occur. Anemia develops because of right-atrial turbulence and
shear-induced mechanical hemolysis, with perhaps microan-
giopathic hemolysis resulting from platelet activation and
fibrin formation. Azotemia develops and death usually occurs
in 1-3 days. Phlebosclerosis and thrombosis in the caudal vena
Arteries 85
in the pulmonary arteries. Vena caval syndrome also occurs in
cats, and untreated has a poor prognosis and high mortality
rate in both dogs and cats; the treatment of choice is surgical
removal of the heartworms.
The major features of dirofilariasis are shown in eFig. 1-28.
Further reading
Atkins CE, et al. Heartworm infection in cats: 50 cases (1985-1997).
J Am Vet Med Assoc 2000;217:355-358.
Bourguinat C, et al. Genetic polymorphism in Dirofilaria immitis. Vet
Parasitol 2011;176:368-373.
González-Miguel J, et al. Surface associated antigens of Dirofilaria
immitis adult worms activate the host fibrinolytic system. Vet Para-
sitol 2013;235-240.
McCall JW, et al. Heartworm disease in animals and humans. Adv
Parasitol 2008;66:193-285.
McHaffie J. Dirofilaria immitis and Wolbachia pipientis: a thorough
investigation of the symbiosis responsible for canine heartworm
disease. Parasitol Res 2012;110:499-502.
Paes-de-Almeida EC, et al. Kidney ultrastructural lesions in dogs exper-
imentally infected with Dirofilaria immitis (Leidy, 1856). Vet Parasi-
tol 2003;113:157-168.
Reddy MV. Human dirofilariasis: an emerging zoonosis. Trop Parasitol
2013;3:2-3.
Simón F, et al. Immunopathology of Dirofilaria immitis infection. Vet
Res Commun 2007;31:161-171.
Simón F, et al. Human and animal dirofilariasis: the emergence of a
zoonotic mosaic. Clin Microbiol Rev 2012;25:507-544.
To KKW, et al. A novel dirofilaria species causing human and canine
infections in Hong Kong. Clin Microbiol 2012;50:3534-3541.
Strongylus vulgaris in horses.  Horses are commonly
infected with both large and small strongyles (see Vol. 2, Ali-
mentary system and peritoneum), but by far the most damaging
to the host is the large strongyle Strongylus vulgaris. Although
the adults of S. vulgaris share their large intestinal habitat with
many other strongylids, S. vulgaris is the only strongylid to
undergo development in the horse’s arterial system.
The usual route of migration of S. vulgaris is as follows.
Infective third-stage larvae are ingested; exsheath in the small
intestine; penetrate the mucosa and submucosa of the small
intestine, cecum, and colon within 3 days of infection; and
molt to fourth-stage larvae by day 7. The larval penetration of
the gut can cause the formation of large subserosal hemor-
rhages, called hemomelasma ilei. The fourth-stage larvae, which
are about 1 mm long, penetrate submucosal arterioles, migrate
by the internal elastic lamina from penetrating to the media,
and reach the cranial mesenteric artery, the predilection site
for further development, between day 11 and 21. After 3-4
months, the larvae molt to the fifth stage (immature adults,
10-18 mm long), return to the wall of the cecum and colon
via the intestinal arteries, and are encapsulated in subserosal
nodules before returning to the gut lumen as adults, when the
nodules rupture. The adults require another 6-8 weeks to
reach sexual maturity. The prepatent period of S. vulgaris is
thus about 6-7 months.
Virtually all horses are infected with S. vulgaris and have
arterial lesions resulting from larval migration, although the
prevalence of continuing S. vulgaris infection has been
 85.e1

Dirofilariasis
Dog is primary host
Many species accidental hosts
Dirofilaria immitis is genetically heterogeneous

Clinical signs Life cycle

Cough, exercise intolerance, dyspnea
Ascites
In severe cases, vena caval
syndrome and renal failure
Microfilaria from host ingested by
mosquitoes develop to infective stage
Introduced via mosquito to new
host; develops over 3-4 months
Adults reside in pulmonary artery

Pathology Disease pathogenesis

Obstructive, proliferative pulmonary
endoarteritis leading to right sided failure
Eosinophilic pneumonitis and granulomatosis
Membranoproliferative glomerulonephritis
With massive worm burden, vena cava
occluded by adult worms leading to
hemolytic anemia and hepatic failure
Predominantly the result of pulmonary
arterial proliferative endoarteritis and sclerosis
Leads to pulmonary hypertension
(cor pulmonale) and right sided heart failure
Accompanied by pulmonary granulomas

eFigure 1-28  Major features of canine dirofilariasis.

85.e2

Further reading
Atkins CE, et al. Investigation of caval syndrome in dogs experimentally
infected with Dirofilaria immitis. J Vet Intern Med 1988;2:36-40.
Bazzocchi C, et al. Immunological role of the endosymbionts of Diro-
filaria immitis: the Wolbachia surface protein activates canine neu-
trophils with production of IL-8. Vet Parasitol 2003;117:73-83.
Boreham PFL, Atwell RB, editors. Dirofilariasis. Boca Raton, Fla: CRC
Press; 1988.
Buoro IBJ, et al. Angles of branching and the diameters of pulmonary
arteries in relation to the distribution of pulmonary lesions in canine
dirofilariasis. Res Vet Sci 1983;35:353-356.
Calvert CA, et al. Pulmonary and disseminated eosinophilic granulo-
matosis in dogs. J Am Anim Hosp Assoc 1988;24:311-320.
Cornegliani L, et al. Two cases of cutaneous nodular dirofilariasis in the
cat. J Small Anim Pract 2003;44:316-318.
Frank JR, et al. Systemic arterial dirofilariasis in five dogs. J Vet Intern
Med 1997;11:189-194.
Goggin JM, et al. Ultrasonographic identification of Dirofilaria immitis
in the aorta and liver of a dog. J Am Vet Med Assoc 1997;210:1635-
1637.
Kaiser L, Williams JF. Dirofilaria immitis: worm burden and pulmonary
artery proliferation in dogs from Michigan (United States). Vet
Parasitol 2004;124:125-129.
Kitagawa H, et al. Comparison of laboratory test results before and
after surgical removal of heartworms in dogs with vena caval syn-
drome. J Am Vet Med Assoc 1998;213:1134-1136.
Mar PH, et al. Specific polymerase chain reaction for differential diag-
nosis of Dirofilaria immitis and Dipetalonema reconditum using
primers derived from internal transcribed spacer region 2 (ITS2). Vet
Parasitol 2002;106:243-252.
McCracken MD, Patton S. Pulmonary arterial changes in feline dirofi-
lariasis. Vet Pathol 1993;30:64-69.
Mupanomunda M, et al. Dirofilaria immitis: heartworm infection
alters pulmonary artery endothelial cell behavior. J Appl Physiol
1997;82:389-398.
Peribanez MA, et al. Histochemical differentiation of Dirofilaria immitis,
Dirofilaria repens and Acanthocheilonema dracunculoides microfi-
lariae by staining with a commercial kit, Leucognost-SP. Vet Parasi-
tol 2001;102:173-175.
Rawlings CA, et al. Pulmonary thromboembolism and hypertension
after thiacetarsamide vs melarsomine dihydrochloride treatment of
Dirofilaria immitis infection in dogs. Am J Vet Res 1993;54:920-
925.
Ro JY, et al. Pulmonary dirofilariasis: the great imitator of primary or
metastatic lung tumor. A clinicopathologic analysis of seven cases
and a review of the literature. Hum Pathol 1989;20:69-76.
Strickland KN. Canine and feline caval syndrome. Clin Tech Small Anim
Pract 1998;13:88-95.
86 CHAPTER 1  •  Cardiovascular System
markedly diminished by benzimidazole and macrocyclic
lactone anthelmintics. A degree of host resistance to vermin-
ous arteritis is slowly acquired under natural conditions, but
horses of all ages remain susceptible to infection. Lesions
range from the very common, but insignificant, tortuous
intimal tracks, to the less common, but more serious, occlusive
thrombotic lesions. Lesions of verminous arteritis are often
incorrectly called “verminous aneurysms,” but these dilations
are usually thick-walled resulting from inflammation and scar-
ring, rather than thinned. Saccular or fusiform aneurysms may
occasionally result from weakening of the arterial wall. Lesions
occur most frequently in the cranial mesenteric artery and its
extension, the ileo-cecocolic artery. This apparent larval predilec-
tion has been suggested to fit a “random-walk” model in which
the larvae sense blood vessel curvature, rather than direction
of blood flow, migrate longitudinally along arteries, and are
essentially trapped in the cranial mesenteric artery because of
its perpendicular connection with the aorta, a border which
most of the larvae do not cross. Larvae that spill over into the
aorta may be considered as aberrant and lost to their species,
in that they are unlikely to return to the cranial mesenteric
artery and hence to the gut.
Tortuous intimal tracks consist of fibrin, necrotic debris,
and a mixture of inflammatory cells, including eosinophils, in
the intima. The tracks become covered by endothelium, the
fibrin is removed, and the tracks are converted to fibromus-
culoelastic thickenings. More extensive larval migration causes
more extensive thromboarteritis (Figs. 1-88, 1-89). Small
mural thrombi are formed about the larvae attached to the
intima, and there is a reactive leukocytic infiltration, edema,
and resultant degeneration of the elastic and muscle fibers of
the underlying media. The initial acute inflammation persists
as long as the parasite remains but is soon accompanied by a
productive connective-tissue response, initiated by smooth
muscle cells from the media, with attempted organization of
the overlying thrombus and the accumulation of large numbers
of mononuclear leukocytes (Fig. 1-90). The proliferating con-
nective tissues of the intima and adventitia may ultimately
replace the normal structure of the arterial wall with the
affected walls becoming solid and very thick. The luminal
surfaces of active arterial lesions are always rough and covered
with layered thrombi in which the parasite is found partially
Figure 1-88  Hemorrhage, ulceration and inflammation of the
cranial mesenteric artery, with Strongylus vulgaris larva (arrow).
(Courtesy University of Minnesota Veterinary Diagnostic
Laboratory.)
Arteries
embedded. It is usual to find some worms, both fourth-stage
larvae and immature adults, in the thrombi, but the number
of worms in any location in any one case varies from a few to
several hundred. Following migration of the fifth-stage larvae
back to the intestine, or destruction of the larvae by anthel-
mintics, the intimal lesions resolve as fibrous intimal thicken-
ings, and the luminal diameter will hence increase. The arterial
wall thickness also decreases.
The lesions and accompanying worms are most common in
the cranial mesenteric artery, although they are also found
elsewhere, including the aorta, the renal arteries, the celiac
artery and its branches, and the spermatic vessels. They may
be in any branch of the cranial mesenteric artery but are
concentrated largely in the right division and the colic artery,
which is its continuation, and, to a slightly lesser extent, in
the cranial branch and its continuation, the right colic artery.
The worms are rarely found in the aorta caudal to the origin
of the renal vessels; they are relatively common about the
origin of the cranial mesenteric and celiac arteries, and less
common again in the thoracic aorta. Although this statement
on the prevalence of lesions in the thoracic aorta applies to
actively thrombotic lesions containing worms, it is probable
that older, warty, mineralized lesions of the type often seen in
the intima of the aortic arch have this origin; they occur
Figure 1-89  Focally dilated cranial mesenteric artery with hem-
orrhage, ulceration and inflammation of the vessel wall. (Courtesy
A. G. Armien.)
Figure 1-90  Chronic fibrosing arteritis of the cranial mesenteric
artery caused by Strongylus vulgaris infection in a horse, with
larvae present in one of the smaller vessels. Masson trichrome.
(Courtesy R. Kovi.)
Diseases of the Vascular System
frequently in sites where active lesions occur. The lesions in
the aortic bulb are located immediately proximal to the aortic
valves on the cranial wall of the bulb and in the adjacent
cranial aortic and caudal right aortic sinuses, but rarely in the
caudal wall and the left sinus. This localization has been
explained on the basis of the curve of the aortic arch and the
axis of systolic ejection, which should, theoretically, provide
a zone of turbulence and relatively low velocity of blood flow
in the cranial segment of the aortic bulb.
The sequelae of verminous arteritis caused by S. vulgaris are
varied and depend upon the location of the arteritis. Involve-
ment of the cranial mesenteric artery is almost constant in
horses, but untoward sequelae are much less common, no
doubt resulting from the extensive collateral arterial circulation
to the equine intestine, which may mitigate against the effects
of frequent thromboembolic episodes. Colic, which is com-
monly caused in horses by S. vulgaris if parasite control is poor,
may occur for a number of reasons: thromboembolism and
intestinal ischemia or infarction; interference with innervation
of the gut, resulting from pressure on abdominal autonomic
plexuses; or, release of toxic products from degenerating larvae.
Fatal acute intestinal infarction occasionally ensues, with isch-
emia of large areas of the cecum or colon. Thromboembolism
of the cecal and colic arteries may also lead to mucosal ulcer-
ation and diarrhea, and occasionally death. Hematochezia has
been reported in a horse as a consequence of fistulous con-
nections between a verminous cranial mesenteric arterial aneu-
rysm and the cecum and ileum. As a result of successful
suppression of S. vulgaris by anthelmintics, drug-resistant cya-
thostomes (small strongyles) have supplanted S. vulgaris as the
most important cause of verminous colic. Coronary arterial
thrombosis and occlusion, which occurs most commonly in the
right coronary artery, can lead to myocardial infarction and
death; similar consequences follow the development of ver-
minous aortic valvular endocarditis, a rare event in strongylosis.
Embolism of the brachiocephalic trunk can occur and is especially
significant when the emboli contain larvae that subsequently
migrate in the brain causing encephalomalacia and either
chronic incoordination or progressive fatal encephalitis. Renal
arterial verminous arteritis and thromboembolism have resulted
in renal infarction and, on rare occasions, passage of larvae in
the urine. Aortic-iliac thrombosis may be a consequence of
strongyle-related thromboembolism, but its pathogenesis
remains uncertain. Thrombosis of the celiac artery and embo-
lism of its branches is usually inconsequential.
The major features of Strongylus vulgaris infection are
shown in eFigure 1-29.
Further reading
Chapman MR, et al. Prevalence of strongyle nematodes in naturally
infected ponies of different ages and during different seasons of
the year in Louisiana. J Parasitol 2003;89:309-314.
DeLay J, et al. Verminous arteritis in a 3-month-old thoroughbred foal.
Can Vet J 2001;42:289-291.
Hubert JD, et al. Clinical signs and hematologic, cytokine, and plasma
nitric oxide alterations in response to Strongylus vulgaris infection
in helminth-naive ponies. Can J Vet Res 2004;68:193-200.
Ogbourne CP, Duncan JL. Strongylus vulgaris in the Horse: Its Biology
and Veterinary Importance. 2nd ed. Farnham Royal, UK: Common-
wealth Agricultural Bureaux; 1985.
Reinemeyer CR, Nielsen MK. Parasitism and colic. Vet Clin North Am
Eq Pract 2009;25:233-245.
Arteries 87
Onchocerciasis (parasitic aortitis).  Onchocerca armillata
is a parasite of the wall of the aorta of cattle, water buffaloes,
goats, and camels, in south Asia and equatorial Africa. As with
other filarids, O. armillata also contains the endosymbiotic
bacterium, Wolbachia, whose presence is not only essential for
the normal development of the parasite larvae and embryo,
but also contributes to the pathogenesis of the disease. Several
other Onchocerca spp. are described with tendons and aponeu-
roses under diseases of muscle in Vol. 1, Muscle and tendon.
The life cycle and vectors involved in the transmission of O.
armillata are unknown; however, black flies (Simulium) and
midges (Culicoides) are the intermediate hosts of other Oncho-
cerca spp.
Although virtually all older cattle may be infested in enzo-
otic areas, the lesions produced are apparently not of clinical
significance. The preferential site is the arch of the aorta. With
chronicity, lesions extend cranially to include the brachioce-
phalic trunk, costocervical arteries, and brachial arteries, and
caudally to include the abdominal aorta to the level of the
iliac bifurcation. The intima is corrugated, and numerous
sinuous tunnelings end in small nodules in the intima and media;
the nodules protrude into the vascular lumen or through the
adventitia. The males, which are about 7 cm long, inhabit the
nodules, along with the anterior end of the female, which bears
the vaginal opening, and the microfilariae, which escape into
the bloodstream. The body of the female lies in the sinuous
tracts, from which the complete specimen cannot be readily
dissected, but its length is estimated as >100 cm. Parasitic
tunnels in the inner media have a thin fibrous tissue lining
without cellular infiltration. There may be acute transmural
aortitis with a predominance of eosinophils, but subacute or
chronic focal granulomatous inflammation is more frequent and
occurs around tunnels containing dead, degenerate, or mineralized
worms. The granulomas in the media and adventitia become
encapsulated by fibrous tissue to form nodules of 0.5-2.5 cm
diameter containing caseous material and intact and/or dead
worms, and eventually dry mineralized debris. The granulo-
matous reaction will resolve with time, and, in very old cattle,
the aortic wall becomes thinner, has a corrugated lining with
irregular mineralized ridges, and may develop aneurysms up
to 3.5 cm in diameter. The suggested causes of the granulo-
matous aortitis include hypersensitivity to the parasite, foreign
body reaction to degenerate and dead onchocercal worms, and
the release of toxic factors from the parasites.
Microfilariae can be found in the blood of infected animals
at all times, but there is a tendency to nocturnal periodicity;
infection can be detected by examination of skin snips for
microfilariae. In some bulls with large numbers of circulating
microfilariae, repetitive episodes of collapse and tetanic con-
vulsion have been observed and attributed to the microfilariae.
Some of the bulls showing convulsions eventually developed
acute or recurrent ophthalmitis with ophthalmoscopic evi-
dence of retinal pigmentary degeneration and other changes
similar to those seen in ocular onchocerciasis in humans.
Further reading
Mtei BJ, Sanga HJ. Aortic onchocercosis and elaeophorosis in tradi-
tional TSZ-cattle in Tabora (Tanzania): prevalence and pathology. Vet
Parasitol 1990;36:165-170.
Neary JM, et al. Onchocerca armillata contains the endosymbiotic bac-
terium Wolbachia and elicits alimited inflammatory response. Vet
Parasitol 2010;174:267-276.
 87.e1

Strongylus vulgaris
Vasculitis

Vascular lesions Life cycle

Larvae mostly in cranial mesenteric 3rd stage larvae ingested and
and iliocecocolic artery penetrate gut
Lesions sometimes found in 4th stage larvae penetrate
other major arteries [aorta] submucosal arterioles
Essentially a thromboarteritis that varies from and migrate to cranial
intimal tracks to severe thickening of vessel wall mesenteric artery

Vascular lesions Sequelae Life cycle

Acute focal vasculitis that heals by
fibromusculoelastic thickening
Chronic infections result in connective
tissue response with prominent
vascular smooth muscle proliferation
Vascular wall greatly thickened
with narrowed lumen
Thromboembolism leading to
infarction/ischemia of areas of
cecum and colon
Coronary arterial thrombosis
from larvae in aorta [rare]
Neurologic disease from emboli
from brachiocephalic trunk [rare]
After 3-4 months 4th stage
larvae molt to 5th stage
5th stage larvae return to colon and
cecum via mesenteric arteries,
Larvae remain in subserosa
then return to gut lumen
Prepatent period 6-7 months

eFigure 1-29  Major features of Strongylus vulgaris infection.

87.e2

Further reading
Aref S. A random walk model for the migration of Strongylus vulgaris
in the intestinal arteries of the horse. Cornell Vet 1982;72:64-75.
Drudge JH, Lyons ET. Large strongyles: recent advances. Vet Clin North
Am Equine Pract 1986;2:263-280.
Herd RP. The changing world of worms: the rise of the cyathostomes
and the decline of Strongylus vulgaris. Compend Contin Educ Pract
Vet 1990;12:732-736.
Kiper ML, et al. Hematochezia attributable to cranial mesenteric arterial
aneurysm with connecting tracts to cecum and ileum in a horse.
J Am Vet Med Assoc 1988;193:1278-1280.
Klei TR, et al. Effects of repeated Strongylus vulgaris inoculations and
concurrent ivermectin treatments on mesenteric arterial lesions in
pony foals. Am J Vet Res 1990;51:654-660.
Morgan SJ, et al. Histology and morphometry of Strongylus vulgaris-
mediated equine mesenteric arteritis. J Comp Pathol 1991;104:89-
99.
Morgan SJ, Van Houten DS. The ultrastructure of Strongylus vulgaris-
mediated equine chronic mesenteric arteritis. Vet Res Commun
1990;14:41-46.
Pauli B, et al. Arterial repair after mechanical injury by migrating fourth-
stage larvae of Strongylus vulgaris in the horse. (A light and electron
microscopic study.). Beitr Pathol 1975;155:357-378.
Slocombe JOD, et al. Strongylus vulgaris in the tunica media of arteries
of ponies and treatment with ivermectin. Can J Vet Res 1987;51:232-
235.
Thamsborg SM, et al. Impact of mixed strongyle infections in foals after
one month on pasture. Equine Vet J 1998;30:240-245.
 87.e3

Further reading
Atta El, et al. Onchocerca armillata: prevalence and pathology in Suda-
nese cattle. Ann Trop Med Parasitol 1984;78:619-625.
Awad MA, et al. Note on Onchocerca armillata in the Sudanese camel
(C. dromedarius). A histological and anatomo-pathological
approach. Rev Elev Med Vet Pays Trop 1990;43:345-348.
Cheema AH, Ivoghli B. Bovine onchocerciasis caused by Onchocerca
armillata and O. gutturosa. Vet Pathol 1978;15:495-505.
Wahl G, et al. Bovine onchocercosis in north Cameroon. Vet Parasitol
1994;52:297-311.
88 CHAPTER 1  •  Cardiovascular System
Ogundipe GA, et al. The prevalence, gross lesions and histopathology
of aortic onchocerciasis in Nigerian cattle. Vet Q 1984;6:85-89.
Tamarozzi F, et al. Onchocerciasis: the role of Wolbachia bacterial endo-
symbionts in parasite biology, disease pathogenesis and treatment.
Clin Microbiol Rev 2011;24:459-468.
Elaeophoriasis.  The genus Elaeophora is another filarial
parasite. Three species of interest are E. poeli and E. schneideri,
which infect ruminants, and E. bohmi, a parasite of horses.
Elaeophora poeli occurs frequently in the aorta of cattle
and related species in tropical areas of the Far East, but is of
little clinical significance. Its life cycle is unknown. These are
thread-like worms, the female of which may be up to 30 cm
long. The lesions are found in the aorta and can be distin-
guished from those of Onchocerca armillata because the
females of E. poeli are attached to the vessel by the head, with
the body free in the lumen of the vessel (eFig. 1-30). The
males become encysted in intimal fibrous nodules that also
contain the head of the female. In light infestations, the lesions
are found chiefly on the dorsal wall of the aorta about the
openings of the intercostal arteries. Heavy infestations are
more diffuse and may provoke a prominent fibrous thickening
of the vessel wall.
Elaeophora schneideri is commonly found in the arteries
of mule deer and black-tailed deer, as well as in white-tailed
deer, domestic sheep and goats, elk (wapiti), moose, and
bighorn sheep in mountainous areas of the western and south-
western United States and southwestern Canada, and in
white-tailed deer in the southeastern United States. Mule deer
and black-tailed deer are little affected by the parasite, and
are considered the normal definitive hosts. Horseflies of the
genera Hybomitra and Tabanus are the intermediate hosts.
When the horsefly feeds, infective larvae invade the host and
migrate to the leptomeningeal arteries, where they develop to
immature adults that migrate against the blood flow to reside
in the common carotid arteries. The parasites reach sexual
maturity ~6 months later and begin producing microfilariae.
Although adult worms normally inhabit the carotid arteries
and their branches, they may be found in many other arteries
through the body. Adult females are 6-12 cm long by
0.6-0.9 mm thick, and adult males are 5.5-8.5 cm long by
0.4-0.7 mm thick; adults live 3-4 years. Microfilariae are about
280 µm long by 18 µm thick, and are found in the capillaries
of the forehead and face.
When larvae develop in the leptomeningeal arteries of elk,
moose, domestic sheep and goats, sika deer, and possibly
white-tailed deer, they can cause ischemic necrosis of brain
tissue, resulting in “clear-eyed” blindness or sudden death. In
elk, adult worms in the intracranial arteries cause mechanical
irritation and hence endothelial damage, intimal proliferation
and fibrosis, thrombosis, and embolism, which result in focal
ischemia and infarction in the brain, eyes, optic nerves, ears,
muzzle, nostrils, and other tissues of the head. Adult worms
usually cause only mild intimal sclerosis in deer and sheep,
and only rarely do they cause granulomatous verminous
thrombosis. Microfilariae can cause multifocal myocardial
infarction, myocarditis, and fibrosis in deer. Oral food impac-
tions have been associated with E. schneideri in white-tailed
deer, but a causal relationship has not been established.
Young domestic sheep and goats may develop nervous
signs and die suddenly 3-5 weeks after infection as a result  course through the liver to join the caudal vena cava. Other
of thrombosis of cerebral and leptomeningeal arteries. In
Veins
survivors, the most important consequence of elaeophorosis
in sheep is filarial dermatosis (sorehead), an often severe exu-
dative dermatitis affecting the poll, face, abdomen, and lower
parts of the legs, in up to 1% of sheep in enzootic areas. Sto-
matitis and rhinitis also occur. The lesions are due to microfi-
lariae released by adult females located in arteries supplying
the affected areas. Microfilariae can be demonstrated micro-
scopically in the lesions, and they are responsible for intense
leukocytic infiltration, chiefly of eosinophils and mononuclear
cells. There is hemorrhage, vesiculation, and ulceration of the
epidermis with exudation of serum and leukocytes to form
crusts. These lesions have the character of an allergic reaction
and are presumably related to the alien nature of the 
sheep as a host, because they rarely occur in deer. The skin
lesions are intensely pruritic and often lead to severe self-
trauma. Lesions often persist for 3-4 years and will regress
spontaneously following the death of adult parasites 
and microfilariae.
Elaeophora bohmi was found in ~6% of a sample of Aus-
trian horses, the vessels involved being arteries and veins of
the metacarpus, metatarsus, and more distal extremities. The
parasites rather selectively involve the media of the vessels
avoiding the intima and adventitia, although the fibrous reac-
tion that develops may cause stenosis of the lumen. The
worms are coiled and entwined amongst the tissue layers,
provoking parasitic granulomas with intense infiltration by
eosinophils and macrophages. In cases of longer standing,
diffuse or nodular fibrous thickenings are visible and palpable
in the vessel walls. Microfilariae were found in the blood of
14 of 161 horses (9%) sampled in Iran. The infection appears
to be of little clinical significance.
Further reading
Couvillion CE, et al. Elaeophoriasis in white-tailed deer: pathology of
the natural disease and its relation to oral food impactions. J Wildl
Dis 1986;22:214-223. (E. schneideri).
LeVan IK, et al. High elaeophorosis prevalence among harvested Colo-
rado moose. J Wildl Dis 2013;49:666-669. (E. schneideri).
Mirzayans A, Maghsoodloo H. Filarial infection of equidae in the Tehran
area of Iran. Trop Anim Health Prod 1977;9:19-20. (E. bohmi).
Mtei BJ, Sanga HJ. Aortic onchocercosis and elaeophorosis in tradi-
tional TSZ-cattle in Tabora (Tanzania): prevalence and pathology. Vet
Parasitol 1990;36:165-170. (E. poeli).
VEINS
Venous disorders may be of clinical significance by predisposing
to thrombosis and subsequent embolism, or by obstructing venous
return and hence causing passive congestion of the affected areas.
Obstruction of venous outflow may be followed by the devel-
opment of collateral venous drainage.
Anomalies of veins occur uncommonly. Arteriovenous fistulas
have been discussed previously with arterial anomalies. A
variety of congenital portosystemic anastomoses occur in dogs
and cats and allow portal blood, with its absorbed toxic sub-
stances, such as ammonia, to bypass the liver and cause hepatic
encephalopathy. The most common of these defects is persis-
tent ductus venosus a persistence of the normal fetal circulation
wherein the umbilical veins enter the ductus venosus, which
portosystemic anastomoses occur extrahepatically between
 88.e1

eFigure 1-30  Intimal fibrous nodules in bovine aorta contain

males and the heads of females of Elaeophora poeli; the body of
the female swings free in the aortic lumen. (Courtesy P.B. Little
and Canadian Veterinary Journal.)
88.e2

Further reading
Boyce W, et al. Elaeophorosis in bighorn sheep in New Mexico. J Wildl
Dis 1999;35:786-789. (E. schneideri).
Hibler CP, Adcock JL. Elaeophorosis. In: Davis JW, Anderson RC, editors.
Parasitic Diseases of Wild Mammals. Ames, Iowa: Iowa State Uni-
versity Press; 1971. p. 263-278.
Kemper HE. Filarial dermatosis of sheep. J Am Vet Med Assoc
1957;130:220-224. (E. schneideri).
Little PB. A Malaysian experience with animal disease. Can Vet J
1979;20:13-21. (E. poeli).
Pessier AP, et al. Probable elaeophorosis in a moose (Alces alces) from
eastern Washington state. J Vet Diagn Invest 1998;10:82-84. (E.
schneideri).
Santin-Duran M, et al. Elaeophorosis in red deer from Spain. J Wildl
Dis 2000;36:779-782. (E. elaphi).
Diseases of the Vascular System Veins 89

the portal vein and various branches of the caudal vena cava
or the azygous vein. As well, portosystemic anastomoses may
be acquired because of portal hypertension, which in turn is
caused by impedance of blood flow through a diseased liver,
an obstructed portal vein, or a kinked intrathoracic caudal
vena cava. Hepatic microvascular dysplasia can occur in dogs
and cats in the absence of macroscopic portosystemic 
shunts, and result in similar clinical signs. Portosystemic anas-
tomoses and hepatic encephalopathy are discussed in more
detail in Vol. 3, Liver and biliary system.
Dilation of a vein, variously termed phlebectasia, varicosity,
or aneurysm, occurs but is of little or no importance. A
common type of dilation is the so-called “varicocele” of the
pampiniform plexus. Dilation may also occur because of con-
genital defects, such as venous diaphragms, agenesis, hypopla-
sia, or ectopia, or secondary to trauma, neoplasia, or surgical A
intervention. The initial dilation causes insufficiency of the
venous valves, and the veins may become dilated, elongated,
and tortuous. Thrombosis or sclerosis may be sequelae. The
acquired portosystemic anastomoses noted above usually
result from dilation of pre-existing microscopic venous anas-
tomoses to produce collateral venous drainage.
Hepatic telangiectasis, peliosis hepatis, and hepatic “veno-
occlusive disease” are described with diseases of the liver in
Vol. 3, Liver and biliary system.
Rupture of a large vein, usually the result of physical
trauma, may result in fatal hemorrhage. Spontaneous idio-
pathic rupture of the venae cavae or portal vein of horses
occurs occasionally; rupture of the great coronary vein of the
heart is a rare cause of unexpected death in horses.
Veins may be invaded by neoplasms (Fig. 1-91A, B), which
may then metastasize, and may cause thrombosis or B
obstruction.
Figure 1-91  A. Invasion from adrenal gland tumor (pheochromo-
cytoma) into the caudal vena cava of a dog. B. Vena cava opened
to show invasion of a pheochromocytoma in a dog.
Further reading
Christiansen JS, et al. Hepatic microvascular dysplasia in dogs: a retro-
spective study of 24 cases (1987-1995). J Am Anim Hosp Assoc
cattle recumbent for >4-6 hours results in thrombosis of the
2000;36:385-389.
femoral tributaries (“downer cows”). Venous infarction com-
Koide K, et al. Congenital hepatic arteriovenous fistula with intrahe-
monly ensues, and necrosis of the medial muscle masses and
patic portosystemic shunt and aortic stenosis in a dog. J Vet Med
sciatic nerves causes permanent paraplegia.
Sci 2004;66:299-302.
The thickened, congested, red-black mucosa of the gastric
Leeman JJ, et al. Multiple congenital portosystemic shunts in a dog:
fundus in swine with acute septicemia is a venous infarct result-
case report and literature review. J Am Aim Hosp Assoc 2013;49:281-
ing from thrombosis of veins of the mucosa and submucosa,
285.
probably as a sequel to endothelial damage. Gastrointestinal
Zwingenberger AL, et al. Imaging diagnosis—portal vein aplasia and
infarction and ulceration can occur in phenylbutazone-
interruption of the caudal vena cava in three dogs. Vet Radiol
intoxicated horses as a result of degeneration of veins and
Ultrasound 2011;52:444-447.
phlebothrombosis. Thrombosis of the jugular veins follows
unsuccessful or repeated venipuncture, injection of irritant
solutions, and the use of indwelling catheters, especially if
Phlebothrombosis and thrombophlebitis contaminated with bacteria. Important sequelae to jugular
Venous thrombosis (phlebothrombosis) results from the usual thrombosis are pulmonary embolism, and, if the emboli are
pathogenetic factors and often leads to inflammation of the septic, valvular endocarditis and pulmonary abscessation.
vein wall, and hence becomes thrombophlebitis. Conversely, Endophlebitis may result from the implantation of bacteria
phlebitis inevitably leads to thrombosis. Spontaneous thrombo- carried in the blood stream, as in salmonellosis, and from 
sis affects the venae cavae and portal veins occasionally, and the injection of irritant solutions. An important form of 
the inciting factors are usually unknown. Neoplastic invasion, acute suppurative endophlebitis is the omphalophlebitis of the
for instance, by pheochromocytoma, is one cause of thrombo- newborn resulting from infection of the uncicatrized umbilical
sis of the caudal vena cava. Thrombosis of the renal vein and cord. The resultant bacteremia may result in acute death 
vena cava occasionally occurs in dogs with the nephrotic syn- or give rise to widespread suppurative lesions, often polyar-
drome as a result of urinary loss of antithrombin and resulting thritis. Hepatic thrombophlebitis is especially common in
hypercoagulability of the blood. Stasis of venous blood of “navel-ill.”
 89.e1

Further reading
Allen JR, et al. Spontaneous rupture of the great coronary vein in a
pony. Equine Vet J 1987;19:145-147.
Cornelius L, Mahaffey M. Kinking of the intrathoracic caudal vena cava
in five dogs. J Small Anim Pract 1985;26:67-80.
Fernandez del Palacio MJ, et al. Persistent left cranial vena cava associ-
ated with multiple congenital anomalies in a six-week-old puppy.
J Small Anim Pract 1997;38:526-530.
Reimer JM, et al. Diagnosis and surgical correction of patent ductus
venosus in a calf. J Am Vet Med Assoc 1988;193:1539-1541.
Valentine RW, Carpenter JL. Spleno-mesenteric-renal venous shunt in
two dogs. Vet Pathol 1990;27:58-60.
White RN, Burton CA. Anatomy of the patent ductus venosus in the
cat. J Feline Med Surg 2001;3:229-233.
90 CHAPTER 1  •  Cardiovascular System Veins

A B

C D

Figure 1-92  The vasculitis of feline infectious peritonitis. A. Renal vasculitis. (Courtesy E. Olson.)
B. Vasculitis within the choroid of the eye. H&E. C. Vasculitis within a small caliber renal vein.
H&E. D. Serial section of (C) immunostained with anti–feline infectious peritonitis virus
antibody.

In feline infectious peritonitis, phlebitis occurs as a result of

antigen-antibody complex deposition in the walls of small
veins and venules, which is followed by complement fixation
and neutrophil chemotaxis. Neutrophils cause tissue necrosis,
and hence thrombophlebitis, which is followed by the focal
pyogranulomatous reaction typical of this disease (Fig. 1-92).
Phlebitis very commonly occurs by extension from areas of
inflammation, and importantly provides for the hematogenous
dissemination of infection. The entire thickness of the wall of
the vein is inflamed, and thrombosis occurs rapidly. If the
thrombus is infected, it is likely to soften, disintegrate, and
produce emboli. An important example of this pathogenetic
sequence is thrombosis of the caudal vena cava in cattle, which
occurs as a sequel to rumenitis and hepatic abscessation (Fig.
1-93, eFig. 1-31). Perivascular hepatic abscesses often involve Figure 1-93  Thrombi in pulmonary vessels associated with val-
the vena cava causing thrombophlebitis and a variety of conse- vular endocarditis caused by Trueperella sp. in an ox. (Courtesy
quences: pulmonary thromboembolism and arteritis, pulmo- R.W. Cook.)
nary abscessation, or pulmonary arterial aneurysms that may
rupture and cause massive pulmonary hemorrhage. Valvular
endocarditis is an occasional sequel. As well, the abscess may
erode the wall of the vena cava wall and rupture into the vena
cava, causing massive septic embolization and sudden death.
 90.e1

eFigure 1-31  Thrombophlebitis of caudal vena cava originating

from hepatic abscess: bovine.
Diseases of the Vascular System
Further reading
Braun U. Clinical findings and diagnosis of thrombosis of the caudal
vena cava in cattle. Vet J 2008;175:118-125.
Dias DPM, de Lacerda Neto JC. Jugular thrombophlebitis in horses: a
review of fibrinolysis, thrombus formation and clinical manage-
ment. Can Vet J 2013;54:65-71.
Edwards JF, et al. Staphylococcus-associated abortions in ewes with
long-term central venous catheterization. Vet Pathol 2008;45:881-
888.
LeGrange SN, et al. Thrombosis of the caudal vena cava presenting as
an unusual cause of an abdominal mass and thrombocytopenia in
a dog. J Am Anim Hosp Assoc 2000;36:143-151.
Respess M, et al. Portal vein thrombosis in 33 dogs: 1998-2011. J Vet
Intern Med 2012;26:230-237.
Saridomichelakis MN, et al. Extensive caudal vena cava thrombosis
secondary to unilateral renal tubular cell carcinoma in a dog. J Small
Anim Pract 2004;45:108-112.
Schoster A, Anderson MEC. Caudal vena cava thrombosis-like syn-
drome in a horse. Can Vet J 2010;51:891-894.
Simpson KM, et al. Caudal vena caval thrombosis following treatment
of deep digital sepsis. Can Vet J 2012;53:182-186.
Parasitic thrombophlebitis
Schistosomes are important venous parasites in tropical Africa
and Asia, and are discussed at length later. Gurltia paralysans,
a metastrongyle, causes paralytic disease in domestic cats in
South America. The adults lodge in the veins of the thigh and
lumbar spinal cord and cause thrombosis and ectasia.
Schistosomiasis (bilharziasis)
Schistosomiasis, a snail-borne fluke infection, is prevalent in
domestic animals in Asia, Africa, and other tropical and subtropi-
cal areas, but does not usually occur as clinical disease; the
importance of the disease may increase as irrigation projects
enhance the habitat for the intermediate snail host. Damage
and clinical effects are the result of localization of adult flukes
and their eggs in blood vessels of the liver, lungs, alimentary and
urogenital tracts, and the nasal cavity. Schistosomiasis is often
a disease of long duration.
Members of the family Schistosomatidae are the blood
flukes of mammals and birds; species that parasitize mammals
include those of the genera Schistosoma, Heterobilharzia, and
Orientobilharzia.
It is characteristic of the trematodes, including the blood flukes,
that the intermediate stages of the parasite are selective in their
choice of hosts, mollusks, and that the infective and final phases
do quite well in a variety of definitive hosts, although there is
some host preference. The distribution of particular species of
schistosomes is closely linked to the geography of the obligate
intermediate hosts. The human schistosome, especially Schis-
tosoma japonicum, may be found in domestic animals, and the
other mammalian schistosomes may be discovered in man as
patent or nonpatent infestations.
Based on distribution, host specificity, egg morphology, and
intermediate snail hosts, the species that occur in domestic
animals may be grouped as follows:
1. S. haematobium group—S. bovis in the portal and mesen-
teric veins of ruminants and occasionally horses, camels,
and pigs, in southern Europe and tropical areas of Africa
and Asia; S. mattheei in the portal and mesenteric veins,
plus veins of the urogenital tract and stomach, of ruminants
Veins 91
in central and southern Africa; S. curassoni in ruminants in
West Africa; S. margrebowiei and S. leiperi in wild artiodac-
tyls in Central Africa
2. S. mansoni group—S. rodhaini in dogs and other carnivores
in Central Africa
3. S. indicum group, present in India and Southeast Asia—S.
spindale in mesenteric veins of ruminants and, occasionally,
of horses and dogs; S. nasale in nasal mucosal veins of
cattle and, occasionally, of goats and horses; S. indicum in
portal and mesenteric veins of herbivores; S. incognitum in
swine and dogs
4. S. japonicum group—S. japonicum, human by preference,
in all domestic animals in the Far East; S. mekongi in dogs
and humans in Southeast Asia
Based on genomic analysis, schistosomes have been placed
in 6 defined clades that correlate with the geographic distribu-
tions of the parasites (Fig. 1-94). It also appears that all schis-
tosomes are of Asian origin, with the S. japonicum group as
the original ancestor. S. bovis and S. japonicum are the most
pathogenic of the schistosomes of cattle and sheep. Mixed
infections with more than one species of schistosome occur;
hybridization may occur in this circumstance.
Other members of the family Schistosomatidae of veteri-
nary significance include Orientobilharzia turkestanicum in
mesenteric veins of herbivores and cats in the Near East,
Russia, China, and Mongolia; O. dattai and O. bomfordi in
artiodactyls in India; and Heterobilharzia americana in the
southern United States, especially Texas and Louisiana in its
definitive host the raccoon.
The life cycles of the schistosomes are comparable to those
of other flukes and follow the general pattern described else-
where for the liver fluke, Fasciola hepatica. As a point of dif-
ference, the redia phase of F. hepatica in the intermediate host
is replaced in the schistosome by a generation of daughter
sporocysts.
The eggs of the schistosome are laid in the vessels that the
adult parasites inhabit. When laid, the eggs are immature, but
contain a miracidium by the time they have worked their way
through the overlying mucous membrane to escape to the
exterior. The eggs hatch in water, and the miracidia actively
penetrate the soft tissues of aquatic snails to which they are
physiologically adapted. The fork-tailed cercariae that emerge
from the snail are the infective phase, and they enter the
definitive host by burrowing through the skin; patent infesta-
tions can also develop if the cercariae are ingested with water.
They will invade the skin of hosts that are quite alien to them,
provoking allergic reactions and dermatitis (swimmer’s itch,
swamp itch in humans).
Cutaneous lesions develop as a result of penetration of the
skin by cercariae. They occur only on those portions of the
skin that come in contact with infested water and are seldom
observed in animals except under experimental conditions.
The cutaneous lesions are tiny petechiated nodules in which
there is a sharp leukocytic reaction to the parasite. Passage of
a large number of parasites through the lungs will produce
pneumonia. Ectopic localization in various organs, such as the
kidney, produces small hemorrhages and inflammatory foci.
In the definitive host, the cercariae lose their tails and
become schistosomula, which enter venules in the dermis and,
thereafter, are conveyed passively in the blood, through the
lungs, and into the systemic circulation. Once in the blood,
there is probably no selective migration; those that are distrib-
uted to the vessels of their final habitat develop further, and
 91.e1

Further reading
Bressler C, et al. Portal vein and aortic thromboses in a Siberian
husky with ehrlichiosis and hypothyroidism. J Small Anim Pract
2003;44:408-410.
Clements CA, et al. Splenic vein thrombosis resulting in acute anemia:
an unusual manifestation of nephrotic syndrome in a Chinese shar
pei with reactive amyloidosis. J Am Anim Hosp Assoc 1995;31:411-
415.
Grosslinger K, et al. Iliopsoas abscess with iliac and femoral vein throm-
bosis in an adult Siberian husky. J Small Anim Pract 2004;45:113-
116.
Howard J, et al. Blastomycosis granuloma involving the cranial vena
cava associated with chylothorax and cranial vena caval syndrome
in a dog. J Am Anim Hosp Assoc 2000;36:159-161.
Lankveld DP, et al. Factors influencing the occurrence of thrombophle-
bitis after post-surgical long-term intravenous catheterization of
colic horses: a study of 38 cases. J Vet Med A Physiol Pathol Clin
Med 2001;48:545-552.
Meschter CL, et al. Vascular pathology in phenylbutazone intoxicated
horses. Cornell Vet 1984;74:282-297.
Sottiaux J, Franck M. Cranial vena caval thrombosis secondary to inva-
sive mediastinal lymphosarcoma in a cat. J Small Anim Pract
1998;39:352-355.
Van Winkle TJ, Bruce E. Thrombosis of the portal vein in eleven dogs.
Vet Pathol 1993;30:28-35.
Weiss RC, Scott FW. Pathogenesis of feline infectious peritonitis: patho-
logic changes and immunofluorescence. Am J Vet Res 1981;42:
2036-2048.
92 CHAPTER 1  •  Cardiovascular System Veins

99 Schistosoma ovuncatum

Schistosoma sinensium
Central and
100 Schistosoma japonicum S. japonicum clade
S. E. Asia
100 Schistosoma malayensis
Schistosoma mekongi

98 Schistosoma edwardiense
Africa S. hippopotami clade
Schistosoma hippopotami
Orientobilharzia turkestanicum Central Asia,
100 Near East Proto - S. mansoni clade
Schistosoma incognitum and E. Europe
100
Schistosoma mansoni
Africa S. mansoni clade
100 Schistosoma rodhaini
Schistosoma nasale

100 Schistosoma spindale India and

S. indicum clade
S. Asia
100
Schistosoma indicum
100
Schistosoma margrebowiei

Schistosoma leperi
100
Schistosoma mattheei
100 Schistosoma kisumuensis
97
80 Schistosoma intercalatum Africa S. haematobium clade

84 Schistosoma haematobium

Schistosoma guineensis
100
100 Schistosoma curassoni
99 Schistosoma bovis

Figure 1-94  Schistosoma clades. Summary schematic phylogeny of the interrelationships of members of the species within the Schisto-
soma genus estimated with a Bayesian analysis of combined partial lsrDNA, complete ssrDNA, and partial cox1. cox1, cyclooxygenase 1;
lsr, large subunit ribosomal; ssr, small subunit ribosomal. (From Lawton SP, et al. Genomes and geography: genomic insights into the
evolution and phylogeography of the genus Schistosoma. Parasit Vectors 2011;4:131-141.)

those that are distributed to other organs die. Schistosoma
nasale develops in the veins of the nasal mucosa; all other
species develop in veins of the abdominal cavity, principally
in the portal vessels, until sexual maturity is attained, when
they migrate out to the smaller veins of the mesentery. In
long-standing infections, S. mattheei may reside in veins of the
urinary bladder as well as in portomesenteric veins. The pre-
patent period in the mammalian host ranges from 30-77 days.
As would be expected, not all the eggs move in the proper
direction. Some break into lymphatics and are conveyed to
the regional nodes to produce granulomas but, more impor-
tantly, a great many of them pass to the liver, producing portal
phlebitis and granulomatous hepatitis, in concert with the
adult flukes. In heavy infestations and possibly by means of
venous shunts developed in the liver, many eggs may pass in
venous blood to and beyond the lungs, producing granuloma-
tous endoarteritis and adjacent granulomas wherever they
lodge. The development of hepatic lesions follows the same
course as for those that develop in the intestinal wall. In the
liver, the eggs break out of the portal venules to become
enclosed by granulomas. Sooner or later, they die and are
mineralized, and by that time have provoked extensive  may bear polypoid and papillary proliferations. The mesentery
surrounding fibrosis. The above course of events occurs simi-
larly in urinary schistosomiasis caused by S. mattheei, wherein
hematuria accompanies excretion of eggs in the urine, and
granulomatous cystitis and ureteritis result from the host’s
immunologic response to the schistosome eggs trapped in the
tissues.
Clinical signs of schistosomiasis of portomesenteric distri-
bution include lethargy, anemia, and weight loss. Diarrhea or
dysentery occur at the time of patency, persist for a few weeks,
and, in the absence of reinfection, may be followed by spon-
taneous recovery as the immune response of the host elimi-
nates the parasites and suppresses the egg laying of survivors.
The eggs can be found in the feces together with some mucus
and blood. Blood loss leads to anemia and hypoalbuminemia,
which may contribute to the presence of fluid in serous
cavities.
Gross and microscopic findings include thickening of the
wall of the intestine, chiefly the large bowel, by inflammatory
and scar tissue, and the wall may contain small granulomas
and lymphoid nodules. Scarring begins in the mucosa and
extends to involve all layers, including the serosa. The mucosa
Diseases of the Vascular System
is thickened and shortened by fibrous tissue, and the mesen-
teric nodes are enlarged and fibrotic. The adult parasites,
which are about 1-3 cm long, can be found in the mesenteric
and portal vessels (eFig. 1-32). There is fibrosis of the liver of
variable degree affecting particularly the portal vessels. The
liver may be enlarged or small depending on the course and
severity of the infestation. On cut surface, the periportal
nature of the fibrosis is quite apparent but, with time and
more severe infestations, the fibrosis becomes more diffuse
and the surface of the liver may have a hobnailed appearance
or be studded by numerous minute granulomas.
Proliferative granulomatous nasal lesions produced by S.
nasale result in clinical signs of dyspnea and mouth
breathing.
Granulomatous lesions are frequently present in the
urinary bladder and ureters of cattle with S. mattheei infection;
lesions in the ureters, and occasionally renal pelvis, are linear,
whereas those in the bladder become very extensive and
polypoid.
The stage of oviposition and extrusion of eggs through the
tissues and mucous membranes is the stage in which most damage
is done. In fact, a host inflammatory response is necessary for
the eggs to move across the mucosa of organs such as the
intestine and bladder. The mated schistosomes, in permanent
copula, move out into the smallest venous radicles, and the
eggs are deposited first in the lumen of the vessel. They adhere
to, and are eventually covered by, the endothelium. The eggs
of some species are spinous, and this probably facilitates
passive migration into the tissue. The migration does appear,
however, to be partly active by virtue of secretions elaborated
by the developing miracidium, which diffuse through the shell
of the egg into the tissues. These secretions may be also in
part responsible for inciting the inflammatory reaction to the
eggs. Initially, most of the eggs are deposited in the lamina
propria of the intestine, and break into the lumen with little
more than mechanical injury. Rupture of congested mucosal
venules accounts for the characteristic dysentery of schistoso-
miasis. Also contributing to diarrhea, loss of body condition,
and failure to thrive are ganglionitis and degeneration of the
enteric nervous system, which may result from a localized
type I hypersensitivity reaction involving mast cell–derived
chemical mediators.
As the disease progresses and the adults are excluded from
smaller venules resulting from endophlebitis, eggs are laid in
veins in deeper tissues, where antigens released by the mira-
cidium induce a delayed hypersensitivity response and forma-
tion of small granulomas (“pseudotubercles”). The granulomas
are characterized initially by the infiltration of leukocytes,
chiefly eosinophils, and later by the accumulation of mono-
nuclear leukocytes, epithelioid and giant cells, and reactive
fibrosis. Microabscesses occasionally form and rupture into the
gut lumen. Eggs in submucosal granulomas degenerate and are
removed, or may be mineralized and remain for a longer
period of time. Some of the mature or disintegrating eggs may
be coated with a bright eosinophilic deposit (the Splendore-
Hoeppli reaction), the result of antigen-antibody complex for-
mation. The granulomas gradually regress and are replaced by
fibrous tissue. Host cell responses to eggs are primarily the
result of host hypersensitivity to soluble egg antigens, and, to
a much lesser degree, resulting from physical and chemical
stimuli.
Adult schistosomes in mesenteric and portal veins elicit eosino-
philic endophlebitis, often with irregular intimal proliferation, and
Veins 93
may be found within thrombi. Adults may similarly cause reac-
tions in veins of the pancreas and the mesenteric and portal
lymph nodes, and in pulmonary arterioles. Dead parasites are
removed by a granulomatous reaction that is often followed
by the formation of a grossly visible lymphoid nodule. The
lumen of the vein may be occluded, and the venous wall
obliterated, by this lymphoid response. There may also be
diffuse intimal proliferation and endophlebitis of intrahepatic
portal veins, medial hypertrophy, and adventitial inflammation
and fibrosis leading to prominent portal fibrosis, which may
appear grossly as “clay pipe-stem” portal fibrosis. Irregular
dilated vascular bypasses develop in the portal areas. The
adults ingest erythrocytes and regurgitate hematin pigments,
which are picked up by the monocyte-macrophage system,
especially in the regional lymph nodes and liver; these black
iron-porphyrin pigments may be responsible for the gray color
of the liver and lungs in severe cases of schistosomiasis.
Heterobilharzia americana infection.  Heterobilharzia
americana, in the family Schistosomatidae, causes schistoso-
miasis in dogs as an accidental infection. The raccoon is the
definitive host. Dogs, among many other species, are acciden-
tal hosts, including the bobcat, armadillo, Brazilian tapir,
beaver, coyote, mountain lion, mink, nutria, opossum, red
wolf, swamp rabbit, and white-tailed deer. The trematode is
found in the southeastern United States, especially the Gulf
coast and southern Atlantic states, and the infection in the
vertebrate host is limited by the geographic distribution of the
intermediate host. Granulomas incited by H. americana have
been reported to occur in the liver, and uncommonly, in other
tissues of horses.
The life cycle of the trematode is well defined, with the
intermediate host a lymnaeid freshwater snail Bakerilymnaea
cubensis or Pseudosuccinea columnella. It follows the classic
schistosome pathway of cercariae—the cercariae penetrating
the skin of the vertebrate host, migrating via the blood to the
lungs and liver before finally coming to reside in the mesen-
teric and intrahepatic portal veins, where they mature into
adults. Eggs, assisted by the secretion of proteolytic enzymes,
move from the capillary lumen into the intestinal tract and
are expelled in feces. On contact with water, miracidia are
released from the eggs and actively seek the snail intermediate
host, which completes the life cycle. Clinical signs of the
infection in dogs include mucoid to bloody diarrhea, lethargy,
weight loss, vomiting, anorexia, and ascites. A distinctive
finding is the presence of hypercalcemia in >50% of cases,
which is thought to be the result of the synthesis and release
of calcitriol from macrophages as part of the granulomatous
reaction to egg migration. With or without hypercalcemia,
there may be areas of dystrophic tissue mineralization, espe-
cially of schistosome eggs, in the intestine and liver. At post-
mortem, the abdominal cavity may contain excess fluid, the
intestinal wall thickened, and the liver, small, pale, and nodular,
containing numerous 1-2 mm pale gray to white areas extend-
ing throughout the parenchyma. The lungs and kidneys may
contain similar lesions. Histologically, lesions in the liver,
intestinal submucosa, pancreas and lungs are multifocal lym-
phoplasmacytic, eosinophilic to granulomatous reactions in
response to deposited eggs that are sometimes arranged in
linear arrays (Fig. 1-95A, B). The eggs are often heavily min-
eralized. The liver, in particular, may exhibit additional lesions
of periportal to bridging fibrosis, lobular collapse, nodular
regeneration, bile duct hyperplasia, and cholestasis. Confirma-
tion of the suspected diagnosis of H. americana, even from
 93.e1

eFigure 1-32  Adult schistosome (arrow) in a mesenteric vein in

a lamb.
94 CHAPTER 1  •  Cardiovascular System
A
B or secondary:
Figure 1-95  Heterobilharzia americana infection in a dog.
A. Liver showing chronic inflammatory reaction, including
multinucleated giant cells, to H. americana eggs. H&E. B. Close
proximity of multinucleated giant cells to parasite eggs. H&E.
(From an Armed Forces Institute of Pathology Wednesday Slide
Conference, 2011.)
formalin-fixed tissue, can be achieved through the use of PCR
to demonstrate the presence of H. americana–specific small
subunit ribosomal RNA.
Further reading
Corapi WV, et al. Multi-organ involvement of Heterobilharzia ameri-
cana infection in a dog presented for systemic mineralization. J Vet
Diagn Invest 2011;23:826-831.
Corapi WV, et al. Natural Heterobilharzia americana infection in horses
in Texas. Vet Pathol 2012;49:552-556.
Fabrick C, et al. Clinical features and outcome of Heterobilharzia amer-
icana infection in dogs. J Vet Intern Med 2010;24:140-144.
Fradkin IM, et al. Elevated parathyroid hormone-related protein and
hypercalcemia in two dogs with schistosomiasis. J Am Anim Hosp
Assoc 2001;37:349-355.
Hams E, et al. The schistosoma granuloma: friend or foe? Front
Immunol 2013;4:89, 1-8.
Johnson FM. Canine schistosomiasis in North America: an underdiag-
nosed disease with an expanding distribution. Compend Contin
Educ Vet 2010;32:E1-E4.
Kusel JR, et al. The schistosome in the mammalian host: understanding
the mechanisms of adaptation. Parasitol 2007;134:1477-1526.
Lymphatics
Lawton SP, et al. Genomes and geography: genomic insights into the
evolution and phylogeography of the genus Schistosoma. Parasit
Vectors 2011;4:131-141.
Lu DB, et al. Contrasting reservoirs for Schistosoma japonicum between
marshland and hilly regions in Anhui, China—a two-year longitu-
dinal parasitological survey. Parasitol 2010;137:99-110.
Mourão MM, et al. Recent advances in Schistosoma genomics. Parasite
Immunol 2012;34:151-162.
LYMPHATICS
The richness of the lymphatic plexuses in almost all tissues
and their important role as drainage channels for interstitial
fluid makes for almost inevitable involvement of lymphatics
by any inflammation and by the many neoplasms that metas-
tasize via lymph channels. In most instances, the lymphatic
lesions are so small as to have no significance, but in some
cases, the consequence of lymphatic involvement may be the
major presenting clinical sign or lesion. Such, for example, is
the case when attention is drawn to papillary carcinoma of
the canine ovary by severe ascites; disrupted portions of the
neoplasm permeate and obstruct the ventral diaphragmatic
lymphatics, which are the main efferent channels of the peri-
toneal cavity.
Lymphedema is defined as swelling of a part of the body by
an increased quantity of lymph resulting from a lymphatic system
disorder. The term should not be used to describe edematous
swellings resulting from venostasis, hypoproteinemia, heart
failure, or cellulitis. Lymphedema may be classified as primary
• Primary lymphedema, which is usually congenital, and may
be hereditary, is due to anomalous development of the
lymphatic system.
• Secondary lymphedema occurs because of obstruction of
previously normal lymphatics, resulting from inflamma-
tion, neoplasia, surgery, or trauma.
Lymphedema is of significance because it may predispose
the affected area, usually a limb, to secondary bacterial infec-
tion and poor wound healing. Prolonged lymphedema leads to
fibrosis.
A lymphocele is a lymph-filled space that does not have a
distinct endothelial lining, and may be the result of disruption
of lymphatics by trauma or surgery.
Congenital anomalies
There are many degrees of variation of the standard disposi-
tion of the large lymphatic vessels, but these are of no clinical
importance. Epicardial lymphatics in horses and dogs are occa-
sionally dilated and tortuous, and may be anomalous; they are
of no apparent significance (Fig. 1-96).
Congenital hereditary lymphedema is a rare condition that
has been reported in calves, dogs, and pigs. The lymphatic
abnormality is inherited as an autosomal dominant trait in
most cases examined. One of the regulators of lymphatic
vasculature formation is T1α/podoplanin, a mucin-type trans-
membrane glycoprotein that is predominantly expressed by
lymphatic endothelium and is regulated by the lymphatic-
specific gene Prox1. T1α/podoplanin (−/−) mice die at birth
and have defects in lymphatic vessel formation, with conse-
quent congenital lymphedema.
The central lymphatic system normally forms as out-
growths from the endothelium of primitive veins, and
 94.e1

Further reading
Balemba OB, et al. Lesions of the enteric nervous system and the pos-
sible role of mast cells in the pathogenic mechanisms of migration
of schistosome eggs in the small intestine of cattle during Schisto-
soma bovis infection. Vet Parasitol 2000;90:57-71.
Bartsch RC, Van Wyk JA. Studies on schistosomiasis: 9. Pathology of
the bovine urinary tract. Onderstepoort J Vet Res 1977;44:73-94.
Buergelt CD, Greiner EC. Fibrosing granulomas in the equine liver and
peritoneum: a retrospective morphologic study. J Vet Diagn Invest
1995;7:102-107.
De Bont J, et al. The prevalence and pathology of Schistosoma nasale
Rao, 1933 in cattle in Sri Lanka. Parasitol 1989;98(Pt 2):197-202.
Ferreras MC, et al. Histopathological and immunohistochemical study
of lambs experimentally infected with Fasciola hepatica and Schis-
tosoma bovis. J Vet Med B Infect Dis Vet Public Health 2000;47:763-
773.
Ferreras-Estrada MC, et al. A pathological study of experimental long-
standing Schistosoma bovis infection in sheep. J Comp Pathol
1998;119:479-484.
Flowers JR, et al. Heterobilharzia americana infection in a dog. J Am
Vet Med Assoc 2002;220:193-196.
Fransen J, et al. Pathology of natural infections of Schistosoma spindale
Montgomery, 1906, in cattle. J Comp Pathol 1990;103:447-455.
Lawrence JA. The pathology of Schistosoma mattheei infection in the
ox: 1. Lesions attributable to the eggs. 2. Lesions attributable to
the adult parasites. J Comp Pathol 1978;88:1-14, 15-29.
Lindberg R, et al. Experimental Schistosoma bovis infection in goats:
the inflammatory response in the small intestine and liver in various
phases of infection and reinfection. J Parasitol 1997;83:454-459.
Losos GJ. Infectious Tropical Diseases of Domestic Animals. Harlow, UK:
Longman Scientific & Technical; 1986. p. 903-938.
Lu DB, et al. Evolution in a multi-host parasite: chronobiological circa-
dian rhythm and population genetics of Schistosoma japonicum
cercariae indicates contrasting definitive host reservoirs by habitat.
Int J Parasitol 2009;39:1581-1588.
Van Wyk JA, et al. Schistosoma mattheei infection in cattle: the course
of the intestinal syndrome, and an estimate of the lethal dose of
cercariae. Onderstepoort J Vet Res 1997;64:65-75.
Vercruysse J, et al. Pathology of Schistosoma curassoni infection in
sheep. Parasitol 1985;91(Pt 2):291-300.
Vercruysse J, Gabriel S. Immunity to schistosomiasis in animals: an
update. Parasite Immunol 2005;27:289-295.
Diseases of the Vascular System
Figure 1-96  Dilation of epicardial lymphatics in a foal.
Figure 1-97  Congenital lymphedema, especially of limbs of a
calf. (Courtesy F. Riet-Correa.)
subsequent outgrowths form the peripheral lymphatic system.
The primary lymph nodes develop from the primitive central
lymphatic anlagen, the jugular and iliac lymph sacs. Secondary
and tertiary lymph nodes later form along the peripheral
lymphatic system and are the most severely affected nodes in
congenital lymphedema. The earlier the stage at which lym-
phatic malformation occurs, that is, the more central the mal-
formation, the more severe the clinical manifestations and the
earlier their onset.
Grossly, the most severely affected individuals have gener-
alized subcutaneous edema and fluid in serous cavities and are
either stillborn or must be delivered by cesarean section. The
mortality rate of Ayrshire cows with lymphedematous fetuses
has been high. Moderate degrees of lymphedema are seen as
symmetrical swelling of the head, neck, limbs, and tail (Fig.
1-97). The ears of lymphedematous calves often have edema-
tous accessory lobes. Lesser degrees of lymphedema affect the
distal parts of the limbs, especially the hindlimbs, and may not
develop for several weeks postnatally. Mild regional lymph-
edema may be of little significance, although chronic subcu-
taneous edema will lead to fibrosis and may predispose to
Lymphatics 95
secondary bacterial infection. Mild lymphedema affecting
only the hindlimbs will in some cases disappear, presumably
resulting from postnatal development of the peripheral lym-
phatic system. The peripheral lymph nodes are usually smaller
than normal or absent in affected animals. Although obstruc-
tion may be demonstrated by lymphangiography, nodal hypo-
plasia or absence does not necessarily lead to obstruction.
Afferent and efferent nodal sinuses may be dilated and may
be evident on gross examination. The thoracic duct may be
dilated and tortuous in generalized lymphedema.
Histologically, a wide range of lymphatic abnormalities
may be seen in the edematous, and possibly fibrotic, subcutis
of affected areas. The lymphatics may be aplastic, that is, no
lymphatics are found; hypoplastic, in which case lymphatics
are too few or too small; or hyperplastic, or varicose, in which
case lymphatics are excessive in size and number, and dilation
has resulted in valvular incompetence and lymphostasis.
Ectatic lymph channels are commonly present around and
within hypoplastic peripheral lymph nodes. Central nodes are
similarly affected in animals with generalized lymphedema,
and will be absent in cases of lymphovascular agenesis.
Further reading
Fossum TW, Miller MW. Lymphedema. Etiopathogenesis. J Vet Intern
Med 1992;6:283-293.
Kang JH, et al. Secondary malignant lymphoedema after mastectomy
in two dogs. J Small Anim Pract 2007;48:579-583.
Schacht V, et al. T1α/podoplanin deficiency disrupts normal lymphatic
vasculature formation and causes lymphedema. EMBO J 2003;
22:3546-3556.
Yamaguchi R, et al. Congenital lymphedema in a calf with lymph node
dysplasia or aplasia. J Vet Med Sci 1995;57:797-799.
Dilation and rupture of lymphatics
Dilation of normally developed lymphatic vessels (lymphangiec-
tasis) almost invariably results from some form of obstruction and
leads to the accumulation of excess interstitial fluid in the drain-
age area. Causes of such lymphatic obstruction include infil-
trating neoplasms that may obstruct the lymphatic vessel or
the drainage node, inflammatory thrombosis and sclerosis of
the channels or nodal sinuses, and postsurgical scarring. The
vessels become irregularly dilated and tortuous distal to the
obstruction, and the accompanying increase in interstitial
fluid, if persistent, will cause an increase in interstitial and
subcutaneous fibrous tissue.
Intestinal lymphangiectasis is the most common cause of
protein-losing enteropathy in dogs, and contributes to intestinal
protein loss in cattle with Johne’s disease and other enteritides.
Dilated lacteals in intestinal villi rupture or leak their contents
into the intestinal lumen, and severe hypoproteinemia can
result. Leakage of protein from capillaries in the villi may also
be an important contributor to protein loss. Chyle may leak
from dilated subserosal lymphatics and contribute to the
hypoproteinemia-induced ascites.
Chylothorax, the result of leakage or rupture of the thoracic
duct, occurs infrequently in dogs and cats. The cause of chy-
lothorax in the absence of another complicating lesion is
usually not apparent; rupture resulting from thoracic trauma
is often postulated but rarely proven. An injured thoracic duct
has limited capacity for spontaneous healing. Reported com-
plicating causes of chylothorax include neoplasia, right-sided
 95.e1

Further reading
Carmichael NG, et al. Secondary lymphoedema in a dog. J Small Anim
Pract 1986;27:335-341.
Reynhout KM, et al. Lymphocele in a cat. J Am Vet Med Assoc
1994;204:400-403.
Schild AL, et al. Hereditary lymphedema in Hereford cattle. J Vet Diagn
Invest 1991;3:47-51.
van der Putte SCJ. The pathogenesis of congenital hereditary lymph-
edema in the pig. Lymphol 1978;11:10-21.
96 CHAPTER 1  •  Cardiovascular System Lymphatics

heart failure, dirofilariasis, thrombosis of the cranial vena cava,

congenital anomaly of the thoracic duct, fungal infections, and
lung lobe torsion. Obstruction of thoracic duct drainage may
lead to lymphangiectasis of intrathoracic lymphatics and
leakage of chyle. Chylopericardium is an unusual accompani-
ment of chylothorax. The diagnosis of chylothorax is confirmed
by analysis of the pleural fluid, which is opalescent to opaque,
milky-white to yellow, and on standing, forms a top layer of
cream (chylomicron fat) that is ether soluble. Microscopically,
the fluid contains large numbers of lymphocytes, a few neu-
trophils, red cells, plasma cells, and fat globules. The site of
the rupture is often difficult to locate surgically or at postmor-
tem. Ligation of the thoracic duct leads to the development
of alternative lymphaticovenous anastomoses, and cessation of
the chylothorax.
Chylous ascites results from rupture of the cisterna chyli,
and is a rare event.
Figure 1-98  Granulomatous lymphangitis in Johne’s disease in a
cow. (Courtesy J. Collins.)
Further reading
Myers NC, et al. Chylothorax and chylous ascites in a dog with medi-
Synonyms include Monday morning disease, bigleg, and weed.
astinal lymphangiosarcoma. J Am Anim Hosp Assoc 1996;32:263-
The disease is ushered in by acute lameness and severe cording
269.
of the lymphatics, although this is usually palpable only where
Schuller S, et al. Idiopathic chylothorax and lymphedema in 2 whippett
the lymphatics lie near the saphenous vein on the inner aspect
littermates. Can Vet J 2011;52:1243-1245.
of the thigh. The limb swells rapidly, the swelling beginning
Simmerson SM, et al. Clinical features, intestinal histopathology, and
about the pastern or metatarsus and reaching its zenith in 3
outcome in protein-losing enteropathy in Yorkshire Terrier dogs.
or 4 days, by which time it has usually extended beyond the
J Vet Intern Med 2014;28:331-337.
stifle. There are transient general disturbances associated with
Singh A, et al. Idiopathic chylothorax: pathophysiology, diagnosis,
fever. Recovery is usual, although repeated attacks may occur
and thoracic duct imaging. Compend Contin Educ Vet 2012;
and some cases are fatal, presumably as a result of septicemia.
34:E2.
There is edema of the connective tissues of the distal portion
of the limb, with very rapid fibroplasia. Above the stifle, the
edema is largely confined to the subcutis, this probably
Lymphangitis depending on the arrangement of fascia there. The lymphatics
Lymphangitis with anatomic specificity is a prominent feature are dilated, and the larger ones contain thick pus or a 
of a number of specific diseases. Most of the diseases are dis- thinner mixture of pus and lymph. There is regional acute
cussed elsewhere, but warrant brief mention here also. A lymphadenitis.
feature of the restricted form of anthrax is acute thrombotic The cause and pathogenesis of sporadic lymphangitis are
lymphangitis, the thrombi containing large numbers of bacilli, unknown. Various pyogenic organisms have been recovered
with a marked tendency towards necrosis, and is seen in pigs, from the lesions, but it appears that, in the usual case, the
dogs, and horses. Granulomatous lymphangitis occurs typi- initial acute infection is rapidly overcome. The occurrence of
cally in mycobacterial infections; the mesenteric lymphatics the disease after a period of inactivity, and the experimental
stand out like threads beneath the serosa in Johne’s disease, production of a similar lesion by inoculation of bacteria into
and are often beaded in intestinal tuberculosis; they bear the skin of the pasterns in undernourished horses, suggests that
specific microscopic lesions of these infections (Fig. 1-98). The “stocking” of the hindlimbs (stagnant edema that is common
spread of actinobacillosis can often be discerned as long rows in debilitated horses in periods of inactivity) predisposes to
of small granulomas from the site of primary infection on the the progress of infection. However, most horses with stocking
way to the regional nodes. The corded and nodular ulcerating of the hindlimbs do not develop lymphangitis. The entry of
lymphangitis of cutaneous glanders in horses must be distin- infection is probably traumatic.
guished from the specific forms of lymphangitis discussed
below. Lymphangitis is often a prominent development in
cutaneous streptothricosis in cattle, and can occur in various Further reading
species with cutaneous sporotrichosis. Lipogranulomatous lym- Hamid ME. Epidemiology, pathology, immunology and diagnosis of
phangitis has been found in association with intestinal lym- bovine farcy: a review. Prev Vet Med 2012;105:1-9.
phangiectasis in dogs. Kull PA, et al. Clinical, clinicopathologic, radiographic and ultrasono-
Bovine farcy is a chronic granulomatous disease of cattle graphic characteristics of intestinal lymphangiectasia in dogs: 17
in the tropics, and is characterized by nodular suppurative cases (1996-1998). J Am Vet Med Assoc 2001;219:197-202.
dermatitis, lymphangitis, and lymphadenitis. Most cases of Schubach TM, et al. Pathology of sporotrichosis in 10 cats in Rio de
bovine farcy are caused by Mycobacterium farcinogenes or M. Janeiro. Vet Rec 2003;152:172-175.
senegalense. Watson VE, et al. Focal intestinal lipogranulomatous lymphangitis in 6
Sporadic lymphangitis, a nonspecific, nonulcerative lym- dogs (2008-2011). J Vet Intern Med 2014;28:48-51.
phangitis affecting the hindlegs of horses, is relatively common.
 96.e1

Further reading
Birchard SJ, et al. Chylothorax in the dog and cat: a review. Lymphol
1995;28:64-72.
Campbell-Beggs CL, et al. Chyloabdomen in a neonatal foal. Vet Rec
1995;137:96-98.
Kull PA, et al. Clinical, clinicopathologic, radiographic, and ultrasono-
graphic characteristics of intestinal lymphangiectasia in dogs: 17
cases (1996-1998). J Am Vet Med Assoc 2001;219:197-202.
Peaston AE, et al. Combined chylothorax, chylopericardium, and
cranial vena cava syndrome in a dog with thymoma. J Am Vet Med
Assoc 1990;197:1354-1356.
White SD, et al. Acquired cutaneous lymphangiectasis in a dog. J Am
Vet Med Assoc 1988;193:1093-1094.
96.e2

Further reading
Hamid ME, et al. Differentiation between Mycobacterium farcinogenes
and Mycobacterium senegalense strains based on 16S-23S ribo-
somal DNA internal transcribed spacer sequences. J Clin Microbiol
2002;40:707-711.
Meschter CL, et al. Intestinal lymphangiectasia with granulomatous
lymphangitis in a dog. J Am Vet Med Assoc 1987;190:427-430.
Tufvesson G. Lymphangitis in horses. Nord Vet Med 1952;4:529-576,
729-744, 817-860, 1047-1058. (Nonspecific Monday-morning
type.).
Diseases of the Vascular System
Ulcerative lymphangitis
This is a chronic progressive inflammation of the subcutaneous
lymphatics of horses. Corynebacterium pseudotuberculosis
(ovis) is the cause of the classic condition, but similar lesions
may be caused by other pyogenic organisms, including strep-
tococci, staphylococci, Rhodococcus equi, and Pseudomonas
aeruginosa. Two biotypes of C. pseudotuberculosis are recog-
nized: a nitrate-negative type isolated from sheep and goats,
and a nitrate-positive type isolated from horses and cattle.
Corynebacterium pseudotuberculosis produces a potent phos-
pholipase exotoxin that attacks the sphingomyelin of vascular
endothelial cells, and may be important in aiding the spread
of the bacteria by acting as a permeability factor. Ulcerative
lymphangitis was an important cause of debility in the horse
era, but is now sporadic and rather rare.
Some features of the biology of C. pseudotuberculosis are
discussed with caseous lymphadenitis (see Vol. 3, Hematopoi-
etic system). In that disease, as in ulcerative lymphangitis, the
infection begins in cutaneous wounds. Ulcerative lymphangitis
typically begins about the fetlocks of the hindlimbs. As a result
of lymphangitis, there is diffuse swelling in the leg, soon fol-
lowed by development of dermal nodules. These are abscesses
that ulcerate and discharge thick white to light yellow viscous
pus that may be bloodstained. Only a small area of skin may
be sloughed so that, usually, the margins of the ulcer are
undermined. The ulcers heal and leave small areas of depil-
ated, depigmented skin. As the primary ulcers heal, new
nodules form in adjacent skin, suppurate, ulcerate, and cica-
trize, and in this way, the disease progresses slowly. As the new
nodules develop, the lymphatics between them become
corded and as much as 1-2 cm thick, and fresh abscesses
develop along the inflamed vessels. In uncontrolled infections,
over a course of many months much of the skin of the body
and neck as well as the limbs may be affected, and this leads
to death. Typically, the regional lymph nodes, although mod-
erately enlarged, do not become suppurative or fibrotic. In rare
instances, bacteremia results in internal dissemination, espe-
cially to the kidneys.
Ulcerative lymphangitis also occurs in cattle, but as well as
affecting the distal portions of the limbs, as in horses, the
initial lesions may also develop within the dermis or subcutis
of the neck, shoulder, or flank. The initial abscesses are large
and may be >5 cm in diameter. Extending away from them
are thickened lymphatics, along which new abscesses develop.
The abscesses ulcerate on the skin and the ulcers persist,
oozing a serum-like exudate. There is early lymphadenitis
with swelling of the node and its fixation to the surrounding
tissue. The inflammation spreads slowly, and there is progres-
sive suppurative lymphadenitis.
The equine biotype of Corynebacterium pseudotuberculosis
causes deep pectoral and ventral abdominal wall abscesses
(“pigeon fever”) in horses in the southwestern United States.
The transmission of C. pseudotuberculosis in these cases is
obscure, but may be by arthropod vectors. Ulcerative lym-
phangitis does not occur; dissemination is by bacteremia.
Untoward sequelae include prolonged resolution of the
abscesses, multiple and internal abscessation, and abortion.
Further reading
Abu-Samra MT, et al. Ulcerative lymphangitis in a horse. Equine Vet J
1980;12:149-150.
Lymphatics 97
Nogradi N, et al. Musculoskeletal Corynebacterium pseudotuberculosis
in horses: 35 cases (1999-2009). J Am Vet Med Assoc 2012;241:771-
777.
Szonyi B, et al. Re-emergence of Pigeon fever (Corynebacterium
pseudotuberculosis) infection in Texas horses: epidemiologic inves-
tigation of laboratory diagnosed cases. J Equine Vet Sci
2014;34:281-287.
Epizootic lymphangitis
Epizootic lymphangitis, or pseudofarcy, is caused by Histo-
plasma capsulatum var. farciminosum (HCF) and clinically
resembles ulcerative lymphangitis and cutaneous glanders
(“farcy”). Epizootic lymphangitis occurs almost exclusively in
horses and mules. “Equine histoplasmosis” is probably a more
appropriate name, because HCF infection may be manifest as
keratoconjunctivitis or pneumonia in the absence of past or
concurrent lymphangitis.
Epizootic lymphangitis is enzootic in some Mediterranean
countries, Africa, and the Near and Far East. The organism
apparently exists as a soil saprophyte, and enters the body
through skin wounds of the lower limbs to cause the classic
epizootic lymphangitis, but may also invade castration wounds,
ruptured abscessed lymph nodes after strangles, and gastric
ulcers. Histoplasma farciminosum may cause sinusitis, and/or
pneumonia via inhalation of contaminated dust; may cause
rhinitis by contact with skin lesions; and may be transmitted
by flies (Musca and Stomoxys) to cause keratoconjunctivitis.
The initial cutaneous lesion, or focus of infection in a
wound, has a tendency to ulcerate, or it may undergo alternat-
ing periods of discharge and closure for some weeks before
healing and scarifying. The infection may resolve, but often
spreads centripetally in the adjacent tissues and along the
lymphatics. In the adjacent tissues, which are swollen, small
nodules of ~1 cm diameter develop and, in the course of a
few days, these ulcerate to discharge, at first, a viscid gray
exudate and, later, pus. The initial lesions are intradermal and
are freely movable over the subcutaneous tissue. Spread of 
the infection is solely via the lymphatics, and these convey the
organisms into the subcutaneous and, occasionally, into the
deeper tissues. The inflamed lymphatics are thickened and
hard, and along their course new nodules form, ulcerate, dis-
charge, and eventually heal with scarification, although there
may be alternating periods of activity and quiescence with the
growth of excessive granulation tissue. Sometimes the ulcers
continue to enlarge and may coalesce. In this way, the cutane-
ous infection spreads gradually but irregularly, but is always
characterized by intradermal and subcutaneous nodules, ulcers,
and irregularly swollen lymphatics. In the early stages, the skin
between the lesions remains normal and mobile, but in areas
of extensive ulceration, it becomes very thick, indurated, and
firmly fused to the underlying tissues. When the thickened
skin is incised, it presents the lardaceous appearance of granu-
lation tissue in the horse and contains a number of small,
yellow, purulent foci, between which course the lymphatics,
dilated and filled with pus and serous fluid.
The regional lymph nodes are regularly involved and swollen.
In the early stages, the swollen nodes contain many small foci
of softening, but later the foci coalesce and are heavily encap-
sulated. The nodes may rupture. The condition is usually
chronic, persisting for 3-12 months, and causes considerable
debility, but low mortality.
 97.e1

Further reading
Aleman M, et al. Corynebacterium pseudotuberculosis infection in
horses: 538 cases (1982-1993). J Am Vet Med Assoc 1996;209:804-
809.
Costa LR, et al. Comparative molecular characterization of Corynebac-
terium pseudotuberculosis of different origin. Vet Microbiol
1998;62:135-143.
Steinman A, et al. Ulcerative lymphangitis and coronet lesions in an
Israeli dairy herd infected with Corynebacterium pseudotuberculo-
sis. Vet Rec 1999;145:604-606.
98 CHAPTER 1  •  Cardiovascular System
The disease may begin quite frequently on the conjunctiva
or nictitating membrane, producing at first a small papule and
a serous conjunctival discharge. The papules ulcerate to form
flat, button-like growths of granulation tissue, the eyelids
become severely swollen, and the inflammation extends to the
tissues of the forehead.
Nasal infection is usually accompanied by a mucopurulent
discharge containing large numbers of the fungus, and may be
bloodstained. The lesions begin as yellow papules or nodules
on the nasal mucosa, and these soon break down to form
craterous granulating ulcers that bleed easily. The nasal lesions
are usually found near the external nares, and they may extend
from there on to the muzzle, or they may be found deep in
the nasal cavity and in the pharynx. Similar lesions may occur
in the nasal sinuses, the larynx, and the bronchi.
The pulmonary lesions may be solid granulomatous areas,
or they may be liquefied with pus-like contents. When ulcer-
ative lesions are present on the nasal mucosa, there is suppura-
tive regional lymphadenitis. The typical nodules of epizootic
lymphangitis and the liquefied foci that form in deep tissues
may also be found in the pleura, spleen, liver, testes, tunica
vaginalis, and bone marrow.
The diagnosis of epizootic lymphangitis depends upon
demonstration of the fungus, which is usually present in very
large numbers in the contents of the nodules and fresh dis-
charges from ulcers. The parasitic phase of the fungus is yeast-
like, gram positive, globose or oval in shape, and 2-3 µm in
diameter. It occurs extracellularly and intracellularly in  from hemangiomas may be difficult. Hemangiopericytoma is
macrophages. The fluorescent antibody test is an effective
means of diagnosis. In histologic sections, the organism is
similar to H. capsulatum, consisting of a basophilic nuclear
mass and thin capsule that can be demonstrated by stains  coma, arising from vessel walls, especially in the aorta or
for polysaccharides.
Further reading
al-Ani FK. Epizootic lymphangitis in horses: a review of the literature.
Rev Sci Tech 1999;18:691-699.
Ameni G. Preliminary trial on the reproducibility of epizootic lymphan-
gitis through experimental infection of two horses. Vet J
2006;172:553-555.
Parasitic lymphangitis
Filarid worms of the genus Brugia (synonym Wuchereria),
family Filariidae, parasitize the lymphatic system of dogs and
cats in tropical areas. Brugia malayi occurs in cats and primates
in India and Malaysia; cats may be reservoir hosts for human
infection. B. patei occurs in dogs and cats in Africa, B. pahangi
in dogs and cats in Africa and the East, and B. ceylonensis in
dogs in Sri Lanka. Brugia spp. are transmitted by mosquitoes,
and their life cycles are similar to those of other filarial worms.
Infective larvae enter peripheral lymphatics, migrate to the
nearest lymph node and develop for 2 weeks before migrating
down afferent lymphatics, where they mature and produce
granulomatous lymphangitis, lymphangiectasis, and lymphadeni-
tis, but do not usually cause lymphedema and elephantiasis as
occurs in humans, resulting from infection with B. malayi or
the closely related Wuchereria bancrofti. The main importance
of Brugia spp. lies in the differentiation of their microfilariae
from those of Dirofilaria immitis, and in their role in human
infections.
Vascular Neoplasms
Further reading
Areekit S, et al. Molecualr genetics analysis for co-infection of Brugia
malayi and Brugia pahangi in cat reservoirs based on internal tran-
scribed spacer region 1. Southeast Asian J Trop Med Public Health
2009;40:30-34.
Chirgwin SR, et al. Tissue migration capability of larval and adult Brugia
pahangi. J Parasitol 2006;92:46-51.
Hise AG, et al. Innate immune responses to endosymbiotic Wolbachia
bacteria in Brugia malayi and Onchocerca volvulus are dependent
on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM.
J Immunol 2007;178:1068-1076.
VASCULAR NEOPLASMS
Tumors of endothelial origin are classified as benign or malig-
nant, that is, angiomas or angiosarcomas. Benign tumors consist
of easily recognized vascular channels lined by a monolayer of
relatively normal endothelial cells. Malignant tumors may not
form well-organized vascular channels, are more cellular, and
display cytologic anaplasia. Intermediate forms exist, hence
immunohistochemistry, particularly CD31, CD34, and factor
VIII–related antigen, is commonly used to more definitively
diagnose vascular neoplasms.
Differentiation of vascular malformations or proliferations
discussed with skin neoplasms (see Vol. 1, Skin and append-
ages). There are rare reports of non-endothelial tumors, for
instance, leiomyosarcoma, malignant melanoma, chondrosar-
pulmonary artery.
The nomenclature of benign vascular tumors or malforma-
tions is confusing, and includes hemangioma, hemangioendo-
thelioma, hamartoma, vascular malformation, telangiectasis,
and angiokeratoma. Rare variants include angiolipoma, angio-
fibrolipoma, angioleiomyoma, arteriovenous hemangioma, and
papillary endothelial hyperplasia.
• Hemangioma, a benign tumor of endothelial cells, is sup-
posedly a true neoplasm capable of independent growth.
Some of the clinically observed “growth” of a hemangioma
may be due to congestion, hemorrhage, and thrombosis.
Hemangiomas may be present at birth or soon after in
children and foals, suggesting that they may in fact be non-
neoplastic vascular malformations.
• Hemangioendothelioma (HE) describes a benign vascular
tumor with hypertrophic endothelial cells forming small
hypercellular vascular channels, and is essentially a very
cellular capillary hemangioma. In medical pathology, HE is
used to describe a vascular tumor that is histologically and
clinically intermediate between hemangioma and angiosar-
coma. Reports of rare variants of HE include kaposiform
HE in a dog and a cow, epithelioid HE in a dog, epithelioid/
spindle cell HE in a calf, and retiform hemangioendothelioma
in 2 dogs.
• Hamartoma is a general term that refers to focally disor-
dered overgrowth of mature tissue that is indigenous to the
organ involved. Because vascular tissue is ubiquitous, vas-
cular hamartomas may occur in any site of the body; some
authors refer to angiomas as vascular hamartomas. Most
hamartomas are present at birth, and their growth is coor-
dinated with that of the surrounding tissue.
 98.e1

Further reading
Ameni G, Terefe W. A cross-sectional study of epizootic lymphangitis
in cart-mules in western Ethiopia. Prev Vet Med 2004;66:93-99.
98.e2

Further reading
Chansiri K, et al. PCR based method for identification of zoonotic
Brugia malayi microfilariae in domestic cats. Mol Cell Probes
2002;16:129-135.
Denham DA, Fletcher C. The cat infected with Brugia pahangi as a
model of human filariasis. Ciba Found Symp 1987;127:225-235.
Fader RC, Ewert A. Evolution of lymph thrombi in experimental Brugia
malayi infections: a scanning electron microscopic study. Lymphol
1986;19:146-152.
Sakamoto M, et al. Perturbation of lymphatic endothelial cells in exper-
imental Brugia malayi infections. Microcirc Endothelium Lymphatics
1985;2:487-498.
Snowden KF, Hammerberg B. The lymphatic pathology of chronic
Brugia pahangi infection in the dog. Trans R Soc Trop Med Hyg
1989;83:670-678.
Diseases of the Vascular System
• Vascular malformation is obviously a very broad term that
may be included under the term hamartoma, and may
include arteriovenous fistula in which thick-walled vessels
occur, in contrast to the thin-walled vessels of the other
benign vascular proliferations.
• Telangiectasis refers to congenital or acquired foci of abnor-
mally dilated capillaries, sinusoids, arterioles, or venules,
usually seen as small masses in the skin and mucous
membranes.
• Angiokeratoma is a rare benign tumor, usually of the nic-
titans and conjunctiva of dogs, in which dilated vascular
channels are associated with hyperplastic epithelium.
Fortunately, these distinctions, although of pathogenetic
interest, are of little practical importance because the lesions
described are uniformly benign, and excision, if possible, is
curative.
Angioma
Hemangioma is a benign tumor of endothelial cells and may
be classified as capillary or cavernous based on the size of the
vascular channels formed. The tumor may be difficult to dif-
ferentiate from vascular malformations and granulation tissue.
Hemangiomas occur most commonly in older dogs, and are
seen less frequently in other species. These tumors arise from
vascular endothelium and hence may be found in any site in
the body, but are most common in the dermis and subcutis, espe-
cially of the legs, flank, neck, face, and eyelid. The cutaneous
and ocular lesions may arise following exposure to ultraviolet
radiation. Hemangiomas are usually single, ovoid, red-black
masses of 0.5-3 cm in diameter, which ooze blood when cut.
Histologically, blood-filled vascular spaces are lined by a single
layer of well-differentiated endothelium, and may be throm-
bosed. The vascular spaces are separated by variable amounts
of connective tissue stroma. Hemangiomas are not encapsu-
lated, are not invasive, and do not recur after complete surgical
excision. A rare form of cavernous hemangioma, analogous to
the human hemangioblastoma, is reported in dogs, and is char-
acterized by thin-walled capillaries separated by pleomorphic
“stromal cells” of indeterminate origin. An epithelioid variant
of hemangioma and hemangiosarcoma has also been described.
Disseminated cavernous hemangioma is rare, but has been
reported in calves, and a similar multifocal hemangioma has
been reported in a pig. Multiple small tumors are present  in old dogs, but is less common than hemangioma. German
in skin, subcutis, gingiva, and internal organs. The condition
has been termed generalized congenital hemangiomatosis and
juvenile bovine angiomatosis, to include calves having either
solitary, for instance, gingival or spinal canal, or multiple angio-
matous lesions. Hemangiomas occur in the urinary bladder of
cattle affected with enzootic hematuria, which is discussed in
Vol. 2, Urinary system.
A number of hemangioma-like lesions occur in domestic
animals. Bovine cutaneous angiomatosis of adult dairy cows
is reported from Britain, France, and the United States.
Nodular dermal vascular proliferations occur anywhere in the
skin, but especially along the back, may have a considerable
inflammatory component, and resemble “pyogenic granuloma”
of humans. Varicose tumor of the scrotum of dogs is a benign
vascular proliferation that resembles cavernous hemangioma
when fully developed. Lesions resembling hemangioma occa-
sionally develop in the skin of the scrotum or perineum of
boars, or the vulva, mammary glands, or ovaries of sows.
Meningioangiomatosis, a rare condition reported in dog,
horse, and cow, is characterized by benign focal proliferation
Vascular Neoplasms 99
of blood vessels and meningothelial cells in the leptomeninges
and underlying brain parenchyma.
Although most vascular proliferations are idiopathic, there
is evidence that various Bartonella spp. (Bartonella vinsonii
subsp. berkhoffii, B. henselae, B. koehlerae) may contribute to
the pathogenesis of systemic reactive angioendotheliomatosis
(and hemangiopericytomas) in animals.
Formerly thought to be due to neoplastic proliferation of
endothelial cells and hence termed malignant angioendothelio-
matosis, intravascular lymphoma is a rare large cell lymphoma,
seen in humans, dogs, and a cat, in which neoplastic lympho-
cytes proliferate within the lumens of blood vessels. Lympho-
matoid granulomatosis (angioinvasive lymphoma) is a rare
pulmonary disorder of middle-aged dogs, characterized by
infiltration of lung and various other organs by neoplastic
mononuclear cells admixed with eosinophils, lymphocytes,
and plasma cells; originally thought to be angiocentric, this
pulmonary neoplasm is now thought to be an atypical T-cell
lymphoma that is angioinvasive.
Lymphangioma is a rare, benign tumor that consists of
lymph channels forming capillary, cavernous, or cystic tumors.
Lymphangiomas may occur as congenital malformations
(hamartomas) or may develop spontaneously in adults. Cav-
ernous and cystic lymphangiomas may progressively enlarge,
dissect along fascial planes, and be difficult or impossible to
remove surgically.
Glomangiomas (glomus tumors) of nonhuman primates,
dogs, cats, and horses are rare benign (even more rarely malig-
nant) neoplasms of the neuromyoarterial thermal receptors,
primarily in the digits, characterized by branching vascular
channels in a fibrous stroma that contains nests of specialized
glomus cells, a type of smooth muscle cell. Glomus jugulare
and glomus pulmonale tumors have been reported in dogs.
The glomus jugulare and pulmonale are chemoreceptors, and
tumors of these bodies resemble other chemodectomas,
namely, nests of monomorphic rounded cells with scant cyto-
plasm separated by thin septa. The tumor is encapsulated and
grows expansively.
Angiosarcoma
Hemangiosarcoma (malignant hemangioendothelioma), a
malignant tumor of endothelial cells, occurs most frequently
Shepherd dogs (Alsatians) are most commonly affected, and
some other breeds are over-represented. Hemangiosarcoma
occurs infrequently in cats, horses, cows, and sheep.
There is a current focus on a number of receptor tyrosine
protein kinases, such as platelet-derived growth factor
receptor-β and Src, as well as CD117(c-Kit) and vascular endo-
thelial growth factor-3, which are overexpressed in hemangio-
sarcomas. This suggests involvement of growth factor signaling
pathways, if not in the genesis, then in the development of the
tumor. The p16-cyclinD1-retinoblastoma pathway has also
been implicated. There is also increasing evidence that the
tumor cells arise from hematopoietic stem cell precursors. The
tumor may arise in any site of the body. The most common
primary sites in dogs are spleen, skin/subcutis, right atrium, and
liver; in cats, spleen, intestines, and subcutaneous tissue; in
horses, ocular, cutaneous, and multicentric. Hemangiosarcoma
is the most common primary cardiac tumor of dogs, and the tumor
usually occurs subepicardially in the wall of the right atrium at
the entrance to the auricle near the coronary groove (Fig. 1-99)
or in the auricular appendage. Hemangiosarcoma probably
100 CHAPTER 1  •  Cardiovascular System
arises de novo and not from pre-existing hemangiomas. The
tumors have a gray to red-black hemorrhagic appearance, and
may reach a diameter of 30 cm in the spleen as a result of
hemorrhage within the tumor. Large hemorrhagic masses can
often be found in the spleens of dogs; some are hematomas
Figure 1-99  Hemangiosarcoma in the right auricle of a dog.
(Courtesy D. Hayden.)
A B
C
Figure 1-100  Metastatic hemangiosarcoma in a dog. A. Lung. (Courtesy I. Matise.) B. Liver.
(Courtesy D. Hayden.) C. Brain. (Courtesy M. Bouljihad.)
Vascular Neoplasms
rather than either hemangiomas or hemangiosarcomas. The
distinction is important because splenic hemangiosarcomas
carry a very poor prognosis. However, the distinction can often
be difficult because splenic hemangiosarcomas often hemorrhage,
and if the resultant hematoma is not sampled carefully, its neoplas-
tic origin will be missed. Following rupture, implants of splenic
tissue or tumor may be found on the peritoneum. Hemangio-
sarcomas typically metastasize widely, especially to the lungs
(“cannonball” metastases) (Fig. 1-100A-C). Histologically,
these tumors consist of vascular spaces lined by elongated,
plump, anaplastic endothelial cells (Fig. 1-101A). Vascular
spaces must be identified in tumors with a highly cellular
stroma to differentiate hemangiosarcoma from fibrosarcoma.
Hemorrhage and necrosis commonly occur within these
tumors, and death may occur because of hemorrhage into the
peritoneal cavity, pericardial sac, or brain. When metastases are
widespread, the primary tumor site may be difficult to deter-
mine, and multicentric origin is a possibility. Poorly differenti-
ated hemangiosarcomas may usually be differentiated from
spindle cell sarcomas or other non-endothelial neoplasms by
immunohistochemical staining for factor VIII–related antigen
(Fig. 1-101B), a marker of endothelial cells, and claudin-5
protein, a tight-junction protein normally found on endothelial
cells. Ulex europaeus lectin, a marker of neoplastic human
endothelial cells, is unreliable as a marker of canine vascular
tumors. Ultrastructurally, Weibel-Palade bodies (granules
Diseases of the Vascular System
A tumour-like lesions. APMIS Suppl 2008;125:19-40.
B Pirie CG, et al. Canine conjunctival hemangioma and hemangiosar-
Figure 1-101  Hemangiosarcoma in a dog. A. Plump, pleomor-
phic, closely packed tumor cells, some forming vascular channels.
H&E. B. Tumor cells stain strongly for the presence of factor VIII
antigen.
containing factor VIII) are present in at least some of the typical
neoplastic endothelial cells.
Lymphangiosarcoma (malignant lymphangioendotheli-
oma) is an extremely rare tumor in domestic animals. The
tumor is histologically similar to hemangiosarcoma, but the
irregular vascular channels contain few red cells; it may be
diffusely invasive and metastasize widely. Ultrastructurally,
lymphangiosarcoma is distinguished from hemangiosarcoma,
at least in cats and humans, by the general lack of a basal
lamina, few micropinocytotic vesicles, few intercellular junc-
tions, lack of pericytes, and a discontinuous endothelial cell
layer in lymphangiosarcoma. Immunohistochemistry (factor
VIII, vimentin, laminin) and lectin histochemistry (RCA-I,
PHA-E) may be other useful adjuncts in differentiating the 2
tumors. As well, lymphatic vessels are characterized by the
expression of lymphatic vessel endothelial receptor-1 (LYVE-
1) and prospero-related homeobox gene-1 (PROX-1).
Further reading
Arenas-Gamboa AM, Mansell J. Epithelioid haemangiosarcoma in the
ocular tissue of horses. J Comp Pathol 2011;144:328-333.
Asa SA, et al. Expression of platelet-derived growth factor and its
receptors in spontaneous canine hemangiosarcoma and cutaneous
hemangioma. Histol Histopathol 2012;27:601-607.
Vascular Neoplasms 101
Beerlage C, et al. Bartonella vinsonii subsp. berkhoffii and Bartonella
henselae as potential causes of proliferative vascular diseases in
animals. Med Microbiol Immunol 2012;201:319-326.
Burns RE, et al. Glomus tumours in the skin and subcutis of three
horses. Vet Dermatol 2011;22:225-231.
Chandler HL, et al. Immunohistochemical analysis of ocular hemangio-
mas and hemangiosarcomas in dogs. Vet Ophthalmol 2009;12:83-
90.
Dickerson EB, et al. Imatinib and Dasatinib inhibit hemangiosarcoma
and implicate PDGFR-β and Src in tumor growth. Transl Oncol
2013;6:158-168.
Galofaro V, et al. Glomangioma in the prepuce of a dog. Reprod Dom
Anim 2006;41:568-570.
Gamlem H1, Nordstoga K. Canine vascular neoplasia—histologic clas-
sification and inmunohistochemical analysis of 221 tumours and
Jackson DE, et al. Locally invasive lymphangiosarcoma in a young
domestic shorthair. J Fel Med Surg 2011;13:796-799.
Jakab C, et al. Claudin-5 protein is a new differential marker for his-
topathological diagnosis of canine hemangiosarcoma. Histol Histo-
pathol 2009;24:801-813.
Jennings RN, et al. Comparison of CD34, CD31, and factor VIII–related
antigen immunohistochemical expression in feline vascular neo-
plasms and CD34 expression in feline nonvascular neoplasms. Vet
Pathol 2012;49:532-537.
Lombardini ED, Summers BA. Two canine malignant vascular tumours
with features of human retiform haemangioendothelioma. J Comp
Pathol 2013;148:225-229.
Park CH, et al. Malignant glomus tumor in a German shepherd dog.
Vet Dermatol 2009;127-130.
Pires I, et al. Kaposi-like vascular tumor of the urinary bladder in a cow.
J Vet Med Sci 2009;71:831-833.
coma: a retrospective evaluation of 108 cases (1989-2004). Vet
Ophthalmol 2006;9:215-226.
Pirie CG, Dubielzig RR. Feline conjunctival hemangioma and heman-
giosarcoma: a retrospective evaluation of eight cases. Vet Ophthal-
mol 2006;9:227-231.
Roperto S, et al. Multiple glomus tumors of the urinary bladder in a
cow associated with bovine papillomavirus type 2 (BPV 2) infection.
Vet Pathol 2008;45:39-42.
Sabattini S, Bettini G. An immunohistochemical analysis of canine
haemangioma and haemangiosarcoma. J Comp Pathol 2009;140:
158-168.
Schoniger S, et al. Arteriovenous haemangioma in two dogs and a cat.
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Smith AN. Hemangiosarcoma in dogs and cats. Vet Clin North Am
Small Anim Pract 2003;33:533-552.
Tambarini BA, et al. Gene expression profiling identifies inflammation
and angiogenesis as distinguishing features of canine hemangio-
sarcomas. BMC Cancer 2010;10:619.
Vincek V, et al. Kaposiform hemangioendothelioma: the first reported
case in a nonhuman animal species. Vet Pathol 2004;41:695-697.
Warren AL, Summers BA. Epitheloid variant of hemangioma and hem-
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Yonemaru K, et al. The significance of p53 and retinoblastoma path-
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For more information, please visit the companion site:
PathologyofDomesticAnimals.com

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Belanger MC, et al. Invasive multiple lymphangiomas in a young dog.
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Bildfell RJ, et al. Cutaneous vasoproliferative lesions in goats. Vet Pathol
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Finnie JW, et al. Two haemangioendotheliomas in a bovine brain.
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Lopez MJ, et al. Generalized congenital hemangiomatosis in a calf.
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Machida N, et al. Epithelioid haemangioendothelioma of the lung in a
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CHAP TER 2 
Hematopoietic System
V. E. O. (Ted) Valli  •  Matti Kiupel  •  Dorothee Bienzle (with R. Darren Wood)
BONE MARROW 103
General considerations 103
Sample procurement and processing 107
Disorders of leukocytes 109
Disorders of erythrocytes 112
Disorders of platelets 128
Hematopoietic neoplasia 129
Other hematopoietic conditions 136
LYMPHOID ORGANS 138
Developmental diseases of the lymphoid system 139
Immunodeficiency 139
THYMUS 141
Structure and function of the normal thymus 141
Developmental diseases of the thymus 144
Thymic involution and atrophy 144
Thymic hemorrhages/hematoma 147
Inflammatory diseases of the thymus 148
Hyperplastic and neoplastic diseases of the thymus 150
Thymic hyperplasia 150
Thymic cysts 151
Thymic neoplasms 151
SPLEEN AND HEMOLYMPH NODES 158
Structure and function of the normal spleen 158
Developmental diseases of the spleen 162
Degenerative diseases of the spleen 163
Rupture of the spleen 165
Volvulus of the spleen 167
Splenomegaly and splenic nodules 167
Circulatory diseases of the spleen 169
Specific infections of lymphoid tissues 171
Anthrax 171
Leishmaniasis 174
Theileriosis 176
Tick-borne fever 178
Classical swine fever 178
African swine fever 181
Inflammatory diseases of the spleen 182
Tularemia 184
Histoplasmosis 186
Melioidosis 188
Hyperplastic diseases of the spleen 189
Splenic cysts 189
Lymphoid hyperplasia 189
Nodular hyperplasia 189
Fibrohistiocytic nodules 190
Hematopoietic alterations 191
Neoplastic diseases of the spleen 191
Jembrana disease 195
LYMPH NODES 196
Structure and function of normal lymph nodes 196
Developmental diseases of lymph nodes 198
102
Degenerative diseases of lymph nodes 198
Hyperplasia of lymph nodes 200
Inflammatory diseases of lymph nodes 202
Caseous lymphadenitis 204
Streptococcal adenitis in swine 208
Streptococcal adenitis in dogs 209
Pseudotuberculosis 209
Porcine circovirus-associated diseases 210
Parasitic infestations of lymph nodes 212
Neoplastic metastatic diseases of lymph nodes 212
Lymphoid neoplasms 213
Clinical features of lymphomas 214
Diagnosis of lymphomas 214
Classification of lymphomas 215
HISTIOCYTIC PROLIFERATIVE DISEASES 243
Canine cutaneous histiocytoma 243
Canine cutaneous Langerhans cell histiocytosis 245
Feline pulmonary Langerhans cell histiocytosis 246
Canine reactive histiocytosis 247
Cutaneous reactive histiocytosis 247
Systemic reactive histiocytosis 249
Histiocytic sarcoma 250
Feline progressive histiocytosis 253
Hemophagocytic histiocytic sarcoma 254
DISORDERS OF HEMOSTASIS 255
Platelet plug formation 255
Adhesion 256
Aggregation 256
Platelet disorders 257
Evaluation of platelet function 257
Thrombocytopenia 258
von Willebrand disease 258
Intrinsic disorders of platelet function 259
Acquired platelet disorders 260
Thrombin formation 260
Initiation 260
Amplification of thrombin generation 261
Fibrin formation 262
Laboratory evaluation of thrombin and fibrin formation 262
Disorders of thrombin formation 263
Inherited disorders 263
Acquired disorders 264
Disorders of fibrin formation 265
Regulation of coagulation: endogenous anticoagulants 265
Inhibitor disorders 266
Fibrinolysis 266
Endothelium-mediated fibrinolysis 266
Plasma-mediated fibrinolysis 266
Systemic inflammation and neoplasia: dysregulation
of hemostasis 267
 Bone Marrow 103

ACKNOWLEDGMENTS of the marrow space of bones to concentration in marrow

We gratefully acknowledge the contributions to past editions of
this chapter by Drs. Ken Jubb, Peter Kennedy, Nigel Palmer, Bruce
Parry, and Patricia Gentry. We thank the image archive of Michi-
gan State University for use of its images.
BONE MARROW
General considerations
The hematopoietic system is broadly divided into myeloid and
lymphoid tissues. The myeloid tissues consist of bone marrow
and the blood cells derived from it (e.g., red blood cells, white
blood cells, and platelets), whereas primary lymphoid tissues
include the lymph nodes, spleen, thymus, and circulating lym-
phocytes. Hematopoiesis refers to the generation of blood
cells, which in mammals proceeds from the mesonephric
region in the embryo to the liver in the fetus, and then to bone
marrow prior to birth. During maturation from neonate to
adult, hematopoietic activity contracts from occupying most
space of axial bones (skull, vertebrae, ribs, sternum, pelvis) and
the proximal regions of the humerus and femur. In healthy
adult animals, this active bone marrow appears grossly red and
is composed of a dynamic composite of hematopoietic and
adipose tissue. Marrow in the distal appendicular bones con-
sists predominantly of adipocytes and appears white-yellow.
The relative proportion of hematopoietic and adipose tissue
in marrow is highly variable, reflecting age-related increases
in the proportion of fat and the relative demand for blood
cells. Although adult marrow contains few lymphocytes, cells
of both myeloid and lymphoid tissues are derived from
common precursor cells in bone marrow. Such hematopoietic
stem cells (HSC) have self-renewing and pluripotent differ-
entiating ability, and give rise to all blood and lymphoid tissue
cells (Fig. 2-1).
Bone marrow comprises 2-5% of body weight in adult
animals, and hematopoietic tissue is identified grossly as red
marrow amidst the labyrinth of boney trabeculae in flat bones
and the proximal parts of long bones. A layer of endosteal cells

Hematopoietic
stem cell

Multipotent
Lymphoid Myeloid
precursor
progenitor progenitor

T-cell B-cell
thymus lymphoid CFU-GM CFU-Meg-E
tissue

Mitotic
Committed activity
precursor

Monoblast Myeloblast Mega- Erythro-

karyoblast blast

Terminally
committed
precursor
Pro- Neutrophil Eosinophil Basophil Mega- Basophilic
monocyte metamyelocyte karyocyte rubricyte
Distinct cell
morphology
Mature
blood cells

Monocyte Neutrophil Eosinophil Basophil Platelets Erythrocyte

Figure 2-1  Production of blood cells proceeds in an orderly and highly regulated manner from
hematopoietic stem cells through multiple precursor stages to mature blood cells. CFU, colony-
forming unit; GM, granulocyte-macrophage; Meg-E, megakaryocyte-erythrocyte.
104 CHAPTER 2  •  Hematopoietic System
covering cortical and trabecular bone surfaces lines the marrow
cavity containing hematopoietic cells. Endosteal cells are mul-
tipotent mesenchymal progenitor cells with ability to give rise
to osteoblasts, osteocytes, and osteoclasts; all are cells that
are commonly identified at endosteal surfaces. Together with
specialized endothelial cells, macrophages and nerve cells,
endosteal cells comprise a HSC niche or microenvironment.
Trabecular bone homeostasis is interconnected with hemato-
poiesis, and altered hematopoiesis may be associated with
changes in density or diameter of the boney trabeculae. Bone
marrow has a vascular supply through nutrient arteries that
enter through cortical bone, branch to run parallel to the long
axis of bone, and give rise to arterioles directed toward the
marrow periphery. Anastomosis with venous sinuses leads to
venules that drain into a central longitudinal vein, which in
turn feeds into nutrient veins. The sinusoidal network in bone
marrow is extensive, but most sinusoids are very small and
inconspicuous, and may be entirely inapparent in biopsy sec-
tions. Bone marrow lacks lymphatic vessels. Other compo-
nents of the hematopoietic microenvironment are nerve cells,
adventitial barrier cells, adipocytes, macrophages, and mesen-
chymal cells.
Mature blood cells are derived from precursor cells through
orderly and hierarchical maturation under the precise influ-
ence of transcription factors and lineage-specific growth
factors. HSC and committed precursor cells lack distinct mor-
phologic features, and are defined by functional assays such as
in vitro colony formation or expression of specific antigens.
Committed precursor cells are morphologically recognizable as
rubriblasts, myeloblasts, or megakaryoblasts. Precursor cells
without distinct morphologic features are infrequent in bone
marrow, and are rarely enumerated for diagnostic purposes.
However, during times of hematopoietic stress, HSC may be
mobilized from bone marrow, travel via the circulation to
tissues outside the bone marrow, and establish extramedullary
foci of hematopoiesis. Healthy animals, particularly dogs and
cats, frequently have hematopoietic activity in the red pulp of
the spleen, and virtually any other tissue, but most commonly
liver and lymph nodes, may acquire hematopoietic activity in
stress or disease states.
Hematopoiesis is a highly dynamic process, given the short
life-span of blood cells. Neutrophils circulate for 8-10 hours
after release from bone marrow, platelets for 10-14 days, and
erythrocytes for 70 (cats) to 150 days (cows). Hence it is
common to observe mitotic activity in bone marrow samples
from healthy animals, which may be markedly increased
during sustained inflammation, or in response to blood loss or
premature destruction of blood cells. Chronic blood loss or
inflammation in an otherwise healthy animal may increase the
proportion of marrow hematopoietic relative to adipose tissue
from ~50% to >90% within a few weeks. Further prolonged
increased demand for blood cells results in progressive conver-
sion of adipose tissue first in distal trabecular bone regions of
the metaphysis, and then in areas lacking trabecular bone
toward the diaphysis. Such expanded hematopoiesis depends
on formation of new HSC niches through interaction with
endosteal cells, and is grossly apparent as a red line along the
endosteal surface of long bones. High proliferative capacity
also renders hematopoietic tissue uniquely susceptible to
injury from cytotoxic drugs, toxins, and infectious agents. The
ratio of hematopoietic to adipose tissue in red marrow is
80-90% to 10-20% in healthy animals <1 year of age (Fig. 2-2).
With progressive age, the proportion of marrow space taken
Bone Marrow
up by adipocytes increases, and in healthy geriatric animals,
hematopoietic tissue may comprise only 10% of red marrow.
Hematopoiesis within the microenvironment of the bone
marrow takes place in the interstitium, and maturing cells
acquire properties that allow them to transit across a special-
ized blood–bone marrow barrier. This barrier consists of a
single layer of endothelium and a discontinuous basement
membrane with adventitial cells, which together regulate
cell transition and release into the blood stream. Erythropoi-
esis occurs in discrete clusters, whereas granulopoiesis is
more dispersed as individual cells throughout the interstitium.
Megakaryocytes are typically located adjacent to sinusoids.
The term “myeloid” refers to all hematopoietic cells in bone
marrow exclusive of lymphocytes, but is often also applied
to cells of only the neutrophil lineage or to spinal cord tissue.
Therefore specific terminology such as “granulocytic” and
“erythrocytic” should be used to describe cells in the marrow.
Rubriblasts are the first recognizable erythrocyte precursor.
Rubriblasts are medium-sized round cells with darkly staining
cytoplasm, a small Golgi zone, high nuclear-to-cytoplasmic
ratio, and one or several nucleoli. With maturation, rubriblasts
progress to rubricytes that progressively synthesize cytoplas-
mic hemoglobin, which imparts initially a purple cytoplasmic
hue and eventually bright orange-pink staining to metarubri-
cytes, immature anucleated reticulocytes, and mature anucle-
ated erythrocytes (Fig. 2-3). Concurrent with homogeneous
cytoplasmic hemoglobin synthesis, rubricyte nuclei progres-
sively condense and decrease in size. Late-stage rubricytes have
small, round, and intensely dark-staining nuclei that are
expulsed prior to transition across the blood–bone marrow
barrier. Rubriblasts and different stages of maturing rubricytes
may comprise clusters surrounding macrophages (“nurse
cells”) that provide trophic factors and iron for synthesis of
hemoglobin. Rubricyte maturation follows a continuum with
mitotic capability throughout, and reliably identifying indi-
vidual cell stages is challenging. Thus, for practical purposes,
synchronous erythropoiesis is characterized by low number of
rubriblasts and immature large rubricytes with round, cen-
trally located nuclei and a moderate amount of blue cyto-
plasm, and high number of late-stage small rubricytes with
increasingly hemoglobinized cytoplasm. Immature (polychro-
matophilic) erythrocytes are difficult to distinguish from mature
erythrocytes in hematoxylin and eosin (H&E)-stained sec-
tions, but are readily identified on cytology preparations.
Maturation from rubriblast to reticulocyte takes ~6 days
under homeostatic conditions, but may be accelerated relative
to the degree of hypoxic stress. Rubricytes are not normally
released from bone marrow, and their presence in blood in the
absence of regenerative anemia suggests altered blood–bone
marrow barrier function, abnormal splenic erythropoiesis, or
lead toxicity. Specific causes of altered blood–bone marrow
barrier function include injury caused by hyperthermia or
chemotherapy, and disruption resulting from granulomatous
inflammation, hematopoietic neoplasia, myelofibrosis, or met-
astatic neoplasia.
Myeloblasts are the precursors of neutrophils, eosinophils, and
basophils. They are larger than rubriblasts, have pale-staining
and abundant cytoplasm, and have one large nucleolus, or,
more commonly, several small nucleoli. Myeloblasts are con-
centrated adjacent to trabeculae (Fig. 2-4) and generate
differentiating granulocytes of progressive maturity toward
the sinusoids in the center of the marrow cavity. Recogniz­
able sequential stages of granulocyte differentiation are
 Bone Marrow 105

A B

C D

E F
Figure 2-2  Bone marrow biopsy sections from a healthy young dog. A. Bone marrow is comprised
of ~70% hematopoietic and 30% adipose tissue. B. Myeloblasts are concentrated adjacent to tra-
beculae, erythrocytes are inconspicuous, and hemosiderin is not yet apparent given the age of the
dog. C. Periodic acid–Schiff stain highlights megakaryocyte and granulocyte cytoplasm. D. CD31
immunohistochemistry identifies small collapsed sinusoids that are difficult to appreciate on H&E
stains. E. Silver impregnation for reticulin is negative in normal bone marrow. F. Masson trichrome
stains erythrocytes and granulocyte and megakaryocyte nuclei red. Extracellular collagen is absent.
106 CHAPTER 2  •  Hematopoietic System Bone Marrow

# *

* *
*

A
Figure 2-3  Bone marrow aspirate with erythroid hyperplasia.
Rubriblast has dark basophilic cytoplasm (#). Promyelocytes have
slightly granular and light blue cytoplasm (*). Metarubricytes
(arrows) are frequent.

promyelocytes with round nuclei, single or multiple nucleoli

and faint cytoplasmic primary granules; myelocytes that are
smaller and have specific cytoplasmic granules identifying
them as committed to neutrophil, eosinophil or basophil dif-
ferentiation; metamyelocytes with indented nuclei; and granu-
locytes with band-shaped and segmented nuclei. Monocytes
are derived from a granulomonocytic precursor cell shared
with granulocytes. Three morphologic stages are recognized:
monoblasts that have round to oval nuclei, one or several
nucleoli, and pale blue cytoplasm; promonocytes that lack
nucleoli and have more angular nuclei; and monocytes with B
butterfly- or horseshoe-shaped nuclei, pale blue cytoplasm,
and frequent cytoplasmic vacuoles. Ultrastructurally, mono-
cytes have scant electron-dense cytoplasmic granules. Fine
pink granules may be apparent in cytology preparations in
monocytes from animals with inflammatory disease. Matura-
tion of monoblast to monocyte requires 1-2 days. Monocytes
and their precursors are very infrequently observed in bone
marrow.
Megakaryocytes are giant cells with multilobulated nuclei
that release cytoplasmic fragments as platelets. A bipotential
megakaryocyte-erythroid progenitor gives rise to megakaryo-
blasts, which further differentiate to megakaryocytes under the
influence of thrombopoietin. Megakaryoblasts are larger than
rubriblasts or myeloblasts, have 1 or 2 nuclei, intensely dark
basophilic cytoplasm, and an irregular cytoplasmic membrane
with frequent small protrusions. Megakaryoblasts are unique C
relative to other cells by undergoing endomitosis without
cytoplasmic separation during differentiation to megakaryo- Figure 2-4  Bone marrow from a dog with chronic inflammation
cytes. This process results in polyploid giant cells containing up and leukocytosis. A. Granulocytes mature from myeloblast/
to 32 nuclei. During maturation, megakaryocytes form an promyelocyte (*) with a large round nucleus and basophilic cyto-
extensive cytoplasmic demarcation membrane system and plasm, to myelocyte (arrows) with faint cytoplasmic granules, to
cytoplasmic granules, which are then transferred to platelet metamyelocytes (arrowheads), band, and segmented neutrophils.
progeny. In general, megakaryocytes with low ploidy have B. Myeloblasts are concentrated in paratrabecular regions
high replicative potential and limited platelet production, (bracket). C. Maturing granulocytes and rubricytes are randomly
whereas high ploidy corresponds to low replicative potential interspersed in small groups.
and abundant platelet production. Mature megakaryocytes
reside proximal to sinusoids, and release platelets from cyto-
plasmic extensions into the sinusoids. In health, individual or
clustered hematopoietic cells and adipocytes are distributed
 Bone Marrow
Table • 2-1  poietic cells. Hematologic manifestations of such conditions
Histologic evaluation of bone marrow
Magnification Features of normal bone marrow
Low power Intact nonfragmented trabeculae with ≥3
intertrabecular spaces free of artifact
Randomly distributed hematopoietic and
adipose cells
Inconspicuous sinusoids and lack of
extravasated red blood cells
Cellularity 10% (old age) to 90% (young
age)
Randomly distributed megakaryocytes (2-5
per intertrabecular space) of different
maturational stages
Iron stores, except in young animals and
cats
Lack of aggregated lymphocytes, plasma
cells, or histiocytes
High power Granulocytic to erythrocytic (G : E) cell
ratio ~1 : 3 (large animals) to ~3 : 1
(small animals)
Differentiated granulocytes
(metamyelocytes, band, and segmented
neutrophils) and rubricytes outnumber
myeloblasts and rubriblasts by >5 : 1
Undifferentiated blast cells, apoptotic or
mitotic cells each comprise <5% of all
cells
randomly throughout the interstitium of the bone marrow,
with maturing granulocytes and rubricytes in similar propor-
tions throughout. Individual megakaryocytes should also be
randomly distributed and encompass a range of maturational
stages and sizes. Clustering of megakaryocytes is indicative of
altered extracellular matrix or hematopoiesis. Other nonhe-
matopoietic cells that may be routinely observed in marrow
include plasma cells, neurons, and stromal cells.
Bone marrow needs to be evaluated systematically and inter-
preted in light of peripheral blood findings. Each cell line has to
be identified and assessed for synchronous maturation reflected
by a low proportion of immature cells and high proportion of
differentiated rubricytes and granulocytes (Table 2-1). The
ratio of granulocytes to rubricytes normally ranges from 1 : 3
in large animals to 3 : 1 in small animals. Blast and mitotic cells
should be rare, and iron should be apparent in all species
except cats. Hematopoietic cells should be closely apposed to
each other, denoting high cell density. Hemorrhage, as indi-
cated by extravasated erythrocytes, should be absent, but bone
marrow biopsies frequently contain artifactual hemorrhage.
Diseases of hematopoietic tissue have a propensity to also
involve lymphoid tissues, for instance, neoplasms of hemato-
poietic cells preferentially spread to lymph nodes, spleen, and
liver, whereas neoplasms of lymphoid tissue frequently also
involve bone marrow. Conditions that alter bone marrow
architecture, such as myelofibrosis, granulomatous inflam­
mation, or metastatic cancer, can disrupt the blood–bone
107
marrow barrier and interfere with orderly release of hemato-
are presence of immature precursor cells, such as rubricytes
and myelocytes, in blood. Concurrence of nonregenerative
anemia with circulating immature leukocytes and rubricytes
has been termed leukoerythroblastic anemia, and reflects
severely disturbed hematopoiesis in myeloid neoplasia or
myelofibrosis.
Myeloid metaplasia is replacement of an extramedullary
mature tissue type by mature hematopoietic tissue, sometimes
including osteocytes, osteoid, and endosteal cells. Myeloid
metaplasia has been described in mixed mammary carcinoma
of dogs. The condition “myelofibrosis with myeloid metapla-
sia” occurs in people, and has also been termed “agnogenic
myeloid metaplasia” and “idiopathic myelofibrosis.” In people,
this is a clonal myeloproliferative neoplasm with proliferation
of nonmalignant bone marrow stromal cells caused by factors
produced by neoplastic hematopoietic cells. Affected people
have massive splenomegaly, neoplastic cytosis (such as
increased erythrocytes in polycythemia vera or increased
platelets in essential thrombocythemia), and cytopenia of at
least one cell line. In essence, in this condition the hematopoi-
etic neoplasm is translocated to spleen because of filling of
marrow cavities with fibrous tissue. All of the above terms
have also been variably used in veterinary medicine; however,
lack of well-documented clinical cases and inability to accurately
distinguish clonal from nonclonal hematopoiesis and fibroplasia
have precluded clear understanding of pathogenesis. Extensive
splenic hematopoiesis is observed in animals with malignant
(myeloid neoplasia) and nonmalignant (myelofibrosis) bone
marrow failure. If such splenic hematopoiesis consists pre-
dominantly of a single cell line with asynchronous maturation,
and there is concurrent lymphoid atrophy and organomegaly,
myeloid neoplasia is likely and should prompt comprehensive
hematologic and bone marrow assessment in the animal. If
splenic hematopoiesis involves multiple cell lines, there is
preservation of white and red pulp organization, and there is
lack of organomegaly, benign extramedullary hematopoiesis sec-
ondary to prolonged high demand for blood cells or nonma-
lignant bone marrow failure should be considered.
Iron for hemoglobin synthesis is stored bound to proteins as
hemosiderin in marrow macrophages of all domestic animals
except cats, which typically lack iron in bone marrow during
health, but have iron stores in spleen and liver. Iron stores are
absent in neonates, and at 6-12 months of age become appar-
ent in bone marrow samples.
Sample procurement and processing
Comprehensive assessment of hematopoietic tissue includes
cytologic preparations for identification and enumeration of
individual cell stages and infectious agents, and sections of fixed
bone marrow tissue to determine the relative proportions of
hematopoietic and adipose tissue, changes in tissue architec-
ture, and presence of myelofibrosis, metastasis, or inflamma-
tion. Cell stage identification is challenging on histopathology
because of subtle changes in cytoplasmic features that distin-
guish immature monocytes from granulocytes, and that char-
acterize different maturational stages of leukocytes and
rubricytes. Therefore in vivo investigation of hematopoietic
disease should include assessment of both types of sample. Bone
marrow core biopsies should be obtained prior to aspiration
of bone marrow for smear preparation to maximize tissue
108 CHAPTER 2  •  Hematopoietic System Bone Marrow

architectural preservation. To collect bone marrow core

samples of adequate size and quality requires special trephine
needles and substantial technical expertise. Suitable sites for
core biopsy are the ilium, proximal femur, and proximal
humerus in small animals, and tuber coxae and sternum in
large animals. Given the small size of some dogs and of cats,
biopsies <1 cm in length are often submitted, which do not
yield an adequately representative sample, particularly if arti-
fact from tissue handling is also present. In general, an artifact-
free biopsy 1.5 cm in length prior to fixation will yield at least
3 intact intertrabecular spaces, which is the minimum required
for representative assessment. Cores should be appropriately
fixed in buffered formalin before demineralization and sec-
tioning. Given the thin nature of trabecular bone, demineral-
ization for 10-15 minutes is adequate for bone marrow
biopsies. Central metaphyseal samples collected at autopsy A
often lack trabecular bone and do not require demineraliza-
tion. To maximize identification of individual cells, bone
marrow cores should be sectioned at 2-3 µm thickness. Bone
marrow aspirates should be obtained from accessible flat
bone sites, such as ilium or sternebrae, or if these sites are
deemed unsuitable, from the proximal humerus or femur.
Preparation of high-quality thin bone marrow smears requires
special effort to minimize sample clotting and hemodilution,
to concentrate particles of loosely adherent hematopoietic
cells on the glass slide, and to avoid drying artifact.
Grossly, normal bone marrow fat is firm and opaque, and
processing dissolves fat to leave empty adipocytes on histol-
ogy. In serous atrophy from malnutrition or malassimilation,
there is gelatinous transformation of bone marrow fat to
glycosaminoglycan, which has a translucent and soft gross
appearance. Histologically, adipocytes are atrophied, and with
hemotoxylin and eosin (H&E) staining, amorphous pink- B
staining glycosaminoglycan matrix is apparent. This matrix
material stains with acidic Alcian blue (Fig. 2-5). Serous
atrophy of fat reflects advanced cachexia. Hematopoiesis
is frequently impaired in animals with such severe cachexia,
and can result in hypocellular bone marrow and blood
cytopenias.
Hematopoietic tissue is preserved relatively well postmor-
tem, possibly because of the physical barrier to infectious
agents imposed by cortical bone. This allows reasonable esti-
mates of cellularity and some estimates of cell composition
after death, but cell identification is limited. Postmortem bone
marrow should be sampled from grossly red (active) marrow,
and sections should be prepared as for biopsies. Only samples
obtained within ~30 minutes after death yield acceptable
cytologic preparations of bone marrow. Associated with death,
mature granulocytes appear to frequently transit from perisi- C
nusoidal locations into the vasculature; therefore a relative
paucity of mature neutrophils is a common finding in post- Figure 2-5  Bone marrow from a horse with serous atrophy
mortem samples and does not necessarily indicate antemor- of marrow fat caused by starvation. A. Cytologic preparations
tem leukopenia. Most bone marrow sections are adequately have a ground-glass background appearance and drying artifact.
assessed with routine H&E staining, but special stains may be B. There is hematopoietic tissue and serous atrophy. C. The gelati-
applied to estimate iron stores (Prussian blue), and to assess nous material stains with Alcian blue (pH 2.5).
presence of reticulin fibers (Gomori silver impregnation) or
collagen (Masson trichrome). Iron may leach during acidic
demineralization; therefore assessment of iron stores may be
underestimated, and cytologic preparations yield more accu- detection of clonally rearranged lymphocyte antigen receptor
rate estimates. Additional techniques useful for diagnosis and genes or clonality in nonlymphoid cells, and immunohisto-
characterization of hematopoietic neoplasms are automated chemistry. These assays have proven value for identification
hematology analysis of marrow aspirate suspensions, flow and characterization of lymphoid cells, but are at the devel-
cytometric analysis of cell antigen expression, PCR-based opmental stage for nonlymphoid hematopoietic cells.
 Bone Marrow
Further reading
Beeler-Marfisi J, et al. Gelatinous marrow transformation and hemato-
poietic atrophy in a miniature horse stallion. Vet Pathol 2011;
48:451-455.
Keller SM, Moore PF. A novel clonality assay for the assessment of
canine T cell proliferations. Vet Immunol Immunopathol 2012;145:
410-419.
Tan E, et al. Automated analysis of bone marrow aspirates from dogs
with haematological disorders. J Comp Pathol 2014;151:67-79.
Tattoli L, et al. Postmortem bone marrow analysis in forensic science:
study of 73 cases and review of the literature. Forensic Sci Int
2014;234:72-78.
Travlos G. Histopathology of bone marrow. Toxicol Pathol 2006;
34:566-598.
Disorders of leukocytes
Blood cells are maintained in clearly defined limits during
health, and are easily counted in automated hematology ana-
lyzers. Therefore numerical changes such as leukocytosis and
leukopenia are readily identified, and many associated condi-
tions are well characterized. Leukocytosis is most commonly
of a reactive nature in response to inflammation, infection, or
increased concentration of systemic mediators, such as gluco-
corticoids or epinephrine. Healthy adult dogs, cats, and horses
normally have more circulating neutrophils than lymphocytes,
whereas lymphocytes outnumber neutrophils in healthy adult
ruminants. The number of neutrophils in blood reflects a
dynamic equilibrium of cell release from bone marrow, release
of cells from storage pools such as splenic and hepatic sinu-
soids, entry from marginating into circulating pools in larger
blood vessels, and extravasation followed by cell death. During
homeostasis, few neutrophils persist in extravascular sites;
therefore numbers in circulation directly reflect bone marrow
production.
Neutrophil production is increased in response to cyto-
kines and growth factors elaborated during inflammation and
infection. The major pathway involves increased production
of granulocyte colony-stimulating factor (G-CSF) and
granulocyte-macrophage colony-stimulating factors (GM-
CSFs) through stimulation of bone marrow stromal cells and
T lymphocytes by interleukin-1 (IL-1) and tumor necrosis
factor. If tissue demand for neutrophils exceeds storage pools,
immature band neutrophils, metamyelocytes, or more imma-
ture forms are released from bone marrow and constitute a
blood left shift. The degree of left shift in blood is proportional
to the acuteness and magnitude of inflammation. For example,
acute pancreatitis in dogs is commonly accompanied by a
moderate blood neutrophilia and a left shift. Immune hemo-
lytic anemia with intravascular destruction of red blood cells
is frequently associated with marked neutrophilia and a
marked left shift, presumably because of extensive intravas-
cular complement activation. Other factors that increase
blood neutrophil concentration are glucocorticoids, which are
thought to decrease neutrophil extravasation, and catechol-
amines and vigorous exercise, which are thought to decrease
neutrophil margination. Effects of catecholamines on leuko-
cytes are particularly evident in young animals, and will also
result in lymphocytosis. In general, neutrophilia from increased
glucocorticoids or catecholamines remains below twice the
upper reference limit, and may include a mild left shift. Other
causes of persistent and marked neutrophilia are prolonged
109
exposure to estrogens, pyometra, extensive tissue necrosis,
ectopic production of G-CSF by nonhematopoietic cancers
such as carcinoma or leiomyosarcoma (paraneoplastic neutro-
philia), leukocyte-adhesion deficiency (LAD), and neutro-
philic leukemia. LAD in cattle and dogs is caused by an
autosomal recessive mutation, resulting in lack of expression
of the integrin subunit CD18. Without expression of CD18,
functional integrins composed of CD11/CD18 heterodimers
are not formed, and neutrophils are unable to adhere to endo-
thelial cells, extravasate, and migrate toward a chemotactic
stimulus. Affected animals have extreme blood neutrophilia
but lack tissue neutrophils at sites of inflammation or infec-
tion, and die because of recurrent infections.
Toxic changes in neutrophils consist of cytoplasmic clear
spaces from organelle dispersion, cytoplasmic basophilia
because of increased RNA concentration, and cytoplasmic
basophilic aggregates (Döhle bodies) composed of RNA and
endoplasmic reticulum. Toxic changes in neutrophils reflect
accelerated or stress granulopoiesis. Bacterial infections, par-
ticularly those involving production of bacterial leukotoxins,
are associated with the most pronounced toxic changes in
neutrophils, but intense noninfectious inflammation such as
pancreatitis can also cause marked neutrophil toxic changes.
An example of a bacterial infection causing severe toxic
changes in neutrophils is Salmonella enteritis in horses.
Neutropenia indicates that demand for neutrophils exceeds
release from bone marrow or storage pools. Neutrophils are
the first line of defense against infection, and prolonged or
severe neutropenia renders animals highly susceptible to
sepsis and death. Acute overwhelming inflammation from
bacterial infection is the most common cause of neutropenia,
with salmonellosis in horses as a classic example. Cattle have
more limited storage and mobilization of bone marrow neu-
trophils than nonruminants, and are particularly prone to
become neutropenic during bacterial infections such as acute
mastitis, metritis, or pneumonia. Other causes of neutropenia
are inadequate production as a result of hematopoietic
progenitor cell injury from drugs or infection by viruses,
premature destruction of neutrophils by immune-mediated
mechanisms, or myelophthisis resulting from leukemia, meta-
static cancer, or myelofibrosis. Parvovirus in dogs and cats
infects dividing cells in the intestinal epithelium and bone
marrow, resulting in cell death or lack of normal proliferation.
Neutropenia is an early effect, and concurrent with a compro-
mised epithelial barrier, permits systemic invasion of intestinal
bacteria in a host unable to mount an effective inflammatory
response. Affected animals are at risk of fatal secondary infec-
tions. Many retroviruses may cause neutropenia, either
through direct infection of hematopoietic precursor cells
(feline leukemia virus) or through indirect mechanisms (feline
immunodeficiency virus [FIV]). Bovine viral diarrhea virus
(BVDV) infects hematopoietic precursor cells, and infection
manifests with neutropenia and thrombocytopenia in cattle.
Immune-mediated neutropenia in neonatal animals caused
by maternal immune response to polymorphic paternal or
unknown antigens occurs in piglets, calves, foals, kittens, and
puppies. Antibodies transferred either in utero or postnatally
via colostrum bind to antigens on neutrophils (and often also
erythrocytes and platelets) and induce either direct cell lysis
or removal of antibody-coated cells by splenic macrophages.
In foals, concurrent neutropenia, thrombocytopenia, and
ulcerative dermatitis have been described, suggesting concur-
rent immune reactivity with antigens on hematopoietic and
 109.e1

Further reading
Auler P, et al. Myeloid metaplasia in canine mixed mammary tumors:
occurrence and characterization. Vet Q 2011;31:173-177.
Mochizuki H, et al. Demonstration of the cell clonality in canine hema-
topoietic tumors by X-chromosome inactivation pattern analysis.
Vet Pathol 2015;52:61-69.
Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic
stem cells. Nature 2014;505:327-334.
Tefferi A. The forgotten myeloproliferative disorder: myeloid metapla-
sia. Oncologist 2003;8:225-231.
Wilkins BS. Pitfalls in bone marrow pathology: avoiding errors in
bone marrow trephine biopsy diagnosis. J Clin Pathol 2011;64:
380-386.
Wilkins BS, Clark DM. Making the most of bone marrow trephine
biopsy. Histopathol 2009;55:631-640.
110 CHAPTER 2  •  Hematopoietic System
epithelial cells. In cattle, an adjuvanted inactivated BVDV
vaccine administered to breeding age cows in Europe and
New Zealand caused a widespread condition termed “bovine
neonatal pancytopenia” in offspring. Approximately 50% of
affected calves died because of massive internal and external
hemorrhage. Affected animals also had an increased incidence
of infectious diseases. Detailed analysis of hematologic find-
ings showed that affected calves had predominantly thrombo-
cytopenia and neutropenia, and became anemic as a result of
hemorrhage. Allo-immunization against polymorphic antigens
incorporated into the vaccine from in vitro producer cells was
considered to be the cause of this neonatal immune-mediated
cytopenia.
Several genetic causes of congenital neutropenia have been
identified. Trapped neutrophil syndrome occurs in Border
Collies across the world, and is caused by an autosomal reces-
sive deletion in the gene coding for vesical protein sorting 13B
(VPS13B). The carrier rate of the mutation is 4-8%, and
affected dogs have neutropenia, slender extremity bones, poly-
arthritis, and microencephaly. The cause of the neutropenia is
unclear, but is likely related to impaired generation and trans-
port of neutrophil granules. Canine cyclic hematopoiesis occurs
in Collie-like dogs and is the result of an autosomal recessive
insertion into the gene coding for an adapter protein subunit
important in trafficking of vesicles and proteins, such as neu-
trophil elastase. Concentration of all blood cells, not just neu-
trophils, fluctuates in this condition, and affected animals also
have limited melanin pigmentation of hair follicles resulting
in a “gray” phenotype.
Abnormally large granules in neutrophils and other cells
occur in animals with Chediak-Higashi syndrome (CHS).
CHS is caused by mutations in the lysosomal trafficking regu-
lator LYST gene that result in reduced or absent formation,
migration, and exocytosis of lysosomes. Mutations that pro-
foundly reduce the LYST protein correlate with a more severe
clinical phenotype than those that generate a truncated
protein. Abnormal granule formation may be observed in
many cell types. In neutrophils, lack of transcellular movement
and extrusion of abnormally large lysosomes impairs
phagosome-lysosome fusion and microbial killing. Affected
animals generally have normal neutrophil counts but reduced
innate immunity. Granules of cytotoxic and natural killer lym-
phocytes also are not extruded properly; platelets have
reduced dense granules, impairing aggregation and resulting in
a bleeding diathesis; and animals with CHS have partial or
complete albinism from reduced transfer of melanin-
containing granules. The condition occurs in cattle, cats, mink,
humans, mice, and other species. CHS has been described in
Hereford, Brangus, and Japanese black cattle that have partial
oculocutaneous albinism and leukocyte and platelet defects.
CHS is the cause of the blue smoke fur color variant in Persian
cats and the light blue-grey fur color in Aleutian mink. Affected
mink have normal neutrophil and platelet number, giant neu-
trophil granules, and reduced platelet aggregation. All mink
are susceptible to infection by a parvovirus that results in
neuropathy, hyperglobulinemia, anemia, and progressive
weight loss. Mink with the Aleutian trait have particularly
severe and fatal disease, and it has been speculated that the
cause is defective innate immune function as a result of CHS.
Pelger-Huët anomaly (PHA) is caused by a genetic muta-
tion that in heterozygotes manifests with band-shaped or
bilobed instead of segmented granulocyte nuclei. In affected
humans, the lamin B receptor (LBR) that stabilizes nuclear
Bone Marrow
membrane interactions with heterochromatin, and contrib-
utes to nuclear segmentation, is mutated. Identical morpho-
logic changes in granulocytes of animals suggest that mutation
is LBR is also the cause of PHA in animals, but the actual
genetic defect remains to be mapped. In PHA, neutrophil and
eosinophil nuclei are hyposegmented but have condensed
clumped chromatin like normal mature granulocytes. PHA is
usually an incidental finding on a complete blood count
(CBC), given that the hyposegmented granulocytes are not
functionally impaired. PHA has been reported in multiple dog
breeds, a few cats, and 2 Arabian horses, and is inherited as a
dominant or co-dominant trait. Homozygous mutation of the
LBR gene in people results in more severely hyposegmented
nuclei, skeletal abnormalities, and frequent fatality, and a
similar phenotype occurs in homozygous cats. Absence of
toxic changes in neutrophils and clinical signs of infection
distinguish PHA from a severe left shift. Acquired PHA, also
called pseudo-PHA, is also characterized by hyposegmented
granulocyte nuclei, but in the absence of bacterial or fungal
infection. Acquired PHA has been described in association
with retroviral infection, chemotherapy, myeloid neoplasia,
and myelodysplastic syndrome. Thorough clinical history,
repeat CBCs, and hematologic evaluation of related animals
will distinguish the different entities.
Overall, genetic causes of neutropenia and abnormal neu-
trophil morphology or function are rare in animals, but serve
as useful models of corresponding human conditions.
Some agents infect neutrophils and cause profound neu-
trophilia. Hepatozoon is a large genus of hemogregarine para-
sites for which vertebrates serve as the intermediate host and
invertebrates as the definitive host. Hepatozoon gamonts infect
leukocytes in mammals and birds, and erythrocytes in reptiles.
Dogs infected with H. canis or H. americanum have marked
neutrophilia. Hepatozoon parasites have a life cycle distinct
from other vector-borne protozoa because they are acquired
by vertebrates through ingestion of an invertebrate host such
as a tick containing oocysts, rather than being transmitted via
saliva by a tick during a bite.
Hepatozoon canis is prevalent in Africa, Asia, southern
Europe, and South and North America, and causes predomi-
nantly infection of hemolymphoid organs. H. americanum
occurs in dogs in the southern and central United States, and
causes myositis and severe lameness. Several ticks, including
Rhipicephalus sanguineus in Europe and Amblyomma ovale in
South America, transmit H. canis. Sporozoites ingested with
the tick migrate through the intestinal wall of the dog, invade
mononuclear cells and disseminate via blood or lymph to
hemolymphatic organs, liver, kidney, and lungs. Merogony
with formation of micromerozoites and macromerozoites
occurs in host tissues, and mature meronts released from
tissues invade neutrophils and monocytes to develop into
gamonts that can be observed on blood smears. The tick
Amblyomma maculatum transmits H. americanum, but it
appears that H. americanum can also be acquired by predation
of other infected mammalian hosts and through intrauterine
transmission.
Infection of dogs with H. canis can result in subclinical
illness or severe life-threatening cachexia, lethargy, and
anemia. A mild subclinical infection is most common and
associated with <5% of leukocytes on blood films containing
H. canis gamonts and mild anemia. Severe illness with marked
parasitemia and neutrophilia occurs in immunocompromised
or debilitated dogs, or with concurrent other infections. Other
 Bone Marrow
abnormalities in H. canis infection are polyclonal hyperglobu-
linemia, and increased creatine kinase and alkaline phospha-
tase activity. Periostitis is uncommon. Diagnosis is usually
based on observing gamonts on blood films, or meronts in
tissue biopsies.
Infection with H. americanum results in more severe
disease and is fatal after several months unless treated. Target
organs of H. americanum are skeletal and cardiac muscle
where infected macrophages form cysts composed of zoites
surrounded by layers of glycosaminoglycan. Merogony fol-
lowed by rupture of the cyst and release of merozoites causes
intense myositis. Massive neutrophilia of up to 200 × 109/L is
observed in H. americanum infection, although the number of
infected neutrophils on blood smears is typically <0.1%.
Hence diagnosis may require biopsy of affected muscle for
demonstration of cysts. Affected dogs have fever, muscle pain
and atrophy, mucopurulent ocular discharge, and bone pain.
Chronic infection with persistent hyperglobulinemia may
result in renal amyloidosis, glomerulonephritis, and uveitis.
Untreated infection with H. americanum results in debilitation
and death.
Hepatozoonosis has been reported in cats from several
countries with H. canis infection, but neither the species of
Hepatozoon nor the definitive host is identified. Infection was
associated with meronts in myocardium and skeletal muscle,
and low levels of parasitemia.
Another vector-borne agent of leukocytes is Anaplasma
phagocytophilum, which is the current name of the former
Ehrlichia equi, Ehrlichia phagocytophila, and human granulo-
cytic ehrlichiosis agent. Anaplasma phagocytophilum is a widely
distributed, obligate intracellular, gram-negative bacterium
transmitted by various ixodid ticks. The bacterium infects and
survives in neutrophils by interfering with phagocytosis, oxida-
tive burst, motility, and endothelial adhesion. Groups of aggre-
gated bacteria in endosomes of neutrophils may be observed
during acute infection and are called morulae. Infection can
variably cause fever, leukopenia, thrombocytopenia, edema,
petechiation, and reluctance to move. Infection in domestic
and nondomestic ruminants in Europe with A. phagocytophi-
lum is called tick-borne fever. Equine granulocytic anaplasmosis
is associated with fever, neutropenia, thrombocytopenia,
ataxia, and icterus. Experimentally infected dogs have tran-
sient high fever, thrombocytopenia, and leukopenia. In immu-
nocompetent animals, infection with A. phagocytophilum is
self-limiting and induces robust antibody responses. Infection
is diagnosed by observing morulae on blood films, rising anti-
body titers, and PCR detection of bacterial nucleic acids.
Canine monocytotropic ehrlichiosis is caused by Ehrlichia
canis, which is transmitted by the brown dog tick Rhipicepha-
lus sanguineus. Infection of dogs, and rarely cats, occurs world-
wide. German Shepherd dogs are suggested to be particularly
susceptible to infection. Acute infection is similar to that with
A. phagocytophilum, except that ophthalmic lesions are more
common and consist of anterior uveitis, chorioretinitis, papill-
edema, and retinal hemorrhage, and thrombocytopenia is
moderate to severe. Infection progresses from an acute phase
to a subclinical phase, and in some cases to a chronic phase.
Dogs in the chronic phase of monocytotropic ehrlichiosis are
severely ill and have marked weight loss. Morulae may be
observed in monocytes on blood films during the acute phase.
In dogs with advanced disease, marked lymphocytosis com-
posed of large granular lymphocytes has been observed, which
is an immune, rather than a neoplastic, response.
111
Other vector-borne rickettsial infections of domestic
animals, such as salmon poisoning disease caused by Neorick-
ettsia helminthoeca and equine neorickettsiosis (Potomac horse
fever, also called equine monocytic ehrlichiosis), caused by
Neorickettsia risticii, are covered in later sections of this
chapter and other chapters.
Lymphopenia is most often the result of redistribution of
lymphocytes to lymphoid organs rather than an absolute
decrease in body lymphocytes. Causes for such altered distri-
bution include increased endogenous and exogenous gluco-
corticoids, and acute bacterial or viral infection. Absolute
lymphopenia may result from intestinal loss of lymphatic fluid
in lymphangiectasia or severe enteropathy, immunosuppres-
sion, chemotherapy, and radiation. Rare causes of absolute
lymphopenia are congenital severe combined immunodefi-
ciency caused by impaired DNA repair in Arabian horses, or
lack of cytokine signals in various dog breeds as a result of
mutation in the cytokine receptor subunit shared by IL-2,
IL-4, IL-7, IL-9, IL-15, and IL-21. Of note, blood lymphocyte
concentration is generally higher in healthy young than adult
animals; hence lymphopenia in young animals should prompt
assessment of immune competency.
A common cause of lymphocytosis is endogenous catechol-
amine release. Hypoadrenocorticism in dogs, and infections
with bacterial and protozoal agents, such as Ehrlichia, Ana-
plasma, Theileria, and Babesia, may manifest with lymphocy-
tosis. Retroviruses such as feline leukemia virus (FeLV), equine
infectious anemia virus (EIAV), FIV, and bovine leukemia
virus (BLV) establish permanent infections that may result in
transient lymphocytosis. Lymphocyte concentration is gener-
ally lower in BLV-seropositive than seronegative healthy cows,
but ~30% of infected cows develop persistent non-neoplastic
B-cell lymphocytosis. Neoplastic lymphocytosis occurs in leu-
kemic lymphoma or leukemia.
Causes of monocytosis are chronic infections, excess glu-
cocorticoids, histiocytic proliferative diseases, and myelopro-
liferative neoplasia.
Eosinophilia can be seen in animals with extensive tissue
parasite migration, allergic responses, or as a paraneoplastic
condition. Blood eosinophil transit can be very brief as
reflected by blood concentrations that are normal or only
slightly increased despite substantial tissue eosinophil accu-
mulations. This is considered to result from prolonged tissue
eosinophil survival in the presence of cytokines such as IL-5.
Massive blood eosinophilia and tissue eosinophil infiltrates are
observed in cats, and distinction between reactive and neo-
plastic proliferation may be difficult in these cases.
Basophilia is rarely observed in animals, and is associated
with parasitic and neoplastic conditions such as heartworm
infection, or mast cell and myeloproliferative neoplasms.
Further reading
Allen KE, et al. Hepatozoon spp infections in the United States. Vet
Clin North Am Small Anim Pract 2011;41:1221-1238.
Allison RW, Little SE. Diagnosis of rickettsial diseases in dogs and cats.
Vet Clin Pathol 2013;42:127-144.
Anistoroaei R, et al. A frameshift mutation in the LYST gene is
responsible for the Aleutian color and the associated Chediak-
Higashi syndrome in American mink. Anim Genet 2013;44:
178-183.
Baneth G. Perspectives on canine and feline hepatozoonosis. Vet Para-
sitol 2011;181:3-11.
 111.e1

Further reading
Aroch I, et al. Clinical, biochemical, and hematological characteristics,
disease prevalence, and prognosis of dogs presenting with neutro-
phil cytoplasmic toxicity. J Vet Intern Med 2005;19:64-73.
Baird JD, Arroyo LG. Historical aspects of Potomac horse fever in
Ontario (1924-2010). Can Vet J 2013;54:565-572.
Dallap Schaer BL, et al. Identification of predictors of Salmonella shed-
ding in adult horses presented for acute colic. J Vet Intern Med
2012;26:1177-1185.
de Caprariis D, et al. Evolution of clinical, haematological and bio-
chemical findings in young dogs naturally infected by vector-borne
pathogens. Vet Microbiol 2011;149:206-212.
Deshuillers P, et al. Pelger-Huët anomaly in a cat. Vet Clin Pathol
2014;43-337-341.
Dotta L, et al. Clinical, laboratory and molecular signs of immunodefi-
ciency in patients with partial oculo-cutaneous albinism. Orphanet
J Rare Dis 2013;8:168.
Harrus S, Waner T. Diagnosis of canine monocytotropic ehrlichiosis
(Ehrlichia canis): an overview. 2011;187:292-296.
Meng R, et al. Neutrophil elastase-processing defect in cyclic hemato-
poietic dogs. Exp Hematol 2010;38:104-115.
Perkins GA, et al. Ulcerative dermatitis, thrombocytopenia, and neu-
tropenia in neonatal foals. J Vet Intern Med 2005;19:211-216.
Petterino C, et al. Paraneoplastic leukocytosis in a dog with a renal
carcinoma. Vet Clin Pathol 2011;40:89-94.
Shearman JR, Wilton AN. A canine model of Cohen syndrome: trapped
neutrophil syndrome. BMC Genomics 2011;12:258.
112 CHAPTER 2  •  Hematopoietic System
Brovik L, et al. Pelger-Huët anomaly and a mild skeletal phenotype
secondary to mutations in LBR. Am J Med Genet A 2013;
161A:2066-2073.
Carrade DD, et al. Canine granulocytic anaplasmosis: a review. J Vet
Intern Med 2009;23:1129-1141.
Demasius W, et al. Bovine neonatal pancytopenia (BNP): novel insights
into the incidence, vaccination-associated epidemiological factors
and a potential genetic predisposition for clinical and subclinical
cases. Res Vet Sci 2014;96:537-542.
Gleich S, Hartmann K. Hematology and serum biochemistry of feline
immunodeficiency virus-infected and feline leukemia virus-infected
cats. J Vet Intern Med 2009;23:552-558.
Mason SL, et al. Presentation and management of trapped neutrophil
syndrome (TNS) in UK border collies. J Small Anim Pract 2014;
55:57-60.
Nagahata H. Bovine leukocyte adhesion deficiency (BLAD): a review. J
Vet Med Sci 2004;66:1475-1482.
Reissmann M, Ludwig A. Pleiotropic effects of coat colour-associated
mutations in humans, mice and other mammals. Semin Cell Dev
Biol 2013;24:576-586.
Swenson CL, et al. Impact of bovine leukemia virus infection on neu-
trophil and lymphocyte concentrations in dairy cattle. J Am Vet Med
Assoc 2013;243:131-135.
Zimmerman KL, et al. Leukocyte adhesion deficiency type I in a mixed-
breed dog. J Vet Diagn Invest 2013;25:291-296.
Disorders of erythrocytes
Anemia is a reduction in the red blood cell (RBC) mass and
therefore in oxygen-carrying capacity. Causes of anemia are
reduced erythrocyte production, premature destruction, and
blood loss (Table 2-2). The degree of anemia is generally cat-
egorized as mild, moderate, or marked if the hematocrit is
within 13 , within 2 3 , or > 2 3 below the lower reference interval,
respectively. Anemia is further characterized as regenerative if
there is an increased concentration of polychromatophilic
RBC or reticulocytes in blood and an increased proportion of
rubricytes in bone marrow, or as nonregenerative if production
of RBCs is not increased. Mechanistically, there are 3 main
categories of anemia: blood loss, hemolytic, and decreased
production.
Blood loss anemia
Acute blood loss anemia is usually the result of trauma. Most
external blood loss is readily identifiable, whereas internal
blood loss may be obscured. In both instances, there is a rapid
shift of water from the interstitial fluid compartment into the
vasculature to restore blood volume, which results in hemo-
dilution and a lowered hematocrit and protein concentration.
Reduced oxygen delivery stimulates erythropoietin produc-
tion in the kidney, which in turn increases proliferation of
committed erythroid progenitor cells in bone marrow. Newly
released erythrocytes appear in blood in 3-5 days, depending
on the intensity of the erythropoietic stimulus and the capac-
ity of the host to respond. Horses release very few reticulocytes
from bone marrow in regenerative anemia; these few reticulo-
cytes may be detectable with automated analyzers that scru-
tinize large numbers of cells, but they are typically not
identified on blood smear review. However, newly released
erythrocytes in horses and other species are larger than mature
erythrocytes and have lower hemoglobin concentration, trans-
lating to higher mean cell volume (MCV), and lower mean
cell hemoglobin concentration (MCHC). Therefore regenera-
Bone Marrow
tive anemia is usually macrocytic and hypochromic. Hemorrhage
into tissues results in recycling of the iron in hemoglobin, and
therefore a more robust regenerative response than hemor-
rhage into the gastrointestinal tract or other external sites with
loss of iron.
Chronic blood loss leads to iron deficiency. Dietary iron
deficiency is the most common human nutritional disorder in
the world. Diets for domestic animals are generally iron
replete, therefore iron deficiency in adult animals is rare and
virtually always the result of whole-body blood loss. Iron
metabolism is tightly regulated: dietary iron is absorbed by
duodenal enterocytes, and transferred from enterocytes to
plasma through interaction with ferriportin and oxidative
enzymes. In plasma, iron is bound to transferrin and trans-
ported to rubricytes and macrophages for incorporation into
hemoglobin and storage, respectively. Free iron is highly toxic;
therefore iron is always bound to proteins such as ferritin, and
blood ferritin concentration is a good indicator of body iron
stores. Intracellular partially degraded ferritin aggregates into
hemosiderin granules. The iron in hemosiderin reacts with
potassium ferrocyanide and turns blue-black, which is the
Prussian blue stain reaction. Multiple additional proteins regu-
late iron transport within and across cells. Hepcidin is a central
regulator of iron metabolism. Increased hepcidin inhibits iron
transfer from enterocytes into plasma, and iron release from
macrophages, leading to loss of iron with enterocyte sloughing
and iron retention in macrophages. In iron-replete states, hep-
cidin concentration is high, which limits iron absorption and
iron mobilization from macrophage stores. In iron-deficient
states, hepcidin concentration is low, which enhances iron
transfer from enterocytes. However, hepcidin is also increased
in chronic inflammation and disease, which inhibits enterocyte
iron transfer and iron mobilization from storage in macro-
phages, leading to the conundrum of abundant stainable
iron in bone marrow and spleen despite a functional iron-
limited anemia. Anemia of chronic inflammation and disease
is most common in dogs, but is also seen in other domestic
species.
Iron deficiency resulting from blood loss develops gradu-
ally, usually weeks to months. With modern hematology ana-
lyzers, changes in erythrocytes caused by iron-limited
erythropoiesis can be detected long before there is iron defi-
ciency characterized by lack of stainable iron in bone marrow
and spleen, and reduced blood iron and ferritin concentration.
Neonatal animals have very limited iron stores, and milk is
low in iron, resulting in physiologic iron deficiency during the
first few months of life. By 4-6 months of age, bone marrow
and/or spleen iron stores become apparent, and persistent lack
of stainable iron and anemia are abnormal. The most common
cause of anemia in juvenile animals is blood loss caused by gas-
trointestinal parasites, such as strongyles in horses, Haemonchus
contortus and Trichostrongylus spp. in ruminants, and hook-
worms and ascarids in dogs and cats. Heavy ectoparasite infes-
tation can also cause iron deficiency anemia. Piglets in intensive
production systems are born severely iron deficient and gener-
ate iron stores very slowly; therefore, despite routine paren-
teral iron supplementation, piglets remain highly susceptible
to debilitating or fatal anemia from blood loss. In adult pet
dogs and cats, iron deficiency anemia is most often secondary
to a bleeding gastrointestinal neoplasm. Internal bleeding and
epistaxis associated with vascular erosion in guttural pouch
mycosis may cause anemia, and occasionally iron deficiency
anemia, in horses. Bleeding into the esophagus, stomach, and
 Bone Marrow 113

Table • 2-2 
Classification of anemia by mechanism
Mechanism Hematologic and clinical findings Examples, affected breeds

Blood Loss
  Acute Low to normal hematocrit, low to normal plasma Trauma with external blood loss
protein concentration, normal MCV
  Chronic Low hematocrit, normal plasma protein concentration, Gastrointestinal or urogenital bleeding
low to normal MCV
Hemolysis
  Immune- Marked anemia, spherocytosis, agglutination, marked Primary (autoimmune), drug-induced, transfusion
mediated jaundice, splenomegaly, hemoglobinuria reaction, infectious agents, paraneoplastic
  Infectious Mild to marked anemia, spherocytosis, mild or absent Babesiosis, anaplasmosis, cytauxzoonosis, hemotropic
jaundice, mild or absent splenomegaly mycoplasmosis, equine infectious anemia
  Mechanical Mild to moderate anemia, poikilocytosis, RBC Endocardiosis, endocarditis, vasculitis, intravascular
trauma fragmentation, mild or absent jaundice coagulation, burns
  Toxic injury Mild to moderate anemia, poikilocytosis, Heinz bodies, Oxidant injury, clostridial sepsis, leptospirosis,
mild or absent jaundice hyperglycemia, snake venom
  Hereditary Pyruvate kinase (PK) deficiency—dog: mild to moderate Various small to medium-sized dog breeds; Somali,
hemolytic anemia, persistent reticulocytosis, Abyssinian, and domestic shorthair cats
splenomegaly, develop myelofibrosis and
osteosclerosis; cat: mild or absent anemia, persistent
reticulocytosis
Phosphofructokinase (PFK) deficiency: mild to moderate Spaniel-type dogs, Whippets, mixed-breed dogs
anemia worsened by exercise, persistent
reticulocytosis
Glucose-6-phosphate dehydrogenase (G6PD) deficiency: American Saddlebred
episodic mild to moderate anemia, jaundice
Erythrocyte flavin adenine dinucleotide (FAD) deficiency: Spanish Mustang, Kentucky Mountain Saddle Horse
eccentrocytosis, pyknocytosis, methemoglobinemia,
normal hematocrit
Cytochrome b5 reductase deficiency: normal Multiple dog breeds, domestic shorthair cats
hematocrit, methemoglobinemia, cyanosis
Stomatocytosis: mild to moderate anemia Standard Schnauzer, Alaskan Malamute, Patrijshond
Spherocytosis: mild to moderate anemia Golden Retriever
Elliptocytosis: normal hematocrit Various dog breeds

Decreased Production
Chronic inflammation with iron sequestration: Cancer, polyarthritis, enteritis, etc.; common in dogs;
normocytic normochromic or microcytic hypochromic uncommon in other species
anemia
Iron deficiency: macrocytic or normocytic hypochromic All species; most common in dogs
anemia progressing to microcytic hypochromic
anemia
Erythropoietin deficiency: normochromic normocytic Chronic kidney disease; all species
anemia
Cobalamin deficiency: mild to moderate anemia, Giant Schnauzer, Australian Shepherd, Border Collie,
leukopenia, megaloblastic change in hematopoietic Shar Pei, Beagle
cells
Immune or toxin-mediated progenitor cell injury: Pure red cell aplasia (lack of RBC production);
moderate to severe anemia +/− other cytopenia aplastic anemia (lack of production of all
hematopoietic cells); all species
Primary hematopoietic neoplasm: acute myeloid or All species and ages
lymphoid leukemia, myelodysplasia,
myeloproliferative neoplasm; marked cytopenia of
one or several cell lineages
Metastatic hematopoietic neoplasm: mild cytopenia Myeloma, carcinoma, mast cell tumor
MCV, mean cell volume; RBC, red blood cell.
114 CHAPTER 2  •  Hematopoietic System
Figure 2-6  Blood smear from a dog with iron deficiency anemia.
Note severely hypochromic erythrocytes, acanthocytes (arrow-
heads), and rare polychromatophilic cells (arrows).
proximal small intestine allows partial digestion and reabsorp-
tion of heme and globins, and therefore more gradual develop-
ment of iron deficiency than blood loss into the distal small
or large intestine. Hemoglobin in digesta increases protein
absorption and catabolism, and therefore blood urea concen-
tration. Morphologically, erythrocytes in iron deficiency anemia
are hypochromic and microcytic, fragmented erythrocytes are
common, and there is often a thrombocytosis composed of
microcytic platelets (Fig. 2-6).
Further reading
Lipinski P, et al. Benefits and risks of iron supplementation in anemic
neonatal pigs. Am J Pathol 2010;177:1233-1243.
Schaefer DMW, Stokol T. The utility of reticulocyte indices in distin-
guishing iron deficiency anemia from anemia of inflammatory
disease, portosystemic shunting, and breed-associated microcytosis
in dogs. Vet Clin Pathol 2015;44:109-119.
Hemolytic anemia
Hemolysis of erythrocytes can be intravascular or extravascu-
lar, or both. Immune-mediated hemolysis is most common in
animals, and involves premature removal of antibody-coated
erythrocytes by splenic macrophages. The antibodies may be
directed against antigens on erythrocytes recognized as foreign
as a result of changes in conformation, exposure of hidden
epitopes, or other reasons, or may be directed against infec-
tious agents or drugs absorbed onto, or inducing altered
expression of, membrane components. In dogs with immuno-
hemolytic anemia, the life-span of antibody-coated erythro-
cytes is usually reduced from 120 days to <10 days, resulting
in intense erythropoietic stress. Partial phagocytosis of
antibody-coated erythrocyte membranes by splenic macro-
phages changes the erythrocyte shape from discoid to spher-
oid, with morphologically identifiable spherocytes on blood
smears (Fig. 2-7). Spherocytes have reduced deformability in
splenic red pulp sinusoids, leading to phagocytic removal.
Other mechanisms likely also contribute to immunohemo-
lytic anemia. Apoptosis of erythrocytes has been termed
Bone Marrow
eryptosis, and is characterized by cell shrinkage, extracellular
exposure of phosphatidylserine, membrane blebbing, and
intracellular protease activation. In people, eryptosis is consid-
ered to be a major contributor to anemia of toxic injury, fever,
metabolic derangement, and erythrocyte infection. Intermedi-
aries of the eryptotic pathway have been identified in eryth-
rocyte membranes of dogs with immunohemolytic anemia,
but detailed understanding of this process in the pathogenesis
of anemia is lacking.
Intravascular hemolysis results from activation of com­
plement, and is characterized by presence of erythrocyte
ghosts on blood smears, free plasma hemoglobin, and hemo-
globinuria and hemosiderosis in renal tubular cells from reab-
sorbed filtered hemoglobin. Free plasma hemoglobin is highly
oxidative, and rapidly bound to haptoglobin. Hemoglobin-
haptoglobin complexes have reduced glomerular filtration and
are scavenged by tissue macrophages expressing the CD163
receptor. Once the capacity of haptoglobin to bind free hemo-
globin is exceeded, hemoglobinemia, methemoglobinemia,
and hemoglobinuria ensue. Myoglobin does not have a carrier
protein and is filtered rapidly across the glomerulus; therefore
discolored plasma is the result of free hemoglobin and not
myoglobin. However, both urinary hemoglobin and myoglo-
bin result in grossly indistinguishable pigmenturia.
Immunohemolytic anemia manifests differently in cats than
in dogs. Onset in cats is often <2 years of age, concurrent
neutropenia and thrombocytopenia are common, evidence of
cell regeneration in blood or bone marrow may be absent, and
prolonged or even lifelong immune suppression is required to
normalize blood cell counts. Thus the conditions in cats may
be more appropriately termed immune-mediated cytopenia
(IMC). Although IMC appears increasingly frequent in cats,
pathogenic mechanisms and detailed epidemiologic and clini-
cal characterization remain to be determined.
All erythrocyte parasitic infections have the potential to
cause anemia by multiple mechanisms, including direct eryth-
rocyte lysis, immune-mediated recognition and removal,
shortened life-span caused by oxidative stress, and blood loss
resulting from endothelial disruption or inadequate platelet
function.
Infectious agents of erythrocytes induce predominantly extra-
vascular hemolysis that manifests with hyperbilirubinemia,
jaundice, anemia, and splenomegaly. Depending on the type
of organism, anemia and jaundice may be subtle, such as in
cats infected with Mycoplasma haemofelis and horses with
piroplasmosis, or profound, as in cattle infected with Ana-
plasma marginale, or cats infected with Cytauxzoon felis.
Severity of illness is often variable and influenced by the
genetic background in the host, age of the host at the time of
infection, preexisting immunity, and concurrent other illness.
Erythrocyte infections that are either widespread or economi-
cally important are described in detail later.
Equine infectious anemia.  Species Equine infectious
anemia virus (EIAV) is a member of the Lentivirinae subfam-
ily of retroviruses that infects horses, mules, and donkeys.
Infection occurs worldwide and is lifelong. Diagnosis of EIAV
infection by detection of antibodies (by the agar gel immuno-
diffusion “Coggins test,” or now by enzyme-linked immuno-
sorbent assay [ELISA]) has aided in establishing control
measures in many countries. The virus is transmitted by
various flies, and transmission is mechanical not biological, and
may also occur accidentally by contaminated needles, syringes,
and tattoo equipment, or experimentally by parenteral
 114.e1

Further reading
Powers JM, Buchanan GR. Diagnosis and management of iron defi-
ciency anemia. Hematol Oncol Clin North Am 2014;28:729-745.
 Bone Marrow 115

A B

C D
Figure 2-7  Samples from a dog with immunohemolytic anemia and intravascular hemolysis.
A. There are numerous ghost cells (arrows), spherocytes (arrowheads), and polychromatophilic
erythrocytes in the blood smear. The nucleated cell is a rubricyte. B, C. The bone marrow aspirate
and section show marked rubricyte hyperplasia but orderly maturation. D. Renal tubules contain
heme pigments reabsorbed from urinary filtrate.

administration of blood or virus. Infected horses are the sole
source of viral transmission.
Infection causes acute severe illness that may be fatal, then
cycles of illness characterized by thrombocytopenia and
anemia, and eventual asymptomatic infection. However, even
horses without clinical signs of illness remain a reservoir of
infectious virus. The cyclic nature of infection corresponds to
an intense immune response that drives selection of viral
escape mutants in a manner akin to immunity to the human
immunodeficiency virus in humans.
EIAV infects cells of the monocyte-macrophage system, and the
mechanism for thrombocytopenia and anemia is thought to
be a combination of premature removal of platelets and eryth-
rocytes coated with immune complexes, and direct infection
of megakaryocytes. Hemolysis is predominantly intravascular,
and during chronic infections, the bone marrow becomes
hypoplastic with plasma cell hyperplasia. Acute disease is
characterized by pyrexia and marked depression, with
anorexia, jaundice, weight loss, and pitting and dependent
edema. There are petechial hemorrhages on the ventral surface
of the tongue but also on ocular and vulvar mucosae that
reflect thrombocytopenia. Mild icterus develops after a short
febrile period and is accompanied by pallor of mild to marked
degree. The febrile periods may progress to death in less than
a week, or regress and recur at irregular intervals. Rarely, an
acute episode is followed by many years of an asymptomatic
carrier state.
During acute illness anemia is severe and sufficient to cause
death, with hemoglobin of 25-50 g/L, and hematocrits of
0.08-0.15 L/L. There is consistent thrombocytopenia during
febrile periods, with resulting petechiae. Anemia is initially
regenerative as indicated by anisocytosis and macrocytosis,
and later becomes nonregenerative. There may also be leuko-
penia as a result of neutropenia and lymphopenia, and at
least a relative monocytosis. Monocytes may contain ingested
erythrocytes (sideroleukocytes) within 2-3 days of a febrile
episode. Grossly, horses that die or are euthanized have edema
of the ventral abdominal wall and in the suspensory ligaments
of the viscera. The spleen is enlarged, turgid, and fleshy with
capsular hemorrhages; a bulging but not oozing cut surface;
and inapparent lymphoid follicles. The liver is enlarged,
dark, and turgid, with a fine lobular pattern and focal capsular
hemorrhages. Petechial hemorrhages are present on the
renal capsules and in the perirenal tissues. On cut surface,
116 CHAPTER 2  •  Hematopoietic System
there are multiple fine hemorrhages throughout the cortex
and medulla. The most significant gross lesions occur in bone
marrow, where the degree of reddening is in direct proportion
to the duration of the disease. In acute cases, the conversion
of fat to hematopoietic tissue in the femoral marrow occurs
first in proximal cancellous and then subendosteal diaphyseal
and distal cancellous areas. The red and yellow areas are ini-
tially firm and opaque, often with focal areas of hemorrhagic
infarction. In chronic cases, the red conversion may include
all of the medullary marrow and is alternately pink and trans-
lucent in areas of serous atrophy of fat, and cyanotic where
congested sinuses have dilated as adjacent hematopoietic
areas atrophy.
Microscopic lesions occur in most tissues, but are most promi-
nent in the heart, lungs, liver, spleen, kidney, bone marrow, and
lymph nodes. Their severity varies with chronicity, and they are
described here in the fully developed state. The myocardium
has fiber atrophy in chronic cases, and interstitial edema in
acute cases, with perivascular lymphocytic aggregations that
irregularly permeate the surrounding interstitium. There is
mild pulmonary alveolar thickening and an overall appearance
of hypercellularity. Occasionally, hemosiderin-bearing macro-
phages are found in alveolar walls and are likely intravascular.
The liver presents a spectrum of changes, which varies from
mild periportal lymphocytic infiltrates to atrophic cords with
sinusoidal dilation, Kupffer cell hyperplasia, broad loosely
arranged periportal lymphoid infiltrates, and increased inter-
stitial connective tissue. As the disease progresses, hepatic
hemosiderosis increases, largely in Kupffer cells. Generalized
endothelial prominence, along with sinusoidal Kupffer cells
and infiltrates, gives an overall picture of hypercellularity. In
subacute cases, there is periacinar fatty vacuolation, and in
acute cases hemorrhage and necrosis. In animals in which the
disease has been quiescent for some months, hepatocytes
appear normal and lymphoplasmacytic infiltrates subside but
sinusoidal hemosiderin-bearing macrophages remain as evi-
dence of previous hemolysis.
Splenic follicles are variably enlarged but hypocellular,
often with a “bull’s-eye” appearance resulting from a sharp
distinction between the cells of the follicular center and the
mantle and marginal layers, and a sharp transition to conges-
tion in the surrounding sinusoids. In acute cases, the spleen is
congested and, being largely composed of unsupported red
cells, fractures on sectioning. Lymph nodes are edematous and
have medullary hemosiderosis with persistence of follicles and
thin moth-eaten paracortical areas. In chronic disease, there is
sclerosis and lymphoid atrophy. Renal lesions in acute disease
are largely hemorrhagic with some glomeruli obscured by
erythrocytes and fibrin. Lymphocytic infiltrates may be intense
and separate tubules in an irregular manner. There is some
degree of epithelial atrophy and mild pigmentation that
appears to be both bilirubin and hemosiderin.
Bone marrow in acute disease is 60% or more cellular, and
cells are densely packed. Megakaryocytes are not increased,
which suggests that the thrombocytopenia is at least partially
the result of ineffective production. With chronicity and
repeated febrile periods, there is a progressive reduction of fat
cells until the marrow is completely converted to hematopoi-
esis. At the same time, cellular packing decreases and sinusoi-
dal expansion occurs so that marrow that appears red grossly
is nevertheless histologically hypocellular. Stromal cells are
increased, endothelial nuclei are prominent, and there is
diffuse plasmacytosis.
Bone Marrow
Figure 2-8  Blood smear from a cow with severely hypochromic
erythrocytes and numerous round purple Anaplasma marginale
organisms. There is one large lymphocyte and several platelets.
Further reading
Cook RF, et al. Equine infectious anemia and equine infectious anemia
virus in 2013: a review. Vet Microbiol 2013;167:181-204.
Anaplasmosis.  Bovine anaplasmosis is a caused by infec-
tion of erythrocytes by Anaplasma marginale and extravascu-
lar removal of infected erythrocytes leading to anemia. Three
species infect large animals in the genus Anaplasma, family
Ehrlichiaceae, order Rickettsiales: A. marginale and A. centrale
infect cattle; A. ovis infects sheep and goats. These obligate
intracellular bacteria are spherical or oval, from 0.3-1.0 µm in
diameter, and situated as membrane-bound bodies (initial
bodies) near the erythrocyte margin (A. marginale and A. ovis)
or in the center of the cell (A. centrale). A. centrale rarely
causes disease in cattle (Fig. 2-8).
Anaplasma marginale is transmitted biologically by ixodid
ticks such as Dermacentor and Rhipicephalus, referring to
development of the bacterium in the tick. A. marginale is
transmitted mechanically by bloodsucking flies of the genera
Tabanus and Stomoxys, several mosquito species, and blood-
contaminated hypodermic needles and instruments used for
dehorning, castration, and ear tagging. There is geographic
variation in the type of vector that transmits A. marginale, and
some strains are neither infective for, nor transmitted by, ticks.
Anaplasmosis has worldwide distribution and poses a major
constraint on cattle production. In North America, bovine
anaplasmosis is enzootic throughout the southern, western,
and midwestern United States, and sporadic outbreaks occur
in most other states and in several Canadian provinces. Non-
domestic ruminants in contact with domestic cattle may
provide a source of infected ticks.
Naive cattle become ill ~20-40 days after infection, and
within 5-10 days thereafter, organisms are detectable on blood
smears. The numbers of organisms increase rapidly during the
acute phase, and greater than 70% of erythrocytes may be
parasitized. Infected cells are removed by the monocyte-
macrophage system, resulting in mild to marked anemia and
jaundice. Intravascular hemolysis is minimal, and therefore
animals have neither hemoglobinemia nor hemoglobinuria.
 116.e1

Further reading
Issel CJ, et al. A perspective on equine infectious anemia with an
emphasis on vector transmission and genetic analysis. Vet Microbiol
1998;17:251-286.
Payne SL, Fuller FJ. Virulence determinants of equine infectious anemia
virus. Curr HIV Res 2010;8:66-72.
 Bone Marrow
However, marked bilirubinemia results in bilirubinuria, which
gives an intense yellow-brown color to urine. Hemoglobin
concentration may be as low as 30-40 g/L, and hematocrit
0.10-0.15 L/L, and there typically is a leukocytosis because of
neutrophilia. About 1 week after onset of parasitemia, eryth-
rocyte regeneration appears on blood smears. Clinical illness
consists of fever, weight loss, reduced milk production, abor-
tion, lethargy, and death, in particular in animals older than 2
years. Mortality rates of 50-60% are observed in naive adult
animals first infected with A. marginale, although this varies
by bacterial strain, geographic region, and nutritional status of
cattle. High-producing dairy cows appear most susceptible to
severe illness and high mortality from acute anaplasmosis.
Animals resist movement, have a rapid heart rate and increased
respiratory rate, and may have incoordination. Cattle that
survive become persistently immune carriers with cyclical
low-level parasitemia and do not develop clinical illness upon
reinfection.
Anaplasmosis, distinct from babesiosis, does not cause
intravascular erythrocyte lysis, and therefore no hemoglobin-
uria. Recycling of iron and globins by splenic and hepatic
macrophages is considered to be the main reason for more
effective erythrocyte regeneration in anaplasmosis relative to
babesiosis, in which hemoglobin is lost externally via the
urinary system. Erythrocytes are the only target cell of A.
marginale, and are frequently sphered in acute disease, likely
because of removal of parasitized erythrocyte membrane com-
ponents by splenic macrophages. Identifying organisms on
blood smears is a useful diagnostic test in acute infection, but
in chronically infected carrier animals, very few erythrocytes
contain organisms, and other tests such as ELISA or PCR must
be applied.
There are no pathognomonic gross lesions of anaplasmosis.
There is pallor of all tissues and mild to marked icterus, with
relatively good body condition in those animals dying acutely,
and cachexia in chronic cases. The lungs are pale and discol-
ored and may have bullous emphysema if there has been
severe terminal dyspnea. There are frequently ecchymotic
hemorrhages on the epicardium, and the heart is flabby and
dilated. The liver is pale and icteric, and the gallbladder is
usually distended. The spleen is enlarged, turgid, and con-
gested in acute cases, and firm, dark red, and fleshy in chronic
ones. The enteric tract is unremarkable, and the bladder may
contain deeply bilirubin-stained urine. The marrow hemato-
poietic space is variably expanded, depending on the stage
of the disease, and there may be serous atrophy with
chronicity.
Anaplasma centrale produces a natural infection of cattle,
but is also used, being a mild pathogen, as an immunizing
agent against A. marginale in some areas of endemic infection.
A. centrale infection usually produces a mild disease, although
sometimes it can be severe, with fever and anemia but no
icterus. Immunity to A. centrale does not protect against infec-
tion by all strains of A. marginale, and coinfections have been
reported. A. centrale also causes a persistent infection.
Anaplasmosis in sheep and goats is caused by A. ovis. A.
ovis is highly prevalent in sheep in many Eurasian and south-
ern European countries, but rarely associated with overt clini-
cal disease unless animals have concurrent other infections,
debilitation, or poor nutrition. However, infection of goats
more often results in anemia and clinical disease, and there
are reports of infection of humans in Cyprus with an Ana-
plasma organism genetically similar to A. ovis via tick bite.
117
Although cattle are not susceptible to A. ovis, sheep and goats
develop a latent infection if inoculated with A. marginale. The
economic impact of widespread ovine anaplasmosis on sheep
production has not been fully determined.
Further reading
Kocan KM, et al. The natural history of Anaplasma marginale. Vet
Parasitol 2010;167:95-107.
Renneker S, et al. Can Anaplasma ovis in small ruminants be neglected
any longer? Transbound Emerg Dis 2013;60(Suppl. 2):105-112.
Babesiosis.  The apicomplexan protozoan Babesia parasit-
izes erythrocytes of a wide range of mammals, including humans.
Similar to Anaplasma, Babesia infects and replicates exclu-
sively in erythrocytes. The number of Babesia spp. recognized
has increased dramatically over the past decade, given applica-
tion of molecular tools, and morphologically similar organisms
may be genetically distinct. Classification of Babesia is not
reviewed here, but rather the pathogenesis and pathology of
natural infections. Babesia has high host specificity, and is
transmitted by ticks. During the tick bite, sporozoites are
injected with tick saliva into the host and directly infect eryth-
rocytes. Sporozoites in erythrocytes divide asexually into 2 or
4 pear-shaped merozoites (“piroplasm”) that are then capable
of infecting new erythrocytes (Fig. 2-9). Some merozoites
develop into extracellular gametocytes, which if ingested by
ticks replicate in their gut. Some Babesia spp. have transovarial
transmission in the tick, implying potentially prolonged sur-
vival in ticks without feeding on vertebrate hosts. Transmission
by biting insects or contaminated instruments appears to be
less common than for Anaplasma, which may be because
of preferential location of erythrocytes in capillaries rather
than veins.
The severity of the disease produced in the mammalian
host depends more on the strain and species of infecting
Babesia than on the number of organisms inoculated. Patho-
genic effects are, in most infections, related directly to lysis of
red cells by emerging parasites, but other mechanisms, including
sludging of infected red cells, hemoglobinuric nephrosis, and
release of vasoactive peptides, contribute to the signs and are
Figure 2-9  Blood smear from a cow with Babesia bigemina
infection.
 117.e1

Further reading
Stuen S, Longbottom D. Treatment and control of chlamydial and
rickettsial infections in sheep and goats. Vet Clin North Am Food
Anim Pract 2011;27:213-233.
118 CHAPTER 2  •  Hematopoietic System
responsible for death. The severity of anemia and illness is
enhanced by splenectomy, which is used commonly in patho-
genetic studies. Splenectomy is a risk factor for human babe-
siosis, and likely also for some veterinary infections. B. bovis
merozoites are smaller than those of B. bigemina.
“Tick fever” in cattle is caused by one or several of A.
marginale, B. bovis, and B. bigemina. Babesia bovis causes the
most severe disease. Bos indicus cattle breeds are relatively more
resistant to the effects of this parasite than Bos taurus, which
has led to the suggestion that the organism evolved in these
breeds. Young cattle have pronounced resistance to severe
infection. Colostral antibodies transiently protect young
calves, and infection of young animals induces long-term
immunity. Hence, in endemic areas, there often is a high level
of herd immunity, and outbreaks result from interruption in
exposure to ticks or introduction of naive animals. For these
reasons, the disease is mostly seen in adult cattle recently
introduced from tick-free areas, or in areas of greatly fluctuat-
ing tick populations.
Infection by B. bovis causes severe febrile illness, which
begins ~2 weeks after exposure to ticks. The animal may
become extremely ill before severe anemia, parasitemia, or
hemoglobinuria are apparent, and sometimes the clinical
picture is dominated by neurologic signs such as seizures,
hyperesthesia, and paralysis, likely associated with the ten-
dency for parasitized red cells to sludge in cerebral capillaries.
Animals progress to weakness, fever, hemoglobinuria, and
anemia; the latter is more severe in animals surviving more
than a week. Causes of death are shock and respiratory dis-
tress. The parasite is never numerous in circulating erythro-
cytes, rarely being seen in >5% of circulating erythrocytes.
Parasitized erythrocytes are more likely to be found in smears
of blood prepared from cut skin capillaries than in routine
blood samples from large veins. Recovery is usually fairly
rapid in animals that survive the acute phase, although chronic
ill thrift has been described. Photosensitization may occur
in the convalescent phase, probably as a result of reduced
excretion of phylloerythrin in animals with severe
hyperbilirubinemia.
The most typical postmortem findings are those to be expected
of an acute intravascular hemolytic crisis. There is anemia, vari-
ably severe jaundice and hemoglobinuria, and the kidneys are
deep red-brown throughout as a result of hemoglobin staining
and intense congestion of capillaries. There is capillary conges-
tion of most organs; the spleen is grossly swollen, soft, and
dark; and the liver is acutely congested and may be heavily
stained with bile pigment. The gallbladder is distended with
thick, dark, viscous bile.
In some acute cases, the lungs are congested and edema-
tous, and the larger airways contain stable foam. Recent hem-
orrhages are common in the thoracic serosal membranes. The
most characteristic macroscopic feature of B. bovis infections is
striking, uniform congestion of the gray matter throughout the
brain, imparting to it a dramatic, deep pink color (the cerebral
flush), which contrasts strongly with the white matter; the
latter is often stained faint yellow by unconjugated bilirubin.
In some peracute cases, there is minimal hemoglobinuria or
jaundice, but the brain still has characteristic capillary conges-
tion, and imprint preparations yield many intraerythrocytic
organisms.
Histologically, there is thickening and congestion of pulmo-
nary capillaries with hemosiderin in intravascular macro-
phages. Kidneys and liver have the histologic lesions to be
Bone Marrow
expected of an acute hemolytic disease. There is variably
severe hemoglobinuric nephrosis with severe congestion, focal
hemorrhage and hemosiderin in tubular epithelium, and
diffuse vacuolar degeneration with interstitial mixed mono-
nuclear cell reaction. There is hepatic periacinar congestion
with uninfected red cells, and vacuolar degeneration in
midzone and periacinar hepatocytes, accompanied by cana-
licular cholestasis. There is hemosiderin accumulation in both
hepatocytes and Kupffer cells, and the latter contain both
infected and noninfected red cells. Lymphocytes and plasma
cells accumulate in portal areas and around central veins.
Parasitized erythrocytes may be seen in vessels in all tissues, but
they are particularly common in interstitial capillaries in the
kidney, in the gray matter of the brain, in the heart, and espe-
cially in skeletal muscle; in these locations, nearly every eryth-
rocyte packed into the distended capillaries appears to contain
1-2 parasites. The organisms are faint blue in routine sections,
and are best demonstrated in imprint preparations of fresh tissue.
In sections, Giemsa stain demonstrates them as small paired
or single spherical bodies with denser staining at one pole. In
well-fixed fresh brain of acute cases, there may be edema of
the neuropil around the clogged capillaries.
Animals that die with peracute disease have necrosis of
lymphocytes in germinal centers of node and spleen, although
there may be some degree of recovery in animals surviving a
week, and general depletion of lymphocytes in those dying
after protracted illness. Characteristic changes in the medul-
lary region of nodes include sinus histiocytosis with extensive
erythrophagocytosis. The histology of the spleen is often
unhelpful, the organ being so suffused with intracorpuscular
and extracorpuscular hemoglobin that evidence of erythro-
phagocytosis is obscured. There is little extramedullary hema-
topoiesis in liver or spleen. The bone marrow has hyperplasia
of immature rubricytes and, in animals that survive the acute
stage, there is strong reticulocytosis and slow recovery of
anemia. There is increased hemosiderin in bone marrow, sug-
gesting that marrow is also a site of erythrolysis.
Babesiosis results in metabolic disease more complex than a
simple syndrome of intravascular hemolysis. Severely affected
animals may die before significant anemia has set in, and in
these cattle, the intense visceral congestion and pulmonary
edema suggest that death may be at least partly the result of
circulatory shock. This has been supported by studies that
have shown that the parasite is the source of proteases that
activate plasma kallikrein, which, as well as being a hypoten-
sive agent, may activate bradykinin, another potent vasodila-
tory agent. Rather unexpectedly, metabolic alkalosis occurs in
B. bovis infections, whereas acidosis is the rule in severe B.
canis infections. The result of these profound metabolic upsets is
a syndrome of circulatory failure, likely because of extensive
plugging of microvasculature by sequestered red cells. The
apparent anemia is therefore caused in considerable measure
by the vasodilatory effects of kallikrein and shift of red cells
away from large veins. Although plasmin activation occurs, the
effects on the coagulation system are unlikely to be a signifi-
cant factor in the pathogenesis because hemorrhage is not a
major part of the morbid picture.
The actual mechanism of penetration of red cells by the mero-
zoites of Babesia is unclear. Parasites remodel the erythrocyte
surface with their variable erythrocyte surface antigen (vesa)
proteins, which changes the membrane mechanical and adhe-
sive properties. The organism causes complement activation
by the alternative pathway, and by C3b achieves adherence
 Bone Marrow
and later invasion. The mechanism of hemolysis is also obscure.
Immune mechanisms do not appear to play a significant role
in the early stages of the disease, but they may be a factor in
delayed recovery. Osmotic fragility is markedly increased in
nonparasitized cells. Generation of intravascular fibrin may
contribute to capillary erythrocyte sludging.
Babesia bigemina infection may be transmitted by the
same tick as B. bovis, and both parasites may cause losses in
the same geographic area. B. bigemina, however, usually causes
much less severe illness, although parasitized erythrocytes cir-
culate early, sometimes before clinical signs are apparent, and
in much greater numbers than in B. bovis infection. B. bigemina
also causes erythrocyte destruction, but this appears to be
directly proportional to the level of parasitemia, unlike B. bovis
infection. There are few of the vasoactive and erythrocyte
adherence effects, thus profound shock-like signs are usually
absent. Anemia in severe cases may be marked before the
animal becomes ill and, as in any case of severe anemia, death
may occur suddenly as a result of myocardial failure. Fever is
not usually as severe as in B. bovis infection.
The pathology of B. bigemina and B. bovis infections is
similar, except that in B. bigemina infection there is little capil-
lary congestion of the viscera and none of the cerebral gray
matter impact, the presence or absence of the cerebral flush being
the most reliable gross feature for differentiating the 2 infections.
Pulmonary edema may be more often seen in fatal cases of B.
bigemina infections, probably because the greater severity of
anemia causes terminal left ventricular failure.
Babesia divergens and B. major are more or less restricted
to northern and western Europe and Asiatic Russia and, for
the most part, are of relatively minor importance to the cattle
industries there, although significant outbreaks of disease and
death may occur. Although B. divergens is small and resembles
B. bovis in size, and B. major is as large as B. bigemina, the
pathology and pathogenesis of the disease produced by these
organisms is apparently very similar to that produced by B.
bigemina. Thus there is intravascular hemolysis with little or
no capillary agglutination of erythrocytes, and death results
primarily from severe anemia. Spontaneous splenic rupture has
been reported in B. major infections, a complication rarely, if
ever, reported in other bovine babesial infections.
Differential diagnosis of bovine babesial infections in coun-
tries where more than one species of Babesia is present is impor-
tant and at times difficult, and may be complicated by dual
infections and by the additional possibility of Anaplasma
infection. B. bovis and B. bigemina may be distinguished from
one another in well-prepared blood smears, but erythrocytes
parasitized by B. bovis are rare in jugular blood, or even in
blood from deep skin punctures. They are best demonstrated
in smears of blood expressed from a superficial skin scrape;
this is most conveniently obtained from the tail-tip in the live
animal. B. bigemina–containing erythrocytes, on the other
hand, are quite numerous in circulating blood while clinical
signs are severe. The morphology of the parasites will usually
be insufficiently preserved in postmortem material to allow
distinction, but the preference of B. bovis for capillaries of
organs such as kidney, heart, and brain will, in most cases, serve
to distinguish the infections. It must be remembered that
Sarcocystis spp. may be present in smears of myocardial blood.
Serologic tests are available for antemortem diagnosis, and PCR
tests for postmortem samples. It is necessary to demonstrate
a very heavy parasite burden in cerebral capillaries if brain
smears are to be relied on as evidence of active B. bovis
119
infection, as most clinically normal carriers of this organism
have some parasitized erythrocytes in this site.
In the last 2 decades, it has been recognized that canine
babesiosis is caused by different organisms transmitted by spe-
cific vectors and has highly variable pathogenesis. Large babe-
sial organisms in dogs include B. canis, B. rossi, B. vogeli, and an
as yet unnamed Babesia in North America. B. canis occurs
mostly in southern and central Europe, is transmitted by Der-
macentor reticulatus and causes disease of variable severity
consisting of fever, hemolytic anemia, and jaundice in adult
dogs, and less severe disease in young dogs. B. rossi is restricted
to sub-Saharan Africa, is transmitted by Haemaphysalis ellip-
tica, and causes severe peracute and acute illness with 10-20%
mortality. Clinical disease results from severe hemolytic
anemia, acid-base derangement, hypoxia, and a systemic
inflammatory response. Death is attributed to multiple organ
failure as manifested by hepatopathy and hypoglycemia, acute
kidney failure, cerebral ischemia, and respiratory distress. Con-
trary to most babesial infections, B. rossi affects young dogs as
severely as adult dogs. B. vogeli occurs in tropical and sub-
tropical regions of most continents, including North America,
and is transmitted by the brown dog tick Rhipicephalus san-
guineus. Disease associated with B. vogeli infection is less
severe than that of other large babesial organisms in dogs, and
may be subclinical in immunocompetent animals. However,
young dogs are also more likely to be clinically ill with hemo-
lytic anemia and thrombocytopenia. The unnamed large
babesial organisms in dogs were identified in splenectomized
or immunosuppressed animals in North America and Britain,
and were also associated with severe anemia and thrombocy-
topenia. Large babesial organisms in dogs are morphologically
indistinguishable.
Small Babesia of dogs were until recently thought to all
be B. gibsoni, but are now recognized to belong to at least 5
different taxa: B. gibsoni (sensu stricto), B. conradae, a B.
microti–like organism, Theileria annae, and an unnamed Thei-
leria spp. The number of organisms in erythrocytes is often
high, but disease associated with small babesial organisms in
dogs is usually mild. Anemia results mostly from extravascular
erythrocyte removal and not intravascular hemolysis.
In dogs with pathogenic babesiosis at postmortem, there
is staining of tissues with both bilirubin and hemoglobin.
The kidneys are dark brown, and there is splenomegaly and
copious thick bile in the gallbladder. In addition, there is evi-
dence of vascular injury in the form of hemorrhages and
edema, which may be severe in the lung (eFig. 2-1). Parasit-
ized erythrocytes may be found plugging capillaries in smears
and sections of cerebral cortex, reminiscent of B. bovis infec-
tion, but the phenomenon is never as severe as in that disease.
Disseminated intravascular coagulation is a consistent occur-
rence in severe B. rossi and B. canis infection, and is presum-
ably related to, and is likely to aggravate, the hemolysis and
the vascular damage. Microthrombi can be demonstrated in
many tissues.
Piroplasmosis in horses is caused by Theileria equi and
Babesia caballi. T. equi was previously classified as B. equi, but
is molecularly distinct from other Babesia spp. and was reclas-
sified. Also, during initial infection, T. equi sporozoites invade
lymphocytes, monocytes, and macrophages, and develop
schizonts and then merozoites in those cells. Merozoites are
released to invade erythrocytes. This property is more like
other Theileria spp. than Babesia spp. Infection with either
organism is widespread, and their distinct ixodid ticks are also
 119.e1

B
eFigure 2-1  Babesiosis in a dog. A. Babesia canis can be detected
as single or paired, piriform organisms within erythrocytes in a
vessel within the stomach. B. Centrilobular congestion and hepa-
tocellular degeneration and extramedullary hematopoiesis. (Cour-
tesy E.P. Lane.)
120 CHAPTER 2  •  Hematopoietic System Bone Marrow

widely distributed. North America is generally considered free
of equine piroplasmosis, although sporadic outbreaks have
occurred in Florida and Texas. T. equi infection is considered
to be more widespread and causes more severe disease. Clini-
cal disease in acute infection with either organism is similar,
and consists of fever, lethargy, petechiation, ventral and peri-
orbital edema, thrombocytopenia, jaundice, hemoglobinuria,
splenomegaly, and intravascular hemolysis leading to anemia.
T. equi are small piroplasms, and 1-5% of erythrocytes may
contain organisms during acute infection, whereas B. caballi
are large piroplasms, and <1% of erythrocytes are infected.
Mortality is low in immunocompetent horses, but experimen-
tal infection of foals with severe combined immunodeficiency
results invariably in fulminant infection and death. Following
acute infection, most horses become persistently infected
clinically inapparent carriers resistant to illness from subse-
quent exposure. Such horses constitute a source of infection
for naive animals. It has been suggested that some horses clear
B. caballi infection over time without treatment. Immunity to
one organism does not cross-protect against infection by the
other piroplasm.
Babesial infection of cats is uncommon worldwide except
in southern Africa. The small B. felis piroplasm causing infec-
tion in those areas induces severe hemolytic anemia. Several
other small and large piroplasms have been reported in domes-
tic and nondomestic cats, but neither disease association nor
classification is well established.
Babesial infections of other species are for the most part
mild or clinically inapparent. The course of these diseases in
general follows the pattern described for B. bigemina infection,
in that there is quite severe parasitemia, anemia caused by
intravascular hemolysis, with hemoglobinuria in acute cases.
At autopsy, there is splenomegaly and variably severe jaundice
and, in some cases (notably B. trautmanni infection in pigs),
edema, and petechiae. An organism resembling B. divergens
may infect white-tailed deer, and mice are susceptible to
numerous Babesia organisms.
the tick vector, in addition to clades of distinct Theileria and
Cytauxzoon organisms.
Cytauxzoon felis is naturally transmitted by ixodid ticks,
and can be transmitted experimentally by fresh and cryopre-
served blood or tissue homogenates from infected animals.
Infection of domestic cats results in acute febrile illness and
death in ~19-21 days. Clinically ill cats have fever, depression,
pallor, icterus, dark urine, and occasionally dyspnea. Hematol-
ogy is characterized by nonregenerative anemia and frequently
neutropenia and thrombocytopenia. Lack of erythrocyte regen-
eration and neutropenia distinguish C. felis from hemotropic
Mycoplasma infection. Babesia felis piroplasms are indistin-
guishable from C. felis, but infection with the former is not
usually characterized by leukopenia (Fig. 2-10). Cytauxzoon
organisms in erythrocytes are variable in shape, but most
common are signet ring forms with a thickened nuclear area
at one point of the ring. The level of parasitemia is low, with
piroplasms in 1-4% of peripheral blood erythrocytes, but in
terminal stages of illness; infected macrophages may be in
blood samples from larger veins and therefore on blood films.
Macrophages containing schizonts can be readily identified in
imprints from virtually any organ at postmortem, in particular
lung and spleen. In the early hemolytic stages of the disease,
the urine is highly concentrated, acidic with high levels of

Further reading
Gohil S, et al. Bovine babesiosis in the 21st century: advances in
biology and functional genomics. Int J Parasitol 2013;43:
125-132. A
Penzhorn BL. Why is Southern African canine babesiosis so virulent?
An evolutionary perspective. Parasit Vectors 2011;4:51.
Schnittger L, et al. Babesia: a world emerging. Infect Genet Evol
2012;12:1788-1809.
Wise LN, et al. Equine piroplasmosis. Vet Clin North Am Equine Pract
2014;30:677-693.

Cytauxzoonosis.  Cytauxzoonosis is caused by a protozoal

piroplasm with an erythrocytic and tissue macrophage stage.
Cytauxzoon spp. infect wild ungulate species in Africa, includ-
ing the kudu, eland, and giraffe, as well as domestic and wild
felids in North America. Babesia, Theileria, and Cytauxzoon
are closely related non–pigment-forming piroplasms that
infect erythrocytes. Theileria also forms schizonts in lympho-
cytes, and Cytauxzoon forms schizonts in intravascular and B
subendothelial macrophages. These life-cycle features corre-
spond to recent molecular taxonomic characterization, which Figure 2-10  Acute cytauxzoonosis in a cat with numerous mero-
suggests that there are multiple clades of different Babesia, in zoites in erythrocytes (A), and a giant schizont in bone marrow
part characterized by presence or absence of development in (B). (Courtesy J. Tarigo.)
 120.e1

Further reading
Johnsson NN, et al. Productivity and health effects of anaplasmosis and
babesiosis on Bos indicus cattle and their crosses, and the effects
of differing intensity of tick control in Australia. Vet Parasitol
2008;155:1-9.
Short MA, et al. Outbreak of equine piroplasmosis in Florida. J Am Vet
Med Assoc 2012;240:588-595.
 Bone Marrow
protein and large amounts of bile and blood, including intact
red cells and bilirubin crystals. Consistent with a rapidly fatal
course of disease, animals at postmortem are generally in good
body condition with adequate adipose tissue. There is exten-
sive vascular obstruction from schizont-containing macro-
phages, leading to congested edematous lungs, reddened
lymph nodes, petechial and ecchymotic hemorrhages, and
pleural, pericardial, and peritoneal effusion.
North American bobcats are considered to be a reservoir
of C. felis, and generally do not become ill after experimental
tick infection. Inoculation of cats with blood from parasitemic
bobcats induces parasitemia in cats, but not severe illness. This
is thought to be because transferred piroplasms are unable to
undergo schizogony in recipient cats without a developmental
stage in ticks. Other nondomestic cats also harbor C. felis
without apparent clinical illness.
The host-pathogen relationship between C. felis and
domestic cats appears to evolve. Recently, infection in domes-
tic cats has been identified over an expanded range of the
southern and midwestern United States, and domestic cats
have been recognized as parasitemic over several years but
healthy. Anecdotally, cats that have survived C. felis infection
may be resistant to subsequent challenge, and immunosup-
pressive treatment may increase parasitemia. These findings
suggest that a more benign host-pathogen relationship of C.
felis and domestic cats may be emerging.
Further reading
Meinkoth JH, Kocan AA. Feline cytauxzoonosis. Vet Clin North Am
Small Anim Pract 2005;35:89-101.
Rizzi TE, et al. Prevalence of Cytauxzoon felis infection in healthy cats
from enzootic areas in Arkansas, Missouri, and Oklahoma. Parasit
Vectors 2015;8:13.
Trypanosomiasis.  Trypanosomes are insect-transmitted
protozoa, uniform in type but varying in morphologic details.
Some species are morphologically stable, whereas others are
polymorphic, and the differentiation of species by morphol-
ogy is challenging (Fig. 2-11).
Figure 2-11  Trypanosoma vivax trypomastigote in blood smear
from a cow.
121
The trypanosomes important to human and animal health
are transmitted by insects that carry the metacyclic stages in
either their oral or anal tracts. Thus, Trypanosoma cruzi, the
cause of Chagas disease in humans and animals in South
America, is known as a stercorarian parasite because it is
spread by passage in the feces of the reduviid insects (Triato-
minae subfamily); after the insects bite (often around the
mouth or eye), they defecate, and the trypanosomes gain entry
to the host through the bite wound, often assisted by the host
scratching. The important African trypanosomes of animals
(T. congolense, T. vivax, T. brucei brucei) and of humans
(T. brucei rhodesiense and T. brucei gambiense) are called sali-
varian parasites because of their transmission through the
salivary glands of the tsetse fly. Other biting and sucking
insects, such as tabanids, stable flies or fleas, and vampire bats
may transmit trypanosomes mechanically. Infection of the
definitive host, the tsetse fly, is probably lifelong.
Trypanosoma equiperdum, the cause of dourine, does not
require a vector host but is transmissible by direct contact
with mucous membranes. It is described in Vol. 3, Female
genital system.
Not all species of Trypanosoma of mammals are pathogenic,
and among the common nonpathogenic species of veterinary
interest are T. melophagium, ubiquitous in sheep and trans-
mitted by the ked, Melophagus ovinus; T. theileri, which is
widespread in cattle and transmitted by several types of biting
flies, including Tabanidae; T. theodori, which occurs in goats
in the Middle East, transmitted by the hippoboscid fly, Lipo-
ptena caprina, and probably synonymous with T. melophagium;
and T. lewisi of rats, which is of much interest as a convenient
subject for research on the genus. T. rangeli of South Ameri-
can cats, dogs and humans is also apparently nonpathogenic
to the vertebrate hosts but differs from the above in that it
can be transmitted by inoculation or contamination, the
vector being the triatomine Rhodnius prolixus. The species of
trypanosomes listed above, although widespread in their hosts,
are ordinarily sparse in blood and seldom observed unless
specifically looked for in thick smears, after splenectomy, or
by culture. Occasionally, however, T. melophagium and T. thei-
leri are found in very large numbers in the blood of cattle and
sheep suffering from a primary and usually an immunosup-
pressive disease. It is not clear whether T. theileri may become
pathogenic in the compromised host; however, its increase in
number in association with other diseases suggests that it may
be of secondary importance.
In endemic areas, the incidence of infection by pathogenic
species varies depending on such factors as the availability of
mammalian reservoirs, the density of vector tsetse flies, and
the systems of husbandry adopted, but, as a rule, domestic
animals and trypanosomes cannot coexist. Trypanosomiasis pro-
hibits domestication of livestock in perhaps 1 4 of the total land
surface of Africa. Knowledge of host-parasite relationships is
not fully understood, neither for the vector nor the mamma-
lian hosts. Within a species of the organism, local strains may
be distinct in their basic and predominant antigens, but within
the host in the course of chronic infections, a series of geneti-
cally regulated antigenic variants appears in succession so that
the animal exhausts itself without clearing the infection. Suc-
cessive waves of parasite and antibody dominance account for
the characteristic recrudescences of the infection and for the
known difficulty in producing an effective vaccine.
The pathogenic trypanosomes differ widely in virulence and
are apparently nonpathogenic in mammalian reservoir hosts.
122 CHAPTER 2  •  Hematopoietic System
Most of them are parasites of a variety of domestic and wild
animals, in some of which they produce fulminating disease,
in some chronic disease, and in others mild or unapparent
infections. Strains within a species of the parasite also differ
greatly in virulence, some strains producing rapidly fatal infec-
tions, some producing chronic infections with premunition,
and some allowing complete recovery and acquired immunity.
Much of the knowledge of trypanosomiasis has been gained
by studies of T. brucei, which conveniently infects dogs, rabbits,
rats, and mice, and poses little problem of dissemination in
developed countries, where it has served as a research model.
In terms of the overall problem, T. brucei is not nearly as
important as T. vivax and T. congolense and the pathogenic
trypanosomes of humans. Of the latter organisms, only T.
congolense is studied with any frequency outside their natural
habitats because the other trypanosomes are thought to con-
stitute too great a hazard of dissemination, even under condi-
tions of laboratory restraint. Most of the research on T. vivax
and T. congolense has been directed at defining the disease in
British breeds of cattle. Efforts are now being made to under-
stand the host-parasite relationship in indigenous species of
animals, such as the Thomson’s gazelle, wildebeest, Cape
buffalo, and eland, which are heavily exposed and apparently
carry the organisms, but rarely, if ever, have clinical disease.
The components of pathogenicity of trypanosomes are largely
unknown. Their effects vary with their tissue tropism. The
edema and interstitial reactions caused by T. brucei are the
result of the fact that this parasite resides in perivascular
tissues, in contrast to the more serious pathogens of humans
and animals, which are obligate intravascular parasites. In
many respects, bovine trypanosomiasis is similar clinically and
pathogenetically to equine infectious anemia in that infection
is followed by an asymptomatic period until antibody devel-
ops. There is then anemia and generalized compensatory
hyperplasia of the mononuclear phagocyte system, which ulti-
mately results in cachexia and hematopoietic and lymphoid
exhaustion.
Bovine trypanosomiasis.  In cattle, parasitemia occurs a
week after inoculation with 105 or more organisms that have
been passed in rats and column separated (see Fig. 2-11). By
the second week of infection, there is a sharp drop in the red
cell count and hemoglobin levels, accompanied by an ery-
throid shift and macrocytosis, anemia being the predominant
aspect of the disease. There is concurrent thrombocytopenia of
moderate degree and hypocomplementemia. Fibrinogen is
reduced to about half of normal levels, and there is irregular
appearance of fibrin degradation products as animals go
through febrile periods. Kinetically, the erythrocyte life-span
is reduced to a half or less of normal, and iron utilization is
initially rapidly increased, but slows down with cachexia and
inhibition of the erythroid response because of inflammatory
changes. The platelet life-span is not shortened in infections
with T. congolense, although it may be with T. vivax. In the
former, the truncation appears to result from proliferation of
marrow megakaryocytes that are impaired in their maturation
and produce fewer platelets that survive normally, thus con-
stituting an ineffective response. The disease tends to stabilize
at ~4-6 weeks in well-fed animals under laboratory conditions,
and to proceed to death from secondary causes in animals that
are forced to forage for feed as well as maintain their immune
defenses.
Red cells are destroyed by erythrophagocytosis as a result
of adsorbing toxic and metabolic products of the trypano-
Bone Marrow
somes, and as a product of direct injury from parasite-derived
neuraminidases, such as trans-sialidases. There may be competi-
tion among precursor cells for erythroid and granulocytic differ-
entiation, which may explain the clinical finding that animals
with severe anemia are more susceptible to secondary infection
by bacteria and viruses. A dilutional component to the anemia
has been suggested, but no increase in blood volume has been
detected. Calves infected during the first week of life have less
severe hematologic disease than calves infected at 6 months
or older. Some of these animals become cachectic and die,
although it appears that infection at an early age results in a
more tolerant host-parasite relationship that is less injurious
to the host. T. vivax and T. congolense differ in that T. vivax
tends to circulate relatively freely and uniformly in the vascu-
lar system, and, in this respect, the level of parasitemia gives
a reasonable estimate of the total parasitic burden. In contrast,
T. congolense “homes” to the microvasculature of the brain and
skeletal muscle, and the paucity of organisms in the peripheral
blood makes diagnosis and estimates of total burden difficult.
It appears that the tissue tropism of T. congolense is a response
to developing immunity and is antibody mediated. It is not
known why brain and muscle are selectively parasitized, but
the phenomenon may be related to trypanosomal energy
requirements, because the endothelial cells in these areas tend
to have more mitochondria than in other tissues.
Trypanosoma vivax is more virulent than T. congolense.
Whereas both cause anemia and cachexia, infection with T.
congolense regularly results in chronic disease, and in a high
percentage of animals infected with T. vivax, there is sudden
death from salmonellosis or other infections. Infected animals
are moderately stunted in growth, although this effect is less
apparent on body weight than on dressed weight (the part of
the carcass that is edible). This disparity is the result of the
fact that infected animals pool fluid in the intestinal tract and
become pot-bellied while failing to deposit muscle and fat.
When viewed from behind, infected animals have poorly
covered bony prominences, poor “spring of rib,” and a deep
and pendulous abdomen. The skin is scurfy and rough, par-
ticularly about the head, ears, and hindquarters. There is
chronic low-grade pyrexia with intermittent temperature
increases, and periodic watery diarrhea with passage of poorly
digested ingesta of normal color. There is irregular oculonasal
discharge, but no loss of appetite, and the animals continue to
eat. There is mild mucosal pallor without petechial hemor-
rhages, and the urine may be dark but never blood tinged. The
heart and respiratory rates are not remarkably altered under
laboratory conditions but are increased in nonspecific response
to anemia under field conditions, and animals may show open-
mouth breathing on forced exercise. In the absence of second-
ary infection, there is little or no depression or abnormal
behavior despite high levels of cerebral parasitism.
Anemia is of moderate degree, with hemoglobin generally
between 50 and 80 g/L, is initially macrocytic and normo-
chromic, and later becomes normochromic, normocytic, and
poorly responsive. In the well-developed disease, there are
always some hypochromic red cells and at least mild poikilo-
cytosis. In the early stages of infection, the radio-iron uptake
time is reduced from a normal of ~3 hours to about half that
figure but in chronic disease is only mildly reduced. There is
increased osmotic fragility of red cells without spherocytosis.
The platelets are 100-200 × 109/L and are often lower during
intercurrent infection. The leukocyte count is reduced to
about half of normal (5-6 × 109/L) as a result of an absolute
 Bone Marrow
reduction in both neutrophils and lymphocytes. Changes are
less severe in neonatally infected animals. Biochemical changes
consist of a reduction in total protein, largely because of
reduced albumin, but there are no consistent changes in trans-
aminases or bilirubin. There is a consistent reduction in total
serum lipids, cholesterol, and triglyceride, and erythrocyte
phospholipid levels are consistently elevated, which may indi-
cate that there is an acquired injury to red cell membranes
that contributes to shortened life-span. Aspirated marrow is
hypercellular with an erythroid shift that drops the
granulocytic:erythrocytic ratio to 0.4 or lower in animals
infected with T. congolense. There is a less marked erythroid
response in T. vivax infection.
There are no pathognomonic gross lesions of trypanosomiasis.
Chronically affected animals are cachectic and have a rough
haircoat, and there is increased clear fluid in body cavities.
There is generalized lymph node enlargement to 2-4 times
normal, and the hemal nodes become prominent in subcuta-
neous areas and in association with the para-aortic and pelvic
nodes, where they may reach 1 cm in diameter or larger. The
lungs are heavy and have increased density on palpation, and
may show intercurrent cranioventral bronchopneumonia. The
heart is generally flabby, with serous atrophy of pericardial fat,
and there may be white foci 1-2 mm in diameter on the epi-
cardium and on the cut surface. The liver and kidneys are
symmetrically enlarged and constitute a greater than normal
percentage of body weight. The liver is unusually firm and not
easily penetrated by digital pressure, and there is a fine lobular
pattern visible through the capsule and on cut surface. Renal
medullary fat has serous atrophy. There are fine focal, raised,
reddened areas 1-2 mm in diameter throughout both layers
of the omentum. The enteric tract is unremarkable, except
that the small intestine is atonic and contains an excessive
amount of normal-appearing fluid content. The most remark-
able changes occur in lymph nodes, which have generalized
medullary pigmentation, and in bone marrow, where there is
a regular increase in hematopoietic areas, which may occupy
all of the cancellous and diaphyseal fatty areas in animals that
have been infected 6 months or more. The spleen is uniformly
enlarged and bulges, but does not ooze blood, on cut surface.
The Malpighian corpuscles are generally visible grossly.
Microscopically, there is a generalized increase in septal
width in the lungs and accumulation of intravascular
hemosiderin-bearing macrophages. There are multifocal areas
of fiber atrophy with sclerosis and lymphoplasmacytic prolif-
eration in the myocardium, most prominently in those animals
that have succumbed to the disease. The bone marrow goes
through a cycle of changes similar to those in equine infec-
tious anemia. There is early conversion of fatty to hematopoi-
etic marrow with high cell density, erythroid shift, and
plasmacytosis, followed by a reduction in cellular packing and
dilation of sinusoids, and ultimately by reduction in hemato-
poiesis and serous atrophy of the remaining tissue. The rubri-
cytes are increased in number and are relatively synchronous
in maturation with numerous mature cells, suggesting late
asynchrony associated with poor availability of iron. There is
a variable degree of hemosiderosis, depending on the duration
of the disease, and erythrophagocytosis may be observed in
the marrow. Marrow granulocyte reserves are reduced, and, as
a result, there is mild early asynchrony, although it is likely
that with the expanded volume of hematopoietic marrow
there is a normal volume of granulopoietic tissue. Megakaryo-
cytes are increased in number to about twice the normal
123
level, and the nuclei are increased in diameter, but the cyto-
plasmic volume is reduced, indicating ineffective thrombopoi-
esis. There is a mild generalized increase in endothelial and
true reticular cells in bone marrow, but myelofibrosis is not
severe. Trypanosomes may be found free and phagocytosed in
small vessels throughout the body, but are most commonly
observed in the liver and cerebral cortex. Hepatic changes
are constant, and consist of atrophy of hepatocellular cords
with sinusoidal dilation and periportal lymphoplasmacytic
proliferation. There is increased interstitial stroma, without
change in lobular organization, and generalized Kupffer cell
hyperplasia.
Changes in the lymphoid tissue are remarkable and constant
in all areas of the body. There is first follicular hyperplasia, with
a competent response and the formation of large and densely
cellular germinal centers. These changes are accompanied by
variable paracortical hyperplasia, and the paracortex has a
moth-eaten appearance because of the many large lympho-
blasts and tingible body macrophages. At this time, the lymph
nodes are physically enlarged, and there is thinning of the
capsules with focal colonization of perinodal fat and a histo-
logically compressed peripheral sinus. In chronic disease, the
nodes remain enlarged, but this is due, at least in part, to a
marked increase in capsular and intranodal stroma with
numerous collagenous septa extending from the medulla to
the capsule. The medullary follicles remain, but their cellular-
ity is reduced, and there is marked atrophy of paracortical
areas. Concurrently, there is sinus histiocytosis and at least
some degree of hemosiderosis without medullary cord hyper-
plasia. The changes are thus those of continuing stimulation with
an initial competent response followed by hyperplasia, then
atrophy and sclerosis.
Concurrent with the changes in lymph nodes, there is
remarkable atrophy of the thymus, with the reduction most
prominently affecting cortical regions. With the loss of cortical
volume, there is a reduction in cell density and an increase in
size of nuclei in cortical thymocytes. The splenic lymphoid
changes reflect those in other areas of the body, with atrophy
of periarteriolar cuffs and the formation of large hypocellular
follicles, occasionally with “target” ringing of mantle cell and
marginal zone layers. The number of follicles is not increased.
The most marked splenic change is sinus hyperplasia charac-
terized by a marked increase in fixed cells in the Billroth cord
(splenic cord, red pulp cord) areas, which contain within their
interstices many macrophages and plasma cells, with increased
hemosiderin and an irregular appearance of extramedullary
thrombopoiesis and erythropoiesis. Renal changes consist of a
moderate generalized increase in interstitial connective tissue
with mild epithelial atrophy and the appearance of large lym-
phoid cuffs around arterioles at the corticomedullary junction.
Glomeruli are regularly increased in diameter and in cellular-
ity and occasionally contain hemosiderin-laden macrophages.
There are focal adhesions between the visceral and parietal
layers of Bowman’s capsule, and a mild epithelioid appearance
to the central areas of the tuft. The nuclei of the juxtaglo-
merular cells are unusually prominent, and there is mild pig-
mentation by both iron and bilirubin in the proximal
epithelium. The overall changes in glomeruli are compatible
with membranoproliferative glomerulonephritis.
Subtle changes are consistently present in skeletal muscu-
lature and consist of an overall hypercellularity with a mild
reduction in fiber diameter and increased perivascular lym-
phocytes. The reddened foci in the omentum consist of focal
124 CHAPTER 2  •  Hematopoietic System
venous ectasia with mild interstitial sclerosis and perivascular
lymphoplasmacytic reaction.
Trypanosomiasis in other species.  Trypanosoma brucei
rhodesiense and T. b. gambiense are human pathogens causing
African sleeping sickness and are not important in domestic
animals, although T. gambiense has produced meningoenceph-
alitis in experimental goats and cats. These trypanosomes are
morphologically indistinguishable from each other and from
T. brucei, from which they are presumed to have evolved.
Trypanosoma brucei brucei is a cause of nagana in most
domestic species in Africa; humans are refractory to infec­
tion. Transmission is by Glossina spp. or mechanical. Equids,
small ruminants, camels, and dogs are very susceptible; the
disease is more chronic in cattle; and pigs may recover. Inco-
ordination and spinal paralysis are reported in horses and dogs.
Dogs may also develop parasitism and inflammation of the
anterior segments of the eye. The neurologic signs are undoubt-
edly the result of invasion of cerebrospinal fluid and to inflam-
mation of meninges, brain, and cord. Diagnosis depends on
demonstration of the organism in blood in acute or relapsing
febrile cases, or otherwise in lymph nodes by direct smear,
inoculation into the very susceptible laboratory mouse, or
cultivation.
Trypanosoma evansi was originally shown to be the cause
of surra in horses and camels, but it is pathogenic for most
domestic species and distributed in North Africa, Asia, and
Central and South America. Transmission is mechanical,
chiefly by Tabanidae, but also by other blood-sucking flies, and
apparently by vampire bats in the Americas. The disease in
horses and dogs is severe, and probably uniformly fatal in the
absence of adequate treatment. Cattle are mildly affected and
act as reservoirs, although acute disease may occur in suscep-
tible cattle introduced to endemic areas.
Trypanosoma equinum occurs in South America as the
cause of mal de caderas of horses, a disease that resembles
surra. The parasite is transmitted mechanically by tabanids. It
is probably a stable variant of T. evansi.
Trypanosoma suis is a West African species transmitted
by tsetse flies. It produces a nagana-like disease in pigs but is
apparently nonpathogenic for other domestic animals.
Trypanosoma simiae was originally isolated from African
monkeys. Although its pathogenicity for pigs is unpredictable,
it is ordinarily highly virulent and causes death in a few days.
Pathogenicity for other domestic species is insignificant. Trans-
mission is cyclical in tsetse flies. Trypanosomes of the species
T. congolense, T. dimorphon, T. vivax, and T. uniforme are causes
of nagana in Africa. Most domestic species are susceptible to
infection, although dogs are resistant to T. vivax. There is
considerable variation in the pathogenicity of different strains,
especially of T. congolense.
Trypanosoma cruzi is the cause of American trypanoso-
miasis (Chagas disease), which is an uncommon illness of
children, although infection of human adults and animals is
apparently common. The reservoir hosts are chiefly wild
species, but cats, dogs, and pigs can be infected and act as
reservoirs. Sheep and goats are susceptible to experimental
infections. This trypanosome is of zoologic interest because,
both in the tissues of the vertebrate host and in the alimentary
canal of the vector, it forms developmental phases resembling
the other genera Leptomonas, Crithidia, and Leishmania of the
family Trypanosomatidae.
Whereas some of the manifestations of T. cruzi infection
may be attributable to parasitemia with the trypanosomal
Bone Marrow
form, the disease is characterized by invasion of mesodermal
tissues, and the growth therein of the leishmanial forms of the
organism, which show a preference for cardiac and skeletal
muscle. It has been suggested that, because the cysts are focal
and the interstitial reaction may be widespread and diffuse,
there may be an autoimmune component to the myocarditis
associated with release of fiber proteins associated with para-
sitic injury.
Further reading
Guegan F, et al. Erythrophagocytosis of desialylated red blood cells is
responsible for anaemia during Trypanosoma vivax infection. Cell
Microbiol 2013;15:1285-1303.
Omotainse SO, Anosa VO. Comparative histopathology of the lymph
nodes, spleen, liver and kidney in experimental ovine trypanosomo-
sis. Onderstepoort J Vet Res 2009;76:377-383.
Van den Bossche P, et al. A changing environment and the epidemiol-
ogy of tsetse-transmitted livestock trypanosomiasis. Trends Parasitol
2010;26:236-243.
Hemotropic mycoplasmas.  Hemotropic mycoplasmas, also
called hemoplasmas, are cell wall–less unculturable bacteria
that attach to erythrocyte membranes and cause variably
severe anemia. The organisms were previously known as
Eperythrozoon or Haemobartonella spp., but based on nucleic
acid sequences, they are most similar to Mycoplasma, and
have all been renamed as such. All hemotropic mycoplasmas
are considered to be vector transmitted, although the specific
vector has been identified in only a few cases. Based on
sequence analysis, multiple mycoplasmal agents are identified
in blood in most species, but association with disease is infre-
quent. Mycoplasmas are at or below the limit of resolution of
light microscopy, and identification of organisms on blood
films is an insensitive method of diagnosis (Fig. 2-12).
In cats, there are currently 3 hemoplasmas: M. haemofelis,
M. turicensis, and M. haemominutum. Only M. haemofelis is
consistently associated with anemia, and can be identified by
light microscopy as rings or short chains of perimembranous
organisms. M. turicensis and M. haemominutum are only identi-
fied by PCR. Cats that survive acute infection with M. hae-
mofelis mount an immune response coincident with increase
in hematocrit and disappearance of organisms from blood
smears. It is unclear whether cats subsequently clear infection
or become subclinical carriers. Dogs are also host to multiple
hemoplasmas, but only M. haemocanis has been associated
with anemia, and only in splenectomized or immunosup-
pressed dogs. Cattle are host to M. wenyonii and M. hemobos.
M. wenyonii has been associated with anemia, edema, lymph-
adenopathy, and fever in dairy cattle. The pathogenicity of M.
hemobos is unclear. Similarly, infection of sheep with M. ovis
only rarely causes hemolytic anemia. M. haemolamae is preva-
lent in llamas and alpacas, and acute infection or infection in
crias or stressed adults may cause anemia with a large number
of erythrocyte organisms (see Fig. 2-12).
Acute infection with M. suis in young pigs results in illness
characterized by fever, hemolytic anemia, and hypoglycemia.
Older pigs may be infected, but clinical disease is usually
not apparent. As for other erythrocytic infectious agents, M.
suis-induced anemia is multifactorial, and physical damage
leading to premature splenic removal, induction of immune
responses to erythrocyte and parasite components, eryptosis,
 124.e1

Further reading
Anosa VO, et al. The haematology of Trypanosoma congolense infec-
tion in cattle. I. Sequential cytomorphological changes in the blood
and bone marrow of Boran cattle. Comp Haematol Int
1997;7:14-22.
Batista JS, et al. Highly debilitating natural Trypanosoma vivax infec-
tions in Brazilian calves: epidemiology, pathology, and probable
transplacental transmission. Parasitol Res 2012;110:73-80.
Forsberg CM, et al. The pathogenesis of Trypanosoma congolense
infection in calves. IV. The kinetics of blood coagulation. Vet Pathol
1979;16:229-242.
Gutierrez C, et al. Trypanosomosis in goats. Ann N Y Acad Sci
2006;1081:300-310.
Magona JW, et al. A comparative study on the clinical, parasitological
and molecular diagnosis of bovine trypanosomosis in Uganda.
Onderstepoort J Vet Res 2003;70:213-218.
 Bone Marrow
A A
B B
Figure 2-12  A. Mycoplasma haemofelis are minuscule epicel-
lular erythrocyte bacteria associated with regenerative anemia.
B. M. haemolamae can cause massive parasitemia in young or
debilitated camelids.
and endothelial activation from attachment of infected cells
all likely contribute to disease.
Rangelia vitalii is a tick-transmitted piroplasmic proto-
zoon that infects endothelial cells and hematopoietic cells of
dogs in South America. Infection is frequently fatal in domes-
tic dogs, and the most prominent clinical feature is bleeding
from pinnae. An unusual feature of R. vitalii infection is pre-
dominant targeting of endothelial rather than hematopoietic
cells. As a result, organisms are present in low number or
transiently in erythrocytes or leukocytes, although infected
dogs have immunohemolytic anemia with splenomegaly and
jaundice. Thrombocytopenia is variable, and not considered
to be the primary cause of bleeding. Organisms are most
readily identified in capillaries of lymph node and other tissues
(Fig. 2-13).
Further reading
França RT, et al. Canine rangeliosis due to Rangelia vitalii: from first
report in Brazil in 1910 to current day—a review. Ticks Tick Borne
Dis 2014;5:466-474.
Hoelzle LE, et al. Pathobiology of Mycoplasma suis. Vet J 2014;
202:20-25.
125
10 m
Figure 2-13  Rangelia vitalii cytoplasmic zoites in bone marrow
cell (A) and in an endothelial cell (B) from a dog. (Courtesy
A.P. Loretti.)
Sykes JE. Feline hemotropic mycoplasmas. Vet Clin North Am Small
Anim Pract 2010;40:1157-1170.
Mechanical, physical, and chemical causes of hemolytic
anemia.  Hemolytic anemia from mechanical trauma is caused
by physical damage to erythrocytes in vessels where turbulent
blood flow and pressure gradients exert shear forces. This
may be observed in animals with disseminated intravascular
coagulation (DIC), vasculitis, endocarditis, endocardiosis,
hemangiosarcoma, and burn wounds. DIC is characterized
by microangiopathy with luminal narrowing from fibrin
strands and platelet aggregates, which generates fragmented
erythrocytes (schistocytes) that are removed prematurely by
splenic macrophages. Anemia caused by mechanical trauma is
generally only mild, and jaundice is absent or mild. Both
intravascular and extravascular hemolysis induce erythropoi-
etic stress.
Many substances have the ability to cause oxidative injury.
Hemoglobin, normally maintained in a reduced state by eryth-
rocyte enzymes, is an abundant target for substances with
oxidative potential. Oxidized hemoglobin undergoes confor-
mational change and forms membrane-bound precipitates
 125.e1

Further reading
dos Santos AP, et al. Complete genome sequence of Mycoplasma
wenyonii strain Massachusetts. J Bacteriol 2012;194:5458-5459.
126 CHAPTER 2  •  Hematopoietic System
Figure 2-14  Blood smear from a cat with Heinz body hemolytic
anemia as a result of marked hyperglycemia. Note numerous
Heinz bodies (arrows) and erythrocyte ghosts (arrowheads).
called Heinz bodies (Fig. 2-14). Erythrocytes containing Heinz
bodies have reduced deformability and are removed by splenic
macrophages. The process of Heinz body removal may yield
deformed cells called “bite cells.” Oxidative substances associ-
ated with Heinz body hemolytic anemia in animals are red
maple leaves (horses), acetaminophen, Brassica and onion
ingestion, copper, zinc, propofol (cats), hyperglycemia, vitamin
K1 and K3, and others. The oxidative effect may cause minor
Heinz body formation without anemia (for example, repeated
administration of propofol in cats) or intravascular and extra-
vascular hemolysis with severe anemia (red maple leaf and
copper toxicity). Multiple factors such as excess dietary con-
centration, changes in intracellular transporters, decreased
excretion or imbalance with other trace elements contribute
to massive hepatocyte copper accumulation in sheep. Sudden
release of hepatocyte copper as a result of hepatic hypoxia,
parasitism, or stress increases blood concentration; free copper
ions enter erythrocytes and oxidize hemoglobin, leading to a
frequently fatal hemolytic crisis.
Certain bacterial hemolysins can directly lyse erythrocyte
membranes through phospholipase C or lecithinase activity
(Clostridium haemolyticum, C. novyi type D, C. perfringens), or
induce erythrocyte membrane changes resulting in immuno-
hemolytic anemia (C. perfringens type A in horses). Leptospira
spp. infection in cattle, lambs, and pigs may induce hemolysis
and marked jaundice, although the mechanism remains
unclear. Direct hemolysins have not been identified in Lepto-
spira, and the mechanism of hemolysis is assumed to be the
result of vasculopathy. Different types of snake venom contain
enzymes, including phospholipases A2 and metalloprotein-
ases, with potential to lyse erythrocytes and digest tissue to
induce hemorrhage, respectively. In most instances, hemolytic
anemia caused by venom is among the less severe outcomes
of snakebites.
Inherited erythrocyte enzyme deficiencies causing hemo-
lytic anemia are uncommon autosomal recessive conditions
that are informative regarding their normal enzymatic func-
tion and the effect of chronic hemolysis-stimulated erythro-
poiesis (see Table 2-2). Pyruvate kinase (PK) deficiency
diminishes generation of adenosine triphosphate (ATP) in
erythrocytes, which shortens their life-span and results in
Bone Marrow
anemia. Affected dogs are young, have macrocytic hypochro-
mic highly regenerative anemia, and develop hemosiderosis,
hemochromatosis, and eventual liver fibrosis, as well as myelo-
fibrosis and osteosclerosis from excessive iron absorption
resulting in iron overload. PK deficiency in cats is rarely associ-
ated with clinical disease, and anemia is only mild and associ-
ated with reticulocytosis. Phosphofructokinase (PFK) deficiency
impairs glycolysis in erythrocytes and myocytes, resulting in
persistent but compensated hemolytic anemia. Hemolytic
crises occur after vigorous exercise or in alkalemia because
PFK-deficiency erythrocytes have increased alkaline fragility.
Affected dogs develop hepatic hemosiderosis but not myelo-
fibrosis. Cytochrome b5 reductase deficiency causes methemo-
globinemia. The condition is usually clinically silent and
identified incidentally in dogs or cats with cyanotic mucus
membranes and brown discolored venous blood. Other eryth-
rocyte enzyme deficiencies have no or only limited clinical
consequence (see Table 2-2).
Hereditary abnormalities in erythrocyte membrane con-
stituents, such as spectrin and cationic transporters, are associ-
ated with elliptocytosis, spherocytosis, or stomatocytosis in
dogs. Although these shape changes are very noticeable on
microscopic review of blood films, they are usually incidental
findings and cause only mild hemolytic anemia compensated
for by increased reticulocyte production.
Hemolytic anemia is virtually always associated with
increased reticulocytes in blood and an increased proportion
of rubricytes in the bone marrow. Erythropoiesis may be
increased more than 10-fold in animals with chronic hemo-
lytic anemia and adequate nutrition and iron stores. Many
causes of hemolytic anemia also induce a systemic inflamma-
tory response, and therefore increased granulopoiesis and
overall bone marrow hypercellularity. Splenomegaly and
hepatomegaly are prominent features of extravascular hemo-
lysis, and less prominent in intravascular hemolysis. The
degree of hyperbilirubinemia and jaundice reflect the rate of
heme breakdown, and also liver capacity to conjugate and
excrete bilirubin. Dogs with immunohemolytic anemia are at
increased risk of venous and arterial thrombosis, and particu-
larly pulmonary thromboembolism. Induction of tissue factor
and abundant anionic phospholipid exposed on fragmented
cell membranes are thought to activate the coagulation
cascade.
Further reading
Alward A, et al. Red maple (Acer rubrum) leaf toxicosis in horses: a
retrospective study of 32 cases. J Vet Intern Med 2006;
20:1197-1201.
Goddard A, et al. Clinicopathologic abnormalities associated with
snake envenomation in domestic animals. Vet Clin Pathol
2011;40:282-292.
Owen JL, Harvey JH. Hemolytic anemia in dogs and cats due to eryth-
rocyte enzyme deficiencies. Vet Clin North Am Sm Anim
2012;42:73-84.
Anemia of decreased production
The most common causes of inadequate erythrocyte produc-
tion are chronic disease with persistent systemic inflamma-
tion, chronic kidney disease, and iron deficiency. Anemia
resulting from decreased erythrocyte production is nonregen-
erative, as indicated by lack of reticulocytosis and reduced
 126.e1

Further reading
Auza NJ, et al. Diagnosis and treatment of copper toxicosis in rumi-
nants. J Am Vet Med Assoc 1999;214:1624-1628.
Harvey JH. Pathogenesis, laboratory diagnosis, and clinical implications
of erythrocyte enzyme deficiencies in dogs, cats, and horses. Vet
Clin Pathol 2006;35:144-156.
 Bone Marrow 127

proportion of erythrocyte precursors in bone marrow. Changes

in erythrocyte and reticulocyte indices on the hemogram may
indicate the cause of anemia.
Anemia of inflammatory disease (AID) is very common
among hospitalized dogs, and less common in hospitalized
other species. AID is associated with a wide range of chronic
conditions that have an inflammatory component, such as
dermatitis, arthritis, enteritis, and microbial infections. Animals
with cancer also often have AID, although inflammation may
not be obvious. The predominant mechanism leading to AID is
thought to be increased production of inflammatory mediators,
such as IL-6, that stimulate hepatic production of hepcidin.
In turn, hepcidin reduces transfer of iron from enterocytes
into plasma and inhibits iron export from macrophages to
erythroid precursors in bone marrow. As a result, despite
abundant hemosiderin in bone marrow and splenic macro- A
phages, erythroid precursors are starved of iron for synthesis
of hemoglobin, and anemia ensues. Most AID is normocytic
and normochromic, but in some cases, microcytosis may be
present. Other factors thought to contribute to AID are
reduced erythropoietin production, reduced precursor cell
erythropoietin sensitivity, and reduced erythrocyte life-span.
AID is distinguished from true iron deficiency by presence of
ample hemosiderin in tissues, and normal to high serum fer-
ritin concentration.
Chronic renal disease is very common in older cats, and
virtually all affected cats have anemia. Anemia also occurs in
other species with chronic kidney disease, and is a major cause
of morbidity in people with kidney disease and hemodialysis.
Causes are reduced erythropoietin production by renal inter-
stitial cells and altered iron use, but altered sensing of oxygen
tension, reduced erythrocyte life-span, and blunted erythro-
poietin responsiveness are also likely factors. Exogenous sup- B
plementation with erythropoiesis-stimulating agents has
Figure 2-15  A, B. Bone marrow sections from a cat with FeLV
ameliorated anemia in cats, but therapeutic efficacy and ideal
infection, myelofibrosis, and lymphoid aggregates. Also note
hematocrit and iron concentration are ill defined. Morphologi-
coarse hemosiderin, not normally found in cat bone marrow.
cally, bone marrow in animals with anemia of chronic kidney
disease has reduced erythropoiesis despite abundant tissue
iron stores. Beagles. Lack of this receptor impairs intestinal absorption and
Iron deficiency anemia, as discussed previously, is physio- renal tubular reabsorption of intrinsic factor/cobalamin com-
logic in neonatal animals, and pathologic in adult animals. The plexes and other proteins. Cobalamin and folic acid are
cause is almost always chronic blood loss. Iron-limited eryth- required for synthesis of thymidine in DNA. In affected dogs,
ropoiesis is initially responsive with bone marrow erythroid defective DNA synthesis manifests with normochromic nor-
hyperplasia, and blood reticulocytosis, macrocytosis, and mocytic anemia, leukopenia, megaloblastic change in hema-
hypochromasia. With progressive iron depletion, microcytic hypo- topoietic and intestinal cells, and metarubricytosis. Dogs, in a
chromic erythrocytes become predominant in blood. In animals difference from people, do not have macrocytosis. Decreased
with anemia caused by iron deficiency, bone marrow and serum folate concentration, thought to result from lack of
splenic hemosiderin stores are absent or sparse. Cats normally absorption in primary gastrointestinal disease or from cobala-
do not store hemosiderin in bone marrow, but iron deficiency min deficiency, has been identified in Golden Retriever and
is nevertheless characterized by microcytic hypochromic Boxer dogs. It is unknown whether affected dogs also have
anemia, and low serum iron and ferritin concentration. Hemo- anemia.
siderin, sometimes very coarsely aggregated, may be seen in Pure red cell aplasia (lack of bone marrow erythroid
bone marrow of cats with myelofibrosis, feline leukemia precursors) and aplastic anemia (lack of all hematopoietic
virus (FeLV) infection, and myeloproliferative neoplasms precursor cells) result from cytotoxic viral infections, and
(Fig. 2-15). immune- or toxin-mediated injury to progenitor cells. In
Other causes of anemia from reduced erythrocyte produc- young animals, parvovirus or pestivirus infection are possible
tion are portosystemic shunting, cobalamin deficiency, and pure etiologies, whereas in adult animals, idiosyncratic drug reac-
red cell aplasia. The anemia of portosystemic shunting is tions or autoimmune destruction are more likely etiologies. In
usually microcytic and normochromic, and thought to result most cases, a definitive cause cannot be identified. The pres-
from reduced hepatic production of proteins involved in iron ence of lymphocytes and plasma cells in bone marrow sections
transport. Cobalamin (vitamin B12) deficiency from nonfunc- otherwise devoid of hematopoietic cells, and improvement of
tional cubam receptors has been described in Giant Schnauzers, cytopenia in response to immune suppression, supports an
Australian Shepherd dogs, Border Collies, Shar Peis, and immune-mediated etiology (Fig. 2-16) in some cases. Drugs
128 CHAPTER 2  •  Hematopoietic System
A B
C D
Figure 2-16  Bone marrow biopsy sections from an older dog with aplastic anemia. A, B. The bone
marrow is profoundly hypocellular, sinusoids are prominent, and there are lymphocytes and plasma
cells. C. CD3-positive lymphocytes around blood vessels. D. Occasional CD79a-positive B
lymphocytes.
with known potential to cause hematopoietic precursor cell
injury are chloramphenicol, phenylbutazone, trimethoprim-
sulfamethoxazole, and cephalosporins. Prolonged high estro-
gen concentration, either from endogenous production by
Sertoli cell tumors in dogs, granulosa cell tumors in horses and
other species, adrenal tumors in ferrets, or from exogenous
administration, may cause precursor cell injury and bone
marrow hypoplasia or aplasia. Bracken fern (Pteridium aquili-
num) ingestion causes hematuria (enzootic bovine hematuria)
and bone marrow suppression in ruminants caused by ptaqui-
loside toxin. Antiproliferative therapy with chemotherapeutic
agents or irradiation also affects bone marrow. Neutropenia is
the main manifestation of toxicity, and to a lesser degree
thrombocytopenia, reflecting their 8-hour and 10-day life-
spans, respectively. Overall, hematopoietic stem cells are
thought to be highly resistant to fatal injury, and with suffi-
cient time, protection from opportunistic infections and cell
replacement through transfusion, there can be recovery of
normal hematopoiesis in many instances.
Erythrocytosis is most often the result of dehydration, and
may be very severe in animals with extreme external loss of
free water or internal water sequestration. Neonatal bovine
diarrhea, parvoviral enteritis, and equine salmonellosis are
conditions typically associated with severe hemoconcentra-
Bone Marrow
tion. Physiologic erythrocytosis results from hypoxic stimula-
tion of erythropoietin production in animals with chronic
cardiac or pulmonary disease. Paraneoplastic erythrocytosis is
the result of ectopic production of erythropoietin by malig-
nant tumors, most often carcinomas. Lymphoid tumors, and
specifically renal lymphoma in dogs, have also been shown to
produce erythropoietin and induce erythrocytosis.
Further reading
Fyfe JC, et al. Selective intestinal cobalamin malabsorption with pro-
teinuria (Imerslund-Gräsbeck syndrome) in juvenile Beagles. J Vet
Intern Med 2014;28:356-362.
Weiss DJ. Bone marrow pathology in dogs and cats with non-
regenerative immune-mediated haemolytic anaemia and pure red
cell aplasia. J Comp Pathol 2008;138:46-53.
Disorders of platelets
Platelets are produced as cytoplasmic fragments of bone
marrow megakaryocytes and function in primary hemostasis,
inflammation, and repair (see also later section, Disorders of
hemostasis). Platelet number on the complete blood count
(CBC) is the most widely used indicator of adequate platelets,
 128.e1

Further reading
Aroch I, et al. Peripheral nucleated red blood cells as a prognostic
indicator in heatstroke in dogs. J Vet Intern Med 2009;23:
544-551.
Chalhoub S, et al. Anemia of renal disease: what it is, what to do and
what’s new. J Fel Med Surg 2011;13:629-640.
Cortinovis C, Caloni F. Epidemiology of intoxication of domestic animals
by plants in Europe. Vet J 2013;197:163-168.
Dandrieux JR, et al. Canine breed predispositions for marked hypoco-
balaminaemia or decreased folate concentration assessed by a labo-
ratory survey. J Comp Pathol 2013;54:143-148.
Durno AS, et al. Polycythemia and inappropriate erythropoietin con-
centrations in two dogs with renal T-cell lymphoma. J Am Anim
Hosp Assoc 2011;47:122-128.
Seguro AC, Andrade L. Pathophysiology of leptospirosis. Shock
2013;39:17-23.
Shmukler BE, et al. Cation-leak stomatocytosis in Standard Schnauzers
does not cosegregate with coding mutations in the RhAG, SLC4A1,
or GLUT1 genes associated with human disease. Blood Cells Mol
Dis 2012;48:219-225.
Waldner CL, Blakley B. Evaluating micronutrient concentrations in liver
samples from abortions, stillbirths, and neonatal and postnatal
losses in beef calves. J Vet Diagn Invest 2014;26:376-389.
 Bone Marrow 129

but as for erythrocytes, platelet volume is variable in health,
higher in recently released platelets, and lower in iron defi-
ciency and immune-mediated destruction. Therefore platelet-
crit (analogous to hematocrit) is actually a more meaningful
indicator of total platelet mass, and its use will become more
widespread because modern automated hematology analyzers
determine plateletcrit, platelet number, and platelet volume.
Thrombocytopenia results from increased consumption, pre-
mature destruction, or decreased production. Increased con-
sumption occurs in conditions such as hemorrhage, enteritis,
anticoagulant toxicity, pancreatitis, necrosis, endotoxemia,
envenomation, and vasculitis, and usually causes mild throm-
bocytopenia. Many hemotropic infectious agents can infect all
blood cells, including platelets; Anaplasma platys specifically
targets platelets. Bovine viral diarrhea virus (BVDV) has
tropism for megakaryocytes, and either direct toxicity or
immune-mediated injury render thrombocytopenia a common
feature of BVDV infection. FeLV infection of megakaryocytes
may also cause thrombocytopenia.
Immune-mediated thrombocytopenia (IMT) is a relatively
common primary autoimmune disease in dogs. The pathogen-
esis involves premature removal of antibody-coated platelets
by splenic macrophages. The nature of antigens targeted by
antibodies is poorly characterized. Platelet concentration and
plateletcrit in IMT are usually very low, and megakaryocytes
in bone marrow sections are markedly increased. Concurrent
immune destruction of erythrocytes and platelets (Evans syn-
drome) also occurs in dogs. IMT in cats is also most commonly
of an autoimmune nature, and often part of a generalized
antihematopoietic cell immune response, leading to multiple
cytopenias. Treatment with immune suppression appears to
be more effective in dogs than cats. IMT in horses is more
commonly associated with the use of drugs such as penicillin,
cephalosporins, and sulfonamides, which are presumed to act
as a hapten for induction of antiplatelet antibody responses.
Decreased platelet production is most often the result of
myeloproliferative or infiltrative bone marrow diseases, such
as leukemia or myeloma. Regeneration of platelets can be
monitored in a similar manner as for erythrocytes by detecting
increased mean platelet volume (MPV).
Thrombocytosis is a frequent finding in dogs with a variety
of illnesses, including inflammation and cancer. Increased
platelet number does not consistently correlate with increased
plateletcrit, and clinical associations of thrombocytosis have
not clearly been identified.
Further reading
Fielding CL, et al. Rattlesnake envenomation in horses: 58 cases (1992-
2009). J Am Vet Med Assoc 2011;238:631-635.
Schwartz D, et al. Platelet volume and plateletcrit in dogs with pre-
sumed primary immune-mediated thrombocytopenia. J Vet Intern
Med 2014;28:1575-1579.
Hematopoietic neoplasia
Integration of cellular, genetic, molecular, and immunologic
features of primary hematopoietic neoplasms with prognosis
over the past decade has established 3 main categories in
people: acute myeloid leukemia (AML), myeloproliferative neo-
plasm (MPN, formerly called “chronic leukemia”), and myelo-
dysplastic syndrome (MDS). Despite limited knowledge about
genetic and molecular features, most myeloid neoplasms in
animals can be grouped into one of these broad categories,
based on careful morphologic and immunochemical charac-
terization (Table 2-3).
Acute myeloid leukemia.  Animals with AML are usually
acutely but nonspecifically ill and have profound cytopenia in
one or several cell lines. Undifferentiated blast cells may be
absent in peripheral blood or may comprise a massive leuko-
cytosis. By definition, either bone marrow or blood, or both,
contain >20% blast cells for a diagnosis of AML. Blast cells are
large cells with round to oval nuclei, 1 or 2 nucleoli, and
basophilic cytoplasm. Blast cells lack differentiated features
such as granules that would allow classification into lineage.
Identification and enumeration of blast cells is best accom-
plished on cytology; determining the extent of myelophthisis
and presence of myelofibrosis or myelonecrosis requires
histopathology. Thus accurate diagnosis and classification of
AML requires, at minimum, a CBC, bone marrow cytology,
and histopathology. Bone marrow films should be differen-
tially counted (500 nucleated cells) to determine the propor-
tion of blast cells, the proportion of differentiated granulocytic
and erythrocytic cells, and the granulocytic:erythrocytic (G : E)

Table • 2-3 
Categories of myeloid neoplasms
Category Definition Subcategory

Acute myeloid leukemia
(AML)
Myeloproliferative neoplasms
(MPN, old term = chronic
leukemia)
Myelodysplastic syndrome
(MDS)
Cytopenia and ≥20% blast
cells in blood or bone
marrow
Cytosis of mature appearing
cells in blood, hypercellular
bone marrow, <5% blasts
Nonregenerative cytopenia,
dysplasia, 5-20% bone
marrow blast cells,
+/− myelofibrosis
According to cell morphology and/or immunophenotypic
features of cells: acute undifferentiated leukemia (AUL);
AML with neutrophilic differentiation; AML with
granulomonocytic differentiation; AML with
megakaryoblastic differentiation; etc.
According to cell morphology: polycythemia vera (PV); essential
thrombocythemia (ET); chronic neutrophilic leukemia (CNL);
chronic monocytic leukemia (CMoL); mastocytosis; etc.
According to most pronounced cytopenia, termed: refractory
anemia with excess blasts (RAEB); refractory neutropenia
with excess blasts (RNEB); refractory thrombocytopenia with
excess blasts (RTEB)
 129.e1

Further reading
O’Marra SK, et al. Treatment and predictors of outcome in dogs with
immune-mediated thrombocytopenia. J Am Vet Med Assoc 2011;
238:346-352.
130 CHAPTER 2  •  Hematopoietic System Bone Marrow

ratio. Concurrent assessment of CBC and bone marrow cytol-
ogy is essential for interpreting bone marrow histopathology,
and at times serial CBCs and repeated bone marrow biopsies
are required to arrive at a definitive diagnosis. Recovery from
hematopoietic stem cell injury, parvovirus, and acute feline
immunodeficiency virus (FIV) infection can cause transient
cytopenia and excess bone marrow blast cells, which needs to
be distinguished from AML by repeated CBCs.
AML is a highly heterogeneous cancer. In some cases, the
entire bone marrow consists of blast cells, and animals have
severe cytopenia; in other cases, blast cells encompass only
20-30% of bone marrow cells, with partial differentiation into
granulocytes or rubricytes (Figs. 2-17, 2-18). There usually is
lack or severe decrease in rubricytes, granulocytes, or mega-
karyocytes. Although animals are presented with acute illness,
retrospectively, cytopenia has often existed for weeks or
months before diagnosis of AML. Bone marrow cellularity in
AML is also highly variable and can range from 10-100%.
Investigations in people have shown that the molecular lesions
in AML are heterogeneous and mirror the variable clinical and
morphologic features of this cancer. Some understanding of
the molecular basis of AML in dogs is emerging with muta-
tions identified in the oncogenes RAS, FLT3, and C-KIT, trans-
location of BCR to ABL, copy number changes in PTEN and
BRCA1, and large deletions. Clonality in AML and other
hemolymphatic tumors has been identified in dog tissues with
a PCR assay targeting polymorphic regions of the androgen
receptor gene located on the X chromosome. Usefulness of
this assay is currently limited because ~50% of female dogs
normally lack heterozygosity at this gene locus.
Practically, once a diagnosis of AML has been derived by
the above criteria, the cancer should be subcategorized based
on morphology (Figs. 2-19, 2-20; see Table 2-3). In cases of
acute undifferentiated leukemia, flow cytometric analysis of
fresh aspirated bone marrow cells may be useful to rule out
lymphoid cell type, and to classify blast cells as monocytic
(CD11c/CD14/major histocompatibility complex II [MHC
II]), granulomonocytic (CD4/CD11b/CD11c), or megakaryo-
cytic (CD9/CD41/CD61). Detection of CD34 is consistent
with acute leukemia, but does not differentiate between acute
myeloid or acute lymphoid leukemia. Specialized laboratories
performing flow cytometry generally apply a panel of 10-20
antibodies and derive interpretation about blast cells from
detecting presence or absence of a combination of antigens.

A B

C D
Figure 2-17  Acute myeloid leukemia with neutrophilic differentiation in a dog. A. The blood
smear shows anemia, neutropenia, thrombocytopenia, and numerous blast cells. B. Bone marrow
aspirate has lack of rubricytes and segmented neutrophils, and increased immature granulocytes.
C, D. There were green masses throughout the mesentery and in kidney. (Courtesy R. Fraser.)
 Bone Marrow 131

E F
Figure 2-17, cont’d  E, F. Bone marrow sections have a predominance of blast cells with single
or multiple nucleoli, and reduced metamyelocytes and band neutrophils.

A B

C D
Figure 2-18  Samples from a dog with acute myeloid leukemia with rubricytic differentiation.
A. Bone marrow aspirate is devoid of granulocytes; blast cells are sparse in this field. B. The pro-
portion of blast cells is >20%, there is differentiation to rubricytes, granulocytes are rare. C. The
spleen is enlarged, mottled, and firm. D. There are clusters of rubricytes in many tissues; shown
here is a pulmonary arteriole.
132 CHAPTER 2  •  Hematopoietic System
A A
B B
Figure 2-19  Acute myeloid leukemia with neutrophilic differen-
tiation, in a dog. A, B. Blast cells comprised 25%, but differentia-
tion to band and segmented neutrophils is apparent.
IHC is useful to differentiate acute T-lymphocyte (CD3 posi-
tive) or B-lymphocyte (CD79a or CD20 positive) leukemia
from AML, but few additional antibodies specific for leuko-
cyte antigens are reactive with formalin-fixed tissue. Antibody
to canine CD18 reactive with formalin-fixed tissue labels all
leukocytes, but granulocytic and monocytic cells stain more
intensely than lymphocytes. Some antibodies to canine MHC
II are also reactive with formalin-fixed tissue, and label mono-
cytic cells and macrophages (Fig. 2-21). Infidelity in antigen
expression on neoplastic leukocytes is relatively common in
human leukemia, and has also been described for leukemic
cells of dogs. Hence interpretation of antigen expression
should always be based on absence or presence of multiple
antigens, and not only a single antigen.
All subcategories of AML (see Table 2-3) have been
reported in dogs and most other domestic animals. Granulo-
monocytic and megakaryoblastic AML appear to be more
common than neutrophilic or other subcategories in dogs,
whereas erythroblastic AML in association with FeLV infec-
tion was most common in cats. However, overall data on
prevalence of well-characterized AML cases in animals are
sparse, and much remains to be learned about this cancer. As
might be expected for a morphologically heterogeneous
Bone Marrow
Figure 2-20  Undifferentiated acute myeloid leukemia, in a dog.
A, B. Blast cells comprise >80% of cells, and mitotic figures are
frequent. At low power, individual rubricytes and granulocytes are
apparent, but megakaryocytes are absent.
cancer, response to therapy and prognosis are also very vari-
able. Although many cases of AML have life-threatening
thrombocytopenia or neutropenia at diagnosis, and the animal
dies within days despite therapy, survival in dogs of a year and
longer has also been reported. Organomegaly caused by leu-
kemic infiltrates is usually subtle, and in decreasing order of
frequency involves spleen, liver, lymph nodes, and any other
tissue. Several subcategories of AML have been reported in
horses, and clinical presentation usually consisted of hemor-
rhage and thrombocytopenia.
Acute lymphoid leukemia (ALL) arises from large precur-
sor lymphocytes in bone marrow. Morphologically, lympho-
blasts and myeloblasts are indistinguishable, but in most cases,
ALL cells express markers such as CD3, CD4, CD5, CD8,
CD20, CD21, or CD79a to indicate lymphoid origin. Dogs
with ALL are more likely to have severe neutropenia and
thrombocytopenia than dogs with AML. B-ALL is more com-
monly reported than T-ALL in dogs, but it is unknown whether
there are differences in natural history for either subcategory
(Fig. 2-22). The mean age of dogs with ALL is higher (8.0
years) than that of dogs with AML (6.3 years). Canine mul-
ticentric stage V leukemic lymphoma may be challenging to
distinguish from ALL with enlarged lymph nodes. Usually,
 Bone Marrow 133

A A

B B

C C
Figure 2-21  Acute myeloid leukemia with monocytic differentia- Figure 2-22  B-lymphocyte acute myeloid leukemia, in a dog.
tion in a dog. A. Blood smear shows pancytopenia with occasional The dog had mild anemia and no morphologically abnormal cells
monocytes. B. Bone marrow section has predominance of large on the blood smear. A. Bone marrow aspirate shows a uniform
blast cells with a single nucleolus. C. Immunohistochemistry for population of hyperchromatic blast cells and many lysed cells
major histocompatibility complex II expression labels approxi- (arrowheads). B. Bone marrow section is >80% cellular, and mega-
mately half of the blast cells. karyocytes and hemosiderin are rare. C. Cells have indistinct
cytoplasm, uniformly round nuclei, and prominent central
nucleoli.

dogs with stage V lymphoma have greater tissue tumor burden
than those with ALL, and lymph nodes are more massively
enlarged. Also, expression of CD34 on leukemic cells is very
strongly suggestive of ALL rather than stage V lymphoma. In
horses, ALL is more commonly reported than AML, whereas
in dogs and cats AML is slightly more commonly reported
than ALL. Infection of cats with certain strains of FeLV results
in relatively frequent AML, most commonly of erythroblastic
type (erythremic myelosis), but monoblastic AML and ALL
have also been described.
134 CHAPTER 2  •  Hematopoietic System Bone Marrow

Further reading
Comazzi S, et al. Acute megakaryoblastic leukemia in dogs: a report
of three cases and review of the literature. J Am Anim Hosp Assoc
2010;46:327-335.
Comazzi S, et al. Immunophenotype predicts survival time in dogs with
chronic lymphocytic leukemia. J Vet Intern Med 2011;25:
100-106.
Juopperi TA, et al. Prognostic markers for myeloid neoplasms: a com-
parative review of the literature and goals for future investigation.
Vet Pathol 2011;48:182-197.
Novacco M, et al. Prognostic factors in canine acute leukaemias: a
retrospective study. Vet Comp Oncol 2015 Jan 26. [Epub ahead of
print].
Tan E, et al. Automated analysis of bone marrow aspirates from
dogs with haematological disorders. J Comp Pathol 2014;151:
A
67-79.
Usher SG, et al. RAS, FLT3, and C-KIT mutations in immunophenotyped
canine leukemias. Exp Hematol 2009;37:65-77.
Vernau W, Moore PF. An immunophenotypic study of canine leukemias
and preliminary assessment of clonality by polymerase chain reac-
tion. Vet Immunol Immunopathol 1999;69:145-164.
Willmann M, et al. Chemotherapy in canine acute megakaryoblastic
leukemia: a case report and review of the literature. In Vivo
2009;23:911-918.

Myeloproliferative neoplasms.  Myeloproliferative neo-

plasms (MPN) are the former chronic leukemias, also previ-
ously called myeloproliferative diseases. The terminology was
changed in the most recent World Health Organization clas-
sification of human myeloid neoplasms, to make clear that
these are neoplasms, although their natural progression is B
usually very gradual. The hallmarks of MPN are accumulation
Figure 2-23  Myeloproliferative neoplasm, chronic neutrophilic
of a large number of relatively normal-appearing cells in blood,
leukemia in a dog. A, B. The dog had mild anemia and thrombo-
bone marrow, spleen, and eventually other organs, and mild or
cytopenia, and a neutrophil count of 109 × 109/L. The bone
absent cytopenia. Splenomegaly may be massive, and reflects a
marrow consists predominantly of differentiated segmented and
large tumor burden. Bone marrow biopsy is usually not
band neutrophils, with ~5% blast cells. Rubricytes and mega-
needed for diagnosis, but, if performed, bone marrow is
karyocytes are much reduced. The dog had an increasing neutro-
highly cellular, with numerous terminally differentiated cells
phil count over 18 months prior to presentation for fatigue and
(Figs. 2-23, 2-24).
poor appetite.
MPN are rare in animals but are readily diagnosed and
categorized (see Table 2-3). Typically, a large number of
mature erythrocytes, granulocytes, monocytes, platelets, or tions. MPN may eventually progress to “blast transformation”
mast cells are discovered incidentally on the CBC of animals with appearance of immature or blast cells in circulation and
with no or vague illness. Retrospectively, hematocrit or leuko- progressive cytopenia. Chronic myelogenous leukemia (CML)
cyte concentration in affected animals often have increased is a distinct MPN entity in humans characterized by a recipro-
gradually over more than a year, and the diagnosis is estab- cal translocation resulting in expression of a constitutively
lished relatively late in the life of the neoplasm. Hematocrit active tyrosine kinase. Translocation of equivalent regions has
in polycythemia vera may be twice normal, and associated been identified in several dogs with MPN.
hyperviscosity can cause retinal or brain ischemic events man-
ifesting with seizures or other neurologic abnormalities. Simi-
larly, animals with chronic neutrophilic leukemia often have Further reading
neutrophil concentrations exceeding 10 times the upper refer- Culver S, et al. Molecular characterization of canine BCR-ABL-positive
ence interval, and in essential thrombocythemia, platelet con- chronic myelomonocytic leukemia before and after chemotherapy.
centration and plateletcrit exceed twice the upper reference Vet Clin Pathol 2013;42:314-322.
interval. The molecular pathogenesis of MPN in people Vardiman JW, et al. The 2008 revision of the World Health Organiza-
involves mutations that constitutively activate kinases involved tion (WHO) classification of myeloid neoplasms and acute leukemia:
in growth factor receptor signaling. Hence in some respects, rationale and important changes. Blood 2009;114:937-951.
MPN may be considered accumulations of relatively normal cells
unable to perceive signals to stop growth. All hematopoietic cells
in MPN share key molecular lesions, but predominant pheno- Myelodysplastic syndrome.  Myelodysplastic syndrome
type is determined by cell lineage-specific additional muta- (MDS) is defined as a condition with persistent nonregenerative
 134.e1

Further reading
Adam F, et al. Clinical pathological and epidemiological assessment of
morphologically and immunologically confirmed canine leukaemia.
Vet Comp Oncol 2009;7:181-195.
Figueiredo JF, et al. Acute myeloblastic leukemia with associated
BCR-ABL translocation in a dog. Vet Clin Pathol 2012;41:
362-368.
Fischer C, et al. Erythroleukemia in a retrovirus-negative cat. J Am Vet
Med Assoc 2012;240:294-297.
Giantin M, et al. Evaluation of tyrosine-kinase receptor c-KIT (c-KIT)
mutations, mRNA and protein expression in canine leukemia: might
c-KIT represent a therapeutic target? Vet Immunol Immunopathol
2013;152:325-332.
Mochizuki H, et al. Demonstration of the cell clonality in canine hema-
topoietic tumors by X-chromosome inactivation pattern analysis.
Vet Pathol 2015;52:61-69.
Valentini F, et al. Use of CD9 and CD61 for the characterization of
AML-M7 by flow cytometry in a dog. Vet Comp Oncol
2011;10:312-318.
Wilkerson MJ, et al. Lineage differentiation of canine lymphoma/
leukemias and aberrant expression of CD molecules. Vet Immunol
Immunopathol 2005;106:179-196.
134.e2

Further reading
Cruz-Cardona JA, et al. BCR-ABL translocation in a dog with chronic
monocytic leukemia. Vet Clin Pathol 2011;40:40-47.
Perez M, et al. Partial cytogenetic response with toceranib and pred-
nisone treatment in a young dog with chronic monocytic leukemia.
Anticancer Drugs 2013;24:109-1103.
 Bone Marrow 135

A A

B B
Figure 2-24  Myeloproliferative neoplasm, mastocytosis in a dog.
The dog had mild anemia and a low number of mast cells on
routine blood smear review. A. Bone marrow shows rubricytes,
granulocytes, megakaryocytes, and a moderate number of round
granular cells. B. Toluidine blue staining identifies numerous mast
cells.

cytopenia, dysplasia of blood or bone marrow cells, and presence

of 5-20% blast cells in bone marrow. MDS may be more
common than AML in specialty small animal practice, but
unlike in people, causes and prognosis of MDS in animals are
ill defined. Hematopoietic cells in primary MDS of people
have clonal molecular lesions, which is likely also the case in
at least a proportion of primary MDS in animals. Primary
MDS has not been described in large animals, which may
reflect lack of investigation. Cytopenia, in most cases anemia,
is usually severe in MDS. Dysplasia can manifest as asynchro-
nous cytoplasmic and nuclear maturation or binucleation in
rubricytes, neutrophil hypersegmentation or gigantism, plate-
let gigantism, and other morphologic abnormalities (Figs.
2-25, 2-26). Despite severe nonregenerative cytopenia, the
bone marrow is usually hypercellular and has an excess pro-
portion of blast cells. Some dogs with MDS progress to AML,
sometimes within weeks of diagnosis, but morphologic char-
acteristics to identify those individuals are lacking. Other dogs
with MDS either remain static, become transfusion dependent
if they have anemia, or progress to develop additional cytope-
nias and bone marrow failure. Myelofibrosis is a common feature
C
Figure 2-25  Myelodysplastic syndrome, severe anemia and
thrombocytopenia in a dog. A. The blood smear has giant neutro-
phils with condensed poorly segmented nuclei. B. Similar atypical
neutrophils on bone marrow cytology. C. The bone marrow is
hypercellular but lacks megakaryocytes and adequate rubricytes.
Blast cells comprise 18%.
of MDS in dogs, and presumed to be the result of excess pro-
duction of growth factors, such as transforming growth factor
(TGF)-β or platelet-derived growth factor (PDGF) in a bone
marrow with disturbed cytokine environment. In people,
MPN with MDS is recognized as a separate category of
136 CHAPTER 2  •  Hematopoietic System
A Gomori), and should be absent in normal bone marrow (Fig.
B may induce severe MF, anemia, and bone marrow lymphoid
Figure 2-26  Acute myeloid leukemia with neutrophilic differen-
tiation and dysplasia in a dog. A, B. Blast cells comprise 41% of
cells, and there is severe rubricytic hypoplasia. Neutrophils have
abnormal nuclear segmentation (arrows).
myeloid tumors. Clear diagnostic features for such a category
are lacking for animals.
Cytopenia and dysmyelopoiesis morphologically indistinguish-
able from primary MDS may result from idiosyncratic responses
to drugs such as phenobarbital; treatment with chemothera-
peutic drugs; altered hematopoiesis in immune-mediated
hematologic disease; precursor cell infection with vector-
borne pathogens such as Anaplasma platys, Leishmania infan-
tum, Babesia vogeli, and Hepatozoon canis; and bracken fern
myelotoxicity. It is essential to distinguish primary from sec-
ondary MDS because discontinuation of particular drugs or
toxin exposure or treatment of immune-mediated or infec-
tious disease may resolve dysmyelopoiesis. A thorough clinical
history and repeated hematologic assessment can differentiate
these etiologies.
Further reading
De Tommasi AS, et al. Evaluation of blood and bone marrow in selected
canine vector-borne diseases. Parasit Vectors 2014;7:534-541.
Jacobs G, et al. Neutropenia and thrombocytopenia in three dogs
treated with anticonvulsants. J Am Vet Med Assoc 1998;212:
681-684.
Bone Marrow
Vardiman J. The classification of MDS: from FAB to WHO and beyond.
Leuk Res 2012;36:1453-1458.
Weiss DJ. Recognition and classification of dysmyelopoiesis in the dog:
a review. J Vet Intern Med 2005;9:147-154.
Other hematopoietic conditions
Myelofibrosis.  Myelofibrosis (MF) is excessive production of
collagen by bone marrow fibroblasts causing cytopenia and even-
tual bone marrow failure. MF is suspected in animals with
cytopenia (usually anemia), deformed tear-drop shaped or
oval erythrocytes on blood smears, and inability to aspirate
bone marrow. Thus diagnosis of MF requires assessment of a
core biopsy. Deposition of fine type 3 collagen fibrils can be
detected with silver impregnation stains (Warthin-Starry or
2-27). With progressive MF, coarse type 1 collagen fibers
appear that can be highlighted with trichrome stains. In
people, primary MF is a clonal disorder diagnosed by compos-
ite assessment of clinical, laboratory, and molecular features.
Secondary MF is a not a clonal disorder, and results from
chronic hyperstimulated hematopoiesis in conditions such as
chronic hemolytic anemia, response to bone marrow micro-
environment injury, and cytokine dysregulation. Many people
with MPN eventually develop MF.
Clear diagnostic criteria and clonality assays to distinguish
primary from secondary MF are lacking for animals. MF in
dogs is most often attributed to bone marrow injury and
cytokine dysregulation, or identified as part of MDS. A pro-
portion of dogs with MF respond to immune suppression and
antifibrotic drugs, whereas some dogs with MF and MDS
progress to AML. Infection of cats with some strains of FeLV
aggregates, which is an irreversible and progressive lesion.
Chronic lymphocytic leukemia.  Chronic lymphocytic leuke-
mia (CLL) is the most common leukemia in dogs. Approxi-
mately 70% are of T-cell type, arise in the splenic red pulp,
and have minimal bone marrow involvement. The other 30%
are of B-cell type, arise in bone marrow, are frequently associ-
ated with a monoclonal gammopathy, and cause gradual
myelophthisis. CLL should be suspected in middle-aged to
older dogs with lymphocytosis of small- to medium-sized
cells. Lymphocytosis may be mild or extreme. Immunopheno-
typing distinguishes neoplastic from reactive polyclonal lym-
phocytosis of inflammatory conditions. CLL is an indolent
leukemia, and survival of more than 1 year after diagnosis is
common for both T- and B-cell types. In a small proportion
of dogs, CLL cells do not express typical T- or B-cell antigens,
and these dogs have shorter survival. Diagnosis of CLL may
be incidental during CBC for another indication; thus the
duration of CLL prior to diagnosis may be highly variable and
affect data concerning survival.
CLL occurs in older cats, and is also an indolent leukemia.
The T-cell type is much more common than the B-cell type,
organomegaly is uncommon, and mild anemia, likely resulting
from myelophthisis, is common. Mean survival with chloram-
bucil treatment was >1 year. CLL in old horses is a rare condi-
tion, and both B-cell and T-cell types have been reported.
Advanced small cell lymphoma with leukemia may be dif-
ficult to distinguish from advanced CLL with involvement of
lymph nodes. Clinical history and historical laboratory data
may distinguish the conditions that, at an advanced disease
state, have similar prognosis and therapy.
 136.e1

Further reading
Perez-Alenza MD, et al. Clinico-pathological findings in cattle exposed
to chronic bracken fern toxicity. N Z Vet J 2006;54:185-192.
Weiss DJ, Aird B. Cytologic evaluation of primary and secondary myelo-
dysplastic syndromes in the dog. 2001;32:67-75.
 Bone Marrow
A teinuria. Bleeding diatheses, including epistaxis, gingival bleed-
B proteins detected in serum or urine. Lytic bone lesions are
C by identifying morphologically abnormal and highly frequent
Figure 2-27  Myelofibrosis in a dog. A. The dog had anemia,
and teardrop-shaped (arrowhead) and oval (arrows) erythrocytes
in the blood smear. B, C. Bone marrow was patchy with fibrous
tissue and areas of hematopoietic cells.
Mastocytosis.  Bone marrow involvement in mast cell neo-
plasia of dogs is most often the result of metastatic spread of
high-grade solid mast cell tumors to multiple hemolymphatic
sites. Mastocythemia in cats is rare, and in most instances
reflects release of cells from visceral (usually splenic) or cuta-
neous mast cell tumors. Primary bone marrow mastocytosis is
137
a rare MPN in dogs and cats not associated with solid mast
cell tumors. Animals have gradually progressive myelophthisis
(see Fig. 2-24).
Multiple myeloma.  Multiple myeloma (MM) is a malignant
tumor of plasma cells that occurs in older animals. In dogs and
horses, the tumor is most often located in the medullary cavity
of bones with active bone marrow, and frequently at multiple
sites. Animals with MM are usually presented with a history
of lameness or paresis secondary to spinal cord compression,
or the neoplasm may be suspected from the radiographic
evidence of multiple foci of bone lysis. Other clinical signs are
usually nonspecific and include lethargy, weakness, and
anorexia. Hypercalcemia may occur in the course of disease
as a result of bone lysis, and polyuria, polydipsia, and kidney
disease occur secondary to hypercalcemia and light-chain pro-
ing, retinal hemorrhage, and, less frequently, melena or
hematuria, are common. In cats, malignant plasma cell tumors
are more often located at extramedullary sites, either in
abdominal organs or skin. In most MM, the neoplastic cells
secrete a clonal immunoglobulin (also called paraprotein or M
protein) that is detectable by serum electrophoresis as a mono-
clonal protein. Free light chains readily cross the glomerulus;
therefore, in many cases, urine protein electrophoresis is a
sensitive means of identifying clonal immunoglobulin light
chains (Bence Jones proteins) that may not accumulate in
serum.
Diagnostic criteria for MM in people are applicable to dogs,
and require presence of neoplastic cells in bone marrow plus either
serum or urine monoclonal proteins or osteolytic lesions. In cats,
diagnostic criteria for MM are presence of a plasma cell tumor,
either in abdominal organs or bone marrow, plus monoclonal
uncommon in cats. Cutaneous plasma cell tumors in cats may
also be associated with monoclonal gammopathy, and have a
better prognosis than those involving abdominal organs. The
diagnosis of MM is usually made by fine-needle aspiration or
bone marrow core biopsy from an area of bone lysis. Immu-
noglobulin G (IgG) followed by IgA gammopathies are most
common.
Nonsecretory MM has been reported, and differentiation
from plasmacytoid lymphoma is based on the location of
MM in the bone medullary cavity causing bone lysis. Cellular
features of MM are similar to those of plasma cells, and
can include binucleation or multinucleation and moderate
anisokaryosis and anisocytosis. Some infectious agents such
as Ehrlichia and Leishmania may induce clonal immunoglobu-
lin production, which needs to be differentiated from MM
plasma cells, and with serologic assays. Plasma cell features
in bone marrow supportive of a diagnosis of MM are propor-
tion >5% of nucleated cells, occurrence in clusters, and abnor-
mal morphology, such as binucleation or multinucleation,
anisocytosis, and anisokaryosis. Clustering of bone marrow
plasma cells is best identified on histopathology, and in
some cases proximity to osteoclasts indicates bone lysis
(Fig. 2-28).
Circulating nonhematopoietic neoplastic cells.  Cancers
that metastasize via the blood stream frequently shed low
numbers of cells that may be detectable in blood with highly
sensitive techniques such as flow cytometry. Sufficient
numbers to be apparent on routine review of blood smears
may occur with disseminated histiocytic sarcoma, high-grade
138 CHAPTER 2  •  Hematopoietic System
A
B animals, the bone marrow and the thymus as well as the liver
C organized tissues that include the tonsils and Peyer’s patches
Figure 2-28  Multiple myeloma in a dog. A. Plasma cells in bone
marrow aspirate are morphologically normal but very numerous.
B. Bone marrow biopsy shows uneven cell density at low magni-
fication. C. At high magnification, plasma cells predominate in
dense areas.
mast cell tumors, and widely metastatic carcinomas. In most
instances, prominent neoplastic cells on blood or bone marrow
films reflect bone marrow metastases and advanced cancer.
Morphology is generally sufficient for distinction from neo-
plastic leukocytes.
Lymphoid Organs
Further reading
Campbell MW, et al. Chronic lymphocytic leukaemia in the cat: 18
cases (2000-2010). Vet Comp Oncol 2013;11:256-264.
Comazzi S, et al. Immunophenotype predicts survival time in dogs with
chronic lymphocytic leukemia. J Vet Intern Med 2011;25:
100-106.
Giraudel JM, et al. Monoclonal gammopathies in the dog: a retrospec-
tive study of 18 cases (1986-1999) and literature review. J Am Anim
Hosp Assoc 2002;38:135-147.
Mellor PJ, et al. Myeloma-related disorders in cats commonly present
as extramedullary neoplasms in contrast to myeloma in human
patients: 24 cases with clinical follow-up. J Vet Intern Med
2006;20:1376-1783.
Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, risk-
stratification, and management. Am J Hematol 2014;89:915-925.
LYMPHOID ORGANS
The lymphatic system consists of lymphatic organs and a
conducting network of lymphatic vessels that carry the circu-
lating lymph directly toward the heart. Because the lymphatic
vessels are a major component of the circulatory system, they
have been discussed in the chapter on cardiovascular diseases.
The bone marrow, lymph nodes, spleen, thymus are classified
in the Nomina Anatomica Veterinaria as lymphoid organs.
However, these organs are also part of the immune system,
which is more complex and includes a number of other organs
and tissues. Central or primary lymphoid organs provide lym-
phoid precursor cells that circulate and take up residence in
peripheral or secondary lymphoid organs. In most domestic
are considered primary lymphoid organs. Peripheral lymphoid
organs include the spleen and the lymph nodes, which are
responsible for production of antibodies and cell-mediated
immune responses. Furthermore, there are numerous types
of mucosa-associated lymphoid tissues (MALTs) that repre-
sent local collections of lymphoid tissue that underlie the
submucosa, such as the gastrointestinal tract–associated lym-
phoid tissue (GALT) or the bronchus-associated lymphoid
tissue (BALT). Other such locations of lymphoid tissues at
various sites of the body include the conjunctival-associated
lymphoid tissue (CALT); the nasal-associated lymphoid tissue
(NALT); the larynx-associated lymphoid tissue (LALT); the
duct-associated lymphoid tissues (DALT) of different salivary
glands, including mammary glands; and the skin-associated
lymphoid tissue (SALT). MALT can be further divided into
and diffuse lymphoid cells in epithelial layers and their under-
lying connective tissue that are not organized into a structure
such as the SALT. The Peyer’s patches are a major site of
B- and T-cell production after thymic involution, and can
therefore be classified as primary and secondary lymphoid
organs.
In other chapters, pathologic changes have been character-
ized based on primary or secondary disease processes affecting
a particular organ system. This is extremely difficult for the
lymphoid organs because they play a central role in many
immune-mediated disease processes that manifest in nonlym-
phoid organs. In most disease processes, the lymphoid organs
have a vital immunologic function; however, the pathophysi-
ologic processes of the lymphoid cells do not necessarily
 138.e1

Further reading
Amati M, et al. Carcinocythaemia (carcinoma cell leukaemia) in a dog:
an acute leukaemia-like picture due to metastatic carcinoma. J
Small Anim Pract 2012;53:476-479.
Blackwood L, et al. European consensus document on mast cell
tumours in dogs and cats. Vet Comp Oncol 2012;10:e1-e29.
Cian F, et al. Leukemic small cell lymphoma or chronic lymphocytic
leukemia in a horse. Vet Clin Pathol 2014;42:301-306.
Geigy C, et al. Multiple myeloma in a dog with multiple concurrent
infectious diseases and persistent polyclonal gammopathy. Vet Clin
Pathol 2013;42:47-54.
Hikasa Y, et al. Connective tissue-type mast cell leukemia in a dog. J
Vet Med Sci 2000;62:187-190.
Piviani M, et al. Significance of mastocytemia in cats. Vet Clin Pathol
2012;42:4-10.
Ramos-Vara JA, et al. Immunohistochemical detection of multiple
myeloma 1/interferon regulatory factor 4 (MUM1/IRF-4) in canine
plasmacytoma: comparison with CD79a and CD20. Vet Pathol
2007;44:875-884.
Weiss DJ. Bone marrow pathology in dogs and cats with non-
regenerative immune-mediated haemolytic anaemia and pure red
cell aplasia. J Comp Pathol 2008;138:46-53.
Workman HC, Vernau W. Chronic lymphocytic leukemia in dogs and
cats: the veterinary perspective. Vet Clin North Am Small Anim Pract
2003;33:1379-1399.
 Lymphoid Organs
manifest as changes in the lymphoid organs themselves. For
those diseases, the reader is referred to the appropriate chapter
with the manifestation of the immunologic function within
that organ. Furthermore, the bone marrow is also the major
component of the myeloid tissues and has therefore been
discussed previously. However, the division of myeloid and
lymphoid organs is arbitrary given that some disorders of
erythrocytes are caused by antibody formation and could also
be classified as a disease of lymphocytes. The liver, together
with the yolk sac, plays a major part as the primary site of
blood cell formation during early ontogeny and may be,
together with bone marrow, the primary site of maturation or
production of B lymphocytes in mammals. This is evidenced
by the large number of islets of hematopoietic cells within the
parenchyma of the fetal liver. Similarly, the yolk sac may also
represent a site of production of immature hematopoietic
cells. Regardless, detailed discussions of the liver, the yolk sac,
and the MALT can be found in the appropriate chapters. This
section will only discuss disease processes that manifest within
the thymus, spleen, and lymph nodes.
Developmental diseases of
the lymphoid system
Immunodeficiency
Immunodeficiency syndromes are characterized by an
increased risk of the host becoming infected by various patho-
gens, including less virulent or even commensal organisms or
uncommon pathogens, and to be less responsive to standard
antimicrobial therapies. These syndromes are a reflection of
the immune system’s inability to protect the host against
infectious disease or the development of neoplastic diseases.
In general, antibody deficiencies are associated with bacterial
infections, and cell-mediated deficiencies are associated with
protozoal, fungal, viral, or obligate intracellular bacterial infec-
tions. The vast majority of immunodeficiencies are caused by
an acquired impairment of the immune system that can be
caused by malnutrition, aging, neoplastic or infectious dis-
eases, or chronic diseases. Such immunodeficiencies are also
referred to as secondary immunodeficiencies. In contrast, primary
immunodeficiencies are caused by genetic or congenital defects.
Most of these deficiencies manifest themselves early in life,
and the affected animal is often clinically described as “poor
doing” or failing to thrive. However, in some animals, primary
immunodeficiencies may manifest clinically only later in life.
The type of infection in affected animals often indicates which
component of the immune system may be defective. This
chapter will only discuss primary immunodeficiencies character-
ized by an absence or defect in a class or subclass of lymphocytes
derived either from bone marrow or thymus. Primary immuno-
deficiencies caused by defects of phagocytic cells, or of com-
plement, or secondary immunodeficiencies, or the failure to
passively transfer immunoglobulin from dam to offspring are
not included in this chapter. Primary defects in adaptive
immune response can be partial or combined, affecting either
only T cells or B cells or both. Such conditions usually lead to
severe combined immunodeficiency.
Immunoglobulin deficiencies.  These primary immunode-
ficiencies are characterized by an immunoglobulin deficiency
that can affect all 3 types of major immunoglobulins (agam-
maglobulinemia) or appear as selective deficiencies of indi-
vidual classes of immunoglobulins (selective immunoglobulin
deficiency).
139
Agammaglobulinemia is characterized by lack of all types
of major immunoglobulins and an absence of mature B cells
and plasma cells. It occurs in male foals, and affected horse
breeds include Thoroughbreds, Quarter Horses, and Standard-
breds. Equine agammaglobulinemia resembles Bruton con-
genital X-linked agammaglobulinemia of human infants in
both expression and progression. In humans, there is a muta-
tion in the BTK gene encoding Bruton tyrosine kinase, which
is closely related to the Src kinase family. This kinase is
required for B-cell maturation, and B-cell development is
arrested in the pre-B stage. Histologically, there is an absence
of plasma cells and germinal centers in lymph nodes, Peyer’s
patches, and tonsils, but the thymus is normal.
Selective deficiencies of immunoglobulins can be observed
in any class of immunoglobulins, but selective IgM and IgA
deficiencies have been reported in dogs and horses. These
diseases are characterized by serum levels of the affected
immunoglobulin being at least 2 standard deviations below
normal values, but B-cell counts are normal. Clinical signs
commonly manifest after degradation of maternal antibodies.
An IgM deficiency occurs in foals of Quarter Horse and Arabian
breeding, and both sexes are affected. IgM deficiencies
are very rare in humans. In affected foals, immunoglobulin
levels vary from undetectable to 10% of normal, and the
lymphocyte counts are normal, with normal proportions of
B- and T-derived classes. These animals have neutrophilic leu-
kocytosis without anemia and are presented for examination
at 4-8 months of age with febrile disease involving the respira-
tory tract. Most animals die as a result of septicemia or pneu-
monia before 10 months of age. The few surviving horses will
have recurrent respiratory infections, and most die before
reaching full adulthood. In dogs, an IgA deficiency has been
reported in Beagles, German Shepherd dogs, Irish Setters, and
Shar Peis. IgA deficiencies are the most common deficiency in
humans in the United States. They are usually asymptomatic,
but can be associated with autoantibodies to IgA, recurrent
respiratory diseases, allergies, and autoimmune diseases. In
dogs, affected animals may have disease manifestation in the
skin, gastrointestinal tract, or respiratory tract. Atopy is
common. The number of lymphocytes, and plasma cells in
affected dogs appear normal, suggesting an inability to produce
or secrete IgA.
Severe combined immunodeficiency.  Severe combined
immunodeficiency (SCID) describes a group of diseases that
are characterized by defects in both humoral and cellular immu-
nity. In most cases, both B- and T-cell lineages are affected,
and animals with SCID have lymphopenia, nonresponsiveness
of lymphocytes to antigen stimuli, and minimal levels of
immunoglobulins or responses to immunization. Although
numerous defects have been shown to cause SCID in humans,
and mouse models of SCID have been developed, in domestic
animals, SCID has only been described in foals, primarily of
the Arabian breed, and Basset hounds, Cardigan Welsh Corgi,
and Jack Russell Terrier dogs.
SCID occurs in ~2% of Arabian and Arabian-crossbred foals,
but the incidence of phenotypically normal heterozygotes will
be much higher. Both sexes are affected, and the disease is the
result of an autosomal recessive trait expressed as an absence of
both B- and T-lymphocyte functions. The genetic defect is a
spontaneous frame-shift mutation of the PRKDC gene encod-
ing the catalytic subunit of DNA-dependent protein kinase
(DNA-PKcs) located on chromosome 9. The mutation causes
a complete loss of function of DNA-PKcs, which is required
140 CHAPTER 2  •  Hematopoietic System
for formation of functional V regions during recombination of
immunoglobulin heavy-chain and T-cell receptor genes. This
results in an inability to produce functional T and B cells.
Furthermore, DNA-PKs have an important function in DNA
repair, and affected horses have been shown to have defects
in their DNA repair mechanism. Homozygous horses rarely
live beyond 5 months of age; heterozygous horses have a
higher risk of developing equine sarcoids in the skin. Whether
a single allele mutation in PRKDC predisposes such horses to
the development of neoplastic disease is unknown as is the
potentially synergistic effect of the mutation and bovine papil-
lomavirus 1 and 2 infection, which has been associated with
the development of equine sarcoids.
Foals with SCID are normal at birth, but at ~10 days of
age develop a range of diseases, including pneumonia and
diarrhea, that are commonly associated with equine adenovi-
ruses, Cryptosporidium parvum, and Pneumocystis carinii infec-
tions. Foals commonly develop bilateral nasal discharge that
becomes sufficiently profuse to impair suckling. There is pro-
gressive weight loss and intermittent pyrexia with coughing,
depression, and rough haircoat. Intractable respiratory disease
is the most common clinical sign, but diarrhea and swollen joints
are also observed. In spite of intensive therapy, affected foals
die at 3-5 months of age.
Hematologically, the animals are profoundly lymphopenic,
and it is suggested that counts of <1 × 109/L are diagnostic for
the disease. Lymphopenia is present from birth and is constant
throughout life. Because IgM is synthesized by the normal
equine fetus, absence of IgM from serum of foals that have not
suckled supports a diagnosis of SCID. In animals from 1-100
days of age, the serum IgM and IgA levels are low and remain
between 0.2 and 0.6 g/L. The IgG, which is maternally
derived, progressively drops from 8.0 g/L shortly after birth
to 2.0 g/L in foals that approach 100 days of age. There is
usually mild anemia that increases in severity with resistant
and repeated infections, but is often masked by dehydration.
Leukocyte counts are highly variable, being primarily depen-
dent on the numbers of neutrophils. Reduced lymphocyte
levels in blood are usually more than compensated by neutro-
philia, so that total leukocyte counts are usually in the normal
range.
The characteristic lesions in foals with SCID are bilateral
cranioventral bronchopneumonia in association with hypoplasia
of all lymphoid tissue, including thymus, lymph nodes, and spleen.
The thymus is identified only as a thin mediastinal raphe
cranial to the heart. The bone marrow is unusually reactive
for the age of the animal, and hematopoiesis persists in cancel-
lous bone and partially occupies the central femoral cavities.
Terminally, areas of marrow that appear red grossly may be
hypoplastic with dilated sinusoids. Histologically, the lesions
in the lung are typical of a suppurative bronchopneumonia,
but basophilic adenoviral inclusion bodies are usually present
in the epithelial nuclei of bronchi and bronchioles as well as
other organs. The primary SCID lesion is marked lymphoid
hypoplasia of all lymphoid organs. The spleen has no lymphoid
follicles, the small arterioles are devoid of lymphocytic cuffs,
and there are no plasma cells. The lack of connective tissue
stroma in follicular sites helps to differentiate this hypoplastic
lesion from atrophy. Some spleens have increased extramedul-
lary hematopoiesis. The lymph nodes consist of a stromal
framework that is essentially an unoccupied superstructure.
The capsule is delicate, with the peripheral sinus often heavily
colonized by macrophages and granulocytes. Some lymph
Lymphoid Organs
nodes, particularly from the mediastinal area, may have corti-
cal microabscesses. Follicles are absent, and the cortex consists
of a reticular framework in which there are small foci of lym-
phocytes around small arterioles. Postcapillary venules have
high vesicular endothelium and are usually well demonstrated
because of the lack of perivascular and intramural lympho-
cytes. Medullary cords are collapsed, and medullary sinuses
are dilated and contain neutrophils and macrophages. If
thymus can be identified, it consists of small lobules of 1-2 mm
diameter surrounded by normal fat. The lobules have normal
stromal capsulation and consist almost entirely of medullary
structures with central Hassall’s corpuscles and a vesicular
reticular network with a very low lymphocyte population. The
presence of the Hassall’s corpuscles is worthy of note because,
besides identifying the tissue as thymus, their presence also
indicates that there has been successful embryologic migration
of the epithelial duct system. In human infants, the corpuscles
are present only in SCID patients with an enzyme deficiency
of adenosine deaminase (ADA), whereas in X-linked SCID
the thymus only contains lobules of undifferentiated epithelial
cells resembling fetal thymus.
An X-linked SCID has been reported in Basset Hounds and
Cardigan Welsh Corgi dogs that is characterized by defects in
the gene encoding the gamma chain that is common to the
receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and
IL-21. Affected dogs therefore cannot complete the signal
transduction pathways of any of these interleukins. Different
mutations in the gamma chain of the IL-2 receptor are also
the most common mutations encountered in SCIDs in
humans. Similarly, different mutations have been detected in
Basset Hounds (4 base-pair deletion in exon 1) and Cardigan
Welsh Corgi dogs (single base-pair insertion in exon 4), and
the location of the mutation within target genes influences
the spectrum of diseases observed in affected animals. Because
the mechanisms of gene rearrangement are not impaired,
affected dogs have lymphocytes that express mature T- and
B-cell markers. Therefore this variant of SCID is characterized
by only moderate lymphopenia, with normal percentages of
circulating B lymphocytes and low to normal percentages of
mature, but nonfunctional, T cells. There is a decrease in cir-
culating CD8-positive cells, and the ratio of CD4 to CD8 cells
is ~15 : 1 compared to 2 : 1 in normal dogs. Affected dogs also
have normal serum level concentrations of IgM. In contrast,
serum IgG and IgA concentrations are significantly reduced or
not detectable, respectively. Only antibodies of the IgM class
are produced, which is consistent with an inability to class-
switch to IgG and IgA. Affected puppies fail to produce anti-
bodies in response to immune stimuli, including vaccination
and are highly susceptible to bacterial and viral infections.
They rarely live more than 3-4 months. As with SCID in
horses, lymphoid organs are severely hypoplastic, and tonsil,
thymus, Peyer’s patches, or lymph nodes are often grossly
undetectable. The histologic changes are similar to those
described in horses. The small lobules of the thymus have few
to no lymphocytes, and there is no corticomedullary demarca-
tion. The ratio of CD8 to CD4 lymphocytes has markedly
shifted toward CD8-positive cells. Similar to human X-linked
SCID, Hassall’s corpuscles are not detectable.
An autosomal recessive SCID as a result of a mutation in
DNA-PKcs has also been described in Jack Russell Terriers
(Fig. 2-29). Both the mechanisms and the pathology, including
adenoviral hepatitis, are similar to reports in Arabian foals. A
single litter of Rottweiler puppies was suspected to have SCID
 Thymus
A median survival times of 7 months. This syndrome is similar
B Don-van’t Slot HP, van der Kolk JH. Severe combined immunodeficiency
Figure 2-29  Severe combined immunodeficiency (SCID) in a
dog. A. Thymic hypoplasia characterized by small lobules that
have few to no lymphocytes and no corticomedullary demarca-
tion. B. Immunohistochemistry for CD3 highlights the loss of T
cells.
based on few T cells and few follicles with B cells in lymphoid
tissues and abnormally low IgA levels. The mechanisms of this
syndrome were not investigated.
T-cell immunodeficiency.  Rare T-cell immunodeficiencies
have been reported in dogs and cattle. In Weimaraners, a
growth hormone deficiency has been reported that was associ-
ated with constant severe bacterial infections and poor growth
rates. Affected puppies not only had decreased levels of
growth hormones, but also low T-cell counts. The thymus was
small, and there was loss of corticomedullary delineation
because of the absence of T cells. Affected puppies had normal
leukocyte counts and gammaglobulins and were able to
produce antibody in response to bacterial challenges. The
underlying mechanisms are unknown. Treatment with bovine
growth hormone was beneficial. In humans, mutations in the
STAT5b gene have been described causing a combined phe-
notype of growth hormone insensitivity and immunodefi-
ciency because of T-cell lymphopenia. Clinical findings
included congenital growth hormone deficiency that mani-
fested as persistently low growth rate, severely delayed bone
age, and postnatal growth failure as well as recurrent infec-
tions of the skin, severe chronic lung disease, and multiple
141
episodes of herpetic keratitis because of T-cell immunodefi-
ciency. Growth hormone receptors and IL-2 receptors share
STAT5 proteins for their signaling pathways, which would
explain the dual deficiency. Whether similar mutations exist
in Weimaraners is unknown.
In Bull Terrier dogs, an autosomal recessive acrodermatitis has
been associated with an ultimately fatal syndrome character-
ized by growth retardation, progressive acrodermatitis, chronic
pyoderma, diarrhea, pneumonia, and abnormal behavior.
Affected puppies had decreased plasma zinc concentrations
and a reduced lymphocyte response to antigenic stimulation.
Clinically, they had neutrophilia, parakeratosis, hyperkeratosis,
superficial bacterial infections of the skin, bronchopneumonia,
and dilation of the cerebral ventricles. There was a severe
decrease of T cells in all lymphoid organs. Affected dogs had
to acrodermatitis enteropathica in humans that is associated
with thymic atrophy and a selective decline of CD4-positive
T helper cells.
A similar autosomal recessive disease, called lethal trait
A46, has been described in Friesian and Shorthorn cattle. The
disease is characterized by a reduced capacity to absorb zinc
through the intestinal tract, causing anorexia, diarrhea, alope-
cia, and hyperkeratosis. Furthermore, affected cattle have a
reduced lymphocyte response to antigenic stimulation,
reduced levels of CD4-positive T cells, and a relative decrease
of B cells.
Further reading
Bell TG, et al. Autosomal recessive severe combined immunodeficiency
of Jack Russell terriers. J Vet Diagn Invest 2002;14:194-204.
disease (SCID) in the Arabian horse. Tidschr Diergeneeskd
2000;125:577-581.
Flaminio MJ, et al. Common variable immunodeficiency in horses is
characterized by B cell depletion in primary and secondary lymphoid
tissues. J Clin Immunol 2009;29:107-116.
Perryman LE. Molecular pathology of severe combined immunodefi-
ciency in mice, horses, and dogs. Vet Pathol 2004;41:95-100.
Tallmadge RL, et al. Expression of essential B cell development genes
in horses with common variable immunodeficiency. Mol Immunol
2012;51:169-176.
Verfuurden B, et al. Severe combined immunodeficiency in Frisian
Water Dogs caused by a RAG1 mutation. Genes Immun
2011;12:310-313.
THYMUS
Structure and function of the normal thymus
The thymus is a composite organ of epithelial and lymphoid
tissues, both of which have distinct developmental origins. The
thymic anlage develops from the third paired branchial (pha-
ryngeal) pouch of the foregut endoderm. Endodermal diver-
ticula arise bilaterally from the middle series of the branchial
pouches. Following outgrowths of the epithelial component to
the cranial mediastinal area, the ducts connecting the diver-
ticula to the pharynx soon disappear, setting the thymus anlage
free. While extending laterally and backward, the diverticula
grow into the surrounding mesoderm and neural crest–derived
mesenchyme of the branchial arch and give rise to the capsule,
trabeculae, and blood vessels. The diverticula lose their lumina,
and their lower ends enlarge and migrate caudally toward the
 141.e1

Further reading
Crisman MV, Scarratt WK. Immunodeficiency in horses. Vet Clin North
Am Equine Pract 2008;24:299-310.
Felsburg PJ, et al. Canine X-linked severe combined immunodeficiency.
Vet Immunol Immunopathol 1999;69:127-135.
Fox-Clipsham LY, et al. Population screening of endangered horse
breeds for the foal immunodeficiency syndrome mutation. Vet Rec
2011;169:655.
Hutchison JM, et al. Immunodeficiency syndrome associated with
wasting and opportunistic infection in juvenile llamas: 12 cases
(1988-1990). J Am Vet Med Assoc 1992;201:1070-1076.
Meek K, et al. SCID dogs: similar transplant potential but distinct intra-
uterine growth defects and premature replicative senescence with
SCID mice. J Immunol 2009;183:2529-2536.
Moroff SD, et al. IgA deficiency in Shar-Pei dogs. Vet Immunol Immu-
nopathol 1986;13:181-188.
Nolte T, et al. Oxazolone and ethanol induce colitis in non-obese
diabetic-severe combined immunodeficiency interleukin-2R (null)
mice engrafted with human peripheral blood mononuclear cells.
Clin Exp Immunol 2013;172:349-362.
Roth JA, et al. Thymic abnormalities and growth hormone deficiency
in dogs. Am J Vet Res 1980;41:1256-1262.
Tallmadge RL, et al. Fell Pony syndrome: characterization of develop-
mental hematopoiesis failure and associated gene expression pro-
files. Clin Vaccine Immunol 2012;19:1054-1064.
Taylor SD, et al. Protective effects of broadly neutralizing immuno-
globulin against homologous and heterologous equine infectious
anemia virus in horses with severe combined immunodeficiency.
J Virol 2011;85:6814-6818.
142 CHAPTER 2  •  Hematopoietic System
thorax and become the thoracic lobes. The upper ends either
atrophy or persist as cervical lobes. In ruminants and pigs, both
large cervical lobes and thoracic lobes exist, whereas the cervi-
cal lobes vary in size in cats, are small in horses, and absent in
dogs. The thoracic lobe develops in all domestic animals in the
ventral portion of the cranial mediastinum, except in rumi-
nants, where it can be found dorsally.
There are 2 streams of epithelial migration, with that from
the uppermost part of the pharyngeal pouch forming the
thymic duct epithelium and later the Hassall’s (thymic) cor-
puscles, and that from the lower part of the pouch forming
the reticular epithelial component of the cortex and medulla of
the adult thymic lobule. Embryologically, the reticular epithe-
lial component first invades the mediastinal interstitium with
irregular, solid, rosette-like buds that enlarge to form the pri-
mordial lobules. This reticular epithelium forms loose cuffs
around small vessels that persist in adult life and become
obvious following lymphoid atrophy. The second component
migrates as a system of branching ducts that ramify in the
interlobular stroma and penetrate the lobules to form a central
cord that broadly communicates between the lobules of a
single lobe. In early development, this tubular system has a
basement membrane and layered epithelium that becomes
solid and cystic and loses the outer membrane in the mature
thymic medullary corpuscle. In terms of induction, it appears
that these medullary ducts are essential to colonization of the
thymic anlage by thymocytes (T lymphocytes at different
stages of development), and are the source of trophic thymic
hormones. The colonizing lymphocytes are derived from
Thymic cortical
epithelial cell Trabeculae
Thymocyte Capsule
Subcapsular
epithelium
Cortex
Medulla
Macrophage Hassall’s
Thymic medullary
(bone marrow origin) corpuscle
epithelial cell
Figure 2-30  Normal thymus in a dog. The illustration on the left depicts the thymic structure
and cell populations; the image on the right parallels the microscopic appearance of these
structures.
Thymus
blood islands of the primordial yolk sac. A further cell type,
which resembles striated muscle fibers, is of indefinite origin, but
has importance in the pathogenesis of myasthenia gravis.
These relationships are pertinent to the histologic interpreta-
tion of the thymus in pathologic states; as in dysplasia, atrophy,
regeneration, and hyperplasia, these components recapitulate
their embryologic relationships.
In most species, the thymus reaches maximal development
at about the time of puberty. It can become hyperplastic,
and in calves given repeated injections of endotoxin can
extend from the rami of the mandibles to the base of the
heart. Normally, the thymus regresses in adult life, and this
regression may be accelerated during severe or chronic illness,
but it never entirely disappears. Even a very small organ
weighing <10 g can be immunologically potent in autoim-
mune dysfunction.
The thymus differs from the spleen and lymph nodes in a
number of important aspects: There are no lymphoid follicles
and B lymphocytes in the normal thymus; there are no affer-
ent lymphatics, and the cortex is composed of small, densely
packed T-cell precursors and T lymphocytes at various stages
of proliferation and differentiation as well as apoptotic cells;
the medulla does not contain sinusoids, but instead represents
a mesenchymal-endothelial reticular network that contains
Hassall’s corpuscles and large numbers of lymphocytes (Fig.
2-30, eFig. 2-2). The thymic epithelial cells are best high-
lighted by immunohistochemistry for cytokeratins; pancyto-
keratin antibodies MNF116 or AE1/AE3 are most commonly
used to detect the different subpopulations of epithelial cells
Corticomedullary
junction
 142.e1

eFigure 2-2  Normal thymus in a cat.

 Thymus
and to visualize their multiple delicate interconnecting cyto-
plasmic processes. The lymphoid component is best character-
ized immunohistochemically by CD3. Cortical thymocytes
(immature T lymphocytes) will have cytoplasmic expression,
whereas medullary thymocytes are usually positive for both
membranous and cytoplasmic CD3. CD1a is only available
for frozen sections, and antibodies against terminal deoxynu-
cleotidyl transferase (TdT) or CD99 have only been estab-
lished in humans for cortical thymocytes. There is also an
appreciable number of CD20-positive B lymphocytes in the
medulla that may be the cells from which mediastinal large
B-cell lymphomas arise. These cells commonly synthesize IgG,
IgM, and IgD.
Thymic cortical lymphocytes are small cells with nuclei
slightly larger than erythrocytes, little internal nuclear detail,
and minimal cytoplasm. Despite their small size and lack of
nucleoli, there is intense lymphopoiesis in the peripheral
thymic cortex and continual migration of cells to the periph-
ery from this area. Most (99%) of this proliferation is ineffec-
tive and balanced by a high rate of cell death, apparently in a
process of immunologic selection. A complete turnover of
cells is believed to occur within 3-4 days. In normal states,
cortical lymphocytes are closely packed so that the cortex
appears uniformly dark histologically. In conditions of stress
and atrophy, cortical epithelial cells and phagocytes become
prominent, and these larger cells with ingested nuclear debris
give the cortex a moth-eaten appearance.
Thymic medullary lymphocytes are larger than their corti-
cal precursors and have a more vesicular nucleus with small
nucleoli and more cytoplasm. They appear less tightly packed
than the cortical cells and, with the higher density of epithelial
cells and the greater variability in nuclear size and shape, cause
the medullary areas to appear less dense histologically, giving
the thymus its characteristic corticomedullary differentiation. In
many disease states where the animal is faring poorly, this
corticomedullary boundary is indistinct and blurred by dilu-
tion of the cortical cells and an increase in macrophages in
both regions. In normal states, the squamous ductal epithe-
lium is obvious in central medullary areas, but the reticular
epithelium of the cortex and medulla is not apparent in the
background of cells and only becomes apparent following
atrophy of the lymphocyte population.
Physiologically, prothymocytes from bone marrow colonize the
outer cortex of the thymus, where they proliferate and are selected
and trained by the cortical epithelium. In this region, the epi-
thelial cells form large membrane-lined cavities called caveo-
lae in which the marrow-derived lymphocytes divide and
undergo phenotypic development. On release from the
marrow, prothymocytes have the ability to home selectively
to the thymus, but they lack helper, suppressor, or killer func-
tions. In contrast, peripheral T lymphocytes are characterized
phenotypically by CD4 (cluster derived, helper) or CD8 (sup-
pressor) expression, functionally by the major histocompati-
bility complex (MHC) determinants they recognize, and by
their collective inability to react against normal self-antigens.
The naive T cells arriving in the thymus from the bone marrow
express CD34 and CD7 and are pluripotent in their ability to
become types of T cells as well as dendritic or natural killer
(NK) cells. They undergo a sequential pattern of antigen
expression as a function of orderly gene rearrangements
encoding the T-cell receptor (TCR), which requires the activ-
ity of the recombinase genes (RAG-1 and RAG-2). The earli-
est T-cell development occurs in the outer cortex with the
143
expression of CD2 and CD44, and such cells are termed
“triple-negative” as they do not yet express CD3, CD4, or
CD8. Most T cells develop a TCR heterodimer composed of
α and β chains, and a much smaller proportion develop the
γδ TCR configuration. This rearrangement process brings vari-
able (V), diversity (D), and joining (J) gene segments together.
The numerous combinations among the V, D, and J segments,
together with non–template-encoded nucleotides (N) by ter-
minal deoxynucleotidyl transferase, for instance, V-N-D-N-J,
create the large repertoire of T-cell types within the αβ and
γδ T-cell lineages. Although intrathymic dendritic cells were
originally thought to derive from progenitors with lymphoid
potential, it has recently been shown that thymic dendritic
cells are also derived from myeloid-restricted progenitors.
Besides becoming CD3-positive with this level of maturation,
the young thymocytes expressing the αβ form of TCR also
express CD4 and CD8 molecules and are known as double-
positive cells during the time they express both molecules.
Those cells that recognize antigen in association with class II
MHC gain additional CD4 expression and lose CD8. Simi-
larly, those cells that recognize antigen in association with class
I MHC persist as CD8-positive cells. A much smaller popula-
tion of γδ T cells form a cytotoxic T-cell population as mature
cells. Thymocytes that do not pass the applied selection crite-
ria usually die through apoptosis.
Prothymocyte development is believed to occur within the
caveolae of the large epithelial “nurse cells.” Nurse cells tend to
express either MHC II, primarily in the cells of the outer
cortex and dendritic cells of the inner cortex, or, in association
with the more flattened reticular epithelium of the medulla,
expressing both type I and II determinants. This close apposi-
tion of epithelium and young lymphocytes permits the trans-
mission of inductive signals for proliferation and development,
or for death of the great majority of the cells produced. The
thymic nurse cells themselves produce interleukin-1 (IL-1),
which drives lymphoproliferation, and in the course of matu-
ration, the T cells acquire receptor and production capability
for IL-2, as well as other reactive lymphokines.
The progeny of this system are the recognition and regulation
specialists of the adult immune system. They identify antigens
presented to them by other cells as having either the MHC I
or II determinants, and determine the presence or absence
of foreign antigen, which is handled by killing or by stimula-
tion of antibody development. T-cell development involves
the rearrangement of the T-cell receptor genes analogous
to the same process by which the B cells gain antibody diver-
sity. Whereas B cells recognize antigen on the basis of molecular
shape, T-cell recognition is on the basis of peptides. Because
antigen is presented to the T cell by antigen-processing
phages and dendritic cells, denaturation of antigen is of no
consequence because it is the amino-acid sequence that is
detected as foreign. In nonhematopoietic cells, internal antigen
is displayed within a groove in the MHC I molecule on cell
membranes so that viral infection or tumor antigen are avail-
able for recognition by T lymphocytes. This process of cell
recognition is accomplished by intracellular transporter pumps
that display all of the proteins (self or foreign) produced
within the cell on the cell surface. The diversity of T-cell rec-
ognition appears to be a function of receptor diversity and
permits survival of cells with acceptable recognition of self
to avoid “holes” in antigen detection. Thus most NK cells
recognize targets without MHC restriction, whereas the
CD8+ cytotoxic cells with appropriate antibody mediate
144 CHAPTER 2  •  Hematopoietic System
antibody-dependent cytotoxicity (ADCC). Cytotoxic T cells
and NK cells can induce apoptosis in adjacent cells by releasing
cytotoxic granules called perforins or granzymes, both of which
act in a Ca2+-dependent manner.
Cells exiting the thymus have not only managerial recep-
tors but also “homing” receptors to guide them to appropriate
areas in the peripheral nodes and Peyer’s patches. Only 1-3%
of thymocytes bear homing receptors, all of which are in the
cortex and all of which are phenotypically mature. Thus it
appears that the homing direction is added last, with most of
the cortical cells homed to nodes and likely medullary cells homed
to Peyer’s patches.
It appears that the thymic epithelium, besides making
trophic hormone for the immune system, also makes the pep-
tides oxytocin and vasopressin in common with the pituitary,
thus indicating a mechanism for the interaction of the nervous,
endocrine, and immune systems.
In terms of ontogeny, lymphocytes first appear in the
thymus of the fetal lamb at day 43, nodes at day 45, spleen
at day 54, and Peyer’s patches at day 65. These relationships
are altered by fetal infection (see Vol. 3, Female genital
system). In the dog, the thymic epithelial anlage is present by
a gestational age of 23 days, lymphopoiesis begins by day 33,
and corticomedullary differentiation with formation of Has-
sall’s corpuscles is first evident at ~38 days.
Further reading
Cejalvo T, et al. Ephrin-B-dependent thymic epithelial cell-thymocyte
interactions are necessary for correct differentiation and thymus
histology organization: relevance for thymic cortex development. J
Immunol 2013;190:2670-2681.
Cheng G, et al. IL-2R signaling is essential for functional maturation of
regulatory T-cells during thymic development. J Immunol
2013;190:1567-1575.
Coquet JM, et al. Thymic epithelial cells use macroautophagy to turn
inside out for CD4 T cell tolerance. J Exp Med 2013;210:
715-728.
Farley AM, et al. Dynamics of thymus organization and colonization in
early human development. Development 2013;140:2015-2026.
Developmental diseases of the thymus
Thymic hypoplasia is commonly observed in a number of
immunodeficiencies that affect T cells. Nude mice have a
specific defect that results in developmental arrest of the
thymus and a defective cell-mediated immune response. In
humans, a condition called DiGeorge syndrome is caused by an
embryologic development defect of the third and fourth pha-
ryngeal pouches. The defect is caused by a deletion mutation
of a gene located on chromosome 22q11 and results in low
number of T cells in blood and lymphoid organs. Affected
individuals are predisposed to viral and fungal infections.
Although rare forms of right persistent aortic arch have been
associated with mutations in the DiGeorge syndrome critical
region of the canine chromosome 26, there have been no
reports of thymic hypoplasia caused by a DiGeorge-like syn-
drome in domestic animals.
In domestic animals, thymic hypoplasia most commonly
occurs as part of severe combined immunodeficiencies in foals or
certain breeds of dogs. In affected animals, the thymus is small
and consists of 1-2 mm diameter lobules that are almost
entirely depleted of lymphocytes, and thymic cortex is
Thymus
replaced by adipocytes. The only recognizable structures are
the thymic medulla and central Hassall’s corpuscles. In
X-linked SCID, Hassall’s corpuscles are not detectable.
A case of hypotrichosis and concurrent thymic hypoplasia
has been reported in a single litter of Birman kittens that all
died within the first 13 weeks of life. The condition is believed
to be autosomal recessive inherited.
Further reading
Casal ML, et al. Congenital hypotrichosis with thymic aplasia in nine
Birman kittens. J Am Anim Hosp Assoc 1994;30:600-602.
Philipp U, et al. A rare form of persistent right aorta arch in linkage
disequilibrium with the DiGeorge critical region on CFA26 in
German Pinschers. J Hered 2011;102(Suppl. 1):S68-S73.
Thymic involution and atrophy
The reduction of the size of the thymus is caused by alteration
of its cellular density and/or cellular composition. A physio-
logic, age-associated decrease of cellularity is called thymic
involution, whereas induced shrinkage of thymic lobules
caused by inadequate nutrition, intoxications, infectious
agents, lack of antigenic stimuli, medical therapy, and so on,
is referred to as thymic atrophy. Thymic involution is part of
the normal process of ageing that is gradual and irreversible. It
normally begins at sexual maturity and may be slowed by
dietary restriction or gonadectomy or can be accelerated by
toxic insult. The morphologic change of thymic involution
reflects its functional change from lymphocyte production to
recirculation.
Atrophy of the thymus is commonly observed in cachectic
animals and has been associated with vitamin B6, fatty acid,
or zinc deficiencies, all of which cause immunosuppression.
The recognition that a number of environmental and dietary
contaminants may accelerate immune deterioration has
resulted in the development of testing protocols specifically
designed to assess adverse effects of this nature. In a general
sense, thymic atrophy can be used as an index of disease severity
and duration in young animals, in which the organ would
normally be much larger.
The thymus is the most sensitive of the lymphoid tissues
to fluctuations in sex hormone levels, and changes in adreno-
cortical hormone levels or growth hormone levels. Elevated
levels of glucocorticosteroids as induced by stress can result in
significantly reduced thymic weight. Apoptosis of cortical thymic
T cells with secondary digestion by macrophages occurs
within hours of treatment with corticosteroids. However,
thymic atrophy secondary to stress-induced glucocorticoste-
roid levels is reversible upon removal of the stressor.
A further form of thymic atrophy occurs as a result of
exposure to a variety of environmental contaminants, with the
most serious effects being those caused by exposure to various
forms of dioxin and various congeners of the polychlorinated
and polybrominated biphenyls (PCB, PBB). Heavy metal ions
such as lead or mercury have direct effects on cell membranes,
organelles, or cell enzymes, causing apoptosis of cortical thy-
mocytes. Mycotoxins such as fumonisins B1 and B2 produced
by fungi of the genus Fusarium or aflatoxins can cause severe
lymphocytolysis of the thymic cortex.
The thymus is also highly sensitive to a wide variety of
immunotoxicants. Many physical, chemical, or other agents,
including anticancer drugs or radiation treatment, can cause
 144.e1

Further reading
Ardavin C, et al. Thymic dendritic cells and T cells develop simultane-
ously in the thymus from a common precursor population. Nature
1993;362:761-763.
Cowan JE, et al. the thymic medulla is required for Foxp3+ regulatory
but not conventional CD4+ thymocyte development. J Exp Med
2013;210:675-681.
LeFrancois L, Puddington L. The role of the thymus in intestinal intraepi-
thelial T-cell development. Ann NY Acad Sci 1996;778:36-46.
Pezzano M, et al. Questionable thymic nurse cell. Microbiol Mol Biol
Rev 2001;65:390-403.
Suster S, Rosai J. Histology of the normal thymus. Am J Surg Pathol
1990;14:284-303.
Wilson CB. The ontogeny of T lymphocyte maturation and function.
J Pediatr 1991;118:S4-S9.
 Thymus
Figure 2-31  Thymic atrophy in a dog. Infection with canine
distemper virus caused multilobular acute hemorrhage. Histologi-
cally, there was marked depletion of lymphocytes.
immune dysfunction resulting in immunosuppression evident
in marked thymic atrophy. Because the generation of T cells
in the thymus is especially important in the early stages of life,
immune system toxicants often have profound effects in even
low doses during prenatal and postnatal periods. Immunotox-
icity most commonly manifest as immunosuppression that
causes T-cell apoptosis and manifests as a decrease in relative
thymic weight in young animals. Very high doses of immuno-
toxicants can also cause degeneration of epithelial cells and
proliferation of glandular epithelial structures.
Many viruses, including canine parvovirus (CPV-2) and
canine distemper virus (CDV) in dogs (Fig. 2-31), feline pan-
leukopenia virus (FPV), feline leukemia virus (FeLV) and
feline immunodeficiency virus (FIV) in cats, equid herpesvirus
(EHV-1) in horses, classical swine fever virus (CSF) and
porcine reproductive and respiratory syndrome virus (PRRSV)
in pigs, and bovine viral diarrhea virus (BVDV) in cattle can
cause severe thymic atrophy.
Cats that succumb to feline parvoviral infection (panleuko-
penia) have marked thymic atrophy to the extent that the
organ may not be identifiable grossly, and can only be exam-
ined histologically by systematically sampling the cranial
mediastinal tissues. Microscopically, the thymus is character-
ized by collapsed lobules with angular facets to the lobes that
become flattened and triangular. The changes are uniform in
each lobule and consist of complete thymic atrophy with only
a very narrow rim of small lymphocytes 1-2 cells thick beneath
the capsule. Hassall’s corpuscles are prominent, and the
lobules in effect consist of a condensation of medullary tissue
and a prominent epithelial/stromal background that contains
a few large lymphoblasts (Fig. 2-32). Small lymphocytes
typical of cortical cells are virtually absent from the medullary
areas.
Cats infected with FeLV suffer thymic cortical atrophy of
variable degree, and a reduction in functional capability of
neutrophils that may persist for a year after viremia is cleared.
The p15E envelope protein appears to be the major factor in
impaired T-cell function, apparently by inhibition of IL-2 pro-
duction and responses. Interferon-γ production is inhibited,
and NK-cell cytolytic function is impaired, but binding to
target cells is unaffected. Circulating immune complexes con-
145
Figure 2-32  Thymic atrophy in a cat. Infection with feline pan-
leukopenia virus caused lobular collapse, and only a narrow rim
of lymphocytes remains beneath the capsule. Hassall’s corpuscles
are prominent, and there is condensation of medullary tissue.
tribute to the impairment of defenses, and some improvement
in condition can be achieved by their removal. There is an
age-related response to infection, with cats infected at <8
weeks of age surviving ~3 months, and cats 4 months of age
at infection surviving about a year. There is an early stage of
lymphoid hyperplasia accompanied by weight loss, and fol-
lowed by lymphoid depletion, lymphopenia, reduced lympho-
cyte response to lectins, hypogammaglobulinemia, ulcerative
stomatitis, diarrhea with necrosis of crypt epithelium, and
death. Thymic atrophy occurs in all cats that die, and termi-
nally there is marrow hypoplasia.
The lesions associated with FIV are largely those of immune
activation and secondary invaders, and the most specific
changes are in tests of immune cell number and function.
Neonatal cats infected with FIV will develop chronic thymic
atrophy and degeneration that is associated with decreasing
productive viral infection and low-level viremia. However,
fetal cats infected with FIV develop acute thymic atrophy at
birth associated with peak viremia. The thymus will partially
regenerate ~6 weeks postpartum because of decrease of pro-
ductive infection, and thymic size and architecture, including
cell numbers, will normalize. Infected cats maintained in a
clean environment survive indefinitely, but have reduced
numbers of CD4 lymphocytes and reversal of the CD4/CD8
ratio, suggesting specific infection of the helper cell popula-
tion. Lymphocyte response to lectins is reduced, and there is
reduced IL-2 production by cells from infected cats. The
disease process is likely accelerated when FeLV and FIV
coexist, which occurs in ~1% of sick cats. Both viruses may
be present in cats with lymphoma.
In foals aborted because of equid herpesvirus 1 infection, the
thymus is grossly normal or of reduced size with edema. There
is lack of distinction between cortical and medullary areas
given the loss of cortical cells. Cytologically, there is extensive
lymphocytolysis in the subcapsular areas, with pyknotic
nuclear debris persisting in these areas. The necrotic lesions
tend to be patchy, but there is an overall reduction in cell
density, with edema of the lobules and separation of lympho-
cytes by clear fluid (eFig. 2-3). Hassall’s corpuscles may be
surrounded by relatively clear spaces, and viral inclusion
 145.e1

eFigure 2-3  Thymic necrosis in a horse. Focally extensive necro-

sis caused by equine herpesvirus.
146 CHAPTER 2  •  Hematopoietic System Thymus

A
Figure 2-33  Thymic necrosis in a horse. Equine herpesvirus
caused extensive necrosis of lymphocytes. Pyknotic nuclear debris
persists in the multiple necrotic foci.

bodies are often present in medullary epithelial cells. There is,

in addition, a mild increase in monocytes and granulocytes in
the interlobular connective tissue. The presence of nuclear
debris in the outer cortices indicates acute lympholysis (Fig.
2-33). Foals that survive 1-2 days may remove the cellular
debris, and the cortices are then characterized by hypocellu-
larity alone.
Regardless of the mechanism, the end result of thymic involu-
tion or atrophy is loss of cortical lymphocytes and lobular shrink-
age, and the histologic changes are similar for both pathways.
Microscopically, there is apoptosis of cortical thymocytes that B
leads to cortical T-cell depletion and thinning of the thymic
cortex (Fig. 2-34). The process is accompanied by an increase
of tingible body macrophages. Perivascular spaces at the cor-
ticomedullary junction become prominent, and there is accu-
mulation of perivascular B cells and plasma cells that may
form lymphoid follicles with prominent germinal centers.
During the later stages of either disease process, the interlobu-
lar septa become more prominent, adipocytes infiltrate, and
ultimately the medulla has a higher cellular density than the
cortex. There is some degree of epithelial cell proliferation
occurring during that process that can lead to various degrees
of epithelial cell pleomorphism and architectural rearrange-
ment. Epithelial cords, tubules or even cysts may form during
that process.
It is basically impossible to differentiate thymic involution from
atrophy histologically, and the age of the animal and clinical C
presentation should be considered when making the diagnosis. It
is important to recognize that complete involution does not Figure 2-34  Thymic involution in a cat. A. Apoptosis of cortical
occur in any species, and remnants of thymic epithelial cells thymocytes leads to thinning of the thymic cortex, and there is
can usually be found embedded in some stroma in older loss of corticomedullary demarcation. Interlobular septa become
animals (Fig. 2-35). This may explain why thymomas can be more prominent. B. Immunohistochemistry (IHC) for CD3 high-
primarily found in dogs or cats older than 10 years. lights the loss of T cells. C. There is some degree of epithelial cell
Rarely, dystrophic mineralization secondary to renal or para- proliferation and architectural rearrangement that can be appreci-
thyroid disease and focal areas of fibrosis (Fig. 2-36) secondary ated with IHC for pancytokeratin.
to localized inflammation have been reported.

Further reading
Day MJ. Review of thymic pathology in 30 cats and 36 dogs. J Small
Anim Pract 1997;38:393-403.
 146.e1

Further reading
Chu I, et al. Subchronic toxicity of 3,3′,4,4′,5-pentachlorobiphenyl in
the rat. I. Clinical, biochemical, hematological and histopathological
changes. Fundam Appl Toxicol 1994;22:457-468.
Keenan KP, et al. The effects of overfeeding and moderate dietary
restriction on Sprague-Dawley rat survival, pathology, carcinogenic-
ity and the toxicity of pharmaceutical agents. Exp Toxic Pathol
1996;48:2-3.
Little S, et al. Feline leukemia virus and feline immunodeficiency virus
in Canada: recommendations for testing and management. Can
Vet J 2011;52:849-855.
National Toxicology Program. Mirex. Rep Carcinog 2011;12:273-275.
Orandle MS, et al. Selective thymocyte depletion and immunoglobulin
coating in the thymus of cats infected with feline immunodeficiency
virus. AIDS Res Human Retrovir 1997;13:611-620.
146.e2

A
eFigure 2-5  Thymic hemorrhage, in a dog. Extensive hemor-
rhage expands the thymic capsule and has largely replaced cortex
and medulla.

B
eFigure 2-4  Thymic hematoma in a dog. A. A well-circumscribed
single hematoma in the thymus. B. Idiopathic thymic hemorrhage
resulting in hemothorax in a dog. (Courtesy D.J. Patrick.)
 Thymus
Figure 2-35  Thymic remnant in a dog. Complete thymic involu-
tion does not occur, and thymic remnants can usually be found
embedded in some mediastinal stroma in older animals.
Figure 2-36  Thymic fibrosis in a dog. Focal areas of fibrosis occur
most commonly secondary to localized inflammation.
Kolenda-Roberts HM, et al. Immunopathogenesis of feline immunode-
ficiency virus infection in the fetal and neonatal cat. Front Biosci
2007;12:3668-3682.
Maranghi F, et al. Dietary exposure of juvenile female mice to polyha-
logenated seafood contaminants (HCBD,BDE-47,PCB-153, TCDD):
comparative assessment of effects in potential target tissues. Food
Chem Toxicol 2013;56:443-449.
Pathak S, Kundu R. Short-term PCB (Aroclor 1254) toxicity on few
phosphatases in mice brain. Dose Response 2013;11:1-8.
Pearse G. Histopathology of the thymus. Toxicol Pathol 2006;34:
515-547.
Thymic hemorrhages/hematoma
Severe thymic hemorrhage or thymic hematoma occurs most
commonly in young dogs that are presented with acute, severe
mediastinal hemorrhage, and they often die suddenly because
of hypovolemic shock. Affected dogs commonly exhibit
marked pallor in multiple organs consistent with anemia as a
result of massive blood loss into the thymus and thorax.
Grossly, the thymus and adjacent connective tissue are
147
Figure 2-37  Thymic hematoma in a dog. The thymus contains a
single, large, well-demarcated area of hemorrhage.
Figure 2-38  Idiopathic thymic hemorrhage in a dog. Extensive
hemorrhage expands the thymic capsule and interlobular septa,
and also extends into the thymic cortex and medulla.
extended by a large hematoma (Fig. 2-37), and severe hemor-
rhages are commonly found in the thoracic cavity causing
compressive atelectasis of the lungs (eFig. 2-4). Microscopi-
cally, there is extensive hemorrhage expanding the thymic
capsule and interlobular septa and also extending into the
thymic cortex and medulla and adjacent connective tissue
(Fig. 2-38, eFig. 2-5). Within hemorrhagic areas, there is a
mixture of fibrin, edema fluid, and inflammatory cells, pre-
dominantly neutrophils and macrophages. The affected
thymic parenchyma commonly undergoes lymphoid necrosis
(Fig. 2-39).
There is a wide range of causes for thymic hemorrhage,
including thoracic trauma, overstretching of the neck, rupture
of dissecting aortic aneurysms, bleeding thymic neoplasms, or
intoxication with anticoagulant rodenticides (Fig. 2-40). In
addition, a spontaneous idiopathic form has also been reported.
The suggested underlying cause for idiopathic thymic hemor-
rhages is thymic involution causing the thymus to become
fragile. Under these conditions, thin-walled thymic vessels
148 CHAPTER 2  •  Hematopoietic System
Figure 2-39  Idiopathic thymic hemorrhage in a dog. Hemor-
rhagic areas commonly contain foci of fibrin accumulation
admixed with variable numbers of inflammatory cells and necrotic
lymphocytes.
Figure 2-40  Thymic hematoma in a dog. Intoxication with anti-
coagulant rodenticides is one of the most common causes of
thymic hemorrhages/hematomas. (Courtesy K.G. Thompson.)
would lack support from the adjacent, lymphocyte-depleted
parenchyma and would be predisposed to hemorrhage in cases
of sudden increase of blood pressure or microtrauma. A single
case was reported in a puppy following transportation in an
unpressurized cargo chamber of an airplane during a multi-
hour flight. Idiopathic thymic hemorrhages are diagnosed in
young dogs following exclusion of other causes and morpho-
logic evidence of thymic involution, including depletion of
cortical lymphocytes and more pronounced Hassall’s corpus-
cles within an adipose tissue framework. Anticoagulant roden-
ticide poisoning must be excluded as the primary differential,
because it may cause localized fatal thymic hemorrhages
similar to those observed in the idiopathic form. However,
poisoned dogs may also have abnormalities in the intrinsic,
extrinsic, and common coagulation systems, including pro-
longed activated partial thromboplastin time, prolonged pro-
thrombin time, and prolonged activated clotting time. Stomach
content and liver should be collected to screen for anticoagu-
lants in cases of thymic hemorrhage.
Thymus
Further reading
Coolman BR, et al. Severe idiopathic thymic hemorrhage in two lit-
termate dogs. J Am Vet Med Assoc 1994;205:1152-1153.
Liggett AD, et al. Thymic hematoma in juvenile dogs associated with
anticoagulant rodenticide toxicosis. J Vet Diagn Invest 2002;
14:416-419.
Inflammatory diseases of the thymus
Inflammation of the thymus, thymitis, is a rather uncommon
lesion. Many infectious diseases, specifically viral diseases,
attack lymphoid cells, causing destruction of the lymphoid
component of the thymus. Viral infections most commonly
result in atrophy rather than an exudative or cellular inflam-
matory response, and atrophy can be the result of lysis of
lymphocytes or net emigration. Marked lymphocytolysis with
severe atrophy occurs in foals aborted because of infection
with equid herpesvirus 1, in cats with feline panleukopenia
virus, or in pigs with chronic classical swine fever virus infec-
tion, as discussed previously. In calves with epizootic bovine
abortion and dogs with salmon poisoning (rickettsiosis), there
is both lymphocytolysis and infiltration with inflammatory
cells. Bacteremia can cause thymitis, but suppurative inflam-
mation is uncommon, and abscesses have rarely been observed
(Fig. 2-41).
Epizootic bovine abortion, also known as foothill abortion,
is a tick-transmitted reproductive disease of pregnant cattle
that graze on foothill pastures in California and adjacent
states. The disease has recently been associated with a unique
16S deltaproteobacterial rDNA gene sequence that was detected
in 90% of thymus tissues from aborted fetuses. Intracytoplas-
mic bacterial rods were detected in thymuses of aborted
calves by using silver stains and immunohistochemistry by
using hyperimmune serum from infected cattle. Thymic
lesions develop late in the course of the disease and are char-
acterized by decreased size of thymic lobules. Histologically,
there is loss of cortical T cells and infiltration of the medullary
region with macrophages. The interlobular septa of the thymus
are distended with fibrin, hemorrhage, and inflammatory
cells, predominantly macrophages and fewer lymphocytes
(Fig. 2-42).
Neorickettsia helminthoeca (salmon poisoning disease) is
a North American rickettsial disease that occurs mainly in the
northwestern United States and western Canada and is trans-
mitted by the trematode Nanophyetus salmincola. The trema-
tode harbors the rickettsiae throughout its life-cycle stages.
The miracidia (ciliated larvae) develop from eggs in water and
enter snails (Oxytrema silicula) as the intermediate host. Free-
swimming larvae (cercariae) enter fish, the second intermedi-
ate host, mainly of the family Salmonidae. In salmon or trout,
metacercariae localize largely to the kidney, but can be found
in the eyes, liver, intestinal wall, musculature, and fins. When
an infected fish is ingested by the definitive host, adult trema-
todes attach and penetrate the intestinal mucosa of such fish-
eating mammals, including dogs. The flukes apparently cause
minimal damage or clinical signs to dogs, which shed fluke
eggs within about a week after ingestion of infected salmon
and continue to shed for ~8 months. The rickettsiae are inocu-
lated into the intestinal mucosa by the fluke via an unknown
mechanism. Dogs are apparently susceptible to the infection
at all ages, with the disease characterized by lethargy and
pyrexia with splenomegaly, generalized lymphadenopathy,
 148.e1

Further reading
Sheafor SE, Couto CG. Anticoagulant rodenticide toxicity in 21 dogs.
J Am Anim Hosp Assoc 1999;35:38-46.
van der Linde-Sipman JS, van Dijk JE. Hematomas in the thymus in
dogs. Vet Pathol 1987;24:59-61.
 Thymus
B Figure 2-42  Epizootic bovine abortion (foothill abortion) in a
Figure 2-41  Suppurative thymitis in a horse. A. Bacteremia can
cause suppurative thymitis, but grossly visible inflammation is
uncommon and abscesses are rarely observed. B. Histologically,
there is localized vasculitis with associated lymphocytolysis and
infiltration with inflammatory cells.
vomiting, and diarrhea. Following initial replication of the
rickettsiae in villar epithelial cells, the organisms are dissemi-
nated by histiocytic cells to the lymph nodes, spleen, tonsils,
thymus, liver, lungs, and brain. Dogs succumbing to infection
with salmon poisoning have marked enlargement of spleen
and lymph nodes with focal hemorrhages in the thymus
and pale often swollen liver with an exaggeration of the
lobular pattern visible through the capsule. In the thymus,
infection with N. helminthoeca causes depletion of lymphocytes,
foci of necrosis with neutrophilic infiltrates, and increased numbers
of histiocytes in the cortex and medulla (Fig. 2-43). Affected
lymph nodes are characterized by massive lympholysis and
loss of germinal centers and generalized cortical depletion of
cells. In animals that survive 10-12 days, there is prominent
node enlargement because of diffuse paracortical hyperplasia
with a prominent “starry-sky” appearance, but without the
development of germinal centers (eFig. 2-6). Splenic lesions
are characterized by follicular lympholysis in the acute phases
of the disease, as well as loss of cells in the periarteriolar
lymphoid sheaths. There is marked congestion of sinus areas
with numerous macrophages containing ingested debris as
well as the neorickettsial organisms. Hepatic lesions consist of
isolated foci of necrosis with macrophage reaction. The
149
calf. A. Thymic lesions develop late in the course of disease and
are characterized by decreased size of thymic lobules and pete-
chiae. B. Histologically, there is necrosis of cortical thymocytes,
and interlobular septa are distended with fibrin and inflammatory
cells. (Courtesy M.L. Anderson.)
gram-negative, 0.3-2.0 µm, pleomorphic organisms are located
exclusively within macrophages. They appear blue-purple with
blood stains, and blue with Macchiavello stain. At the time
dogs are showing acute signs of salmon poisoning, there are
usually large numbers of operculated fluke eggs in fecal
smears. Mortality rate is very high, and approaches 100% in
untreated animals. Organisms are present in virtually all
lymph nodes.
Salmon poisoning needs to be distinguished from a related
disease known as Elokomin fluke fever, named after the river
in Washington State where the disease was first recognized.
There are antigenic differences between the agent of salmon
poisoning and that of Elokomin fever (Neorickettsia elokomi-
nica), which were initially distinguished on the basis of the
specificities of the antibody reaction in surviving animals
applied in fluorescent antibody staining of the infectious
agents. The lesions in both diseases are similar.
Further reading
Anderson ML, et al. Histochemical and immunohistochemical evidence
of a bacterium associated with lesions of epizootic bovine abortion.
J Vet Diagn Invest 2006;18:76-80.
 149.e1

B
eFigure 2-6  Neorickettsia helminthoeca (salmon poisoning
disease) in a dog. A. N. helminthoeca causes increased numbers of
histiocytes in the cortex. B. Lower magnification of the lymph
node shows loss of lymphoid follicles and infiltrating histiocytes
in the cortex. (Courtesy R.J. Bildfell.)
150 CHAPTER 2  •  Hematopoietic System
A
B
Figure 2-43  Neorickettsia helminthoeca (salmon poisoning
disease) in a dog. A. N. helminthoeca causes cortical depletion of
lymphocytes and increased numbers of histiocytes in the cortex
and medulla. (Courtesy R.J. Bildfell.) B. The gram-negative,
0.3-2.0 µm, pleomorphic organisms are located exclusively within
macrophages and appear blue-purple with Wright stain. (Cour-
tesy J.L. Johns.)
Headley SA, et al. Neorickettsia helminthoeca and salmon poisoning
disease: a review. Vet J 2011;187:165-173.
Sykes JE, et al. Salmon poisoning disease in dogs: 29 cases. J Vet Intern
Med 2010;24:504-513.
Hyperplastic and neoplastic diseases
of the thymus
Thymic hyperplasia
Hyperplasia of the thymus is an often misleading term because
the size of the thymus varies widely and a larger thymus in a
young animal may simply represent physiologic variation.
Regardless, diffuse enlargement or large thymuses are com-
monly referred to as diffuse hyperplasia (Fig. 2-44). This
process may occur in any species, but is most commonly
observed in calves, rabbits, and birds that have been repeatedly
immunized. Grossly, the glands may fill the cranial mediasti-
num and extend up the neck in calves. The capsules remain
thin and delicate and the lobulation is distinct. The ratio of
cortical and medullary components is similar to that of a
Thymus
Figure 2-44  Diffuse thymic hyperplasia in a horse. Diffuse
enlargement or large thymuses are commonly referred to as
diffuse hyperplasia, but may simply represent a physiologic
variation.
Figure 2-45  Thymic follicular hyperplasia in a dog. Thymic fol-
licular hyperplasia indicates chronic inflammation or another
immunologic response, for instance, immune hemolytic anemia
or systemic lupus erythematosus.
normally sized thymus. Thymic enlargement is usually
observed as an incidental finding on autopsy, and no clinical
signs have been reported.
In most cases, thymic hyperplasia consists of lymphoid hyper-
plasia characterized by the development of B-cell germinal centers
and therefore referred to as follicular lymphoid hyperplasia. A
much less common form of lymphoid hyperplasia is called
focal lymphoid hyperplasia.
Follicular hyperplasia is the result of typical B-cell germi-
nal centers forming, usually at the corticomedullary junction
(Fig. 2-45). Follicular hyperplasia most commonly appears in
animals >6 months of age. The presence of hyperplastic lym-
phoid follicles in the thymus is independent of the size of the
actual thymus, and may be concurrent with thymic involution
or atrophy. In most cases, thymic follicular hyperplasia indi-
cates chronic inflammation or another immunologic response.
Follicular development has been reported in dogs with
 Thymus
immune hemolytic anemia and systemic lupus erythematosus,
but the frequency is not documented. Follicular hyperplasia
may also be found in association with thymoma, suggesting
some period of immune dysfunction preceding development
of the tumor. In humans, thymic follicular hyperplasia is
strongly associated with autoimmune disease, particularly
myasthenia gravis, and 75% of patients with myasthenia gravis
develop thymic follicular hyperplasia. Histologically, germinal
centers in the thymus may be surrounded by a thin layer of
epithelial cells and physiologically can be considered to be
outside of the thymus and do not indicate immune
dysfunction.
Focal hyperplasia is an unusual and incidental finding in
older animals, and is most often of the nonimmune type. It is
an appropriate term for lesions characterized by proliferation
of cortical lymphocytes in one or more lobules of the gland,
usually with compression of surrounding, often atrophic,
lobules, suggesting an attempt at regeneration. The lesions are
usually lightly encapsulated, often with some laminar infiltra-
tion of the perithymic tissues. Single epithelial cells are usually
scattered through a relatively diffuse area of lymphoid prolif-
eration. Focal hyperplasia of the thymic cortex is visible on
architectural or low-power examination by the presence of
increased numbers of large tingible body macrophages impart-
ing a “starry-sky” appearance, similar to that seen in a reactive
germinal center.
Epithelial hyperplasia is seen most frequently in the
thymus of rats, especially females, but has rarely been observed
in dogs. Treatment with diethylstilbestrol has caused similar
lesions in mice. In rats, the hyperplastic change is age associ-
ated and can be focal or diffuse, and is characterized by loosely
defined aggregates of cells arising at the corticomedullary
junction (Fig. 2-46). These aggregates are recognizable on
low-power examination by increased density because of a
greater proportion of small cells than the surrounding thymic
medulla. Epithelial cells are columnar to cuboidal and often
form cords or tubules. Tubular epithelial cells are commonly
ciliated and contain secretory material. Hassall’s corpuscles
appear not to be present within epithelial hyperplastic foci.
The significance of epithelial hyperplasia is unclear, but the
Figure 2-46  Thymic epithelial hyperplasia in a dog. Proliferating
epithelial cells are columnar to cuboidal and often form cords or
tubules.
151
lesion does not appear to undergo neoplastic transformation.
No clinical signs have been reported, and the lesion is primarily
important because of its resemblance to thymomas. In thymic
hyperplasia, there is always normal separation of cortex and
medulla, whereas thymomas have a diffuse architecture and
loss of corticomedullary delineation.
Pseudoepitheliomatous hyperplasia has rarely been
reported within thymic cysts in young dogs as a regenerative
response to thymic injury or inflammation. The hyperplastic
lesions are characterized by 1-8 layers of plump to slightly
attenuated polygonal squamous epithelial cells lining thymic
cysts. Scattered lymphocytes and Hassall’s corpuscles are com-
monly admixed within the squamous epithelial lining. The
squamous epithelial cells have indistinct cell borders; variable
amounts of wispy, pale eosinophilic cytoplasm; and vesicular
nuclei with peripheralized chromatin. Mitotic figures are
absent. The pleomorphic presentation of thymic pseudoepi-
theliomatous hyperplasia is similar to some variants of
thymoma; however, the association with thymic cysts and the
early onset of the lesion help distinguish the 2 entities.
Rarely, ectopic thymic tissue has been reported in some
animals.
Thymic cysts
Thymic cysts can occur in both the developing and mature
thymus, or persist during involution in the cranial mediasti-
num in all domestic species. Congenital thymic cysts are usually
thin walled and unilocular, whereas acquired thymic cysts are
often thick walled and multilocular. Cysts are lined by ciliated
columnar to cuboidal epithelial cells, indicating their origin
from the remnants of the branchial arch epithelium (eFig.
2-7). There are commonly histologic differences of the epi-
thelium within an individual cyst. Areas of ciliated epithelium
interchange with pseudostratified epithelium (Fig. 2-47).
Some epithelial cells may have elongated ovoid nuclei, whereas
others have narrower, indented nuclei. Although most cases
are incidental findings, if the cysts become large, they may
cause dyspnea. In other cases, thymic cysts may be formed
secondary to compression and distortion of the normal thymic
parenchyma by a neoplastic process.
Thymic neoplasms
Primary neoplasms of the thymus are uncommon. The most
commonly observed neoplasms include thymic epithelial
tumors (thymomas and thymic carcinomas) and thymic lym-
phomas. Rare neoplasms include thymic germ cell tumors.
The distinction between thymomas with benign cellular fea-
tures from thymic carcinomas is often straightforward;
however, accurate diagnosis and subclassification of thymomas
with benign cellular features can be difficult. Most thymic
epithelial neoplasms have a favorable long-term prognosis follow-
ing surgical removal, but a small subset will recur or metastasize.
Furthermore, like other thymic diseases, thymic epithelial
neoplasms increase the risk of having one or more autoim-
mune disorders, most notably myasthenia gravis. Thymomas
in the cat may be associated with a type of chronic exfoliative
dermatitis. The successful management of autoimmune disease
remains one of the biggest challenges, especially in dogs.
Unfortunately, there is little information available that would
allow predicting the likelihood of occurrence of paraneoplas-
tic syndromes, such as myasthenia gravis or erythema multi-
forme, based on the observed thymic epithelial neoplasm
subtype.
 151.e1

eFigure 2-7  Thymic cyst in a dog. The cyst is lined by ciliated

columnar and attenuated epithelial cells.
152 CHAPTER 2  •  Hematopoietic System Thymus

A B
Figure 2-47  Thymic cyst in a dog. A. Cysts are lined by ciliated columnar to cuboidal epithelial
cells indicating their origin from the remnants of the branchial arch epithelium. B. Immunohisto-
chemistry for pancytokeratin is useful for identifying the epithelial lining.

Table • 2-4 
The WHO classification of thymic epithelial neoplasms as applied for use in animals
Histologic subtype Histologic criteria

Type A thymoma Neoplastic thymic epithelial cells are spindle/oval shaped, lack nuclear atypia, and are accompanied
by few, if any, non-neoplastic lymphocytes.
Micronodular thymoma Neoplastic spindle-shaped epithelial cells form nodules that are separated by large aggregates of
predominantly B cells. Immunohistochemistry for pancytokeratin highlights the distinct separation
of the 2 cell components. This thymoma is probably a subtype of type A thymoma.
Type AB thymoma Neoplastic epithelial cells have cellular features of type A thymoma and are admixed with foci of
non-neoplastic lymphocytes. The segregation of such foci can be sharp or indistinct, and a wide
range exists in the relative amount of the 2 components.
Type B1 thymoma Neoplastic epithelial cells closely resemble the normal thymus with an appearance almost
indistinguishable from thymic cortex with some areas resembling thymic medulla.
Type B2 thymoma Neoplastic epithelial cells are plump with vesicular nuclei and distinct nucleoli and are scattered
among a heavy population of non-neoplastic lymphocytes. Perivascular spaces are common and
prominent.
Type B3 thymoma Neoplastic epithelial cells are round or polygonal and exhibit no or only mild atypia. They are
admixed with a minor component of non-neoplastic lymphocytes, which results in a sheet-like
growth of neoplastic epithelial cells.
Thymic carcinoma Neoplastic epithelial cells have malignant cellular features and are named based on their
differentiation status. They lack immature lymphocytes, and lymphocytes within the tumor tend
to be mature and are usually admixed with plasma cells.
Combined thymoma Benign thymic tumors that demonstrate a combination of thymoma subtypes.
Thymoma (type X) with anaplasia Subgroup of tumors with morphologic features between a thymoma and thymic carcinoma.
WHO, World Health Organization.

Thymic epithelial tumors are uncommon cranial mediastinal
neoplasms that are derived from the thymic epithelial components
of ectodermal origin with the potential to differentiate toward
either a cortical or medullary phenotype. They are highly vari-
able histologically, making their diagnosis and classification
difficult. In human medicine, different histologic classifica-
tions have been proposed for thymic epithelial tumors to
better correlate their histology with clinical behavior, but
the 2004 World Health Organization (WHO) classification
scheme for thymic epithelial tumors is most widely used. This
classification has also been shown to be applicable to thymic
epithelial tumors in dogs (Table 2-4). The morphologic basis for
this classification is the cell morphology of the neoplastic epithelial
cells and the relative proportion of non-neoplastic lymphocytes. It
is rare for thymic epithelial tumors to be purely epithelial, and
the association of lymphocytes with epithelium, even in meta-
static sites, suggests that the latter retains some lymphoid
inductive capacity, notwithstanding the malignant state. The
2004 WHO classification system for thymic epithelial tumors
identifies encapsulated or invasive thymomas and thymic
 Thymus
Figure 2-48  Thymoma in a dog. The vast majority of thymomas
in dogs or cats are heavily encapsulated.
Figure 2-49  Thymoma in a dog. Large, well-circumscribed mass
in the cranial mediastinum with multifocal hemorrhages.
carcinomas. Because invasive thymomas can only be distin-
guished from encapsulated thymomas when the entire neo-
plasm is available for histologic examination, this distinction
is rarely applicable in veterinary medicine. Furthermore, the
vast majority of thymomas in dogs or cats tend to be slow
growing, heavily encapsulated, and rarely metastasize (Fig.
2-48). Dogs with surgically excised thymomas have a favor-
able long-term prognosis for both invasive and noninvasive
thymomas. Given their rarity and their generally favorable
postsurgery outcome, thymic epithelial neoplasms have not been
extensively studied in most animal species and are commonly only
classified as thymomas or thymic carcinomas, with the latter
being exceedingly rare. In dogs, cats, horses, and occasionally
cattle, thymic epithelial neoplasms most commonly occur
with clinical signs of respiratory and/or cardiovascular impair-
ment, whereas they are usually seen as incidental findings at
autopsy in sheep and goats.
Thymomas.  Thymomas occur in dogs and cats 10-12 years
of age (Fig. 2-49, eFig. 2-8). They have historically been clas-
sified on the basis of cellular composition and the type and
degree of atypia of the epithelium as lymphocytic, epithelial, or
mixed. A clear cell thymoma variant has been described in a
153
Figure 2-50  Compressed thymic remnant in a dog. Remnant of
normal thymus has been compressed to the periphery of the
thymic capsule by the expanding thymoma.
Figure 2-51  Thymoma in a goat. Large mediastinal masses in
female, adult goats, most likely represent thymomas. (Courtesy
K.G. Thompson.)
single dog. Regardless of their histologic appearance, thymo-
mas tend to be localized to one lobe, or, more commonly, a
remnant of benign thymus may be found compressed to the
periphery of the thymic capsule (Fig. 2-50). In the cat, thy-
momas may occasionally occur as an ectopic mass in the
mid-cervical area and are often focally cystic. Goats, especially
female goats, have a high likelihood of developing thymomas
at 7-8 years of age (Fig. 2-51). Most caprine thymomas are
completely contained within the thoracic cavity and vary
in size from 3-8 cm in diameter. They are encapsulated,
often cystic, and may have large areas of ischemic infarction
(Fig. 2-52).
A more accurate classification of thymomas is based on
2 major histologic thymoma phenotypes that demonstrate
 153.e1

B
eFigure 2-8  Thymoma in a dog (A) and a sheep (B). A. The
thymoma appears as an expansile mass in the mediastinum.
B. Cross section of a large well-circumscribed thymoma with
multifocal areas of cyst formation.
154 CHAPTER 2  •  Hematopoietic System
Figure 2-52  Thymoma in a goat. The thymoma is encapsulated,
cystic, and areas of neoplasm have undergone ischemic infarction.
(Courtesy K.G. Thompson.)
benign cellular features. Type A thymomas are composed of
spindle-shaped cells, and type B thymomas are composed of epi-
thelioid cells. Admixtures of spindle-shaped cells and epitheli-
oid cells are designated as type AB thymomas. Type B thymomas
are further subdivided into type B1, B2, or B3 thymomas. The
relative ratio of the epithelial cell population compared to
non-neoplastic lymphocytes is the major distinguishing feature
between the different type B thymomas. A major diagnostic
difficulty involves the recognition of epithelium in the lym-
phocytic type, which distinguishes it from thymic lymphoma.
Because some thymomas may have marked intratumoral het-
erogeneity, they are also classified as combined thymomas
with a percentage of each component noted. Occasionally,
cystic changes may become so prominent that the neoplasm
might be misdiagnosed as a thymic cyst. Rare clear cell or
plasma cell–rich variants have been observed in dogs.
The spindled epithelium in type A thymomas is usually
arranged in storiform, fascicular, or pericytomatous pattern
(Fig. 2-53). These cells have uniform elongated nuclei with
dense chromatin and inconspicuous nucleoli. Mitoses are
absent. Rare signet ring cells and pseudorosettes are observed.
In many cases, there is focal formation of microcystic or glan-
dular spaces that may even contain secretory material. These
cystic structures are branchial duct remnants and have a lining
that varies from squamous to columnar and ciliated, and may
change abruptly from one form to the other. They most likely
do not represent true glandular structures, but are formed by
stromal edema. Lymphocytes are usually rare to absent and
represent a more mature medullary lineage. This subtype rep-
resents ~10% of canine thymomas.
Micronodular thymoma is probably an unusual variant of
type A thymoma and exceedingly rare (Fig. 2-54). Most com-
monly, features of this type of thymoma can be observed in
some lobules of type A thymomas. It is characterized by mul-
tiple nodules composed of epithelial spindle cells with similar
morphology to what has been described with type A thymoma.
These nodular structures are separated by an abundance of
lymphocytes that may form follicular centers. Many lympho-
cytes are actually B cells admixed with a few T cells. Immu-
nohistochemistry for pancytokeratin helps to visualize the
total separation between the epithelial and lymphoid
Thymus
A
B
Figure 2-53  Type A thymoma in a dog. A. Neoplastic cells are
spindle-shaped, lack nuclear atypia, and are accompanied by a few
non-neoplastic lymphocytes. B. Neoplastic spindle cells are posi-
tive for pancytokeratin with immunohistochemistry.
aggregates. There are no epithelial cells in the lymphoid com-
ponent, whereas lymphocytes still infiltrate the epithelial
component.
Type B thymomas are the most common subtype of canine
thymomas, representing ~70% of all cases, with types B1
(24%) and B2 (36%) being most common. They are also fre-
quently seen in cattle, sheep and goat, and rarely in horses.
Grossly, they appear as irregularly shaped masses 5-15 cm in
diameter, with irregular rounded projections, and most often
firm fibrous encapsulation. Type B1 thymomas represent the
greatest diagnostic challenge because they most closely resem-
ble the normal thymus and have the most dense lymphocyte
population that may be misdiagnosed as a lymphoid neoplasm
(Fig. 2-55). Type B1 thymomas appear as lobulated masses
that resemble an exaggeration of normal thymic structure and
are separated by fibrous septa. Among the most characteristic
features are randomly distributed foci of pale-staining medul-
lary differentiation, which may be misdiagnosed as pale-
staining proliferation centers in chronic B-cell lymphocytic
leukemia on low magnification, and the background of epi-
thelial cells with large ovoid nuclei and small nucleoli that can
be easily recognized on high magnification. Epithelial cells do
not form aggregates. Scattered poorly developed Hassall’s
 Thymus 155

A A

B B
Figure 2-54  Micronodular thymoma in a dog. A. Multiple
nodules composed of neoplastic epithelial spindle cells separated
by an abundance of lymphocytes. B. Immunohistochemistry for
pancytokeratin shows the epithelial character of the proliferating
spindle cells.

corpuscles are present singly and in cornified clusters and help

distinguish these neoplasms as thymomas. The infiltrating thy-
mocytes are mostly immature T cells. Immunohistochemistry
for cytokeratin will highlight the neoplastic epithelial cells.
Cytologically, type B1 thymoma is difficult to distinguish from
lymphoma on fine-needle aspirates and relies on the recogni-
tion of epithelial cells with large, pale nuclei and abundant
cytoplasm throughout the material obtained. If epithelial cells
are not readily apparent in the aspirate, immunocytochemistry C
for cytokeratin might prove helpful.
Type B2 thymomas also have prominent lobulation. Figure 2-55  Type B1 thymoma in a dog. A. Type B1 thymomas
Neoplastic epithelial cells are plump with vesicular nuclei closely resemble the normal thymic cortex, and dense populations
and distinct nucleoli and are scattered singly or as clusters of small lymphocytes can mask the large neoplastic epithelial cells
among a heavy population of non-neoplastic lymphocytes in the background. B. In foci of pale-staining medullary differen-
(Fig. 2-56). In contrast to type B1 thymomas, epithelial cells tiation, lymphocytes are less densely packed. C. Immunohisto-
are more easily recognized and stand out more easily from the chemistry for pancytokeratin highlights neoplastic epithelial cells
lymphocytic background. Although immature non-neoplastic in the background.
lymphocytes are abundant, they are less prominent than in
type B1 thymomas. Lymphoid follicles with germinal centers particularly myasthenia gravis and less often polymyositis.
may be observed. Prominent germinal centers with plasma Perivascular spaces are common and prominent. These peri-
cells present in their vicinity and along the fibrous septa have vascular spaces are characterized by cuffs of palisading epithe-
especially been reported in dogs and cats, where such follicular lial cells around small veins that create a clear space resembling
activity has been associated with autoimmune disease, a lymphatic. Immunohistochemical staining for cytokeratins
156 CHAPTER 2  •  Hematopoietic System
A
B
Figure 2-56  Type B2 thymoma in a dog. A. Epithelial cells form
discrete groups surrounded by lymphocytes and are easily recog-
nizable. B. Clear cells can be the dominant neoplastic cell type in
thymomas, and these cells are rich in glycogen.
will highlight the palisading epithelial cells and the striking
resemblance to perivascular spaces in the normal thymus.
Type B3 thymomas are characterized by lobules of round
or polygonal epithelial cells that exhibit no or only mild atypia
and separated by thick fibrous septa (Fig. 2-57). They are
admixed with a minor component of non-neoplastic imma-
ture T lymphocytes, which results in a sheet-like growth of
neoplastic epithelial cells. Palisading of epithelial cells around
small veins or fibrous septa is prominent, but perivascular
spaces tend to be narrow or may undergo hyalinization. The
epithelial cells have oval to irregular nuclei with inconspicu-
ous nucleoli and ample eosinophilic cytoplasm that often
shows some perinuclear clearing. Some cells have a squamous
appearance. Few mitoses can be found. It is not uncommon
to find a transition from B2 to B3 thymomas in the same
neoplasm.
Type AB thymomas represent ~15% of canine thymomas.
This type of thymoma is seen most frequently in the goat and
sheep as space-occupying lesions. They tend to appear as well-
formed lobules composed of the lymphocyte-poor type A
thymoma component and the lymphocyte-rich type B
thymoma component (Fig. 2-58). The percentage of each
component will vary among neoplasms and even within the
same neoplasm, with one component being predominant in
Thymus
Figure 2-57  Type B3 thymoma in a dog. Neoplastic epithelial
cells are round to polygonal and admixed with only small numbers
of non-neoplastic lymphocytes.
Figure 2-58  Type AB thymoma in a dog. Sharply demarcated
areas of type A thymoma on the right and type B thymoma on
the left.
one area but not the other. Both components can appear as
histologically distinct areas or intermixed with each other. In
the latter form, the spindled epithelial cells of the type A
component commonly form septum-like structures that sur-
round the type B component. These tumors often have firm
encapsulation with regular, but coarse septation, but with
minimal stroma in the pseudolobular areas. Cystic spaces are
frequently present as part of the type A component and
are not seen in pure type B thymomas. Lymphocytes in the
type B component commonly have smaller nuclei with
indistinct nucleoli than usually observed in B1 or B2 thymo-
mas. Hassall’s corpuscles are rarely present in the type B
component.
Malignant thymomas are classified as thymic carcinomas
(Fig. 2-59). Thymic carcinomas are further subdivided into
additional subtypes based on the presence of histologic
features that are not found in the normal thymus, for
instance, squamous cell carcinoma, clear cell carcinoma, and
lymphoepithelioma-like carcinoma. All of these entities are
rare; squamous cell carcinomas are the most commonly
 Thymus
Figure 2-59  Thymic carcinoma in a dog. Anaplastic malignant
epithelial cells are arranged in tubulopapillary structures.
observed thymic carcinoma in dogs. These neoplasms are
lobulated, have ample hyaline stroma, and neoplastic cells
have pleomorphic, vesicular nuclei. Mitoses are common, and
a high mitotic index (>10 mitoses/high-power field [HPF])
carries a worse prognosis. Islands of neoplastic cells undergo
squamous differentiation with various degrees of keratiniza-
tion, and are surrounded by desmoplastic stroma that is com-
monly infiltrated by plasma cells and mature lymphocytes.
Thymic carcinomas are highly invasive and have to be dif-
ferentiated from pulmonary squamous cell carcinomas that
invade the mediastinum. Accurate diagnosis is relevant because
pulmonary carcinomas carry a worse prognosis. In humans,
thymic carcinomas are commonly positive for KIT; a similar
expression profile has not been described in domestic animals.
Thymoma (type X) with anaplasia is the suggested diag-
nostic term for a very uncommon group of thymomas that
demonstrate morphologic features that do not fit into either
the thymoma or thymic carcinoma categories.
Myasthenia gravis is an autoimmune disorder of humans,
dogs, and cats, characterized by progressive muscle weakness
and reduced exercise tolerance. Specific areas of involvement
include the facial and extraocular muscles with the develop-
ment of megaesophagus associated with difficult swallowing,
regurgitation, and aspiration pneumonia. It can be congenital
or acquired. Only acquired myasthenia gravis commonly
occurs secondary to thymic abnormalities, especially thymoma
in dogs and thymic follicular hyperplasia in humans. All of the
physiologic features of the acquired myasthenia gravis can be
accounted for by the reduction in functional acetylcholine recep-
tors of neuromuscular junctions (see Vol. 1, Muscle and tendon).
The disease arises as an immune-mediated phenomenon,
whereby an antibody reaction is developed against the thymic
myoid cells that express intact acetylcholine receptors. The myoid
cells tend to be associated with Hassall’s corpuscles and the
germinal centers, which resemble those of antigen-activated
lymph nodes, and diffuse areas of B-cell proliferation that are
centered on the medullary areas with sparing of the cortex,
which is often reduced in volume. It has been hypothesized
that thymic epithelial cells present epitopes from the isolated
acetylcholine receptor subunits, which they express and auto-
immunize helper T cells. These helper T cells induce an early
antibody response directed against the rare thymic myoid
157
Figure 2-60  Thymic lymphoma in a dog. A large, homogeneous,
pale mass expands the cranial mediastinum.
cells. The autoantibodies diversify in the resulting germinal
centers and recognize native acetylcholine receptors. Myasthe-
nia gravis is primarily caused by the attachment of antibodies to
skeletal muscle acetylcholine receptors of the postsynaptic mem-
brane, leading to decreased of functional receptors. In addition,
antibodies against titin and ryanodine receptors have been
shown to be associated with more severe disease, an older
onset, or the presence of a thymoma in humans and dogs.
Although the physiologic role of titin is unknown, ryanodine
receptors act as calcium-release channels in skeletal muscle
and are therefore important for excitation/contraction cou-
pling in skeletal muscle. In a thymoma model in mice, even
in the absence of acetylcholine receptor antibodies, antibodies
against ryanodine receptors caused severe skeletal muscle
weakness. Recent studies in humans strongly suggest that
myasthenia gravis may develop after viral infections, leading to
interferon I overexpression, together with the activation of
innate immunity pathways in thymoma-associated myasthe-
nia gravis. This hypothesis is supported by detection of neu-
tralizing antibodies against interferon I in thymoma-associated
myasthenia gravis patients, but not in patients with thymomas
without muscular disease or those with normal thymuses.
However, no specific viral etiology has been described. Surgi-
cal removal of the neoplastic or hyperplastic thymus has been
reported to restore muscle function.
Thymic lymphomas.  In general, lymphoid tumors of the
cranial mediastinum in cats and cattle, and less commonly dogs,
are most commonly precursor T-lymphoblastic lymphomas (see
details of the histologic and immunohistochemical features
under lymphomas) that can be easily misdiagnosed as
lymphocyte-rich thymomas (eFig. 2-9). A less common type
of thymic lymphoma that has rarely been observed in dogs is
a large B-cell lymphoma (Fig. 2-60). Because these neoplasms
have rarely been reported, there is limited data on whether
they truly resemble mediastinal B-cell lymphoma in humans
or are actually diffuse large B-cell lymphomas arising in the
mediastinal lymph nodes.
In the cat, mediastinal lymphomas can reach a large size,
with dorsocaudal displacement of the lungs before they are
presented for clinical examination (Fig. 2-61). There is a wide
age distribution of feline thymic lymphoma, with 90% occur-
ring relatively evenly between 1 and 10 years of age.
 157.e1

B
eFigure 2-9  Thymic lymphoma in a dog (A) and a pig (B). A. A
large, homogeneous, pale mass has displaced the lungs caudally.
(Courtesy K.G. Thompson.) B. Thymoma and mediastinal lym-
phoma are often difficult to differentiate grossly.
158 CHAPTER 2  •  Hematopoietic System
A tic germ cells seen in seminomas, and are large, discrete, rounded,
B 515-547.
Figure 2-61  Thymic lymphoma in a cat. A. The thymic lym-
phoma has displaced the lungs caudodorsally. There are mul­
tifocal areas of necrosis and petechiae throughout the mass.
B. Precursor T-cell lymphoblastic lymphoma characterized by
diffuse, dense infiltrates of monomorphic, intermediate-sized lym-
phoid cells with oval or folded convoluted nuclei with dispersed
chromatin and indistinct nucleoli.
Involvement of the lung, even by direct extension, is unusual,
although there may be infiltration into the atria and through
the pericardium into the base of the heart and around the
origins of the great vessels. Infiltration beneath the sternal
pleura is consistently present. Metastases may be widespread,
but they are rare and small compared to the mediastinal neo-
plasm, suggesting that these lesions spread by local expansion
until late in the disease.
Thymic lymphoma in cattle characteristically occurs in
yearlings of the beef breeds, and is not associated with infec-
tion with bovine leukemia virus (BLV). Typically, there is
swelling, sometimes massive, at the base of the neck, and
brisket edema. Bloating and dysphagia associated with esopha-
geal compression are common. The animals are seldom leu-
kemic, although in advanced cases there are usually neoplastic
lymphocytes in the peripheral blood without changes in abso-
lute numbers of cells, and neoplastic cells may be identified
in sternal marrow aspirates. The thymic lymphoma may
extend from the rami of the mandibles to the base of the
heart, with a constriction at the entrance to the thoracic cavity,
and may weigh 20 kg or more. They are lightly encapsulated
Spleen and Hemolymph Nodes
and infiltrate the surrounding tissues, often with smooth,
rounded, shiny implants appearing on the pulmonary and
parietal pleura. There is compression of the lungs by tumor
and excess pleural fluid. The lungs themselves may be focally
invaded but are rarely extensively involved. Invasion of the
pericardial sac produces pericardial effusion that contains neo-
plastic lymphocytes in large numbers. On cut surface, the
tumors are gray with irregular yellow areas of infarction that
have hyperemic borders, and they tend to have coarse col-
lagenous septation.
Thymic germ cell tumors.  Rarely, primary germ cell
tumors, resembling seminomas, occur in the thymus in the
absence of a primary neoplasm in the testicle. However, the
possibility of a previously removed testicular neoplasm should
always be excluded. The neoplastic cells closely resemble neoplas-
or polygonal. The cytoplasm is eosinophilic or palely baso-
philic and scanty, finely granular, and encloses a relatively
large, central, oval, or rounded nucleus with usually a single
prominent nucleolus. Rare karyomegaly and binucleated cells
occur. Areas of necrosis and foci of lymphocytes are typically
present. Necrotic foci cause a characteristic feature of thymic
seminomas that manifests as variable numbers of round clear
spaces throughout the neoplasm, which give the lesion a moth-
eaten appearance. Neoplastic cells are immunohistochemi-
cally positive for Oct4 and negative for CD45 and CD18.
Further reading
Lara-Garcia A, et al. Cervical thymoma originating in ectopic thymic
tissue in a cat. Vet Clin Pathol 2008;37:397-402.
Pearse G. Histopathology of the thymus. Toxicol Pathol 2006;34:
Ponce F, et al. A morphological study of 608 cases of canine malignant
lymphoma in France with a focus on comparative similarities
between canine and human lymphoma morphology. Vet Pathol
2010;47:414-433.
Rickman BH, Gurfield N. Thymic cystic degeneration, pseudoepithelio-
matous hyperplasia, and hemorrhage in a dog with brodifacoum
toxicosis. Vet Pathol 2009;46:449-452.
Robat CS, et al. Clinical features, treatment options, and outcome in
dogs with thymoma: 116 cases (1999-2010). J Am Vet Med Assoc
2013;243:1448-1454.
Suster S, Moran CA. Histologic classification of thymoma: the World
Health Organization and beyond. Hematol Oncol Clin North Am
2008;22:381-392.
Tepper LC, et al. Diagnosis of erythema multiforme associated with
thymoma in a dog and treated with thymectomy. J Am Anim Hosp
Assoc 2011;47:19-25.
Tillman H, et al. Application and clinical relevance of the WHO histo-
logical classification system to canine thymomas. Vet Pathol
2009;46:1043.
Zitz JC, et al. Results of excision of thymoma in cats and dogs: 20 cases
(1984-2005). J Am Vet Med Assoc 2008;232:1186-1192.
SPLEEN AND HEMOLYMPH NODES
Structure and function of the normal spleen
The spleen is a peripheral lymphoid organ that, together with
the hemal nodes, is also part of the blood circulatory system,
and functions as an effective filter of blood through a sinusoidal
system.
 158.e1

Further reading
Hadlow WJ. High prevalence of thymoma in the dairy goat. Report of
seventeen cases. Vet Pathol 1978;15:153-169.
Oksanen A. Fine structure of epithelial thymus cysts in dogs. Acta
Pathol Microbiol Scand [A] 1977;85:470-480.
Rottenberg S, et al. Thymoma-associated exfoliative dermatitis in cats.
Vet Pathol 2004;41:429-433.
Shelton GD, et al. Titin and ryanodine receptor autoantibodies in dogs
with thymoma and late-onset myasthenia gravis. Vet Immunol
Immunopathol 2001;78:97-105.
Willcox N, et al. Autoimmunizing mechanisms in thymoma and thymus.
Ann N Y Acad Sci 2008;1132:163-173.
 Spleen and Hemolymph Nodes
The spleen develops between the serosal membranes that
are part of the dorsal mesogastrium that connects the stomach
to the cranial abdominal wall and from which the greater
omentum develops. The spleen is a highly elastic organ of
purple-gray color that tends to be darker in herbivores and
redder in carnivores. There are significant differences in shape,
structure, attachment, and function of the spleen among
domestic animals, but all spleens are flattened, elongated
organs. The spleen is located primarily in the intrathoracic
portion of the abdominal cavity in the left cranial hypogastric
region. It is attached to the greater curvature of the stomach
by the gastrosplenic ligament, except in ruminants, where it
closely adheres to the dorsolateral aspect of the rumen. The
position of the spleen depends in carnivores and, to a lesser
degree in horses, on the amount of food in the stomach. Espe-
cially in dogs, large amounts of food content can displace the
spleen far caudally. Each spleen has a parietal or diaphrag-
matic surface and a visceral surface, a cranial and a sharp
caudal border, as well as a proximal and distal end. In carni-
vores, the spleen is dumbbell shaped with a wider distal end,
whereas in pigs it remains uniformly strap-like. In cows, the
spleen has the shape of an elongated oval, whereas in sheep
or goats it is more triangular or quadrangular, respectively. In
horses, the spleen is falciform with a broad dorsal end and a
pointed ventral end. On the visceral surface is the splenic hilus,
which is characterized by insertion of the greater omentum
and the splenic arteries and veins as well as the beginning of
the gastrosplenic ligament. In ruminants, the hilus appears as
a small grove only while the spleen is fused through connec-
tive tissue with the rumen at a serosa-free region. In rumi-
nants, the spleen is also anchored through the phrenicosplenic
ligament that connects the dorsal portion of the spleen to the
diaphragm. In horses, the gastrophrenic ligament becomes
the phrenicosplenic and splenorenal ligaments and connects
the spleen to the left kidney and the transverse colon.
On macroscopic examination, 3 components of the splenic
structure are recognizable: the splenic capsule and connective
tissue trabeculae, the red pulp, and the white pulp. A strong
capsule surrounds the spleen of all domestic animals, and the
trabeculae extend from the capsule internally. The chambers
between the trabeculae are filled with the soft splenic paren-
chyma, the splenic pulp. This pulp is composed of darker red,
blood-rich areas—the red pulp—that surround lighter-colored
areas that are devoid of erythrocytes—the white pulp.
Except for the serosal-free area in ruminants, the spleen is
covered by the peritoneum that continues onto the splenic
ligaments. The internal coat of the capsule, also called the
elastic coat, is formed by fibrous connective tissue with a high
percentage of elastic fibers, and in contrast to humans, up to
80% of this coat is composed of smooth muscle fibers. In
ruminants and pigs, a large percentage of smooth muscle fibers
can also be found in the red pulp. In carnivores, the internal
capsule is formed by a single layer, whereas in ruminants and
horses, 2 layers can be identified. The trabeculae extend from
the capsule into the splenic parenchyma and form, together
with the reticulum, the supporting stroma. The high percent-
age of elastic fibers combined with the capsular and trabecular
musculature allows for tremendous expansion of the spleen
in domestic animals and enables the spleen to store blood.
Spleens with such storage capacity are classified as storage
spleens, and horses and carnivores have the highest capacities
of domestic animals. Approximately 13 of the blood volume
can be stored in the spleen of dogs, and half of the circulating
159
blood volume can accumulate in the spleen of horses. Pigs and
ruminants have less capacity. Spleens that have limited storage
capacity are classified as defense spleens. Such spleens have
fewer elastic fibers and smooth muscles in their trabeculae and
capsule, and examples include the spleens of humans and
rabbits. The autonomic nervous system regulates the ability of
storage spleens to actively contract through innervation by
vagal and sympathetic fibers and release of catecholamines.
The spleen has no cortex or medulla, but the parenchyma
is composed of 2 distinct compartments: the white pulp and
red pulp (Fig. 2-62). The white pulp represents macrophages,
antigen-presenting cells, and B and T lymphocytes in the peri-
arteriolar lymphoid sheaths (PALS), the splenic follicles (Mal-
pighi bodies), and the marginal zone. The red pulp is composed
of a meshwork of reticular fibers, reticular cells, and associated
monocytes/macrophages, and surrounds the red pulp vascular
spaces.
To understand the structure and function of the red pulp
and white pulp, it is necessary to have a detailed understand-
ing of the blood circulation through the spleen. Blood vessels
are an important component of the splenic architecture and,
whereas arteries and veins are similar in all domestic animals,
the capillary beds of the red pulp differ. In cats and dogs, the
red pulp is richly supplied with an anastomosing network of
sinusoids, and the spleen is classified as a sinusoidal spleen. All
other domestic animals have a nonsinusoidal or reticular spleen
in which the penicillary arterioles empty into the red pulp
vascular space and only small numbers of venous capillaries
can be found in the red pulp. The main anatomic differences
between sinusoidal and nonsinusoidal spleens can be found
in the arterial vasculature. In dogs, arterial capillaries either
continue into the described venous sinusoids, or they termi-
nate into the red pulp vascular spaces. The continuous lining
by endothelium as observed for the circulation through the
sinusoids is called a closed system, whereas the interruption
of endothelial lining in vascular spaces is referred to as an
open system. Dogs and cats have therefore a closed and an open
system, whereas all other domestic animals have an open
system.
The spleen receives its blood from the splenic artery, which
comes from the celiac artery, and the blood drains through
the splenic vein into the portal vein. Approximately 2.5% of
the cardiac output flows through the spleen. The splenic
artery divides into multiple branches, each of which functions
as an end artery that supplies a specific segment of the spleen.
These arteries enter the spleen through the hilus and continue
within the capsule or trabeculae as trabecular arteries. Trabecu-
lar arteries have the typical wall structure of muscular arteries
and carry the splenic nerves in their adventitia. The returning
trabecular veins have an intima that is directly integrated into
the trabecular tissue. Cats have the most extensive trabecular
vascular system of all domestic animals. As the trabecular
arteries branch and enter the white pulp, they become
ensheathed, with cuffs of T lymphocytes forming the periar-
teriolar lymphoid sheaths (PALS). The arteries surrounded by
these PALS are now identified as central arterioles. Irregularly
along the length of these sheathed central arterioles, the lym-
phoid tissue widens eccentrically to the arteriole and forms
the B-cell–derived splenic follicles (Malpighian bodies).
Although the PALS are not vascularized, and oxygen is
provided through diffusion from the central artery, the splenic
follicles have their own capillary bed that provides both sus-
tenance and antigen exposure. The first branches of the central
160 CHAPTER 2  •  Hematopoietic System Spleen and Hemolymph Nodes

Periarteriolar macrophage
sheath (PAMS)

Trabecula Splenic cord

Trabecular Periarteriolar lymphoid

artery sheath (PALS)

Splenic
sinusoid
Central
arteriole Marginal
sinus

Penicillar
arterioles
Closed
circulation

Open
circulation
Splenic
follicle

Marginal zone
Red pulp with ending
capillaries

Trabecular Radial
vein arteriole

Nonsinusoidal Sinusoidal
spleen spleen
Figure 2-62  Schematic drawing of normal spleen. The left side depicts a nonsinusoidal spleen as
observed in most domestic animals; the right side shows a sinusoidal spleen characteristic of dogs.

arterioles form a vascular plexus surrounding the splenic fol-
licles. The capillaries of this plexus, the follicular capillaries, are
characterized by dense zonulae occludens. Numerous follicu-
lar capillaries emerge on the surface of the splenic follicles and
form anastomoses. These thin-walled vascular spaces separate
the splenic follicles from the periphery and are known as
marginal sinuses. Because the marginal sinuses are supplied by
the first branches of the central arterioles, the splenic follicles
are the first to be exposed to antigens transported to the
spleen.
The marginal areas surrounding the whole white pulp,
including the PALS, are called the marginal zone and are char-
acterized by a very fine reticular meshwork. The marginal
sinuses have uniform endothelial coverage on the follicular
side, but an incomplete endothelial layer on the peripheral
side. The blood percolates through the marginal sinuses via
this incomplete coverage, and enters the meshwork of the
marginal zone. Although most blood flows directly from the
marginal zone into the adjacent splenic sinusoids (fast
pathway), some blood enters the red pulp vascular spaces
(slow pathway).
Ultimately, the central arterioles terminate in the arboriz-
ing penicillar arterioles when entering the red pulp. Penicillar
arterioles can be divided into 3 segments: pulp arterioles, macro-
phage sheathed portions, and terminal arterial capillaries. Shortly
after branching, the pulp arterioles are ensheathed by macro-
phages that form the periarteriolar macrophage sheath (PAMS).
These structures have historically been called ellipsoids.
 Spleen and Hemolymph Nodes
Subsequently, penicillar arterioles lose their media and become
capillaries. The sheathed arterioles are lined by elongated
endothelial cells that are isoprismatic on cross section and
contain large numbers of vimentin filaments. Adjacent endo-
thelial cells are not joined by junctions, and they therefore
form a lattice-work through which blood and plasma cells
readily permeate. Blood passes from the capillaries into the
surrounding mantles that form up to 200 µm–long structures
sheathing capillaries. Integrated into this reticular network
composed of type III collagen reticular fibers are macrophages
that are exposed to the migrating red blood cells. Blood passes
through the reticular meshwork into the surrounding red pulp
vascular spaces. In all domestic animals, capillaries emerging
at the distal end of the splenic cords terminate in rounded
excavations (ampullae of Thoma) from which blood empties
into the red pulp vascular space. Actin filaments in the endo-
thelial cells forming these ampullae might indicate the ability
to actively regulate the blood flow. In dogs, some capillaries
enter into the splenic sinusoids as previously described. The
space between the sinusoids is occupied by loose reticular
stroma in which macrophages, lymphocytes, and plasma cells
are enmeshed, called splenic cords (cords of Bilroth). Splenic
cords are irregularly supported by encircling reticular fibers,
like the staves and hoops of a barrel. Regardless of the differ-
ences in blood flow in different animals, erythrocytes are
subject to surveillance by macrophages that are located peri-
vascularly around sinusoids, in the red pulp vascular spaces,
and splenic cords, depending on the animal species. Blood
from the red pulp vascular spaces collects in the venous capil-
laries that have an open connection to the meshwork of the
pulp reticulum. The venous capillaries and the splenic sinu-
soids drain the blood into trabecular veins and ultimately the
splenic vein. The splenic vein drains blood directly into the
portal vein, and therefore any increase in portal pressure
increases the blood volume of the spleen, leading in long-
standing conditions to congestive splenomegaly.
In domestic animals, the red pulp functions as both storage
compartment, as described previously, and the red pulp mac-
rophages together with the marginal zone macrophages have
essential functions in phagocytizing foreign material, bacteria,
and senescent or defective erythrocytes. The red pulp is com-
posed of splenic cords and vascular spaces; cylinders of pulp
spaces that are organized in a reticular meshwork, fed by a
peripheral ring of arterial capillaries, and drained by a central
venule. In dogs, it also consists of venous sinusoids. The red
pulp macrophages are derived from bone marrow monocytes
and are CD11d positive. Macrophages are integrated into the
reticular meshwork composed of type III collagen and reticu-
lar fibers. They use a number of different mechanisms to
recognize senescent erythrocytes. Although decreased meta-
bolic activity, morphologic alterations, including decreased cell
volume, and changes in cell shape predispose erythrocytes to
removal, macrophages can also detect senescent cells through
surface receptors. Such receptors can bind to Amadori
products—aminoketoses that are the result of nonenzymatic
browning, the nucleophilic addition of an amine to the car-
bonyl function of a reducing sugar, with formation of glyco-
sylamines that occurs over time on the surface of erythrocytes.
Other surface alterations in aging erythrocytes include
decreased levels of sialic acid and CD47, which result in
binding of autologous immunoglobulins and opsonins that can
be recognized by macrophages. In dogs, macrophages remove
entire erythrocytes, a process called erythrophagocytosis, but
161
also nuclear remnants and red blood cell membranes. Nuclear
remnant–containing erythrocytes are pitted of their inclusions,
such as Howell-Jolly bodies, as they squeeze through the
interendothelial slits of venous sinusoids in their passage out
of the spleen, and return to the circulation. The observation
of excessive amounts of nuclear remnants in erythrocytes
often indicates a splenic disease. In dogs, ~90% of blood passes
through the splenic sinusoids and bypasses the red pulp vas-
cular space. The remaining blood perfuses the splenic cord
areas, where sorting and processing by macrophages is carried
out to remove senescent or injured red cells. The flow rate
through the spleen is relatively large, and even with this low
sorting fraction, all of the blood passes through the splenic cord
system once per day. Because the spleen plays a central role in
removing senescent erythrocytes, it also has a central role in
iron metabolism. Iron is scavenged by macrophages when
removing senescent red blood cells from circulation and ini-
tially stored as a protein-iron complex ferritin, but ferritin can
be incorporated by phagolysosomes to form hemosiderin
granules.
The vascular system of the spleen does not include lym-
phatics. As a consequence, all antigens reach the spleen
through the blood, which determines that primary sensitiza-
tion and antibody production take place in the spleen only if
the first contact with antigen occurs by hematogenous sensitiza-
tion (Fig. 2-63). On subsequent challenge, the splenic follicles
of the spleen play an important role in the humoral anamnes-
tic response, both by local production of antibodies and by
the provision of committed B memory cells to the peripheral
lymphoid organs. The clearance of bacteria from the blood by
the spleen predominates only if systemic opsonization is defi-
cient. In other circumstances, the clearing appears to occur
mainly in hepatic Kupffer cells. Thus splenectomy increases
susceptibility to a number of blood-borne infections, including
bacterial septicemia and protozoal infections such as malaria,
anaplasmosis, and hepatotrophic mycoplasmal infection
(hemobartonellosis). All of these hazards can be prevented by
specific immunization that brings the hepatic Kupffer cells to
an alerted state following splenectomy.
The white pulp is composed of macrophages, antigen-
presenting cells, and B and T lymphocytes in the periarteriolar
Figure 2-63  Splenic babesiosis in a dog. Babesia canis can be
detected as single or paired, piriform organism within erythro-
cytes of a severely congested spleen. (Courtesy E.P. Lane.)
162 CHAPTER 2  •  Hematopoietic System
lymphoid sheaths (PALS), the splenic follicles (Malpighi bodies),
and the marginal zone. Splenic follicles are also often referred
to as lymphoid follicles. The PALS are localized around the
central arterioles as previously described. They are formed by
concentric layers of flat reticular cells and fibers forming a
reticular meshwork that is populated by a dense inner layer
of small, predominantly CD4+ T cells and a slightly less dark–
staining layer of small- to medium-sized T and B cells admixed
with macrophages. During immunostimulation, large numbers
of plasma cells may be observed in the outer layer. The splenic
lymphoid follicles are continuous with the PALS and usually
located eccentrically to the PALS at the bifurcations of the
central arterioles. Their structure is typical of a lymphoid fol-
licle. Under antigenic stimulation, these follicles develop ger-
minal centers characterized by a dark zone composed of
centroblasts and immunoblasts and a light zone of centroblasts
and centrocytes admixed with tingible body macrophages.
The germinal centers are surrounded by the mantle cell layers,
a narrow cuff of small, inactive, mature, naive B lymphocytes.
Immunophenotyping is highly useful to visualize these struc-
tures. One of the most valuable aspects of phenotypic identi-
fication of B- and T-cell areas of the spleen is the opportunity
to understand that the spleen is a highly ordered immune struc-
ture that varies in morphology as predictably as lymph nodes in
response to various stimuli. In addition, the dissection of the
phenotypic structure of the spleen clearly demonstrates the
differences between hyperplastic and neoplastic lymphoid
proliferations arising from the different portions of the splenic
follicles (see Lymphoma). Outside of the mantle cell cuff is
the marginal zone, located at the interface between white and
red pulp. A band of macrophages, the metallophilic macro-
phages, and the marginal sinus separate the marginal zone
from the PALS and lymphoid follicles. The marginal zone is
composed of a thick ring of medium-sized B cells admixed
with dendritic cells, macrophages, T cells, and reticular cells.
The marginal zone region receiving the blood exiting the
germinal center is the area most densely populated with cells
that have recently arrived from the general circulation. As a
consequence, animals with marked neutrophilia will have
many neutrophils in the area immediately surrounding the
corona of the splenic follicle. Increased neutrophils in this area
are more likely to be seen in the cat, dog, and horse, which
respond to infectious diseases such as salmonellosis by strong
neutrophilia, whereas in calves and mature cattle, bands and
metamyelocytes may be found in this area. Because many of
these animals die with neutropenia, neutrophil accumulation
in this site is less frequently observed.
Hemal nodes (hemolymph nodes) occur in ruminants, and
a similar structure occurs in rats. They are enclosed by a fibro-
muscular capsule and have a general architecture similar to
that of lymph nodes (Fig. 2-64, eFig. 2-10). Hemal nodes have
a blood vascular circulation and afferent and efferent lymphatics,
although the former are apparently much diminished in com-
parison to lymph nodes. The arteries entering through the
hilar area arborize peripherally and are followed closely by
veins that apparently communicate through a trabecular
structure similar to that of the spleen. Hemal nodes have
germinal centers, but the paracortical areas are much reduced
in comparison to those of lymph nodes. Unlike lymph nodes,
where the subcapsular sinus is poorly cellular, hemolymph
nodes contain red cells in density similar to that of peripheral
blood. Red cells are not present in the afferent lymphatics,
and very few are present in the efferent lymphatics; however,
Spleen and Hemolymph Nodes
Figure 2-64  Normal hemal node in a cow. The architecture of
hemal nodes is similar to that of lymph nodes, with a thick fibro-
muscular capsule, germinal centers with a reduced paracortical
area, and a subcapsular sinus expanded by large numbers of
erythrocytes.
the larger sinuses of the hemal nodes may be filled with blood
and more closely resemble sinus areas of the spleen. Macro-
phages occupy the trabecular areas, and phagocytosis occurs
as in the spleen. Myelopoiesis does not occur in hemal nodes
either under normal circumstances or under conditions of
hematopoietic stress.
Further reading
Cesta MF. Normal structure, function, and histology of the spleen.
Toxicol Pathol 2006;34:455-465.
Elmore SA. Enhanced histopathology of the spleen. Toxicol Pathol
2006;34:648-655.
Elmore SA. Enhanced histopathology of the immune system: a review
and update. Toxicol Pathol 2012;40:148-156.
Marx A, et al. Functional splenic pathology and differential diagnosis
in splenectomy. Pathologe 2008;29:109-114.
Wluka A, Olszewski WL. Innate and adaptive processes in the spleen.
Ann Transplant 2006;11:22-29.
Zidan M, Pabst R. Histology of the hemal nodes of the water buffalo
(Bos bubalus). Cell Tissue Res 2010;340:491-496.
Developmental diseases of the spleen
The spleen may be congenitally absent. Although this condi-
tion is common in some strains of inbred mice, it is rare in
humans and domestic animals, where it usually occurs in
conjunction with multiple other anomalies. In nude mice and
rats with thymic deficiency, there is loss of the periarteriolar
lymphoid sheaths of the spleen. The significance of splenic
aplasia in domestic animals, in particular its importance for
the immune function, is unknown. Asplenia in mice has been
associated with higher mortality and a higher risk for proto-
zoal infections. Splenectomy in adult animals increases the
risk of bacterial infections.
Accessory spleens occur quite commonly in the gastro-
splenic omentum of domestic animals (Fig. 2-65) and can
either be congenital or acquired; most commonly they repre-
sent implants of splenic parenchyma following traumatic
 162.e1

eFigure 2-10  Normal hemal node in a cow. In contrast to lymph

nodes, the subcapsular sinus is expanded by large numbers of
erythrocytes.
162.e2

Further reading
Dullmann J, et al. Lectin histochemistry of the spleen: a new lectin
visualizes the stromal architecture of white pulp and the sinuses of
red pulp. J Histochem Cytochem 2000;48:923-931.
Schmidt EE, et al. Circulatory pathways in the sinusal spleen of the
dog, studied by scanning electron microscopy of microcorrosion
casts. J Morphol 1983;178:111-123.
 Spleen and Hemolymph Nodes
Figure 2-65  Accessory spleen in a dog. The smaller spleen on the
gastrosplenic ligament most likely represents an implant of splenic
parenchyma following trauma to the spleen.
rupture of the main organ (see Rupture of the spleen). Acces-
sory splenic tissue has rarely been reported in the pancreas of
dogs and cats as an incidental finding, but care should be taken
to not misdiagnose such splenic nodules as neoplasms. Intra-
pancreatic accessory spleens appear grossly as firm, well-
demarcated, dark red nodules.
Duplication of the spleen is occasionally observed in normal
swine and as one of multiple visceral defects in nonviable
calves and lambs. Ectopic pancreatic tissue, either exocrine or
endocrine, is occasionally observed in spleens that are other-
wise developmentally normal.
Splenic hypoplasia occurs most commonly as part of severe
combined immunodeficiencies as the result of lymphoid
hypoplasia. Affected spleens are grossly small, firm, and pale
red, and histologically lack lymphoid follicles and periarterio-
lar lymphoid sheaths.
Splenic fissure is a congenital abnormality that has been
mainly described in horses and appears as a smooth elongated
indentation parallel to the splenic edge that is covered by
normal splenic capsule (Fig. 2-66).
Further reading
Knostman KA, et al. Intrahepatic splenosis in a dog. Vet Pathol
2003;40:708-710.
Ramírez GA, et al. Intrapancreatic ectopic splenic tissue in dogs and
cats. J Comp Pathol 2013;148:361-364.
Rossi F, et al. B-mode and contrast-enhanced sonographic assessment
of accessory spleen in the dog. Vet Radiol Ultrasound 2010;51:
173-177.
Degenerative diseases of the spleen
Senile atrophy affects the spleen, as it does other lymphoid
tissues, and is seen particularly in old dogs and old horses.
Atrophy also accompanies cachexia and is seen in wasting
disease caused by starvation, malignant neoplastic diseases, or
malabsorption syndromes. Chronic radiation can also cause
severe atrophy of the spleen and red pulp fibrosis. Atrophied
spleens are small, and their capsule is contracted and thick-
163
Figure 2-66  Splenic fissure in a horse. Splenic fissures occur as
smooth elongated indentations that are covered by normal splenic
capsule. (Courtesy R.L. Amorim.)
ened. Microscopically, there is lymphoid atrophy affecting
both lymphoid follicles and periarteriolar sheaths. The severity
of atrophy is an indication of the duration and severity of the
atrophic process. The sinus areas appear fibrous as a result of
condensation of the sinusoids, and lack of blood and resident
hematopoietic cells. Contraction without atrophy of lym-
phoid tissue can be observed in storage type spleens, most
commonly because of catecholamine release or activation of
the autonomic innervation. Common causes include splenic
rupture, “fight and flight” situations, heart failure, and hypo-
volemic, cardiogenic, or septic shock.
In hyperimmune states, there are characteristic changes in
the germinal centers of animals that are severely stressed.
Lympholysis occurs, and germinal centers appear epithelioid
and hypocellular. If the cell loss is acute, there will be promi-
nent tingible body macrophages, as in foals aborted because
of equid herpesvirus 1 infection. If the reaction has persisted
for more than a day, cellular debris is absent and only dendritic
cells remain. Various vascular changes occur, consisting of
hyaline changes in small arterioles that may proceed to
mineralization.
Old dogs often have yellow encrustations along the splenic
margins, or even covering most of the capsule (Fig. 2-67, eFig.
2-11). Microscopically, there is condensation and thickening
of the capsule, trabeculae, and perivascular tissue. The yellow
or brown encrustations are known as siderotic plaques or
Gamna-Gandy bodies, and represent deposits of bilirubin,
hemosiderin, and/or calcium in connective tissue, usually the
trabeculae (Fig. 2-68, eFig. 2-12). The salts become encrusted
on connective tissue and elastic fibers, which are swollen,
refractile, and stain with hematoxylin. The encrusted fibers
occasionally are misinterpreted as fungal hyphae. In associa-
tion with ceroid, these nodules likely represent the residual
effects from areas of hemorrhage. Although siderotic plaques
occur primarily in older dogs, they are often interpreted as an
incidental aging change, but their deposition on the capsular
margins suggests a dystrophic lesion secondary to previous
trauma.
Amyloidosis of the spleen occurs as part of generalized
amyloidosis and can be either primary (AL) or secondary
(AA), but the deposits in the spleen may not be detectable
 163.e1

Further reading
Movitz D. Accessory spleens and experimental splenosis. Principles of
growth. Chic Med Sch Q 1967;26:183-187.
163.e2

A
eFigure 2-12  Splenic siderotic plaques in a dog. Yellow bilirubin
pigment surrounded by extensive fibrosis.

B
eFigure 2-11  Splenic siderotic plaques in a dog. A. Yellow
encrustation along the splenic margin. B. Multiple siderotic
plaques on the capsular surface.
164 CHAPTER 2  •  Hematopoietic System Spleen and Hemolymph Nodes

A A

B B

C C
Figure 2-67  Splenic siderotic plaques in a dog. A. Yellow encrus- Figure 2-68  Splenic siderotic plaques in a dog. A. Yellow biliru-
tation along the splenic margin. B. Some cases can have extension bin pigment surrounded by extensive fibrosis. B. Extensive fibrosis
of siderotic plaques over the whole capsule. C. Depending on the is highlighted in blue with a trichrome stain. C. Hemosiderin
content of bilirubin, hemosiderin, calcium, and the extent of pigments stain blue, and bilirubin stains orange with Prussian blue
fibrosis, the color of plaques varies from white to yellow or green, staining.
as shown in is this remarkably hypoplastic spleen.

grossly or histologically without appropriate stains (Fig. 2-69).
Amyloidosis of an obvious degree is not common, and when
present it involves the germinal centers and may spare the red
pulp vascular spaces completely (eFig. 2-13). This distribution
of amyloid gives the organ the “sago-spleen” appearance (gray
or white, opaque 2-mm spherules) in which the enlarged and
waxy follicles protrude from the cut surface. The spleen is not
enlarged. The deposition of amyloid occurs first in the small
arteries of the lymphoid nodules, and minor deposits are
common.
 164.e1

B
eFigure 2-13  Splenic amyloidosis in a dog (A) and in a horse (B).
A. Cross section of spleen shows a follicular distribution of
amyloid resulting in a “sago” spleen appearance. B. Eosinophilic
hyalinized germinal center as a result of amyloid deposition.
 Spleen and Hemolymph Nodes
A A
B B
Figure 2-69  Splenic amyloidosis in a dog (A) and in a horse (B).
A. Uniformly pale orange, slightly swollen spleen, with a waxy
consistency. B. Multifocal eosinophilic hyalinized foci of amyloid
that involve the germinal centers and spare the red pulp vascular
spaces.
Most lysosomal storage diseases (see Vol. 1, Nervous system)
will ultimately result in accumulation of the undegradable
substrate in histiocytes that accumulate in the spleen and
lymph nodes. Such accumulation causes a uniformly enlarged,
firm, often pale red spleen.
Hemosiderin is a storage form of iron and the only splenic
pigment of importance (Fig. 2-70). The amount and form of
storage iron vary greatly in normal animals with age and
species. The pigment is usually present only in macrophages,
but in long-standing iron accumulation, it may be encrusted
on fibers of connective tissue. The amount of hemosiderin is
significant only when it is in excess to the point of causing
tissue injury and fibrosis, and justifies the name hemosiderosis.
Iron is absorbed in excess in any anemia where it is sufficiently
available. Increased iron is one of the splenic changes in hemo-
lytic anemias. The patterns of iron storage in the spleen and
marrow can yield information about the type of anemia. In
nonresponsive anemias, the iron is mainly aggregated into
large coarse granules within the phagocytes, which themselves
are inapparent. In responsive hemolytic anemias where there
is rapid iron turnover, there is a spectrum of iron deposition
from barely stainable, diffusely or focally distributed ferritin,
to coarse hemosiderin. In the anemias of chronic disease, there
165
Figure 2-70  Splenic hemosiderosis in a cow. A. Phagocytosed
hemosiderin appears as aggregates of large coarse granules. B.
Pigment can be confirmed as hemosiderin through blue staining
with Prussian blue.
is increased coarse splenic iron as a result of continued scav-
enging of the transferrin system by the acute phase–reacting
proteins.
Further reading
Cole PA. Association of canine splenic hemangiosarcomas and hema-
tomas with nodular lymphoid hyperplasia or siderotic nodules. J Vet
Diagn Invest 2012;24:759-762.
Murakami T, et al. Atypical AA amyloid deposits in bovine AA amyloi-
dosis. Amyloid 2012;19:15-20.
Rupture of the spleen
A normal spleen can be ruptured by the level of trauma that
cats and dogs suffer regularly in automobile collisions or
through blunt trauma, for instance, kicks. The result is more
or less severe loss of blood into the abdomen often causing
death. Pathologic rupture may occur in any species with only
minor trauma if the spleen is enlarged and the capsule thinned.
Severe diffuse splenomegaly or focal splenic nodules may
develop secondary to a variety of causes, including diffuse
passive congestion, hyperemia secondary to septicemia,
 165.e1

Further reading
Day MJ, et al. A review of pathological diagnoses made from 87 canine
splenic biopsies. J Small Anim Pract 1995;36:426-433.
166 CHAPTER 2  •  Hematopoietic System
Figure 2-71  Splenic hematoma in a dog. Localized hematoma
covered by stretched capsule with focal tear. (Courtesy S.
Kesdangsakonwut.)
Figure 2-72  Splenic scar in a dog. Healing of a focal tear resulted
in contracted scar tissue. (Courtesy E.P. Lane.)
hyperplastic or neoplastic cell proliferations, infarcts, or hema-
tomas. As a result of rupture, the spleen may be fully divided
into 2 or more parts, or have a merely focally torn capsule. In
some cases, only the red pulp will be ruptured resulting in a
localized hematoma covered by the intact capsule (Fig. 2-71).
Early hematomas appear as solitary, large, dark red, bulging
masses that are prone to rupture, causing hemoabdomen and
death resulting from hypovolemic shock. Over time, splenic
hematomas may resolve and develop into soft brown masses
that are histologically characterized by infiltrated macro-
phages that have phagocytized erythrocytes. Breakdown of
hemoglobin into bilirubin and hemosiderin is responsible for
color changes. Complete healing will usually result in con-
tracted scar tissue (Fig. 2-72). In areas of a ruptured capsule,
the spleen is normally contracted, and clotted blood may
adhere to the tear (Fig. 2-73, eFig. 2-14). Small non–life-
threatening ruptures will heal, and scarring lines of healing
can produce notches and fissures.
Spleen and Hemolymph Nodes
Figure 2-73  Splenic rupture in a dog. The ruptured spleen is
contracted and clotted blood adheres to the tear. (Courtesy R. L.
Amorim.)
Figure 2-74  Splenosis in a dog. Widespread seeding of splenic
explants onto the serosal surfaces following rupture. (Courtesy S.
Kesdangsakonwut.)
Concurrent hepatic lacerations are usually characterized by
a rise in transaminases, indicating an additional source of
abdominal hemorrhage. Following rupture of the splenic
capsule and spilling of the sinus cells into the abdominal
cavity, there may be widespread seeding of splenic explants
onto the serosal surfaces, called splenosis (Fig. 2-74). These
accessory spleens are functional, and there may be hundreds
on the omentum with a few on the peritoneum. They appear
grossly like hemal nodes and histologically like normal spleen.
Following splenectomy, any splenic implants present will
increase in size and may give some protection against infec-
tious diseases.
Further reading
Tian J, et al. Evaluation and establishment of a canine model of delayed
splenic rupture using contrast-enhanced ultrasound. Mol Med Rep
2012;6:483-487.
 166.e1

A B

C
eFigure 2-14  Splenic rupture in a dog. A. Contracted spleen with clotted blood adhering to the
tear. B. Ruptured splenic hematoma. (Courtesy R.L. Amorim.) C. Following complete rupture,
the scared splenic fragments are shown as “multiple” spleens.
166.e2

Further reading
Pollock S, et al. Traumatic subcapsular splenic cystic hematoma in the
dog/a case study. Vet Med Small Anim Clin 1978;73:600-606.
 Spleen and Hemolymph Nodes
Figure 2-75  Splenic volvulus in a dog. Volvulus of the spleen and
stomach occurs mainly in deep-chested dogs.
Volvulus of the spleen
Volvulus affecting only the spleen (commonly referred to as
splenic torsion) occurs in pigs, dogs, and humans, and rarely
in horses. Volvulus of the spleen and stomach occurs mainly in
deep-chested dogs (Fig. 2-75). When the whole spleen is twisted
around the gastrosplenic ligament, there is severe congestion
and hemorrhagic infarction because of occlusion of the vein
and ultimately blockage of the artery. When the distal portion
is twisted, only the vein tends to be occluded, causing hemor-
rhagic infarction and congestion.
Splenic volvulus in the dog occurs in large breeds and is
characterized by enlargement of the upper abdomen with
painful guarding on palpation, and the passage of dark brown
urine. Hematologically, there is a characteristic brown discol-
oration of plasma as a result of leaching of blood pigments
through the capsule as it becomes necrotic. Associated signs
consist of the postsplenectomy state with many distorted
red cells, hypersegmented neutrophils, and the presence of
Howell-Jolly bodies and red cell pits, which are unusual in the
peripheral blood of the dog with a normally functional spleen.
Grossly, the spleen is diffusely enlarged, dark blue-black, and
often folded so its visceral surfaces touch each other in a “C”-
shaped form. On surgical removal, such spleens may weigh as
much as 5 kg and contain a large proportion of the original
red cell mass. Following splenectomy, there is risk of infection
by organisms normally controlled by the spleen. In the dog,
hemotropic mycoplasmal infections and severe hemolytic
anemia are the most likely adverse sequelae.
Splenic volvulus in pigs usually occurs in sows, and
often several are affected in the same herd over a period of
a few days. Circumstantial evidence suggests that a change
from once- to twice-daily feeding will prevent further losses,
but other factors are most likely involved. Affected animals
usually die acutely. Grossly the spleen is blue-black, massively
and uniformly enlarged, and twisted 180 degrees about its
long axis.
Further reading
Grange AM, et al. Evaluation of splenectomy as a risk factor for gastric
dilatation-volvulus. J Am Vet Med Assoc 2012;24:461-466.
167
A
B
Figure 2-76  Splenomegaly in a dog (A) and a pig (B). A. Try-
panosoma evansi can cause diffuse splenic congestion, a so-called
“bloody” spleen. (Courtesy S. Kesdangsakonwut.) B. Erysipelothrix
rhusiopathiae commonly causes noncongested splenomegaly, a
so-called “meaty” spleen.
Sartor AJ, et al. Association between previous splenectomy and gastric
dilatation-volvulus in dogs: 453 cases (2004-2009). J Am Vet Med
Assoc 2013;242:1385-1391.
Weber NA. Chronic primary splenic torsion with peritoneal adhesions
in a dog: case report and literature review. J Am Anim Hosp Assoc
2000;36:390-394.
Splenomegaly and splenic nodules
Splenomegaly is a descriptive term for a diffusely enlarged
spleen and provides little information about the underlying
disease mechanism. The degree to which splenic size departs
from normal is difficult to assess, but weight is always a useful
parameter, particularly in animals that die without exposure
to barbiturate anesthetics. Splenomegaly is common, espe-
cially in animals with a storage spleen, and the interpretation
of splenic size at autopsy can be gained by reference to the
whole carcass and to the cut surface of the organ.
Enlarged spleens can be divided into congested, so-called
“bloody” spleens, or noncongested, so called “meaty” spleens
(Fig. 2-76). Congested spleens are usually dark red to blue-
black, and the red pulp bulges on cross section and oozes
 167.e1

Further reading
Neath PJ, et al. Retrospective analysis of 19 cases of isolated torsion of
the splenic pedicle in dogs. J Small Anim Pract 1997;38:387-392.
Wendt M. Stomach torsion in swine. Tierarztl Prax 1987;15:375-376.
168 CHAPTER 2  •  Hematopoietic System
blood. Noncongested spleens feel firmer, hence the descriptive
term “meaty,” and do not ooze blood on their cut surface. The
color of such enlarged noncongested spleens varies depending
on the underlying disease process, and hyperplastic follicles
may be visible grossly.
Congested splenomegaly is most commonly the result of
circulatory disturbances (see later) and the process can result
from acute hyperemia, for instance, septicemia, passive con-
gestion; or euthanasia with barbiturates, splenic volvulus,
acute hemolytic anemia; or infectious disease, for instance,
babesiosis or trypanosomiasis. Noncongested splenomegaly can
be caused by a number of different disease mechanisms,
including phagocytosis, cell proliferation, or storage material.
Each of these conditions is described in more detail under
inflammatory, neoplastic, or degenerative diseases of the
spleen. Although many acute bacterial septicemias can cause
diffuse splenic congestion, subacute to chronic infections are
often associated with noncongested splenomegaly, for instance,
salmonellosis (Fig. 2-77). The following is an arbitrary list of
diseases to be considered when congested splenomegaly is
present.
Cattle and sheep
Anthrax
Salmonellosis
Babesiosis
Hemolytic disease
Horses
Equine infectious anemia
Isoimmune hemolytic anemia
Salmonellosis
Anthrax
Barbiturates
Pigs
Volvulus
Salmonellosis
Isoimmune hemolytic anemia
Mycoplasma haemosuis
African swine fever
Figure 2-77  Congested splenomegaly in a pig. Salmonella
choleraesuis can cause severe diffuse splenic congestion. A
normal spleen is shown below for comparison. (Courtesy S.
Kesdangsakonwut.)
Spleen and Hemolymph Nodes
Dogs and cats
Barbiturates
Acquired hemolytic anemias
Leishmaniasis
Volvulus (dogs)
Trypanosomiasis
The absence of splenomegaly does not eliminate any of
these causes, but makes them unlikely. Multiple focal lesions
normally do not cause splenomegaly, although hemangiomas
of the canine spleen and metastatic melanomas of the equine
spleen are exceptions.
In contrast to diffuse splenomegaly, single or multiple
nodules are also commonly encountered in the spleen. In
similar fashion as diffuse splenomegaly, splenic nodules can
be further divided into “bloody” nodules and “firm” nodules
(Fig. 2-78). The most common types of bloody nodules are
splenic hematomas or vascular neoplasms, for instance, hem-
angioma, hemangiosarcoma (Fig. 2-79). Hematomas can occur
secondary to trauma or can be caused by vascular neoplasms.
Splenic hyperplastic nodules can also become engorged
with blood and may closely resemble hematomas grossly (Fig.
2-80, eFig. 2-15). Acute splenic infarcts may also grossly
resemble “bloody” nodules, but their marginal distribution and
shape usually allow differentiation on gross examination.
B
Figure 2-78  Splenic nodules in a dog. A. Splenic hematoma
representing a “bloody” nodule. B. Cross section of splenic nodular
hyperplasia representing a “firm” nodule.
 Spleen and Hemolymph Nodes 169

A A

B B
Figure 2-80  Splenic hyperplastic nodule in a dog. A. Hyperplas-
tic nodules can become engorged with blood and appear as
“bloody” nodules. B. A few splenic follicles surrounded by severely
congested splenic parenchyma are indicative of the pathogenesis
of this “bloody” nodule.

sarcomatous have been classified as fibrohistiocytic nodules

(see later).

Circulatory diseases of the spleen

C erysipelas of swine, and Streptococcus pneumoniae infection in
Figure 2-79  Splenic vascular neoplasms representing a “bloody”
nodule, in a dog. A. Cross section of well-circumscribed, encap-
sulated, multilocular splenic hemangioma. B. Hemangiosarcomas
can cause focal splenic hematomas. C. Neoplastic, anaplastic
endothelial cells form incomplete vascular channels.
Incompletely contracted areas of spleen may appear similar to
infarcts. Firm nodules can represent a number of different
disease processes, including hyperplastic nodules, neoplastic
nodules, abscesses, and granulomas. Hyperplastic nodules
occur most commonly in the spleen of old dogs, and lesions
that are difficult to differentiate as hyperplastic versus
Active hyperemia is common in acute systemic infections and
also occurs in some acute bacterial intoxications, such as
anthrax infections in cattle, clostridial enterotoxemia of calves,
neonatal calves and goats. Passive congestion of the spleen
may arise as a result of disturbances in the systemic and portal
circulation, and is a feature of some of the acute hemolytic
anemias. The most common cause of passive congestion is the
use of barbiturates for euthanasia or anesthesia in horses and
dogs, or the earlier described splenic volvulus in dogs or pigs
(Fig. 2-81). Central (cardiac or pulmonary) venous congestion
does not usually cause congestion of the spleen in animals,
partly because they usually do not live long enough, and partly
because the splenic capsule is not elastic as in sheep, or is
highly muscular as in the dog and horse and not easily dis-
tended. Portal obstruction, with chronic hepatic fibrosis and
hepatic congestion, causes significant splenic enlargement in
humans, but this sequence of events is rare in animals.
 169.e1

eFigure 2-15  Splenic hyperplastic nodule, in a dog. Hyperplastic

nodules may become very large and are prone to rupture.
170 CHAPTER 2  •  Hematopoietic System
Figure 2-81  Diffuse splenic congestion, in a dog. Euthanasia
with barbiturates can cause diffuse congested splenomegaly.
With acute hyperemia, the spleen becomes moderately
enlarged and oozes blood on cut section. Histologically, acute
hyperemia is first observed in the marginal zones, followed by
the splenic cords. In acute septicemia, such as anthrax, disten-
tion with blood may represent the only finding. In more
chronic cases, neutrophils and macrophages may accumulate
in marginal zones and splenic cords, and there is a marked
increase in fixed cells in the red pulp and heavy sinus coloniza-
tion with macrophages and hemosiderin. A passively congested
spleen is extremely enlarged, moderately turgid, and cyanotic
with the capsule blue-black. The normal architecture is not
discernible on the cut surface, and the pulp is red-black,
bulges, and progressively exudes blood. Microscopically, the
splenic sinuses are dilated with packed red cells, and the ger-
minal centers are widely separated, and trabeculae are thinned.
The severity of acute hyperemia may make histologic exami-
nation difficult in the horse because the tissue, being largely
clotted blood, fragments on sectioning. Splenic samples from
horses destroyed with barbiturate should be taken from a thin
marginal area where the parenchyma is supported on 2 sides
by capsule.
Spleens that are enlarged for any reason are prone to
thrombosis and infarction. Thrombosis of the splenic vein has
been observed in association with traumatic reticulitis and
portal thrombosis in cattle, arterial thrombosis in cattle with
theileriosis, and with splenic abscesses in horses. Thrombosis
of both arteries and veins is seen in hypercoagulable states,
such as immune hemolytic anemias, purpura, and hemor-
rhagic pancreatitis. Infarcts are most commonly observed in
the subcapsular areas because the red pulp in these areas is
poorly perfused and has a reduced venous return (Fig. 2-82).
Acute infarcts might be difficult to visualize because they
appear as diffusely hemorrhagic, sharply demarcated areas
that raise the splenic capsule. In more chronic stages, infarcts
appears as wedge-shaped areas, extending from the capsule
into the parenchyma, that are sharply demarcated and change
in color from dark red to gray-white as the lesion becomes
more organized (Fig. 2-83, eFig. 2-16). Ultimately, infarcts will
resolve as fibrous scars. In acute classical swine fever in pigs,
there is widespread endothelial damage and fibrinoid throm-
bosis of splenic follicular arterioles, resulting in raised dark
infarcts 0.2-2.0 cm in diameter in the splenic capsule. Severe
Spleen and Hemolymph Nodes
Figure 2-82  Splenic infarct in a pig infected with classical swine
fever virus, formalin-fixed spleen. Acute infarcts appear as dif-
fusely hemorrhagic, sharply demarcated areas that raise the
splenic capsule (bottom), whereas chronic infarcts (top) change
in color from dark red to gray-white and become more organized.
(Courtesy S. Kesdangsakonwut.)
Figure 2-83  Splenic infarct as a result of metastasizing carcinoma
in a dog. Sharply demarcated, wedge-shaped, gray-white chronic
infarct extending from the capsule into the splenic parenchyma.
endothelial damage secondary to septicemic salmonellosis has
been observed to cause splenic infarcts in pigs, and there are
a few reports of Mycoplasma haemosuis also causing splenic
infarcts. In dogs, infarcts occur most likely with various splenic
neoplasms, including myeloma, lymphoma, or myeloid leuke-
mias, as a result of thrombocytopenia, procoagulant content
of hypogranular promyelocytic leukemia, or hyperviscosity
associated with myelomas (Fig. 2-84). The spleen may suffer
infarction secondary to hyperviscosity syndrome caused by
massive hyperproteinemia most commonly associated with a
monoclonal gammopathy, but hyperviscosity can also be
caused by leukemia, polycythemia vera, essential thrombocy-
tosis, or myelodysplastic disorders. Embolism with infarction is
uncommon. The outcome has the usual dependence on
whether the emboli are septic or bland. Emboli are frequently
derived from valvular vegetative endocarditis. In dogs, Dirofi-
laria immitis may cause thromboembolism (Fig. 2-85).
Incompletely contracted splenic areas occur most com-
monly in dogs secondary to disseminated intravascular coagu-
lation, where small thrombi prevent vascular outflow of
segments of spleen. Lesions develop when spleens contract
during cardiogenic shock or following a parasympathetic
 170.e1

B
eFigure 2-16  Splenic infarcts in dogs. A. Hemangiosarcoma
causing multiple wedge-shaped infarcts along the splenic margins.
B. A metastasizing carcinoma causes vascular emboli and multifo-
cal splenic infarcts.
 Spleen and Hemolymph Nodes
A spores of most remarkable durability. It is the combination of
B natural excretions, as well as pathologic exudates, and these
Figure 2-84  Splenic thrombosis in a dog. A. Splenic infarcts in a
dog with multiple myeloma. B. Fibrin thrombus in splenic follicu-
lar arterioles, resulting in acute hemorrhagic infarcts.
Figure 2-85  Splenic infarcts in a dog. Dirofilaria immitis can
cause severe thromboembolism.
stimulus and affected areas fail to empty. Such lesions are
grossly indistinguishable from splenic infarcts and are also
located along the splenic margins.
Specific infections of lymphoid tissues
Anthrax
Anthrax is caused by Bacillus anthracis, a large, gram-positive,
spore-forming organism that is highly pathogenic for most her-
bivorous animals and humans, whereas carnivorous birds and
reptiles are resistant. Domestic animals are susceptible to B.
171
anthracis in the decreasing order of goats, sheep, cattle, horses,
pigs, and dogs. Farmed mink are highly susceptible. In rumi-
nants, the disease is usually brief and septicemic; in horses,
pigs, and dogs, it is frequently localized to the throat or intes-
tine and may be fatal before invasion of the blood occurs.
When the disease is septicemic, as it usually is in herbi-
vores, the blood and tissues of the animal swarm with vegeta-
tive organisms which, when exposed to air or oxygen, form
these 2 factors, the number of organisms and the resistance
of spores, which is of paramount importance in the epidemiology
of the disease.
Bacillus anthracis probably has limited capacity for growth
in the external environment, due in part to antagonistic soil
bacteria. Growth may occur in alkaline soils with much decay-
ing vegetable matter, and alternate periods of rain and drought
and temperatures in excess of 15.5° C may also facilitate
growth. The spores are known to remain viable in soil for at
least 15 years, and probably much longer, because they have
been noted to retain their vitality and virulence for 50 years
in the laboratory. Natural survival of vegetative organisms is
rather short, equivalent to the short duration of an infection;
vegetative organisms do not survive in a carcass, but are
rapidly killed by putrefactive bacteria. In the terminal stages
of the disease, large numbers of bacilli are excreted in all
organisms sporulate and perpetuate infections. As a general
rule, the spores are very resistant to methods of disinfection, with
the exception of chemical disinfectants that are oxidizing
agents. Spores on skin have even survived tanning processes
to become a hazard for humans.
Reliable details on how spontaneous infections are initiated
in animals are not available, but the disease in wild herbivores
often follows construction requiring excavation, such as
fencing and excavation of dug-outs for watering livestock. It
is accepted that dogs and pigs acquire the infection as a result
of eating an animal that had anthrax, and deaths in humans
have occurred after eating inadequately cooked meat from a
goat dead of anthrax. Anthrax in pigs has been traced to the
ingestion of bone meal that was not sufficiently sterilized.
Vegetative bacilli are unlikely to cause the disease because
they are rapidly destroyed in the acid medium of the stomach.
Cattle and sheep are presumed to obtain the infection by
ingestion of contaminated food and water, entry through
mucous membranes possibly being aided by local trauma.
Cutaneous infection is rare in cattle but has been reported in
India, and pulmonary anthrax resulting from the inhalation of
spore-laden dust can occur. Infection through the skin is occa-
sionally seen in sheep, and may be assisted by grass seed
infestation. Ingestion is an important mode of infection in
horses and dogs, as indicated by the common occurrence of
lesions in the throat. It is also thought that infection can be
transmitted to horses by blood-sucking insects. Intestinal
anthrax in pigs probably reflects infection by ingestion.
The pathogenesis of anthrax is an initial lymphangitis and
lymphadenitis that develops into septicemia. This sequence is
especially well illustrated in the pulmonary form of the exper-
imental disease. Spores that are inhaled are ingested by cells
lining alveoli and transported in them to the tracheobronchial
nodes, in which vegetation and true initiation of the infection
occur. Spread to the blood is via lymphatics as well as by
lymphovenous connections within lymph nodes, and numer-
ous bacilli spread in the lymph from node to node as the
172 CHAPTER 2  •  Hematopoietic System
filtering mechanism of each is successively swamped. Bacilli
that enter the blood are taken up in other parts of the mono-
nuclear phagocyte system, especially the spleen, to establish
secondary centers of infection and proliferation.
There is notably little response on the part of a susceptible
animal to the local establishment of anthrax infection. Physi-
ologic disturbances, clinical signs, and death depend on the devel-
opment of a massive septicemia. In immune animals, for instance,
guinea pigs, infection is followed by a period of 2-4 hours in
which the bacilli proliferate; the area then becomes infiltrated
by leukocytes, and the bacilli fragment with little or no phago-
cytosis of intact organisms. The lysis of bacilli, of which the
first sign is loss of capsule and staining properties followed by
fragmentation, is apparently caused by anthracidal substances
in plasma or, more likely, liberated from leukocytes. Anthrax
has always been regarded as dependent on invasiveness rather
than toxigenicity, but it appears that antitoxic immunity does,
in some manner, inhibit invasiveness.
Vegetative cells produce a small array of toxins. The organ-
isms themselves and the capsular material are virtually non-
toxic, although the capsular material may act as a spreading
factor and inhibit the activity of leukocytes. The activity of
toxins in septicemic anthrax is well illustrated by the demon-
stration that, once the degree of bacteremia passes a certain
threshold, which is ~0.3% of the usual maximum, death will
occur even though all bacilli may have been destroyed by
antibiotic therapy. The toxin consists of 3 complementary com-
ponents designated factors I, II, and III, or edema factor, protective
antigen, and lethal factor, respectively. Edema factor is an adenyl-
ate cyclase that increases cyclic AMP after activation by
calmodulin. Protective antigen is likely a receptor-binding
protein that appears to be essential for the biological effects
of edema and lethal factors. Lethal factor is a central nervous
system (CNS) depressant, but its major effects may be else-
where. The toxins have been assessed only in experimental
laboratory animals, between species and strains, of which there
are considerable differences in sensitivity. The 3 toxins are
serologically distinct and, because there is autostimulation, it
is not surprising that they do not produce lesions when
injected separately. The combined effects of the 3 toxins are
injury and inactivation of phagocytes, increased capillary per-
meability, anticomplementary activity, and impairment of
coagulation.
Immunity to anthrax appears to depend on the neutraliza-
tion of toxin. Antibodies against the bacterial cells and cap-
sules are useless, as is evident from the experience that
completely avirulent or dead bacilli are not immunogenic; in
fact, the most potent vaccines are of bacilli that proliferate
and cause acute local inflammation but do not invade the
blood. The antigen that provokes antitoxic immunity is the
protective antigen that is presently regarded as being a non-
toxic degradation product (toxoid) of the very labile toxin
found in the blood of affected animals. The vaccine of Pasteur
apparently resulted from the loss of a temperature-sensitive
plasmid that encoded for the protective antigen.
When an animal is suspected of having died of anthrax,
organisms should be detected in smears of blood or local
exudate. All bacilli in internal organs are likely to be destroyed
in 48 hours or less by putrefaction. Hence it is best to obtain
blood for diagnostic purposes from close to the coronet or the tip
of the tail, places that are likely to be involved last by putrefac-
tive processes that destroy the vegetative bacilli. Bacillus
anthracis occurs in blood in pairs or in short chains of 3-4 cells.
Spleen and Hemolymph Nodes
They are large truncate organisms that are easily observed.
They are differentiated from putrefactive bacteria by their distinct
capsule, which stains pink with old methylene blue, and by having
square ends when these are apposed. The free ends of B. anthra-
cis are often rounded as in Clostridium spp. The organism can
be cultured readily from putrefied exudates if advantage is
taken of its aerobic requirements and the heat resistance of
the anthrax spores, to separate it from nonsporulating organ-
isms and sporulating anaerobes. The organism can also be
purified in guinea pigs by applying the inoculum to scarified
skin. In nonsepticemic anthrax, such as occurs in swine and
dogs, it is best to look for the organism in the local exudates
and affected lymph nodes. For the diagnosis of anthrax, when
other methods have failed or the tissues are old and dry, the
Ascoli agar-gel precipitin test is useful but not completely
specific.
Bovine anthrax is usually septicemic, and sudden death is
usually the first indication of its presence in a herd. Even when
cattle are observed closely, they may be dead within 1 hour
of showing signs of illness, although some will show general
signs of illness for about 24 hours before death. The signs of
illness vary with the route of entry and when, as usually
happens, entry is by inhalation or ingestion with no area of
localization, the animals are depressed and listless. On exami-
nation, there is high fever, increased heart and respiratory
rates, and congested and terminally cyanotic mucosae that
show evidence of bleeding. Animals that survive for a day may
have dysentery, abortion, edematous swellings of the perineum,
throat and abdominal wall, and blood-stained milk. Although
infection may be virtually synonymous with disease and death
in goats and sheep, it is not necessarily so in cattle, in which
species some infected animals probably recover. This is suggested
by the recovery of some animals that are experimentally inoc-
ulated and by the occurrence of transient febrile reactions
attributable to no other causes, in herds in which fatal anthrax
is occurring. For most animals, however, treatment to be effec-
tive must be administered early before there is marked septi-
cemia and toxin production.
The carcass of an animal dead of this disease putrefies quickly,
becomes very rapidly distended with putrefactive gases, and
blood exudes from the natural orifices. These changes are, of
course, not diagnostic, but when they are observed in an
animal that has died suddenly in an area in which anthrax is
endemic or has at any time occurred, examination of smears of
blood should always precede autopsy. Anthrax in the fulminat-
ing disease is very largely an intravascular infection, with most
of the organisms in the blood and the rest in the spleen. Sep-
ticemia in anthrax is a terminal event, and smears of blood
may not be helpful when prepared more than a few hours
before death.
The morbid picture of the disease in cattle is characterized
by splenomegaly, multiple hemorrhages, and edematous effu-
sions in connective tissues. A very large soft spleen is the most
significant lesion, and very rarely is it absent (Fig. 2-86). Sple-
nomegaly occurs in other diseases of cattle, but rarely is it as
large in association with sudden death. In anthrax, the spleen
is soft, sometimes it ruptures spontaneously, and when it is
incised, the pulp exudes very thick black-red blood that
brightens in color on exposure to air. Smears and sections of
the spleen reveal very large numbers of bacilli if the carcass
is fresh (eFig. 2-17), but, when decomposition is advanced,
they are destroyed by putrefactive changes. In some cases,
splenomegaly is the only lesion. The histology of the spleen is
 172.e1

B
eFigure 2-17  Anthrax, in a cow. A. The red pulp is expanded by
sludged red cells admixed with numerous leukocytes and bacilli
in chains. B. Cytologic smears of sections of spleen stained with
M’Faydean stain reveal very large numbers of bacilli. (Courtesy
R.B. Moeller.)
 Spleen and Hemolymph Nodes
A The vessels are intensely congested, and hemorrhage extends
B as hard circumscribed nodules. The disease in sheep takes the
C described for swine. When septicemia occurs, the morbid
Figure 2-86  Anthrax in a cow. A. Severe splenomegaly with very
thick black-red blood draining from cross sections. (Courtesy
A.W. Layton.) B. The red pulp is expanded by sludged red cells
admixed with numerous leukocytes and bacilli in chains. C. Cyto-
logic smears of sections of spleen reveal very large numbers of
bacilli. (Courtesy R.B. Moeller.)
not revealing. The sinus areas are distended with sludged red
cells, and the lymphoid follicles are widely separated and
hypocellular, but numerous leukocytes and bacilli in chains
are present. It is typical of septicemic anthrax that the organ-
isms are always intravascular.
173
Cattle are moderately resistant to B. anthracis so that local
lesions may occur at the site of entry. Local lesions are usually
in the small intestine and take the form of ulcerative hemor-
rhagic enteritis, but acute inflammation in the abomasum and
large intestine may also occur. The most severe lesions may be
over the lymphoid tissues of the intestine, or extend for a
considerable distance from these. The mucous membrane is
intensely red, and is sprinkled with small hemorrhages. The
contents of the intestine are then deeply stained with blood.
Superficial necrosis and ulceration occur in some areas of most
intense hyperemia. The corresponding mesentery, up to the
regional nodes, is infiltrated with gelatinous fluid as a result of
acute lymphangitis, and the fluid may be stained with blood.
The regional nodes have the appearance of the spleen. They
are enlarged, red-black, and on cut surface are moist and shiny.
into the peripheral sinuses and cortex. Bacilli are numerous
and leukocytes are present, but there is no necrosis.
In some cases in which the organisms gain entry through
the oropharynx, there is hemorrhagic lymphadenitis of the
nodes of the throat and edema of the connective tissues in
these regions. The occasional case of pulmonary anthrax in
cattle is characterized by acute congestion and consolidation
of a portion of the lung with larger areas of interstitial edema,
edema of the mediastinum, and regional hemorrhagic lymph-
adenitis. The pulmonary lesion is exudative, but lacks the full
gamut of inflammatory change unless another cause of pneu-
monia is superimposed.
Sheep are more susceptible to B. anthracis than are cattle,
and local lesions do not occur except in the unusual instances
of percutaneous infection, in which the lesion may take the
form of spreading edema from the outset or initially appear
same course as that in cattle except that it is even more rapid.
Splenomegaly is not as prominent in sheep as in cattle, likely
because of the greater level of collagen in the splenic capsule
of sheep. The parenchyma is, however, dark and soft. Edema-
tous effusions do not occur in sheep.
Clinical signs of anthrax in horses may last for several days
and are characterized by colic or by large edematous swellings.
The swellings, which can be very extensive, occur on the
ventral part of the abdomen and thorax, the legs, in the peri-
neal region, and about the external genitalia. Dysentery may
accompany the acute colic. When ingestion is the route of
infection in horses, the primary lesion may be in the throat or
the intestine, and death may occur from the local reaction and
without septicemia. Intestinal lesions are similar to those
described for cattle, and pharyngeal lesions are similar to those
changes are the same as in cattle, including very prominent
enlargement and congestion of the spleen.
Pigs are relatively resistant to anthrax. They acquire the
infection from eating infected flesh, and the infection remains
localized to the throat or intestine. Because septicemia is
exceptional, splenomegaly is not a prominent part of the gross
picture. The characteristic sign is swelling of the pharyngeal
region and neck. Some pigs have diarrhea and dysentery, but
it is unusual to have intestinal localization without pharyngeal
localization. Anthrax without illness has been observed in
swine; in such cases, the disease is limited to isolated mesen-
teric or pharyngeal nodes.
The local lesion of anthrax in swine is a typical carbuncle
at the point of entry, with acute regional lymphadenitis and
174 CHAPTER 2  •  Hematopoietic System
lymphangitis. Some bacilli no doubt reach the blood, but they
do not establish septicemia. Bacteria may localize in liver,
spleen, or kidney to produce a metastatic carbuncle but,
usually, only individual nodes near the site of entry are
involved. The lymphadenitis may be diffuse or focal but in
both cases it is, in the initial stages, hemorrhagic. An intense
leukocytic infiltration occurs, all cells within the affected por-
tions of the node die, and the focus becomes encapsulated.
With necrosis, the affected tissue changes from a brick-red to
a gray friable mass that can be easily shelled-out when the
gland is incised.
In primary intestinal anthrax in pigs, the initial lesion is focal
or multifocal hemorrhagic enteritis, with a central zone of
diphtheresis that eventually ulcerates. The adjacent serosa and
mesentery are thickened with edema fluid and yellow, with
foci and streaks of hemorrhage; they are the site of focal
hemorrhagic necrosis resulting from acute necrotizing vascu-
litis and lymphangitis. These mesenteric lesions extend only
as far as the regional nodes, which show the type of lymph-
adenitis characteristic of anthrax in swine.
Dogs are reputedly quite resistant to B. anthracis, but a
number of outbreaks have been observed in kennels in which
the dogs have inadvertently been fed meat from an animal
that has died of the disease. Anthrax in dogs may pursue a
peracute course to sudden death, it may be of the pharyngeal
type in which extensive edema develops in the face, head, and
neck, or it may be of the intestinal type with signs of acute
gastroenteritis. Anthrax may occur in mink with high mortal-
ity after feeding fresh meat from infected animals.
Further reading
Biswas PK, et al. Risk factors associated with anthrax in cattle on
smallholdings. Epidemiol Infect 2012;140:1888-1895.
Epp T, et al. Case-control study investigating an anthrax outbreak in
Saskatchewan, Canada - summer 2006. Can Vet J 2010;51:
973-978.
Liu S, et al. Anthrax lethal and edema toxins in anthrax pathogenesis.
Trends Microbiol 2014;22:317-325.
Mongoh MN, et al. Risk factors associated with anthrax outbreak in
animals in North Dakota, 2005: a retrospective case-control study.
Public Health Rep 2008;123:352-359.
Sweeney DA, et al. Anthrax lethal and edema toxins produce
different patterns of cardiovascular and renal dysfunction and syn-
ergistically decrease survival in canines. J Infect Dis 2010;202:
1885-1896.
Twenhafel NA. Pathology of inhalational anthrax animal models. Vet
Pathol 2010;47:819-830.
Leishmaniasis
The genus Leishmania includes protozoal parasites within the
family Trypanosomatidae. Species of the genus are parasites of
humans, dogs, and other mammals. Sandflies of the genus Phle-
botomus in the Old World and the genus Lutzomia in the New
World are the intermediate hosts. The tick Rhipicephalus may
act as mechanical vector. Direct transmission and vertical
transmission may occur in kenneled dogs.
In the mammalian host, Leishmania is found in macro-
phages in the amastigote form. Amastigotes are round to ovoid,
2.0-5.0 µm in diameter with a basophilic, vesicular nucleus
and smaller, rod-shaped, darker-staining kinetoplast, but no
flagellum. They are best visualized by Giemsa staining.
Spleen and Hemolymph Nodes
Amastigotes proliferate by binary fission and then rupture out
of macrophages and infect new cells. When sandflies ingest
blood from infected hosts, they also ingest host cells infected
with amastigotes. In the midgut of the sandfly, amastigotes are
released from cells and transform into their flagellated, procy-
clic, promastigote form and replicate. Promastigotes are leaf-
shaped with a single flagellum arising at the anterior pole.
Following sufficient replication and a number cell surface
changes, the promastigotes transition to the infectious meta-
cyclic form that detaches from the midgut and migrates to the
mouthpart, where it is injected into the host with saliva.
Leishmaniasis is important as a disease of humans, and
wherever it occurs in humans, it may also occur in dogs.
Although the human population may be the only reservoir for
some Leishmania spp., for instance, L. donovani, for other
Leishmania spp., for instance, L. infantum or L. braziliensis,
dogs, cats, and other carnivores, including rats, serve as reser-
voir hosts. Leishmaniasis may occur in 3 clinical forms:
• Cutaneous leishmaniasis (“oriental sore”) is the most
common clinical presentation and caused by different
Leishmania spp. in different parts of the globe. In the
Eastern Hemisphere, cutaneous leishmaniasis can be
caused by L. tropica, L. major, L. aethiopica, L. infantum,
and L. donovani. In the Western Hemisphere, the disease
is caused by the L. mexicana spp. complex (L. mexicana,
L. amazonensis, L. venezuelensis) or the L. braziliensis spp.
complex (L. braziliensis, L. guyanensis, L. panamensis, L.
peruviana).
• Mucocutaneous leishmaniasis (“espundia”) represents the
spread of cutaneous infection to the naso-oropharyngeal
mucosa and is caused by the L. braziliensis spp. complex.
• Visceral leishmaniasis (“kala-azar”) is the most severe form
and can occur with a wide variety of clinical signs. It is
usually caused by the species L. donovani and L. infantum
(L. chagasi).
The species of Leishmania are not well distinguished. Spe-
ciation depends on degrees of cross-immunity, different clini-
cal manifestations, geographic location, and reservoir hosts.
However, sequence data on kinetoplast DNA on several
species permits their molecular identification. In situ hybrid-
ization is available to identify leishmanial organisms and to
speciate these in formalin-fixed tissues.
Infections of animals with Leishmania spp. are common in
endemic areas, but many dogs may have subclinical disease.
Rate of infection in dog populations is usually based on sero-
logic data combined with immune response and detection of
parasitic DNA in tissues. Both cutaneous and visceral forms of
the disease have been described in dogs, as well as cases of vis-
ceral disease in which the organisms are diffusely present in
the dermis. Leishmaniasis is a disease of the monocyte-
macrophage system, and the visceral disease mimics histoplas-
mosis. The protozoa are not cytopathogenic in the usual sense,
and destruction of host macrophages appears to be purely a
mechanical consequence of proliferation of the protozoa in
the cytoplasm.
Cutaneous leishmaniasis in dogs can occur as generalized
or focal, exfoliative dermatitis with alopecia that commonly
starts around the limbs or the face and the ears, as ulcerative
dermatitis, as multinodular dermatitis, as mucocutaneous pro-
liferative dermatitis, and as papular dermatitis. The organisms
are inoculated by the biting insect and are soon ingested by
histiocytes. Rapid proliferation of the protozoa disrupts the
phagocytes, and the released organisms are ingested by other
 174.e1

Further reading
Dragon DC, et al. A review of anthrax in Canada and implications for
research on the disease in northern bison. J Appl Microbiol
1999;87:208-213.
 Spleen and Hemolymph Nodes
Figure 2-87  Leishmaniasis in a dog. Leishmania infantum can
cause severe lymphadenomegaly. (Courtesy R.C. Menezes.)
phagocytic cells to repeat the process. Lymphocytes and
plasma cells surround the lesion, and neutrophils are attracted
to the debris. When the inflammation extends to the overlying
epithelium, ulceration occurs especially over bony prominences
and along mucocutaneous junctions. Numerous parasites are
present within macrophages, and some are free in the tissue.
Many dogs will develop concurrent conjunctivitis, uveitis, and
blepharitis. Lymphadenomegaly of multiple subcutaneous
nodes is common (Fig. 2-87, eFig. 2-18). Onychogryphosis and
epistaxis develop in some affected dogs.
The clinical signs of visceral leishmaniasis in the dog are
of chronic debilitation and often recurrent oculonasal dis-
charge, with some crusting of the nose, and recurrent diarrhea.
Many dogs lose weight despite a ravenous appetite. There are
often focal scurfy skin lesions, but generally, in visceral leish-
maniasis, the presentation is of a mature dog in poor body condi-
tion with a rough haircoat. Other clinical signs may include
locomotion disturbances resulting from neuralgia, footpad
clefts, interdigital ulcers, or, rarely, paraparesis. There may be
mild enlargement of lymph nodes, and the spleen is always
symmetrically enlarged 2-3 times or more normal size and is
dark brown to black on the capsular surface (Fig. 2-88, eFig.
2-19). The oral and cervical viscera are normal and the lungs
generally have mild tan mottling but are otherwise normal, as
is the heart. The liver may contain numerous granulomas and
is symmetrically enlarged and dark brown. Renal disease is
common, and the kidneys are darker than normal, and while
of normal contour, a severe immune-complex glomerulone-
phritis can lead to chronic renal failure. The bone marrow is
uniformly reddened in midfemoral shaft in well-developed
cases, but the fat is generally of normal character. Other less
common lesions include non-erosive polyarthritis, polymyosi-
tis, osteolysis and osteoarthritis, proliferative periostitis, pan-
creatitis, meningitis, or chronic colitis.
The microscopic lesions in the spleen initially are of hemic-
lymphatic hypertrophy with macrophage proliferation and
focal granulomas. Splenic follicles are hyperplastic, often with
follicular hyalinosis. In advanced cases, there is atrophy of
lymphoid follicles, and the sinus areas may be diffusely occu-
pied by large macrophages heavily laden with intracytoplas-
mic organisms, and numerous plasma cells (Fig. 2-89). The
175
Figure 2-88  Leishmaniasis in a dog. Spleens infected with Leish-
mania infantum are symmetrically enlarged 2-3 times or more
normal size. (Courtesy R.C. Menezes.)
lesions in bone marrow may be focal, but consist of clusters
of epithelioid macrophages with phagocytosed organisms. In
the dog with a well-developed infection, the bone marrow will
have remarkable plasma cell hyperplasia that may approach
50% of cells present, and there is characteristically hypergam-
maglobulinemia. The protein is broadly polyclonal, and the
plasma cells lack atypia. Renal changes are variable and may
consist of interstitial scarring with some parasitic involvement;
however, the effects of hyperproteinemia and immune com-
plexes appear to injure the kidney indirectly. Animals with
leishmaniasis and amyloidosis have been described, and there
may be concurrent changes caused by both processes.
Diagnosis is based on the demonstration of the organism in
cytologic or in histologic preparations, the former being easily
achieved by aspiration of marrow, node, spleen, or liver. There
are now several tests based on immunoglobulin titers by
ELISA or PCR, immunohistochemistry, or in situ hybridiza-
tion to detect organisms in tissue.
Further reading
Barral-Veloso L, et al. A β-mercaptoethanol-modified enzyme linked
immunosorbent assay for diagnosis of canine visceral leishmaniasis.
J Vet Diagn Invest 2013;25:239-242.
Figueredo LA, et al. Clinical and hematologic findings in Leishmania
braziliense-infected dogs from Pernambuco, Brazil. Rev Bras Para-
sitol Vet 2012;21:418-420.
Koutinas AF, Koutinas CK. Pathologic mechanisms underlying the clini-
cal findings in canine leishmaniasis due to Leishmania infantum/
chagasi. Vet Pathol 2014;51:527-538.
Menezes RC, et al. Sensitivity and specificity of in situ hybridization for
diagnosis of cutaneous infection by Leishmania infantum in dogs.
J Clin Microbiol 2013;51:206-211.
Nascimento MS, et al. Naturally Leishmania infantum-infected dogs
display impairment of chemokine and chemokine-receptor expres-
sion during visceral leishmaniasis. Vet Immunol Immunopathol
2013;153:202-208.
Rigo RS, et al. Renal histopathological findings in dogs with
visceral leishmaniasis. Rev Inst Med Trop São Paulo 2013;55:
113-116.
 175.e1

eFigure 2-19  Leishmaniasis in a dog. Spleens infected with Leish-

mania infantum are symmetrically enlarged 2-3 times or more
normal size. (Courtesy R.C. Menezes.)
eFigure 2-18  Leishmaniasis in a dog. Leishmania infantum can
cause severe lymphadenomegaly. (Courtesy R.C. Menezes.)
176 CHAPTER 2  •  Hematopoietic System
A lestoquardi. Because T. parva and T. annularis only migrate to
B ceptibility of the cattle, and indigenous animals may have
C characterized by icterus, anemia, and occasionally hemoglo-
Figure 2-89  Leishmaniasis in a dog. (Courtesy R.C. Menezes.)
A. The splenic red pulp is expanded by large numbers of macro-
phages heavily laden with intracytoplasmic Leishmania infantum
organisms. B. Immunohistochemistry for L. infantum shows large
numbers of organisms in the cytoplasm of macrophages. C. In situ
hybridization for L. infantum shows intracytoplasmic organisms.
Theileriosis
Theileria spp. are obligate intracellular protozoal parasites of
the order Piroplasmida, family Theileriidae. The 2 most impor-
tant species in cattle and water buffalo are T. parva, which
causes East Coast fever of east and central Africa, and T.
annulata, which causes Mediterranean or tropical theileriosis
Spleen and Hemolymph Nodes
across North Africa and central Asia. Other Theileria spp.,
including T. mutans, T. velifera, T. taurotragi, T buffeli, and T.
sergenti, usually cause asymptomatic infection or can increase
severity of East Coast fever and tropical theileriosis. In small
ruminants, T. lestoquardi is the most virulent species and
occurs in Asia, the Middle East, and parts of Africa and Europe.
T. separate and T. ovis can also infect sheep and goats. Although
Theileria spp. can easily be identified with Giemsa stains in
blood smears or lymph node biopsies or at autopsy in impres-
sion smears of many different tissues, species differentiation
requires DNA-based molecular or serologic assays.
Theileria spp. are spread by biological tick vectors. Rhipi-
cephalus appendiculatus is the primary vector for T. parva, but
R. zembeziensis and R. duttoni are also carriers in parts of
Africa. Hyalomma spp. are the vectors for T. annulata and T.
the acinar cells of the tick salivary gland and mature after the
tick attaches to a host, ticks have to stay attached for a number
of days to the host prior to infecting it. Protozoal parasites are
excreted in the saliva between 3-5 days after ticks start feeding.
Under high temperatures, Theileria spp. might mature in unat-
tached ticks and can enter the host right after the tick attaches.
Transovarial transmission has not been reported. Within the
host, Theileria spp. reproduce by schizogony in lymphocytes (leu-
kocytic or tissue phase) and are subsequently found in red cells
(erythrocytic phase). A related genus is Cytauxzoon, which
reproduces by schizogony primarily in macrophages and by
fission in red cells.
Both, East Coast fever and tropical theileriosis are most
severe when susceptible animals are introduced to endemic
areas and mortalities can reach 100% and 90%, respectively.
The outcome of exposure is largely determined by the sus-
a morbidity rate of 100%, but mortality is usually <5%.
The incubation period for either disease ranges between
8-21 days.
Clinical signs are similar for East Coast fever and tropical
theileriosis and include high fever, depression, drooling,
lacrimation, diarrhea, anorexia, and weight loss, as well as
decreased milk production. Abortions are common. Petechiae
and ecchymoses occur in the conjunctiva and oral mucous
membranes. Corneal opacity is commonly observed. Severe
pulmonary edema with dyspnea and a frothy nasal discharge
is common and terminal in many animals, whereas others
become prostrate and comatose. These signs associated with
progressive and prominent enlargement of the superficial
lymph nodes give the disease a close clinical resemblance to
malignant catarrhal fever. Tropical theileriosis is furthermore
binuria because the parasites also destroy red blood cells.
Some animals with East Coast fever may develop a fatal con-
dition called “turning sickness,” which is characterized by neu-
rologic signs as a result of capillary impairment by parasites
in the CNS.
Sporozoites, of tick origin, invade and infect host lympho-
cytes and macrophages. Cell entry occurs through receptor-
mediated parasite-directed phagocytosis. Infected lymphocytes
are transformed in vitro into lymphoblastic cells. Macroschizonts
develop in the cytoplasm of the transformed cells and then
divide synchronously with the host lymphocytes to infect
their daughter cells (Fig. 2-90). After a few days, macroschiz-
onts enter the microschizont stage, in which the host cells are
destroyed and merozoites are released to invade erythrocytes.
 Spleen and Hemolymph Nodes 177

Figure 2-90  East Coast fever in a cow. Bovine lymphoblasts Figure 2-91  East Coast fever caused by Theileria parva in a cow.
containing numerous intracytoplasmic Theileria parva schizonts. Enlarged, diffusely pale lymph node with multiple petechiae.
(Courtesy Plum Island Animal Disease Center, U.S. Department (Courtesy Plum Island Animal Disease Center, U.S. Department
of Agriculture.) of Agriculture.)

Merozoite entry into red cells occurs by a similar process.

During the acute phase of the disease, more than 60% of
lymphocytes may contain schizonts, also called Koch’s bodies.
The acute disease appears to be caused by massive lympholysis
and progressive anemia. Leukopenia is progressive from the
onset of fever, and, terminally, very few leukocytes may be
seen in blood smears. The total white count is seldom >2 ×
109/L, and often only a fraction of this, with the remaining
cells primarily neutrophils and lymphocytes. There is brief
initial stimulation of myelopoiesis, but as disease progresses,
neutropenia with immaturity and toxemia develops. Ulti-
mately, there is loss of precursors and trilineage depression
with accumulation of hemosiderin in macrophages. Termi-
nally, the bone marrow is hypoplastic, and the remaining cells
consist of large blastic parasitized lymphocytes and atypical
erythroblasts. In tropical theileriosis, destruction of erythro-
cytes is intimately related to fission of the piroplasm forms in
erythrocytes. Figure 2-92  East Coast fever caused by Theileria parva in a cow.
Gross lesions in acute disease resemble those of malignant Periacinar hepatocellular necrosis and inflammation with irregular
catarrhal fever. There is enlargement of lymphoid tissues, canalicular cholestasis. (Courtesy E.P. Lane.)
including Peyer’s patches. On cut surface, the lymph nodes
are diffusely discolored with a red-brown cortex containing
focal hemorrhages, and a dark red-brown medullary area (Fig. and fibrinous exudate throughout the cortical areas of nodes.
2-91). Serous effusion and gelatinous or hemorrhagic edema Lympholysis is prominent in germinal centers, and there is a
of connective tissues are common. The spleen is enlarged in general loss of small lymphocytes, with those that remain
the acute disease, but in cases with a prolonged course, it may appearing large and blastic. There is early splenic lymphoid
be shrunken and strap-like. There is ulcerative abomasitis. The hypertrophy that is later followed by lympholysis. Germinal
so-called “infarcts” of the liver and kidney are actually prolif- centers remain prominent and are surrounded by areas of
erative foci of perivascular lymphocytes. These foci, which hemorrhage. The hypocellular follicular centers are usually
project slightly, produce a mottling of small gray-white patches occupied by fibrinous or hyaline exudate similar to that seen
visible on the surface of the liver and kidney. The lungs are in lymph nodes. There is hepatic periacinar and, to a lesser
congested and edematous with increased texture on palpation, extent, periportal lymphocytic infiltration and, in addition,
and increased weight. Small hemorrhages associated with foci there are focal infiltrations of the hepatic capsule that give rise
of hyaline degeneration occur in the muscles, and petechiae to the raised foci seen grossly. In some cases, there is periacinar
are commonly present under the tongue and in the vulva. hepatocellular necrosis and irregular canalicular cholestasis
Erosive or catarrhal enteritis overlies lymphocytic hyperplasia with foci of inspissated bile (Fig. 2-92). The kidneys are
and infiltration of the gut mucosa. remarkably congested with focal hemorrhage, and there is
Histologically, in the early stages of infection, there is diffuse interstitial infiltration with lymphocytes. The lymphocytic
lymphoid hyperplasia. In animals that have died with East infiltration is prominent around vessels, and often around the
Coast fever, there is widespread lympholysis with hemorrhage parietal layer of Bowman’s capsule. There is a variable level
 177.e1

eFigure 2-20  East Coast fever caused by Theileria parva infection

in a cow. Multifocal myocardial necrosis with intracytoplasmic
protozoa. (Courtesy E.P. Lane.)
177.e2

Further reading
Bakheit MA, et al. Serological diagnostic tools for the major tick-borne
protozoan diseases of livestock. Parassitologia 2007;49(Suppl. 1):
53-62.
Mbassa GK, et al. Theileria parva infection in calves causes massive
lymphocyte death in the thymus, spleen and lymph nodes without
initial proliferation. Vet Parasitol 2006;142:260-270.
 177.e3

Further reading
Tinkler SH, et al. Premature parturition, edema and ascites in an
alpaca with Anaplasma phagocytophilum. Can Vet J 2012;53:
1199-1202.
178 CHAPTER 2  •  Hematopoietic System
Figure 2-93  “Turning sickness” caused by Theileria parva in a
cow. Parasitized lymphocytes localize by embolism or sequestra-
tion in cerebrospinal vessels and produce hemorrhagic infarcts.
(Courtesy E.P. Lane.)
of parenchymal necrosis with the formation of hyaline casts
and brown pigmentation of the remaining epithelium. The
pulmonary changes are characteristic and consist of lympho-
cytic infiltration of the septa and interstitial tissues, resulting
in widespread severe interstitial alveolitis. The bone marrow
is hypocellular with early asynchrony of the granulocytic
system and a less severely affected erythroid system accom-
panied by proliferation of large lymphocytes similar to those
infiltrating other tissues. In cases of “turning sickness,” parasit-
ized lymphocytes localize by embolism or sequestration in
cerebrospinal vessels and produce hemorrhagic infarcts (Fig.
2-93, eFig. 2-20). Infarcts of various ages may be found in
other organs, especially kidney and spleen, but are small and
easily overlooked.
Further reading
Bishop R, et al. Theileria: intracellular protozoan parasites of wild and
domestic ruminants transmitted by ixodid ticks. Parasitol 2004;
129(Suppl.):S271-S283.
Glass EJ, et al. Living with the enemy or uninvited guests: functional
genomics approaches to investigating host resistance or tolerance
traits to a protozoan parasite, Theileria annulata, in cattle. Vet
Immunol Immunopathol 2012;148:178-189.
Shaw MK. Cell invasion by Theileria sporozoites. Trends Parasitol
2003;19:2-6.
Stockham SL, et al. Theileriosis in a Missouri beef herd caused by
Theileria buffeli: case report, herd investigation, ultrastructure, phy-
logenetic analysis, and experimental transmission. Vet Pathol
2000;37:11-21.
Tick-borne fever
Tick-borne fever of sheep and goats and pasture fever of cattle
is transmitted by the vector tick Ixodes ricinus and occurs in
Great Britain, Ireland, the Netherlands, Norway, and Finland.
The causative agent is Anaplasma phagocytophilum (for-
merly Cytoecetes phagocytophila, Rickettsia phagocytophila),
which is also the agent of human granulocytic ehrlichiosis in
Europe and North America (where the vector tick is Ixodes
Spleen and Hemolymph Nodes
scapularis or I. pacificus). The infection is transmitted stage to
stage in ticks, but not hereditarily, and other blood-sucking
arthropods may also transmit the agent. Similar diseases have
been reported in sheep and cattle in North Africa.
Tick-borne fever is a transient and mild illness that causes
some loss of condition. The disease is, however, of some sig-
nificance because it appears to predispose sheep to cerebro-
spinal inflammation in louping ill and to staphylococcal
pyemia (tick pyemia), the virus of louping ill being conveyed
by the ticks and Staphylococcus aureus being first established
as an infection in the tick bites. Tick-borne fever also appears
to predispose animals to pasteurellosis.
Clinically, adult ruminants are more susceptible to tick-
borne fever than are the young. After incubation for 2-6 days,
or a few days longer in cattle, there is sudden onset of moder-
ate fever. The fever lasts 2-3 days if the agent is of relatively
low virulence and subsides quickly. If more virulent organisms
are involved, the febrile reaction may be prolonged for nearly
2 weeks, the decline to normal temperature being gradual.
Ewes in late pregnancy may abort. In terms of laboratory
diagnosis, with the onset of fever, the organism is detectable in
circulating granulocytes and large lymphocytes. The most useful
stains are Giemsa and polychrome methylene blue. As the
fever declines, the organisms disappear from smears, and there
is progressive and quite severe neutropenia for a few days,
after which the neutrophil count returns to normal. Organ-
isms are no longer visible in smears unless there is a recrudes-
cence with fever, but they do persist in the blood in some
animals for a year or more. During fever, up to 95% of the
neutrophils may contain parasites. The parasites are restricted
to the cytoplasm and are of varied morphology, the variations
probably representing developmental stages of the parasite.
They may be round, rod-shaped, or irregular masses measur-
ing 0.75-3 µm in diameter present either singly or in clusters,
ring-shaped bodies 2-3.5 µm in size breaking up into irregular
fragments, round or oval morulae of 2.5-3.5 µm in diameter
containing many small granules, or in occasional cells, there
are small masses of ~0.5 µm in diameter.
Persistence of infection after the febrile period is associated
with a state of labile premunition, resistance to reinfection
being demonstrable at ~5 weeks after the primary infection.
Reactions to reinfection are usually much milder than those
to the initial infection, but the situation is complicated by the
immunologic differences and differences in virulence of strains
of the organism. It is probable that in endemic areas sheep
remain infected for life, reinfection occurring at each season
of tick activity.
Further reading
Adaszek L, et al. Three clinical cases of Anaplasma phagocytophilum
infection in cats in Poland. J Feline Med Surg 2013;15:333-337.
Stuen S, et al. Anaplasma phagocytophilum variants in sympatic red
deer (Cervus elaphus) and sheep in southern Norway. Ticks Tick
Borne Dis 2013;4:197-201.
Woldehiwet Z. Anaplasma phagocytophilum in ruminants in Europe.
Ann N Y Acad Sci 2006;1078:446-460.
Classical swine fever
Classical swine fever (CSF, hog cholera, European swine
fever) is caused by species Classical swine fever virus (CSFV),
an enveloped single-stranded RNA virus of positive polarity
 Spleen and Hemolymph Nodes 179

in the family Flaviviridae, genus Pestivirus. There is only one

serotype with minor antigenic variants. CSFV has a close
antigenic relationship with bovine viral diarrhea virus (BVDV)
and border disease virus (BDV) of sheep. Although CSFV has
been eradicated from the United States and Canada, it is
endemic in Asia, in the wild boar population in Europe, and
disease outbreaks have been reported in the Yucatan peninsula
of Mexico.
Pigs, including wild boars, are the only natural reservoir of
CSFV. Transmission of the virus occurs primarily through the
fecal-oral route, but infection can occur through the conjunc-
tiva, mucous membranes, skin abrasions, insemination, and
iatrogenic means. Blood, tissues, semen, secretions, and excre-
tions contain CSFV. Contact with infected pigs is the principal
source of infection with CSFV. Feeding of raw or insufficiently
cooked meat or contaminated food (access of infected wild
boars to food source) is a potent source of CSFV. Airborne
transmission is not thought to be important. Mechanical Figure 2-94  Classical swine fever in a pig. Lymph nodes with
vectors such as insects may carry CSFV; however, CSFV does diffuse edema and hemorrhage in sinusoids creating a “marbled”
not replicate in invertebrate vectors. Rodents and working appearance.
personnel play a crucial role as carriers. Transplacental infec-
tion with viral strains of low virulence often results in persis-
tently infected piglets. Persistently infected pigs do not
produce neutralizing antibodies to CSFV and have a lifelong
viremia. In a protein-rich environment, CSFV is very stable
and can survive for months in refrigerated meat and for years
in frozen meat.
Clinical signs of CSF are highly variable and strongly
determined by the virulence of the strain, age of the pigs
and to a lesser extent the breed and condition of the animals.
CSF occurs in an acute, a subacute, a chronic, or a persistent
form. Virulent and moderately virulent strains of CSF cause
the acute and subacute form of the disease, whereas strains of
low virulence induce a relatively high proportion of chronic
infections that may be inapparent or atypical. Adult pigs
tend to be less severely affected. Congenital infection by viru-
lent CSFV strains will cause abortions or small litter sizes, A
mummified, stillborn, and weak-born pigs. Congenital tremors,
malformation of the visceral organs, limb deformation, arthro-
gryposis, and cerebellar hypoplasia or aplasia occur rarely. Pigs
with acute CSF exhibit high fever, severe depression, reduced
appetite, cutaneous cyanosis, conjunctivitis, anorexia, consti-
pation followed by severe diarrhea (“cholera”), convulsions,
and ultimately die. The subacute form is characterized by
pyrexia, diarrhea, central nervous disease, and low mortality.
Chronic disease is more prolonged with intermittent periods
of depression, anorexia, and fever, alternating diarrhea and
constipation, and recovery is occasionally seen in mature
animals. Poor reproductive performance may be the only sign
of disease caused by low virulence strains of CSFV.
CSF is an acute hemorrhagic disease that is characterized by
disseminated intravascular coagulation, thrombocytopenia, and
immunosuppression. The most common lesion observed in pigs
B
dying of acute CSF is hemorrhage, especially in the kidneys
and lymph nodes. Kidneys have cortical and less commonly Figure 2-95  Classical swine fever in a pig. A. Multifocal acute
medullary petechiae or ecchymoses. Lymph nodes frequently hemorrhagic infarcts. B. Chronic splenic infarcts. (Courtesy J.P.
have diffuse edema and hemorrhage in sinusoids creating a Teifke.)
“marbled” appearance (Fig. 2-94). Frequent gross lesions also
include mucosal hemorrhage in the urinary bladder, splenic small and large intestine. Accumulations of straw-colored fluid
infarcts (Fig. 2-95), and laryngeal and epiglottal hemorrhages. in the peritoneal and thoracic cavities and in the pericardial
Characteristic, but less frequent lesions are multifocal caseous sac may be present. The lungs are congested and hemorrhagic
necrosis of tonsillar crypts (Fig. 2-96) and diffuse subserosal and have secondary bronchopneumonia. In chronic cases, the
hemorrhages and/or catarrhal mucosal inflammation in the colonic mucosa contains multifocal ulcers with white caseous
180 CHAPTER 2  •  Hematopoietic System Spleen and Hemolymph Nodes

A
Figure 2-96  Classical swine fever in a pig. Multifocal necrosis of
palatine tonsils. (Courtesy J.P. Teifke.)

necrotic centers, also known as “button ulcers” (Fig. 2-97).

Chondrodysplasia causing widening of the costochondral
junction of the ribs and at the growth plates of long bones
may be observed in growing pigs that survive more than 30
days postinfection. In pigs infected transplacentally, the most
common lesions are hypoplasia of the cerebellum, thymus
atrophy, ascites, and deformities of the head and limbs. Edema
and petechiae of the skin and the internal organs occur at the
terminal stage of the disease.
Microscopically, vasculitis and lymphoid necrosis are the
most prominent and consistent lesions (Fig. 2-98). CSFV repli-
cates in macrophages and vascular endothelial cells and high B
virulent strains cause a dramatic increase of proinflammatory Figure 2-97  Classical swine fever in a pig. A. Multiple “button”
cytokines interleukin-1 (IL-1), IL-6, and IL-8 as well as an ulcers in colon. (Courtesy J.P. Teifke.) B. Histologic appearance of
increased expression of coagulation factor, tissue factor, vascu- button ulcer characterized by mucosal ulceration and caseous
lar endothelial growth factor (VEGF), and activation of the necrotic centers in lymphoglandular complexes.
transcription factor nuclear factor kappa B (NF-κB). There is
commonly necrosis and variable hemorrhage in the subman-
dibular, gastrohepatic, renal, and mesenteric lymph nodes. The
spleen may have multifocal marginal infarcts. Endothelial
infections cause endothelial swelling in affected vessels that
may occlude the lumen. Edema and reticular cells expand the
intima. The media may be thickened by edema fluid or hyaline
through fibrinoid necrosis. Vessels may be surrounded by
hemorrhage. Glomerular capillaries and splenic and colonic
submucosal arteries are often thrombosed. In contrast, arteries
in the brain rarely contain thrombi, but are surrounded by
prominent cuffs of lymphocytes, especially in the Virchow-
Robin spaces. There may also be small multiple discrete foci
of glial proliferation in the white matter. Epithelial infections
may occur throughout the digestive tract and in the tonsils
and sometimes cause crypt necrosis and abscesses. Changes in
the small and large intestine may include catarrhal, hemor-
rhagic, or ulcerative enterocolitis.

Further reading
Ji W, et al. Studying classical swine fever virus: making the best of a Figure 2-98  Classical swine fever in a pig. Lymphoid necrosis in
bad virus. Virus Res 2015;197C:35-47. Peyer’s patches.
Lange A, et al. Pathogenesis of classical swine fever—similarities to viral
haemorrhagic fevers: a review. Berl Munch Tierarztl Wochenschr
2011;124:36-47.
 180.e1

Further reading
Gómez-Villamandos JC, et al. Morphological and immunohistochemi-
cal changes in splenic macrophages of pigs infected with classical
swine fever. J Comp Pathol 2001;125:98-109.
Gregg D. Update on classical swine fever (hog cholera). J Swine Health
Prod 2002;10:33-37.
 Spleen and Hemolymph Nodes 181

Moennig V, et al. Clinical signs and epidemiology of classical swine

fever: a review of new knowledge. Vet J 2003;165:11-20.
Petrov A, et al. Comparative analyses of host responses upon infection
with moderately virulent classical swine fever virus in domestic pigs
and wild boar. Virol J 2014;11:134.

African swine fever

African swine fever (ASF) is a viral hemorrhagic disease with
high mortality rates in domestic pigs, but clinical presentation
and pathology depend on the virulence of the viral strains/
isolates and the immunologic status of infected pigs. The
disease is caused by species African swine fever virus (ASFV),
a large, double-stranded DNA virus that is the only virus in
the family of Asfarviridae. The virus is endemic to sub-Saharan
Africa. Natural hosts include warthogs and bushpigs, in which
ASFV causes only inapparent infections. The natural cycle of
transmission of ASFV occurs between warthogs and the soft Figure 2-99  African swine fever in a pig. Renal petechiae and
tick vector Ornithodoros moubata that is infective throughout ecchymoses, and diffuse hemorrhages in lymph nodes.
the various nymph stages, and there is trans-stadial, trans-
ovarial, and sexual transmission in Ornithodoros ticks. Orni-
thodoros erraticus ticks became infected during outbreaks on
the Iberian Peninsula. Stable flies (Stomoxys calcitrans) can
harbor high levels of the virus for up to 2 days. Transmission
of disease to domestic pigs can occur by tick bites or through
ingestion of warthog tissues or secretions. In domestic pigs
with clinical disease, all body fluids and tissues contain large
amounts of virus, and transmission can be through oronasal
contact, ingestion of pig meat products, or iatrogenic means.
Transplacental infection with viral strains of low virulence
may result in persistently infected piglets. In a protein-
rich environment, ASFV is very stable and can survive for
months in refrigerated meat and for years in frozen meat.
Following inhalation or ingestion, ASFV replicates in the
tonsils as well as head and neck lymph nodes. This is followed
by marked viremia. Macrophages are the primary target cells
of infection, especially mature macrophages expressing
CD163 and CD107a. Viral glycoproteins p12, p30, and p54 Figure 2-100  African swine fever in a pig. Acute splenic hemor-
play a major role in attaching to and entering target cells. rhage and necrosis. (Courtesy J. Arzt, Agricultural Research
During later stages of disease, additional cell types, including Service–U.S. Department of Agriculture.)
megakaryocytes, tonsillar epithelial cells, hepatocytes, renal
epithelial cells, and endothelial cells, become infected. Hemad-
sorption is observed in hepatic sinusoids, lymph sinuses, organs (Fig. 2-100, eFig. 2-21); hemorrhages on serosal sur-
and splenic red pulp. ASFV induces replication of infected faces, renal cortical, medullary, and pelvic hemorrhage; hydro-
cells and secretory activation: increased levels of proinflam- pericardium; and hydrothorax. Affected lymph nodes are
matory cytokines IL-1, IL-6, and tumor necrosis factor-α. Pro- severely swollen and appear grossly like blood clots because
inflammatory activation and changes in levels of acute-phase of severe hemorrhage and necrosis. The spleen is severely, dif-
proteins are the initial causes of clinical signs and lesions, fusely enlarged, friable, and dark black (Fig. 2-101). The
including fever. meninges can be congested, edematous, or hemorrhagic. Leu-
In acute forms of ASF, affected pigs have high fever and kopenia and thrombocytopenia are both characteristic for
anorexia, lethargy, weakness, recumbency, and erythema, as acute and subacute disease. Lymphopenia is associated with
well as cyanosis of ears, tails, lower legs, and abdomen. Preg- lymphoid depletion in primary and secondary lymphoid
nant sows frequently abort. Death often occurs within 7-10 organs caused by apoptosis (Fig. 2-102, eFig. 2-22). Aborted
days. Pigs with subacute disease most commonly display fetuses can have anasarca, and livers may be mottled.
dyspnea, vomiting, and nasal and conjunctival discharges. Chronic disease is mainly characterized by low fever, loss
Fever tends to be transient, and affected pigs either die or of appetite, swollen joints, occasional diarrhea and vomiting,
recover within 3-4 weeks. ASFV induces severe vascular changes and general poor doing. Lesions include lymphoid hyperplasia,
that cause pulmonary edema, disseminated intravascular coagu- fibrous pleuritis and pericarditis, and pneumonia.
lation, and hemorrhages in different organs: melena, epistaxis,
erythema, renal petechiae, and diffuse hemorrhages in lymph
nodes (Fig. 2-99). Besides endothelial damage, hemorrhages Further reading
have also been attributed to marked thrombocytopenia. Con- Alonso C, et al. African swine fever virus-cell interactions: from virus
sistent lesions include hemorrhage and necrosis of lymphoid entry to cell survival. Virus Res 2013;173:42-57.
 181.e1

A
eFigure 2-21  African swine fever in a pig. Acute splenic hemor-
rhage and necrosis. (Courtesy J. Arzt, Agricultural Research
Service–U.S. Department of Agriculture.)

B
eFigure 2-22  African swine fever in a pig. A. Tonsil with severe
lymphoid necrosis. B. Immunohistochemistry depicting African
swine fever virus (red) in macrophages. (Courtesy J. Arzt, Agri-
cultural Research Service–U.S. Department of Agriculture.)
182 CHAPTER 2  •  Hematopoietic System Spleen and Hemolymph Nodes

A
Figure 2-101  African swine fever in a pig. Severely and diffusely
enlarged, dark black spleen. (Courtesy J. Arzt, Agricultural
Research Service–U.S. Department of Agriculture.)

Blome S, et al. Pathogenesis of African swine fever in domestic pigs

and European wild boar. Virus Res 2013;173:122-130.
Galindo I, et al. African swine fever virus infects macrophages, the
natural host cells, via clathrin- and cholesterol-dependent endocy-
tosis. Virus Res 2015;200:45-55.
Gómez-Villamandos JC, et al. Pathology of African swine fever: the
role of monocyte-macrophage. Virus Res 2013;173:140-149.
Sánchez-Vizcaíno JM, et al. An update on the epidemiology and
pathology of African swine fever. J Comp Pathol 2015;152:9-21.

B
Inflammatory diseases of the spleen
Systemic inflammation causes a regular and fairly predictable
pattern of response in the spleen. The phagocytic function of
the spleen is critical in the immune response to blood-borne
pathogens. Therefore all blood passes at least one time every
day through the spleen. Septicemia and bacteremia result in
microbial deposition in the splenic sinus areas, where the
abundance of phagocytic cells usually leads to their rapid
destruction. In septicemia and following injection of endo-
toxin or gram-negative bacteria, there is rapid accumulation
of neutrophils in the splenic marginal zone and the surround-
ing red pulp vascular spaces become congested and form a
concentric ring. There is bacterial destruction and processing
of antigen in this area followed by a predictable pattern of
migration. This consists of foreign material moving in special-
ized macrophages (metallophils) successively into the marginal C
zone and then to the small-lymphocyte corona, reaching the
germinal center in 10-12 hours. In contrast, immune com- Figure 2-102  African swine fever in a pig. (Courtesy J. Arzt,
plexes appear to move by flow and not by cellular transport. Agricultural Research Service–U.S. Department of Agriculture.)
Overwhelming infections result in acute hyperemia and A. Lymph node with severe lymphoid necrosis. B. Immunohisto-
severe lympholysis of the follicular center cells, characterized chemistry depicting African swine fever virus in macrophages.
by accumulation of nuclear debris. Severe lymphoid necrosis is C. Multichannel indirect immunofluorescence technique detects
also a feature of numerous viral diseases, for instance, rinder- African swine fever virus in macrophages in the tonsil. The virus
pest (Fig. 2-103, eFig. 2-23), canine distemper, equine herpes- (red) co-localizes to CD163-expressing macrophages (aqua)
viral infection (Fig. 2-104), canine parvoviral enteritis, feline within and subjacent to a deep epithelial crypt. Cytokeratin-
panleukopenia, and bovine viral diarrhea. The nuclear frag- expressing (green) cells are spared. Nuclei are labeled blue.
ments are rapidly removed in 1 day so that the follicular
center appears empty, with the nuclei of the dendritic cells
relatively widely spaced and surrounded by their densely pink
cytoplasm, and epithelioid macrophages. These epithelioid
 182.e1

B
eFigure 2-23  Rinderpest in a cow. A. Acute hyperemia and
severe lymphocytolysis of the follicular center cells in a splenic
follicle. B. Lymphoid necrosis with intranuclear inclusions.
 Spleen and Hemolymph Nodes
Figure 2-103  Rinderpest, in a cow. Acute hyperemia and severe
lymphocytolysis of the follicular center cells in a splenic follicle.
Figure 2-104  Equid herpesvirus, in a horse. Severe lymphoid
necrosis in the spleen.
germinal centers are seen in a variety of acute toxemic diseases
in young animals. In older animals, the changes occurring in
splenic germinal centers are often more severe and long
lasting, and consist of a depopulation of the follicular center
cells and transudation of plasma proteins into the germinal
centers to form a fairly persistent coagulum recognized as
intrafollicular hyalinosis. These fibrinous exudates may be
removed, with restitution of the follicular center cells or, if
there is extensive vascular damage, they may become mineral-
ized and result in involution of the germinal center. In very
acute diseases, such as anthrax in cattle, the reaction is almost
solely vascular. In the less severe septicemias, such as erysipelas
in swine, there is moderate reactive hyperplasia that may be
more developed than that seen in acute fulminant gram-
negative septicemias such as salmonellosis.
Marked hyperplastic changes of the sinus areas are a feature
of some diseases, such as malaria, trypanosomiasis, equine
infectious anemia, and malignant catarrhal fever, although
involution characterizes some infections. Some pyogenic bac-
teria, for instance, Francisella tularensis, Yersinia pestis, and
Brucella spp., will cause more widespread liquefactive necro-
sis. Red pulp macrophages proliferate, especially in response
183
A
B
Figure 2-105  Mycobacteriosis in a horse (A) and a beaver (B).
A. Multiple granulomas disseminated over splenic capsule.
B. Multiple granulomas throughout splenic parenchyma. (Cour-
tesy E.P. Lane.)
to intracellular bacteria, for instance, Mycobacterium spp. (Fig.
2-105); fungi (Fig. 2-106, eFig. 2-24), for instance, histoplas-
mosis; or in chronic hemolytic conditions. Blood monocytes
may also accumulate in the red pulp. Such reactions can
appear as focal or diffuse granulomatous inflammation. Some
blood parasites, for instance, Cytauxzoon felis, infect macro-
phages and can cause severe histiocytosis (Fig. 2-107).
Splenic abscesses may be miliary or large and focal, but both
types are uncommon (Fig. 2-108). Abscessation occurs most
commonly secondary to septicemia or bacteremia by pyogenic
bacteria, including Trueperella (Arcanobacterium) pyogenes,
Fusobacterium necrophorum (Fig. 2-109, eFig. 2-25), Rhodococ-
cus equi, Burkholderia pseudomallei, Corynebacterium pseudo-
tuberculosis, and Streptococcus equi. Abscesses are usually
localized in the red pulp, where they develop after failure of
the monocyte-macrophage system to kill them. They usually
bulge over the surface, stretching the splenic capsule and
contain white or yellow pus. Purulent splenitis may develop by
local extension in cattle from penetrating wounds of the retic-
ulum and, in horses, by extension from the stomach as a result
of penetrating ulcers caused by Habronema spp. Inflammation
of the abdominal serosal membranes may extend to the
 183.e1

A
eFigure 2-25  Fusobacterium necrophorum in a cow. Splenic
necrosis with sequestration.

B
eFigure 2-24  Aspergillus terreus in a dog. A. Pyogranulomatous
splenitis with intralesional fungal hyphae. B. Hyphae are difficult
to recognize on routine H&E sections and require special stains,
for instance, periodic acid–Schiff.
184 CHAPTER 2  •  Hematopoietic System
Figure 2-106  Aspergillus terreus in a dog. Pyogranulomatous
splenitis with intralesional fungal hyphae.
Figure 2-107  Cytauxzoon felis in a cat. Diffuse severe splenic
histiocytosis with intracytoplasmic organisms.
Figure 2-108  Splenic abscess in a horse. Streptococcus equi is a
rare cause of splenic abscesses.
Spleen and Hemolymph Nodes
Figure 2-109  Fusobacterium necrophorum in a cow. Multifocal
splenic necrosis with sequestration.
Figure 2-110  Feline infectious peritonitis in a cat. Spleen with
severe pyogranulomatous serositis.
splenic capsule, as feline infectious peritonitis causes severe
fibrinosuppurative splenic serositis in cats (Fig. 2-110).
Tularemia
Tularemia (deer fly fever) is caused by Francisella tularensis.
The disease was first described in Tulare county of California
and is still more common in the western United States than
elsewhere. The organism is a small, gram-negative, pleomor-
phic, non–spore forming, facultative intracellular bacillus that
is strictly aerobic and shares many cultural and epidemiologic
features with Yersinia pestis, the cause of bubonic plague.
Francisella tularensis is found worldwide except for Australia
and Antarctica, but the biovar tularensis (type A) is found only
in North America, whereas biovar holarctica (type B) occurs
throughout the Northern Hemisphere. Type A is associated
with the terrestrial tick-rabbit cycle of infection and causes
severe illness in humans, cats, and rabbits. Type B is more
commonly found in aquatic species, including beavers and
muskrats. Although both type A and B have been isolated
from cats, type A generally causes more severe disease.
The organism is abundant in nature as an infection of many
species of rodents, and it is from these, either directly or by the
 Spleen and Hemolymph Nodes
A
B
Figure 2-111  Tularemia in a beaver. Francisella tularensis causes
multifocal miliary necrosis in mesenteric lymph nodes (A) and
spleen (B).
mediation of insect vectors, that humans and domestic animals
acquire the infection. The organism is able to penetrate intact
skin and mucous membranes, but it is also infective by inges-
tion, inhalation, and inoculation by biting insects and ticks.
Affected cats usually display fever, marked depression, lymph-
adenopathy, and on palpation hepatomegaly and splenomeg-
aly. Lingual and oral ulcers, icterus, and panleukopenia are
common.
Tularemia in cats is a severe systemic disease, with various
manifestations, depending on dissemination or localization.
Grossly, tularemia in cats is recognized by the presence of
miliary white foci 2 mm or more in diameter in the liver, spleen,
and lymph nodes (Fig. 2-111). They are indistinguishable
grossly from the lesions caused by Yersinia spp. Other differ-
entials include nocardiosis, mycobacteriosis, or even crypto-
coccosis. Histologically, the lesions are characterized by focal
areas of severe necrosis (Fig. 2-112). Neutrophils and pus may
be present early and macrophages accumulate, but in slightly
older and larger lesions, there is total liquefactive necrosis with
a granularity that resembles caseation. Degenerate neutrophils
admixed with cellular debris surround areas of necrosis and,
in older lesions, fibroblasts and macrophages may demarcate
the lesion. In contrast to Yersinia pseudotuberculosis, bacteria
are difficult to visualize on regular H&E-stained sections, but
immunohistochemistry (IHC) will readily demonstrate large
185
Figure 2-112  Tularemia in a cat. Francisella tularensis causes
severe liquefactive splenic necrosis.
Figure 2-113  Tularemia in a cat. Immunohistochemistry detects
abundant Francisella tularensis organisms not recognizable on
routine histology.
clumps within necrotic centers and also within macrophages
(Fig. 2-113). The lesions in lymph nodes are often larger than
those in the liver and may be readily visible grossly as wedge-
shaped areas of cortical necrosis demarcated by a narrow zone
of intense reactive hyperemia. Lymphadenitis may be general-
ized or restricted to the nodes draining the site of infection
which, if visible, is an ulcerated papule.
Naturally acquired infections with F. tularensis have been
observed in dogs, but, as a general rule, dogs are highly resistant
to the disease. Most dogs develop short periods of listlessness
and low-grade fever; lymphadenomegaly, uveitis, and conjunc-
tivitis are rather rare. Fatalities caused by tularemia have been
observed in foals and sheep in association with heavy infesta-
tions by ticks, and it is probable that the disease is endemic
in sheep in areas where the reservoir rodents and ticks, espe-
cially Dermacentor andersoni and Amblyomma americanum,
abound. The disease in foals is characterized by a systemic and
febrile illness with, at autopsy, enlargement of liver, spleen,
and kidneys, and the presence of the typical small necrotic
foci of this disease. Affected sheep have high fever, stiffness of
gait, depression, diarrhea, and hyperpnea. Lesions may be
186 CHAPTER 2  •  Hematopoietic System
confined to the superficial lymph nodes or show the more
classic localization. Pneumonia, probably of other cause, and
anemia caused by the ticks are frequently present.
Further reading
Larson MA, et al. Francisella tularensis bacteria associated with feline
tularemia in the United States. Emerg Infect Dis 2014;20:
2068-2071.
Sjöstedt A. Tularemia: history, epidemiology, pathogen physiology, and
clinical manifestations. Ann N Y Acad Sci 2007;1105:1-29.
Wobeser G, et al. Tularemia, plague, yersiniosis and Tyzzer’s disease in
wild rodents and lagomorphs in Canada: a review. Can Vet J
2009;50:1251-1256.
Histoplasmosis
Histoplasmosis is caused by Histoplasma capsulatum, a soil-
borne, facultative intracellular, dimorphic fungus that infects
macrophages, and is characterized by diffuse involvement of
the mononuclear phagocyte system. Histoplasmosis has a
worldwide distribution. H. capsulatum var. capsulatum is fre-
quently diagnosed in the Mississippi, Ohio, and St. Lawrence
River valley areas of North America. H. capsulatum var. far-
ciminosum has been reported in Japan, and H. capsulatum var.
duboisii causes African histoplasmosis.
Like all dimorphic fungi, H. capsulatum exists in a free-
living mycelial form that produces small, smooth, globose
2-3 µm in diameter microconidia, and a large, thick-walled,
globose 5-18 µm in diameter macroconidia, and in a yeast
form. Infection originates most commonly from soil that is rich
with bird or bat feces, and occurs primarily through inhalation
of microconidia. Transmission from dog to dog has been estab-
lished, but it is not known if dogs can transmit the disease to
humans. Inhaled microconidia convert in the infected animal
to the yeast form, which reproduces through budding. Yeast
organisms are phagocytosed by the monocyte-macrophage
system and continue to undergo further intracellular replica-
tion. In most cases, organisms are killed through cytokine-
mediated macrophage killing, and infection is cleared through
T-cell immunity. However, even in immunocompetent hosts,
H. capsulatum may become dormant and is not entirely elimi-
nated from the phagocytic system. Such dormant infections can
persist for many months and years. Yeast organisms are more
resistant to host immune defenses because they are more
invasive and can impair the immune system by raising the
intracellular pH and stimulating IL-4 production. The myce-
lial form is only rarely encountered on valve leaflets from
animals with endocarditis.
Most animals are subclinically infected, and clinical disease
occurs most frequently in dogs and cats, but has been reported
in other species, including humans, swine, cattle, horses, and
birds. Cats are at least as likely as dogs to develop clinical
disease and, in fact, histoplasmosis is the second most common
systemic fungal disease in cats in North America. Persian cats
as well as Weimaraner, Pointers, Terriers, Brittany Spaniels, and
sporting or working dogs are at higher risk to develop disease.
In most cases, infection is limited to the respiratory system
and associated lymph nodes, but lymphatic and hematogenous
dissemination may occur quickly in immune-compromised
hosts or animals infected with a high dose of spores. When
histoplasmosis becomes apparent clinically, the infection is
disseminated, and the disease is then progressive and always
Spleen and Hemolymph Nodes
Figure 2-114  Histoplasma capsulatum in a dog. Diffuse severe
splenomegaly with multiple white foci.
fatal. Given that intestinal and skin lesions have been observed
without respiratory tract lesions, the intestinal tract or skin
may also represent primary routes of infection. However, in
disseminated disease, the intestine could be secondarily
infected like many other tissues.
Cats with advanced histoplasmosis show nonspecific clini-
cal signs, including weight loss, mental depression, anorexia,
dyspnea and tachypnea, and pale mucous membranes. Dogs
may have similar signs; however, most cases of disseminated
histoplasmosis will involve the intestinal tract, causing emacia-
tion, persistent large-bowel diarrhea, or even voluminous
watery diarrhea associated with protein-losing enteropathy,
tenesmus, and fresh blood in the stool. Both dogs and cats
with disseminated histoplasmosis commonly have an enlarged
spleen (Fig. 2-114, eFig. 2-26), lymph nodes, and liver, in
combination with icterus.
Animals with histoplasmosis most consistently have mild
nonresponsive, normochromic normocytic anemia. Leuko-
cytic changes vary with the reserves of the animal and the
stage of the disease. If the animal is in good body condition,
the bone marrow is competent, and there is neutrophilic
leukocytosis with some degree of monocytosis. Later with
debilitation, the leukocyte count drops to normal levels or
lower with left shift and marked toxic changes, including the
appearance of Döhle bodies. There is usually lymphopenia and
eosinopenia. The organisms are readily recognized on micro-
scopic examination, hence fine-needle aspiration of liver, spleen,
enlarged lymph nodes, marrow, or skin provides adequate mate-
rial for diagnosis in appropriate cases. Occasionally, the organ-
ism may be diagnosed in fine-needle aspirates of lung or
bronchoalveolar lavage fluids, or lavage of the turbinates in
animals with sinusitis. Cytologically, the organisms are present
in the cytoplasm of macrophages, unless the cells have been
injured, and are somewhat larger than when seen in histologic
preparations.
Grossly, the pulmonary lesions of histoplasmosis may be in
the form of gray, rounded nodules 1-2 cm in diameter, and
with a distinct tendency to become confluent, or there may
be a diffuse increase in the consistency of the lungs. Intestinal
lesions are located chiefly in the lower part of the small intes-
tine. The mucosa is the site of nodular thickenings or of cor-
rugations similar to those seen in Johne’s disease of cattle. The
 186.e1

Further reading
Gyuranecz M, et al. Tularemia of European brown hare (Lepus euro-
paeus): a pathological, histopathological, and immunohistochemi-
cal study. Vet Pathol 2010;47:958-963.
Stundick MV, et al. Animal models for Francisella tularensis and Burk-
holderia species: scientific and regulatory gaps toward approval of
antibiotics under the FDA Animal Rule. Vet Pathol 2013;50:
877-892.
186.e2

eFigure 2-26  Histoplasma capsulatum in a dog. Severe multifo-

cal granulomatous lymphadenitis.
 Spleen and Hemolymph Nodes 187

A
Figure 2-115  Histoplasma capsulatum in a horse. Severe multi-
focal granulomatous lymphadenitis.

thickenings are the result of infiltration of lymphocytes,

plasma cells, and macrophages in the lamina propria and sub-
mucosa, and they may extend also through the wall to the
subserosa, giving the gut a thickened pipestem appearance.
When the thickening is extreme, ischemic ulcerations occur.
The lymph nodes are greatly enlarged, but are discrete and
without adhesions (Fig. 2-115). There may be no indication
of normal architecture on the cut surface, with the uniformity
resembling lymphoma, except that the nodes are firm and dry.
Histologically, there are coalescing granulomas with histiocy-
tosis, and cortical replacement by the reaction. The spleen is
enlarged sometimes to several times its normal size, gray, and
firm. There is marked sinus expansion and filling by fixed cells
of stromal origin and by colonization with macrophages, many
of which contain the ingested organisms. There is lymphoid
atrophy, varying in degree with the stage of debility of the
animal. The liver is uniformly enlarged, firm, and gray. The
discoloration is diffuse and related to capsular thickening
without focal lesions. The infiltrating cells collect in miliary
foci in the portal triads and sinusoids, causing extensive dis-
placement and atrophy of the parenchyma. The adrenal glands
are often involved— the medulla, the cortex, or both—n
histoplasmosis that is allowed to run its full course. Scant
normal tissues may then remain in these organs. Approxi-
mately 1 4 of all cats with histoplasmosis will develop ocular
lesions characterized by granulomatous blepharitis, conjuncti-
vitis, chorioretinitis, panuveitis or panophthalmitis, retinal
detachment, and optic nerve neuritis. Dermatitis, osteomyeli-
tis, and arthritis, as well as myelitis, are less common.
The enlargement of organs is the result of extensive prolifera-
tion and infiltration with monocytes and epithelioid macrophages
in whose cytoplasm many of the typical yeasts in small or large
numbers are found (Fig. 2-116). The yeast bodies in sections
when stained with H&E appear as basophilic dots with a clear
halo. The halo is part of the yeast’s cell wall and can be dem-
onstrated by stains for bound glycogen, the organism then
appearing as a ring. IHC testing is available, but not necessary
when the yeasts are plentiful. Necrosis of tissues is not often
present in histoplasmosis, although central caseation without
mineralization may occur in large, dense accumulations of
macrophages. Giant cells are seldom seen, and there is only
mild fibrosis.
B
Figure 2-116  Histoplasma capsulatum in a horse. A. Spleen
with extensive infiltration of histiocytes containing abundant
intracytoplasmic yeasts. B. Immunohistochemistry to detect His-
toplasma capsulatum in histiocytic cells.
Responsibility of H. capsulatum for gross or microscopic
lesions can only be claimed when the fungus can be demon-
strated histologically in the lesion. There is seldom any diffi-
culty in demonstrating organisms in sections, although Grocott
stain, IHC, and PCR are more sensitive than H&E, and clini-
cally they are readily cultured. Culture should not be under-
taken without precautions to prevent the inhalation of
microconidia. Biopsy of enlarged lymph nodes and aspiration
biopsy of bone marrow are useful for diagnostic purposes. In
some cases, the organisms can be demonstrated in circulating
monocytes, but they are never plentiful, so examination is best
performed on buffy coat preparations.
Further reading
Aulakh HK, et al. Feline histoplasmosis: a retrospective study of 22
cases (1996-2009). J Am Anim Hosp Assoc 2012;48:182-187.
Cordeiro RA, et al. Serological evidence of Histoplasma capsulatum
infection among dogs with leishmaniasis in Brazil. Acta Trop
2011;119:203-205.
Gilor C, et al. DIC and granulomatous vasculitis in a dog with dissemi-
nated histoplasmosis. J Am Anim Hosp Assoc 2011;47:26-30.
 187.e1

Further reading
Bialek R, et al. Comparison of staining methods and a nested PCR assay
to detect Histoplasma capsulatum in tissue sections. Am J Clin
Pathol 2002;117:597-603.
Tyre E, et al. Histoplasmosis in a dog from New Brunswick. Can Vet J
2007;48:734-736.
188 CHAPTER 2  •  Hematopoietic System
Melioidosis
Melioidosis is a zoonotic infection caused by the gram-negative
bacillus Burkholderia pseudomallei. This organism is a ubiq-
uitous soil saprophyte endemic to Southeast Asia and North
Australia, and the South Pacific. In humans, infection is spread
via direct contact with broken skin, inhalation, or by ingestion,
and disease is most common in severely immunocompromised
patients. Melioidosis has been reported in many domestic and
wild animals. Susceptibility to the infection varies between
species, with sheep and goats being particularly susceptible
and bovine species being rarely infected. Dogs, horses, cats,
and pigs are also considered to have a high natural resistance
to B. pseudomallei. Cases have been reported from Vietnam,
Malaysia, and Australia.
The location of lesions is believed to be associated with the
route of infection. Inhalation of aerosols will produce abscess
formation in the bronchial region, and ingestion will affect the
mandibular lymph nodes and liver. Clinical signs are uncom-
mon, and abscesses may be detected at autopsy without prior
clinical signs. Melioidosis can occur as an acute, subacute, and
chronic form, and lung, spleen, lymph nodes, and liver are most
commonly affected. Young animals are at higher risk to develop
acute, septicemic melioidosis causing death, but localized
respiratory, gastrointestinal, or neurologic disease; arthritis
causing lameness; osteomyelitis; mastitis; and orchitis have
been reported. Clinical signs are dependent on the organ
system affected and include fever, anorexia with progressive
emaciation, discharge from nose and eyes, coughing, dyspnea,
uncoordinated gait, and diarrhea. In small ruminants, pulmo-
nary disease is most common, with sheep being more severely
affected then goats. Aortic aneurysms and mastitis occur most
commonly in goats. Although young pigs are at risk for septi-
cemic melioidosis, adult pigs typically have a more chronic
form with few clinical signs (Fig. 2-117). Sows may abort or
have stillbirths, and orchitis can occur in boars. Various forms
of melioidosis occur in horses, and signs include weakness,
emaciation, edema and lymphangitis of the limbs, mild colic,
diarrhea, coughing and nasal discharge, cutaneous eczema, or
papular lesions. Neurologic disease is rare, but septicemia fol-
lowed by death may occur. Cattle rarely contract B. pseudom-
allei, and clinical disease is usually limited to fever, dyspnea,
Figure 2-117  Melioidosis in a pig. Burkholderia pseudomallei
causes splenic abscessation. (Courtesy S. Kesdangsakonwut.)
Spleen and Hemolymph Nodes
drooling, and arthritis. Dogs may occasionally develop acute,
septicemic melioidosis associated with fever, severe diarrhea,
and fulminant pneumonia. More common are subacute or
chronic lesions characterized by dermatitis with abscessation,
lymphangitis with edema of the limbs, and lymphadenitis.
There are only a few reports of melioidosis in cats, and affected
animals displayed icterus and anemia that led to death.
B. pseudomallei causes multifocal necrotizing inflammation
in multiple organs; foci tend to coalesce to form larger
abscesses that contain thick, caseous, green to yellow or white
pus (Fig. 2-118). Mineralization, in contrast to mycobacterio-
sis, does not occur. In small ruminants, severe, suppurative
bronchopneumonia with abscessation is commonly observed.
Abscesses and ulcers also occur in the nasal mucosa. Even
though rarely reported as a clinical disease, melioidosis may
be a common cause of abscesses in various organs in older
animals. In food animals, lesions may only be detected during
slaughter and if undetected may pose a serious risk for human
infection. Mycobacterium spp. as well as Trueperella pyogenes
may cause similar lesions and definitive diagnosis of melioido-
sis requires bacterial culture.
A
B
Figure 2-118  Melioidosis in a pig. A. In the bronchial lymph
nodes, Burkholderia pseudomallei causes multiple abscesses that
contain thick, caseous, yellow or white pus. (Courtesy S. Kesdang-
sakonwut.) B. Within the center of an abscess is a small eosino-
philic, club-shaped aggregate (Splendore-Hoeppli reaction)
surrounded by degenerate neutrophils.
 Spleen and Hemolymph Nodes 189

Further reading
Najdenski H, et al. Experimental Burkholderia pseudomallei infection
of pigs. J Vet Med 2004;51:225-230.
Sprague LD, Neubauer H. Melioidosis in animals: a review on epizooti-
ology, diagnosis and clinical presentation. J Vet Med B 2004;51:
305-320.

Hyperplastic diseases of the spleen

Splenic cysts
Splenic cysts are unusual. Occasionally, Cysticercus tenuicollis
and hydatids are found. Pseudocysts may result from cystic
degeneration of hematomas. Neoplastic cysts are hemangiomas
or hemangiosarcomas. The latter are relatively common in the
dog and have a rather characteristic history of repeated bouts
of malaise and weakness, with apparent recovery over 2-3
days. Severe anemia accounts for the weakness. Pallor may be
noticed and results from rupture of the tumor with abdominal
hemorrhage. The recovery over a few days is too rapid for new
red cell production, and indicates autotransfusion of the
extravasated blood. The hematologic picture is also typical
with distorted red cells, even in the absence of abdominal
hemorrhage, because of the effects of abnormal vascular walls
and arteriovenous shunts. After hemorrhage, the red cell dis-
tortion is much worse—the formerly extravasated red cells
appear tattered and effete—and the plasma is brown as a
result of extensive hemolysis. There are usually Howell-Jolly
bodies in the blood along with hypersegmented neutrophils.
If abdominocentesis is performed, the presence of an occa-
sional rubricyte is an indication of hemorrhage from the
spleen rather than from another abdominal site.
Lymphoid hyperplasia
Lymphoid hyperplasia of the spleen may be diffuse or seg-
mental affecting only the germinal centers (Fig. 2-119). The
germinal centers in hyperimmune states increase in both size
and density, and the accentuation of the marginal zone, mantle
cell corona, and follicular center cells is increased, often result-
ing in a “target” appearance. The germinal centers increase in
size through proliferation of lymphocytes as evidenced by
high mitotic activity. The vast majority of these lymphocytes
quickly undergo apoptosis, and nuclear debris becomes promi-
nent. Debris is phagocytized by tingible body macrophages, and
immunoblasts leave follicular centers and differentiate to
plasma cells. The number of plasma cells in the spleen often
correlates with the degree of follicular hyperplasia. As the
immune response decreases, germinal centers are still enlarged,
but fewer in number and the reduction of immunoblasts
causes dendritic cells to become more visible. Such hypocel-
lular appearance can also be seen in dogs with prolonged
steroid treatment. Alternatively, there may be hyperplasia of
the periarteriolar lymphoid sheath with prominent broad
cords of lymphocytes surrounding the branches of the
medium-sized arterioles. In contrast to both of these changes,
there may be hyperplasia of marginal zone cells that promi-
nently surround all germinal centers and may fuse with
adjacent germinal centers or actually surround adjacent peri-
arteriolar lymphoid sheaths. These follicular structures are
usually not apparent on gross examination unless there is
hyperplasia or neoplasia involving some or all of these lym-
phoid compartments. Because sinus and follicular hyperplasia
A
B
Figure 2-119  Lymphoid hyperplasia of the spleen in a cow
(A) and a dog (B). A. Diffuse lymphoid hyperplasia is apparent
on cross section. (Courtesy R.L. Amorim.) B. The splenic white
pulp becomes grossly prominent as multiple white nodules.
(Courtesy S. Kesdangsakonwut.)
of the spleen tend to occur together, their concurrence results
in an overall increase in splenic weight.
Nodular hyperplasia
Nodular hyperplasia is frequently observed in the spleens of
old dogs, occasionally in old bulls, and rarely in other species
(eFig. 2-27). Most nodules are up to 2 cm in diameter and
project hemispherically above the capsule, but may be 5 cm
or more in diameter (Fig. 2-120). On cut surface, the nodules
vary from gray to pink to a variegated red and white, with
yellow necrotic areas in the larger ones. The variegated pattern
is the result of persistent islands of vascular spaces in a field
of lymphocytic proliferation. Architecturally, the nodules are
unencapsulated but compress adjacent trabeculae, and irregu-
larly meld with surrounding vascular spaces that have a much
higher density of red cells (Fig. 2-121). Lacking germinal
centers, the benign nodules consist of monomorphic medium
or large lymphocytes with moderate cytoplasmic volume and
small nucleoli. Mitoses are common. In some hyperplastic
nodules, lymphocytes can be admixed with erythroid and
myeloid cells and megakaryocytes. Hyperplastic nodules
can become engorged with blood closely resembling hemato-
mas with rare lymphofollicular structures surrounded by red
blood cells.
More solid hyperplastic nodules must be differentiated
from follicular type lymphomas. Accurate diagnosis may
require immunophenotyping and PCR for antigen receptor
 189.e1

Further reading
Choy JL, et al. Animal melioidosis in Australia. Acta Trop 2000;74:
153-158.
O’Brien CR, et al. Disseminated melioidosis in two cats. J Feline Med
Surg 2003;5:83-89.
189.e2

eFigure 2-27  Splenic nodular hyperplasia in a dog. A hyperplas-

tic nodule projects above the capsule.
190 CHAPTER 2  •  Hematopoietic System
Figure 2-120  Splenic nodular hyperplasia in a dog. A hyperplas-
tic nodule projects hemispherically above the capsule.
Figure 2-121  Splenic nodular hyperplasia in a dog. The varie-
gated pattern is the result of persistent islands of vascular spaces
in a field of lymphocytic proliferation.
rearrangements (PARR) testing (see section on Lymphoma
for more details). Architecturally, benign focal lymphoid hyper-
plasia in the spleen tends to be arranged in large irregular
islands that are loosely facetted in a relatively cohesive mass.
In contrast, lymphomas of a mantle cell or marginal zone type
can be seen to be related to the arteriolar structure of the
spleen in multiple smaller foci, some of which contain rem-
nants of germinal centers. Proliferation immediately surround-
ing fading germinal centers of small cell type is likely of mantle
cell lymphoma. If the proliferation can be seen in some foci
to surround the outside of the mantle cell cuff and is com-
posed of intermediate-sized cells, then the lesion is likely
marginal zone lymphoma. It is uncertain whether hyperplastic
nodules may progress to become follicular type lymphomas,
but the vast majority has no clinical significance. However,
severe expansion with blood may lead to formation of a
hematoma that is prone to rupture causing potential hemoab-
domen (Fig. 2-122). Focal lymphoid proliferations in the
spleen, either hyperplastic or neoplastic, may also become
clinically apparent because of effects of the expanding mass
Spleen and Hemolymph Nodes
Figure 2-122  Ruptured splenic hyperplastic nodule in a dog.
Splenic hyperplastic nodules can become engorged with blood
and are prone to rupture causing hemoabdomen.
Figure 2-123  Splenic fibrohistiocytic nodule in a dog. Grossly,
fibrohistiocytic nodules appear similar to nodular hyperplasia, but
do not undergo differentiation toward hematoma.
on adjacent vascular sinuses, resulting in vascular pooling and
thrombocytopenia.
Fibrohistiocytic nodules
The term splenic fibrohistiocytic nodule has been used by
veterinary pathologists to prognosticate those lesions in which
it is difficult to differentiate among nodular hyperplasia, follicular
type lymphoma, and splenic sarcoma. Although the use of
immunohistochemistry (IHC) and PARR testing allows for
proper identification of follicular type lymphomas, differenti-
ating splenic sarcomas from hyperplastic lesions based on
morphology alone still presents a major challenge. Grossly,
fibrohistiocytic nodules appear similar to nodular hyperplasia,
but occur as highly cellular masses that do not undergo dif-
ferentiation toward hematoma (Fig. 2-123). Histologically,
fibrohistiocytic nodules are composed of mixed populations
of lymphoid cells, histiocytes, and spindle cells, referred to as
“fibrohistiocytic” cells, admixed with hematopoietic elements
(Fig. 2-124). They essentially present a morphologic contin-
uum between nodular hyperplasia and either follicular
 Spleen and Hemolymph Nodes
Figure 2-124  Splenic fibrohistiocytic nodule in a dog. Fibrohis-
tiocytic nodules are composed of mixed populations of lymphoid
cells, histiocytes, and spindle cells referred to as “fibrohistiocytic”
cells.
lymphoma or histiocytic or splenic sarcoma (eFig. 2-28). The
proportion of lymphocytes and fibrohistiocytic cells has been
used to grade fibrohistiocytic nodules. Grade 1 nodules are
composed of 70% or more lymphocytes, and grade 2 nodules
have 40-70% lymphocytes. Both grade 1 and grade 2 fibrohis-
tiocytic nodules most likely represent nodular hyperplasia, but
follicular lymphoma should be excluded, especially for grade
1 nodules by using immunophenotyping and PARR testing.
Grade 3 nodules are composed of <40% lymphocytes and
most likely represent splenic sarcomas, but histiocytic sarco-
mas have to be excluded by using IHC for CD18 and CD204.
When combined with the mitotic index, dogs with grade 1
and 2 fibrohistiocytic nodules with >40% lymphocytes and
<10 mitoses/high-power field (HPF) had an 87% survival
probability of 12 months or more following splenectomy. In
contrast, dogs with grade 3 fibrohistiocytic nodules with >10
mitoses/HPF were associated with only 55% survival probabil-
ity at 12 months postsplenectomy.
Hematopoietic alterations
Extramedullary hematopoiesis (EMH) results when there
is cytokine induction for increased cell production and plu-
ripotent hematopoietic stem cells available. These cells nor-
mally circulate in very low numbers and, in preparation for
EMH, they return to embryonic sites of colonization, sparing
the germinal centers and periarteriolar lymphoid sheaths.
Although EMH is commonly found to some degree within
the spleen of normal dogs, extensive EMH occurs with chronic
anemia, chronic respiratory or cardiovascular disease, various
bacterial septicemias, or with certain neoplastic conditions, for
instance, hemophagocytic histiocytic sarcoma. Grossly, the
spleen appears unremarkable or mildly enlarged. Histologi-
cally, EMH is characteristically includes all 3 lineages (Fig.
2-125), but one cell line may predominate, such as the granu-
locytic system in canine pyometra or the erythroid system in
hemolytic anemia. Megakaryocytes are the most obvious
hematopoietic precursor and characteristically lie adjacent to
the smooth muscle trabeculae when stimulation is mild, but
may become diffusely distributed in the sinus areas when
stimuli are pronounced and prolonged. Splenic erythropoiesis
191
Figure 2-125  Splenic extramedullary hematopoiesis in a dog.
Histologically, extramedullary hematopoiesis includes all 3 lin-
eages, but one cell line may predominate.
is coincident with increased splenic red cell destruction in
immune hemolytic anemias.
Myeloid metaplasia in spleen and other sites of embryonic
hematopoiesis occurs in myelofibrosis (MF), myelodysplastic
syndrome (MDS), myeloproliferative neoplasia (MPN), and
combinations of MF with MDS or MPN. If the animal has
idiopathic myelofibrosis in bone marrow, myeloid metaplasia
in spleen is benign, and typically consists of all hematopoietic
lineages with synchronous maturation. Grossly, the spleen is
uniformly enlarged with turgid capsule and rounded borders.
The parenchyma is dry and light pink owing to hematopoietic
tissue, rather than dark and cyanotic as in congestion. If the
animal has MDS or MPN, there is predominance of one cell
lineage, most often granulocytes, but other cell lineages may
also be present. The predominant cell lineage typically has
dysplastic changes, and fills the splenic sinusoids. Dyspoiesis
may affect only one cell lineage, or more commonly all 3, and
may consist of multinucleated rubricytes, incipient Howell-
Jolly bodies, giant metamyelocytes and band neutrophils,
donut-shaped nuclei, and hypolobulated megakaryocyte
nuclei. Myeloid metaplasia is often accompanied by lymphoid
hyperplasia, hemosiderosis, and splenic fibrosis. With increas-
ing splenic myeloid metaplasia, there is gradual reduction in
the lymphoid compartment, and eventual lymphoid atrophy.
Small infarcts develop and are likely the result of loss of plas-
ticity, and fibrous impairment of vascular structures.
Rarely, the spleen contains a myelolipoma, which appears
grossly as a focal pale nodule on cut surface. Histologically,
myelolipomas are composed of well-differentiated adipocytes
with large fat vacuoles that are sharply demarcated from
the normal splenic parenchyma (Fig. 2-126). Adipocytes are
admixed with hematopoietic and largely erythropoietic cells
that can be sparse or dominate the neoplastic mass. Myeloli-
pomas are usually incidental findings.
Neoplastic diseases of the spleen
The vascular tumors of the spleen are described in Vol. 3,
Cardiovascular system, and leukemic diseases involving the
spleen are described with the myeloproliferative and lympho-
proliferative diseases (this chapter). The spleen is expected to
 191.e1

eFigure 2-28  Splenic fibrohistiocytic nodule in a dog. Fibrohis-

tiocytic nodules are composed of mixed populations of lymphoid
cells, histiocytes, and spindle cells referred to as “fibrohistiocytic”
cells.
192 CHAPTER 2  •  Hematopoietic System
Figure 2-126  Splenic myelolipoma in a dog. Myelolipomas are
composed of well-differentiated adipocytes with large fat vacu-
oles admixed with hematopoietic and largely erythropoietic cells,
and sharply demarcated from the normal splenic parenchyma.
be involved in systemic malignancies of the lymphoid system,
but this is not always the case or apparent. In a review of
lymphomas, there was splenic involvement in only 41 of 72
cases (57%) in dogs, 35 of 81 cases (43%) in cats, and 27 of
90 cases (30%) in cattle. Although the spleen may not be invaded
in lymphoma, it is much more likely to be involved in lymphoid
and myeloid leukemia.
The size of the spleen or the absence of splenic masses
cannot be taken in itself as evidence for the presence or
absence of neoplastic processes, especially round cell neo-
plasms. Careful microscopic examination must be carried out
to determine whether a suspect neoplastic cell population can
be detected. Even when nodular masses are detected grossly,
differentiating hematomas or blood-distended hyperplastic nodules
from hemangiosarcomas will often require examination of numer-
ous sections of tissue around the margins of the splenic mass.
Most hemangiosarcomas will appear grossly as dark red,
blood-filled cystic masses (eFig. 2-29), but small more solid,
gray-white nodules can occur (Fig. 2-127). Microscopically,
hemangiosarcomas may be characterized by well-differentiated
endothelial cells forming incomplete vascular spaces that are
supported by a collagenous and fibrous stroma and commonly
thrombosed (Fig. 2-128). Alternatively, they can appear as
sheets of haphazardly arranged, anaplastic spindle cells with
rare slit-like vascular spaces. Such lesions may require IHC for
CD31, factor 8–related antigen, or CD34 for confirmation.
Hemangiosarcomas of the spleen occur most commonly in the
dog and often result in hemoabdomen. Primary splenic hem-
angiosarcomas rapidly metastasize to the liver and often seed
the mesentery. Metastatic hemangiosarcomas from the subcu-
tis or other sites are also common. Regardless, the prognosis
is poor. Despite careful staging prior to splenectomy, there are
frequent micrometastases at the time of surgery.
When the spleen is symmetrically enlarged to a mild or
greater degree, the histologic infiltration is usually diffuse, as
occurs in leukemia, and occupies all of the vascular spaces.
There is initially, at least, mild atrophy of the germinal centers
and periarteriolar lymphoid sheaths. A diagnosis of lymphoma
in the spleen may be difficult when there is a prominent fol-
licular pattern, and IHC and PARR testing are often required.
Spleen and Hemolymph Nodes
A
B
Figure 2-127  Splenic hemangiosarcoma in a dog. A. Some hem-
angiosarcomas appear as small more solid, gray-white nodules.
B. More commonly, hemangiosarcomas appear as dark red, blood-
filled cystic masses.
In the horse and dog, lymphoma may be nodular in the spleen
and has to be differentiated from nodular hyperplasia.
Non-angiogenic, nonhematogenic splenic sarcomas occur
with some frequency in older dogs with no or vague clinical
signs (Fig. 2-129). This group of sarcomas includes a number
of morphologic variants, including osteosarcoma, fibrosar-
coma, leiomyosarcoma, liposarcoma, chondrosarcoma, myxo-
sarcoma, rhabdomyosarcoma, and undifferentiated sarcoma.
The lack of distinct morphologic characteristics among fibro-
sarcomas, leiomyosarcomas, fibroblastic osteosarcoma, or
undifferentiated sarcomas has led to the use of the common
term “splenic sarcoma” for this group (eFig. 2-30). Although
malignant fibrous histiocytoma of the canine spleen has been
proposed as a distinct entity, the term is confusing because it
is based on the microscopic feature of multinucleated giant
cells rather than histiocytic differentiation and should be
avoided. In general, splenic sarcomas appear grossly as rela-
tively well-circumscribed, gray, often multilobular masses that
are raised above the splenic capsule and commonly undergo
necrosis (Fig. 2-130). Microscopically, these neoplasms are
unencapsulated, invasive, and composed of polygonal to spin-
dyloid neoplastic cells that can become highly anaplastic with
large, bizarre nuclei, and prominent nucleoli (Fig. 2-131, eFig.
2-31). Multinucleated giant cells are common. Neoplastic
cells are often arranged in a storiform or fingerprint pattern
(Fig. 2-132, eFig. 2-32). Large areas of necrosis are commonly
observed. Neoplastic cells are positive for vimentin and vari-
ably positive for muscle specific actin, desmin, and S100,
suggesting either ambiguous morphologic findings or the
 192.e1

eFigure 2-29  Splenic hemangiosarcoma in a horse. Most com- eFigure 2-30  Splenic sarcoma in a dog. A non-angiogenic, non-
monly, hemangiosarcomas appear as dark red, blood-filled cystic hematogenic splenic sarcoma appears as a multinodular, white,
masses. firm, highly destructive mass in the splenic parenchyma.

A B
eFigure 2-31  Splenic sarcoma in a dog. A. A non-angiogenic, nonhematogenic splenic sarcoma
composed of sheets of polygonal neoplastic cells arranged in a storiform pattern that is unencap-
sulated and highly invasive. B. Although necrosis can be extensive, neoplastic cells surrounding
blood vessels tend to be more viable.
192.e2

eFigure 2-32  Splenic sarcoma in a dog. Neoplastic cells are often

arranged in a storiform or fingerprint pattern.
 Spleen and Hemolymph Nodes 193

A
Figure 2-130  Splenic sarcoma in a horse. Well-circumscribed,
firm, gray mass that is raised above the splenic capsule.

B
Figure 2-128  Splenic hemangiosarcoma in a dog. A. Well-
differentiated neoplastic endothelial cells form incomplete vascu-
lar spaces that are supported by a collagenous and fibrous stroma.
B. Thrombosis is commonly observed within hemangiosarcomas.

Figure 2-131  Splenic sarcoma in a dog. A non-angiogenic, non-

hematogenic splenic sarcoma composed of sheets of polygonal
neoplastic cells that are unencapsulated and highly invasive.

Figure 2-129  Splenic sarcoma in a dog. A non-angiogenic, non-

hematogenic splenic sarcoma appears as a multinodular, white,
firm, homogeneous mass rising above the capsular surface. (Cour- Figure 2-132  Splenic sarcoma in a dog. Neoplastic cells are often
tesy S. Kesdangsakonwut.) arranged in a storiform or fingerprint pattern.
194 CHAPTER 2  •  Hematopoietic System Spleen and Hemolymph Nodes

Figure 2-134  Sertoli cell tumor metastatic to the spleen in a

Figure 2-133  Carcinoma metastasizing to the spleen in a dog. horse. A large multinodular mass in the splenic parenchyma with
Multifocal metastases of a mammary carcinoma with “umbilica- cystic spaces and extensive areas of necrosis.
tion” caused by central necrosis. (Courtesy S. Kesdangsakonwut.)

possibility of a common histogenesis from smooth muscle

trabeculae or a distinct population of splenic myofibroblasts.
Most cases are negative for KIT, excluding a metastasizing
gastrointestinal sarcoma as a differential. In some neoplasms,
there is extensive inflammatory cell infiltration, especially
small lymphocytes and dendritic cells, making differentiation
from lymphohistiocytic hyperplastic lesions extremely diffi-
cult. IHC for CD18 and CD204 should be used to differenti-
ate splenic sarcomas from histiocytic sarcomas and CD31 and
factor 8–related antigen for differentiation from hemangiosar-
comas that both may present similar microscopic features.
Whether some splenic sarcomas arise from hyperplastic
nodules is unclear. Although one should also try to reach an
accurate diagnosis, for lesions that lack distinct features of
malignancy and appear as proliferative lesions composed of
lymphocytes, histiocytic cells, and spindle cells, classification
as a fibrohistiocytic nodule of a distinct grade may still provide
additional clinical information. Regardless, splenic sarcomas Figure 2-135  Splenic mastocytosis in a cat. The spleen is dif-
often metastasize to the liver, invade adjacent organs, and are fusely infiltrated by neoplastic mast cells that have a finely granu-
more common in small- rather than large-breed dogs. Median lated, poorly stained cytoplasm with no recognizable mast cell
survival times are only 4 months with 80-100% mortality after granules.
12 months. The mitotic index closely correlates with biological
behavior of primary splenic non-angiogenic, nonhematogenic sar-
comas, and dogs with neoplasms with a mitotic index <9 had
significantly longer survival times than dogs with neoplasms blue or Giemsa. For feline splenic MCTs, widespread dissemi-
with a higher index. nation and metastasis are common. Regardless, splenectomy
Metastatic neoplastic disease of the spleen is uncommon. It is of cats with splenic MCTs has been associated with median
not likely that migration of tumor cells to the spleen is unusual, survival times of more than a year.
but rather that the functional efficiency of the cord and sinus
macrophages usually prevents colonization. Metastatic carci-
noma involving the spleen usually arises from the pancreas, Further reading
liver, or reproductive system (Fig. 2-133). Carcinomatous Cole PA. Association of canine hemangiosarcoms and hematomas with
implants originating from other abdominal viscera can mimic nodular lymphoid hyperplasia or siderotic nodules. J Vet Diagn
peritoneal tuberculosis (Fig. 2-134). Mast cell tumors (MCT) Invest 2012;24:759-762.
in dogs and cats can metastasize to the spleen, but primary Eberle N, et al. Splenic masses in dogs. Part 1: epidemiologic, clinical
visceral MCTs affecting the spleen are not uncommon in cats. characteristics as well as histopathologic diagnosis in 249 cases
Affected spleens are enlarged and may appear mottled, (2000-2011). Tierarztl Prax Ausg K Kleintiere Heimtiere 2012;40:
nodular, or irregular. Histologically, feline neoplastic mast cells 250-260.
have a finely granulated, poorly stained cytoplasm, and typical Gamlem H, et al. Canine vascular neoplasia—a population-based clini-
mast cell granules are not usually recognizable on H&E (Fig. copathologic study of 439 tumours and tumour-like lesions in 420
2-135). Cytoplasmic granules may not stain with toluidine dogs. APMIS Suppl 2008;125:41-54.
 Spleen and Hemolymph Nodes 195

Malinckrodt MJ, Gottfried SD. Mass-to-splenic volume ratio and splenic

weight as a percentage of body weight in dogs with malignant and
benign splenic masses: 65 cases (2007-2008). J Am Vet Med Assoc
2011;239:1325-1327.
Moore AS, et al. Histologic and immunohistochemical review of splenic
fibrohistiocytic nodules in dogs. J Vet Intern Med 2012;26:1164-
1168. Erratum in J Vet Intern Med 2013;27:215.
Sharpley JL, et al. Color and power Doppler ultrasonography for char-
acterization of splenic masses in dogs. Vet Radiol Ultrasound
2012;53:586-590.
Spangler WL, Kass PH. Pathologic and prognostic characteristics of
splenomegaly in dogs due to fibrohistiocytic nodules: 98 cases. Vet
Pathol 1998;35:488-498.
Spangler WL, Kass PH. Splenic myeloid metaplasia, histiocytosis and
hypersplenism in the dog (65 cases). Vet Pathol 1999;36:
583-593. A
Watson AT, et al. Safety and correlation test results of combined
ultrasound-guided fine-needle aspiration and needle core
biopsy of the canine spleen. Vet Radiol Ultrasound 2011;52:
317-322.

Jembrana disease
Jembrana disease is a severe acute disease that occurs in Bali
cattle (Bos javanicus) in Indonesia, with a case fatality rate of
20%. Mild or subclinical disease occurs in other cattle species
and buffalo. The cause is species Jembrana disease virus
(JDV), family Retroviridae, genus Lentivirus, which is closely
related to bovine immunodeficiency virus. Virus titers are high
in blood in the acute disease, and virus is present in saliva and
milk; direct transmission may then occur to susceptible cattle
via conjunctival, intranasal, or oral routes. During the height
of viremia, virus may also be transmitted mechanically by
hematophagous arthropods. Recovered cattle may have per-
sistent low-level viremia, but are probably an infrequent
source of infection. Cattle of European breeds and sheep are
resistant to the disease, although subclinical carrier status may
persist for many months.
Clinically, following an incubation period of 5-10 days after
infection, there is transient fever, dullness, and anorexia. Mild
oculonasal discharge, pallor of the mucosae, and diarrhea with
blood-stained feces are common. Superficial lymph nodes are
visibly enlarged, whereas examination of the blood during the
febrile period usually reveals anemia, leukopenia, thrombocy-
topenia, and in some cases, which may be fatal, an elevated
blood urea level. Basophilic cytoplasmic inclusions are occa-
sionally seen in circulating mononuclear cells.
At autopsy, lesions may not be remarkable, but several are
constant and of diagnostic value. Enlargement of lymph nodes
with slight edema and blurred corticomedullary junctions are
widespread but most marked when regional to other affected
organs, for instance, lungs and liver. During the acute phase,
there is splenomegaly, and on incision the surface shows small
gray-red foci. Scattered petechiae or ecchymoses occur irregu-
larly in the serosae of the heart, gastrointestinal tract, kidneys,
and below the endocardium. The myocardium and liver
contain gray 1-3 mm foci. Pulmonary lesions are subtle, but
can be detected in the cranial lobes, which are firmer than
normal, blue-red, finely mottled, and slightly edematous.
Adjacent lobules show mild overinflation. Shallow erosions
may occur in the gastrointestinal tract and caudal tongue,
where an occasional ulcer is also possible. The kidneys are
consistently pale and have small numbers of gray foci.
B
Figure 2-136  Jembrana disease in a cow. A. Lymph node with
intense proliferation of large lymphoid cells sparing lymphoid
follicles. B. The bone marrow is infiltrated by proliferating large
lymphoid cells. (Courtesy M. O’Hara.)
The general picture may be complicated by concurrent
infections, which have included Pasteurella pneumonia and
helminths of the liver, pancreas, or alimentary tract.
Histologically, 3 phases can be recognized in the acute
disease process of ~6 weeks. During the first week, there is a
general response by the lymphoreticular system, but in the
second phase, up to the fifth week approximately, there is
intense nonfollicular proliferation of reticular and large lym-
phoid cells (Fig. 2-136, eFig. 2-33). A similar infiltrative
process occurs in the liver, kidneys, adrenal medulla, and
choroid plexus systems of the brain, although the central
nervous tissue shows little change. In the cranial lung lobes,
alveolar cells are enlarged, pleomorphic, and proliferative
alongside infiltrating mononuclear cells (Fig. 2-137, eFig.
2-34). Mid-sized pulmonary veins and arteries may be filled
with large numbers of intravascular macrophages. In the third
phase, the follicular lymphoid system is reactivated, and
plasma cells appear progressively. The sequence is consistent
with a transient immunosuppressive disease. Indeed, the
humoral immune response can be suppressed and delayed in
JDV-infected cattle. Histologic lesions regress, but traces of
change can be seen up to 60 days after infection.
Pleomorphic basophilic cytoplasmic inclusions are present in
all affected tissues. By light microscopy, clumps of minute
 195.e1

Further reading
Locke JE, Barber LG. Comparative aspects and clinical outcomes of
canine renal hemangiosarcoma. J Vet Intern Med 2006;20:
962-967.
Spangler WL, et al. Primary mesenchymal (nonangiomatous/
nonlymphomatous) neoplasms occurring in the canine spleen: ana-
tomic classification, immunohistochemistry, and mitotic activity cor-
related with patient survival. Vet Pathol 1994;31:37-47.
Yang TJ, Gawlak L. Lymphoid organ weights and organ:body weight
ratios of growing beagles. Lab Anim 1989;23:143-146.
195.e2

eFigure 2-33  Jembrana disease in a cow. The bone marrow is eFigure 2-34  Jembrana disease in a cow. Pulmonary capillaries,
infiltrated by proliferating large lymphoid cells. (Courtesy M. veins and arteries may be filled with large numbers of intravascu-
O’Hara.) lar mononuclear cells. (Courtesy M. O’Hara.)
196 CHAPTER 2  •  Hematopoietic System
Figure 2-137  Jembrana disease in a cow. Mid-sized pulmonary
veins and arteries may be filled with large numbers of intravascu-
lar mononuclear cells. (Courtesy M. O’Hara.)
coccoid bodies about 0.5 µm, and larger, pleomorphic intravac-
uolar structures occur in reticular and large lymphoid cells,
macrophages including Kupffer cells, pulmonary alveolar cells,
and occasionally in vascular endothelium.
Further reading
Desport M, Lewis J. Jembrana disease virus: host responses, viral
dynamics and disease control. Virology 2010;404:261-268.
Stewart M, et al. TaqMan real-time reverse transcription-PCR and
JDVp26 antigen capture enzyme-linked immunosorbent assay to
quantify Jembrana disease virus load during the acute phase of in
vivo infection. J Clin Microbiol 2005;43:5574-5580.
LYMPH NODES
Structure and function of normal lymph nodes
Lymph nodes, like the spleen, are variably involved in myelo-
poiesis in the fetal stage of development, and convert to
lymphopoiesis shortly after birth. The actual level of lymph
node development at birth varies widely with different species.
Calves and foals have well-developed lymph nodes at birth,
and may have germinal center formation if there has been
intrauterine infection. In contrast, nestlings at birth have
readily recognizable lymph nodes in the neck, mediastinal and
mesenteric areas; the nodes have a loose reticular structure,
very low lymphocyte density, and only limited organization
into cortex and medulla (Fig. 2-138).
The microcirculation of the mammalian lymph node is
closely related to its function, and governs the architectural
development of the node. Afferent lymphatics enter the capsule
and bathe the cortex via the peripheral sinus. Small lymphatic
ducts perforate the inner capsule of the peripheral sinus and
form spherical microanastomotic networks that correspond in
size to the germinal centers. On the medullary aspects of these
spherical networks, the lymphatics anastomose into larger
ducts that drain into the medullary sinuses and then into the
major hilar efferent lymphatics. In contrast, blood vessels both
enter (arteriole) and leave (vein) through the hilar region,
Lymph Nodes
Lymphoid follicle
in outer cortex
Paracortex
Medullary sinus
Efferent lymphatic
vessel
Vein
Artery
Paratrabecular
sinus
Subcapsular sinus
Capsule
Afferent lymphatic
vessel
Figure 2-138  Schematic drawing of lymph node. Sectioning at
various levels of lymphoid follicles will results in different histo-
logic appearances.
with small vessel arborization in the cortical area. In the outer
cortex, small arteries form meta-arterioles or precapillary arte-
rioles that perfuse the germinal centers and mantle cell corona.
The transition to capillaries occurs at this site, and these
vessels then enlarge to form the postcapillary or high-endothelial
venules (HEV) of the paracortex, across which there is heavy
traffic of lymphocytes from the blood to the lymph node
parenchyma. These vessels then unite to form progressively
larger veins that follow the medullary stroma to form the
efferent hilar vein. In pigs, the cortex and medullary areas of
lymph nodes are inverted, but the afferent lymph passes in
lymphatics to the center of the node, where the germinal
centers are normally located. Like other mammals, recirculat-
ing lymphocytes enter lymph nodes through postcapillary
HEV and distribute to T and B areas, and emigrate directly
into the peripheral venous system rather than the efferent
lymphatics as in other mammals.
The various vascular structures of lymph nodes form char-
acteristic associations with nodal tissue. The lymphatics are
identifiable as major ducts entering the peripheral sinus, but
the intranodal lymphatics are not obvious, except for the large
medullary sinuses and the efferent hilar vessels. The arteries
can be identified entering the medullary or hilar area of the
node, and they follow the fibrous trabeculae to the medullary
sinuses. In this area, the arterioles form a regular and obvious
network with the medullary cords, such that the arterioles are
centrally placed in the sinuses and connected by a network of
reticular stroma to the thin limiting membranes of the medul-
lary cords. The smaller arterioles of the paracortex are irregu-
larly visible, as are the terminal arteriolar vessels of the
germinal centers and the mantle cell cuffs. In the adjacent
paracortex, the postcapillary venules are readily identified.
These vascular structures of the blood and lymphatic systems
through their interactions form 3 endothelium-lined compart-
ments: intravascular, intralymphatic, and interstitial, which
 196.e1

Further reading
Tenaya IW, et al. Flow cytometric analysis of lymphocyte subset kinetics
in Bali cattle experimentally infected with Jembrana disease virus.
Vet Immunol Immunopathol 2012;149:167-176.
196.e2

Further reading
Belisle C, Sainte-Marie G. Blood vascular network of the rat lymph
node: tridimensional studies by light and scanning electron micros-
copy. Am J Anat 1990;189:111-126.
Spalding H, Heath T. Pathways of lymph flow through superficial ingui-
nal lymph nodes in the pig. Anat Rec 1987;217:188-195.
 Lymph Nodes
provide the functional architecture by which the lymph node
filters lymph, processes antigen, and returns lymphocytes from
blood to tissue.
The microcirculatory arrangement directs antigens enter-
ing the cortical area in lymphatics to the germinal centers and
the outer cortex. The germinal center has a specific polarity
directed at the source of antigen, which in those germinal
centers near the outer cortex can directly be seen to be ori-
ented to lymph flow from the peripheral sinus. The germinal
center is surrounded by an elliptical cuff of small B lympho-
cytes that is thicker at the superficial pole region near the
peripheral sinus and thinner on the deep pole region adjacent
to the deeper areas of paracortex. Within the germinal center
itself, the cells in the superficial area nearer to the peripheral
sinus have smaller nuclei with more abundant cytoplasm. This
produces a lighter staining area on low-power examination. In
contrast, the cells in the deep pole of the germinal center,
nearer to the paracortex, have larger nuclei with minimal
cytoplasm, resulting in this area having a darker appearance.
Within the central area of the germinal center, there are large
macrophages that contain ingested apoptotic debris, repre-
senting lymphocytes that have undergone somatic hypermu-
tation and have not been selected for further development.
Depending on the plane in which the germinal center is sec-
tioned, these large macrophages may form a complete field
with a “starry-sky” effect across the circumference of the ger-
minal center. This polarity of germinal centers is a constant
feature of lymphoid tissue in lymph nodes, tonsil, and Peyer’s
patch, and is always most readily observed in relation to
antigen in those follicles near the peripheral sinus. Recognition
of polarity is an important aspect of differentiating benign follicu-
lar hyperplasia from follicular lymphoma. Germinal centers that
lie deep within the node in cases of follicular hyperplasia do
not have an obvious orientation to the capsule, but it can be
assumed that the deep and superficial poles are oriented to
the source of antigen and the fine network of lymphatics that
drain the peripheral sinus.
Paracortical tissue may appear as a solid band encompass-
ing the germinal centers, as is typical of the young. With
maturity, paracortical areas irregularly recede and regenerate
in loosely defined, but densely aggregated, deep cortical units.
These units are also defined by cellular composition and vas-
cular supply as are the germinal centers, but, in contrast to
the latter, the deep cortical units are thymus-dependent areas
populated by T cells. There are gaps in the inner layer of the
outer sinus by which the entering lymph can pass directly to
the medullary sinuses. Presumably, this route is taken by heavy
but nonthreatening flow as occurs when frank blood enters
the lymph node during biopsy (red cells appear in the medul-
lary sinuses within minutes of the initiating surgical trauma).
The processing of antigen occurs at random in lymph node
cortex but is always associated with a background of dendritic
reticular cells that function as antigen-presenting cells of the
germinal center. A portion, if not all, of the follicular dendritic
cells arise from Langerhans cells that develop contact sensiti-
zation with antigen in epidermal areas drained by the particu-
lar lymph node. Langerhans cells in epithelial areas bind
antigen relatively inefficiently, but within the germinal centers
they undergo maturation in the process of forming tight junc-
tions with other dendritic cells, thus forming a background
network for the lymphoid follicles. Blood monocytes cultured
in the presence of macrophage colony-stimulating factor
(M-CSF) or granulocyte-macrophage CSF and interleukin-4
197
differentiate without proliferation into CD14-positive macro-
phages or CD1A-positive dendritic cells. It is believed that
this process is repeated in lymph nodes for the maturation of
Langerhans cells to dendritic cells of the germinal centers, and
monocytes for differentiation into dendritic cells of the paracortical
areas. The process of B-cell maturation then involves the
interaction of B lymphocytes that have undergone immuno-
globulin chain rearrangement in preparation for antigen-
driven selection by hypermutation. This process takes place
with the assistance of T-helper cells and on the basis of antigen
presentation in the context of major histocompatibility
complex cellular recognition. B lymphocytes bound in this
manner are selected for further division, finally to become
plasma cells or memory B cells. Those that fail to be bound
in the T-lymphocyte interaction undergo programmed cell
death and are removed by follicular macrophages.
In the development of the T and B cells there are 2 major
phases of differentiation that include antigen-independent and
antigen-dependent stages. The antigen-independent differentia-
tion occurs in the primary lymphoid organs of the bone
marrow and the thymus where there is no exposure to foreign
antigen. These early stages are the blast cells of the lymphoid
system that are capable of self-renewal. In the germinal center,
these blast cells on exposure to antigen are able to divide and
become antigen dependent and become less able to prolifer-
ate, and may become memory cells that can last for years.
Tumors of the undifferentiated B cells are of the aggressive
type, whereas those of the differentiated type are likely to be
of indolent type.
The germinal center formation may arise from 3-10 naive
B cells that proliferate to form 10-15,000 B-cells in the more
than 10 generations of cells required to form a germinal center.
The seed cells for the germinal center are derived from the
naive cells of the mantle cell cuff. These cells initially express
immunoglobulin M (IgM) or IgD that assists them in recog-
nizing antigen in collaboration with the helper T cells and
antigen expressed by the dendritic cells. These antigen-
differentiated cells proliferate to fill the dendritic cell mesh-
work in the follicle center in ~3 days after initial antigen
stimulation. These blast cells accumulate in the deep pole or
dark zone of the germinal center, where they lack surface
immunoglobulin (sIg) and switch off the gene for BCL-2
protein and become susceptible to death through apoptosis.
These blasts undergo the somatic mutation of the Ig gene that
alters the affinity for antigen of the antibody they produce.
They may also at this stage switch from IgM to IgG or IgA in
the process of the late primary or secondary immune response.
The blast cells then mature to a smaller cell as the clone
reduces from 5-10 at the centroblast stage to a few as 3 as the
degree of somatic mutation increases. These mutated cells
then mature to centrocytes and accumulate in the superficial
or light pole of the germinal center. This process of Ig muta-
tion produces a marked intraclonal diversity of antibody-
combining sites from that of only a few precursors. As well,
in the germinal center, the BCL-6 gene undergoes mutation
of the 5′ noncoding promoter region that permits these cells
to be identified as having gone through the germinal center
reaction. Those centrocytes that have reduced affinity for
antigen undergo apoptosis and are phagocytized by the ger-
minal center macrophages. Those centrocytes that have
increased affinity for antigen may undergo further differentia-
tion to plasma cells by the action of CD23 on the dendritic
cells.
198 CHAPTER 2  •  Hematopoietic System
The dendritic cells of the germinal centers are long lived and
may retain antigen on their surface membranes for weeks or
months in the process of antigen focusing, by which the speci-
ficity of a germinal center for a specific antigen is maintained.
The dendritic cells of the paracortical nodules are also long
lived and, in superficial nodes of humans and cattle, they often
contain Birbeck granules characteristic of the Langerhans cells
of the skin, consistent with an origin and previous experience
in that area. There is functional logic in this arrangement
because the follicular macrophages and dendritic cells (B area)
are efficient in the digestion and processing of large particulate
antigens, whereas those in the paracortex (T area) are more
efficient in trapping low-molecular-weight substances, such as
agents producing contact sensitization in the skin, where the
resident reticular cells likely had their initial training. In
general, the lymphocytes in the germinal centers are largely B
cells, whereas those in the paracortex are largely T cells. The
subsets of T cells are also segregated, but not as cleanly, with
the suppressor and natural killer (NK) cells confined almost
entirely to the paracortex, whereas the helper cells are largely
in the paracortex but also in the germinal centers and their
small cell corona of mantle cells.
The process by which lymphocytes exiting the marrow and
thymus are directed to specific tissues is regulated by homing
receptors on the lymphocytes, called intercellular adhesion mol-
ecules (ICAMs), which bind to tissue-specific addressins on
high-endothelial or postcapillary venules in the peripheral
lymphoid tissues. The characteristic development and binding
of hematopoietic progenitor cells is mediated by adhesive
functions of cell surfaces, called integrins and selectins, which
are members of the immunoglobulin superfamily and identi-
fied by the CD44 reagent. There are >30 types of integrins,
which are heterodimeric transmembrane proteins, and 3
major subtypes of selectins, each with an affinity for various
ligands of endothelial cells in different areas of the body. By
these means, naive B and T cells leaving the bone marrow are
guided to specific areas of maturation in the thymus, intestine,
skin, and lymph nodes, and memory cells are directed to the
endothelium of specific tissues. It is worth mentioning in
conclusion that all of the hematopoietic-derived cells resident in
lymph nodes are capable of forming malignant tumors, including
the interdigitating reticular cells. This is in contrast to earlier
concepts that the cells of lymphomas of B- and T-cell types
remain relatively confined to the initial site of malignant trans-
formation until late in tumor progression. It is now under-
stood that neoplastic lymphocytes from either bone marrow or
peripheral lymphoid tissues may circulate at low levels early in
the development of disease. Their ability to disseminate is
dependent upon the development of cell surface proteins,
which mimic those of their benign counterparts, and permit
them to bind to endothelium and extravasate to new tissue
sites.
Further reading
Baumjohann D, et al. Persistent antigen and germinal center B-cells
sustain T follicular helper cell responses and phenotype. Immunity
2013;38:596-605.
Brum JS, et al. Eosinophilic sarcoma in a pig. J Vet Diagn Invest
2012;24:807-811.
Harris NL, Ferry JA. Classification of non-Hodgkin’s lymphomas. In:
Knowles DM, editor. Neoplastic Hematopathology. 2nd ed. Lip-
pincott Williams & Wilkins ed; 2001. p. 691-753.
Lymph Nodes
Huang C, et al. Lineage-specific functions of Bcl-6 immunity and
inflammation are mediated by distinct biochemical mechanisms.
Nat Immunol 2013;14:380-388.
Developmental diseases of lymph nodes
The lesions associated with inherited diseases of the immune
system are included in developmental diseases of the thymus.
In severe combined immunodeficiency, lymph nodes lack both
germinal centers and paracortical lymphoid colonization. In
severe T-cell deficiency, germinal centers are present, but para-
cortical areas are hypoplastic and the spleen lacks periarterio-
lar lymphoid sheaths. In severe B-cell deficiency, as occurs in
agammaglobulinemic foals, germinal centers are not formed
in lymph nodes or spleen, and plasma cells are not found. The
paracortical areas have normal cellularity, and cell-mediated
immunity is intact.
Degenerative diseases of lymph nodes
Lymphoid atrophy, with or without architectural alteration,
occurs in a variety of circumstances. The lack of antigenic
stimulation will result in smaller lymph nodes, as observed in
animals that have been raised germ free. Histologically, such
nodes have fewer primary and secondary follicles. Peripheral
lymph nodes of younger animals may appear similar, because
they have not been exposed to the same constant antigenic
stimulation as those nodes associated with the alimentary or
respiratory tract. Lymphoid atrophy associated with marked
dilation of medullary sinuses, termed vascular sinus transfor-
mation, results from blockage of the efferent lymphatics, and
is exacerbated by the development of fibrosis if the venous
drainage is also obstructed. These conditions may follow surgi-
cal intervention for lymphatic cannulation or occasionally
develop in animals that have been recumbent for prolonged
periods and suffered concurrent venous infarction of muscle.
High doses of radiation cause rapid destruction of lympho-
cytes, especially B cells, and thereby result in smaller lymph
nodes. Histologically, there is severe lymphocyte apoptosis
characterized by cell shrinkage, nuclear pyknosis, and frag-
mentation with apoptotic bodies and tingible body macro-
phages. Prolonged high doses of steroids, cytotoxic cancer
drugs, hypoxia, or heat can also cause severe apoptosis (Fig.
2-139). As long as the bone marrow can supply lymphocytes,
the normal lymph node size and architecture will be restored
within a few weeks. However, prolonged radiation will cause
fibrosis. Many viral infections target lymphocytes and will cause
lymphocyte necrosis in germinal center. Histologically, there is
cell swelling with chromatin clumping, karyorrhexis and kary-
olysis, and ultimately abundant eosinophilic cellular debris.
Lymphocyte necrosis is frequently accompanied by inflamma-
tory cells, for instance, neutrophils and phagocytic macro-
phages with intracytoplasmic cellular debris. Examples of
viruses that cause severe lymphocytolysis include equine her-
pesvirus, canine distemper virus, canine parvovirus, feline pan-
leukopenia virus, rinderpest virus, and bovine viral diarrhea
virus.
Cachectic and senile atrophy lead to moderate reduction in
the overall size of body nodes. Aging changes are largely limited
to mild thickening of the capsule and medullary trabeculae,
with reduced density of germinal centers. Senile atrophy is
seldom of note in large domestic animals, and is only seen with
frequency in dogs, cats, and primates. Grossly, senile lymph
nodes are small with edematous fascia, and characteristically
 Lymph Nodes
Figure 2-139  Lymphoid atrophy in a dog. Prolonged high doses
of steroids can cause severe apoptosis of lymphocytes.
Figure 2-140  Lymphoid atrophy and anthracosis in a dog. Lymph
node with marked reduction of size and discoloration by dark
pigment.
have dark-brown pigmentation of medullary areas that may
extend in decreasing concentration to the subcapsular sinus.
Histologically, there is loss of B and T cells and lymphoid fol-
licles. Cachectic atrophy is frequently encountered in old
sheep and goats with dental attrition, but can be encountered
in any animal with chronic debilitating disease caused by
systemic cancer, malabsorption, or prolonged starvation
leading to cachexia (Fig. 2-140). Cachexia leads primarily to
a loss of T cells and decreased T-cell production with little
effect on B cells. Histologically, cachectic atrophy is character-
ized by retention of the overall architecture with marked
reduction in cell density. Germinal centers are small with a
hypocellular mantle cell corona, and paracortical areas are
sparsely populated. In old animals with cachexia, there are
numerous pigment-bearing macrophages in medullary sinuses,
and thin proteinaceous fluid may be present in medullary
cords and sinuses.
Lymphatic sinus ectasia or lymphatic cysts can affect both
the medullary and subcapsular sinuses (Fig. 2-141). Diffuse
sinus ectasia usually occurs together with lymphoid atrophy
and can occur as part of the earlier described senile atrophy
199
Figure 2-141  Lymphatic sinus ectasia in a dog. Lymphatic sinus
ectasia or lymphatic cysts can affect both the medullary and
subcapsular sinuses of lymph nodes.
Figure 2-142  Lymphoid atrophy in a dog. Severe loss of cortical
tissue and diffuse edema in a lymph node with senile atrophy.
(Fig. 2-142). Histologically, dilated or cystic sinuses are lined
by lymphendothelium and filled with pale eosinophilic lymph.
A few lymphocytes, plasma cells, and macrophages may be
admixed with the lymph.
In emphysema of lymph nodes, gas is confined to the
sinuses. It affects the mesenteric nodes of swine in association
with intestinal emphysema. Emphysema of the bronchial
nodes commonly accompanies interstitial pulmonary emphy-
sema of cattle. The lymph nodes are puffy and light. The
sinuses are distended, and their endothelium is lined by large
macrophages and even giant cells, the mobilized cells occur-
ring in small clusters of spotty distribution on the walls of the
sinuses.
Complete or focal infarction of node is rather uncommon
and occurs with obstruction of blood flow. Predisposing condi-
tions include periarteritis nodosa, but in domestic animals,
lymph node infarcts are most commonly observed with large
cell lymphoma, and may be the first sign of disease. Throm-
bosis is seldom observed.
Sinus erythrocytosis, originating from hemorrhages in
tissues drained by the node, may be visible in the cortical or
200 CHAPTER 2  •  Hematopoietic System
Figure 2-143  Sinus erythrocytosis in a pig. Resulting from hem-
orrhage in tissues drained by the node.
Figure 2-144  Lymph node hemorrhage and edema in a pig.
Salmonella choleraesuis causes severe parenchymal hemorrhage
and edema.
medullary sinuses (Fig. 2-143, eFig. 2-35). Red cells delivered
to the node through the afferent lymphatics tend to pass
through the cortex to the medullary sinuses, where they are
ingested by macrophages. The breakdown of erythrocytes
within lymph nodes results in accumulation of hemosiderin,
which is always most prominent in medullary areas. This
finding has to be separated from hemorrhage occurring within
the nodal parenchyma (Fig. 2-144). In cattle and sheep that
die with acute respiratory distress, the cervical nodes are fre-
quently red-black owing to the blood contained in them,
much of which comes from the tracheal mucosa, where
extravasations begin in the lymphoid nodules. Intrasinusoidal
erythrocytes may also be an artifact from euthanasia or tissue
dissection during autopsy, especially in the bronchial or medi-
astinal lymph nodes.
Besides hemosiderin, which is iron-containing and appears
as golden brown granular material in macrophages within the
medullary cords and lymphatic sinuses of nodes with sinus
erythrocytosis, lipofuscin can also be detected in lymph nodes.
Lipofuscin is also a golden brown, finely granular pigment that
Lymph Nodes
Figure 2-145  Anthracosis in a cow. The black pigment detected
on cross section of a pulmonary lymph node is an incidental
finding.
is derived from the breakdown products of cell membrane
lipids. Ceroid is an acid-fast and autofluorescent variant of
lipofuscin. Both pigments are difficult to distinguish from each
other with H&E stains, but can be differentiate by use of an
iron stain (Prussian blue) and a Ziehl-Neelsen acid-fast stain.
Anthracosis is a regular finding in the pulmonary nodes of
dogs that live in industrial areas, and is of lesser frequency and
degree in cats (Fig. 2-145). The carbon is retained solely in
the phagocytes, principally those of the medullary cords, and
therefore only the medulla is black. The pigment is inert and
of no consequence. Melanin maybe found within lymph
nodes. This is a normal finding in some black-skinned animals
and is not considered a lesion. Care has to be taken to dif-
ferentiate neoplastic melanocytes draining to the lymph node
from melanin-containing macrophages in dogs with oral
malignant melanoma. Immunohistochemistry for CD204,
PNL-2, and melan-A are helpful in the distinction. An uniden-
tified black pigment, in appearance like melanin, is present in
the hepatic nodes of sheep and cattle when they have, or have
had, hepatic distomiasis. The same pigment occurs in bile ducts
infested by Fasciola hepatica, and, in the case of F. magna,
wherever the fluke has wandered.
Amyloid is rarely found in lymph nodes, but appears as
amorphous, eosinophilic, and hyalinized extracellular material
that can cause atrophy of the adjacent tissue. Congo red or
thioflavine staining are helpful in the diagnosis.
Further reading
Elmore SA. Histopathology of the lymph nodes. Toxicol Pathol 2006;
34:425-454.
Lanteri G, et al. Acquired melanosis caused by acorn ingestion in the
Nero Siciliano pig. Vet Pathol 2009;46:329-333.
Perillo A, et al. Lesions associated with mineral deposition in the lymph
nodes and lungs of cattle: a case-control study of environmental
health hazard. Folia Histochem Cytobiol 2009;47:633-638.
Hyperplasia of lymph nodes
Lymphadenopathy is defined as a regional or generalized
lymph node enlargement of unknown or unspecified cause.
 200.e1

B
eFigure 2-35  Sinus erythrocytosis in a cow (A) and in a pig (B).
A. Salmonella choleraesuis causes severe parenchymal hemorrhage
and edema. (Courtesy R.L. Amorim.) B. Hemorrhage in tissues
drained by the node results in a marbled appearance.
200.e2

Further reading
Blanchard JL, et al. Generalized amyloidosis in rhesus monkeys. Vet
Pathol 1986;23:425-430.
Ozcan K, Beytut E. Pathological investigations on anthracosis in cattle.
Vet Rec 2001;149:90-92.
 Lymph Nodes
Lymphadenosis, although not commonly used, more correctly
defines generalized lymphoid hypertrophy. Local enlargement
usually reflects a pathologic process limited to the drainage
area, particularly inflammatory or neoplastic disease. General-
ized enlargement of lymph nodes is a more serious finding,
because it indicates a systemic disease or a systemic neoplastic
disease. Infectious causes of generalized lymph node enlarge-
ment include tuberculosis, brucellosis, and protozoal infec-
tions. Generalized lymphadenopathy produced by an
extraordinary degree of paracortical blastogenesis is typical of
the early phases of malignant catarrhal fever and theileriosis
in cattle. There may be mild generalized lymph node enlarge-
ment in adrenal atrophy. Lymphoid hyperplasia to some
degree is transient in most young animals and in mesenteric
lymph nodes because of stimulation with intestinal antigens.
Endocarditis or abscessation may cause generalized lymphade-
nopathy, as will lymphoma. In general, in acute septic inflam-
mation the lymph nodes are normally mobile within the
subcutaneous tissues, but may become fixed with chronic
sepsis. Similarly, lymphadenopathy resulting from lymphoma
usually does not cause fixation of the nodes in the early stages,
but there is usually perinodal colonization with loss of mobil-
ity in advanced stages.
Lymphoid hyperplasia is a benign, non-neoplastic, reactive
response to an immune stimulus. It can involve both B cells
in lymphoid follicles and T cells in the paracortex, suggesting
either a humoral or cell-mediated response, respectively.
The histologic picture in benign lymphoid hyperplasia is vari-
able, with small and large lymphocytes, with cleaved and
noncleaved nuclei, and macrophages, plasma cells, and neu-
trophils. Unless the stimulation is <10 days old, this mixture
of cells should be organized architecturally with evidence of
follicular hyperplasia. Reactive or secondary follicles are
larger than unstimulated primary follicles, and the detailed
histologic appearance has been described under lymphoid
hyperplasia of the spleen. In the early, marked, immune
response, there will be diffuse parafollicular hyperplasia
with effacement of pre-existing follicles. The paracortex has
a moth-eaten appearance owing to the mixture of cells
present, which includes many large macrophages and pale
dendritic reticular cells. In contrast, in lymphomas, there tends
to be a monomorphic or bimorphic cell population and,
in animals in which follicular lymphomas are uncommon,
finding a monomorphic cell population with diffuse architecture
suggests lymphoma. In some lymphomas, macrophages may be
present, and numerous if there is a high mitotic rate in the
tumor and a high rate of cell death. In contrast, plasma cells
and neutrophils tend to be less numerous than in lymphadeni-
tis, although the presence of plasma cells in itself is no guar-
antee of a benign reaction. There are no lymphomas with 3 or
more lymphocyte types regularly present, and this fact tends
to assist in correctly interpreting the early diffuse lymphoid
proliferations.
The most important criteria for distinguishing lymphoma from
hyperplasia are the integrity of normal architecture and the uni-
formity of cell and chromatin type. Architecturally, the periph-
eral sinus is preserved, even in reactive states where there is
perinodal colonization by benign lymphocytes. In contrast, the
outer sinus is regularly encompassed or destroyed by lym-
phoma of advanced stage. One of the most difficult distinc-
tions is between follicular hyperplasia and follicular
lymphomas, and in these cases, the decision must be based
upon both the architectural changes and the character of the
201
cells interpreted in terms of the history and clinical signs.
Benign lymphoid follicular hyperplasia has a characteristic
morphology because of the antigen-oriented polarity of the
normal germinal center that can be highlighted by immuno-
phenotyping (see Lymphoma). For some cases, additional
PCR for antigen receptor rearrangements may be required
to accurately differentiate follicular lymphomas from follicu-
lar hyperplasia. If a firm decision cannot be made, it is fully
justifiable to request a repeat biopsy in 10 days, at which time
a diffuse benign reaction will have developed a follicular
pattern.
Many infectious diseases, for instance, brucellosis and
trypanosomiasis, present no problem in distinction from lym-
phoma, and result in a regular picture of follicular hyperplasia
followed by paracortical atrophy with generalized sclerosis
and medullary cord hyperplasia. In contrast, an unusual type
of follicular hyperplasia occurs in old sheep and goats that are
in poor condition and may have been destroyed because of
debility. There is regular capsular thickening and increased
prominence of medullary trabeculae. The follicles may be
very large, angular, and facetted in an irregular fashion.
Paracortical atrophy is marked, and there is medullary
cord hyperplasia and empty medullary sinuses. The most
marked changes affect the follicular vessels, which are large,
tortuous arterioles with hyalinized media and often mineral-
ized endothelium. The follicular centers include large epithe-
lioid macrophages and often a very marked tingible body
reaction. This reaction resembles angiofollicular lymph
node hyperplasia of the hyaline vascular type as described in
humans.
A nodular reaction of the paracortical areas occurs in lymph
nodes draining malignant tumors as well as other conditions,
and appears to represent an exaggerated thymus-dependent
response. The nodules may be multiple and coexist with fol-
licular atrophy, raising concern that they represent a multifo-
cal diffuse lymphoma. The nodules represent deep cortical units.
They are centered on networks of dendritic reticular cells and
are densely cellular, but with the histologic variation in cell
type characteristic of the paracortex. These paracortical
nodules, unlike germinal centers, are irregularly defined from
the surrounding paracortex by a lighter staining border of
larger pale-staining dendritic cells and macrophages and fewer
small densely stained lymphocytes.
Plasma cell hyperplasia occurs commonly together with
B-cell hyperplasia in animals when the response to antigenic
stimulation requires antibody production. Affected animals
have often enlarged nodes that contain large numbers of
plasma cells and their precursors in the medullary cords. There
may be partial effacement of normal nodal architecture, and
a plasma cell neoplasm may be considered as a potential dif-
ferential. However, the lack of cortical and capsular infiltra-
tion, binucleated, megalokaryocytic, and atypical plasma cells
help differentiate hyperplasia from a plasma cell neoplasm.
Chronic ehrlichiosis or leptospirosis has been associated with
severe lymphoid plasmacytosis.
Macrophage hyperplasia is primarily the result of resident
macrophage proliferation in the sinuses, but can be seen as
aggregates of macrophages within any region of the lymph
node that is, cortical, paracortical, and medullary. When
aggregates of macrophages occur within the lymph node
parenchyma, other terms such as “granulomatous inflamma-
tion,” “granulomatous lymphadenitis,” “histiocyte aggregates/
infiltrates,” and “macrophage aggregates/infiltrates,” have been
202 CHAPTER 2  •  Hematopoietic System
used to describe macrophage hyperplasia. However, the
term “granulomatous” should only be used if there is evidence
of epithelioid macrophages. In addition, some pathologists
only refer to granulomatous lymphadenitis when there is
partial or complete effacement of nodal architecture. Macro-
phage hyperplasia must be differentiated from sinus histiocytosis
that occurs through drainage of large numbers of macrophages
with efferent lymphatics from a tributary site. It is often neces-
sary to closely examine the organs and tissues within the
tributary field to differentiate sinus histiocytosis from sinus
macrophage hyperplasia. Lymph nodes of the respiratory and
alimentary system are constantly stimulated by antigens and
can have both sinusoidal histiocytosis and macrophage
hyperplasia.
Some of the more difficult distinctions between hyperpla-
sia and primary malignancy of lymph nodes must be made in
hyperimmune diseases. Eosinophilic myositis causes a remark-
able alteration in lymph nodes with generalized sclerosis and
thickening of the capsule, which is irregularly colonized by
small lymphocytes and eosinophils in linear arrays, and marked
thickening of the cortical and medullary trabeculae. There is
diffuse follicular hyperplasia with paracortical atrophy, and
medullary cord hyperplasia with prominent plasma cell accu-
mulation. Germinal centers vary markedly in size and shape
and have accentuation of the large and small cell layers, and
sinuses contain a dense matrix of epithelioid macrophages and
eosinophils. Eosinophils are also prominent throughout the
collagenous trabeculae.
One of the more common indications for lymph node
aspiration in dogs and cats are those associated with chronic
dermatitis or otitis. Lymph nodes draining areas of pigmented
skin that have been chronically inflamed frequently contain
melanin-bearing macrophages in the outer cortex, and these
are frequently present in aspirates of draining nodes. Cytologi-
cally, the melanin granules in melanocytes and macrophages from
benign sources are of uniform size, shape, and pigmentary density,
and in the dog resemble tiny rice grains. In contrast, melanin
granules that are associated with pigmented melanomas are
markedly variable in size, shape, and staining density and are
more likely to be associated with a sclerotic reaction in
the node.
In cases of benign chronic pleural effusion, there may be
infiltration of the mediastinal nodes and others draining the
cavities of benign mesothelial cells. These cells have large
vesicular nuclei with irregularly prominent, single, central
nucleoli and abundant cytoplasm and may be mistaken for
metastatic tumor. The exfoliating cells distend the peripheral
and medullary sinuses and stain for cytokeratin. There is no
necrosis. In pigs with porcine proliferative enteropathy, hyper-
plastic crypts may have “metastasized” to the mesenteric
lymph nodes. Drained epithelial cells lodge in the medullary
sinuses and continue to proliferate (Fig. 2-146). Silver stains
can easily identify Lawsonia intracellularis in the apical portion
of those epithelial cells.
Further reading
Elmore SA. Enhanced histopathology of the lymph nodes. Toxicol
Pathol 2006;34:634-647.
MacNeill AL. Cytology of canine and feline cutaneous and subcutane-
ous lesions and lymph nodes. Top Companion Anim Med
2011;26:62-76.
Lymph Nodes
Figure 2-146  Lawsonia intracellularis in a pig. Drained epithe-
lial cells lodge in the medullary sinuses of a mesenteric lymph
node and continue to proliferate.
Inflammatory diseases of lymph nodes
Lymphadenitis results when an infectious agent is present in the
lymph node, as distinguished from benign lymphoid hyperplasia,
in which the node is immunologically reactive, but free of
local invasion. Lymphadenitis may result from drainage to the
node of the products of a distant inflammatory process that
may progress to involve the node directly. It may be possible
to identify the infectious agent responsible for the lymphad-
enitis or to determine the type of invading agent from exami-
nation of the changes in the node. Lymphadenitis may be acute
or chronic, suppurative, caseous, or granulomatous. Distribution
of cell types present, including large macrophages, and the
quality and character of the neutrophil nuclei are indicative
of the cause of the process, which may be apparent if the
phagocytic cells present have ingested bacteria. Needle aspi-
rates from lymph nodes may occasionally yield large numbers
of necrotic cells, and it should be kept in mind that focal
lymphadenopathy may be the result of metastatic tumor.
Grossly in acute lymphadenitis, the lymph nodes are
enlarged, soft, and hyperemic to a variable degree. The capsule
is taut and thinned given the influx of cells, and on the cut
surface, the parenchyma bulges and may exude blood or pus
or lymph. Thus, if imprint preparations are made, it is neces-
sary to repeatedly remove the exuding lymph from the cut
surface to obtain enough adhesion for cellular exfoliation.
There may be focal discoloration resulting from previous pig-
mentation or infarction.
Histologically, acute lymphadenitis is characterized by
marked hyperemia with unusual prominence of small vessels
in cortical areas. Neutrophils are often present, both through
drainage from the subcapsular sinus and by migration from
the postcapillary venules. Some useful distinction can be made
between granulocytes arriving from these 2 sources. In general,
neutrophils in the peripheral and medullary sinuses indicate
inflammation in the tissue area drained and are not necessarily
indicative of local sepsis. On the other hand, foci of neutrophils
in cortical areas are of hematogenous origin and almost always
are reactions to bacterial colonization, as is likely to occur in
the mesenteric node in bacterial enteritis. When the inflam-
mation is caused by pyogenic organisms, abscessation is likely.
Depending on the disease process, eosinophils may constitute
 202.e1

Further reading
Langenbach A, et al. Sensitivity and specificity of methods of assessing
the regional lymph nodes for evidence of metastasis in dogs
and cats with solid tumors. J Am Vet Med Assoc 2001;218:
1424-1428.
 Lymph Nodes
25% or more of the cells present. The chromatin pattern of
lymphocytes in acute lymphadenitis differs from lymphoma
in that large chromocenters persist in small lymphocytes, and
larger lymphocytes, which are presumed to be the prolifera-
tive population, maintain larger chromocenters in benign con-
ditions, but tend to have a more uniform chromatin pattern
characteristic of cells in cycle in lymphomas. Suppurative
lymphadenitis is commonly encountered with bacterial septi-
cemias, for instance, Streptococcus equi, Brucella spp., or True-
perella pyogenes. Although severe pyogenic bacterial infections,
for instance, Francisella tularensis or Yersinia pestis, cause
focally extensive to severe liquefactive necrosis, focal areas of
necrosis are common with many infections, including parasitic
infections, for instance, toxoplasmosis (Fig. 2-147) or bacterial
infections, for instance, salmonellosis or Tyzzer’s disease.
In chronic lymphadenitis, hyperemia and edema are irreg-
ularly present, and the infected nodes are large and firm, and
may be fixed to local tissues if there has been cellulitis. The
capsule is thickened as are the internal trabeculae, and with
prolonged inflammation the node becomes dry and hard.
Lesions can occur as well-encapsulated abscesses (Fig. 2-148,
eFig. 2-36), granulomatous inflammation that can be focal or
diffuse (Fig. 2-149), or a mixed inflammatory reaction com-
Figure 2-147  Toxoplasma gondii in a cat. Necrotizing lymphad-
enitis with intralesional protozoal organisms.
Figure 2-148  Lymph node abscess in a dog. Large amounts of
yellow green pus surrounded by a thick fibrous capsule.
203
posed of follicular hyperplasia, microabscesses, sinus histiocy-
tosis, and fibrosis. Such chronic mixed lymphadenitis is
characteristically present in the supramammary lymph nodes
of cows with brucellosis of long standing, and to a lesser extent
in animals with chronic or recurrent bacterial mastitis. In the
latter cases, marked proliferation of the collagenous septa of
the medulla may completely displace the medullary cords.
Examples of chronic suppurative lymphadenitis leading to
abscessation include streptococcal infections in different
animal species, localized Trueperella pyogenes infections, or
foreign bodies in small animals causing severe peritonitis (Fig.
2-150). A specific example of a caseous lymphadenitis is caused
by Corynebacterium pseudotuberculosis. The classic example of
focal granulomatous lymphadenitis is caused by mycobacterial
infections. Although Mycobacterium bovis causes caseating
granulomas in lymph nodes of the digestive or respiratory tract
in ruminants or humans (Fig. 2-151, eFig. 2-37), Mycobacte-
rium avium complex can cause similar lesions in a wide variety
of species. Most commonly, granulomas appear caseous and
single or multifocal throughout the affected node. Histologi-
cally, they are characterized by caseous necrotic centers that
often become mineralized and are surrounded by epithelioid
macrophages and multinucleated giant cells of Langhans type
(Fig. 2-152). These granulomas are commonly surrounded by
A
B
Figure 2-149  Granulomatous lymphadenitis in a cow (A) and a
horse (B). A. Mycobacterium bovis can cause severe granulomatous
inflammation or caseous necrosis. B. Rhodococcus equi causing
multifocal granulomas.
 203.e1

A
eFigure 2-37  Tuberculosis in a cow. Multifocal caseous necrosis
of lymph node caused by Mycobacterium bovis. (Courtesy R.L.
Amorim.)

B
eFigure 2-36  Lymph node abscess in a cat (A) and a deer (B).
A. The lymph node parenchyma has been replaced by yellow pus
surrounded by a thick fibrous capsule. B. Trueperella pyogenes most
commonly causes abscesses in a variety of species.
204 CHAPTER 2  •  Hematopoietic System
Figure 2-150  Suppurative lymphadenitis in a dog. Severe sup-
purative peritonitis caused by a penetrating foreign body.
A sheep wherever they are raised, but horses, camels, deer,
B of spread in sheep and goats that are routinely corralled on
Figure 2-151  Tuberculosis in a cow. A. Diffuse caseous necrosis
of pulmonary lymph node caused by Mycobacterium bovis. B. M.
bovis causing miliary granulomatous inflammation of retropharyn-
geal lymph node.
Lymph Nodes
rims of lymphocytes, plasma cells, and fibroblasts. In contrast
to tuberculosis, Johne’s disease, caused by Mycobacterium
avium subsp. paratuberculosis, is characterized by noncaseous
granulomas in mesenteric lymph nodes of ruminants (Fig.
2-153, eFig. 2-38). Rhodococcus equi can cause severe granu-
lomatous lymphadenitis in horses that may ultimately result
in diffuse lymph node necrosis (Fig. 2-154, eFig. 2-39). Feline
infectious peritonitis can cause severe, focal, pyogranuloma-
tous lymphadenitis, and lesions may coalesce and efface the
whole node (Fig. 2-155). Many fungal infections, for instance,
blastomycosis (Fig. 2-156), cryptococcosis (Fig. 2-157), and
histoplasmosis, can cause severe diffuse granulomatous lymph-
adenitis. The architecture of an affected node is commonly
completely obliterated and replaced by pyogranulomatous to
granulomatous inflammation with accumulation of epitheli-
oid macrophages admixed with variable numbers of multi-
nucleated giant cells, neutrophils, lymphocytes, and plasma
cells.
Lymphadenitis may be expressed by changes that are
largely degenerative and affect the architecture of the tissue.
Thus, in some acute viral infections, there is rapid lysis of
lymphocytes, as in canine parvoviral infection and in rinder-
pest. In dogs, canine distemper virus causes marked necrosis
of lymphocytes with simultaneous formation of syncytial cells
(Fig. 2-158). In salmon poisoning of dogs, the nodes may be
much enlarged with follicular hyperplasia and accumulation
of macrophages. In some chronic infections, particularly with
the viruses causing immunodeficiency, the nodes are atrophic
with wrinkled capsule and depletion of lymphocytes, and with
sinus histiocytosis if the production of monocytes by the bone
marrow remains competent.
Caseous lymphadenitis
Caseous lymphadenitis (CLA) is a suppurative infection of the
lymph nodes, primarily of sheep and goats, caused by Coryne-
bacterium pseudotuberculosis (ovis). The disease occurs in
mules, and rarely cattle and humans may be affected. Cattle
can develop a pathologic syndrome that resembles that in
sheep, but they do so quite rarely, and the infection generally
remains localized to 1-2 regional nodes draining an infected
surface wound or a segment of intestine. C. pseudotuberculosis
is also the cause of ulcerative lymphangitis in cattle and horses,
and of pectoral abscesses in horses.
There are 2 serotypes, with type I in ovine, caprine and
occasionally bovine isolates, and type II in buffalo and most
infections in cattle. An exotoxin that consists of a phospholi-
pase D is an important aspect of virulence, with effects includ-
ing intravascular hemolysis, necrosis, pulmonary edema, and
shock.
C. pseudotuberculosis survives briefly in the environment
and is able to spread indirectly, which is an important means
the same bed ground to avoid predation. Infection also occurs
in shearing wounds in sheep and butting abrasions in males.
In horses, the disease occurs as ulcerative lymphangitis on
the fetlocks, which is consistent with the concept that skin
abrasions are important in spread of the organism. The sea-
sonal incidence of abscesses in the pectoral and other regions
of horses suggests that the organism may also be borne by
arthropods.
The disease in goats can be more severe than in sheep, the
most frequent lesions being in the lymph nodes of the head
 204.e1

eFigure 2-38  Johne’s disease in a goat. Mycobacterium avium eFigure 2-39  Rhodococcus equi in a horse. Multifocal granulo-
subsp. paratuberculosis causes noncaseous granulomas in mesen- matous inflammation in mesenteric lymph node.
teric lymph nodes.
 Lymph Nodes 205

A A

B B
Figure 2-153  Johne’s disease in a goat. A. Mycobacterium avium
subsp. paratuberculosis causes noncaseous granulomas in mesen-
teric lymph nodes. B. Multifocal granulomatous inflammation
with multinucleated giant cells of Langhans type.

a function of age. Caseous lymphadenitis is widespread in goats,

C enteric or mediastinal nodes grossly.
Figure 2-152  Tuberculosis in a cow. A. Caseating granulomatous
lymphadenitis with dystrophic mineralization of the necrotic
center. B. Large numbers of multinucleated giant cells of Lang-
hans type surround necrotic centers. C. Acid-fast bacilli can be
detected in the cytoplasm of epithelioid macrophages.
and neck. The lesions in goats closely resemble those of pseu-
doglanders or melioidosis (Burkholderia [Pseudomonas] pseu-
domallei), and it is important to distinguish these diseases.
Female goats and intact males have more extensive lesions
than castrated males. In sheep and goats, there is slow spread
of the disease, with the prevalence of abscesses increasing as
and the disease differs from sheep in the distribution of the
abscesses. In goats, the mandibular lymph nodes, followed by
the parotid nodes, are most often involved suggesting that the
organism is acquired through the buccal mucosa, as well as
through skin wounds. Superficial abscesses of the jaw and neck
region are common, and infection is probably acquired from
feed stalls or collars carrying the bacterium. In only a small
proportion of goats does infection spread to involve the mes-
Caseous lymphadenitis (CLA) in sheep almost always
follows a wound infection, usually a shearing wound. The
organism can penetrate the intact skin of freshly shorn sheep,
however, and may be transmitted by dipping fluids. Docking
and castration wounds and the umbilicus are of minor impor-
tance. Occasionally, the infection may be acquired by inges-
tion, as indicated by confinement of the lesions to the nodes
draining the buccal cavity (eFig. 2-40). Less commonly, the
organism is inhaled, producing lung abscesses. Parasitic wounds
of the lower alimentary tract are not a portal of infection.
Although the phospholipase toxin is an important aspect
of pathogenicity, the natural infection in sheep, even when
generalized, gives scant clinical evidence of intoxication,
although the exotoxin facilitates the spread of infection from
 205.e1

eFigure 2-40  Corynebacterium pseudotuberculosis in a sheep.

Severely enlarged lymph node because of abscessation.
206 CHAPTER 2  •  Hematopoietic System Lymph Nodes

A A

B B
Figure 2-154  Rhodococcus equi in a horse. A. Multifocal granu- Figure 2-155  Feline infectious peritonitis in a cat. A. Multiple
lomatous inflammation in mesenteric lymph node. B. Diffuse pyogranulomas distributed throughout the mesenteric lymph
caseous necrosis of lymph node parenchyma. node and along the peritoneal surface. B. Severe pyogranuloma-
tous lymphadenitis.

the primary site. Vaccination with the exotoxin provides a

degree of protective immunity. The leukotoxic surface lipid
allows persistence within inactivated macrophages in which
the organism is effectively a facultative intracellular parasite.
The acquisition of host resistance may also be in part the
result of the selection of a population of macrophages resistant
to and capable of destroying the toxic surface lipids of the
bacteria.
The sequence of events in progressive CLA is infection of a
superficial wound, spread of infection to the local lymph
nodes, which suppurate, and then lymphogenous and hema-
togenous extension to produce abscesses in internal organs.
The progression is slow and may reach the bloodstream only
in older animals, whereas in young animals the disease tends
to be confined to the superficial lymph nodes, most commonly
the precapsular and precrural.
Spontaneous recovery from the primary infection of cuta-
neous wounds, even when they suppurate, is more common Figure 2-156  Blastomyces dermatitidis in a dog. Severe pyo-
than is progression of the infection to the lymph node, as granulomatous lymphadenitis with large numbers of intralesional
judged by results in the experimental disease in which only yeast organisms that exhibit broad-based budding.
~20% of sheep develop abscesses in the nodes. Even when
abscesses develop in the nodes, the primary cutaneous lesion
heals, but secondary cutaneous lesions may develop as fistulae
when the nodal abscess ruptures to the exterior. This occurs
 Lymph Nodes
Figure 2-157  Cryptococcus neoformans in a cat. Granulomatous
lymphadenitis with typical “soap-bubble” appearance caused by
the thick gelatinous capsule of the yeast organisms.
Figure 2-158  Canine distemper virus infection in a dog. Lymph
node with severe lymphoid depletion and formation of multi-
nucleated syncytial cells.
more often in goats than in sheep. As a general rule, once the
infection gains the nodes, it is persistent, although a few infec-
tions may be cleared when the node ruptures and discharges
on to the skin.
The initial lesion in lymphoid tissues is diffuse lymphadeni-
tis that is probably the result of the soluble exotoxin (Fig.
2-159). When the organism reaches the nodes, multiple
microscopic abscesses form in the cortex. Eosinophils are
prominent in the reaction and cause the pus to be green.
These foci rapidly coalesce, and the central areas caseate to
form a structureless mass that contains fragments of nuclear
material and discrete clumps of bacteria. The abscesses are
rapidly encapsulated, and when this occurs, the acute reaction
in the surrounding tissues subsides, but the abscesses continue
to enlarge. With enlargement, there is progressive necrosis and
re-formation of the capsule, which gives the lesion a very
characteristic structure of concentric lamellations (Fig. 2-160).
These are particularly prominent when calcareous granules
are deposited in successive layers at the margin of the expand-
ing lesion. In old lesions, the contents lose their green color,
207
A
B
Figure 2-159  Corynebacterium pseudotuberculosis in a sheep.
A. Diffuse severe, suppurative lymphadenitis resulting in absces-
sation. B. Microscopic abscesses in the cortex of a lymph node.
become inspissated, and resemble putty. The lamellation is
specific to the organism, not the organ involved. The nodal
lesions often attain a diameter of 4-5 cm, and exceptionally,
they may reach 15 cm. The larger lesions in superficial nodes
cause pressure atrophy and depilation of the overlying skin;
they frequently rupture to discharge chronically through a
narrow fistula.
Caseous lymphadenitis is rarely fatal, and indeed, it seldom
even causes debility. Its economic importance results from
regulations concerning the trading of carcasses that show evi-
dence of the disease. When fatalities do occur, they are caused
principally by large pleuropulmonary abscesses. Rarely, C.
pseudotuberculosis causes small outbreaks of polyarthritis in
lambs, but they recover spontaneously.
The mature lesion of CLA is an encapsulated abscess with
pus of a distinct green hue and of caseous or caseopurulent con-
sistency. The initial cutaneous lesion may not be evident,
having resolved, but it is noted that occasional subcutaneous
abscesses, principally of the face and belly, do occur without
relation to known aggregations of lymphoid tissue. Mastitis, as
occasionally observed in sheep and often observed in goats,
probably represents an extension from a wound of the overly-
ing skin; when the mastitis is early and acute, it is diffuse and
suppurative, and when chronic, it is localized to encapsulated
208 CHAPTER 2  •  Hematopoietic System
A
B
Figure 2-160  Corynebacterium pseudotuberculosis in a sheep.
A. Lymph node with multifocal encapsulated abscesses with
characteristic concentric lamellations. (Courtesy S. Kesdangsakon-
wut.) B. Concentric lamellations are also recognizable on micro-
scopic examination. (Courtesy S.D. Fitzgerald.)
abscesses. The disease is easily diagnosed by fine-needle aspira-
tion of the focal lesions, which allows both cytopathology and
bacterial culture.
Spread from the lymph nodes produces lesions in the lungs,
and these are rather common with advancing age. They also
occur in young lambs, in which the progression is more rapid
than in adults. The pulmonary lesions may consist of extensive
bronchopneumonia, when abscesses rupture into bronchi in
which there are soft caseopurulent foci, or there may be dis-
crete nodules of various sizes and numbers. In cases of bron-
chopneumonia, and overlying those nodules that are
immediately subserosal, there is pleuritis, often with adhe-
sions. When the adhesions are few and localized adjacent to
the nodules, the remaining pleural cavity may be normal.
When the adhesions are more diffuse, there is a large amount
of serous fluid in the cavities and a thin layer of fibrin on the
pleura. The nodular lesions in the lung are similar to those in
lymph nodes, and have a narrow zone of bronchopneumonia
outside the capsule. With time, the pulmonary nodules
become sharply circumscribed, encapsulated, subpleural
abscesses. The pulmonary lesions are associated with charac-
teristic lesions in bronchial lymph nodes, which may be much
Lymph Nodes
Figure 2-161  Strangles in a horse. Streptococcus equi var. equi
causing suppurative lymphadenitis of the retropharyngeal lymph
node.
enlarged. Dissemination of the infection from the lungs to
other viscera is uncommon. Lesions are occasionally observed
in the renal cortex as discrete abscesses or as descending
pyelonephritis. Other viscera, chiefly the liver and spleen, may
contain solitary abscesses of the typical form. The organism is
sensitive to a number of antimicrobials, but response to
therapy is poor, both because of the intracellular location of
the organism and the characteristic formation of abscesses into
which drug penetration is ineffective.
Further reading
Baird GJ, Fontaine MC. Corynebacterium pseudotuberculosis and its
role in ovine caseous lymphadenitis. J Comp Pathol 2007;137:
179-210.
Dorella FA, et al. Corynebacterium pseudotuberculosis: microbiology,
biochemical properties, pathogenesis and molecular studies of viru-
lence. Vet Res 2006;37:201-218.
Hoelzle LE, et al. Differences in the antigen structures of Corynebacte-
rium pseudotuberculosis and the induced humoral immune
response in sheep and goats. Vet Microbiol 2013;164:359-365.
Streptococcal adenitis in swine
Jowl abscess is a cervical adenitis caused by Streptococcus
porcinus, and like strangles of horses (Fig. 2-161, eFig. 2-41),
the deep infection follows colonization of the oral cavity and
likely the tonsils. The disease has become less common with
the introduction of better hygiene, age-matched groups, and
feeding equipment designed to avoid sharp projections.
The organism has 8 serotypes, based on carbohydrate antigens,
of which type 4 is most frequently isolated from cervical
lymphadenitis of swine. Baby pigs have passive immunity, and
transmission occurs through direct contact with infected
animals that can shed organisms for months, and also from
contaminated environment. Invasion of the nasopharynx is
followed by mild fever and leukocytosis that resolve, and by
lymph node enlargement in 2 weeks, which less often pro-
gresses to open drainage. The mandibular nodes are most often
involved, followed by the retropharyngeal and parotid nodes.
 208.e1

Further reading
Windsor PA. Control of caseous lymphadenitis. Vet Clin North Am Food
Anim Pract 2011;27:193-202.
208.e2

eFigure 2-41  Strangles in a horse. Streptococcus equi var. equi

causing suppurative lymphadenitis of the retropharyngeal lymph
node.
 Lymph Nodes
Figure 2-162  Jowl abscess in a pig. Streptococcus porcinus causing
cervical lymph node abscesses. (Courtesy S. Kesdangsakonwut.)
The disease is not often of clinical importance, and affected
animals grow well, but losses result from condemnation at
slaughter. Bacterins are less effective than live oral culture in
prevention.
The abscesses are usually multiple and measure 1-10 cm
in diameter. The pus is typically without odor, green, and
creamy in consistency (Fig. 2-162). Streptococcus porcinus, a
β-hemolytic Streptococcus that belongs to Lancefield’s group
E, can be isolated regularly from the pus.
Rhodococcus equi is often present in the submaxillary
lymph nodes of swine and has been proposed as the cause of
lesions typical of tuberculosis in these nodes. Evidence sug-
gests, however, that R. equi is not responsible for the tubercle-
like lesions, which are thought to be caused by Mycobacterium
spp. of one or other variety. Rhodococcus equi has also been
isolated from lymphadenitis in cattle.
Streptococcal adenitis in dogs
Streptococcal adenitis of dogs is similar to the disease in swine.
It occurs in minor endemics in kennels and is characterized
by pharyngitis, fever, conjunctival discharge, and enlargement
of the submaxillary nodes. The illness is transient in most
cases, but in ~10% of dogs, the course is prolonged for 2 weeks
or more, and in these there is a tendency for the nodes to
suppurate. The abscesses may be encapsulated and sterilized,
or they may fistulate on to the skin and heal. Dysphagia and
occasionally asphyxia occur in puppies. Typically, the Strepto-
coccus belongs to Lancefield’s group G and, coincident with
the pharyngeal infection, bitches may have inflammation of
the genital tract caused by the same organism. Cervical adeni-
tis caused by the group G organism may occur in kittens.
Further reading
Martin-Vaquero P, et al. Presumptive meningoencephalitis secondary to
extension of otitis media/interna caused by Streptococcus equi
subspecies zooepidemicus in a cat. J Feline Med Surg 2011;13:
606-609.
Neis C, et al. Investigation of a possible chain of Streptococcus suis
infection in a pig breeding community using PCR-based genotyp-
ing. Berl Munch Tierartzl Wochenschr 2007;120:202-206.
209
Figure 2-163  Yersinia pestis in a cat. Lymph node with focally
extensive liquefactive necrosis with intralesional bacterial colo-
nies and fragmented leukocytes surrounded by macrophages.
Pseudotuberculosis
Yersinia pseudotuberculosis occurs worldwide in wild rodents
and birds and is widespread in nature, recoveries having been
made from soil, milk, and feed. The organism regularly pro-
duces disease, often in epidemic proportions, only in rodents
and birds. Sporadic infections with this organism and occa-
sional outbreaks of disease occur in domestic animals. Cats,
because of their contact with rodents and birds, are the
domestic species most apt to be secondarily involved by out-
breaks of the disease in its natural hosts. Losses of serious
proportion, however, occur in sheep that are exposed to large
numbers of organisms during outbreaks of the disease in
rodents during cold weather. The ovine disease is known as
“pyemic hepatitis.”
The general pattern of this disease is the same in all
species, the variation that occurs with respect to severity and
duration being related to species susceptibility, and numbers
and virulence of the organisms. Y. pseudotuberculosis is a fac-
ultative intracellular parasite, which explains the latent carrier
state and the need for strong cell-mediated immunity for
protection from infection. The route of transmission is by
ingestion and, in susceptible animals, organisms enter the body
through the intestine. Small necrotic foci develop in the
Peyer’s patches of the ileum and colon, and extend as lym-
phangitis to the regional nodes. The organism becomes septi-
cemic and may kill susceptible rodents at this stage; more
typically, and in all domestic species, caseonecrotic foci form in
the mesenteric nodes, spleen, and liver, often in association with
fibrinohemorrhagic inflammation in the small intestine. The
hepatic foci, which are the most obvious, are 1-10 mm in
diameter, white, and have no or scant tendency to encapsula-
tion or softening. They are interspersed with irregular areas of
parenchymal collapse that probably result from vasculitis and
thrombosis. Microscopically, there is necrosis, with bacterial
colonies and fragmented leukocytes surrounded by macro-
phages (Fig. 2-163). Giant cells are absent, even from later-
contracting granulomas. The mesenteric nodes and spleen
contain similar foci, and are enlarged by lymphoid and histio-
cytic hyperplasia. The mesenteric nodes in the cat may be
2-4 cm in diameter and can be grossly confused with intestinal
toxoplasmosis or lymphomatosis.
 209.e1

Further reading
Chalker VJ, et al. Genetic diversity of Streptococcus equi subsp. zooepi-
demicus and doxycycline resistance in kenneled dogs. J Clin Micro-
biol 2012;50:2134-2136.
Jaeger G, et al. Haemorrhagic pneumonia in sled dogs caused by
Streptococcus equi subsp. zooepidemicus—one fatality and two
full recoveries: a case report. Acta Vet Scand 2013;55:67.
Pesavento PA, Murphy BG. Common and emerging infectious diseases
in the animal shelter. Vet Pathol 2014;51:478-491.
210 CHAPTER 2  •  Hematopoietic System
Figure 2-164  Yersinia pestis in a sheep. Abscessation of mesen-
teric lymph node.
Yersiniosis has emerged as a significant cause of disease in
farmed ruminants, including deer. Affected deer may be found
moribund or dead, but animals under observation are systemi-
cally ill with profuse diarrhea. The incidence of disease in
younger age groups rivals that of salmonellosis. In addition to
the mesenteric lymphadenitis (Fig. 2-164) and hepatitis, enteritis
is consistently present and characteristic in its histologic
expression. Numerous bacterial colonies are present in the
lamina propria, associated with multiple suppurative foci or
diffuse suppurative enteritis.
In view of the extraordinarily wide host range of Y. pseu-
dotuberculosis in natural infections, it is surprising that the
infection is not recorded more often. This may be in part
because of a preference of the organism for growth at room
temperature rather than at 37° C. Although susceptible labo-
ratory species, such as guinea pigs and mice, are readily
infected experimentally, there are few pathogenetic studies in
domestic species. The frequency of natural infection in cats
contrasts with the difficulty in establishing experimental
infection in this species, which suggests the need for some
predisposing alteration in the alimentary mucosa. Natural
infection in cats is not treatable with current antimicrobials
and is usually fatal.
The related organism Yersinia enterocolitica causes gastroen-
teritis and mesenteric adenitis in a wide variety of species,
including wild and domestic animals, and is increasingly iso-
lated from cattle. The organism has been isolated from deer,
rabbits, dogs, pigs, horses, mink, various avian species, as well
as sheep and goats. Y. enterocolitica shares an antigen with
Brucella abortus that may result in false-positive agglutination
reactions in serologic testing for brucellosis.
Further reading
Byun JW, et al. Hepatic yersiniosis caused by Yersinia enterocolitica
4:03 in an adult dog. J Vet Diagn Invest 2011;23:376-378.
Warth JF, et al. Yersinia pseudotuberculosis O III causes diarrhea in
Brazilian cattle. Adv Exp Med Biol 2012;954:107-110.
Wobeser G, et al. Tularemia, plague, yersiniosis and Tyzzer’s disease in
wild rodents and lagomorphs in Canada: a review. Can Vet J
2009;50:1251-1256.
Lymph Nodes
Figure 2-165  Postweaning multisystemic wasting syndrome in a
pig. Porcine circovirus 2 causes palpable lymphadenopathy affect-
ing the inguinal lymph nodes. (Courtesy S. Kesdangsakonwut.)
Porcine circovirus-associated diseases
Porcine circovirus 2 (PCV-2)-associated diseases (PCVAD) in
pigs encompass a broad spectrum of diseases, including post-
weaning multisystemic wasting syndrome (PMWS), porcine
dermatitis and nephropathy syndrome (PDNS), congenital
tremors in newborn piglets, and a number of other respiratory,
reproductive, enteric, nervous, and cardiovascular disorders.
Species Porcine circovirus 2 is a member of the family Circo-
viridae and one of the smallest (17-nm diameter) animal
viruses with a non-enveloped capsid and a single-stranded,
circular genome. There are currently 2 types of porcine circo-
virus, PCV-1 and PCV-2. PCV-1 was detected as a contami-
nant of the PK-15 porcine kidney cell line and may also be
the potential cause of congenital tremors in newborn piglets.
PCV-2 was initially identified in the mid to late 1990s in
weaned pigs from North America and Europe with PMWS.
Two subtypes of PCV-2, a and b, have been characterized, and
some reports suggest that PCV-2b may be more virulent or
may escape existing herd immunity stimulated by the previ-
ously circulating subtype PCV-2a. This section will only focus
on PMWS with its characteristic lesions in lymphoid tissues.
PMWS is a wasting syndrome that often occurs after
weaning, when pigs are 4-14 weeks of age. The disease also is
seen in older pigs, particularly finishing stage pigs that weigh
45-70 kg. Morbidity usually ranges from 5-20% in nursery or
finishing pigs, and mortality in pigs that show signs of PMWS
often exceeds 50%. Affected pigs have generalized lymphade-
nopathy, decreased weight gain or wasting in combination
with variably occurring, less specific clinical signs, such as
dyspnea, coughing, fever, diarrhea, pallor, icterus, central
nervous signs, and sudden death.
Characteristic gross lesions include pallor, icterus, diarrhea,
and palpable lymphadenopathy (Fig. 2-165). Inguinal, popli-
teal, internal iliac, mesenteric, bronchiolar, and mediastinal
lymph nodes may be substantially enlarged (Fig. 2-166).
Enlarged lymph nodes are pale and homogeneous on cut
surface (Fig. 2-167). Gross lesions in the lungs may include
failure to collapse, firmness, diffuse pulmonary edema, mot-
tling, and consolidation. The liver may appear icteric and/or
atrophic and have prominent interlobular connective tissue.
The most characteristic microscopic lesion in pigs with PMWS
 210.e1

Further reading
Backhans A, et al. Occurrence of pathogenic Yersinia enterocolitica and
Yersinia pseudotuberculosis in small wild rodents. Epidemiol Infect
2011;139:1230-1238.
Bush JM, et al. Disease transmission from companion parrots to dogs
and cats: what is the real risk. Vet Clin North Am Small Anim Pract
2011;41:1261-1272.
 Lymph Nodes
Figure 2-166  Postweaning multisystemic wasting syndrome in a
pig. Severe lymphadenopathy affecting sublingual and retropha-
ryngeal lymph nodes.
Figure 2-167  Postweaning multisystemic wasting syndrome in a
pig. Enlarged lymph nodes are pale and homogeneous on cut
surface. (Courtesy S. Kesdangsakonwut.)
is granulomatous inflammation with or without unique globular
intracytoplasmic viral inclusion bodies in macrophages (Fig.
2-168). However, severe lymphoid depletion may be the only
lesion in lymphoid organs affecting both lymphoid follicles
and parafollicular zones. Granulomatous inflammation in lym-
phoid tissues is characterized by epithelioid macrophages and
multinucleated giant cells that may contain sharply demar-
cated, spherical, basophilic, often botryoid cytoplasmic inclu-
sion bodies. Less consistent lesions include interstitial
pneumonia, interstitial nephritis, myocarditis, hepatitis with
hepatic atrophy and/or icterus, and perivasculitis in a number
of tissues. Liver lesions have been identified as a frequent
finding and are the most likely cause of icterus and wasting.
Although previous reports indicated that PCV-2 capsid pro-
teins localized predominantly in the nuclei of infected cells,
abundant amounts of PCV-2 capsid proteins were observed
in the cytoplasm of many cells. Vasculitis has been recently
described as a hallmark lesion of the severe form of systemic
PCVAD, and experimental infections with PCV-2b directly
caused acute vasculitis, whereas chronic vasculitis may in part
211
A
B
Figure 2-168  Postweaning multisystemic wasting syndrome in a
pig. A. Granulomatous lymphadenitis with multinucleated giant
cells and characteristic botryoid inclusions. B. Amphophilic intra-
cytoplasmic inclusion bodies can vary from botryoid clusters to
fine cytoplasmic dusting.
be mediated by the immune system. The diagnosis of PMWS
requires detection of (1) clinical signs: wasting or ill thrift with
or without the other earlier described clinical signs; (2) histo-
logic lesions: depletion of lymphoid organs and/or granuloma-
tous inflammation in any organ; and (3) detection of PCV2
infection within characteristic lesions (Fig. 2-169).
PMWS has been reproduced with combined PCV-2 and
porcine parvovirus inoculation, combined PCV-2 and PRRSV
infection, prenatal PCV-2 infection and postnatal porcine par-
vovirus infection, and dual infections with torque-teno virus
(TTV) and PCV-2. PMWS been reproduced in gnotobiotic
pigs with PCV-2 alone, following administration of keyhole
limpet hemocyanin in incomplete Freund’s adjuvant, and has
been reproduced with PCV-2 alone in cd/cd pigs. Intramus-
cular injection of pigs with a vaccine against Mycoplasma
hyopneumoniae or a nonspecific immunomodulating drug
(Baypamun) caused clinical signs, moderate to severe gross
and histologic lesions of PMWS. Vaccination with selective
bacterins increased the severity of lesions in conventional pigs
infected with PCV-2. It has been shown that monocyte
chemoattractant protein-1 (MCP-1) expression, but not
interleukin-8, may play a role in the pathogenesis of granulo-
matous inflammation in pigs with PMWS. There are also
212 CHAPTER 2  •  Hematopoietic System
A
B Vol. 2, Respiratory system) are, in some countries, very
Figure 2-169  Postweaning multisystemic wasting syndrome in a
pig. A. Granulomatous inflammation with multinucleated giant
cells in Peyer’s patches. B. In situ hybridization for porcine circo-
virus 2 shows large amounts of viral DNA in Peyer’s patches.
breed-dependent differences to PCV-associated disease and
lesions.
Further reading
Darwich L, Mateu E. Immunology of porcine circovirus type 2 (PCV2).
Virus Res 2012;164:61-67.
Opriessnig T, Langohr I. Current state of knowledge on porcine circo-
virus type 2-associated lesions. Vet Pathol 2013;50:23-38.
Parasitic infestations of lymph nodes
The lymph nodes are not a final habitat for any nematode, but
some species traverse them in migration, and some lodge there
accidentally. The larvae of lungworms travel by lymphatics
from the intestine to the lungs, but cause little injury. The
first-stage larvae of those lungworms that reside in the alveolar
spaces, Muellerius spp. and Protostrongylus spp. particularly,
often find their way to the bronchial nodes and cause granu-
lomatous lymphadenitis. The nodes become enlarged, hard,
and irregular, and have many firm granulomas and encapsu-
lated caseocalcareous nodules. The larvae of Strongylus spp. in
horses occasionally produce hemorrhagic lymphadenitis of the
abdominal lymph nodes that, when secondarily infected, may
Lymph Nodes
Figure 2-170  Metastatic squamous cell carcinoma in a cat. Clus-
ters of neoplastic epithelial cells in subcapsular sinus of retropha-
ryngeal lymph node.
develop suppurative lymphadenitis. Larval trematodes, prob-
ably Fasciola hepatica, are often found in the mesenteric nodes
of ruminants, as are larvae of Oesophagostomum columbianum
in sheep. Nodules develop in the cortex or medulla, as well
as in capsular tissues. They are 2-5 mm in size and contain
yellow-green pus, which in older lesions becomes caseous and
mineralized. The pus is largely the debris of eosinophils, and
it is surrounded by giant and epithelioid macrophages and a
well-defined capsule. A very similar lesion is produced by the
larvae of Linguatula serrata. The larvae of this parasite (see
common in the mesenteric nodes of sheep and cattle. Viable
larvae can be found in normal nodes, but usually the nodes
show focal or diffuse hyperplasia and edema, with the larvae
lying in cavities that contain a milky fluid resembling chyle.
Apparently, the larvae die in the nodes and become encysted
in abscesses, which may mineralize. In active cutaneous infes-
tations by Demodex spp. in dogs, the parasite is often found in
the peripheral lymph nodes.
Neoplastic metastatic diseases of lymph nodes
The general reaction of lymph nodes to nonlymphoid cancer
is atrophy of greater or lesser degree because of the systemic
effects of cancer, apparently mediated by tumor necrosis
factor. If the tumor causes inflammatory drainage to local
nodes, these will have changes of reactive hyperplasia and
lymphadenitis, as occurs in mesenteric nodes draining an
area of ulceration owing to carcinoma. It is significant that
the specific reaction of local nodes to a local neoplasm is
usually little more substantive than to distant or systemic
malignancies.
In general, the response of local nodes to a local neoplasm is
sinus histiocytosis. If metastases are present, they will originally
consist of single cells and small clusters in the peripheral and
medullary sinuses (Fig. 2-170). The tumor cells appear to pass
through the cortex to the medulla through the cortical gaps,
and largely avoid processing through the cortical system of
antigen surveillance. The sinus macrophages do not appear to
be specifically attracted to the neoplastic cells, even when they
invade the cortical parenchyma. There are minor variations in
the reaction of affected lymph nodes to specific neoplastic cell
 212.e1

Further reading
Madec F, et al. Post-weaning multisystemic wasting syndrome and
other PCV2-related problems in pigs: a 12-year experience. Trans-
bound Emerg Dis 2008;55:273-283.
Segalés J, et al. Porcine circovirus diseases. Anim Health Res Rev
2005;6:119-142.
 Lymph Nodes
types. Highly secretory adenocarcinomas may induce a stron-
ger reaction to their secretory products than to the neoplastic
cells themselves. Metastatic mast cells cause the same reaction
in nodes as in primary sites, but tend not to incite a strong
cellular and stromal reaction even when highly granulated
(Fig. 2-171). As noted earlier, the medullary cords of lymph
nodes form a tissue-vascular boundary similar to marrow, and
extramedullary hematopoiesis will colonize these sites. In leu-
kemias, the neoplastic cells colonize the medullary cords and
benign cells are displaced, in this case to the adjacent medul-
lary sinuses. In the acute myeloid leukemias, the primitive
neoplastic cells have round nuclei and resemble the surround-
ing residual lymphocytes, making recognition of the meta-
static disease difficult with H&E stains. Diagnosis is aided by
the identification of megakaryocytes in either the cords or
sinuses.
Interestingly, detection of regional lymph node metastasis
has not been found to correlate with remission length or
survival times of dogs with various malignancies, for instance,
oral malignant melanomas (Fig. 2-172, eFig. 2-42). This is
Figure 2-171  Metastatic mast cell tumor in a dog. Diffusely
enlarged hepatic lymph node caused by infiltration with neoplas-
tic mast cells.
Figure 2-172  Metastatic malignant oral melanoma in a dog. The
lymph node parenchyma has been diffusely replaced by the
expansile growth of the pigmented melanocytic neoplasm.
213
most likely because of the failure to histologically detect nodal
metastases that were present in some nodes, as well as excision
of nodes based on anatomic location rather than evidence of
drainage. In human medicine, sentinel node detection is com-
monly applied to detect those lymph nodes that actually drain
the area where the primary tumor is localized. Lymphatic
mapping strategies have been devised using a combination of
radio-labeled and colored colloids to define drainage areas
from a particular anatomic site. Serial sectioning of draining
lymph nodes and immunohistochemical labeling for neoplas-
tic cells, for instance, cytokeratin for carcinomas, as well as
RT-PCR for detecting mRNA specific for neoplastic cells, for
instance, mammaglobin, have been used in human medicine
to dramatically improve detection of even single neoplastic
cells in draining lymph nodes.
Further reading
Nyman HT, et al. A review of the sonographic assessment of tumor
metastases in liver and superficial lymph nodes. Vet Radiol Ultra-
sound 2004;45:438-448.
Worley DR. Incorporation of sentinel lymph node mapping in dogs with
mast cell tumours: 20 consecutive procedures. Vet Comp Oncol
2014;12:215-226.
Lymphoid neoplasms
Lymphomas are neoplasms of the hematopoietic system and
can arise in lymph nodes or extranodal locations. In human
medicine, they are divided into Hodgkin- and non-Hodgkin
lymphomas. Although a Hodgkin-like lymphoma has been
reported in cats, the vast majority of lymphomas in domestic
animals closely resemble non-Hodgkin lymphomas in humans
and are simply referred to as lymphoma or malignant lym-
phoma. Although the term “lymphosarcoma” has also been
used in veterinary medicine, it should be avoided especially
for comparative reasons. Historically, lymphoid leukemias and
lymphomas have been viewed as separate entities. The World
Health Organization (WHO) classification postulates that pre-
cursor neoplasms occurring as solid tumors, and those lymphomas
with marrow and blood involvement, are biologically the same
disease with different clinical presentations. An artificial division
using different names has therefore been avoided by using
lymphoma/leukemia for entities that can occur in either form, for
instance, acute lymphoblastic leukemia/lymphoblastic lym-
phoma. Essentially, the presence of neoplastic cells in the bone
marrow and peripheral blood is principally a prognostic factor
that reflects a stage of disease rather than a difference in clas-
sification. However, the biological basis for the different clini-
cal presentations is not fully understood. Because most
precursor lymphoid neoplasms develop in the bone marrow
and are seen as leukemia, the term acute lymphoid leukemia
is still used for the leukemic phase of precursor neoplasms of
T and B cells. For a detailed review of those lymphomas
appearing primarily as leukemias, see Acute lymphocytic leu-
kemia and Chronic lymphocytic leukemia previously.
More important, the WHO classification recently adapted for
animals characterizes different types of lymphomas as specific
disease entities rather than considering lymphoma as a single
biological entity of various morphologic presentations. Although
the previous lymphoma classifications used morphologic fea-
tures such as cell size to grade lymphomas and to predict their
behavior, the WHO classification establishes a new paradigm
 213.e1

eFigure 2-42  Metastatic malignant melanoma in a horse. Axillary

lymph node with multinodular, pigmented, neoplastic masses
replacing the parenchyma.
213.e2

Further reading
Kurosumi M, Takei H. Significance and problems of histopathological
examination and utility of real-time reverse transcriptase-polymerase
chain reaction method for the detection of sentinel lymph node
metastasis in breast cancer. Breast Cancer 2007;14:342-349.
Stroup SP, et al. Preoperative sentinel lymph node mapping of the
prostate using PET/CT fusion imaging and Ga-68-labeled tilmano-
cept in an animal model. Clin Exp Metastasis 2012;29:673-680.
214 CHAPTER 2  •  Hematopoietic System
that identifies lymphomas according to their unique phenotype
and genotype. However, each lymphoma type may appear with
a variety of morphologic features and a range of clinical
behaviors.
Clinical features of lymphomas
Lymphomas are commonly classified according to their ana-
tomic location. The main types of lymphoma include multi-
centric, thymic/mediastinal, gastrointestinal, cutaneous,
extranodal, and central nervous system (CNS). With the adap-
tation of the new WHO classification that integrates clinical
findings with cell morphology and molecular features, such
gross anatomic classification becomes less important. Common
gross presentations and organ systems involved are described
in more detail for each individual species later in this chapter.
Clinically, most commonly a diagnosis of lymphoma is
based on enlargement of lymph nodes or other organs, for
instance, hepatosplenomegaly, or ultrasound findings, for
instance, thickening of the intestinal wall with intestinal lym-
phoma. Clinical signs are based on the primary organ system
affected and range from anorexia, lethargy, and weight loss;
to dyspnea, coughing, and caval syndrome with thymic/
mediastinal lymphoma; vomiting and diarrhea with gastroin-
testinal lymphoma; cutaneous nodules and plaques with cuta-
neous lymphoma; and paralysis, seizures, or paresis with
lymphomas of the CNS. Polyuria and polydipsia are com-
monly observed because of paraneoplastic hypercalcemia of
malignancy. Clinically, staging has been used to prognosticate
multicentric lymphoma:
• Stage I: Involvement restricted to a single lymph node or
organ (not bone marrow)
• Stage II: Regional lymph node involvement (restricted to
one side of diaphragm)
• Stage III: Generalized lymph node involvement
• Stage IV: Involvement of the liver and/or spleen and gen-
eralized lymph node involvement
• Stage V: Involvement of blood and bone marrow and/or
other extranodal sites
As noted earlier, the more recent classification of lympho-
mas according to the WHO provides more accurate prognos-
tic information and therapeutic guidance because it recognizes
lymphomas as a heterogeneous group of distinct diseases that
are unrelated to one another, and not grades of a single disease
entity. The WHO classification predicts the biological behav-
ior of different types of lymphoma by pathologic features (cell
size, proliferation) or clinical features, and thereby fosters
establishment of entity-specific therapeutic approaches.
Laboratory findings are highly variable. Nonregenerative
anemia of various severities is commonly observed. Both lym-
phopenia and lymphocytosis may occur with different types
of lymphomas, and hypercalcemia of malignancy owing to
secretion of parathyroid hormone-related peptide (PTHrP) or
bone lysis has been commonly observed with some lymphoma
entities. More detailed descriptions are provided with each
lymphoma entity.
Diagnosis of lymphomas
The accurate diagnosis of malignant lymphoma requires
proper selection and handling of tissues, and ancillary tests are
essential. Ideally, a combination of cytology and histology is
desired. Touch preparations are important for cytologic assess-
ment; submission of surgical biopsies fixed in 10% neutral
buffered formalin is a good all-purpose approach to allow
Lymph Nodes
histologic evaluation of tissue architecture, immunophenotyp-
ing, and clonality assessment. Clinical pathologists often prefer
B5 fixative for bone marrow sections because the nuclear
morphology will be better preserved; however, standardized
immunohistochemistry (IHC) protocols for B5 fixed, demin-
eralized tissues are lacking. A high quality, 2-4 µm thick,
H&E-stained slide is essential for lymphoma evaluation
because thicker sections make it difficult to assess cytologic
detail. Some pathologists prefer Giemsa stains for more
nuclear detail. The integration of flow cytometry will become
more commonplace in routine lymphoma diagnostics as will
cytogenetic studies.
Lymphoid tissue is very fragile, and artifacts are commonly
induced through tissue compression, delayed fixation, or
drying of tissues. Histologically, the center of a formalin-fixed
lymph node is commonly underfixed or primarily ethanol
fixed, and immunohistochemical stains appear light, or there
is a lack of labeling. Nuclei may be slightly larger with less
dense chromatin. These features are in complete contrast to
the lymph node rim, where overfixation or drying out of the
tissue may result in smaller, more basophilic nuclei, and
intense immunohistochemical labeling. Suboptimal fixation
can be compounded by extensive areas of necrosis caused by
infarction or focal cellular lysis. Identifying areas with good-
quality cell morphology that are representative for the disease
process is essential, because determining tissue architecture, cell
size, and mitotic index are all parts of reaching an accurate
diagnosis. After differentiating a diffuse from a follicular
growth pattern, pathologists should determine cell size. The size
of neoplastic lymphoid cells is based on the size of their nuclei
compared to erythrocytes. Small lymphoid cells have nuclei
1-1.25 times the size of erythrocytes, intermediate lymphoid
cells have nuclei ~1.5 times the size of erythrocytes, and large
cells have nuclei at least 2 times larger than erythrocytes. The
mitotic index is determined as the average number of mitotic
figures in 10 random high-power (40×) fields (HPF) in the
areas of highest mitotic activity. A low mitotic index is defined
as 0-5 mitoses/HPF, a medium mitotic index as 6-10 mitoses/
HPF, and a high mitotic index as >10 mitoses/HPF.
Immunophenotyping is an essential part of an accurate
diagnosis of lymphomas. In domestic animals, CD3 is used to
detect T cells and CD79a for B cells. In dogs and cats, CD20
and Pax-5 are commonly used instead of CD79a because
CD79a commonly causes artifactual nuclear binding. Immu-
nophenotyping is required to reach a conclusive diagnosis
because a number of lymphoma entities are morphologically
homogeneous, but are phenotypically heterogeneous, for
instance, small lymphocytic lymphoma, lymphoblastic lym-
phoma, marginal zone lymphoma versus T-zone lymphoma,
or diffuse large B-cell lymphoma versus peripheral T-cell lym-
phoma. Additional antibodies used for lymphoma diagnosis
include CD45, CD45RO, CD18, CD204, CD34, CD30,
CD90, BCL-2, Ki-67, granzyme B, perforin, CD10, BCL-6,
GCET1, FOXP1, CD204, MUM-1, immunoglobulin and
light-chain antibodies, and, in frozen sections, CD4 and CD8.
Details on their application are listed later under the indi-
vidual lymphoma entities. Although the list appears long,
compared to human medicine, veterinary pathology stills lacks
a number of essential, species-specific antibodies to more
accurately diagnose lymphomas. It is also important to recog-
nize that antibodies targeting epitopes in a particular species
may not react with another species at all and either do not
label target cells or, often even more dangerous, label epitopes
 Lymph Nodes
expressed on other cell types. A good example is Bla.36, which
labels B cells in a variety of species, but will also detect den-
dritic cells in most domestic animals, for instance, histiocytic
sarcomas in dogs. Regardless, immunohistochemical labeling
can only be interpreted in association with the cell morphol-
ogy and has to be correlated to the morphologic diagnosis.
Having a reactive cell background or diffuse infiltration with
T cells or dendritic cells is common, and the pathologists need
to carefully determine immunohistochemical labeling of the
neoplastic cell population. This also includes assessment of the
proper type of labeling, for instance, membranous versus intra-
cytoplasmic versus nuclear. As an example, nuclear labeling
for CD79a is a common artifact and has to be disregarded
when evaluating tissues microscopically.
Numerous lymphoid neoplasms are difficult to differenti-
ate from inflammatory conditions. In particular, enteropathy-
associated T-cell lymphomas of small cell type, or cutaneous
lymphocytosis in cats, and lymphohistiocytic proliferations in
the skin or lymphofollicular proliferations in lymph nodes or
spleen of dogs pose a morphologic challenge to the patholo-
gist. Detection of clonality using the PCR for antigen receptor
rearrangements (PARR) assay of the T-cell receptor γ and/or
immunoglobulin heavy chains has become the gold standard
for differentiating neoplastic (monoclonal) from reactive
(polyclonal) lymphocytes in dogs and cats (Fig. 2-173).
However, PARR testing should never be used independently of
the histologic features, immunophenotype, and clinical findings.
PARR should only be applied after preliminary differential
diagnoses have been established. Testing should be done using
capillary gel electrophoresis to achieve sufficient resolution for
properly differentiating monoclonal from polyclonal popula-
tions. False-negative results can occur because of the limits of
the qualitative sensitivity (the ability of the assay to detect
clonal rearrangement) or quantitative sensitivity (the ability of
the assay to detect a clonal rearrangement in a background of
non-neoplastic lymphocytes). Qualitative sensitivity is espe-
cially affected by the use of species-specific primers and early
primer sets that had been developed based on limited sequence
data. Even the most recently published multiplex PCRs do
not detect all potential gene rearrangements, and aiming for
100% sensitivity may be simply cost prohibitive with the
current methodology. The qualitative sensitivity is most com-
monly reduced by either having a large population of inflam-
matory lymphocytes infiltrating the tissue to be tested or by
having numerous other tissue samples included with the test
material, for instance, numerous endoscopic biopsy samples
of small intestine in a single tissue block with only a few
samples being suspect for lymphoma. In general, PARR testing
has a higher sensitivity in nonlymphoid tissues compared to
lymphoid tissues because the rearranged sequences from
normal lymphocytes compete with amplification of the neo-
plastic DNA. Although PARR assays have been shown to be
highly specific, false-positive results can also occur. Very small
number of inflammatory lymphocytes within a sample or
certain inflammatory conditions, for instance, infection with
Ehrlichia canis, may result in a clonal PCR result. The most
common false-positive results are cause by a procedural error
that causes pseudoclones that occur in up to 10% of per-
formed tests. To avoid pseudoclones, all PARR testing should
be run in duplicate, along with both native and denatured
forms. Furthermore, it is essential not to mistake clonality results
for immunophenotype. The phenotype of a lymphoma should
always be based on expression of CD molecules as determined
215
by IHC or flow cytometry not PARR testing, as neoplastic
lymphocytes may show cross-lineage clonal rearrangement.
The incidence of cross lineage rearrangement in different lym-
phomas has been reported between 7-10%. Even exclusive
amplification of the cross-lineage receptor can be observed
either because of failure of the PARR assay primers to recog-
nize the specific rearrangement within receptor matching the
lymphoma phenotype, or because of chromosomal alterations
within the neoplastic lymphocytes that distorted the sequence
of the primer binding site and resulted in binding failure.
Unfortunately, it is not uncommon practice to aspirate
enlarged lymph nodes and to diagnose a B- or T-cell lym-
phoma based on single-run PARR testing. Failure to properly
diagnose the aspirate based on cell morphology and to deter-
mine the immunophenotype by antibody reaction as well as
not performing PARR testing in duplicate and for both recep-
tors will result in a risk of at least 20% false-positive results.
Alternatively, if the histologic features and immunopheno-
typical results are consistent with a diagnosis of lymphoma
despite a polyclonal PCR result, a diagnosis of a suspected
lymphoma should still be made and additional biopsy sample
from a later date should be tested with PARR.
Classification of lymphomas
Throughout the last century, veterinary pathologists have used
classifications that were developed for non-Hodgkin lympho-
mas in humans to classify malignant lymphomas in domestic
animals, especially dogs. Whereas early classification systems
were based entirely on the morphologic characteristics of
malignant lymphocytes, the ability to further differentiate
cells immunohistochemically led to a revision of the historical
classification systems.
The Rappaport classification from 1966 is one of the earli-
est classification systems applied to canine malignant lympho-
mas and according to this classification, a large number of
canine malignant lymphomas were classified as histiocytic.
With increasing knowledge of the immunologic aspects of
malignant lymphomas, a better understanding of maturation
and differentiation of lymphoid cells, and the advance of
chemotherapy, new classification systems were developed.
Almost simultaneously, the Lukes-Collins classification in
North America and the Kiel classification in Europe were
published. Both systems were based on immunologic concepts
and only differed significantly in the identification of 2 of 13
entities. This difference was mainly because of the different
position of centrocytes within the line of maturation in each
classification. Despite these differences, a translation from one
to the other classification was still possible. In particular, the
Kiel classification was easily adapted for canine malignant
lymphomas.
To avoid further confusion and in attempt to unify the
European and North American classifications, the National
Cancer Institute initiated a multi-institutional study. As a
result, the Working Formulation was published in 1982. In
contrast to the previously described classifications, the working
formulation represents a form of lymphoma “Esperanto,” a
translational system for the existing human non-Hodgkin lym-
phoma classifications. The Working Formulation was strictly
oriented on the clinical outcome and not based on a morpho-
logic principle. The various lymphoma entities in this classifi-
cation were based on groups of human patients with similar
survival curves, and the morphologic features for each group
were described following a classification according to survival.
 [bp] A1 A2 A3 A4 A5 A6 [bp]

300 300

250 250

200 200

150 150

Peak size

Peak size
100 100

75 75
50 50

25 25
15 15

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1.300
15 bp
1.200 105 bp
1.100
Relative fluorescence

1.000
units [RFU x 180]

0.900
0.800 3,000 bp
0.700
0.600
0.500
0.400
0.300
0.200
0.100
0.000
[bp]
15
50
100
150
200
250
300

400
500

3,000

Size
1.500
1.400
15 bp
1.300
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3,000 bp
units [RFU x 180]

1.000
0.900
0.800
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0.200
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500

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Figure 2-173  PCR for antigen receptor rearrangement for T-cell receptor γ in a cat. A. Duplicate
runs with capillary gel electrophoresis result in single strong bands for monoclonal (neoplastic)
cell populations (lanes A1 and A2) or smear for polyclonal (inflammatory) cell populations (lanes
A3 and A4). Negative control (lane A5), positive control (lane A6). B. In the electrophoretogram,
monoclonal (neoplastic) cell populations are characterized by a single dominant narrow peak
(105 bp). C. Polyclonal (inflammatory) cell populations produce a curve or broader peak that is
at least 2 3 shorter (109 bp).
 Lymph Nodes 217

Numerous studies addressed this weakness of the Working

Formulation and strongly opposed use of the Working Formu-
Table • 2-5 
lation as a primary morphologic classification. Unfortunately,
the simplified morphologic categories of the Working Formu-
The classification of lymphoid neoplasms
lation led to adaptation of this classification to canine malig- adopted by the WHO, as applied for use
nant lymphomas and use in daily veterinary oncologic practice in animals
until this day. Such adaptation for canine malignant lympho-
• B-cell neoplasms
mas is even more questionable, given that all survival data
• Precursor B-cell neoplasms
were based on human trials using uniform therapeutic
• B-lymphoblastic leukemia/B-lymphoblastic lymphoma
approaches, and similar studies have rarely been performed in
• Mature (peripheral) B-cell neoplasms
veterinary medicine.
• B-cell chronic lymphocytic leukemia/small lymphocytic
The original Kiel classification had failed to classify ~12%
B-cell lymphoma
of human non-Hodgkin lymphomas, but with the ability
• Diffuse large B-cell lymphoma
to immunohistochemically characterize lymphoid cells, an ■ Centroblastic
“updated” version of the Kiel classification was introduced. ■ Immunoblastic
This “updated” Kiel classification was shown to be applicable ■ Anaplastic
to canine malignant lymphomas, and multiple studies docu- ■ T-cell rich
mented its prognostic significance. This “updated” Kiel classi- ■ Lymphomatoid granulomatosis
fication represented until recently the most valuable prognostic
• Follicular B-cell lymphoma
classification of canine malignant lymphomas. ■ Grades I, II, and III
In the last decade of the past century, the rapidly develop-
• Marginal zone B-cell lymphoma
ing oncology in both human and veterinary medicine high- ■ Nodal marginal zone lymphoma
lighted the pressing need for consistency of diagnostic and ■ Splenic marginal zone lymphoma
prognostic classifications and terminology across various insti- ■ MALT
tutions and also in publications. The WHO system of classifi-
• Mantle cell lymphoma
cation of hematopoietic neoplasms was largely based on
• Burkitt-like lymphoma
proposals made by the International Lymphoma Study Group
• Extramedullary plasmacytoma
(ILSG) who proposed a Revised European-American Classi-
• Multiple myeloma
fication of Lymphoid Neoplasms (REAL). The objectives of
• T-cell and NK-cell neoplasms
the ILSG were to devise a system that did not have obvious
• Precursor T-cell neoplasms
ties to any country or region and to greatly expand criteria for
• T-lymphoblastic leukemia/T-lymphoblastic lymphoma
disease recognition. According to the ILSG proposal, lym-
• Mature (peripheral) T-cell neoplasms
phoid neoplasms were identified for the first time as disease
• Nodal T-cell lymphoma
entities and not simply based on cell types reflecting normal ■ T-zone lymphoma
counterparts of neoplastic cells. This represents a completely ■ Peripheral T-cell lymphoma, unspecified
new paradigm in lymphoma classification because diagnostic ■ Anaplastic large T-cell lymphoma
criteria consist now of all relevant information, including cel- ■ Angioimmunoblastic T-cell lymphoma
lular morphology and cell lineage, lesion topography, and also
• Enteropathy-associated T-cell lymphoma (EATL)
general biology of each neoplasm that defined it as a specific ■ Large cell type: EATL type 1
disease entity. The lack of grading in this system is made up ■ Small cell type: EATL type 2
for by each subtype of lymphoma now representing a well-
• Extranodal T-cell lymphoma
characterized disease. The efficacy of the ILSG and subse- ■ Hepatosplenic T-cell lymphoma
quent WHO system of classification was demonstrated by a ■ Hepatocytotropic T-cell lymphoma
group of MD pathologists of the Non-Hodgkin’s Lymphoma ■ Peripheral T-cell lymphoma, unspecified
Classification Project who achieved an 85% consensus in iden-
• Cutaneous T-cell lymphoma
tifying the major types of lymphoma by using the criteria of ■ Cutaneous epitheliotropic T-cell lymphoma
the ILSG classification system. These results immediately ren-
• Mycosis fungoides
dered other systems of classification obsolete and pointed to
• Pagetoid reticulosis
the need for a similar study to demonstrate the applicability
• Sézary syndrome
of the WHO system to animal neoplasms. Such a study was ■ Cutaneous non-epitheliotropic T-cell lymphoma
performed for canine malignant lymphomas, and the WHO
• Peripheral T-cell lymphoma, unspecified
classification was adapted to canine lymphomas with similar
• Subcutaneous “panniculitis-like” T-cell lymphoma
intraobserver and interobserver consistencies as reported by
• Anaplastic large T-cell lymphoma
the ILSG (Fig. 2-174). In recent years, the WHO classification
• T-cell large granular lymphocytic leukemia
has been applied to lymphomas in other animal species either
• Acute T-cell large granular lymphocytic leukemia
in similar large reviews, for instance, equine lymphomas, or
• Chronic T-cell large granular lymphocytic leukemia
for specific commonly occurring entities, for instance, gastro-
intestinal lymphomas in cats. MALT, mucosa-associated lymphoid tissue; NK, natural killer;
The current WHO classification of canine lymphomas WHO, World Health Organization.
(Table 2-5) is based on the principle that lymphoma subtypes
cannot be classified simply based on their cell morphology,
but accurate identification of each entity requires inclusion of
additional data, in particular the cell phenotype, but also
218 CHAPTER 2  •  Hematopoietic System Lymph Nodes

Follicular Color of fill

Benign follicular hyperplasia
Retention of mantle: cuff of
small dark-staining cells.
Cells have antigen-related
polarity: deep dark zone and
light superficial zone, best
seen in follicles near capsule.
Follicular tingible body
macrophages numerous.
Follicular lymphoma (B-cell)
No mantle cell cuff, with
vessels compressed between
follicles.
Uniform proportion of large to
intermediate cells
(centroblasts to centrocytes)
in all follicles.
Follicular tingible body
macrophages absent.
Grade based on centroblasts
per 400: FL1  0-5;
FL2  6-15; FL3  15.
Marginal zone lymphoma (B-cell)
Primary in spleen or node.
Splenic are locally extensive
arising on end arterioles and
coalescing. Node/spleen follicles
arise on fading GCs. Round
intermediate-sized nuclei with
peripheralized chromatin, very
large prominent single central
nucleoli, abundant lightly stained
cytoplasm, distinct cell boundaries.
Mitoses absent in early cases.
(hyperplasia  mixed with mantle
cells)
Mantle cell lymphoma (B-cell)
Primarily spleen, rare in node.
intermediate-sized nuclei,
smaller than MZL: round,
dense chromatin, small or
inapparent nucleoli, little
cytoplasm, no mitoses in early
cases. Larger nuclei with
nucleoli in blastoid cases.
Resemble large fading GCs.
Surrounded by variable
numbers of MZL cells and
plasma cells.

Nodal T-zone lymphoma

Nuclear size (vs. RBC) Mitotic rate per 400 field Early cases: Small nuclei with no mitoses, dense chromatin without
Color of border Color of font nuclear detail.
Large (2  RBC) Advanced cases: Intermediate-sized nuclei, dense chromatin, faint
Low (0-5/HPF) nucleoli, abundant light cytoplasm, few mitoses, sinus ectasia.
Intermediate (1.5  RBC) Medium (6-10/HPF) Filling of paracortex and cords, does not efface medullary architecture
or subcapsular sinus, prominent postcapillary venules, B follicles are
High (10/HPF) compressed against trabeculae.
Small (1-1.25  RBC)
(Note: Hyperplasia also has DCs, Mq).

Diffuse large B-cell lymphoma (B cell)
Uniform, round or cleft nuclei.
Centroblastic Uniformly shaped nuclei,
multiple nucleoli impinging on nuclear
membrane, scant cytoplasm.
Immunoblastic 90% of cells have
uniform round or oval nuclei with single
central nucleolus.
T-cell–rich large B-cell lymphoma.
Few large B cells amid many small
non-neoplastic T cells. Abundant stroma
with focal ischemic necrosis.
Lymphoblastic lymphoma
intermediate-sized nuclei,
round to oval, moderate
anisokaryosis. Chromatin
dense and dispersed,
multiple obscured small
nucleoli, scant basophilic
cytoplasm. Consistently
high mitotic rate with
chromosomes not sharply
defined.
B cell or T cell (most
T cell).
Anaplastic large cell Peripheral T-cell lymphoma
lymphoma anisokaryosis and poikilokaryosis
Uncommon.
Always some
Lymphoplasmacytic
multinucleated cells, very
lymphoma rare. Nodal, small
irregularly shaped nuclei
nuclei, deeply red cytoplasm,
(horseshoe, elongated);
few mitoses.
often vacuolated cytoplasm.
Mostly T cell, can be B cell.
R/O histiocytic sarcoma. CLL & small lymphocytic
lymphoma rare. Small nuclei,
few mitotic figures.

Diffuse Color of fill

Figure 2-174  Schematic flowchart for the diagnosis of the most common canine malignant lym-
phoma entities. (Based on concept created by J.L. Caswell.) Follicular versus diffuse lymphomas
are divided based on their yellow and blue background color, nuclear sizes are divided based on
the purple, green, and red colors outlining the text boxes, and the mitotic rate is divided based
the red, green, and blue font color. CLL, chronic lymphocytic leukemia; DC, dendritic cell; FL,
follicular lymphoma; GC, germinal center; HPF, high-power field; MΦ, macrophages; MZL, mar-
ginal zone lymphoma; RBC, red blood cell; R/O, rule out.

location of the lesion, its clinical course, and tissue architec-
ture. This understanding was largely driven by the advent of
IHC, which demonstrated that cells with similar morphology
might have a differing phenotype and markedly different
biology in both normal and neoplastic presentations.
The WHO classification of human non-Hodgkin lympho-
mas has been tested clinically and for each lymphoma entity
its frequency of occurrence, median age of affected patients,
ratio of males to females, stage distribution, survival, and
therapeutic response are well known. Basically, the WHO
classification identifies 3 major categories of lymphoma based
on their biological behavior: the indolent, the aggressive, and the
highly aggressive entities. This classification does not necessarily
reflect survival of human patients because current therapeutic
approaches result in a better outcome/curability for
the biologically more aggressive diseases. It is of the utmost
importance that veterinarians do not simply extrapolate survival
and therapeutic response data from human medicine to the spe-
cific lymphoma entities that are now recognized in domestic
animals according to WHO criteria. In human medicine, an
International Prognostic Index (IPI) has been established that
is used concurrently with the WHO classification to accu-
rately prognosticate the various lymphoma entities. This index
includes stage, patient age, number of extranodal sites, perfor-
mance status, and serum lactate dehydrogenase (LDH) levels.
Such index has not been established for domestic animals.
The WHO classification is not a rigid classification, and a
number of disease entities, for instance, cutaneous anaplastic
lymphomas and Burkitt-like lymphomas, still pose difficulties
regarding their prognosis or reproducibility of their diagnosis,
 Lymph Nodes
respectively. Advances in genetics and IHC have helped to
further categorize diffuse large B-cell lymphomas into cases
that respond well or poorly to classic CHOP (cyclophospha-
mide, hydroxydaunorubicin [also known as doxorubicin or
adriamycin], Oncovin [vincristine], and prednisone) therapy.
In a similar manner, the original study of canine lymphomas
focused mainly on nodal lymphomas, because they are the
most common entities in dogs, and ignored other lymphoma
types. Individual studies later reviewed other entities in
domestic animals, for instance, gastrointestinal lymphomas in
dogs and cats, and showed efficacy of the WHO classification
for these entities as well. As a pathologist or oncologist diag-
nosing or treating lymphomas, the most current publications
should be reviewed pertaining to the current understanding
of classification and associated behavior and therapeutic
response of any particular lymphoma entity in any animal
species.
The following text characterizes each lymphoma entity
according to the WHO criteria as far as they have been estab-
lished for animal species (see Table 2-5).
Hodgkin-like lymphoma.  Hodgkin-like lymphoma (HLL)
that meets acceptable criteria as described for Hodgkin lym-
phoma in humans does not occur in animals. Hodgkin-like
lymphoma has been suggested to occur in cats and less com-
monly in dogs. The diagnosis of Hodgkin lymphoma (HL)
rests on the demonstration of one of the types of Reed-
Sternberg cell in a background appropriate for the specific sub-
types of Hodgkin disease, lymphocyte-predominant (LPHL) or
classic, with the subtypes lymphocyte-rich, mixed-cellularity,
nodular-sclerosis, and lymphocyte-depleted HL. These criteria
have not been met in suspected cases of HLL in domestic animals.
The Reed-Sternberg cell has been shown to be of B-cell type
by analysis of single cells derived from human cases, and is
Pax-5 positive. Most cases reported as Hodgkin lymphoma in
dogs and cats most likely represent T-cell–rich B-cell lym-
phoma, a form of diffuse large B-cell lymphoma. Differentiat-
ing T-cell–rich B-cell lymphoma from HLL is extremely
difficult even when using IHC. Although Reed-Sternberg cells
tend to be CD20 and CD79a negative and Pax-5, CD30, and
CD15 positive in classic forms of Hodgkin disease, in LPHL,
CD30 negative, CD20-, and CD79a-positive Reed-Sternberg
cells have been reported. Uniformly strong positive labeling
of the large cell population for CD20 confirms a diagnosis of
T-cell–rich B-cell lymphoma.
HLL has been best described in cats with unilateral man-
dibular or cervical lymphadenopathy. In this study, 9 of 20
cats were classified as having LPHL-type disease and the
remaining 11 cats as classic forms of Hodgkin disease. All cases
had labeling of small- to intermediate-sized lymphocytes for
CD79a, and the different types of Reed-Sternberg cells were
negative for CD79a, CD3, Bla.36, and Mac387. Unfortu-
nately, IHC was not performed for Pax-5, CD20, CD30, and
CD15. Although lesions in these cats were classified according
to the different subtypes of Hodgkin lymphoma in humans,
there were a number of differences. The reported immuno-
histochemical labeling is in contrast to human LPHL where
detection of CD20- or CD79a-positive large cells in a nodule
of CD20- or CD79a-positive small cells is a characteristic
histologic feature. Furthermore, diagnostic Reed-Sternberg
cells were rare in cases of feline mixed cellularity and nodular
sclerosis HLL compared to human Hodgkin disease. In addi-
tion, lymphohistiocytic cells were found in conjunction
with classic Reed-Sternberg cells in mixed-cellularity and
219
nodular-sclerosis feline cases, and lacunar cells were noted in
small numbers in feline LPHD. Whether such cases truly
represent a unique type of HLL in cats or a type of T-cell–rich
B-cell lymphoma requires further studies. Regardless, cats
with solitary lymph node enlargement and a diagnosis of
suspected HLL or T-cell–rich B-cell lymphoma should be
treated differently than cats with diffuse large B-cell lym-
phoma. This entity has been suggested to represents a less
aggressive neoplasm that may not require chemotherapy.
Additional studies are needed to more accurately establish the
behavior and therapeutic response of these neoplasms.
Precursor lymphoblastic leukemia/lymphoma.  Lympho-
blastic lymphomas (LBL) are highly aggressive lymphomas of
B, T, or rarely natural killer (NK) cell lineage that can occur
in the lymph nodes, spleen, and most commonly thymus/
mediastinum in all domestic animals. In dogs, they are most
frequently of T-cell origin (Fig. 2-175). Neoplastic lymphoid
cells form diffuse, dense infiltrates of monomorphic,
intermediate-sized cells that are characterized by oval or folded
convoluted nuclei with a thin nucleolemma, dispersed chromatin,
and indistinct nucleoli. The absence of any parachromatin clear-
ing makes these tumors appear darker when viewed histologi-
cally at low magnification. The volume of the deeply stained
cytoplasm is minimal. They have a high mitotic rate of usually
>10 mitoses/HPF, but the mitotic figures are not as distinct as
in other types of lymphoma. When neoplastic lymphoid cells
infiltrate outside lymphoid tissues, they often appear in a
single-file pattern. Immunophenotyping may be difficult,
because CD20 and CD3 may be negative in B- or T-cell lym-
phoblastic lymphomas, respectively, and a small subset will be
bi-phenotypic, expressing both CD20 and CD3.
With lymphomas of LBL type, it is very important to make
the identification of cell type near the edge of the tissue,
where fixation is rapid for the chromatin to display the dis-
persed quality. One of the values of the Tru-cut biopsy is its
small size, permitting rapid fixation of the whole biopsy. Lym-
phoblastic lymphoma and lymphoblastic leukemia most likely
represent different ends of a spectrum of a single disease
entity. Although the T-cell lymphoblastic lymphoma occurs
commonly in the thymus, the vast majority of B-cell lympho-
blastic neoplasms occur as acute leukemia originating in bone
marrow (see section on Hematopoietic neoplasia). Clinically,
animals with T-LBL frequently have hypercalcemia (Fig.
2-176). Often animals in good body condition suddenly lose
appetite and appear depressed and may show signs of labored
breathing on physical examination.
Mature (peripheral) B-cell neoplasms
B-cell chronic lymphocytic leukemia/small lymphocytic
lymphoma.  B-cell chronic lymphocytic leukemia/small lym-
phocytic lymphoma (B-CLL/SLL) is characterized by prolif-
eration of mature-looking, small lymphoid cells, and only rare
cases occur as lymphomas, whereas the majority occur as
leukemias. A detailed description is therefore provided under
leukemia. Nodal forms of B-SLL efface the lymph node archi-
tecture and are originally localized in the interfollicular zones.
The dark-staining, small lymphoid cells surround lighter-
staining foci that represent proliferation centers. Neoplastic
cells commonly infiltrate the perinodal tissue. Nuclei of neo-
plastic lymphoid cells are small, round, have condensed chro-
matin, and inconspicuous nuclei. The cytoplasm is scant and
the mitotic index is low. Slightly larger, prolymphocytic cells
are dispersed throughout the sheets of neoplastic cells. Immu-
nophenotyping with CD79a will identify B-cell lineage, but
220 CHAPTER 2  •  Hematopoietic System
A
B tinct biological behavior.
C tingible body macrophages. Neoplastic cells are large, and the
Figure 2-175  Precursor T-cell lymphoblastic lymphoma in a dog.
A. Diffuse, dense infiltrates of monomorphic, intermediate-sized
cells that are characterized by oval or folded convoluted nuclei
with a thin nucleolemma, dispersed chromatin, and indistinct
nucleoli. B. Neoplastic T cells are diffusely positive for CD3 by
immunohistochemistry (IHC). C. Rare CD20-positive B cells can
be detected by IHC.
labeling may be weak. Cells may not label with CD20. B-SLL
have a low proliferation activity and the Ki67 index tends to
be low except in the proliferation centers.
Diffuse large B-cell lymphoma.  Diffuse large B-cell lympho-
mas (DLBCLs) are aggressive, rapidly growing neoplasms that
Lymph Nodes
Figure 2-176  Hypercalcemia of malignancy in a dog. Metastatic
mineralization of the kidney in a dog with precursor T-cell lym-
phoblastic lymphoma. (Courtesy K.G. Thompson.)
represent the most frequently encountered lymphoma in most
domestic animals. There are numerous subtypes of DLBCL.
Centroblastic and immunoblastic cell types represent mere
morphologic variants that commonly occur as heterogeneous
populations within the same neoplasm, but distinguishing
these subtypes has not been associated with differences in
clinical behavior or therapeutic response. In contrast, other
subtypes such as T-cell–rich B-cell lymphoma (TCRBCL),
anaplastic large cell lymphomas, or lymphomatoid granuloma-
tosis may pose a major diagnostic challenge, and have a dis-
DLBCL can be found in any tissue, but are most often
found in lymph nodes. They are the most common lymphoma
in dogs (Fig. 2-177). DLBCL can also occur as a mediastinal
mass or primary gastric or ocular lymphoma. Most cases arise
in the dark zone of the germinal center from centroblasts.
They expand diffusely and quickly destroy the lymph node
architecture. Although lymph nodes with DLBCL are most
commonly characterized by generalized enlargement, in the
spleen, DLBCL expands within white pulp areas and com-
presses the red pulp, which leads to grossly visible nodules
that over time may coalesce. Neoplastic cells commonly
invade vessels, and necrosis and infarction are common occur-
rences in larger neoplastic masses.
Histologically, neoplastic cells form large sheets that often
resemble a “starry-sky,” which is the result of interspersed
shape of centroblastic nuclei is highly variable, round, indented,
and irregularly folded. In contrast, the large immunoblasts are
primarily rounded. Regardless, both cell types have euchro-
matic nuclei with vesicular or coarsely granular chromatin and
easily recognizable large, amphophilic nucleoli that appear as
multiple, nucleolemma-associated nucleoli in centroblasts, but
are solitary and centrally located in immunoblasts. Mitoses are
common and atypical forms may be observed. Neoplastic cells
readily label with CD79a or CD20, and the Ki67 labeling
index is very high.
Because DLBCL is the most common form of nodal lym-
phoma in dogs and clinically is commonly seen as generalized
lymphadenopathy, the diagnosis is often based on fine-needle
aspirates detecting large lymphoid cells combined with PARR
 Lymph Nodes 221

A B

C D
Figure 2-177  Diffuse large B-cell lymphoma in a dog. A. The neoplasm expands diffusely and
quickly, destroying the tonsillar architecture. B. Sheets of large centroblastic or immunoblastic B
cells that are interspersed with tingible body macrophages resembling a “starry-sky.” C. Neoplastic
B cells are diffusely positive for CD20 by immunohistochemistry (IHC). D. Rare CD3-positive
non-neoplastic T cells can be detected by IHC.

testing and no immunophenotyping. This practice is very
unfortunate because it carries a risk of misdiagnosis. Peripheral
T-cell lymphomas can appear histologically similar to DLBCL
and account for up to 30% of nodal lymphomas. Fine-needle
aspirates also do not allow for evaluation of the tissue archi-
tecture, and differentiating high-grade follicular lymphomas
or even hyperplastic lesions from DLBCL may present a chal-
lenge. Considering that the sensitivity of PARR testing for IgH
receptor has only a sensitivity of ~65% and that cross-lineage
rearrangement occurs in ~10% of cases, making a diagnosis of
DLBCL based on cytology and PARR testing alone without
immunophenotyping is not acceptable for diagnostic purposes.
DLBCL also pose a therapeutic challenge. Chemotherapy
most commonly consists of CHOP treatment and large number
of cases respond to therapy. However, a subset of DLBCL will
fail therapy during initiation. There are currently no morpho-
logic features that correlate the neoplastic phenotype to thera-
peutic response. In human medicine, DLBCL have been
subclassified into activated B-cell–like (ABC DLBCL) and ger-
minal center B-cell–like (GCB DLBCL) based on gene expres-
sion profiling. Currently, an immunohistochemical algorithm
published by Choi and colleagues (see Further reading, this
section) is used to identify these 2 subtypes by using
antibodies against CD10, GCET1, BCL-6, MUM-1, and
FOXP1. Differentiating these 2 entities is clinically important
because ABC DLBCLs have significantly reduced survival
time despite CHOP therapy, but survival improves when
treated with bortezomib. A similar algorithm has recently
been established for dogs, and preliminary data indicate that
labeling, especially with GCET1 and CD10, predicts CHOP
response in canine DLBCL.
Anaplastic DLBCLs are uncommon lymphoid neoplasms
in dogs that are characterized by neoplastic B cells that have
large, often bizarre nuclei, and abundant amounts of cyto-
plasm. These lymphomas are indistinguishable from the more
common anaplastic large T-cell lymphomas, and also need to
be differentiated from histiocytic sarcomas by IHC. In human
medicine, the diagnosis of anaplastic T-cell lymphomas is
based on positive labeling with anaplastic lymphoma kinase
(ALK), which is usually negative in anaplastic B-cell lympho-
mas, thereby justifying their classification as DLBCL.
TCRBCL is a variant of DLBCL that represents the
most common lymphoma in horses and the most common
nodal lymphoma in cats, but has been reported in dogs (Fig.
2-178). In contrast to DLBCL, TCRBL are primarily com-
posed of sheets of small, reactive T cells admixed with
222 CHAPTER 2  •  Hematopoietic System
A not been performed in dogs or cats. Histologically, these neo-
B and benign follicular hyperplasia is required (Fig. 2-179). Lym-
C inconspicuous. Marginal zone lymphocytes are intermediate-
Figure 2-178  T-cell–rich B-cell lymphoma in a horse. A. Sheets
of small, reactive T cells admixed with histiocytic cells and neo-
plastic, large B cells that represent <10% of the cell population.
B. The reactive T cells are positive for CD3 by immunohisto-
chemistry (IHC). C. Small numbers of large neoplastic B cells are
strongly positive for CD79a by IHC.
histiocytic cells and eosinophils and neoplastic, large B cells
that are usually <10% of the cell population. Because of the
large number of histiocytic cells, the name T-cell/histiocyte–rich
B-cell lymphoma has also been used. The large B cells resemble
centroblasts and immunohistochemically label with CD20 or
Lymph Nodes
CD79a. Although CD79a may work poorly in horses, labeling
with Bla.36 should be avoided because it also labels histiocytic
cells. Clinically, TCRBCLs in horses occur most commonly as
abdominal or cutaneous masses that may wax and wane for
years before progressing to more aggressive DLBCLs that
disseminate.
There is an uncommonly encountered lymphoma in dogs
and rarely in cats that is of mixed cell type and most com-
monly occurs as large neoplastic nodules in the lungs. This
entity is called lymphomatoid granulomatosis (LYG), and it
can also occur in the skin, kidney, or other nonlymphoid loca-
tions. Although earlier studies classified this entity as a T-cell
lymphoma, the morphologic features and recent immunohis-
tochemical studies are more consistent with a special form of
a TCRBCL. However, assessment of clonal rearrangements has
plasms are characterized by a mixed infiltrate of lymphoid
cells composed of small T cells and atypical large B cells
admixed with histiocytic cells. Formation of granulomas is not
uncommon. The large atypical B cells resemble centroblasts
and immunoblasts and are positive for CD20 and CD79a and
often Ki67. CD20-negative Reed-Sternberg-like (multiple or
multilobed nuclei) cells that are positive for CD15 and CD30
have also been reported. There is prominent angiocentricity and
angioinvasion leading to vascular destruction and thrombosis,
followed by severe coagulative necrosis. In humans, LYG has
been variably associated with Epstein-Barr virus infections,
but no viral etiology has been established in animals.
Follicular-derived B-cell lymphomas.  To accurately diag-
nose follicular-derived lymphomas, including marginal zone
lymphomas, mantle cell lymphomas, and follicular lympho-
mas, some understanding of the structure of lymphoid follicles
phoid follicles have a germinal center with a dark and a light
zone that is surrounded by a mantle cuff, followed by a mar-
ginal zone. In lymph nodes, the marginal zone only develops
in long-standing benign hyperplasia. The darker zone of the
germinal center is primarily composed of centroblasts, whereas
the lighter zone is composed of a mixture of cells, including
many centrocytes. Centroblasts have been described under
DLBCL. Centrocytes are intermediate-sized cells with abun-
dant pale-staining cytoplasm and folded, angulated, or
indented nuclei. Nuclei have dense, stippled chromatin that
is lighter-staining than small lymphocytes. Mantle cuff lympho-
cytes are intermediate-sized cells that are slightly larger than
small lymphocytes. The amount of cytoplasm is scant. The
nuclei have variable degrees of indentation and angulation and
can even be round. Chromatin is very dense, and nucleoli are
sized cells with abundant, lightly stained cytoplasm and dis-
tinct borders. The nuclei are mildly vesiculated, with their
chromatin peripheralized against the nuclear membrane and
with a large single central nucleolus. This morphology resem-
bles to some degree immunoblasts that are large cells and need
to be differentiated from marginal zone lymphocyte to avoid
misdiagnosing a DLBCL. The marginal zone stains more
lightly than the mantle cuffs.
Follicular hyperplasia is characterized by follicular polarity
reflected by an eccentric cuff of small mantle cells that are
thicker over the peripherally oriented lighter zone of the
germinal center (Fig. 2-180). Tingible macrophages are usually
visible in germinal centers of hyperplastic follicles. A darkly
staining, well-defined mantle cell cuff is characteristic for
 Lymph Nodes 223

Marginal zone
Marginal zone
Marginal zone lymphoma

Intermediate cell:
Mantle cell
Marginal zone lymphocyte

Mantle zone
Mantle cell lymphoma

Intermediate cell:
Mantle cell lymphocyte
Germinal cell–light zone

Germinal center–light zone

Follicular B cell lymphoma

Intermediate cell: Large cell:

Centrocyte Centroblast

Germinal center–light zone

Germinal cell–diffuse zone Diffuse large B-cell lymphoma

Intermediate cell: Large cell:

Immunoblast Centroblast

Figure 2-179  Schematic drawing of origin of B-cell lymphomas based on normal follicle architec-
ture. (Based on concept created by P.F. Moore.)

A B
Figure 2-180  Follicular hyperplasia in a dog. A. Follicular polarity reflected by an eccentric cuff
of small mantle cells that are thicker over the peripherally oriented lighter zone of the germinal
center. B. Immunohistochemistry for BCL-2 highlights polarity by labeling mantle cells, but not
follicular center cells.

follicular hyperplasia. Polarity and the eccentric mantle cell
cuff are even more easily recognizable when labeling tissues
with CD20. The follicles are discrete and separated by at least
some interfollicular lymphoid tissue. Involution and “fading”
of follicles are commonly observed with follicular-derived
lymphomas. The involution of germinal centers results in for-
mation of aggregates of mantle cells that have collapsed into
the dendritic bed of fading germinal centers. This feature has
been described as fading follicular hyperplasia (FFH). Regard-
less, clonality testing may be required to differentiate neoplas-
tic from hyperplastic follicular proliferations.
Follicular lymphoma (FL) is an uncommon follicle-derived
lymphoma that has been reported in lymph nodes, spleen,
and extranodal tissues of dogs (Fig. 2-181). As with all
224 CHAPTER 2  •  Hematopoietic System Lymph Nodes

A B

C D
Figure 2-181  Follicular lymphoma in a dog. A. Follicles are usually large, uniform in size, lack a
mantle cell cuff, and show no polarity. B. Absence of tingible body macrophages and uniform
proportions of centrocytes and centroblast through follicle, with an absence of a dark zone.
C. Neoplastic B cells in individual and confluent follicles are diffusely and uniformly positive for
CD20 by immunohistochemistry. D. Small rims of immunohistochemically CD3-positive T cells
surround follicles.

follicular-derived lymphomas, FL must be differentiated from
follicular hyperplasia. Low-magnification examination is
essential when differentiating follicular-derived lymphoma
from follicular hyperplasia. A pattern of densely packed fol-
licles throughout the whole parenchyma of a lymph node is
characteristic for follicular lymphoma. The follicles are usually
large, uniform in size, lack a mantle cell cuff (“bare”) and show
no polarity. Paracortical high-endothelial venules are com-
pressed between opposing follicles and cannot be found
within them. Other important features include an absence of
tingible body macrophages and uniform proportions of cen-
trocytes and centroblasts through all follicles, with an absence
of a dark zone. The cellular features of centrocytes and cen-
troblasts have been described previously. Both centroblasts
and centrocytes are positive for CD79a and CD20 and nega-
tive with CD3. The Ki67 index is low. Immunohistochemical
labeling with BCL-2 is used in human FL because normal
follicular center cells are negative for BCL-2. Although similar
BCL-2 labeling has been confirmed in hyperplastic lesions in
dogs, data on canine FL are missing. Vascular invasion, extra-
nodal invasion, and loss of tissue architecture are more obvious
features of FL. In humans, FLs are graded based on the
percentage of centrocytes and centroblasts, with larger
numbers of centroblasts indicating more aggressive biological
behavior. There are no data available for domestic animals and
grading of FL is not performed routinely. Whether high-grade
FLs require more aggressive CHOP-based therapy is unknown.
Marginal zone lymphoma (MZL) is a follicular-derived
B-cell lymphoma that has been described in dogs in the lymph
nodes, spleen, and bronchus-associated lymphoid tissue and
mucosa-associated lymphoid tissue of the respiratory and
intestinal tracts (Fig. 2-182), respectively. In the spleen, MZL
often develops as a nodular mass. It is one of the 6 most
common types of nodal lymphomas in dogs, accounting for
~15% of canine lymphomas. Dogs with MZL usually are in
apparent good health and with an enlarged node or single
nodule in spleen, intestine, or lungs at the early stage of the
disease, progressing to multiple nodes, spleen, and tonsils
being involved in late-stage disease. MZL are considered indo-
lent, slowly progressive lymphomas that should not be treated
with regular CHOP therapy.
MZL originate from the marginal zone of the splenic fol-
licles or from the marginal zone that appears in lymph nodes
in chronic hyperplasia (Fig. 2-183). MZL must be differentiated
 Lymph Nodes 225

A B
Figure 2-182  Mucosa-associated lymphoid tissue (MALT)oma in a cat. A. Intermediate-sized
lymphoid cells forming clusters within crypt epithelium of the small intestine. B. Neoplastic B
cells are positive for CD20 by immunohistochemistry.

A B

C D
Figure 2-183  Marginal zone lymphoma in a dog. A. Homogeneous cuffs of neoplastic marginal
zone lymphocytes surround faded and hemorrhagic germinal centers. B. Cuff of intermediate-sized
marginal zone lymphocytes with mildly vesiculated nuclei with peripheralized chromatin and
a large single central nucleolus. C. Neoplastic marginal zone lymphocytes surround regressing
germinal center. D. Rim of marginal zone lymphocytes is strongly positive for CD20 by
immunohistochemistry.
226 CHAPTER 2  •  Hematopoietic System
from marginal zone hyperplasia (MZH). Both entities are char-
acterized by proliferation of marginal zone lymphocytes in
lymphoid follicles with their germinal centers in regression.
Some degree of MZH may also be observed with prominent
follicular hyperplasia. Usually MZH appears often as discon-
tinuous cuffs of marginal zone lymphocytes admixed with
smaller mantle cells and centroblasts. Cellular features of mar-
ginal zone lymphocytes have been described previously. In
MZL, the proliferating neoplastic cells form more homogeneous
cuffs of marginal zone lymphocytes surrounding a fading germinal
center (eFig. 2-43). During tumor progression, perifollicular
proliferating areas coalesce and commonly cause paracortical
atrophy and marked sinus dilation in the spleen. Cavities are
filled with erythrocytes and neoplastic cells. MZL have been
classified as “early,” “mid,” or “late” MZL according to their
stage of development, which is reflected by the degree of
coalescence of marginal zones, the amount of tissue affected,
and the number of mitoses, which are absent in early cases.
However, the overall mitotic index remains low even in late
cases. Neoplastic lymphoid cells are strongly positive for
CD20 or CD79a and negative for CD3. MZL should be easily
differentiated from DLBCL by its follicular architecture,
except in late cases, and size and amount of cytoplasm of
neoplastic cells. Cellular morphology and the orientation around
fading germinal centers are the main features to differentiate MZL
from FL.
Mantle cell lymphoma (MCL) is a rare follicular-derived
lymphoma that has been described in the spleen of dogs. MCL
present as solitary masses and are far less common than other
follicular-derived B-cell lymphomas (Fig. 2-184). The appear-
ance of MCL in the spleen is determined by the splenic end
arterioles that dictate the regular periodicity of neoplastic
nodules. The neoplasm arises from the inner mantle cuff and
differentiation from splenic follicular hyperplasia is difficult
because both lesions consist predominantly of mantle cells. As
with other follicle-derived B-cell lymphomas, in contrast to
hyperplastic lesions, neoplastic cells surround fading germinal
centers that are commonly hyalinized. The cell morphology
of mantle cells has been described previously. Mitoses are rare.
The MCL cells are B cells and label positive with CD79a and
CD20 and are negative with CD3.
Clinically, MCL has been considered to be an indolent
lymphoma and is grouped with MZL, but small case numbers
are probably the main reason that published evidence is
missing. Classification of MCL as indolent lymphomas is also
based on data from human medicine, where MCLs occur as
an incurable disease with a median survival time of 3-5 years.
Older age, a high Ki67 index, a high mitotic rate (1-3/HPF),
blastoid cell morphology, and mutations in p53 have been
associated with poor prognosis in humans. None of these
factors has been studied in dogs.
Burkitt-like lymphoma (BKL).  Although Burkitt lympho-
mas represent a well characterized entity in humans, Burkitt-
like lymphoma (BKL) is a highly controversial entity that has
been reported in dogs. Burkitt lymphomas in humans are highly
aggressive lymphomas that exist as an endemic form in Africa,
and are strongly associated with Epstein-Barr virus (EBV). In
the sporadic form, the association with EBV is highly variable,
and in acquired immunodeficiency syndrome (AIDS)-associ-
ated Burkitt lymphomas, there is only an association with EBV
in 30% of cases. In addition, the vast majority of Burkitt lym-
phomas have c-Myc translocations. Although seroconversion
to EBV has been reported in dogs and cats, viral DNA was
Lymph Nodes
not detected in blood of seropositive animals. Neither have
mutations in c-Myc been detected in BKL in dogs.
Histologically, canine BKL are diffuse neoplasms that give,
on low-power examination, the impression of a “starry sky”
because of the large number of tingible body macrophages. Neo-
plastic lymphoid cells are of intermediate size with round
nuclei that have a vesicular appearance. Aggregated chromatin
is clumped on the small, but prominent nucleoli and the
nucleolemma with irregular parachromatin clearing. Although
3-5 nucleoli have been reported in human Burkitt lymphoma,
there are usually fewer nucleoli in canine BKL. There is mild
anisokaryosis. The cytoplasm is of moderate volume and stain-
ing density. The mitotic rate is 10 or greater/HPF. During a
blinded review of canine nodal lymphomas, participating
pathologists failed to consistently differentiate BKL from
DLBCL, leading to exclusion of the BKL as an entity from the
review process.
Extramedullary plasmacytoma.  Extramedullary plasma-
cytomas (EMP) occur most commonly in the skin (digits and
ears) of dogs (Fig. 2-185), but are also common in the oral
and colorectal mucosa. Rare cases have been reported in
cats. Overall, EMPs are benign neoplasms with a low Ki67
index, and complete surgical removal of cutaneous masses is
curative. Plasmacytomas occurring in the facial skin have a
higher risk to invade into the underlying parenchyma, includ-
ing bone, but aggressive surgical removal is curative and
metastasis rarely occurs. Regardless, malignant variants occur
and may metastasize widely, but the incidence is <10%.
Colorectal plasmacytomas often pose a greater surgical chal-
lenge, and local recurrence has been reported. Some cases
occur as multiple plasmacytomas throughout the digestive
tract mucosa. Clinically, canine colorectal plasma cell tumors
have been reported to cause hematochezia, tenesmus, and
rectal prolapse. Macroscopically, cutaneous plasmacytomas
are solitary, broad-based, spherical or dome-shaped, hairless
neoplasms up to 3 cm in diameter. Some cutaneous EMPs may
be pedunculated, and ulceration is common. Intestinal EMPs
form solitary, red, raised and smooth, rapidly growing nodules
up to 5 cm in size. EMPs occur in middle-aged to older dogs,
and there is no sex or breed predilection. Urinary Bence-Jones
protein has not been detected in dogs with cutaneous or
intestinal EMPs, and hypergammaglobulinemia, which is com-
monly observed with multiple myeloma, is not a typical
feature of canine EMPs.
Most EMPs are circumscribed but not encapsulated, and
primarily located in the superficial dermis or the intestinal
submucosa, but may extend into the mucosa. Cutaneous neo-
plasms typically create a Grenz zone, and do not involve the
overlying epithelium. EMPs are densely cellular tumors com-
posed of densely packed, round to oval neoplastic cells that
are commonly arranged in cords and single files. A fine reticu-
lar stromal network of capillaries separates the cellular neo-
plastic cells. Neoplastic cells have indistinct cell borders and
round nuclei that are commonly eccentrically placed, and
have coarsely clumped chromatin arranged in a “clockface”
pattern and small solitary nucleoli. Megalokaryosis as well as
binucleate and rare multinucleate cells are a characteristic
feature (eFig. 2-44). Anisocytosis and anisokaryosis are moder-
ate and the mitotic index is usually low (0-1 mitoses/HPF).
There are variable amounts of often deeply amphophilic cyto-
plasm with perinuclear pallor. Some cells contain large eosino-
philic, intracytoplasmic aggregates of immunoglobulin (Russell
bodies). Cells toward the periphery of the neoplasm often
 226.e1

A A

B B
eFigure 2-43  Marginal zone lymphoma in a dog. A. Homoge- eFigure 2-44  Cutaneous plasmacytoma in a dog. A. Rows of
neous cuffs of neoplastic marginal zone lymphocytes surround neoplastic plasma cells surround aggregates of extracellular
faded and hemorrhagic germinal centers. B. Cuff of intermediate- amyloid. B. Megalokaryosis is a common feature of cutaneous
sized marginal zone lymphocytes with mildly vesiculated nuclei plasmacytomas.
with peripheralized chromatin and a large single central
nucleolus.
 Lymph Nodes 227

A B

C D

E
Figure 2-184  Mantle cell lymphoma in a dog. A. Homogeneous cuffs of neoplastic mantle cuff
lymphocytes surround fading germinal centers. B. Splenic end arterioles dictate the regular peri-
odicity of neoplastic nodules. C. Intermediate-sized mantle cuff lymphocytes, which are slightly
larger than small lymphocytes and have chromatin-dense nuclei and inconspicuous nucleoli, form
cuffs around regressed germinal centers. D. Mantle cuff lymphocytes are strongly positive for
CD20 by immunohistochemistry (IHC). E. No CD3-positive T-cells are detected within neoplastic
nodules by IHC.

closely resemble non-neoplastic plasma cells. Different mor-
phologic types have been reported for cutaneous EMPs in
both dogs and cats, including lymphoid, histiocytic, and pleo-
morphic subtypes, this classification has not been applied to
intestinal EMPs. Submucosal, perivascular, and intracellular
amyloid may be demonstrated with thioflavine T or Congo
red stains, and it is most commonly of λlight-chain origin.
Macrophages and foreign-body giant cells usually surround
amyloid deposits. A few cases with metaplastic cartilage and
bone within the amyloid have been reported. Ultrastructural
228 CHAPTER 2  •  Hematopoietic System Lymph Nodes

A B

C D
Figure 2-185  Cutaneous plasmacytoma in a dog. A. Neoplastic plasma cells have indistinct cell
borders and round nuclei that are commonly eccentrically placed; megalokaryosis as well as
binucleate cells are characteristic features. B. Extracellular and intracellular amyloid of λ light-
chain origin can be found in extramedullary plasmacytomas. C. Approximately 80% of cutaneous
plasmacytomas are positive for CD79a by immunohistochemistry (IHC). D. Nuclear labeling
for multiple myeloma oncogene-1 (MUM-1) can be detected by IHC in most cutaneous
plasmacytomas.

studies demonstrated large profiles of rough endoplasmic

reticulum.
Confirmation of the diagnosis of EMP is generally possible
using IHC to detect Mum-1 and immunoglobulins as well as
immunoglobulin light chains, but a combination with CD79a,
CD20, and Pax-5 for B-cells and CD3 for T cells is often
helpful in determining the cell of origin. Approximately 80%
of cutaneous plasmacytomas are positive for CD79a and only
60% for CD20.
Multiple myeloma is a malignant neoplasm of plasma cells
that typically occurs at multiple intramedullary sites (Fig.
2-186) and involves production of a clonal immunoglobulin.
The tumor is described in detail previously under Other
hematopoietic conditions.
T-cell and NK-cell neoplasms
Mature (peripheral) T-cell neoplasms.  Mature T-cell neo-
plasms are lymphomas of mature T cells in contrast to T-cell
lymphoblastic lymphomas. This is an umbrella diagnosis for Figure 2-186  Multiple myeloma in a dog. Neoplastic mass located
numerous T-cell lymphomas, and the WHO classification has in the medullary cavity of femur.
been expanded over the last decade to more accurately
 Lymph Nodes 229

characterize some of the heterogeneous subtypes. Classifying

subtype groups by the primary location of the neoplasm
has resulted in the identification of nodal, extranodal,
enteropathy-associated, and cutaneous T-cell lymphomas. Large
granular lymphocytic T-cell lymphomas have been characterized
as a specific subtype. The remaining group of mature T-cell
lymphomas is simply identified as unspecified peripheral T-cell
lymphomas.
Unspecified, peripheral T-cell lymphomas (PTCL) have
been reported in all species because this heterogeneous group
represents the “basket”-diagnosis for all nonspecific mature
T-cell lymphomas. PTCL can occur in lymph nodes, spleen,
and extranodal tissues, such as the skin or subcutis. In dogs,
up to 20% of nodal lymphomas have been classified as PTCL
(Fig. 2-187). PTCLs are highly aggressive lymphomas that
respond poorly to chemotherapy and together with T-LBLs A
are thereby largely responsible for the reputation of a poor
prognosis of T-cell lymphomas. As individual entities within
the group of PTCL will get recognized over time, some of
these entities may actually carry a different diagnosis, as has
been documented for T-zone lymphomas.
In dogs, about 2 3 of PTCL occur as a single-node enlarge-
ment and the rest with multiple-node involvement. In lymph
nodes, the neoplastic cell infiltrates are paracortical or diffuse.
The cellular composition of PTCL varies from cases to case
and ranges from small to intermediate to large cells, with large
cell PTCL being the most common. Some neoplasms have a
monomorphic cellular infiltrate, whereas others may contain
various inflammatory components, including eosinophils, his-
tiocytes, and plasma cells. Nuclei often have prominent inden-
tations, convolutions, or multilobulation, and chromatin is
granular or coarse. The cytoplasm is moderate to abundant in
volume and can be clear, eosinophilic, amphophilic, or deeply B
stained, with cell boundaries generally being distinct.
Nodal T-cell lymphoma.  Nodal T-cell lymphoma includes
T-zone lymphomas, anaplastic large T-cell lymphomas, and
angioimmunoblastic T-cell lymphomas, and the remaining
variants are currently classified as unspecified peripheral T-cell
lymphomas, which have been discussed previously.
T-zone lymphomas (TZL) are indolent, nodal lymphomas
that have been well characterized in dogs and rarely been
described in horses. Affected dogs almost invariably retain
normal appetite and activity and have one or sometimes more
nodes enlarged at the time of diagnosis. Generalized lymph-
adenopathy may occur. Dogs frequently develop a low-grade
lymphocytosis of 5-15 × 109/L that does not seem to influence
the progression of the lymphoma, which takes an indolent
course. Rarely epitheliotropic proliferations of neoplastic T
cells may occur in different organs during the late course of C
disease. The diagnosis of TZL is primarily based on their char-
acteristic architecture of paracortical proliferation of neoplastic T Figure 2-187  Peripheral T-cell lymphoma in a dog. A. Mixture
cells that causes compression and fading of germinal centers, of large and intermediate-sized neoplastic T cells that have mod-
which are peripheralized against the capsule (Fig. 2-188). The erate amounts of cytoplasm and often indented nuclei with stip-
capsule is thin and peripheral, and cortical sinuses are irregu- pled chromatin and indistinct nucleoli. B. Neoplastic T cells are
larly dilated with low cellularity. There is no involvement of positive for CD3 by immunohistochemistry (IHC). C. Small rem-
perinodal tissues. The proliferating paracortex may on low nants of lymphoid follicular B cells are positive for CD20 by IHC.
magnification be misinterpreted as a follicle-derived B-cell
proliferation, but the proliferating neoplastic cells do not sur-
round fading germinal centers as in marginal zone prolifera- mitotic rate is very low, and no mitoses are seen in single HPFs
tions. High-endothelial venules are prominent. Neoplastic in most cases. In contrast, T-zone hyperplasia is characterized
cells are uniform, small T cells with moderate amounts of pale, by a more heterogeneous population of small lymphocytes,
often water-clear cytoplasm, and densely stained nuclei that macrophages, and dendritic cells resulting in a moth-eaten
have shallow, sharp indentations and inapparent nucleoli. The appearance at low magnification. IHC helps to identify the
230 CHAPTER 2  •  Hematopoietic System Lymph Nodes

A B

C D
Figure 2-188  T-zone lymphoma in a dog. A. Paracortical proliferation of neoplastic T cells causes
compression and fading of germinal centers, which are peripheralized against the capsule.
B. Uniform, small neoplastic T cells with moderate amounts of water-clear cytoplasm and densely
stained nuclei that have shallow, sharp indentations and inapparent nucleoli. C. T cells that
are CD3 positive by immunohistochemistry (IHC) compress and peripheralize germinal centers.
D. Subcapsular remnants of germinal centers are positive for CD20 by IHC.

fading and peripheralized germinal centers that label with
CD79a and CD20. The neoplastic paracortical areas are
eccentric to fading germinal centers and are composed of
solidly CD3-positive neoplastic cells.
Anaplastic large T-cell lymphoma (ALTCL) is a rare
nodal lymphoma that has been reported in dogs and cats, and
carries a poor prognosis. Neoplastic cells have abundant cyto-
plasm and large, irregular, often bizarre, nuclei that are respon-
sible for the name of this entity. Affected nodes are partially
or completely involved, and predominantly sinusoidal growth
is a common feature. Fibrosis of the capsule and parenchyma
is common. Secondary infiltrates of small lymphocytes, plasma
cells, and eosinophils may occur. Histologically, ALTCLs are
indistinguishable from the anaplastic variant of DLBCLs.
However, as discussed previously, in humans, only ALTCLs are
consistently positive for anaplastic lymphoma kinase (ALK).
Neoplastic cells are commonly negative for CD3 and clonal
rearrangements in T-cell-receptor γ may help in the diagnosis.
Neoplastic cells consistently express CD30 and contain cyto-
toxic granule–associated proteins, such as perforin and gran-
zyme B, suggesting a cytotoxic T-cell phenotype. Unfortunately,
expression of ALK and CD30 has not been studied in animals.
ALTCL also have to be differentiated from histiocytic
sarcomas.
Angioimmunoblastic T-cell lymphoma is another nodal
lymphoma rarely reported in dogs. It is characterized by poly-
morph lymphoid infiltrates of affected nodes and associated
systemic disease. Although the node parenchyma is commonly
destroyed by the neoplastic cell proliferation, subcapsular
sinuses often remain open. Prominent high-endothelial capil-
laries spread through the node. Few fading germinal centers
may be observed. The neoplastic cells are of intermediate size
and have round nuclei and often clear cytoplasm. A charac-
teristic feature of this entity is clusters of immunoblastic cells
around vessels that also migrate into the vessels. Although the
neoplastic cells are consistently positive with CD3, infiltration
of B cells and eosinophils is common. Dendritic cells may
form perivascular, spindyloid proliferations. There are limited
data regarding the prognosis of these cases, and an aggressive
behavior has been suggested.
Enteropathy-associated T-cell lymphoma (EATL). 
Enteropathy-associated T-cell lymphomas (EATL) are intesti-
nal tumors of intraepithelial lymphocytes. They are further
subdivided into EATL type 1 (large cell neoplasms) that are
 Lymph Nodes 231

Figure 2-189  Enteropathy-associated T-cell lymphoma type 1 in Figure 2-190  Large granular lymphocyte lymphoma in a cat.
a dog. Neoplastic T cells infiltrating the jejunal mucosa have large Neoplastic T cells in many enteropathy-associated T-cell lym-
round or irregularly folded nuclei with parachromatin clearing phoma type 1 in cats have intracytoplasmic eosinophilic
and prominent central nucleoli of centroblastic nuclear type. granules.

often associated with necrosis and an inflammatory back-

ground and EATL type 2 (small to intermediate cell neoplasms)
that have no inflammatory background and rare necrosis. The
intraepithelial neoplastic cells are αβ T-cells and are consis-
tently CD3 positive and CD20 and CD79a negative. As
expected, EATL type 1 has a significantly higher Ki67 labeling
index than EATL type 2. Regardless of the type, animals with
EATL most commonly appear with weight loss, anorexia,
vomiting, diarrhea, lethargy, polydipsia, and polyuria. The
prognosis of EATL type 1 is much worse than for EATL type
2, which usually occurs as an indolent disease. Animals affected
with EATL type 1 respond poorly to therapy and survival is
limited to a few weeks or months.
EATL type 1 occurs most commonly in older dogs and is
often associated with transmural infiltration (Fig. 2-189). Sim-
ilarly, transmural EATLs in cats have been reported to be most A
commonly type 1 too, and in both species neoplasms occur
most frequently in the jejunum. The neoplastic lymphoid cells
have large round or irregularly folded nuclei with apparent
parachromatin clearing and prominent central nucleoli of cen-
troblastic nuclear type. Strong eosinophilic infiltrates may be
observed in some cases. Neoplastic cells in EATL type 1 often
have intracytoplasmic eosinophilic granules that express the
cytotoxic granule protein, granzyme B, consistent with a diag-
nosis of large granular lymphocyte lymphoma (LGL) (Fig.
2-190). The neoplastic cells of LGL often have abundant
cytoplasm, and IHC for perforin can also be used to aid in the
diagnosis. LGL may be a subentity of EATL type 1, but it is
commonly associated with leukemia.
EATL type 2 has primarily been reported in older cats and
occurs most commonly as intestinal mucosal lymphoma in the
jejunum (Fig. 2-191). EATL type 2 also occurs commonly in B
horses, where it affects the rectum. In both species, EATL type
2 can be diagnosed with full thickness or endoscopic biopsies, Figure 2-191  Enteropathy-associated T-cell lymphoma type 2 in
especially when combining morphologic evaluation with IHC a cat. A. Epitheliotropism is an important feature for diagnosing
and clonality testing. Morphology alone is often unable to this small-cell lymphoma and intraepithelial nests and/or plaques
differentiate the small, dense neoplastic T cells from similar of lymphocytes are highly suggestive of enteropathy-associated
appearing inflammatory T cells. In cats with EATL type 2, the T-cell lymphoma type 2. B. Immunohistochemistry for CD3
pattern of mucosal infiltration of neoplastic lymphocytes greatly enhances the ability to evaluate epitheliotropism of neo-
ranges from discrete, patchy areas to total effacement of the plastic T cells.
232 CHAPTER 2  •  Hematopoietic System
lamina propria. Early cases often show only infiltration of the
lamina propria of individual villi by large number of lympho-
cytes, and adjacent villi may be uninvolved. In other cases,
lymphocytic infiltration may occur as a band that spans the
crypt-villus junction. In advanced cases, the infiltrating neo-
plastic lymphocytes obliterate both the villus and crypt lamina
propria and form a band beneath the crypt epithelium, but
above the muscularis mucosae (eFig. 2-45). Such cases are
commonly associated with villous blunting and fusion as well
as crypt effacement.
Epitheliotropism is an important feature for diagnosing
EATL type 2, and the presence of intraepithelial nests (clusters
of more than 5 intraepithelial lymphocytes) or plaques (5
adjacent epithelial cells overrun by lymphocytes) of lympho-
cytes is highly suggestive of lymphoma. IHC for CD3 greatly
enhances the ability of the pathologist to evaluate epitheliot-
ropism. Although most epitheliotropic lymphocytes are
observed in villi, infiltration of crypt epithelium is an even stron-
ger indication of lymphoma. However, intraepithelial lympho-
cytes are a common immunologic response in the intestine,
and individual intraepithelial lymphocytes are commonly
found in inflammatory conditions, for instance, cats with
inflammatory bowel disease (IBD). The prognosis of cats with
EATL type 2 is still somewhat controversial, and large-scale
prospective studies using a standardized therapeutic approach
are lacking. Data from many studies are also hampered by the
lack of an accurate diagnosis of EATL type 2 versus IBD
because of the lack of TCRG clonality testing. Regardless,
EATL type 2 is considered a slowly progressing, smoldering
disease that may not require aggressive therapy. Overexpression
of Bcl-2 has recently been documented in EATL in cats, which
may prove useful as a therapeutic target.
Extranodal T-cell lymphoma.  Although the majority of
extranodal T-cell lymphomas in most animal species are cur-
rently classified as unspecified peripheral T-cell lymphomas,
hepatosplenic T-cell lymphomas rarely occur in dogs and horses.
Furthermore, hepatocytotropic T-cell lymphoma has recently
been described as an even more rare disease in dogs.
Hepatosplenic T-cell lymphoma (HS-TCL) causes a rapidly
progressive disease in dogs that clinically have lethargy,
anorexia, weight loss, diarrhea, and vomiting. Hepatomegaly
and splenomegaly, regenerative anemia, thrombocytopenia,
and hypoproteinemia are commonly observed. Dogs have
mild icterus and mild toxic changes in neutrophils. Horses
have only been diagnosed after autopsy, and their clinical signs
are not known. Neoplastic T cells are found primarily within
hepatic and splenic sinusoids, ranging from small clusters to
large aggregates that expand sinusoids and in the liver com-
press hepatic cords. Periportal and centrilobular neoplastic cell
infiltrates are also common in the liver. Erythrophagocytic
macrophages, extramedullary hematopoiesis, and fibrin
thrombi with associated ischemic necrosis are all features
commonly observed. Neoplastic lymphocytes have mild to
moderate amounts of eosinophilic to clear cytoplasm, inter-
mediate to large size, round to oval nuclei with indistinct
nucleoli, and variably distinct cell borders. Anisocytosis and
anisokaryosis are mild, and the mitotic index is low with 0-2
mitoses/HPF. Bone marrow and lungs are also consistently
affected. Immunohistochemically, neoplastic T cells are posi-
tive for CD3, T-cell-receptor γδ (TCRγδ), CD11d, and gran-
zyme B and negative for TCRαβ.
Only 2 cases of hepatocytotropic T-cell lymphoma (HC-
TCL) have been described in dogs. The liver was affected in
Lymph Nodes
both cases, whereas involvement of spleen and lung was
minimal. In contrast to HS-TCL, neoplastic lymphocytes in
HC-TCL are not confined to hepatic sinusoids, but invade
hepatic cords individually or in clusters. Neoplastic T cells are
morphologically similar to those described with HS-TCL, but
are CD11d negative. Bile duct epithelium is also infiltrated by
lymphocytes. However, no degenerative changes are apparent
in hepatocytes. Erythrophagocytosis is not an important
feature, and extramedullary hematopoiesis and fibrin thrombi
are absent. Further studies are needed to confirm HC-TCL as
a specific entity.
Cutaneous T-cell lymphoma.  Cutaneous T-cell lympho-
mas (CTCL) are a heterogeneous group of lymphomas
that include epitheliotropic and non-epitheliotropic lymphomas.
Epitheliotropic CTCLs appear as mycosis fungoides (MF),
Pagetoid reticulosis (PR), or Sézary syndrome (SS). Non-
epitheliotropic CTCLs appear as a subcutaneous “panniculitis-
like” T-cell lymphoma or anaplastic large T-cell lymphoma; all
other non-epitheliotropic CTCLs are currently classified as
unspecified peripheral T-cell lymphomas, which have been
described earlier.
Mycosis fungoides (MF) is a disease of older cats, dogs, and
horses. MF may exist originally as patches or plaques in the
skin that commonly progress rapidly to larger neoplastic
masses that invade the deeper dermis and potentially cause
local and distant metastases. In dogs and cats, MF occurs most
commonly around mucocutaneous junctions and feet or other
skin sites. Many affected dogs have a history of chronic der-
matitis, and erythema is the most common clinical sign. Pru-
ritus is sometimes associated with erythema and scaling;
ulcerations, hypopigmentation and alopecia can occur. In
horses, the skin may not be affected, but the mucous mem-
branes are the primary sites. In advanced cases, MF extends to
lymph nodes causing them to become enlarged and firm.
Histologically, in contrast to humans, MF in animals is char-
acterized by a strong tropism of neoplastic T cells for the epider-
mis and adnexal structures, including hair follicles, apocrine
sweat, and sebaceous glands (Fig. 2-192). T cells invading the
epidermis commonly form cavities filled with lymphocytes
called Pautrier’s microabscesses. Early lesions typically appear
as small numbers of T cells infiltrating along the basal level of
the epidermis. As disease progresses, the neoplastic cells
invade the deeper dermis and panniculus, causing larger
nodular masses. Neoplastic T cells are intermediate-sized cells
with a round, hyperchromatic and convoluted nuclei that
occasionally have sharp shallow indentations and large nucle-
oli that are difficult to visualize. The amount of cytoplasm is
minimal and generally water clear. Mitoses are rare.
Pagetoid reticulosis (PR) is considered a more epitheliotro-
pic variant of MF in which the neoplastic T cells form large
plaques that are almost entirely confined to the epidermis (Fig.
2-193). Morphologically, neoplastic cells are similar to those
described with MF. Sézary syndrome is the generalized stage of
MF with secondary lymphadenopathy and leukemia. The immu-
nophenotype of canine epitheliotropic CTCL is markedly dif-
ferent from its human counterpart. In canine epitheliotropic
CTCL, T cells are consistently positive for CD3. In MF, neo-
plastic T cells express CD8, and a smaller percentage of cases
are CD4 and CD8 negative, but CD4 expression has not been
reported. TCRαβ and TCRγδ are expressed in approximately
equal numbers of cases. This is in contrast to human MF,
which is primarily a disease of CD4- and TCRαβ-positive T
cells. Interestingly, T cells in canine PR have a slightly different
 232.e1

B
eFigure 2-45  Enteropathy-associated T-cell lymphoma type 2 in
a cat. A. Epitheliotropism characterized by intraepithelial nests
and/or plaques of lymphocytes is highly suggestive of enteropathy-
associated T-cell lymphoma type 2. B. Immunohistochemistry for
CD3 highlights the marked epitheliotropism of neoplastic T cells.
 Lymph Nodes 233

A B

C D
Figure 2-192  Mycosis fungoides in a dog. A. Epitheliotropic cutaneous T-cell lymphoma that
often infiltrates along the basal level of the epidermis. B. Strong tropism of neoplastic T cells for
the epidermis and adnexal structures, including hair follicles. C. Neoplastic T cells in the dermis
and epidermis are CD3 positive by immunohistochemistry. D. Epitheliotropism of immunohisto-
chemically CD3-positive T cells affecting adnexal structures.

A B
Figure 2-193  Pagetoid disease in a dog. A. A more epitheliotropic variant of mycosis fungoides
in which the neoplastic T cells form large plaques that are almost entirely confined to the epider-
mis. B. Intraepidermal T cells are strongly positive for CD3 by immunohistochemistry.
234 CHAPTER 2  •  Hematopoietic System
immunophenotype characterized also by expression of CD8
in most cases or being negative for CD4 and CD8, but in
contrast to canine MF, all cases of PR are TCRγδ positive.
Subcutaneous “panniculitis-like” T-cell lymphoma is rarely
seen in animals and has only been recognized in the dog (Fig.
2-194). Most cases take an indolent course, and removal seems
A ing from the epithelial basement membrane and irregularly invad-
C
Figure 2-194  Subcutaneous “panniculitis-like” T-cell lymphoma
in a dog. A. Neoplastic T cells infiltrate the panniculus in a lace-
like pattern often rimming large vacuolated adipocytes. B. Karyor-
rhexis and heavy infiltration with histiocytic cells are prominent
features. C. Neoplastic T cells rimming adipocytes are strongly
positive for CD3 by immunohistochemistry.
Lymph Nodes
to be curative. Lesions usually occur as multiple nodules on
the trunk or limbs that are localized in the panniculus and
almost completely spare the dermis. Histologically, neoplastic
T cells infiltrate the panniculus in a lace-like pattern, often
rimming large vacuolated adipocytes. Neoplastic T cells are
usually small- to intermediate-sized cells, but large cells may
dominate. Karyorrhexis is a prominent feature, and some cases
have extensive necrosis. This often leads to heavy infiltration
with histiocytic cells, and there is prominent phagocytic activ-
ity. The histiocytic infiltrates may mask the lesion as a histio-
cytic panniculitis, and IHC and clonality testing are helpful in
reaching an accurate diagnosis. Neoplastic cells are CD3 and
CD8 positive. A CD4-negative cytotoxic phenotype has been
described in humans, but has not been investigated in dogs.
Cutaneous anaplastic large T-cell lymphoma has been
described in middle-aged to older dogs as a highly aggressive
form of non-epitheliotropic CTCL with a poor prognosis (Fig.
2-195). Originally, lesions occur as single or multiple nodules
in the skin that progress remarkably rapidly and cause general-
ized lymphadenopathy. A disseminated form has also been
observed, and the nodal form has been described previously.
The neoplasm occurs as a solid mass of neoplastic T cells extend-
ing the subcutaneous fat. The neoplastic cells grow in solid
B
Figure 2-195  Cutaneous anaplastic large T-cell lymphoma in a
dog. A. Neoplastic T cells have large, often bizarre nuclei, and
abundant amounts of cytoplasm. B. Neoplastic T cells are strongly
positive for CD3 by immunohistochemistry.
 Lymph Nodes
sheets displacing hair follicles and collagen fibers. In deeper
areas, neoplastic T cells surround vessels and infiltrate between
fat cells, forming solid areas of tumor. The morphologic and
immunohistochemical features of the cutaneous form are
identical to the earlier described nodal form. Histiocytic sarco-
mas are the primary differential, and IHC is required for an
accurate diagnosis.
T-cell large granular lymphocytic leukemia.  Large granu-
lar lymphocytic lymphomas (LGL) have already been
described as a special form of EATL type 1, but they can also
occur as a leukemia in dogs. For a detailed description of the
leukemic disease, please see the paragraph on LGL leukemias.
For intestinal LGLs, please see description of EATL type 1.
Viral etiology and lymphomagenesis.  The etiology of most
lymphomas in domestic animal species is unknown, and there
are limited genetic studies. However, feline and bovine retro-
viruses have been shown to cause different types of lympho-
mas in cats and cattle, respectively.
Feline lymphoma may be caused by the horizontally trans-
mitted species Feline leukemia virus (FeLV), genus Gamma-
retrovirus in the oncovirus subfamily of family Retroviridae.
The virus has several subgroups of which FeLV-A, FeLV-B,
and FeLV-C are the most important. Only FeLV-A is conta-
gious and spreads horizontally among cats. The other sub-
groups result from recombination or mutation of FeLV-A in
infected cats and can only replicate under natural conditions
with the help of FeLV-A. The pathogenicity is higher for
multiple subgroup infections, and the envelop proteins of the
different subgroups determine lesion development. FeLV-B
is primarily responsible for development of thymic lympho-
mas in cats.
Neoplastic transformation is caused by insertional mutagen-
esis. Although some retroviruses insert a viral oncogene into
the host genome, causing rapid neoplastic transformation,
FeLV is a slowly transforming oncovirus. When FeLV becomes
integrated near a cellular proto-oncogene, transcription of this
gene can be upregulated by the promoter and enhancer func-
tion of viral long-term repeats (LTR). In cats, insertion occurs
most commonly near c-myc, which leads to uncontrolled
clonal proliferation of the affected cell without inducing an
immune response. Because insertion is random at one of hun-
dreds of proviral common integration sites, not all cats will
develop lymphoma, and neoplastic transformation may only
occur after long-standing infection. In addition to c-myc, other
common insertion loci associated with oncogenesis include
flvi-1, flvi-2 (contains bmi-1), fit-1, pim-1, and flit-1. Although
most insertion sites have been associated with formation of
thymic T-cell lymphoblastic lymphomas, insertion at flvi-1
results in B-cell lymphomas. Although c-myc is an oncogene,
bmi-1, and pim-1 are c-myc collaborators, and fit-1 has been
closely linked to myb. Flit-1 is associated with overexpression
of activin-A receptor type II–like 1 (ACVRL1). Flvi-2 contains
a gene that encodes feline homologs to bmi-1 and pmi-1. A
feline oncovirus cell membrane antigen (FOCMA) has been
detected on the surface of many transformed neoplastic cells,
and many FeLV infected cats will develop antibodies against
FOCMA. The role of FOCMA in protective immunity and its
function are still largely unknown.
Species Bovine leukemia virus (BLV) is an oncogenic del-
taretrovirus. Similar to cats, BLV is a slowly transforming
retrovirus, but does not causes bovine lymphomas through
insertional mutagenesis. It lacks a known oncogene and does
not integrate into preferred sites in the bovine genome. In
235
contrast to simple retroviruses, deltaretroviruses carry addi-
tional genes that encode for several regulatory and accessory
proteins. One of these proteins, Tax, plays a major role in BLV
lymphomagenesis. Tax is an activator of viral gene transcrip-
tion from the LTR and modulates the expression of several
cellular genes. It also induces immortalization of infected cells.
This may be the first step in the BLV-mediated neoplastic
transformation. In contrast to cats, in which FeLV virus pri-
marily causes thymic T-cell lymphomas, BLV infects B lym-
phocytes that express surface immunoglobulin M and causes
B-cell lymphomas. IgG heavy chains are frequently found on
neoplastic mature B cells. Tax immortalizes CD5-positive
IgM-positive B cells and causes their polyclonal expansion.
Missense mutations at codons 206, 207, 241, or 242 of p53
have been identified in more than 50% of BLV-induced lym-
phomas, and suppression of p53 most likely represents the
crucial step in neoplastic transformation in many cases.
However, other genes are most likely involved. Bovine leuko-
cyte antigen (BoLA) significantly contributes to the progres-
sion of BLV infection and the host’s immune response.
Polymorphisms of BoLA influence resistance and susceptibil-
ity to a wide variety of infectious diseases, including BLV, and
the monoclonal expansion of BLV-infected B cells is associated
with specific alleles of BoLA. Furthermore, a polymorphism
in the promoter region of the tumor necrosis factor-α gene
has been associated with the development of bovine
lymphoma.
Species differences.  The general pathology and classifica-
tion of lymphomas are discussed in the preceding sections.
The following sections deal with the clinical and topographic
aspects of lymphoma in the various domestic animal species.
Bovine lymphoma.  In cattle, bovine leukemia virus (BLV)-
associated lymphomas are predominantly diffuse large B-cell
lymphomas. Sporadic cases of precursor T-cell lymphoblastic
lymphomas occur multicentrically or in the thymus, and epi-
theliotropic T-cell lymphomas occur in the skin.
Lymphoma in adult cattle is mainly the enzootic bovine
leukosis form caused by an infection with BLV. The viral onco-
genesis has been described earlier. Because almost any organ
system may be involved with leukemia-associated lymphoma,
it is usually referred to as multicentric. BLV is transmitted
horizontally by direct contact. Small numbers of BLV-infected
lymphocytes can be transmitted through natural breeding,
blood-sucking arthropods, or iatrogenic by contaminated
needles, ear-tagging, and dehorning equipment, and the use of
whole-blood vaccines. Disease is much less common in beef
compared to dairy cattle, where husbandry practices favor
transmission, but shorter life-span may also contribute to a
lower incidence. BLV does not persist outside the animal, so
contact or environmental contamination is not a source of
infection. Infection, once established, is lifelong and character-
ized by the development of circulating antibodies, which are
also present throughout life. Antibody levels tend to increase
with the number of viral antigens recognized, as the animal
passes from an asymptomatic carrier stage to lymphocytosis
and to the tumorous state. Almost all infected cows will
develop detectable serum antiviral antibodies ~5 weeks after
infection. Although lymphocytosis develops in ~30% of
infected cows, lymphoma occurs in <5%. Cows develop neo-
plastic masses usually between 4 to 8 years of age. The low
incidence of neoplastic disease, and even lymphocytosis, has
hindered eradication of the disease. With the development of
an agarose gel immunodiffusion test that can detect antibodies
236 CHAPTER 2  •  Hematopoietic System Lymph Nodes

Figure 2-196  Enzootic bovine leukosis in a cow. Malignant lym- Figure 2-197  Enzootic bovine leukosis in a cow. Diffuse thicken-
phoma in the wall of the uterus. ing of the abomasal submucosa by an infiltrating malignant
lymphoma.

against BLV antigen and culling of infected animals, herds can

be maintained free of BLV.
BLV-associated lymphoma most commonly appears as
multiple enlarged lymph nodes that may appear anywhere in
the body or can be identified by rectal palpation. Enlarged
lymph nodes in the retrobulbar area may cause unilateral or
bilateral proptosis, and lymphadenopathy in the pharyngeal
area can result in dysphagia and stertorous respiration. Other
commonly affected organs include the abomasum, heart, spinal
cord, kidney, and uterus (Fig. 2-196, eFig. 2-46). Abomasal
lymphoma is characterized by diffuse thickening of the
abomasal submucosa with eventual ulceration leading to hem-
orrhagic anemia (Fig. 2-197, eFig. 2-47). Cattle with abomasal
lymphoma may also have vagal indigestion or diarrhea. There
is irregular involvement of the mesenteric nodes associated
with abomasal lymphoma, and these may, at times, be large
enough to cause obstruction. Lymphoma in the myocardium
may cause congestive heart failure (Fig. 2-198, eFig. 2-48).
Hindlimb lameness, which progresses quickly to weakness and Figure 2-198  Enzootic bovine leukosis in a cow. Malignant lym-
paraplegia, reflects the spread of neoplastic cells from sublum- phoma protruding as multinodular masses from the myocardium.
bar nodes to the spinal canal, where there is a relatively diffuse
infiltration into the perineural fat, leading to compression of
the lumbar spinal cord or spinal nerves. Grossly, the perineural
infiltration has only a slight fleshy pinkness to distinguish it
from normal fat, although the distinction is readily made by
an imprint of the affected tissues (Fig. 2-199, eFig. 2-49).
Occasionally, the kidneys are the primary site of gross mani-
festation of lymphoma. Liver and spleen are less commonly
affected, but some cows die rapidly because of splenomegaly
with rupture and abdominal hemorrhage.
The sporadic forms of bovine lymphoma are not associated
with BLV infection. The juvenile multicentric form most com-
monly occurs in calves between 3-6 months of age, but may
be present at birth. It is characterized by symmetrical lymph-
adenopathy and leukemia with leukocyte counts varying from
10-100 × 109/L. Affected animals often have nonresponsive,
normochromic normocytic anemia and thrombocytopenia.
Terminally, there is virtually complete myelophthisis and
marrow infarction with neutropenia and thrombocytopenia,
but without hemorrhage. At autopsy, virtually all nodes are Figure 2-199  Enzootic bovine leukosis in a cow. Malignant lym-
enlarged up to 10 times normal size, and the kidneys are phoma infiltrating the perineural fat, leading to compression of
usually diffusely involved but may not be markedly enlarged. spinal nerves and eventually the lumbar spinal cord.
 236.e1

A A

B B
eFigure 2-46  Enzootic bovine leukosis in a cow. A. Malignant
lymphoma in the wall of the uterus. B. Multifocal infiltrates of
malignant lymphoma throughout the liver. (Courtesy K.G.
Thompson.)

C
eFigure 2-47  Enzootic bovine leukosis in a cow. A. Diffuse thick-
ening of the abomasal wall by malignant lymphoma. B. The
kidneys have multifocal infiltrates of neoplastic lymphocytes
extending through the whole thickness of the cortex. C. Cross
section of spleen with multiple white nodules consistent with
malignant lymphoma.
236.e2

eFigure 2-48  Enzootic bovine leukosis in a cow. Malignant lym- eFigure 2-49  Enzootic bovine leukosis in a cow. Malignant ret-
phoma in the myocardium extending into papillary muscles. robulbar lymphoma. (Courtesy D.G. Sledge.)
 Lymph Nodes
Figure 2-200  Cutaneous lymphoma in a cow. Plaque-like, round,
raised lesions in the skin. (Courtesy K.G. Thompson.)
The liver and spleen may be massively involved, or relatively
spared. Calves may be born with lymphoma with the liver so
enlarged at parturition as to cause dystocia.
Thymic lymphoma occurs in cattle <2 years of age. Clini-
cally, it commonly causes presternal swelling, jugular disten-
tion, and local edema, as well as compression of the esophagus
and respiratory distress owing to displacements of the lungs
by a very large mediastinal mass. Often large areas of the
tumor may be infarcted.
The skin form is the least common type of bovine lym-
phoma, and occurs most often in 2- to 3-year-old cattle (Fig.
2-200). It is characterized by plaque-like, round, raised lesions
that appear on the head, sides, and perineum (eFig. 2-50). The
lesions become depilated, and are frequently ulcerated. The
lesions wax and wane over a period of months with some
regressing entirely and new lesions appearing. Ultimately,
there is deep organ involvement, and the visceral lesions are
then grossly indistinguishable from those of the enzootic type
of bovine lymphoma. This form of mycosis fungoides often
occurs in the advanced state with leukemia (Sézary
syndrome).
Ovine and caprine lymphoma.  Ovine lymphomas most
commonly occur as multicentric disease without leukemia and
bone marrow involvement (Fig. 2-201). A retrovirus indigenous
to sheep shares major proteins with BLV; however, most spon-
taneous lymphomas of sheep, and virtually all of those pro-
duced experimentally, are caused by BLV. Experimentally
infection with BLV causes lymphoma in 30-60% of sheep 2-3
years after infection. In sheep, as in cattle, infection with BLV
once established is lifelong, and the virus persists in the face
of a strong and persistent antibody response that can be
detected with the bovine agarose gel immunodiffusion test.
BLV produces a moderate persistent lymphocytosis in 50% of
sheep at 10-13 months postinfection, and causes neoplastic
masses in ~40% of sheep within 6 years postinfection.
In goats, sporadic forms of lymphoma occur more fre-
quently, and multicentric disease is much less common com-
pared to sheep. Disease presentation can be highly variable,
and lymphoma should be considered as a differential in any
goat >2 years of age with a fast progressing debilitating disease.
The gross and microscopic presentation of BLV-associated
lymphoma in sheep and goats is very similar to that described
237
Figure 2-201  Renal lymphoma in a sheep. The cortex is diffusely
infiltrated by neoplastic lymphocytes.
in cattle. Generalized lymphadenopathy is most commonly
encountered in sheep, and exophthalmos secondary to retro-
bulbar lymphadenopathy has especially been reported in
goats. Lymphoma can also be commonly found in the aboma-
sum, heart, and uterus. Small neoplastic masses are also not
uncommon in the spleen, whereas kidney and liver are rarely
involved. Thymic and cutaneous lymphoma also occur in
sheep and goats, and in goats, thymic lymphoma has to be
differentiated from thymoma because goats have a high preva-
lence of thymoma B1 as previously described. Furthermore,
lymphomas of the central nervous system (CNS) and synovial
lymphomas have been described in goats.
Equine lymphoma.  Lymphoma in the horse occurs primarily
as a subentity of diffuse large B-cell lymphoma, the T-cell–rich
large B-cell lymphoma (TCRLBCL). Peripheral T-cell lym-
phoma and other diffuse large B-cell lymphomas are also
commonly encountered. Lymphomas of the large intestine are
most commonly enteropathy-associated T-cell lymphomas of
small cell type (EATL type 2) and cutaneous lymphomas are
epitheliotropic T-cell lymphomas. Individual cases of other
entities have been reported. The cases reviewed covered 24
breeds, with Thoroughbreds the most prevalent, and the ages
ranged from 2 months to 31 years.
Equine lymphomas do not label well with CD79a, and B
cells in the horse are more efficiently marked with CD20.
Numerous studies used Bla.36 to label horse B cells, but the
antibody has been shown to also label macrophages and den-
dritic cells. The large number of T cells in TCRLBCL and
difficulties in detecting neoplastic B cells in the horse may
have led to misdiagnosis of some cases of multicentric lym-
phoma. Similarly, the large number of Bla.36-positive non-
lymphoid cells in sections of large intestine with EATL type
2 and the small size of neoplastic T cells and their close resem-
blance to inflammatory T cells may have caused an over-
reporting of intestinal B cell lymphomas in the older
literature.
Lymphoma is the most common malignant neoplasm in the
horse. Regardless of the anatomic location, lymphomas in
horses cause a general wasting disease with anorexia and
depression and ventral edema with or without reported hypo-
proteinemia. Pyrexia and anemia are common, and diarrhea
and colic can occur with any form of lymphoma. Multicentric
 237.e1

eFigure 2-50  Cutaneous lymphoma in a cow. Plaque-like, round,

raised lesions in the skin. (Courtesy K.G. Thompson.)
238 CHAPTER 2  •  Hematopoietic System
A
B
Figure 2-202  Abdominal lymphoma in a horse. A. Large, multi-
nodular intestinal masses. B. Neoplastic masses are white, firm,
and homogeneous on cross section.
lymphoma is the most common anatomic form, and the
vast majority of cases are TCRLBCL. In contrast to dogs,
multicentric lymphoma in the horse more commonly occurs
as masses in the abdominal (Fig. 2-202, eFig. 2-51) and tho-
racic cavity, as well as multiple subcutaneous, non-ulcerative
nodules on the trunk or limbs, rather than generalized lymph-
adenopathy. Skin nodules may be very numerous, and the skin
is mobile over these lesions that may wax and wane and
eventually become systemic. Other organs affected include
the pancreas, thyroid gland, spinal cord, and mediastinal
nodes, as well as the liver, spleen, and the gastrointestinal tract.
Although gastrointestinal TCRLBCL occurs as large intestinal
masses, EATL type 2 causes uniform thickening of the intes-
tinal mucosa and affects primarily the large intestine (Fig.
2-203). Rectal biopsies combined with immunohistochemis-
try (IHC) have been shown to be helpful in differentiating
EATL type 2 from lymphoplasmacytic proctitis antemortem.
Subcutaneous nodules are most commonly TCRLBCL, but
epitheliotropic T-cell lymphomas also occur in horses, and
some cases progress to Sézary syndrome.
There is some breed disposition regarding the type of lym-
phoma. Quarter Horses and Thoroughbreds most commonly
develop multicentric lymphomas, followed by cutaneous lym-
phomas; gastrointestinal lymphomas only represent up to 15%
of lymphomas. In contrast, Standardbreds have a higher
Lymph Nodes
Figure 2-203  Intestinal lymphoma in a horse. Multiple white
raised nodules protrude over a uniformly thickened intestinal
mucosa.
Figure 2-204  Nodal lymphoma in a dog. Generalized nodal lym-
phoma is the most common form of malignant lymphoma in dogs.
incidence of gastrointestinal lymphomas and rarely develop
cutaneous lymphoma. EATL type 2 is also much more com-
monly observed in Standardbreds compared to TCRLBCL in
Quarter Horses or Thoroughbreds.
Canine lymphoma.  Lymphomas are the most common
hematopoietic neoplasm in dogs with a reported incidence of
~0.025%. Lymphoma occurs primarily in middle-aged to
older dogs, and large-breed dogs are much more likely to
develop lymphomas. There is no sex predisposition. Breeds
most commonly affected include Golden Retrievers, Labrador
Retrievers, Boxers, Terriers, Cocker Spaniels, Beagles, and
Shih-Tzus.
Generalized nodal lymphoma is the by far the most common
clinical presentation, accounting for ~84% of all canine lym-
phomas (Fig. 2-204, eFig. 2-52). In dogs, the 3 most common
nodal lymphomas are the diffuse large B-cell lymphoma (~50-
60%), the peripheral T-cell lymphoma (~15-20%), and the
T-zone lymphoma (~10%). Other entities, such as lympho-
blastic T- or B-cell lymphomas, follicular B-cell lymphomas,
or marginal zone lymphomas are less common. Most nodal
 238.e1

B
eFigure 2-51  Malignant lymphoma in a horse. A. Mesenteric
lymph node and mesentery are diffusely infiltrated by a homoge-
neous neoplastic mass. B. The malignant lymphoma in the spleen
is white, firm, and has central areas of ischemic necrosis.
238.e2

eFigure 2-52  Nodal lymphoma in a dog. Cross section of lymph

node with diffuse, white homogeneous neoplastic tissue replacing
normal parenchyma.
 Lymph Nodes
lymphomas are clinically silent during the early stages of
disease.
Intestinal lymphomas are not as common in dogs as in cats,
and account for ~6% of all lymphomas. They are most com-
monly enteropathy-associated T-cell lymphomas of the large
cell type (type 1). Clinical signs include weight loss and leth-
argy, vomiting, and diarrhea, and blood may be present in
vomitus or stool. Boxers and Shar Peis are over-represented.
Cutaneous lymphomas account for ~6% of canine lympho-
mas, and are most commonly epitheliotropic T-cell lympho-
mas (mycosis fungoides). The disease is usually seen in dogs
>10 years of age, but the clinical presentation can vary from
single to diffuse disease and from flat plaques to cutaneous
nodules (Fig. 2-205, eFig. 2-53). Half of the affected dogs will
have pruritus.
Mediastinal and extranodal lymphomas are the least
common canine lymphomas, accounting together for ~4% of
canine lymphomas. Mediastinal lymphomas are most com-
monly lymphoblastic T-cell lymphomas arising from the
thymus, and clinically cause respiratory signs and effusions as
well as precaval syndrome. Polyuria and polydipsia occur in
~40% of dogs because of paraneoplastic hypercalcemia of
malignancy. In the spleen, marginal zone lymphomas, and
rarely mantle cell lymphomas, can be encountered,
A
B
Figure 2-205  Cutaneous lymphoma in a dog. (Courtesy M.
Umstead.) A. Erythematous, exfoliative dermatitis of the foot-
pads. B. Similar lesions in the nasal planum with mucocutaneous
depigmentation.
239
representing specific types of follicular lymphomas (Fig.
2-206). Recently, hepatosplenic and hepatocytotropic types
have been characterized. Other primary locations include the
eye (Fig. 2-207, eFig. 2-54), the spinal cord (Fig. 2-208), or
the kidney (Fig. 2-209, eFig. 2-55), and clinical signs depend
on the organ system affected.
Feline lymphoma.  Lymphomas are one of the most common
malignant neoplasms in cats. Historically, ~30% of feline neo-
plasms were lymphomas, and an incidence of 0.2% was
reported. Up to 80% of lymphomas were reported to be asso-
ciated with species Feline leukemia virus (FeLV). However,
there has been a dramatic decrease of the prevalence of
FeLV in cats after cats became routinely vaccinated against
FeLV, and testing and elimination programs have been estab-
lished. The majority of FeLV-associated lymphomas were lym-
phoblastic T-cell lymphomas occurring in the thymus/
mediastinum, especially in cats <3 years of age. FeLV does not
represent a single genomic species, but a family of closely
related viruses, and the genetic variation among these viruses
causes a highly variable disease outcome, including thymic
Figure 2-206  Splenic lymphoma in a dog. Multiple nodules in
the spleen.
Figure 2-207  Ocular lymphoma in a dog. Malignant lymphoma
arising from and largely obliterating the anterior uveal tract and
filling the anterior and posterior chambers. (Courtesy D.G.
Sledge.)
 239.e1

A
eFigure 2-54  Ocular lymphoma in a dog. Malignant lymphoma
arising from and largely obliterating the anterior uveal tract and
filling the anterior and posterior chambers. (Courtesy D.G.
Sledge.)

C
eFigure 2-53  Cutaneous lymphoma in a dog. A. Multinodular
white, homogeneous masses along the lip fold margin. (Courtesy
M. Umstead.) B. Erythematous, exfoliative dermatitis suggestive
of mycosis fungoides. (Courtesy K. Loft.) C. Similar lesions on
the nasal planum and periocular area with mucocutaneous depig-
mentation. (Courtesy M. Umstead.)
239.e2

C
eFigure 2-55  Malignant lymphoma in a dog. A. Multiple white
nodules randomly distributed throughout the myocardium.
(Courtesy S. Kesdangsakonwut). B. Malignant lymphoma in the
urinary bladder occurring as numerous ulcerated intraluminal
nodules. C. Disseminated malignant lymphoma in liver, spleen,
lymph nodes, and kidney.
240 CHAPTER 2  •  Hematopoietic System
Figure 2-208  Spinal cord lymphoma in a dog. Malignant lym-
phoma encompassing the nerve roots of the caudal spinal cord.
Figure 2-209  Renal lymphoma in a dog. A single sharply demar-
cated, white, firm homogeneous mass protrudes from the renal
cortex.
lymphoma of T-cell origin, non–T-cell multicentric lymphoma,
myeloproliferative disorder, or anemia. In one study, a particu-
lar isolate of FeLV caused exclusively multicentric B-cell lym-
phoma affecting liver, kidney, and lungs, but not thymus.
About 15% of cats infected with FeLV are also infected
with feline immunodeficiency virus (FIV); however, the latter
agent is not nearly as infectious as FeLV or as likely to cause
disease. FIV plays an indirect role in lymphomagenesis and
increases the risk of cats to develop lymphoma. FIV-associated
lymphomas are typically of B-cell phenotype and occur most
commonly in the intestine, but the overall incidence of FIV-
associated lymphoma is low.
Up to 90% of cats with thymic/mediastinal lymphomas were
found to be FeLV antigen positive (Fig. 2-210). Most cats with
thymic lymphoma develop pleural effusions, and clinical signs
include dyspnea and regurgitation because of pressure of the
neoplasm on lung and esophagus, respectively. Horner syn-
drome is caused by pressure on sympathetic nerves.
Since the 1990s, the incidence of thymic lymphoma has
decreased, and the most common type of lymphoma in cats
is now intestinal lymphoma (Fig. 2-211, eFig. 2-56). Although
Lymph Nodes
Figure 2-210  Thymic lymphoma in a cat. Thymic lymphomas
expand the cranial mediastinum causing caudodorsal displace-
ment of the lungs.
Figure 2-211  Intestinal lymphoma in a cat. Diffuse circumferen-
tial thickening of the intestinal wall causing luminal obstruction.
(Courtesy J.S. Munday.)
the reported higher incidence of intestinal lymphoma may
partially result from the shift of the proportion of lymphomas
in cats because of a decrease of FeLV, it more likely reflects
our ability to better diagnose intestinal lymphomas in cats.
The majority of intestinal lymphomas in cats are enteropathy-
associated T-cell (EATL) lymphomas of small cell type (type
2) that histologically resemble inflammatory bowel disease
and often require IHC and clonality testing for an accurate
diagnosis. Historically, most intestinal lymphomas have been
reported as B-cell lymphomas. With the establishment of diag-
nostic algorithms to accurately diagnose EATL type 2 based
on molecular techniques even in endoscopic biopsies, it is now
certain that EATL type 2 is by far the most common form of
intestinal lymphoma in cats. Another intestinal lymphoma in
cats is EATL of large cell subtype (type 1), which, like EATL
type 2, occurs most frequently in the jejunum. EATL type 1
is often characterized by intracytoplasmic eosinophilic gran-
ules that express the cytotoxic granule protein, granzyme B,
consistent with a diagnosis of large granular lymphocyte
(LGL) lymphoma. In contrast, gastric lymphomas are most
commonly diffuse large B-cell lymphomas (Fig. 2-212,
 240.e1

B
eFigure 2-56  Intestinal lymphoma in a cat. A. Multifocal circum-
ferential thickening of the intestinal wall and enlargement of the
mesenteric lymph node. B. Thickening of the intestinal mucosa
with linear ulceration over Peyer’s patches.
 Lymph Nodes
Figure 2-212  Gastric lymphoma in a cat. Submucosal thickening
by a diffuse, white, homogeneous infiltrate.
Figure 2-213  Renal lymphoma in a cat. Numerous, sharply
demarcated, white, firm homogeneous masses distributed
throughout the renal cortex.
eFig. 2-57), and this type of lymphoma can also occur at the
ileo-ceco-colic junction or synchronous at both locations.
Multicentric lymphoma is another common type of lym-
phoma in cats, and historically, 70% of cases were positive for
FeLV. The vast majority of cases affect internal organs such as
kidney (Fig. 2-213, eFig. 2-58) or liver, and generalized lymph-
adenopathy is uncommon. Clinical signs vary depending on
the organ system affected. A specific type of nodal lymphoma,
Hodgkin-like lymphoma, is seen most commonly as unilateral
mandibular or cervical lymphadenopathy, but other lymph
nodes may also be the primary sites.
Lymphoma is the most common feline upper respiratory
tract neoplasm. Nasal and nasopharyngeal lymphomas can
occur individually at each location or synchronous at both
sites (Fig. 2-214). The majority of cases are diffuse large B-cell
lymphomas, but epitheliotropic T-cell lymphomas and small
lymphocytic B-cell lymphomas have also been observed.
Interestingly, epitheliotropism has also been described for
some B-cell lymphomas, and FeLV p27 or gp70 antigens have
been detected in ~50% of cases regardless of phenotype.
241
A
B
Figure 2-214  Nasal and nasopharyngeal lymphoma in a cat.
A. Expansile, white firm homogeneous mass that protrudes from
the frontal sinus causing destruction of bone. (Courtesy S. Kes-
dangsakonwut.) B. Plaque-like tonsillar lymphoma. (Courtesy
K.G. Thompson.)
Other extranodal lymphomas in cats include primarily lym-
phomas of the CNS, peripheral nerves (neurolymphomatosis),
cutaneous lymphomas (eFig. 2-59), and ocular lymphomas
(see eFig. 2-58), and account for ~20% of all feline lympho-
mas. None of these types of lymphoma has been associated
with FeLV or FIV infections. The clinical signs vary based on
the organ system affected, for instance, paraplegia with
neurolymphomatosis.
Porcine lymphoma.  Lymphoma is the most common neo-
plasm in pigs. There are no published data that apply the
WHO classification to a large series of porcine lymphomas.
All ages and both sexes are affected, but there is a higher
incidence in female pigs. The multicentric form is most com-
monly characterized by generalized lymphadenopathy affect-
ing visceral lymph nodes rather than peripheral lymph nodes.
Multicentric lymphoma may also primarily affect internal
organs, such as kidney (eFig. 2-60), spleen, and liver (Fig.
2-215). Leukemia occurs commonly at the terminal stage. The
thymic form most commonly occurs as lymphoblastic T-cell
lymphoma and is the most common form of lymphoma in
piglets as young as 3 weeks of age. An autosomal recessive
trait has been reported to have caused B-cell lymphomas in
25% of animals from herds of Large White pigs bearing this
 241.e1

A
eFigure 2-57  Gastric lymphoma in a cat. Cross section of severely
thickened gastric wall by a diffuse white homogeneous
infiltrate.

B
eFigure 2-58  Malignant lymphoma in a cat. A. Ocular lym-
phoma. (Courtesy D.G. Sledge.) B. Renal lymphoma character-
ized by diffuse infiltration of the cortex by neoplastic
lymphocytes.
241.e2

eFigure 2-59  Lymphocytosis in a cat. Solitary area of alopecia eFigure 2-60  Malignant lymphoma in a pig. White, raised nodules
with scaling, erythema, and ulceration. (Courtesy M. Umstead.) randomly distributed throughout the kidney.
242 CHAPTER 2  •  Hematopoietic System
A Durham AC, et al. Two hundred three cases of equine lymphoma clas-
B Mazoub M, et al. Histopathologic and immunophenotypic character-
C Ogihara K, et al. Lymphoid neoplasms in swine. J Vet Med Sci
Figure 2-215  Malignant lymphoma in a pig. A. White, raised
nodules randomly distributed throughout the liver. B. Similar
lesions throughout the renal cortex. C. A large multinodular mass
expands the gastric wall.
defect. Lymphomas were detectable at 2-3 months of age, and
the average survival time was 4-6 months. The disease was
characterized by generalized lymph node enlargement, sple-
nomegaly, hepatomegaly, and involvement of the mesenteric
lymph nodes, stomach, and intestines. There was late-stage
involvement of the bone marrow, and many pigs died as a
result of leukemia, and had widespread hemorrhages because
Lymph Nodes
of thrombocytopenia. Pigs with the inherited form of lym-
phoma have a heavy-chain gammopathy with appearance of
this fragment in the urine.
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 Histiocytic Proliferative Diseases
Valli VE, et al. Canine lymphomas: association of classification type,
disease stage, tumor subtype, mitotic rate, and treatment with
survival. Vet Pathol 2013;50:738-748.
HISTIOCYTIC PROLIFERATIVE DISEASES
Proliferative histiocytic diseases in domestic animals occur
largely in dogs and to a lesser extent in cats. They are likely
present in other species, but have not been adequately
described. It is important to recognize that usage of the term
“histiocyte” has changed over time and that the term “histiocytic
diseases” now encompass all proliferative disease processes of
dendritic cells or macrophages. Gross or histopathology is often
insufficient to properly diagnose these disease processes, and
a basic understanding of the cell biology of histiocytes is
required to use immunohistochemistry (IHC) as a means to
reach an accurate diagnosis.
Histiocytes are derived from hematopoietic CD34+ stem cells
and differentiate into macrophage, nonlymphoid dendritic cell,
and lymphoid dendritic cell lineages. Nonlymphoid dendritic
cells include interstitial and epithelial (Langerhans) dendritic
cells, whereas lymphoid dendritic cells of the T-cell domains
in lymphoid organs, such as spleen or lymph nodes, are called
interdigitating dendritic cells. Langerhans cells initially reside in
the epithelia of the skin, digestive, respiratory, and reproduc-
tive tract as intraepithelial dendritic antigen-presenting cells.
Interstitial dendritic cells can be found in most organs around
vessels, with the exception of the brain. The dendritic cells in
lymph nodes comprise both resident interdigitating dendritic
cells as well as migratory epithelial and interstitial dendritic
cells that have been drained via the lymphatics from their
tributary area. All dendritic cells are part of the adaptive
immune response and act as potent antigen-presenting cells.
By presenting antigens to naive T-cells in the paracortex of
lymph nodes, dendritic cells initiate an immune response.
Most histiocytic diseases in domestic animals originate from
interstitial dendritic cells or Langerhans cells. Only hemophago-
cytic histiocytic sarcomas in dogs have been demonstrated to
originate from macrophages, in particular red pulp macro-
phages from the spleen. The characterization of histiocytic
cells in formalin-fixed tissues is limited by the availability of
species-specific antibodies that will detect the appropriate
epitopes. A number of such antibodies have been developed
for canine and feline tissues and can be used in routinely
formalin-fixed tissues, whereas others are currently only avail-
able for use in frozen sections. Antibodies that can be used to
characterize histiocytic proliferative diseases and function in
formalin-fixed tissues include CD18, CD11d, CD204, CD90,
major histocompatibility complex II (MHC II), and E-cadherin.
Additional antibodies of importance that only work in frozen
sections include CD1a, CD11c (dog only), and CD4. All
dendritic cells express CD1a that, together with MHC I and
MHC II molecules, presents antigens to T cells. Another mol-
ecule that is useful in the diagnosis of histiocytic proliferative
diseases is CD18. CD18 is part of the heterodimeric β-2
integrin adhesion molecule that is composed of 1 of 4 differ-
ent CD11 (a-d) subunits and the CD18 subunit. Therefore all
histiocytic cells express CD18. CD11c is found in all epithe-
lial and interstitial dendritic cells; CD11d can be detected in
macrophages. Macrophage scavenger receptor 1 (CD204) is
expressed on macrophages and interstitial dendritic cells,
where it mediates endocytosis, but not in epithelial or
243
interdigitating dendritic cells or lymphocytes. Furthermore,
epithelial dendritic cells and interstitial dendritic cells can be
differentiated by the expression of CD90 (Thy-1) in intersti-
tial dendritic cells and E-cadherin in epithelial dendritic cells.
Activated dendritic cells express CD4.
Numerous well-defined histiocytic proliferative diseases
have been characterized in dogs and cats. Canine cutaneous
histiocytomas and canine Langerhans cell histiocytosis (LCH)
are both diseases of Langerhans cells with different biological
behavior. A pulmonary form of LCH has rarely been reported
in cats; reports of feline cutaneous histiocytomas are only
anecdotal. Diseases of interstitial dendritic cells include the
cutaneous or systemic forms of reactive histiocytosis, an
inflammatory disorder, and the various entities of histiocytic
sarcoma complex in dogs, as well as histiocytic sarcomas and
feline progressive histiocytosis in cats. Canine hemophago-
cytic histiocytic sarcoma is the only macrophage-derived entity,
and a feline counterpart has recently been suggested. A con-
genital histiocytosis of non–Langerhans cell origin has rarely
been reported in pigs, and the condition most closely resem-
bles juvenile xanthogranuloma in humans, a generally skin-
limited non-Langerhans histiocytic disorder.
A combination of gross presentation, histopathology, and
IHC is sufficient to accurately differentiate most canine his-
tiocytic diseases. In rare cases, additional frozen sections will
be required to confirm the diagnosis. A summary of the immu-
nohistochemical differences of the canine histiocytic diseases
can be found in Figure 2-216.
Canine cutaneous histiocytoma
Cutaneous histiocytoma is a benign common skin disease of
young dogs that usually appears as a single, focal, bulging mass
frequently on the head, ears, and limbs. Although most
common in dogs <3 years of age, histiocytomas can occur in
dogs of all ages. All breeds are affected, but there is a predis-
position in brachycephalic breeds, such as Boxers; Dachs-
hunds, Doberman Pinschers, and Cocker Spaniels are also
more commonly affected. The proliferation is of epidermal
Langerhans cells and usually ulcerates and regresses
spontaneously.
Grossly, canine cutaneous histiocytomas appear as round
1-2 cm dome-shaped skin protrusions that are usually hairless
and may be irritating to the dog, because they are frequently
abraded and ulcerated (Fig. 2-217, eFig. 2-61). Much less
frequently, the lesion may be a flat thickened plaque. If lesions
are left unattended, they usually involute spontaneously, with
complete healing in young dogs, but in older dogs, they are
more persistent. Surgical excision tends to be curative and
recurrence or development of additional masses is rare. Mul-
tiple histiocytomas are also uncommon, but Shar Peis are
more prone to develop multiple lesions. If dogs develop
numerous histiocytomas, such lesions should be better con-
sidered as a form of LCH (see later). Rare spread to lymph
nodes followed by regression has been reported in individual
cases, but may represent a Langerhans cell histiocytosis. Spon-
taneous regression is a major characteristic of canine cutaneous
histiocytomas, but the mechanisms are poorly understood.
Lysis of the histiocytic cells mediated by infiltrating lympho-
cytes, especially CD8+ lymphocytes, has been postulated as
the primary mechanism of regression. Some authors speculate
that tumor cells could facilitate their own destruction by
functioning as antigen-presenting cells, but infiltrating dermal
dendritic cells may also play a major role.
 243.e1

eFigure 2-61  Cutaneous histiocytoma in a dog. A single, pink,

raised, sharply demarcated nodule in the skin. (Courtesy R. Torres
Neto.)
244 CHAPTER 2  •  Hematopoietic System Histiocytic Proliferative Diseases

Histiocytic sarcoma

Cutaneous Hemophagocytic
histiocytoma histiocytic sarcoma

Reactive histiocytosis

Langerhans
histiocytosis

Langerhans DC Interstitial DC Macrophage

CD18 CD204 CD18 CD204 CD18 CD204
CD11c CD11d CD11c CD11d CD11c CD11d
E-cad Thy-1 E-cad E-cad Thy-1
Thy-1, CD4 (CHSH)

Figure 2-216  Classification of canine histiocytic diseases based on cell morphology and immu-
nohistochemical phenotype.

multinucleated cells can be occasionally seen. However,

Figure 2-217  Cutaneous histiocytoma in a dog. A single, pink,
raised, sharply demarcated nodule in the upper eyelid. (Courtesy
M. Coster.)
The histology of the canine cutaneous histiocytomas is very
characteristic and changes with the degree of regression. All
lesions are located in the superficial dermis and line up below
the basement membrane, giving the lesion its typical dome-
shaped appearance (Fig. 2-218). Histiocytic cells are densely
packed in the deep dermis and are more loosely arranged and
in rows near the epidermis (eFig. 2-62). The cells extend from
the dermoepidermal junction to the deep dermis and pannicu-
lus. The neoplasm surrounds dermal vessels, and displaces but
does not destroy adnexal structures. The proliferating cells
may penetrate the surface epithelium, and epitheliotropism is
observed in ~30% of cases. Especially in older dogs, such
tropism may raise concerns of a cutaneous epitheliotropic
T-cell lymphoma as the primary differential. Histiocytic cells
have a highly variable morphology. Nuclei tend to be vesicular
and are ~1.5-2.0 times the diameter of red cells. Round to
oval, reniform, or convoluted shapes are common, and even
marked anisokaryosis or megalokaryosis are not features of
cutaneous histiocytomas. The cytoplasm is relatively abun-
dant, lightly eosinophilic, and, unlike lymphocytes, is of the
same density from the nucleus to the cell margin. The cell
boundaries are generally distinct near the skin surface. The
mitotic index can be highly variable, but is commonly very
high. Although Birbeck granules are a characteristic ultrastruc-
tural feature of Langerhans cells in humans, cats, and many
other species, they have not been detected in canine cutaneous
histiocytomas. It has been speculated that cutaneous histiocy-
tomas in dogs arise from CD14+ dermal precursors of Lang-
erhans cells that invade the epidermis and lack Birbeck
granules.
As lesions regress, deep infiltration of small lymphocytes that
progresses throughout the nodule can be observed. The lympho-
cytes are predominantly CD3+, CD8+ cytotoxic T cells. Infil-
tration of T-cells is mirrored by necrosis of histiocytes. There
may also be mild neutrophilia if the lesion is allowed to prog-
ress to an ulcerated skin lesion. In late stages of regression,
the massive lymphoid infiltrate may be mistaken as a non-
epitheliotropic lymphoma because only a few recognizable
histiocytes remain. Even analysis of clonality of the T-cell
receptor γ will not help in differentiating these 2 entities
because clonal expansion of the cytotoxic T cell has been
documented in 50% of canine cutaneous histiocytomas.
Because the resolution of the infiltrate is the result of the
action of the adaptive immune system, any treatment with
steroids is contraindicated. In both cytologic and histologic
preparations, the proliferating cells of cutaneous histiocytoma
are strongly positive for CD18. The deep infiltrating lympho-
cytes are strongly CD3 positive. Langerhans cells in canine
cutaneous histiocytomas express CD1a, CD11c, CD18, MHC
II, and E-cadherin, but are negative for CD90 and CD204. To
differentiate epitheliotropic T-cell lymphoma from cutaneous
histiocytoma, a panel of CD18, CD3, CD20, and E-cadherin
is most commonly used. It is important to recognize that
Langerhans cells express E-cadherin along the cell membrane,
and to use antibodies that detect the relevant E-cadherin.
 244.e1

B
eFigure 2-62  Cutaneous histiocytoma in a dog. A. Histiocytic
cells have highly variable morphology, and nuclei tend to be round
to oval, but reniform or convoluted shapes are also common.
B. Epitheliotropism occurs in 30% of cases.
 Histiocytic Proliferative Diseases 245

Dermal
vessels

Histiocytic
infiltrate
Subcutis
A B

C D
Figure 2-218  Cutaneous histiocytoma in a dog. A. Cutaneous histiocytomas are located in the
superficial dermis and extend to the basement membrane, resulting in a typical dome-shaped
appearance. B. Schematic drawing of the dermal location of cutaneous histiocytomas that surround
dermal vessels and cause epitheliotropism in 30% of cases. (Adapted from a graphic by P.F. Moore.)
C. Histiocytic cells are more loosely arranged and in rows near the epidermis. D. Immunohisto-
chemistry for E-cadherin labels both epidermal epithelial cells and neoplastic Langerhans cells.

Commonly, expression of E-cadherin is limited to histiocytes
in the superficial portion of the lesion just below the epider-
mis. It may be impossible to detect E-cadherin in severely
ulcerated and regressing tumors, and a panel of antibodies will
be required to accurately diagnose such lesions.
Canine cutaneous Langerhans cell histiocytosis
Although most histiocytomas occur as solitary lesions, some
dogs may develop multiple tumors over time. In dogs with
numerous cutaneous neoplasms that histologically and immu-
nohistochemically resemble cutaneous histiocytomas, a canine
cutaneous LCH should be considered as the primary differen-
tial (Fig. 2-219). LCH always starts as a cutaneous disease
process, but it can also extend to draining lymph nodes and
rarely involve other internal organs. The cutaneous and sys-
temic forms of LCH closely resemble their human counter-
parts. Affected dogs may have hundreds of cutaneous masses,
and secondary self-inflicted trauma commonly leads to severe
inflammation and ulceration. Shar Peis are over-represented,
but other breeds can be affected. The prognosis of LCH is less
favorable than for solitary cutaneous histiocytomas. Delayed
regression of the cutaneous lesions for up to 10 months
commonly leads to extensive ulceration, and euthanasia of
50% of affected dogs has been reported because of secondary
complications. Dogs with systemic spread of LCH have a poor
prognosis, and the reported mortality is 100%, including
euthanasia. Systemic LCH tends to spread to the lymph nodes
first, followed by the lungs, and variably other organs. A peri-
bronchial pattern is most commonly observed in the lungs
(Fig. 2-220).
Histologically, the individual cutaneous masses resemble
cutaneous histiocytomas. Although cutaneous lesions of LCH
tend to be larger and may extend into the subcutis and under-
lying muscle, the occurrence of multiple nodules and delayed
regression are the primary indicators of a LCH versus a cuta-
neous histiocytoma. Some cases have a higher degree of aniso-
karyosis, and multinucleated cells may be observed, but the
cellular morphology most closely resembles those of Langer-
hans cells in cutaneous histiocytomas rather than the highly
anaplastic features of neoplastic interstitial dendritic cells in
histiocytic sarcomas. Lymphatic invasion indicates lymphatic
spread and carries a worse prognosis.
Immunohistochemically, proliferating histiocytic cells in
LCH have features similar to Langerhans cells in cutaneous
246 CHAPTER 2  •  Hematopoietic System
A
B Feline pulmonary Langerhans cell histiocytosis
Figure 2-219  Langerhans histiocytosis in a dog. (Courtesy S.
Kesdangsakonwut.) A. Large numbers of cutaneous neoplasms
each individually resembling canine cutaneous histiocytoma.
B. Cross section of these nodules shows the sharp demarcation
and localization in the superficial dermis.
Figure 2-220  Langerhans cell histiocytosis in a dog. A peribron-
chial pattern is most commonly observed in the lungs.
Histiocytic Proliferative Diseases
Figure 2-221  Pulmonary Langerhans cell histiocytosis in a cat.
Nodular proliferations throughout the pulmonary parenchyma
that coalesce and extend to the pleural surface. (Courtesy F.
Taylor.)
histiocytomas. The cells are positive for CD18 and E-cadherin,
but negative for CD90 and CD204. As described earlier, his-
tiocytic cells in the deeper portion of the cutaneous masses
and those migrating to lymph nodes and internal organs may
lose expression of E-cadherin, and a combination of cell mor-
phology, positive labeling for CD18, but negative labeling for
lymphoid markers and CD204 and CD90 will help differenti-
ate LCH from reactive histiocytosis or histiocytic sarcoma.
In cats, only a pulmonary form of a LCH has been characterized;
cutaneous manifestations of Langerhans cell proliferations
have not been reported. Pulmonary LCH occurs primarily in
cats >10 years of age, and causes progressive respiratory disease
that is ultimately fatal. Clinical signs vary from acute respira-
tory distress, including tachypnea, labored breathing, and open
mouth-breathing, to prolonged chronic pulmonary disease.
Similar to the pulmonary lesions in canine LCH, histiocytic
proliferations affect first the peribronchial parenchyma,
causing nodular proliferations that vary from 2-5 mm in diam-
eter. As the disease progresses, nodules coalesce and lesions
extend to the pleural surface. In advanced cases, the whole
lungs tend to be affected, and all lobes appear diffusely firm
(Fig. 2-221). The tracheobronchial lymph nodes are com-
monly diffusely enlarged and white, firm, and homogeneous
on cut section. In some cats, nodular masses have also been
described in the pancreas and kidneys and their draining
lymph nodes.
Histologically, the nodular masses are centered around ter-
minal bronchioles. Proliferating histiocytes are similar to those
described in canine LCH; however, there is a higher degree of
cellular and nuclear pleomorphism. Aggregates of histiocytes
are usually cohesive, and proliferating cells extend from the
peribronchial parenchyma into the surrounding alveolar septa
and alveoli, eventually effacing the pulmonary parenchyma
(Fig. 2-222, eFig. 2-63). Ultrastructurally, Birbeck granules,
which represent the internalized cell surface receptor langerin
(CD207) cross-linked by an antibody, have been reported in
the cytoplasm of proliferating histiocytic cells, confirming a
Langerhans cell origin. This is in contrast to canine Langerhans
 246.e1

B
eFigure 2-63  Pulmonary Langerhans cell histiocytosis in a cat.
A. Histiocytic aggregates are cohesive, and proliferating cells oblit-
erate the lumen of a respiratory bronchiole and extend into the
surrounding alveoli and alveolar septa. B. Immunohistochemistry
for CD18 detects the infiltrating Langerhans cells.
 Histiocytic Proliferative Diseases
A supported by the clinical behavior of these lesions, which may
B Nodules range in size up to 4 cm in diameter, and solitary
Figure 2-222  Pulmonary Langerhans cell histiocytosis in a cat.
A. Histiocytic aggregates are cohesive, and proliferating cells oblit-
erate the lumen of a respiratory bronchiole and extend into the
surrounding alveoli and alveolar septa. B. Immunohistochemistry
for CD204 fails to detect the infiltrating Langerhans cells, but
labels intra-alveolar macrophages.
cells, which do not have Birbeck granules. Immunohistochem-
ically, histiocytic cells of feline LCH are positive for CD18
and E-cadherin and negative for CD204 in formalin-fixed
tissues. Frozen tissues of feline LCH have not been studied,
and the number of cat-specific antibodies that can be used to
characterize histiocytic cells is limited.
Canine reactive histiocytosis
Reactive histiocytic diseases have only been reported in dogs.
Two forms have been reported based on their clinical presen-
tations: cutaneous reactive histiocytosis is limited to the skin and
draining lymph nodes; systemic reactive histiocytosis affects the
skin and internal organs. It is important to include the term
“reactive” when discussing these disease entities rather than
abbreviating these diseases as cutaneous and systemic histio-
cytosis. This will help preventing a mix-up with the obsolete
term “malignant histiocytosis.” Malignant histiocytosis has for-
merly been used to characterize disseminated histiocytic sar-
comas (see later) and should be avoided, especially since
systemic reactive histiocytosis and disseminated histiocytic
sarcomas both occur commonly in Bernese Mountain dogs,
but represent entirely different diseases and progression from
247
systemic reactive histiocytosis to histiocytic sarcoma has not
been observed.
Most likely, the cutaneous and systemic forms of reactive
histiocytosis emerge from the same cutaneous lesion and rep-
resent an inflammatory disease caused by immune dysregulation
rather than a neoplastic process. In contrast to cutaneous his-
tiocytomas or Langerhans cell proliferative diseases, the pro-
liferating cells in reactive histiocytosis are activated dermal
interstitial dendritic cells and CD8+ T cells. Regression of the
lesion caused by CD8+ T cells, as observed in cutaneous his-
tiocytomas, does not occur in reactive histiocytosis. Although
the lesions appear to be antigen driven, the antigen itself is
unknown, and the T cell may drive the activation of the den-
dritic cells via tumor necrosis factor -α and granulocyte-
macrophage colony-stimulating factor. This hypothesis is
involve spontaneous remission of early cutaneous lesions and
a positive response to immunomodulatory drugs.
Reactive histiocytosis is a lesion of activated dermal interstitial
dendritic cells that are immunohistochemically positive with
CD1a, CD11c, CD18, and MHC II, as well as CD90 and
CD204. They are negative for E-cadherin. Furthermore, the
proliferating cells express CD4, a marker of dendritic cell
activation that is not expressed in histiocytic sarcomas or
Langerhans cell proliferations. Unfortunately, this antibody is
currently only available for frozen sections.
Cutaneous reactive histiocytosis
Cutaneous histiocytosis is a common disease of dogs that is
limited to the skin and subcutis, but may involve draining
lymph nodes (eFig. 2-64). Dogs clinically have multiple
nodules that are grossly similar to cutaneous histiocytomas.
lesions are rare. Numerous breeds are affected, but no predis-
positions have been reported. The disease affects a broad age
range, and affected areas tend to be roughly similar to those
of cutaneous histiocytoma, with an anterior predilection for
skin of the head and neck as well as for the caudal areas of
flanks, perineum, and the scrotum (Fig. 2-223). Occasionally,
mucus membranes of the nasal and conjunctival areas may be
involved. The blood and bone marrow tend to be unaffected
unless there is ulceration sufficient to cause systemic neutro-
philia. Cutaneous lesions may regress at one site and spontane-
ously appear at another site simultaneously.
Histologically, the cutaneous lesions of reactive histiocyto-
sis, both the cutaneous form and the systemic form, have a
distinct morphologic pattern that allows differentiation from
proliferative Langerhans cell diseases. The skin lesions tend to
be deep and angioinvasive, frequently presenting as a lympho-
histiocytic vasculitis. There is often sparing of the superficial
dermis, with the lesions tending to be “bottom heavy” in con-
trast to the characteristic superficial, “top-heavy” topography
of cutaneous histiocytomas (Fig. 2-224). Commonly, lesions
extend into the subcutis, where they may coalesce. Likely
because of the tendency to surround and invade arterioles,
there are small irregular foci of ischemic necrosis that may
contribute to superficial ulceration. The cellular infiltrates are
dominated by lymphocytes and dermal dendritic cells, but
commonly admixed with neutrophils and eosinophils. Prolif-
erating histiocytic cells have abundant cytoplasm of even
density throughout, and their cell boundaries are indistinct.
Their nuclei tend to be round to oval, but can be twisted,
indented, or folded, and there is a fine chromatin distribution
 247.e1

A B

C D
eFigure 2-64  Reactive histiocytosis in a dog. A. Cutaneous reactive histiocytosis characterized by
large numbers of cutaneous nodules widely disseminated throughout the skin. (Courtesy K. Loft.)
B. Systemic reactive histiocytosis with sharply demarcated nodule on the epiglottis. C. Enlarge-
ment of lymph nodes can be observed in either cutaneous or systemic reactive histiocytosis.
D. Large numbers of nodules in the oral cavity of a dog with systemic reactive histiocytosis.
248 CHAPTER 2  •  Hematopoietic System Histiocytic Proliferative Diseases

A B
Figure 2-223  Cutaneous reactive histiocytosis in a dog. (Courtesy K. Loft.) A. Large numbers of
cutaneous nodules widely disseminated throughout the skin. B. Similar sharply demarcated
nodules in the skin of the lower extremities.

A B

Dermal
vessels

Histiocytic
Subcutis infiltrate

C D
Figure 2-224  Cutaneous reactive histiocytosis in a dog. A. Deep dermal and angioinvasive cellular
infiltrates that are dominated by lymphocytes and dermal dendritic cells extend into the subcutis
where they may coalesce. B. Immunohistochemistry for Thy-1 labels activated dermal interstitial
dendritic cells. C. Schematic drawing depicting the “bottom-heavy” topography of reactive histio-
cytosis in contrast to of the superficial, “top-heavy” topography of cutaneous histiocytomas.
(Adapted from a graphic by P.F. Moore.) D. Proliferating histiocytic cells have abundant cytoplasm,
indistinct cell boundaries, and monomorphic round to oval nuclei that can be twisted, indented,
or folded, but features of anaplasia characteristic for histiocytic sarcoma are absent.
 Histiocytic Proliferative Diseases
and small but prominent central nucleoli. Multinucleated or
highly anaplastic cells as observed in histiocytic sarcomas are
not a feature of reactive histiocytosis. Mitotic figures are
absent or rare, and bizarre forms are lacking. Proliferating
histiocytic cells may be found in draining lymph nodes, where
they selectively invade the sinuses and paracortex.
Cutaneous reactive histiocytosis must be differentiated
from Langerhans cell proliferation (cutaneous histiocytoma
and LCH) and from more aggressive types of histiocytic pro-
liferations (histiocytic sarcomas). The clinical presentation
(multiple vs. solitary lesions), the distinct morphologic pattern
(vasocentric “bottom-heavy” vs. commonly epitheliotropic
“top-heavy”), the cellular morphology (well-differentiated his-
tiocytic cells vs. marked anaplasia), and the immunohisto-
chemical features (positive for CD4 [frozen only] CD90, and
CD204 (eFig. 2-65), but negative for E-cadherin) allow for an
accurate differentiation among these 3 entities (Fig. 2-225).
Another major differential diagnosis for cutaneous reactive
histiocytosis is an inflamed cutaneous non-epitheliotropic
T-cell lymphoma. The large component of CD3+ T-cells in
cutaneous reactive histiocytosis may lead to confusion between
A and renal disease have all been reported. As with the cutane-
B
Figure 2-225  Cutaneous reactive histiocytosis in a dog.
A. Lesions are frequently vasocentric and composed of dense
infiltrates of interstitial dendritic cells admixed with focal small
lymphocytic aggregates. B. Immunohistochemistry demonstrates
expression of CD4 in interstitial dendritic cells, a marker of
dendritic cell activation that is not expressed in histiocytic sarco-
mas or Langerhans cell proliferations.
249
both entities. Clusters of atypical T cell will aid a diagnosis of
lymphoma, but in many cases, a definite diagnosis has to rely
on detection of a clonal T-cell expansion in lymphoma cases
by T-cell receptor γ gene rearrangement.
Systemic reactive histiocytosis
Systemic reactive histiocytosis is a much less common disease
of dogs than cutaneous reactive histiocytosis, and essentially
represents a progression of the cutaneous disease to involve inter-
nal organs. Like its cutaneous counterpart, systemic reactive
histiocytosis is also characterized by cutaneous nodules with
the earlier-described histologic features of a “bottom-heavy”
histiocytic proliferation. Although no breed association has
been established for the cutaneous form, the systemic form
has a familial association in Bernese Mountain dogs. It is
important not to misdiagnose systemic reactive histiocytosis
as a disease process in the histiocytic sarcoma complex, and
there is no evidence of progression of this inflammatory condi-
tion into a malignant neoplasm. Systemic reactive histiocytosis
also has a familial component in Irish Wolfhounds and has
been reported to occur in other large breeds, for instance,
Rottweilers and Labrador Retrievers. Young to middle-aged
dogs are most commonly affected. Skin nodules occur most
frequently around the nose (planum, apex), scrotum, and
eyelids, similar to what has been described for the cutaneous
form. This distribution makes distinction between the cutane-
ous and systemic form very difficult during the early stages of
a systemic reactive histiocytosis. As with the cutaneous form,
ulceration of skin masses is very common and occurs most
likely secondary to vascular lesions that cause infarction, as
described earlier. Besides the skin, nodular masses are often
observed in the ocular and nasal mucous membranes, and
lymph nodes are typically enlarged (Fig. 2-226). Involvement
of internal organs is quite variable, and lesions in the lungs,
liver, spleen, bone marrow, kidney, and testis have been
reported. The wide range of internal organs that can be
affected drives the variation of clinical signs and the degree of
their severity. Weight loss, anorexia, respiratory distress, ocular,
ous form, remission and relapse are also features of systemic
reactive histiocytosis.
Figure 2-226  Systemic reactive histiocytosis in a dog. The
lymph node is infiltrated by large numbers of activated dermal
interstitial dendritic cells that are positive for CD90 by
immunohistochemistry.
 249.e1

B
eFigure 2-65  Cutaneous reactive histiocytosis in a dog.
A. Immunohistochemistry for CD204 labels activated dermal
interstitial dendritic cells. B. These cells are negative for E-
cadherin by immunohistochemistry, thus excluding a cutaneous
histiocytoma.
250 CHAPTER 2  •  Hematopoietic System Histiocytic Proliferative Diseases

Histologically, systemic reactive histiocytosis is also char-

acterized by proliferation of activated dermal interstitial den-
dritic cells that form deep-seated cutaneous mass identical to
those described with the cutaneous form. Lesions in internal
organs are also vasocentric, and the mixture of lymphocytes
and histiocytic cells tends to expand from the perivascular
location into the surrounding parenchyma. The immunohis-
tochemical features of the proliferating histiocytic cells are
identical to those described with cutaneous reactive histiocy-
tosis, but only dermal dendritic cells express CD90. Although
histiocytic sarcoma may be considered as a potential differen-
tial based on lesion distribution, histiocytic sarcomas tend to
form significantly larger nodules, whereas systemic reactive
histiocytosis may only manifest histologically in internal
organs. Regardless, the degree of cellular pleomorphism and
anaplasia observed with histiocytic sarcomas is always absent A
in reactive histiocytosis.

Histiocytic sarcoma
Histiocytic sarcomas are principally neoplasms of interstitial den-
dritic cells. However, one distinct entity, hemophagocytic his-
tiocytic sarcoma, is an aggressive malignant neoplasm of
macrophage origin in dogs. This neoplastic entity causes a
distinct disease syndrome that differs in many aspects from
other histiocytic sarcomas of dendritic cell origin and will
therefore be discussed as a separate entity.
Histiocytic sarcoma is a relatively frequently occurring
aggressive malignant neoplasm primarily of dogs and much
less commonly cats. The disease presentation is essentially the
same in both species. Lesions may be localized arising at a
single site or organ or disseminated after metastasis to distant
sites (eFig. 2-66). It is uncertain whether multiple simultane-
ously occurring neoplasms in different organs represent a mul- B
ticentric disease process or distant metastases of a primary Figure 2-227  Histiocytic sarcoma in a dog. A. Small white
mass. The term “malignant histiocytosis” has historically been nodules, which in some areas almost become confluent, randomly
applied to disseminated histiocytic sarcomas, but should be distributed throughout the spleen. (Courtesy K.G. Thompson.)
avoided to prevent confusion of histiocytic sarcomas with the B. Discrete neoplastic masses that protrude above the splenic
earlier described inflammatory disease processes of reactive capsule (Courtesy R.L. Amorim.)
histiocytosis.
Histiocytic sarcomas may develop at various locations, but
primary masses are commonly observed in the spleen (Fig.
2-227), lymph nodes (Fig. 2-228), lung, bone marrow, skin
(Fig. 2-229), the periarticular tissue of the extremities (eFig.
2-67), and even the central nervous system (CNS) (Fig.
2-230). Periarticular histiocytic sarcomas occur most com-
monly around the stifle and elbow joints, but carpus and
coxofemoral joints can also be affected. Masses in the brain
most commonly occur as focal, solitary, subdural masses, and
occasionally as diffuse meningeal infiltrates (Fig. 2-231, eFig.
2-68). Histiocytic sarcomas typically appear as white/cream
to tan, homogeneous masses with a smooth cut surface, but
diffuse organ enlargement by infiltrating neoplastic histiocytic
cells can also occur. Nodules can be solitary or multiple at the
primary site and tend to be highly destructive. Metastatic sites
can include any organ system, but liver (eFig. 2-69), kidneys
(eFig. 2-70), lungs (Fig. 2-232, eFig. 2-71), and draining lymph
nodes are most commonly affected.
Numerous dog breeds have a familial predisposition,
including Bernese Mountain dogs, Golden Retrievers, Labra-
dor Retrievers, Flat-coated Retrievers, and Rottweilers. Periar-
ticular histiocytic sarcomas have been most commonly Figure 2-228  Histiocytic sarcoma in a dog. Cross section of a
reported in Rottweilers and Flat-coated Retrievers. A poly- white, firm, and homogeneous splenic nodule. (Courtesy S.
genic mode of inheritance has been postulated for Bernese Kesdangsakonwut.)
 250.e1

eFigure 2-67  Periarticular histiocytic sarcoma in a dog. Periar-

ticular histiocytic sarcomas appear as multinodular masses around
joint capsules.

B
eFigure 2-66  Histiocytic sarcoma in a dog. A. Small white
nodules randomly distributed throughout the spleen. B. Discrete
neoplastic masses that protrude above the splenic capsule, but
their color resembles the splenic parenchyma.

A B
eFigure 2-68  Histiocytic sarcoma in a dog. A. Submeningeal infiltrates of distinct large, highly
anaplastic histiocytic cells with abundant eosinophilic cytoplasm. B. Neoplastic cells expand
Virchow-Robin spaces and invade the cerebral cortex.
250.e2

A B
eFigure 2-69  Histiocytic sarcoma in a dog. A. Multifocal, sharply demarcated neoplastic nodules
randomly distributed throughout the liver. B. A discrete neoplastic nodule with less well-defined
borders in the liver. (Courtesy S. Kesdangsakonwut.)

eFigure 2-70  Histiocytic sarcoma in a dog. Well-circumscribed eFigure 2-71  Histiocytic sarcoma in a dog. Numerous pulmonary
neoplastic masses in the renal cortex. vessels are obstructed by large numbers of neoplastic histiocytic
cells that are highly pleomorphic.
 Histiocytic Proliferative Diseases 251

A
Figure 2-229  Histiocytic sarcoma in a dog. Severely ulcerated
discrete and coalescing cutaneous nodules. (Courtesy S.
Kesdangsakonwut.)

Figure 2-230  Histiocytic sarcoma in a dog. Well-circumscribed

mass in the cerebral cortex with central necrosis.

C
Figure 2-232  Histiocytic sarcoma in a dog. A. Numerous peri-
bronchial vessels are obstructed by large numbers of neoplastic
histiocytic cells that are highly pleomorphic. B. Multinucleated
giant cells and neoplastic cells with megalokaryosis infiltrating the
hepatic sinusoids. C. Neoplastic histiocytic cells are positive for
CD18 by immunohistochemistry.

Figure 2-231  Histiocytic sarcoma in a dog. Submeningeal infil-

trates of distinct large, highly anaplastic histiocytic cells with
abundant eosinophilic cytoplasm.
252 CHAPTER 2  •  Hematopoietic System
Figure 2-233  Histiocytic sarcoma in a dog. Lymph node with
diffuse infiltrate of highly anaplastic, large, pleomorphic histio-
cytic cells with abundant eosinophilic, often vacuolated cyto-
plasm. Multinucleated cells, megalokaryosis, and bizarre nuclei are
common.
Mountain dogs, and recent research suggests mutations in
tumor suppressor genes PTEN, CDKN2A/B, and RB1 in his-
tiocytic sarcoma genesis in Bernese Mountain dogs and Flat-
coated Retrievers.
Clinical signs reflect the wide range of organ systems
affected and range from anorexia, weight loss, and lethargy, to
respiratory distress, including coughing and dyspnea; neuro-
logic signs, including seizures and paralysis; and lameness with
periarticular neoplasms. Few cases of histiocytic sarcomas
developed hypercalcemia of malignancy. Neoplastic cells are
rarely encountered in peripheral blood, and only a few cases
of dendritic cell leukemia have been reported. Approximately
30,000 to 60,000 atypical histiocytic cells were observed per
microliter.
Histologically, histiocytic sarcomas are composed of sheets
of distinct large, pleomorphic, often highly anaplastic cells
with abundant amounts of often vacuolated or atypical cyto-
plasm (Fig. 2-233). Multinucleated giant cells are common as
are megalokaryosis and bizarre nuclei. The mitotic index is
usually high, and atypical mitotic figures are easily recogniz-
able. Some histiocytic sarcomas, especially those around peri-
articular and articular tissues and in the subcutis can also have
sheets of spindle cells with no distinct cell margins and an
absence of marked cellular pleomorphism (Fig. 2-234). Such
neoplasms are best differentiated from soft tissue spindle cell
sarcomas by their immunohistochemical staining pattern.
Periarticular histiocytic sarcomas commonly have a micronod-
ular growth pattern and are located beneath the intact syno-
vial lining. Secondary inflammatory infiltrates composed of
neutrophils and lymphocytes as well as plasma cells are
common in histiocytic sarcomas around joints and in the skin
and may obscure the primary neoplastic cell population. Large
numbers of mixed inflammatory cells are also commonly
observed in histiocytic sarcomas in the CNS, and lesions must
be differentiated from granulomatous meningoencephalitis.
Histiocytic sarcomas originate primarily in the leptomeninges,
and atypical histiocytic cells can be observed.
Immunohistochemically, histiocytic sarcomas are uni-
formly strongly positive for CD18, CD204, and MHC II, and
Histiocytic Proliferative Diseases
A
B
Figure 2-234  Periarticular histiocytic sarcoma in a dog. A. Some
histiocytic sarcomas occur in the periarticular and articular tissues
around appendicular joints. B. Periarticular histiocytic sarcomas
are often composed of sheets of spindle cells with no distinct cell
margins and an absence of marked cellular pleomorphism.
variably positive for Cd163 in formalin-fixed tissues, and in
frozen sections they are positive for CD1 and CD11c. They
are negative for CD4 and E-cadherin. Only cutaneous histio-
cytic sarcomas express CD90. Periarticular histiocytic sarco-
mas also express the typical interstitial dendritic cell
phenotype, and are CD1a and CD11c positive rather than
CD1a negative and CD11b positive, which would be consis-
tent with synovial type A cells.
Histiocytic sarcoma may occur as solitary or multiple pro-
liferations that are all characterized by very rapid progression
and metastatic spread. Only histiocytic sarcomas in the brain
have not been shown to cause extracranial metastasis, whereas
metastases to the brain are not uncommon. Early surgical
excision of cutaneous or periarticular histiocytic sarcomas
might be potentially curative, but widespread metastasis
occurs early in the course of disease and average survival times
are 5-8 months. Therefore the overall prognosis is grave and
response to chemotherapy usually poor. Recent studies suggest
that histiocytic sarcomas may respond to some tyrosine kinase
inhibitors, for instance, dasatinib. Rupture of the cranial cruci-
ate ligament or traumatic joint injury has been reported as a
sequel to periarticular histiocytic sarcoma.
 Histiocytic Proliferative Diseases 253

Histiocytic sarcoma must be differentiated from reactive

histiocytosis, which is usually accomplished on the basis of the
extent of the lesion and the high degree of anaplasia of the
neoplastic cell population in histiocytic sarcomas. Hemo-
phagocytic histiocytic sarcomas are characterized by erythro-
phagia and express CD11d in formalin-fixed tissues, but not
CD11c in frozen sections. Depending on the primary site of
the histiocytic sarcoma, other differentials include nonlym-
phogenic, non-angiogenic sarcomas in the spleen and synovial
sarcomas or other soft tissue spindle cell sarcomas in periar-
ticular tissue or skin and subcutis, respectively. Historically,
most intra-articular and periarticular sarcomas have been diag-
nosed as synovial sarcomas, but immunohistochemical staining
with CD18 confirmed that the vast majority of these neoplasms
are periarticular histiocytic sarcomas. Immunohistochemistry
(IHC) with CD18 and CD204 is usually sufficient to accu-
rately diagnose histiocytic sarcomas. However, especially syno-
vial sarcomas or soft tissue spindle cell sarcomas can be heavily Figure 2-235  Feline progressive histiocytosis. Alopecic nodules
infiltrated by CD18-positive histiocytic cells and may closely with focal ulcerations on the face of a cat.
resemble histiocytic sarcomas on low magnification. It is
important to closely examine these neoplasms on higher mag-
nification because a population of CD18-negative spindle cells
will be recognizable in nonhistiocytic sarcomas. In our experi-
ence, CD204 often provides a more distinct differentiation
between histiocytic and nonhistiocytic cells. Another soft
tissue spindle cell sarcoma that is characterized by large
numbers of multinucleated giant cells is actually not a neo-
plasm of histiocytic cell lineage, but has been mislabeled as
“malignant fibrous histiocytoma.” The neoplastic cells of this
particular entity most likely represent myofibroblasts that are
negative for CD18 and CD204. Because lymphomas may
express CD18, especially subcutaneous histiocytic sarcomas
should be differentiated from anaplastic large cell lymphomas
by staining for T- and B-cell markers CD3, CD79a, CD20, and
Pax-5.

Feline progressive histiocytosis

Feline progressive histiocytosis (FPH) is a disease of mature
cats 7-17 years of age, with most animals older than 10 years
at presentation. There is no apparent breed predilection, but
female cats tend to be affected more than male. Lesions
develop most commonly on the head, including the face (eFig.
2-72), nose, eyelids, lips, and ears, as well as around the legs
and feet, and with lesser frequency in other areas of the skin
(Fig. 2-235). The disease is initially indolent and may persist
in the skin for prolonged periods before there is involvement
of internal organs, including lymph nodes, lungs, liver, kidney,
and spleen. First signs of FPH most commonly consist of soli-
tary or multiple nodules, plaques, or papules that are neither
painful nor pruritic. Nodules may be up to 1.5 cm in diameter.
During these early disease stages, cats are not irritated by the
lesions and appear to be in good health. As the disease pro-
gresses, the cutaneous lesions tend to coalesce and eventually
to ulcerate. Although some lesions wax and wane, complete
regression as observed with canine cutaneous histiocytomas is not
a feature of FPH. As the disease becomes more invasive, no
treatment appears to be effective, and the animals are eutha-
nized when they develop systemic illness.
In essence, FPH resembles a low-grade histiocytic sarcoma
originating from cutaneous interstitial dendritic cells. Histologi-
cally, the early cutaneous lesions bear some resemblance to
canine cutaneous histiocytomas and are characterized by
nodular to diffuse histiocytic infiltrates in the superficial
Figure 2-236  Feline progressive histiocytosis. Nodular histio-
cytic infiltrate in the superficial portion of the dermis that is
in contact with the basement membrane and causes focal
epitheliotropism.
portion of the dermis (Fig. 2-236). Most infiltrates are in
contact with the basement membrane that is irregularly
breached (epitheliotropism) in ~40% of cases. Some masses
extend into the subcutis (eFig. 2-73). During the initial phase
of FPH, infiltrating histiocytes are well differentiated and
closely resemble inflammatory cells. Special stains for intracel-
lular bacteria, including mycobacteria, and macerated tissue
culture are recommended to exclude an infectious disease
process. As the disease progresses, the degree of anisokaryosis
increases, and the lesion more closely resembles canine histio-
cytic sarcomas (Fig. 2-237). At this stage, neoplastic cells have
irregular, euchromatic nuclei with finely dispersed chromatin
and typically a single moderate-sized central nucleolus. The
cytoplasm is abundant and deeply and uniformly stained, with
cell boundaries generally distinct. More multinucleated cells
are present as is megalokaryosis and a few bizarre nuclei. The
mitotic index varies, and atypical mitotic figures may be
present. The extent of inflammatory cell infiltrates composed
of small lymphocytes and neutrophils varies between indi-
vidual cases. Immunohistochemically, histiocytic cells of FPH
 253.e1

eFigure 2-72  Feline progressive histiocytosis. Alopecic nodules eFigure 2-73  Feline progressive histiocytosis. Deep histiocytic
with focal ulcerations on the face of a cat. infiltrates into the underlying muscle occur during disease
progression.
254 CHAPTER 2  •  Hematopoietic System
Figure 2-237  Feline progressive histiocytosis. As lesions progress,
cellular pleomorphism, nuclear anisokaryosis, and mitotic activity
increase.
have a characteristic interstitial dendritic cell phenotype, and are
positive for CD1a, CD18, and MHC II. Interestingly, some of
the cases express E-cadherin at an earlier disease stage, which
would indicate a Langerhans cell differentiation. About half
the cases in one study expressed CD5. Antibodies specific for
feline CD molecules are limited, and only an antibody specific
for feline CD18 is available for formalin-fixed tissue. The
canine-specific CD18 will not cross react with feline dendritic
cells. The infiltrating lymphocytes are CD3 and CD8 positive.
The location of the lesions, the progression of the disease
process and the cell morphology at the different stage of FPH
in combination with positive IHC for CD18 are used to reach
an accurate diagnosis. Although inflammatory lesions must be
excluded at an early stage of the disease, an atypical large cell
lymphoma should be excluded at late stage by using IHC for
CD3, CD79a, CD20, and Pax-5.
Hemophagocytic histiocytic sarcoma
Hemophagocytic histiocytic sarcoma is the only malignancy of
macrophage origin and occurs primarily in dogs; a few cases have
been reported in cats. There is no known breed or age predis-
position, but commonly affected breeds are similar to those
affected by histiocytic sarcoma of dendritic cell origin. It is
therefore important to recognize that hemophagocytic histio-
cytic sarcoma may occur simultaneously to histiocytic sarcoma,
especially in breeds with a predisposition for the latter disease.
Hemophagocytic histiocytic sarcoma has a unique clinical
picture that differs from that caused by other histiocytic sar-
comas and most closely resembles an immune-mediated hemo-
lytic anemia, or, more specifically, Evans syndrome because
there is concurrent thrombocytopenia. Affected dogs have
splenomegaly and hepatomegaly (Fig. 2-238, eFig. 2-74) and
rapidly progressive, regenerative hemolytic anemia and throm-
bocytopenia, but are Coombs test negative (no erythrocyte-
bound IgG). The pathogenesis of the disease is the result of
the massive level of erythrophagocytosis by the neoplastic histio-
cytes that are primarily located in the spleen, liver, and bone
marrow. Many dogs are icteric at initial presentation and have
marked hyperbilirubinemia. Hypoalbuminemia and hypocho-
lesterolemia are also commonly observed. Because dogs with
hemophagocytic histiocytic sarcomas lack grossly visible
Histiocytic Proliferative Diseases
Figure 2-238  Hemophagocytic histiocytic sarcoma in a dog.
Diffuse splenomegaly with ill-demarcated neoplastic nodules pro-
truding over the splenic capsule.
masses, a neoplasm is often considered less likely as the
primary cause than an immune-mediated disease, and the
ultimate diagnosis is often made through autopsy and histo-
logic examination of the spleen and liver. Adding the poor
response of hemophagocytic histiocytic sarcomas to standard
chemotherapy to the difficulties in reaching an accurate diag-
nosis may help to explain reported median survival times of
<30 days.
Hemophagocytic histiocytic sarcomas are caused by prolif-
eration of neoplastic macrophages that are avidly erythrophago-
cytic (Fig. 2-239). Primary sites are the spleen and the bone
marrow with secondary spread to lung and liver and rarely
kidneys (eFig. 2-75). Grossly, the spleen is markedly diffusely
enlarged with few to many, discolored green-tan to white
splenic infarcts that are visible through the splenic capsule. In
cats, the involvement of the liver may be of solid foci of neo-
plastic cells.
Microscopically, in the spleen, neoplastic cells differentiate
toward red pulp macrophages and cause locally extensive to
diffuse expansion of the red pulp sinuses and frequently oblit-
erate the adjacent white pulp. Focal areas of ischemic necrosis
secondary to vascular thrombosis are common in the splenic
sinuses. Most cases are accompanied paradoxically by inter-
spersed foci of extramedullary hematopoiesis. The neoplastic
histiocytes migrate to the lung and liver, where they insidi-
ously invade hepatic sinusoids. In the lungs, hemophagocytic
neoplastic cells are found primarily in the vasculature. The
bone marrow is also infiltrated by neoplastic hemophagocytic
histiocytes. Most neoplastic cells are severely hemophagocytic
or contain hemosiderin, but it is common to find areas in the
spleen where cells exhibit less erythrophagocytosis. Some neo-
plastic cells may also phagocytose red cell precursors and
granulocytes. Although some atypia of the neoplastic cells is
common, especially in the spleen, in contrast to the highly
pleomorphic cells in histiocytic sarcomas of interstitial den-
dritic cell origin, neoplastic cells of macrophage origin in hemo-
phagocytic histiocytic sarcomas are surprisingly well differentiated.
Especially within the bone marrow, but also liver and lung,
neoplastic cells closely resemble their normal counterpart
except for erythrophagocytosis. In the spleen, occasional
anisocytosis, anisokaryosis, and hyperchromatic nuclei are
 254.e1

eFigure 2-74  Hemophagocytic histiocytic sarcoma in a dog. eFigure 2-75  Hemophagocytic histiocytic sarcoma in a dog. In
Diffuse splenomegaly with ill-demarcated neoplastic nodules pro- the spleen, there is proliferation of neoplastic macrophages that
truding over the splenic capsule. are avidly erythrophagocytic.
 Disorders of Hemostasis
A Valli VE. Histiocytic Neoplasms. Veterinary Comparative Hematopathol-
B designed to ensure that blood clotting is tightly regulated,
Figure 2-239  Hemophagocytic histiocytic sarcoma in a dog.
A. In the spleen, there is proliferation of neoplastic macrophages
that are avidly erythrophagocytic. B. Neoplastic splenic macro-
phages are CD11d positive by immunohistochemistry.
observed, as well as a few multinucleated giant cells. The
abundant cytoplasm is eosinophilic and often vacuolated.
Nuclei are most frequently ovoid or cleaved, and bizarre forms
are rare. The mitotic index is low. Because neoplastic cells
appear well differentiated, the early pattern of invasion into
the liver may be misdiagnosed on fine-needle biopsies as
Kupffer cell hyperplasia or an inflammatory process. IHC has
been helpful for characterizing the distribution of neoplastic
cells in the spleen and liver.
Immunohistochemically, the neoplastic hemophagocytic
histiocytes most closely resemble macrophages of the splenic
red pulp and bone marrow, are positive for CD11d and CD18,
and have variable expression of CD1a, but are negative for
CD11c, which is positive in interstitial dendritic cells. Although
antibodies for canine CD11d are available for formalin-fixed
tissues, there is no feline counterpart and definite confirmation
of hemophagocytic histiocytic sarcomas in cats is still missing.
Further reading
Affolter VK, Moore PF. Localized and disseminated histiocytic sarcoma
of dendritic cell origin in dogs. Vet Pathol 2002;39:74-83.
Affolter VK, Moore PF. Feline progressive histiocytosis. Vet Pathol
2006;43:646-655.
255
Busch MD, et al. Feline pulmonary Langerhans cell histiocytosis with
multiorgan involvement. Vet Pathol 2008;45:816-824.
Friedrichs KR, Young KM. Histiocytic sarcoma of macrophage origin in
a cat: case report with a literature review of feline histiocytic malig-
nancies and comparison with canine hemophagocytic histiocytic
sarcoma. Vet Clin Pathol 2008;37:121-128.
Fulmer AK, Mauldin GE. Canine histiocytic neoplasia: an overview. Can
Vet J 2007;48:1041-1043, 1046-1050.
Moore PF. A review of histiocytic diseases of dogs and cats. Vet Pathol
2014;51:167-184.
Moore PF, et al. Canine hemophagocytic histiocytic sarcoma: a prolif-
erative disorder of CD11d+ macrophages. Vet Pathol 2006;43:
632-645.
Moore PF, Rosin A. Malignant histiocytosis of Bernese Mountain dogs.
Vet Pathol 2006;23:1-10.
ogy. Ames, Iowa: Blackwell; 2007. p. 505-524.
DISORDERS OF HEMOSTASIS
R. Darren Wood
Hemostasis is the process by which interactions between a
series of plasma proteins and cells, including platelets, endo-
thelial, and white blood cells, combine to provide a balance
between anticoagulant and procoagulant functions. It is essen-
tially a host defense mechanism that protects the integrity of
the vascular system after injury. In recent years, the impor-
tance of activated cell membranes to the hemostatic process
has become well understood, and the entire process is now
frequently referred to as the cell-based model of hemostasis.
During health, anticoagulant mechanisms, which are
predominate. When injury to, or activation of, endothelium
occurs, procoagulant proteins are released from these cells,
and circulating platelets and plasma proteins become exposed
to subendothelial tissues, including collagen and fibroblasts.
This promotes a tipping of the balance toward procoagulation,
where platelet-mediated hemostasis initially stems the loss of
blood at the site of the vascular injury via formation of a
platelet plug. Once sufficient platelet activation occurs, initial
thrombin production activates additional platelets, promotes
the conversion of fibrinogen to fibrin, provides positive feedback
amplification to produce more fibrin, and stimulates antico-
agulants and the fibrinolytic system to regulate overall clot
formation. Thrombin has additional roles in cell proliferation,
inflammation, and repair that are mediated through its ability
to engage protease-activated receptors (PARs) on target cells
(Fig. 2-240).
During disease, there are many possible derangements that
can occur, depending on the nature of the abnormality, and
whether it remains localized or becomes disseminated sys-
temically. As a result, disorders of the hemostatic system can
range from poorly detectable but significant pathology, to
overt and potentially catastrophic hemorrhage and/or throm-
bosis. A brief review of important physiology, pathophysiol-
ogy, and disorders follows.
Platelet plug formation
When endothelial cells are injured, or exposed to inflamma-
tory mediators, the cell membrane changes from expressing
an anticoagulant phenotype to one more procoagulant in
nature. The expression of platelet surface receptors that interact
 255.e1

Further reading
Hélie P, et al. Congenital cutaneous histiocytosis in a piglet. Vet Pathol
2013;51:812-815.
Ide K, et al. Disseminated histiocytic sarcoma with excessive hemo-
phagocytosis in a cat. J Vet Med Sci 2009;71:817-820.
Kato Y, et al. The class A macrophage scavenger receptor CD204 is a
useful immunohistochemical marker of canine histiocytic sarcoma.
J Comp Pathol 2013;148:188-196.
Moore PF, et al. Canine cutaneous histiocytoma is an epidermotropic
Langerhans cell histiocytosis that expresses CD1 and specific beta
2-integrin molecules. Am J Pathol 1996;148:1699-1708.
Pinard J, et al. Histiocytic sarcoma in the tarsus of a cat. Vet Pathol
2006;43:1014-1017.
Weiss DJ. Flow cytometric evaluation of hemophagocytic disorders in
canine bone marrow. Vet Clin Pathol 2002;31:36.
256 CHAPTER 2  •  Hematopoietic System
Platelet aggregation
Procoagulant
Inflammation
Kallikrein/bradykinin
THROMBIN
PAF synthesis
Neutrophil activation
Anticoagulation
Activation of
TM–protein
TM – protein C–protein
C – proteinSS
Figure 2-240  Multiple functions of thrombin that include modulation of coagulation, anticoagula-
tion, inflammation, and tissue repair. PAF, platelet activating factor; TM, thrombomodulin.
with von Willebrand factor (vWF) released from endothelial
cells, initiates platelet adhesion, aggregation, and granule
content release at the site of vascular injury. Simultaneously,
tissue factor and procoagulant platelet phospholipids become
available on cell surfaces to initiate thrombin, and then fibrin,
formation.
Adhesion
Platelets are derived from megakaryocytes and circulate as
small discoid cells in an unactivated state. When activated,
they undergo a shape change, becoming more spherical and
with extensions, which is mediated by actin and myosin fila-
ments in the cytoplasm. This is accompanied by alterations in
the cell membrane conformation that activates platelet mem-
brane glycoprotein (GP), or integrin, receptors. These receptors
mediate platelet adhesion to exposed tissue that then pro-
motes further recruitment and adhesion of additional
platelets.
The 2 main proteins required for adhesion of platelets to
each other and to damaged endothelial cells and exposed
fibroblasts are fibrinogen and vWF. Glycoprotein Ib-IX-V is a
constitutively active receptor that causes rapid platelet adhe-
sion to exposed vWF. This receptor is important in blood
vessels with high shear forces because it facilitates stabiliza-
tion of platelet aggregates. The most abundant platelet integrin,
αIIbβIII (or GPIIb/IIIa), undergoes a conformational change
during platelet activation to bind fibrinogen, and to a lesser
extent vWF. This receptor is also expressed in the open cana-
licular system, a feature of most mammalian platelets, which
expands the platelet surface area once shape change occurs.
When fibrinogen binds to αIIbβIII, it connects adjacent plate-
lets, which is critical for the development of platelet
aggregates.
Platelets possess specific membrane thrombin receptors.
These receptors are members of the G-protein–coupled
receptor family that are characterized by a single polypeptide
with a 7-transmembrane domain. Thrombin receptors are
referred to as PARs, because the receptors only acquire trans-
membrane signaling functions after thrombin has cleaved
a peptide from the extracellular domain. Although there
Disorders of Hemostasis
Fibrin formation
Tissue repair
Release of
growth factors
Activation of
fibrinolysis
are others, thrombin is considered the most potent platelet
agonist.
Aggregation
Further recruitment of circulating platelets and their incorpo-
ration into developing platelet aggregates around the site of
already adherent platelets depends on the local accumulation
of platelet agonists and the generation of procoagulant activity
provided by integrin and phospholipid exposure on the surface
of activated platelets. Local agonists include adenosine diphos-
phate (ADP), serotonin, and epinephrine, which are pre-
formed in platelet-dense granules, and newly synthesized
agonists, such as platelet-activating factor (PAF) and thrombox-
ane A2 (TxA2). These agonists interact with their own
G-coupled protein receptors to initiate inside-out signaling.
The activator-receptor interactions increase the avidity of the
glycoprotein-integrin receptors for their ligands and addition-
ally initiate intracellular downstream signaling via several
pathways involving the activation of phospholipases, protein
kinase K (PKC), and adenylate cyclase.
Platelets are maintained in an unactivated state by
regulation of cytoplasmic levels of calcium and cyclic AMP
(cAMP). Upon activation, phospholipase C–mediated hydro-
lysis of the membrane phospholipid phosphatidylinositol-4,5-
bisphosphate (PIP2), results in the release of 2 secondary
messengers, inositol-1,4,5-triphosphate (IP3) and diacylglyc-
erol (DAG); phospholipase A2 hydrolyses phosphatidylcho-
line to PAF and the TxA2 precursor, arachidonic acid.
Intracellular IP3 directly induces calcium release from storage
pools in dense granules; DAG indirectly induces the same
response through activation of PKC. An increase in free cyto-
plasmic calcium, with concurrent reduction in intracellular
cAMP, is a universal response among mammalian platelets and
explains why drugs that function as calcium channel blockers
impact platelet aggregation. Nonsteroidal anti-inflammatory
drugs such as aspirin, which inhibit reactivity of cyclooxygen-
ase enzyme (COX-1), do not interfere with the aggregation
response in platelets from those species, for instance, cow, rat,
and some dogs, that are relatively insensitive to TxA2 as an
agonist.
 Disorders of Hemostasis 257

Vascular Tissue
damage repair Vessel wall
Endothelium
Vascular lumen
TF
FVII PL
FVIIa FIX FIXa FIX
FVIIIa FVIII PDGF
TF-FVIIa Ca2+ EGF

PL
FX FXa FX
Secretion
FVa FV
Ca2+

Prothrombin Thrombin Platelet activation

Fibrinogen Fibrin
(soluble) Adhesion
FXIII FXIIIa
Fibrin Aggregation
(insoluble)

Thrombus formation

Figure 2-241  The tissue factor (extrinsic) pathway that leads to thrombin generation and platelet
activation following vascular damage. The oval structures represent activated phospholipid-
expressing cells. EGF, epidermal growth factor; PDGF, platelet-derived growth factor; PL, phos-
pholipid; TF, tissue factor.

Platelets are additionally essential for endothelial repair
and eventual clot retraction. During aggregation, mediators
such as platelet-derived growth factor (PDGF) and epidermal
growth factor (EGF) are released from α-granules (Fig. 2-241).
Platelet cytoskeleton proteins actin and myosin, in the presence
of increased cytoplasmic calcium, interact in a manner similar
to that in myocytes. The activation of these contractile pro-
teins results in the shrinkage of the platelet–fibrin meshwork,
which results in contraction of the clot. In conjunction with
fibrinolysis, the fibrin clot is eventually removed when repair
is complete.
Further reading
Boudreaux MK. Platelet structure. In: Weiss DJ, Wardrop KJ, editors.
Schalm’s Veterinary Hematology. 6th ed. Ames, Iowa: Wiley-
Blackwell; 2010. p. 561-568.
Boudreaux MK, Catalfamo JL. Platelet biochemistry, signal transduc-
tion, and function. In: Weiss DJ, Wardrop KJ, editors. Schalm’s
Veterinary Hematology. 6th ed. Ames, Iowa: Wiley-Blackwell; 2010.
p. 569-575.
Goggs R, Poole AW. Platelet signaling—a primer. J Vet Emerg Crit Care
2012;221:5-29.
Platelet disorders
Bleeding associated with decreased numbers of functional
platelets is characterized by petechial and ecchymotic hemor-
rhages, which form small pinpoint to coalescing endothelial
lesions in mucous membranes and capillary beds. Epistaxis,
melena, hematuria, and cutaneous bruising can also be
observed. This type of bleeding is not observed in coagulation
disorders involving predominantly thrombin and fibrin gen-
eration because platelet adhesion and aggregation responses
are adequate to seal small lesions in vessels low blood pressure.
For larger wounds, and in vessels with higher blood pressure,
hemostasis requires fully functional platelet aggregation and
fibrin formation so that a stable thrombus can form. Platelet
function disorders associated with prolonged bleeding times,
and normal platelet counts and coagulation profiles, may be
the result of defects in platelet adhesion, aggregation, or
granule release.
Evaluation of platelet function
Platelet concentration is assessed with an automated platelet
count and blood smear examination, typically performed as
part of a complete blood count (CBC). However, enumeration
alone is not sufficient to explain all platelet-related bleeding
disorders, because functional defects can occur despite adequate
numbers.
Platelet function tests are best reserved for patients with
normal platelet concentration, but clinical signs supportive of
a platelet disorder. The buccal mucosal bleeding time (BMBT)
is the time for bleeding to stop after a standardized cut is
made with a commercial spring-loaded device in the mucosal
surface of the upper lip. The BMBT is prolonged when there
is decreased concentration and/or dysfunction of platelets, or
if there is reduced activity of adhesive proteins, such as vWF.
This is a simple and inexpensive test, but difficult to standard-
ize because of inter-operator and animal variability.
The gold standard for assessment of platelet function is the
platelet aggregation test. The ability of platelets to aggregate in
response to in vitro stimulation with various agonists can be
determined in citrated whole blood (impedance) or
258 CHAPTER 2  •  Hematopoietic System
platelet-rich plasma (light transmission), but because this
requires specialized instrumentation and timely evaluation, its
usefulness tends to be limited to research laboratories.
The Platelet Function Analyzer (PFA) 100 and 200 models
provide a benchtop point-of-care alternative to the BMBT, but
tend to be only available in larger referral centers. Similarly,
platelet function can be assessed using viscoelastic technology,
such as thromboelastography (TEG), although the contribution
of platelets to the overall tracing can be difficult to easily
discern and may be compensated for by other components of
hemostasis in this in vitro setting.
Thrombocytopenia
In the absence of any other underlying coagulopathy or plate-
let dysfunction, petechial hemorrhages are usually not
observed in animals unless the platelet count falls below
25-30 × 109/L. In healthy animals, ~30-40% of the total plate-
let pool is sequestered in the spleen, so apparent thrombocy-
topenia may be observed when conditions causing splenomegaly
occur, by resulting in an increase in the splenic platelet pool.
However, because overall platelet mass is not decreased, clini-
cal signs should not occur in this situation.
Inherited thrombocytopenia has been reported in Cavalier
King Charles Spaniels. In this breed, the autosomal recessive
trait in β1-tubulin is asymptomatic, and is characterized by
fewer, but larger, platelets (macrothrombocytopenia). No bleed-
ing occurs because the cells, although decreased in number,
have increased volume. Overall platelet mass is maintained.
Other breeds, including Norfolk Terriers, may have a similar
defect. May-Hegglin anomaly is another disorder that may
result in macrothrombocytopenia. A single Pug dog was
reported to have neutrophil inclusions and large platelets
typical of those observed in people. The lesion is the result of
a mutation in the MYH-9 gene encoding nonmuscle myosin
heavy-chain IIA.
Acquired thrombocytopenia is one of the most commonly
recognized hematologic disorders. Thrombocytopenia associ-
ated with decreased platelet production in the bone marrow
may be the result of megakaryocyte hypoplasia for various
reasons. However, thrombocytopenia can also occur because
of decreased platelet survival in peripheral blood that can be
immune-mediated, infectious agent–mediated, or drug-
mediated. If mean platelet volume (MPV) is increased in a
thrombocytopenic animal, and is not associated with a breed-
associated defect, then active thrombopoiesis is suggested, and
a bone marrow disorder is less likely.
Immune-mediated thrombocytopenia (ITP) has been reported
in many breeds of dogs and in both young and old animals,
but may be over-represented in middle-aged females. Primary
idiopathic, or autoimmune thrombocytopenia, is caused by the
development of autoantibodies without an apparent underly-
ing disease, and may be the result of a loss of immune system
tolerance for platelet antigens. Dogs develop severe thrombo-
cytopenia and variable anemia, because of hemorrhage. There
is currently no specific diagnostic test for ITP, and it continues
to be one of exclusion of other causes.
Neonatal alloimmune thrombocytopenia has been reported
in pigs and horses. In pigs, the disorder usually occurs after 2
or more pregnancies. Piglets are frequently born healthy but
develop thrombocytopenia by 1 week of age. Diagnosis of the
disorder is one of exclusion, sepsis being the usual differential,
because infections are the most common cause of thrombo-
cytopenia in this species.
Disorders of Hemostasis
Secondary immune-mediated thrombocytopenia can be
caused by antiplatelet antibodies or may be the result of anti-
body binding to non–self-antigens that become absorbed onto
platelet membranes. These antibodies are produced in response
to infectious agents, drug exposure, or neoplasia. For example,
many rickettsial agents are associated with thrombocytopenia,
and development of petechiae and ecchymoses can occur in
dogs with these infections. Thrombocytopenia associated with
systemic lupus erythematosus (SLE) has been reported in
dogs, cats, and horses. Thrombocytopenia may accompany
immune-mediated hemolytic anemia in dogs for a few reasons,
but it is suspected some dogs have concurrent immune-
mediated platelet destruction.
Drug-induced thrombocytopenia occurs when administration
of medications either suppresses platelet production in the
bone marrow, or increases the rate of platelet destruction as
a consequence of drug-dependent antibodies that bind to
complementary antigenic sites on platelet membranes. Mac-
rophages in the liver and spleen recognize, engage, and remove
these altered platelets, resulting in thrombocytopenia.
Further reading
Botsch V, et al. Retrospective study of 871 dogs with thrombocytope-
nia. Vet Rec 2009;164:647-651.
Christopherson PW, et al. Evaluation and clinical application of platelet
function testing in small animal practice. Vet Clin North Am Small
Anim Pract 2012;42:173-188.
Gelain ME, et al. A novel point mutation in the (1-tubulin gene in
asymptomatic macrothrombocytopenic Norfolk and Cairn Terriers.
Vet Clin Pathol 2014;43:317-321.
Scott MA, Jutkowitz LA. Immune-mediated thrombocytopenia. In:
Weiss DJ, Wardrop KJ, editors. Schalm’s Veterinary Hematology. 6th
ed. Ames: Wiley-Blackwell; 2010. p. 586-595.
von Willebrand disease
von Willebrand disease (vWD) occurs because of a deficiency or
functional variation in von Willebrand factor (vWF). Considered
an extrinsic platelet disorder, bleeding in vWD is the result of
failure of platelets to adhere and form aggregates at sites of
vascular injury. Although rare in cats, horses, and cattle, vWD
is the most common inherited bleeding disorder in dogs. It occurs
in many breeds, with highest prevalence in Doberman Pin-
schers. In dogs, as in people, it is a heterogeneous group of
disorders that are classified into 3 types on the basis of severity
of bleeding, mode of inheritance, and specific abnormalities of
the vWF protein. The vWF protein is primarily synthesized in
endothelial cells as 2 subunits that subsequently undergo post-
translational assembly into dimers and multimers ranging up
to 100 vWF subunits that are stored in and subsequently
released from Weibel-Palade bodies in endothelial cells. The
larger-molecular-weight multimers are most effective in pro-
moting platelet adhesion.
The release of vWF following endothelial cell stimulation
occurs with a variety of compounds, such as thrombin, hista-
mine, estrogen, thyroxine, and the vasopressin analogue
1-desamino-8-D-arginine vasopressin (DDAVP). Strenuous
exercise also induces an increase in plasma vWF activity. In
some species, such as humans and cats, platelets act as an
additional pool of circulating vWF because they contain
megakaryocyte-derived vWF in their α-granules. However,
canine platelets contain only very small amounts of vWF.
 258.e1

Further reading
Herring J, McMichael M. Diagnostic approach to small animal bleeding
disorders. Top Compan Anim Med 2012;27:73-80.
Pedersen HD, et al. Idiopathic asymptomatic thrombocytopenia in
Cavalier King Charles Spaniels is an autosomal recessive trait. J Vet
Intern Med 2002;16:169-173.
 Disorders of Hemostasis
Plasma vWF circulates in a noncovalent complex with clotting
factor VIII (FVIII), which stabilizes and prolongs the circulat-
ing half-life of FVIII.
Type 1 vWD, which is characterized by decreased activity
of vWF antigen and a proportional decrease in all multimeric
forms, is transmitted in an incompletely dominant pattern. In
contrast, the more clinically severe forms of vWD, types 2 and
3, are recessive traits. In type 3, plasma vWF is virtually absent,
whereas in type 2, high-molecular-weight multimers are dis-
proportionately decreased, and plasma vWF antigen activity
is reduced. In all forms of the disease, bleeding may be exac-
erbated by concurrent thrombocytopenia or administration of
drugs, such as nonsteroidal anti-inflammatory drugs, which
impair platelet function.
Acquired vWD has been reported as a result of increased
degradation of multimers by the enzyme ADAMTS13 (a dis-
integin and metalloproteinase with thrombospondin repeats),
primarily in high-shear conditions, such as those induced with
cardiac valve disease. In ponies, administration of hydroxyeth-
ylene starch solutions as blood volume expanders can also
induce a transient decrease in circulating vWF levels. Tetra-
starch administration in dogs with systemic inflammation
induced a similar effect.
Prolonged BMBT accompanied by a normal platelet count,
and coagulation profile is suggestive of vWD. A prolonged
closure time with the PFA analyzer is also a supportive, but
not specific, result. Diagnosis can only be confirmed by specific
assay of plasma vWF antigen activity by ELISA. A collagen-
binding assay is also available at specialty laboratories to assist
in confirmation of the functional defect that occurs in type 2
vWD. Because vWF is antigenically distinct among mamma-
lian species, plasma samples must be analyzed with appropri-
ate reagents. Molecular testing for vWF based on known
mutations is available for some breeds of dogs.
Further reading
Brooks MB, Catalfamo JL. von Willebrand disease. In: Weiss DJ,
Wardrop KJ, editors. Schalm’s Veterinary Hematology. 6th ed.
Ames, Iowa: Wiley-Blackwell; 2010. p. 612-618.
Burgess HJ, et al. Evaluation of laboratory methods to improve char-
acterization of dogs with von Willebrand disease. Can J Vet Res
2009;73:252-259.
Lozier JN, Nichols TC. Animal models of hemophilia and related bleed-
ing disorders. Semin Hematol 2013;50:175-184.
Intrinsic disorders of platelet function
Inherited intrinsic platelet function disorders are relatively
rare in domestic animals, but have been identified in several
breeds of dogs, horses, and in cattle. Four types of platelet
dysfunction are recognized: disorders of platelet membrane gly-
coproteins, storage pool deficiencies, impairment of intracellular
signaling, and defective platelet procoagulant activity. All appear
to be inherited as autosomal traits. Because each results in
platelet dysfunction, clinical signs are similar among the
defects and cause mucosal bleeding and can be more diffuse
than the petechial hemorrhages observed with thrombocyto-
penia alone. Gingival hemorrhage can occur during shedding
of deciduous teeth in puppies. Epistaxis, cutaneous ecchymo-
ses, hematuria, and prolonged or excessive bleeding at sites of
surgery or trauma are common in adult dogs. In horses and
259
cattle, subcutaneous hematomas and prolonged hemorrhage
from puncture wounds, such as vaccination, ear tagging, and
insect bites, are typically encountered.
Glanzmann thrombasthenia has been documented predom-
inantly in the Otterhound and Great Pyrenees dog breeds,
with a few isolated cases reported in horses. The disorder is
characterized by a decrease in the number of platelet αIIbβ3
(GPIIb/IIIa) membrane receptors for fibrinogen. Therefore
platelets from homozygous-deficient animals exhibit normal
shape-change response following stimulation with agonists
such as ADP, collagen, thrombin, or PAF, but fail to form
stable aggregates. Clot retraction is also impaired or absent.
Because platelet morphology and concentration is normal, a
definitive diagnosis requires the analysis of platelet mem-
branes by flow cytometry, using antibodies specific for α- and
β-subunits of the receptor. All the mutations described thus
far are in the gene encoding GPIIb.
The bleeding disorder component of Chediak-Higashi syn-
drome (CHS) is the result of a dense-granule storage pool
deficiency. The disease has been identified in Hereford,
Brangus, and Japanese Black cattle, in Aleutian mink, Persian
cats, blue and silver foxes, killer whales, and mice. Dense
granules are either absent or indistinct in platelets from
affected animals. The in vitro aggregation response to ADP is
reduced as a result of a decrease in the secretion of ATP, ADP,
and serotonin, which may or may not be accompanied by a
decrease in intracellular calcium mobilization.
A defect in the P2Y12 receptor for ADP on the platelet
surface membrane has been recently described in a Greater
Swiss Mountain dog. There had been no prior bleeding epi-
sodes, but excessive hemorrhage was noted after ovariohyster-
ectomy, which prompted further investigation. The same
defect was present in both related and unrelated dogs of the
same breed.
Defective intracellular signaling transduction pathways have
been identified as the cause of platelet dysfunction in Basset
hounds, Landseer–European Continental Type (ECT), and
Eskimo Spitz dogs, as well as in both purebred and crossbred
Simmental cattle. These result from various mutations in the
gene encoding calcium diacylglycerol guanine nucleotide
exchange factor I (CalDAG-GEFI). This factor is required for
activation of Rap1b, which then produces a conformation
change in GPIIb-IIIa, which permits fibrinogen binding. All
have impaired aggregation responses to most agonists, except
for thrombin. In Basset Hounds, heterozygote prevalence
approaches 25-30%. Only Landseer-ECT dogs are affected,
and the prevalence in this breed is ~10%. In the Spitz dog,
the mutation is distinct from that in Basset Hounds and Land-
seers, and much less prevalent. Affected Simmental cattle may
have mild to severe bleeding, and also have a distinct CalDAG-
GEFI mutation from the dog breeds.
A defect in platelet procoagulant activity has been identified
in a colony of German Shepherd dogs. Similar to the disorder
in people called Scott syndrome, platelet morphology is
normal, and platelet function testing determined by BMBT,
clot retraction, PFA, thromboelastography, and aggregation is
unaffected. The defect is in the exposure of phosphatidylser-
ine on the platelet surface during activation. Because of this,
the platelets cannot provide an appropriate phospholipid
context for the formation of the tenase and prothrombinase
complexes, which reduces the rate of thrombin generation and
fibrin formation. The syndrome therefore causes bleeding more
typically observed with thrombin and fibrin formation
 259.e1

Further reading
Gauthier V, et al. Effect of synthetic colloid administration on coagula-
tion in healthy dogs and dogs with systemic inflammation. J Vet
Intern Med 2015;29:276-285.
260 CHAPTER 2  •  Hematopoietic System
impairment, such as epistaxis, hyphema, hematoma, and pro-
longed bleeding with cutaneous bruising after surgery.
Further reading
Boudreaux MK. Inherited intrinsic platelet disorders. In: Weiss DJ,
Wardrop KJ, editors. Schalm’s Veterinary Hematology. 6th ed.
Ames, Iowa: Wiley-Blackwell; 2010. p. 619-625.
Gentry PA, et al. An inherited platelet function defect in a Simmental
crossbred herd. Can J Vet Res 1997;61:128-133.
Acquired platelet disorders
Besides purposeful inhibition of platelet function with anti-
platelet drugs, acquired platelet dysfunction can occur secondary
to other underlying disorders. In many instances, transient
defects in platelet responses likely occur, but are rarely docu-
mented. This is in part because of the relatively short half-life
of a circulating platelet, so that new, fully functional platelets
are replenishing the circulating pool, and to the fact that
although one intracellular signaling pathway may be altered,
another may compensate. Furthermore, without other abnor-
malities such as vWD or thrombocytopenia, partial or tran-
sient suppression of platelet reactivity may not be enough to
induce clinical signs.
Uremia resulting from renal failure has been identified as
a risk factor for platelet dysfunction. Although abnormal
BMBT, platelet adhesion, and aggregation have been reported
in uremic dogs, the specific mechanisms involved have not yet
been identified.
Certain infectious agents have been implicated as causing
platelet dysfunction. In calves infected with noncytopathic
type 2 bovine viral diarrhea virus, bleeding was thought to
occur because of combined thrombocytopenia and impaired
aggregation. Dogs infected with Ehrlichia canis or Ehrlichia
platys develop thrombocytopenia and exhibit a reduction in
both platelet adhesiveness and aggregation. The mechanism is
not entirely clear, but may be the result of antiplatelet
antibodies.
Other potential causes of platelet dysfunction include
receptor-binding interference from increased fibrinolytic products,
such as occur with disseminated intravascular coagulation and
liver disease; defective adhesion and aggregation associated
with leukemias; and coating of platelets with protein in condi-
tions causing monoclonal gammopathy.
Many drugs are known to inhibit platelet function, either
as an intentional therapeutic benefit, or as an undesired side
effect. Nonsteroidal anti-inflammatory drugs, such as aspirin
and meloxicam, that inhibit the endogenous platelet cyclo-
oxygenase enzymes, inhibit platelet aggregation in most
species. There is species variation in this response, and bovine
platelets tend to be unresponsive to the inhibitory effects of
aspirin. Drugs such as clopidogrel inhibit ADP-induced plate-
let activity by irreversibly binding to P2Y12 receptors. Penicil-
lin antibiotics can bind to platelet membranes and inhibits
glycoprotein receptor-mediated adhesion and aggregation.
There are many drugs that can impact platelet function,
including barbiturates, calcium-channel blockers, hydroxy-
ethyl starches, to name a few.
Although not given as much consideration, platelet hyper-
reactivity can contribute to abnormal hemostasis through
enhanced platelet function, and may result in thrombosis.
Disorders of Hemostasis
Disorders causing hyper-reactivity of platelets include sys-
temic inflammatory disease, neoplasia, protein-losing nephrop-
athy, and diabetes mellitus.
Further reading
Fry MM. Acquired platelet dysfunction. In: Weiss DJ, Wardrop KJ,
editors. Schalm’s Veterinary Hematology. 6th ed. Ames, Iowa:
Wiley-Blackwell; 2010. p. 626-631.
Walz PH, et al. Effect of experimentally induced type II bovine viral
diarrhea virus infection on platelet function in calves. Am J Vet Res
1999;60:1396-1401.
Thrombin formation
Initiation
Exposure of blood to tissue factor (TF), which becomes
expressed on the membrane of activated endothelial cells or
monocytes at sites of vascular injury or during inflammation,
respectively, initiates coagulation in vivo. This mechanism of
thrombin generation is termed the tissue factor or extrinsic
pathway.
In the resting state, TF is a transmembrane glycoprotein
that is sequestered or inactive in endothelial cells and mono-
cytes (and possibly other leukocytes), perhaps because of lack
of appropriate procoagulant phospholipids on the membrane
surface. Upon activation, the extracellular domain of TF is
expressed on the cell surface in a configuration that facilitates
binding of TF to inactive factor VII (FVII), or the active form
of the enzyme, FVIIa. Although FVII is the predominant form
of the protein in blood, ~1% circulates as FVIIa. Binding of
FVII and FVIIa with TF initiates coagulation by activating
additional TF-FVIIa molecules and by converting both factor
IX (FIX) and factor X (FX) to their activated forms, FIXa and
FXa, respectively (see Fig. 2-241).
Factors IXa and Xa can either remain cell associated or
they can diffuse into blood and bind to the surface of nearby
activated platelets that have aggregated at the site of vascular
damage. If they diffuse further away from the developing clot,
an inhibitor inactivates them, to prevent widespread clot for-
mation. Prothrombin (factor II) is rapidly converted to throm-
bin by the prothrombinase complex that consists of FXa,
phospholipid, calcium, and cofactor factor V (FV). During
platelet activation, negatively charged phospholipids, such as
phosphatidylserine, become exposed on the platelet surface.
These phospholipids serve as binding sites for complex forma-
tion of coagulation factors, protein cofactors, and calcium,
which are essential for the rapid propagation of fibrin and
thrombus formation.
The small amount of thrombin generated by the prothrom-
binase complex initiates a positive feedback reaction that
accelerates the rate of prothrombin conversion and causes an
increase in the amount of thrombin generated that subse-
quently increases the rate of fibrin formation (see Fig. 2-241).
Thrombin also directly increases the activity of the prothrom-
binase complex by activating FX to FXa and via proteolytic
cleavage of FV to a more reactive form (FVa). Thrombin
further facilitates thrombus formation at a site of vascular
damage by promoting localized platelet activation, adhesion,
and secretory reactions that culminate in platelet aggregation
(see Fig. 2-241).
 260.e1

Further reading
Boudreaux MK. Characteristics, diagnosis, and treatment of inherited
platelet disorders in mammals. J Am Vet Med Assoc 2008;
233:1251-1259.
Boudreaux MK, Lipscomb DL. Clinical, biochemical, and molecular
aspects of Glanzmann’s thrombasthenia in humans and dogs. Vet
Pathol 2001;38:249-260.
260.e2

Further reading
Kavanagh C, et al. Coagulation in hepatobiliary disease. J Vet Emerg
Crit Care (San Antonio) 2011;21:589-604.
Mullins KB, et al. Effects of carprofen, meloxicam and deracoxib on
platelet function in dogs. Vet Anaesth Analg 2012;39:206-217.
 Disorders of Hemostasis
Amplification of thrombin generation
The small amount of thrombin formation in the initiation
phase cannot maintain further thrombin production enough
to ensure that sufficient fibrin is made to prevent hemorrhage.
This is because of the anticoagulant protein tissue factor
pathway inhibitor (TFPI) that circulates in blood bound to
lipoproteins and platelets, and is present on endothelial cell
membranes with heparan sulfate. TFPI binds to FXa, and then
forms the FXa-TFPI-FVIIa complex, that effectively inhibits
TF pathway thrombin generation. However, the other path-
ways that result in activation of FX, and hence thrombin
production, drive its further production instead (see Fig.
2-241).
Thrombin feedback not only activates FV, but it also acti-
vates factor IX, which converts FVIII to its active form, FVIIIa
(see Fig. 2-241). Factor VIII usually circulates bound to von
Willebrand factor (vWF), but after activation by thrombin,
FVIIIa dissociates and forms a complex with FIXa, calcium,
and phospholipid exposed on the surface of thrombin-
activated platelets. This is referred to as the tenase complex,
which cleaves FX at the same reactive site as TF-VIIa and
hence also produces FXa. This FXa generation results in for-
mation of further prothrombinase complexes, providing a
rapid burst of thrombin formation.
A tenase complex leading to thrombin formation can also
be generated by the contact activation or intrinsic pathway.
The contact activation pathway includes factor XII (FXII) and
factor XI (FXI), prekallikrein (PK), and the protein cofactor
high-molecular-weight kininogen (HMWK) (Fig. 2-242). This
pathway is initiated when FXII interacts with a negatively
charged surface (such as damaged endothelium, activated
neutrophils, polyphosphates) and becomes activated (XIIa),
HMWK PolyP
FXIIa tPa
FXII
FXIa FXI
FIX FIXa
Prothrombin Thrombin
tPa
TAFI
Plasminogen
(fibrin bound)
Plasmin
2-Antiplasmin
Fibrin
Figure 2-242  Interactions between the contact activation (intrinsic) pathway and the fibrinolytic
system. Solid lines represent activation reactions; dashed lines represent inhibitory reactions.
HMWK, high-molecular-weight kininogen; PAI-1, plasminogen activator inhibitor-1; PK, prekal-
likrein; PolyP, polyphosphates; TAFI, thrombin-activatable fibrinolysis inhibitor; tPA, tissue-type
plasminogen activator.
261
resulting in ability to cleave FXI to its proteolytically active
form, FXIa, and to convert PK to kallikrein. This reaction is
accelerated by HMWK. FXIIa can convert HMWK to a modi-
fied form, HMWKa, that exhibits high surface-binding affinity
and brings large amounts of both FXI and PK to the charged
surface in proximity to already adherent FXIIa. FXIa, in the
presence of calcium, is a potent activator of circulating FIX
and thus promotes downstream thrombin formation. Direct
activation of FXI by thrombin is another amplification loop,
which, in turn, results in the generation of additional FIXa
(see Fig. 2-242).
The complete role of the contact activation pathway is not
fully understood because it does not appear to be important
for most circumstances requiring in vivo thrombin generation.
Some species, including cetacean and nonmammalian verte-
brates do not have detectable FXII activity; cats with severe
FXII deficiency do not exhibit a bleeding phenotype. However,
kallikrein not only functions as an activator of the fibrinolytic
system, but it also stimulates both chemotaxis and degranula-
tion of neutrophils attracted to sites of vascular injury (see Fig.
2-242). Hence the contact activation pathway links inflamma-
tion, thrombin formation, and fibrinolysis.
There is some evidence to suggest that this pathway may
be involved in pathologic thrombus development, because FXII-
deficient mice were protected from thrombus formation in an
atherosclerosis model. This has also been observed in primates
where FXII activity was inhibited. Other studies have dem-
onstrated that bacteria may directly engage the contact
pathway via polyphosphate binding. These phosphates are
similar to those contained within platelet-dense granules.
Polyphosphates and histamine have both been demonstrated
to directly active FXII (see Fig. 2-242).
Vessel wall
Endothelium
Vascular lumen
HMWK PolyP
FXIIa
FXII
PK
scuPA
(prourokinase)
Kallikrein
uPA
(urokinase)
Inflammatory
PAI-I responses
Plasminogen
(soluble)
Fibrin degradation
products/D-dimer
Thrombus dissolution
262 CHAPTER 2  •  Hematopoietic System Disorders of Hemostasis

Fibrin formation Laboratory evaluation of thrombin

One of the final steps in clot formation is the conversion of
fibrinogen to an insoluble fibrin strand meshwork in a process
mediated by thrombin and activated factor XIII (FXIIIa) (see
Fig. 2.241). Fibrinogen is a large molecule with 2 pairs of
3-protein chains (Aα, Bβ, γ γ) forming a complex structure
linked via disulfide bonds. Thrombin first cleaves 2 small
peptide chains, fibrinopeptides A and B, from the amino-
terminal end of the Aα and Bβ chains, respectively, which
alters the surface charge of the protein. This produces soluble
fibrin monomers that polymerize by arranging end-to-end and
side-to-side to form a loose mesh connected via covalent
bonds. This net is then converted to a more insoluble fibrin
scaffolding that facilitates stable thrombus formation and
underlying repair. Factor XIIIa, a transpeptidase enzyme acti-
vated by thrombin cleavage of its precursor zymogen, FXIII,
catalyzes the formation of the stable internal peptide bonds
between adjacent γγ and α fibrin chains, in a calcium-dependent
reaction.
Thrombin is additionally important for activation of
thrombin-activatable fibrinolysis inhibitor (TAFI). This inhibitor
prevents premature degradation of the fibrin clot and partici-
pates in the activation of the protein C anticoagulant pathway
(TM-protein C-protein S) that minimizes thrombin genera-
tion outside the localized clot (Fig. 2-243).
Further reading
Licari LG, Kovacic JP. Thrombin physiology and pathophysiology. J Vet
Emerg Crit Care (San Antonio) 2009;19:11-22.
Renné T, et al. In vivo roles of factor XII. Blood 2012;120:4296-4303.
and fibrin formation
Preanalytical considerations, including careful blood sample
collection and sample handling techniques, are essential for
reliable in vitro evaluation of hemostasis. Although blood anti-
coagulated with ethylenediaminetetraacetic acid is required
for accurate platelet counts, citrated plasma is the preferred
sample type for general testing of the coagulation system and
measuring individual components of the procoagulant, fibri-
nolytic, and inhibitory pathways. The volume of blood to
citrate in the tube should be at a 9 : 1 ratio, because over- or
under-citration of the sample may produce erroneous results.
Patient samples should be interpreted in the context of appro-
priately developed species and laboratory-specific reference
values.
Routine hemostatic testing should include determination of
automated platelet concentration and mean platelet volume,
the one-stage prothrombin time (OSPT or PT), the activated
partial thromboplastin time (APTT), and fibrinogen concentra-
tion. The PT assay measures the integrity of the tissue factor
or extrinsic pathway, and the common pathway. The proce-
dure simply involves the addition of a thromboplastin (TF)-
phospholipid reagent to the patient’s plasma, followed by
determination of the time in seconds for a fibrin clot to form
once the sample has been recalcified. For the APTT assay, a
FXII activating agent, such as celite or kaolin, mixed with
phospholipid devoid of TF (partial thromboplastin) is added
to the patient’s plasma prior to recalcification. This assay
therefore determines the integrity of the contact activation or
intrinsic pathway, which includes the formation of the tenase
and prothrombinase complexes. Like the PT assay, it will also
be prolonged if there is a deficiency in the common pathway.

Vessel wall
Endothelium
Vascular lumen
TF FVIIa Thrombin Thrombomodulin

TFPI
Delay of
TM-T TAFI activation
fibrinolysis

FX FXa
APC Protein C
PS
AT
PS
FVIIIai FVIIIa FIXa
FVa FVai
FXa FX

Prothrombin Thrombin
Antithrombin/
heparans

Thrombin-antithrombin

Fibrinogen Fibrin

Figure 2-243  The major anticoagulant pathways. Solid lines represent activation reactions, and
dashed lines represent inhibitory reactions. APC, activated protein C; AT, antithrombin; FV, factor
V; FVai, inhibitory form of FV; FVIIIai, inhibitory form of FVIII; PS, protein S; TAFI, thrombin-
activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor; TM-T, thrombomodulin-
thrombin complex.
 262.e1

Further reading
Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb
Haemost 2001;85:958-965.
 Disorders of Hemostasis
Clotting times for either assay become prolonged once activity
of one or more factors that the test assesses decreases to below
~30% activity of normal pooled plasma. Prolonged clotting
times will also occur if inhibitors are present in the patient’s
plasma.
The activated clotting time (ACT) is similar to the APTT in
that it also assesses integrity of the contact activation or intrin-
sic pathway, and common pathway, but is less sensitive for
detection of deficient activity. For this assay, whole blood is
added directly to a tube containing a contact activator, the
sample is incubated at 37o C, and the time in seconds for initial
clot formation is noted. There is no need to add a source of
phospholipid because this is provided by the patient’s own
platelets in the sample. Therefore severe thrombocytopenia
may produce a longer ACT. The result for this assay becomes
prolonged once activity of one or more factors that the test
assesses decreases to below ~5% activity of normal pooled
plasma.
Fibrinogen concentration can be quantitated by several
methods, including physical and immunologic procedures. A
modified thrombin time assay, which quantifies the amount
of fibrinogen in a diluted test sample on the basis of the rate
of formation of fibrin, is currently most commonly used in
veterinary laboratories.
The individual activity of FXII, FXI, FIX, and FVIII are
determined based on a modification of the APTT assay,
whereas the activity of FVII, FX, and FV are determined
with a modification of the PT assay. The ability of the
patient’s plasma sample to correct the clotting time of a spe-
cific factor-deficient plasma relative to a reference standard is
used to quantitate the activity of a specific factor. Such assays
developed for domestic animals use human factor–deficient
plasma, as species-specific reagents are not readily available.
Some clotting factors can also be assessed using colorimetric
methods, but these are developed for use with human plasma
samples and have not been thoroughly evaluated for use in
animals.
Global assays of hemostasis have recently been validated to
a greater extent in veterinary medicine. Although the technol-
ogy has been available for some time, particularly for visco-
elastic assessment of thrombus formation, widespread use for
diagnosis of hemostatic abnormalities in animals did not occur
until the last decade. The advantages of methods such as
thromboelastography include use of whole blood, rapid analysis,
and assessment of the entire clotting process from clot initia-
tion to fibrinolysis with a single sample. Disadvantages include
requirement for immediate analysis, and poor standardization
between laboratories. It is also unclear exactly how well results
from these methods correlate with those from the traditional
tests of hemostasis. Plasma-based thrombin generation assays
also provide global hemostatic data, but have minimally been
used for animal samples to date.
Further reading
Brooks MB, Catalfamo JL. Current diagnostic trends in coagulation
disorders among dogs and cats. Vet Clin North Am Small Anim
Pract 2013;43:1349-1372.
Kol A, Borjesson DL. Application of thrombelastography/
thromboelastometry to veterinary medicine. Vet Clin Pathol
2010;39:405-416.
263
Disorders of thrombin formation
Inherited disorders
Factor VIII deficiency (hemophilia A) is one the most common
inherited coagulopathies in animals, and has been reported in
many breeds of dogs, in cats, and occasionally in horses and
cattle. It is an X-chromosomal recessively inherited disease in
which heterozygous females, the carriers of the disease, are
clinically asymptomatic. In homozygous-deficient males, the
clinical severity of the disorder varies with the extent of reduc-
tion of FVIII activity. Unlike severely affected animals (<2% of
FVIII activity), mildly affected animals (>5% of FVIII activity)
seldom exhibit spontaneous bleeding. Stress, exercise, vaccina-
tion, surgery, and trauma may induce bleeding episodes. In
puppies, the first clinical signs may be hematomas and gingival
bleeding as permanent teeth erupt. As the dog ages, intermit-
tent shifting leg lameness resulting from hemarthrosis, particu-
larly in the stifle joints, and subcutaneous and intramuscular
hematomas are common. Excessive bleeding resulting in large
scrotal hematomas following castration also occurs. Mildly
affected male dogs can reach sexual maturity, and if they are
bred with a heterozygous female, homozygous-deficient
bitches can result. These animals may exhibit protracted
estrus or postpartum hemorrhage.
Hemophilia A is suggested by signalment, clinical signs,
prolonged ACT or APTT with normal PT, and confirmed by
decreased plasma FVIII activity.
Factor IX deficiency (hemophilia B) is less common than
FVIII deficiency and has been reported in dogs and cats. It has
been described in several breeds of dogs, and is the second
most common inherited disorder in British Shorthair cats.
Like hemophilia A, it is inherited as an X-chromosomal reces-
sive trait and has similar clinical signs, with both the circulat-
ing plasma activity of FIX and the size of the animal influencing
the severity of bleeding. The reduced plasma FIX activity
results in prolonged ACT and APTT, but normal PT. Confir-
mation of reduced FIX activity is required to make a definitive
diagnosis.
Prolonged APTT and normal PT is also expected for
animals with inherited defects involving the other proteins of the
contact activation or intrinsic pathway, including, FXI, FXII,
and PK. The defect in each case is inherited in an autosomal
recessive manner. Of these, only FXI deficiency may cause
affected animals to exhibit spontaneous bleeding, most com-
monly from the urogenital tract. It has been identified in
several dog breeds, including English Springer Spaniels, Kerry
Blue Terriers, and Great Pyrenees dogs, and in Holstein and
Japanese Black cattle. Homozygous cattle have <5% of normal
plasma FXI activity, but the response to trauma or surgery
ranges from almost non-existent to severe hemorrhage devel-
oping 12-48 hours later.
Prekallikrein deficiency is minimally documented, partly
because it is usually clinically asymptomatic. It was only found
fortuitously in a German Short-haired Pointer bitch that sub-
sequently underwent uneventful ovariohysterectomy. Even in
large animals with PK deficiency, such as Miniature and
Belgian horses, bleeding is rare, although it has been reported
in a horse following castration.
Factor XII deficiency is inherited as an autosomal recessive
trait, and has been observed in dogs and cats. Bleeding does
not occur in affected animals, and the defect is often discov-
ered by chance in cats that have an APPT performed for
another reason. The absence of hemorrhage is consistent with
 263.e1

Further reading
Herring J, McMichael M. Diagnostic approach to small animal bleeding
disorders. Top Compan Anim Med 2012;27:73-80.
Lubas G, et al. Laboratory testing of coagulation disorders. In: Weiss
DJ, Wardrop KJ, editors. Schalm’s Veterinary Hematology. 6th ed.
Ames, Iowa: Wiley-Blackwell; 2010. p. 1082-1100.
264 CHAPTER 2  •  Hematopoietic System
observations that FXII activity is absent in nonmammalian
species such as birds, reptiles, and amphibians.
Factor VII deficiency has only been documented in dogs and
people. It has been reported in Beagles, Alaskan Malamutes,
Boxers, Bulldogs, Miniature Schnauzers, and mixed-breed
dogs, and is inherited as an autosomal trait. Adult dogs with
the trait usually have plasma FVII activity of at least 5% of
normal pooled plasma, which appears sufficient to initiate
thrombin generation and induce fibrin formation unless there
are other concurrent abnormalities. For example, FVII defi-
ciency was diagnosed in a mixed-breed dog that exhibited
abnormal bleeding following routine castration and failed to
respond to vitamin K therapy. FVII deficiency is generally mild
and characterized by bruising. Prolonged vaginal bleeding after
whelping can occur in affected bitches. The diagnosis is sus-
pected based on signalment and history, with prolonged PT
and normal APTT. Decreased FVII activity can be documented
with a specific factor assay.
Severe factor X deficiency is inherited as an autosomal
recessive trait, and tends to be lethal in affected dogs because
of its importance for thrombin generation. Dogs with <10%
of normal plasma FX activity are usually stillborn or die
from bleeding as neonates. The defect has been reported in
Jack Russell Terriers and in mixed-breed dogs. Because FX is
part of the common pathway, both the APTT and PT are
prolonged.
Vitamin-K-dependent γ-glutamyl carboxylase deficiency has
been identified in Devon Rex cats, Rambouillet sheep, and in
a single Labrador Retriever dog. Lack of adequate activity of
this enzyme results in synthesis of quantitatively normal, but
nonfunctional, vitamin K–dependent coagulation proteins
(FII, FVII, FIX, FX). In homozygous-deficient sheep, low
levels of activity of all 4 affected proteins are typically found,
whereas heterozygous carrier animals may have normal factor
activities. Lamb mortality can be high, and is related to umbil-
ical and subcutaneous tissue hemorrhages. In affected Devon
Rex kittens, bleeding is severe or fatal and typically manifests
as hematomas and hemarthroses, as well as hemothorax and
hemoabdomen. Administration of vitamin K1 results in rapid
recovery of circulating vitamin K–dependent factor activity to
near-normal levels. In the affected dog, circulating activity
only increased to 50-60% of normal canine pooled plasma
even after 3 months of vitamin K1 therapy.
Further reading
Barr JW, McMichael M. Inherited disorders of hemostasis in dogs and
cats. Top Compan Anim Med 2012;27:53-58.
Bender DE, et al. Molecular characterization of cat factor XII gene and
identification of a mutation causing factor XII deficiency in a
domestic shorthair cat colony. Vet Pathol 2014;52:312-320.
Giger U. Hereditary blood diseases. In: Feldman B, et al., editors.
Schalm’s Veterinary Hematology. 5th ed. Philadelphia: Lippincott
Williams & Wilkins; 2000. p. 955-959.
Lozier JN, Nichols TC. Animal models of hemophilia and related bleed-
ing disorders. Semin Hematol 2013;50:175-184.
Acquired disorders
Vitamin K antagonism.  The primary function of vitamin K
in animals is as a cofactor for γ-glutamyl carboxylase, the enzyme
required for post-translational carboxylation of glutamate
(Gla) residues into γ-carboxyglutamate. Vitamin K hydroqui-
Disorders of Hemostasis
none is the active coenzyme, and its oxidation into vitamin K
2,3 epoxide produces the carboxylation reaction. Vitamin K
is a fat-soluble vitamin, and is widely available in green leafy
plants and vegetables oils and, like γ-glutamyl carboxylase, is
widely distributed throughout the body. Impaired carboxyl-
ation of vitamin K–dependent coagulation proteins is occa-
sionally the result of dietary deficiency or impaired
gastrointestinal absorption of vitamin K, but is more often
caused by ingestion of certain anticoagulant rodenticides.
These vitamin K antagonists inhibit the recycling of vitamin
K 2,3 epoxide back to the hydroquinone form through inhibi-
tion of vitamin K epoxide reductase. The gradual reduction in
vitamin K hydroquinone leads to a decrease in the active
forms of vitamin K. Because the function of Gla residues in
FVII, FIX, FX, and prothrombin is to facilitate binding to
negatively charged phospholipids on the surface of activated
endothelium or platelets, the rate of thrombin formation is
reduced. The nonfunctional forms of these proteins are col-
lectively referred to as PIVKAs (proteins induced by vitamin K
antagonism). There is a plasma-based assay for detecting these
inactive forms.
Rodenticide intoxication is the most common cause of vitamin
K antagonism in dogs, but it has also been reported in cats,
horses, and pigs. The first generation rodenticides (such as
warfarin) had relatively low toxicity and biological half-lives
of <24 hours, which meant that vitamin K therapy often
resulted in rapid and effective resolution of signs. The devel-
opment of rodent resistance to these compounds led to the
development of subsequent-generation agents, such as broma-
diolone, brodifacoum, and diphacinone, which are more
potent, have longer half-lives, and which therefore require
more aggressive longer-term vitamin K therapy in affected
animals.
Clinical signs are dependent on the quantity and type of
agent ingested, and can range from mild hemorrhage to severe
spontaneous bleeding in the form of epistaxis, melena, and
hematuria. It may be several days after ingestion before clini-
cal signs occur and appear acute in onset. If bleeding is severe,
anemia, weakness, and pallor develop; dyspnea can be associ-
ated with hypovolemia from hemothorax. Hemarthrosis has
been reported to occur in some cases.
Cattle, pigs, and rabbits are susceptible to vitamin K antag-
onism if hay or silage containing moldy sweet clover is ingested.
Sweet clover contains coumarin, which is converted to dicu-
marol. Young calves are more susceptible to dicumarol than
are the dams, whereas sheep and horses appear resistant to
this form of vitamin K antagonism.
Because FVII has the shortest circulating half-life (~4-6
hours), it is the first factor to have decreased biological activ-
ity. Therefore, in the initial stages of vitamin K antagonism,
the PT may be prolonged, whereas the APTT is within refer-
ence intervals. However, the APTT soon becomes prolonged
as well because FIX and FX have plasma half-lives of only
14-18 hours. Toxicologic evaluation of stomach contents can
determine the specific agent ingested, which can be useful
information for deciding on the duration of therapy.
Liver disease.  Although many coagulation proteins are
made in hepatocytes, hemorrhage related to liver disease is
infrequent in domestic animals. This may be in part because
severe loss of hepatic parenchyma (<30% remaining) must
have occurred before impairment of protein synthesis is suf-
ficiently affected to prolong the PT and APTT. Additionally,
synthesis of inhibitory proteins, such as antithrombin and
 264.e1

Further reading
Baker DC, et al. Hereditary deficiency of vitamin-K-dependent coagula-
tion factors in Rambouillet sheep. Blood Coag Fibrinol 1999;10:
75-80.
Gentry PA, Ross ML. Coagulation factor XI deficiency in Holstein cattle:
expression and distribution of factor XI activity. Can J Vet Res
1995;58:242-247.
Macpherson R, et al. Factor VII deficiency in a mixed breed dog. Can
Vet J 1999;40:503-505.
Mason DJ, et al. Vitamin-K dependent coagulopathy in a Black Labra-
dor Retriever. J Vet Intern Med 2002;16:485-488.
Soute BAM, et al. Congenital deficiency of all vitamin K-dependent
blood coagulation factors due to a defective vitamin K dependent
carboxylase in Devon Rex cats. Thromb Haemost 1992;68:
521-525.
 Disorders of Hemostasis
protein C, and fibrinolytic proteins, such as antiplasmin, will
also be reduced, potentially resulting in a rebalanced system.
Also, in some inflammatory diseases, the liver can increase the
rate of synthesis of specific clotting factors (acute phase
response), including fibrinogen, FVIII, and vWF, which together
can promote the efficiency of clot formation. Despite this, it
is commonly advised to screen for hemostatic competency
with PT and PTT prior to liver biopsy, because complications
of underlying disease may easily disturb this rebalanced
system. However, there is often no clear correlation between the
results of the screening tests and risk of bleeding postbiopsy.
In a study of 45 cats with liver disease, 98% exhibited at
least one coagulation test abnormality. The more severe the
liver disease, the more likely the cat was to develop clinical
bleeding. Interestingly, one of the more frequent abnormalities
noted was decreased FXIII activity, which was present with
both inflammatory and neoplastic processes. Because of a con-
stellation of other findings, it was concluded that, overall,
coagulation abnormalities in this cohort of cats with liver
disease were the result of consumption rather than decreased
synthesis.
Coagulation was assessed with thromboelastography
(TEG) in 10 dogs with extrahepatic bile duct obstruction. It
was concluded that many of these dogs were actually in a
hypercoagulable state rather than being predisposed to hem-
orrhage. Decreased production of inhibitor proteins may be
to blame. These findings reinforce the idea that hemostatic altera-
tions in hepatobiliary disease are not necessarily predictable, and
are likely multifactorial.
Cholestasis resulting in poor vitamin K absorption, and
therefore formation of inactive FII, FVII, FIX, and FX, may
occur in animals with chronic partial or complete biliary
obstruction. Vitamin K therapy given parenterally can restore
production of activatable proteins.
Further reading
DeClementi C, Sobczak BR. Common rodenticide toxicoses in small
animals. Vet Clin North Am Small Anim Pract 2012;42:349-360.
Dircks B, et al. Haemostatic abnormalities in cats with naturally occur-
ring liver diseases. Vet J 2012;193:103-108.
Mayhew PD, et al. Evaluation of coagulation in dogs with partial or
complete extrahepatic biliary tract obstruction by means of throm-
boelastography. J Am Vet Med Assoc 2013;242:778-785.
Disorders of fibrin formation
Hereditary fibrinogen defects are rare, and have only been rec-
ognized in goats and dogs. Afibrinogenemia has been reported
in a herd of Saanen goats, in which it was associated with
severe umbilical bleeding, hemarthroses, and subcutaneous
and oral bleeding. Inherited hypofibrinogenemia has been
diagnosed in Bernese Mountain, Lhasa Apso, Vizsla, and Collie
dogs. Similar to dysfibrinogenemia in an inbred Borzoi dog
family and in a Border Leicester lamb, these fibrinogen abnor-
malities cause only mild bleeding that can be exacerbated by
stress, trauma, or surgery. Decreased fibrinogen concentration
is more commonly because of decreased synthesis from severe
liver disease, or increased consumption with disseminated
intravascular coagulation.
Hyperfibrinogenemia as a positive acute-phase response is
common in many domestic animals; however, thromboem-
bolic complications are infrequently reported in veterinary
265
medicine. Thromboembolism (TE) does occur in animals,
usually as a secondary consequence of cardiac disease, immune-
mediated hemolytic anemia, neoplasia, hyperadrenocorticism,
protein-losing nephropathy and enteropathy, and sepsis.
Canine immune-mediated hemolytic anemia is a known risk
factor for development of pulmonary TE. Increased expres-
sion of tissue factor, phospholipid-expressing microparticles,
and platelet hyperactivity have been proposed as underling
predisposing mechanisms. Immunosuppressive doses of gluco-
corticoids used for treatment of this disease have also been
suggested to promote hypercoagulability, but the association
and mechanism has not been definitively proven to date.
Elevated fibrinogen concentration, and hypercoagulable
TEG tracings have been observed in dogs with hyperadreno-
corticism, but the overall risk of TE remains unclear. Decreased
antithrombin has been proposed in the development of a
hypercoagulable state in dogs with this disease, but this has
not been borne out in some studies.
Further reading
Kidd L, Mackman N. Prothrombotic mechanisms and anticoagulant
therapy in dogs with immune-mediated hemolytic anemia. J Vet
Emerg Crit Care (San Antonio) 2013;23:3-13.
Mendez-Angulo JL, et al. Thromboelastography in healthy, sick non-
septic and septic neonatal foals. Aust Vet J 2011;89:500-505.
Park FM, et al. Hypercoagulability and ACTH-dependent hyperadreno-
corticism in dogs. J Vet Intern Med 2013;27:1136-1142.
Regulation of coagulation:
endogenous anticoagulants
To prevent widespread and over-exuberant clot formation
when procoagulant mechanisms are invoked, inhibition of acti-
vated enzymes, such as FXa and thrombin, is essential because
they can diffuse away from a developing thrombus into the
general circulation. There are 3 important mechanisms that
perform this function, including antithrombin/heparin, the
protein C pathway, and tissue factor pathway inhibitor (TFPI).
Antithrombin (AT) is the major inhibitor of both thrombin
and thrombin generation. It is a member of the serine protease
inhibitor family of proteins that also includes α1-antitrypsin,
α2-antiplasmin, and α2-macroglobulin. Plasma AT is an α2-
globulin produced by hepatocytes and endothelial cells. It
predominantly inhibits thrombin, FIXa, and FXa, with addi-
tional weak inhibition of other activated factors, including the
TF-FVIIa complex. The inhibitory action of AT arises from
the interaction of its reactive arginine residue with a serine
residue at the reactive site on thrombin, in a 1 : 1 ratio. The
thrombin-AT (TAT) complex prevents thrombin’s ability to cleave
fibrinogen to fibrin (see Fig. 2-243). The inhibitory effect of AT
is enhanced by heparan sulfate complexes on the surface of
activated endothelial cells. Intravenously administered heparin,
or heparin released from mast cells, can also increase the rate
of formation of TAT complexes. Any TAT complexes are
removed from circulation via the mononuclear phagocyte
system or by becoming bound to the endothelial cells, which
results in endocytosis and lysosomal degradation.
The protein C pathway regulates coagulation by inactivating
FVa and FVIIIa. Protein C is synthesized in the liver as a
vitamin K–dependent zymogen. It is converted to an activated
form, APC, on the surface of endothelial cells by thrombin
that has become bound to a membrane protein called
 265.e1

Further reading
Kavanagh C, et al. Coagulation in hepatobiliary disease. J Vet Emerg
Crit Care (San Antonio) 2011;21:589-604.
Waddell LS, et al. Anticoagulant rodenticide screening in dogs: 123
cases (1996-2003). J Am Vet Med Assoc 2013;242:516-521.
265.e2

Further reading
Goodwin LV, et al. Hypercoagulability in dogs with protein-losing enter-
opathy. J Vet Intern Med 2011;25:273-277.
Rose L, et al. Effect of canine hyperadrenocorticism on coagulation
parameters. J Vet Intern Med 2013;27:207-211.
266 CHAPTER 2  •  Hematopoietic System
thrombomodulin (TM) in a thrombin-TM complex (see Fig.
2-243). Thrombomodulin is present on endothelial cells in
arteries, capillaries, veins, and lymphatic vessels. It is present
in high amounts on capillaries where blood flow is slower and
thrombin concentrations are highest, such as in the lungs. APC
cleaves phospholipid membrane-bound cofactors to inactivate
FVa and FVIIIa that then result in suppression of both pro-
thrombinase and tenase activity. Cleavage of these factors
within the phospholipid-enzyme complexes is facilitated by a
vitamin K–dependent cofactor, protein S, that forms a
membrane-bound complex with APC. Only the free circulat-
ing form of protein S binds with APC. This form represents
only ~30% of the total plasma concentration, as most circu-
lates bound to complement regulator C4-binding protein.
Also part of the protein C pathway is endothelial protein C
receptor (EPCR), which amplifies the activation of protein C
by TAT complexes, and also stimulates downstream anti-
inflammatory and cytoprotective effects.
Although antithrombin and the protein C pathway are
more important for regulating elements of the contact or
intrinsic pathway, tissue factor pathway inhibitor (TFPI) per-
forms a similar function for the tissue factor or extrinsic
pathway. TFPI is produced in endothelial cells and inhibits
both TF-FVIIa and TF-FVIIa-FXa complexes. Its activity is
enhanced by heparin-like glycosaminoglycans as well as
protein S. TFPI functions by rapidly inhibiting any free FXa
generated by the TF-FVIIa complex on subendothelial fibro-
blasts during the initiation phase of coagulation.
Inhibitor disorders
Inherited antithrombin deficiency has been described in
people, but it has not been identified in domestic animals.
Acquired deficiencies in AT activity occur in animals with
protein-losing nephropathy, sepsis, and disseminated intravas-
cular coagulation (DIC). Decreased AT activity can be accom-
panied by an increase in TAT complexes. In dogs, the
hypercoagulable state associated with these disorders is at
least partly attributed to decreased plasma AT activity.
Reduced plasma AT was found in a foal with thrombosis of
the brachial artery, and occurs in horses with colic. There are
laboratory assays available for quantification of AT in plasma.
Human-based colorimetric and coagulation laboratory
assays have been validated and are available to quantify the
protein C component of the protein C pathway in dogs. Protein
C activity may be reduced in cases of vitamin K deficiency or
antagonists. DIC-induced consumption of protein C has been
reported in dogs and primates. Protein C concentrations have
been used to facilitate diagnosis of congenital and acquired
liver disease in dogs.
Tissue pathway factor inhibitor activity is not routinely
measured in animals.
Further reading
Bentley AM, et al. Alterations in the hemostatic profiles of dogs with
naturally occurring septic peritonitis. J Vet Emerg Crit Care
2013;23:14-22.
Kubier A, O’Brien M. Endogenous anticoagulants. Top Companion
Anim Med 2012;27:81-87.
Smith S. Overview of hemostasis. In: Weiss DJ, Wardrop KJ, editors.
Schalm’s Veterinary Hematology. 6th ed. Ames, Iowa: Wiley-
Blackwell; 2010. p. 635-653.
Disorders of Hemostasis
Fibrinolysis
The fibrinolytic system results in clot dissolution via proteolytic
degradation of fibrin, once underlying tissue repair has occurred.
The central enzyme mediating fibrinolysis is plasmin, which is
formed from the precursor, plasminogen, by 1 of 2 endogenous
activators: tissue-type plasminogen activator (tPA) and urokinase
(uPA) (see Fig. 2-242). Tissue-type plasminogen activator pre-
dominantly activates plasminogen within the vascular system,
whereas uPA is responsible for extravascular plasminogen acti-
vation. Plasminogen is synthesized by hepatocytes and is a
trypsin-like enzyme with broad substrate specificity. In addi-
tion to degrading fibrin strands, it can degrade fibrinogen, FV
and FVIII, extracellular matrix components, and can activate
other proteases such as matrix-metalloproteinases. Plasmin
formation from plasminogen and its activity are highly regu-
lated. For example, tPA and uPA have very short circulating
half-lives relative to plasminogen, partly because of their rapid
clearance via endothelial cell surfaces. Also, the balance between
inhibitors and activators of plasminogen typically favors inhibi-
tion of plasmin formation in healthy animals. The major inhibi-
tor of plasminogen activation is plasminogen activator
inhibitor-1 (PAI-1), which can block the action of both tPA
and uPA (see Fig. 2-242). PAI-1 is typically in excess over tPA,
so most plasma tPA circulates as an inactive tPA–PAI-1
complex. The balance can be altered by the increased release
of tPA from endothelial cells in response to exercise, vascular
occlusion, or in response to locally generated thrombin at a
site of vascular damage. In plasma, the primary inhibitor of
plasmin activity is α2-antiplasmin, but α2-macroglobulin and
α1-antitrypsin are also capable of acting as inhibitors.
Endothelium-mediated fibrinolysis
Initially during clot formation, activation of plasminogen is
suppressed so that fibrin strands develop. Although thrombin
potently induces synthesis and secretion of endothelial tPA,
this profibrinolytic action is opposed by localized activity of
tissue-activatable fibrinolysis inhibitor (TAFI) (see Figs. 2-242,
2-243). High concentrations of thrombin generated both by
the positive feedback activation of FXI to FXIa and activation
of the tenase complex, combined with binding of thrombin
to thrombomodulin, enhances the activation of TAFI, which
inhibits tPA activation of plasminogen. Most PAI-1 is present
in platelets, which is released from α-granules during platelet
activation.
Once sufficient fibrin has been formed, plasmin formation and
fibrinolysis is promoted. Most fibrinolytic proteins in thrombi
are at concentrations representing 10-30% of their concentra-
tion in plasma, consistent with trapping of plasma proteins in
the developing thrombus. Fibrin itself potentiates fibrinolysis
by bringing together plasminogen and tPA on its surface,
which facilitates enzyme-substrate interactions and protects
tPA from inhibition by TAFI and PAI-1. Plasmin interacts with
fibrin strands at both its active site and at specific lysine-
binding sites, which decreases the ability of α2-antiplasmin to
interact with and inhibit plasmin generated within the fibrin
meshwork (see Fig. 2-242).
Plasma-mediated fibrinolysis
Unlike tPA, uPA readily activates plasminogen in plasma, even
in the absence of fibrin. It is unclear how uPA participates in
hemostasis, but it is evident from transgenic and knockout
mouse models that the tPA and uPA activators can compen-
sate for each other. Fibrin is rapidly deposited after injury, not
 266.e1

Further reading
Fry MM, et al. Protein C activity in dogs: adaptation of a commercial
human colorimetric assay and evaluation of effects of storage time
and temperature. Vet Med Int 2011;2011:751849.
Toulza O, et al. Evaluation of plasma protein C activity for detection of
hepatobiliary disease and portosystemic shunting in dogs. J Am Vet
Med Assoc 2006;229:1761-1771.
 Disorders of Hemostasis
only to prevent blood loss but also to provide a scaffold for
cells required during the subsequent healing process. Plasmin
and uPA are important for the slow dissolution of fibrin that
occurs once underlying tissue repair has occurred. Also in
contrast to tPA, uPA has no specific affinity for fibrin and
thus can activate circulating and fibrin-bound plasminogen
indiscriminately.
Initially, any plasmin generated outside a fibrin clot is
quickly neutralized by α2-antiplasmin. However, if the forma-
tion of plasmin exceeds inhibitor availability, it will begin to
degrade other plasma proteins, such as fibrinogen, FV, and
FVIII. Some bacteria produce plasminogen activators that can
act exogenously, thereby inducing inappropriate plasmin for-
mation. An example is streptokinase, which is produced by
strains of streptococci that use plasmin to their advantage to
increase invasiveness. In many mammals, streptokinase acts by
forming a 1 : 1 complex with either plasminogen or plasmin.
In this form, the general proteolytic action of streptokinase is
decreased, but its plasminogen-activating activity is increased
several fold.
Primary disorders of the fibrinolytic system have not been
characterized in domestic animals. However, alterations of
fibrinolysis associated with severe inflammation are frequently
recognized with disseminated intravascular coagulation.
Laboratory assessment of fibrinolysis in animals is limited to
a few assays, and include determination of fibrin(ogen) degra-
dation products (FDPs) and D-dimers. FDPs derive from both
fibrinogen and fibrin strands; D-dimers form only when cross-
linked fibrin is degraded. Fibrinolysis can also be assessed using
global assays of hemostasis such as thromboelastography.
Further reading
Schaller J, Gerber SS. The plasmin-antiplasmin system: structural and
functional aspects. Cell Mol Life Sci 2011;68:785-801.
Smith S. Overview of hemostasis. In: Weiss DJ, Wardrop KJ, editors.
Schalm’s Veterinary Hematology. 6th ed. Ames, Iowa: Wiley-
Blackwell; 2010. p. 635-653.
Stokol T, et al. Evaluation of latex agglutination kits for detection of
fibrin(ogen) degradation products and D-dimer in healthy horses
and horses with severe colic. Vet Clin Pathol 2005;34:375-382.
Systemic inflammation and neoplasia:
dysregulation of hemostasis
Inflammatory mediators, especially if disseminated widely, can
alter hemostatic equilibrium and cause either hemorrhagic or
thrombotic complications. The role of the contact activation or
intrinsic pathway as a link between hemostasis and inflamma-
tion has long been recognized. In addition to initiating throm-
bin formation through the FXI-tenase pathway (see Fig.
2-242), activation of FXII results in conversion of PK to kal-
likrein, which converts high-molecular-weight kininogen to the
inflammatory mediator bradykinin. Recent reports suggest
that both factor XII and kallikrein can promote activation of
FIX and prothrombin via FXIa, in the presence of polyphos-
phates, such as those found in bacteria or in platelet
granules.
An increase in TF expression on the cell membrane of
monocytes and endothelial cells occurs in response to both
gram-negative and gram-positive bacteria. This can result in
activation of FVII, FX, and thrombin, setting off a series of
intracellular signaling cascades in leukocytes. Inflammatory
267
responses induced include leukocyte recruitment, release of
additional cytokines, and production of reactive oxygen
species. Systemic thrombin generation can result in widespread
cleavage of fibrinogen and deposition of fibrin strands in the
microvasculature of various end organs. The formation of fibrin
strands can benefit the host by encapsulating bacteria; however,
if large numbers of bacteria are protected from phagocytosis
once they are sequestered, additional bacterial proliferation
can occur with further damaging effects. Intravascular fibrin
strands can also have other deleterious effects, including alter-
ation of blood flow and erythrocyte fragmentation.
Platelets are also recognized as inflammatory cells, through
release of certain granule contents, for instance, histamine and
serotonin, or through the formation of cell membrane–derived
neutrophil and monocyte agonists, for instance, PAF and leu-
kotrienes. After activation, mononuclear phagocytes can produce
and release a wide range of inflammatory mediators, including
interleukin-6, which can stimulate increased hepatocyte
fibrinogen synthesis; PAF and prostaglandins, which can induce
further platelet activation; and tumor necrosis factor, which
can initiate fibrinolysis through the release of plasminogen
activators. Thus, in the initial phase of inflammation, a balance
between procoagulant activity, fibrin formation, and the lysis of
formed fibrin can be maintained. However, within several hours
of the initiation of an inflammatory response, the fibrinolytic
system is suppressed as a result of the increased synthesis and
release of PAI-1. The fact that thrombosis is not a consistent
clinical observation during inflammation can be explained by
the thrombin- and/or cytokine-induced activation of the anti-
coagulant protein C pathway (see Fig. 2-243). The suppres-
sion of both thrombin formation and plasmin generation helps
maintain hemostatic balance.
Neoplasia can also precipitate dysequilibrium of procoagulant,
anticoagulant, and fibrinolytic proteins, similar to that which
occurs during systemic inflammation. The association between
hemostatic abnormalities and neoplasia is less well understood
in domestic animals, although bleeding can be a clinical sign
in animals with tumors such as hemangiosarcoma, multiple
myeloma, and mast cell tumors. Hemostatic laboratory abnor-
malities are frequently present in animals with neoplasia. For
example, in a study of 71 dogs with various tumors, the major-
ity exhibited evidence of hypercoagulability on TEG, along
with prolonged APTT and increased fibrinogen. Dogs with
metastatic disease tended to have increases in fibrinolysis indi-
cators. Chemotherapeutic drugs and radiation can also impair
the hemostatic process. For example, L-asparaginase, which
inhibits protein synthesis, and actinomycin D, which directly
antagonizes vitamin K, can produce transient reductions in
activity of multiple clotting factors. Tumor-induced inhibitory
antibody production can also contribute to hemorrhage. These
inhibitors, or circulating anticoagulants, may either be immu-
noglobulins directed against functional epitopes of clotting
factors or antiphospholipid antibodies that interfere with the
normal formation of the tenase and prothrombinase com-
plexes (see Fig. 2-241).
Disseminated intravascular coagulation (DIC) is an
acquired syndrome that occurs when excessive systemic acti-
vation of procoagulant mechanisms result in widespread fibrin
formation, which may or may not eventually be accompanied
by inhibitor consumption and altered fibrinolysis (see also Vol.
3, Cardiovascular system). Thrombosis and/or hemorrhage
may occur at multiple sites, which often cause end-organ
dysfunction or complete failure. DIC is a potential
268 CHAPTER 2  •  Hematopoietic System
complication of any underlying disorder that results in an
increase in expression of tissue factor, or activation of other
proteases that can activate clotting on a systemic basis. In
horses, DIC has been reported most commonly as a sequel to
intestinal disease and colic. In dogs, almost half of those with
immune-mediated hemolytic anemia exhibit evidence of a
hypercoagulable state at the time of clinical presentation.
Animals with sepsis and systemic inflammatory response syn-
drome are at increased risk for DIC and frequently have many
abnormal hemostasis assay results.
In the initial stages of DIC, increased thrombin generation
is compensated for by the anticoagulant systems, such as TFPI,
APC, and antithrombin (see Fig. 2-243). Laboratory results at
this stage can vary, but a hypercoagulable tracing may be
observed with thromboelastography. Further supportive labo-
ratory diagnosis at this stage would require evaluation of
markers such as thrombin-antithrombin (TAT) complexes
(see Fig. 2-243) and peptide fragments such as prothrombin
fragment 1 + 2, which are released during activation of pro-
coagulant factors. These latter tests are, however, not widely
available for animals.
If increased thrombin generation persists, DIC may progress
to an overt hypocoagulable phase. When inhibitor consumption
outweighs production because of increased attempts to con-
strain further clotting, thrombin generation and fibrin forma-
tion proceed in an unrestricted manner. This results in
thrombocytopenia and consumption of all procoagulant pro-
teins, hence the use of the term consumptive, or consumption,
coagulopathy to characterize this stage of DIC. Ultimately, this
results in multisite spontaneous bleeding, and anemia can develop
because of blood loss. Laboratory abnormalities are more pre-
dictable at this stage, and include decreased platelet count,
prolonged PT and APTT, decreased fibrinogen concentration,
decreased antithrombin and protein C activity, and increased
Disorders of Hemostasis
fibrin degradation products (FDPs) and D-dimers. A hypoco-
agulable tracing would be apparent on thromboelastography
with prolonged R time and decreased maximum amplitude
(MA).
The fibrinolytic system is also activated in the initial phase of
DIC, resulting in increased amounts of intravascular plasmin
being generated. Excessive fibrinolysis may exacerbate bleed-
ing in later stages. During plasmin proteolysis of fibrinogen
and fibrin, peptide fragments, known as FDPs and D-dimers,
are released (see Fig. 2-243). Excessive generation of plasmin
and production of FDPs both contribute to end-organ failure,
which is often the ultimate cause of death in animals with
advanced DIC. For example, plasmin can induce vascular and
cellular damage through activation of matrix metalloprotein-
ases that degrade a wide range of cytoskeletal filaments. FDPs
can enhance local inflammatory reactions by triggering the
release of interleukin-1 (IL-1) and IL-6 from monocytes and
macrophages, and can also interfere with platelet function.
Further reading
Andreasen EB, et al. Haemostatic alterations in a group of canine
cancer patients are associated with cancer type and disease pro-
gression. Acta Vet Scand 2012;54:3.
Cesarini C, et al. Association of admission plasma D-dimer concentra-
tion with diagnosis and outcome in horses with colic. J Vet Intern
Med 2010;24:1490-1497.
Piek CJ, et al. High intravascular tissue factor expression in dogs with
idiopathic immune-mediated haemolytic anaemia. Vet Immunol
Immunopathol 2011;144:346-354.
For more information, please visit the companion site:
PathologyofDomesticAnimals.com.
 268.e1

Further reading
Puy C, et al. Factor XII promotes blood coagulation independent of
factor XI in the presence of long-chain polyphosphates. J Thromb
Haemost 2013;11:1341-1352.
Ralph AG, Brainard BM. Update on disseminated intravascular coagula-
tion: when to consider it, when to expect it, when to treat it. Top
Compan Anim Med 2012;27:65-72.
CHAP TER 3 
Endocrine Glands
Thomas J. Rosol  •  Andrea Gröne
GENERAL CONSIDERATIONS 270
Types of hormones 270
Polypeptide hormones 270
Steroid hormones 271
Catecholamine and iodothyronine hormones 271
Proliferative lesions in endocrine glands 271
Characteristics 271
Functional aspects of endocrine tumors 272
Mechanisms of endocrine disease 272
Primary hyperfunction of an endocrine gland 272
Secondary hyperfunction of an endocrine gland 272
Primary hypofunction of an endocrine gland 272
Secondary hypofunction of an endocrine gland 273
Endocrine hyperactivity secondary to diseases of
other organs 273
Hypersecretion of hormones by non-endocrine tumors 274
Endocrine dysfunction resulting from failure of target
cell response 274
Failure of fetal endocrine function 274
Endocrine dysfunction resulting from abnormal degradation
of hormone 275
Syndromes of iatrogenic hormone excess 275
PITUITARY GLAND 276
Development, structure, and function 276
Embryologic development of the pituitary gland 276
Structure of the adenohypophysis 276
Functional cytology of the adenohypophysis 276
Hypothalamic control of the adenohypophysis 277
Structure and function of the neurohypophysis 277
Blood supply to the pituitary gland 278
Diseases of the pituitary gland 278
Hypophyseal changes associated with alterations in
target organs 278
Pituitary cysts 279
Neoplastic diseases of the pituitary 281
Corticotroph (ACTH–secreting) adenoma 281
Pars intermedia (melanotroph) adenoma 282
Somatotroph adenomas 285
Thyrotroph adenoma 286
Lactotroph adenoma 286
Suprasellar germ cell tumor (craniopharyngioma) 287
Hormonally inactive adenoma of the pars distalis 287
Pituitary chromophobe carcinoma 288
Tumors metastatic to the pituitary gland 288
Granular cell tumors of the pituitary 289
Mechanisms of pituitary tumor induction 289
Other diseases and inflammation of the adenohypophysis 289
Diseases of the neurohypophysis 290
CALCIUM-REGULATING HORMONES 291
Parathyroid glands and parathyroid hormone 292
Development and structure 292
Biosynthesis and secretion of parathyroid hormone 292
Biological action of parathyroid hormone 294
Cholecalciferol (vitamin D3) 295
Biosynthesis of 1,25-dihydroxycholecalciferol (calcitriol) 295
Biological action of calcitriol 295
Disorders of vitamin D metabolism 296
Fibroblast growth factor-23 (FGF23) 296
Thyroid C cells and calcitonin 296
Development and structure of thyroid C cells 296
Biosynthesis and secretion of calcitonin 297
Biological action of calcitonin 297
Diseases of the parathyroid gland 297
Parathyroid and related cysts 297
Degenerative changes of the parathyroid gland 297
Chemical-induced injury of parathyroid glands 298
Lymphocytic parathyroiditis and hypoparathyroidism 298
Parathyroid stimulation associated with acute
hypocalcemia near parturition 299
Parathyroid hyperplasia 299
Hyperparathyroidism secondary to renal disease 300
Hyperparathyroidism secondary to nutritional
imbalances 301
Primary parathyroid hyperplasia 301
Parathyroid suppression associated with vitamin D
intoxication from calcinogenic plants and
rodenticides 301
Neoplasms of the parathyroid glands 302
Hypercalcemia associated with neoplasms of
nonparathyroid origin 305
THYROID GLAND 310
Development, structure, and function 310
Embryologic development of the thyroid gland 310
Structure of the thyroid gland 310
Biosynthesis of thyroid hormones 311
Thyroid hormone secretion 312
Action of thyroid hormones 313
Diseases of the thyroid gland 314
Developmental disturbances of the thyroid gland 314
Degenerative changes of the thyroid gland 314
Hypofunction of the thyroid gland 315
Evaluation of thyroid function 319
Hyperplasia of the thyroid gland 320
Thyrotoxic effects of drugs and chemicals 323
Neoplasms of the thyroid gland 326
Follicular cell adenoma 326
Hyperthyroidism associated with thyroid tumors 327
Follicular cell carcinoma 329
Neoplasms of thyroglossal duct remnants 332
Thyroid C-cell (parafollicular) tumors 332
ADRENAL CORTEX 336
Development, structure, and function 336
Embryonic development of the adrenal gland 336
Structure of the adrenal gland 336
Biosynthesis and action of adrenal cortical hormones 337
Diseases of the adrenal cortex 338
Developmental disturbances of the adrenal cortex 338
Congenital enzyme defects of adrenal cortical
steroidogenesis 339
Degenerative changes of the adrenal cortex 339
Inflammation of the adrenal cortex (adrenalitis) 340
Mechanisms of toxicity of the adrenal cortex 340
Adrenal lesions associated with hypoadrenocorticism 341
Hyperplasia of the adrenal cortex 343
269
270 CHAPTER 3  •  Endocrine Glands General Considerations

Neoplasms of the adrenal cortex 343
Myelolipoma 343
Cortical adenoma 344
Cortical carcinoma 345
Hyperadrenocorticism 346
Adrenal tumors in ferrets 347
ADRENAL MEDULLA 348
Development, structure, and function 348
Embryonic development and structure 348
Biosynthesis of catecholamine hormones 348
Neoplasms of adrenal medullary secretory cells 349
Pheochromocytoma and malignant pheochromocytoma 349
Mechanisms of adrenal medullary tumor development 351
Adrenal medullary hyperplasia 352
Neoplasms of cells of the sympathetic nervous
system in adrenal medulla 352
Neuroblastoma 352
Ganglioneuroma 353
Tumors metastatic to the adrenal medulla 353
PARAGANGLIOMAS (CHEMODECTOMAS) 354
Development, structure, and function 354
Aortic body adenoma and carcinoma 354
Carotid body adenoma and carcinoma 355
Heart-base tumors derived from ectopic thyroid 356
Extra-adrenal paragangliomas 356
Orbital (extra-adrenal) paragangliomas 356
MULTIPLE ENDOCRINE NEOPLASIA (MEN) 356

ACKNOWLEDGMENTS transport of raw materials and secretory products between the

We gratefully acknowledge the contributions to previous versions blood and endocrine cells, the peripheral cytoplasmic exten-
of this chapter by Drs. Ken Jubb, Peter Kennedy, Nigel Palmer, sions of capillary endothelial cells have fenestrae covered by
and Charles Capen. a single membrane.

GENERAL CONSIDERATIONS
Endocrine glands are collections of specialized cells that syn-
thesize, store, and release their secretions directly into the
bloodstream. They are sensing and signaling organs capable of
responding to changes in the internal and external environ-
ment to coordinate a multiplicity of activities that maintain
homeostasis.
Secretions of endocrine glands are peptide, steroid, catechol-
amine, or iodothyronine hormones that are transported by the
blood to influence the functional activity of target cells elsewhere
in the body. Other populations of cells are concerned with
hormone degradation after it has exerted its physiologic func-
tion. This is accomplished by peptidases on the cell surface,
uptake by cells and degradation by lysosomal enzymes, or
conjugation with glucuronide or sulfate and excretion in the
bile or urine.
Endocrine glands are small compared with other organs,
widely distributed in the body, and connected with one
another by the bloodstream. They are richly supplied with
blood, and there is a close anatomic relationship between
endocrine cells and the capillary network. To facilitate rapid
Types of hormones
Polypeptide hormones
The primary site of action for polypeptide hormones is the plasma
membrane of target cells. Receptor proteins for the hormone
are present on the outer surface of the plasma membrane.
These hormones are water soluble and have a short half-life in
blood that is usually measured in minutes.
Polypeptide hormones activate target cells by binding to
receptors that belong to the superfamily of G protein–coupled
receptors. Activation of these receptors is followed by a
cascade of intracellular signaling steps. Heterotrimeric G pro-
teins consist of various α, β, and γ subunits that are involved
in conferring specificity to the signaling system (Fig. 3-1). For
example, Gαs activates adenylyl cyclase isoforms, and Gαq
activates phospholipase C, thereby stimulating different intra-
cellular signaling pathways. Downstream responses include
activation of nuclear factor κB (NFκB), mitogen-activated
protein (MAP) kinases, the Wnt/β-catenin pathways, or others.
The specificity of hormone signaling depends on the presence of
the receptor on target cells and ligand preference of the receptor.
For example, the melanocortin receptor family exists in 5
isoforms that are expressed on melanocytes as well as

N GPCR Adenylyl
Phospholipase C (↑) cyclase (↑) extracellular

DAG
C ATP intracellular
PKC q  s
(active) GTP  GTP
Ca2 GDP  cAMP
IP3
G proteins PKA PKA
(active)
Ca2

Figure 3-1  Intracellular signaling by polypeptide hormones depends on G protein subunit

activation and intracellular Ca2+, cAMP, and diacylglycerol activation of cytoplasmic protein
kinases. DAG, diacylglycerol; GDP, guanosine diphosphate; GPCR; G protein–coupled receptor;
GTP, guanosine-5′-triphosphate; IP3, inositol triphosphate; PKA, protein kinase A; PKC, protein
kinase C.
 General Considerations
lymphocytes, the brain, and adrenal cortex. It has a variety of
ligands; however, binding to the melanocortin receptor (MR2)
in the adrenal cortex is restricted to adrenocorticotropic
hormone (ACTH). In addition, the level of receptor expres-
sion and receptor conformation, which can be influenced by
ligands or the presence of accessory or scaffolding proteins,
ensure that hormones exert their specific effects after receptor
binding.
Endocrine cells that produce polypeptide hormones have
a well-developed endoplasmic reticulum with many attached
ribosomes, where the hormone is assembled, and a prominent
Golgi apparatus for packaging hormone into granules for
intracellular storage and transport. Secretory granules are
unique to polypeptide hormone- and catecholamine-secreting
endocrine cells and provide a mechanism for intracellular
storage of substantial amounts of preformed active hormone.
The membrane-limited granules are macromolecular aggrega-
tions of active hormone, often associated with a specific
binding protein and other biologically active factors. When the
cell receives a signal for hormone secretion, secretory granules
are directed by microtubules to the periphery of the endocrine
cell. The limiting membrane of the granule then fuses with
the plasma membrane of the cell. The hormone-containing
granule core is extruded into the extracellular perivascular
space by emiocytosis (secretion of entire secretory granules into
the extracellular space) or exocytosis (fusion with the cell
membrane and release of granule contents into the extracel-
lular fluid). The granule core is subsequently fragmented, and
hormone is rapidly transported through capillary fenestrae
into the circulation. Hormone synthesized in excess of require-
ment is degraded by fusion of the hormone-containing gran-
ules with lysosomes, a process termed crinophagy.
Steroid hormones
Steroid hormone–secreting endocrine cells are characterized by
large lipid vacuoles in the cytoplasm that contain cholesterol
esters and other precursor molecules. The lipid vacuoles are in
close proximity to an extensive tubular network of smooth
endoplasmic reticulum and large mitochondria that contain
the hydroxylase and dehydrogenase cytochrome P450 enzyme
systems. These enzymes function to attach or modify various
side chains to the basic steroid molecule. Steroid-producing
cells lack secretory granules and do not store significant
amounts of preformed hormone. They are dependent on con-
tinued biosynthesis to maintain the normal secretory rate for
a particular hormone.
Steroid hormones originating from cholesterol precursor
molecules account for ~15% of mammalian hormones. They
are lipid soluble, which facilitates their transport through the
cell membrane. In the cytoplasm, steroid hormones bind to
receptors that form homodimers or heterodimers, migrate to
the nucleus, and function as nuclear receptors and transcrip-
tion factors. The steroid hormone receptors have binding  parenchyma is compressed to various degrees, depending
sites for the steroid hormone, specific regions of the genomic
DNA, and accessory regulatory proteins. After binding to the
genomic DNA and accessory proteins, the receptor complexes
either upregulate or downregulate gene transcription of multiple
genes and direct protein synthesis by the target cells. Recent
evidence suggests that nongenomic steroid hormone signaling
exists under specific circumstances. The nongenomic cellular
responses to steroid hormones are very fast and may involve
cell membrane–binding proteins. Steroid hormones have a
long half-life in blood (typically measured in hours) and revers-
271
ibly bind to high-affinity, specific binding proteins for trans-
port in plasma.
Catecholamine and iodothyronine hormones
These hormones are tyrosine derivatives. They account for
approximately 5% of mammalian hormones and include the
catecholamines (epinephrine, norepinephrine) secreted by the
adrenal medulla, and iodothyronines (thyroxine [T4] and triio-
dothyronine [T3]) produced by follicular cells of the thyroid
gland. Catecholamines share similar mechanisms of action
with polypeptide hormones, whereas iodothyronines more
closely resemble the steroid hormones.
Proliferative lesions in endocrine glands
Characteristics
Endocrinologically active (functional) neoplasms derived
from polypeptide hormone–secreting endocrine cells consist
of one predominant cell type and usually are associated clini-
cally with the autonomous secretion of one polypeptide
hormone. However, there is evidence from immunohisto-
chemical and electron microscopic investigations that some
endocrine tumors are composed of more than one type of
neoplastic cell and are capable of synthesizing multiple
hormones.
The histologic separation of nodular hyperplasia, adenoma,
and carcinoma often is more difficult in endocrine glands than in
most other organs of the body. For many endocrine glands (espe-
cially thyroid C cells, secretory cells of the adrenal medulla,
and specific trophic hormone–secreting cells of the adenohy-
pophysis), there is a continuous spectrum of proliferative
lesions between focal hyperplasia and adenomas derived from
a specific population of cells.
It is a common feature of endocrine glands that prolonged
stimulation of a population of secretory cells predisposes to the
subsequent development of a higher than expected incidence of
tumors. Long-term stimulation leads to the development of
clones of cells within the hyperplastic endocrine gland that
grow more rapidly and are more susceptible to neoplastic
transformation when exposed to promoting carcinogens.
Nodular hyperplasia usually appears as multiple small foci,
in one or both (for paired) endocrine gland(s), that are well
demarcated but not encapsulated from adjacent normal cells.
Cells comprising an area of nodular hyperplasia closely resem-
ble the cell of origin; however, the cytoplasmic area may be
slightly enlarged and the nucleus more hyperchromatic than
in the normal endocrine cell.
Adenomas are solitary nodules, in one (or occasionally
both for paired) endocrine gland(s), that are larger than the
multiple foci of nodular hyperplasia. They are sharply demar-
cated from the adjacent normal glandular parenchyma, often
by a thin, partial to complete, fibrous capsule. The adjacent
upon the size of the adenoma. Cells comprising an adenoma
closely resemble the cell of origin morphologically and in their
architectural pattern of arrangement; however, there often are
histologic differences, such as multiple layers of cells lining
follicles or vascular trabeculae and solid clusters of secretory
cells subdivided into packets by a fine fibrovascular stroma.
Carcinomas usually are larger than adenomas and produce
enlargement in one (or occasionally both, for paired) endo-
crine gland(s). The separation between adenoma and carci-
noma of an endocrine gland often is more difficult than in
272 CHAPTER 3  •  Endocrine Glands
other tissues. Histopathologic features that are indicative of
malignancy in an endocrine tumor include intraglandular inva-
sion, invasion into and through the capsule of the gland with
growth in the periglandular fibrous and adipose connective
tissues, formation of tumor cell thrombi within vessels (espe-
cially muscular walled), and particularly the establishment of
metastases at distant sites. The growth of neoplastic cells in a
subendothelial location in highly vascular benign endocrine
tumors should not be mistaken for vascular invasion, and
clusters of neoplastic cells may be artifactually forced into the
lumen of thin-walled vessels and be misinterpreted as tumor
cell emboli. Malignant endocrine cells often are more pleo-
morphic (including oval or spindle shaped) than normal, but
nuclear pleomorphism is not a consistent criterion to distin-
guish adenomas and carcinomas. Mitotic figures may be fre-
quent in malignant endocrine cells, but the significance of this
criterion can vary considerably with the degree of background
stimulation of the endocrine gland.
Functional aspects of endocrine tumors
Many neoplasms derived from endocrine glands are endocri-
nologically active (functional), secrete an excessive amount of
hormone either continuously or episodically, and result in
clinical syndromes of hormone excess. Many examples occur
in different animal species, including hyperadrenocorticism
associated with either ACTH-secreting pituitary corticotroph
adenomas or adrenocortical neoplasms in dogs, hypoglycemia
with β-cell neoplasms of the pancreatic islets in dogs and
ferrets, hyperthyroidism associated with adenomas, and carci-
nomas derived from thyroid follicular cells in cats, among
many others.
Measurement of hormone levels in serum or plasma in the
basal, suppressed, or stimulated state and, in some instances,
hormonal metabolites in the urine over a 24-hour period of excre-
tion is essential to confirm that an endocrine tumor is releasing
hormone at an abnormally elevated rate. An endocrine tumor
also can be interpreted as being endocrinologically active if
either the rim of normal tissue around the tumor or the oppo-
site of paired endocrine glands undergoes atrophy because of
negative feedback inhibition by the elevated hormone levels
or an altered blood constituent. In response to the autono-
mous secretion of hormone by the tumor, these non-neoplastic
secretory cells become smaller than normal, especially in the
cytoplasmic area, and eventually the number of cells is
decreased. Functional pituitary neoplasms secreting an excess
of a specific trophic hormone (e.g., ACTH) will be associated
with hypertrophy and hyperplasia of target cells in the adrenal
cortex (zonae fasciculata and reticularis).
Mechanisms of endocrine disease
Primary hyperfunction of an endocrine gland
In primary hyperfunction of an endocrine gland, cells (often
neoplastic and derived from the gland) synthesize and secrete
hormone at an autonomous rate in excess of the body’s ability
to use and subsequently degrade the hormone, thereby result-
ing in functional disturbances of hormone excess. These include
hyperfunction of parathyroid chief cells, thyroid C (parafol-
licular) cells, β cells of the pancreatic islets, secretory cells of
the adrenal medulla, and follicular cells of the thyroid, among
others.
The autonomous secretion of parathyroid hormone results in
progressive and generalized demineralization of the skeleton,
General Considerations
leading to hypercalcemia, which results in soft tissue miner-
alization and the development of renal calculi. The acceler-
ated osteoclastic resorption of bone results in marked thinning
and osteoclastic tunneling of cortical bone, and predisposes
bone to the development of pathologic fractures in chronic
cases.
The autonomous hypersecretion of thyroxine and triiodothy-
ronine is a common endocrinopathy in older cats. This hyper-
secretion is associated with a spectrum of proliferative lesions
of thyroid follicular cells. The majority of the functional
thyroid lesions are multifocal hyperplasia or adenomas derived
from follicular cells, which can be controlled surgically, chemi-
cally, or with radioactive iodide. Thyroid follicular adenocar-
cinomas that metastasize to regional lymph nodes are rare in
cats. The functional disturbances of hyperactivity, weight loss
despite increased appetite, hyperthermia, and tachycardia
reflect long-term stimulation of multiple populations of target
cells by the abnormally elevated blood levels of thyroid
hormones.
Secondary hyperfunction of an endocrine gland
In secondary hyperfunction of an endocrine gland, a lesion in
one organ (e.g., adenohypophysis) secretes an excess of a
trophic hormone that leads to long-term stimulation and
hypersecretion of hormone by a target organ. An example of
this pathogenic mechanism in animals is the ACTH-secreting
tumor derived from pituitary corticotrophs in the pars distalis or
intermedia of dogs. The clinical signs and lesions in the animal
primarily are the result of the elevated blood cortisol levels
associated with the ACTH-stimulated hypertrophy and
hyperplasia of the zonae fasciculata and reticularis of the
adrenal cortex (see Fig. 3-101D). The syndrome of cortisol
excess in dogs is characterized by progressive alopecia, hyper-
pigmentation, and muscle wasting caused by the protein cata-
bolic effects of glucocorticoids (see Fig. 3-104). Some dogs
have a similar marked adrenocortical enlargement and clinical
evidence of cortisol excess, but without a tumor in the pitu-
itary gland. These dogs may have a change in their set point
to the negative feedback signal (e.g., blood cortisol). This can
be caused by an abnormal accumulation of certain neurotrans-
mitter substances (e.g., serotonin) near neurosecretory neurons
in the hypothalamus that secrete corticotrophic hormone–
releasing factor. The end result is corticotroph hyperplasia,
elevated ACTH levels in the blood, and long-term stimulation
of the adrenal cortex, which results in hyperplasia of the zona
fasciculata and zona reticularis and the clinical syndrome of
cortisol excess.
Primary hypofunction of an endocrine gland
In primary hypofunction of an endocrine gland, hormone
secretion is subnormal because of extensive destruction of
secretory cells by a disease process, the failure of an endocrine
gland to develop properly, or the result of a specific biochemi-
cal defect in the synthetic pathway of a hormone.
• Immune-mediated injury causes hypofunction of several
endocrine glands in animals, including the parathyroid
gland, adrenal cortex, and thyroid gland. Thyroiditis caused
by this mechanism is characterized by marked infiltration
of lymphocytes and plasma cells with progressive destruc-
tion of secretory parenchyma.
• Failure of development also results in primary hypofunction
of an endocrine gland. An example of this mechanism in
animals is the failure of oropharyngeal ectoderm to
 General Considerations
differentiate into trophic hormone–secreting cells of the
adenohypophysis in dogs, resulting in pituitary dwarfism
and a failure to attain somatic maturation (see Fig. 3-8A,
B). A large, multicompartmented cyst is present on the
ventral aspect of the brain in the pituitary region of  reticularis are severely atrophied compared with those in
these dogs. The cyst compresses the normally developed
neurohypophysis and results in disturbances of water
metabolism.
• Another form of primary hypofunction is failure of hormone
synthesis caused by a genetic defect in a biosynthetic pathway
or lack of a specific enzyme. A well-documented example of
this condition is vitamin D–dependent rickets in pigs,
which is caused by lack of 25-hydroxycholecalciferol-  cortex. The majority of thyroid follicles are large, lined by
1-α-hydroxylase in the proximal convoluted tubules of
the kidney. This enzyme is needed to synthesize the  with densely stained colloid because of a lack of TSH.
hormonal form of active vitamin D (calcitriol). Blood
calcium and phosphate levels progressively decrease
because of the subnormal ability of the pig to convert  niferous tubules in the testis are small with little evidence of
25-hydroxycholecalciferol to the biologically active hor-
monal form (1,25-dihydroxycholecalciferol; calcitriol) in
the kidney. The lowered blood concentrations of calcium
and phosphate lead to a failure of mineralization of osteoid
and persistence of cartilage in the physes, resulting in
severe deformities in the skeleton (see Vol. 1, Bones and
joints).
• Congenital dyshormonogenic goiter in sheep, goats, and
cattle is an example of primary hypofunction caused by
failure of hormone synthesis. The low blood thyroxine (T4)
and triiodothyronine (T3) levels and clinical evidence of
severe hypothyroidism in these animals are the result of an
inability of follicular cells to synthesize thyroglobulin. The
molecular defect is faulty processing of the primary tran-
scripts for thyroglobulin messenger ribonucleic acid
(mRNA) and aberrant transport of mRNA from the
nucleus to ribosomes. This results in subnormal amounts
of thyroglobulin mRNA in follicular cells, particularly
mRNA that is attached to membranes of the endoplasmic
reticulum in the cytoplasm. These animals do not have a
defect in the ability of the thyroid to concentrate 131I;
however, there is a greatly reduced ability to iodinate
tyrosyl residues and form thyroid hormones. In the hypo-
thalamus and adenohypophysis, subnormal blood levels of
thyroxine and triiodothyronine, result in an increased
secretion of thyroid-stimulating hormone (TSH) and sub-
sequently activation of the thyroid follicular cells, causing
intense hyperplasia (see Fig. 3-69).
Secondary hypofunction of an endocrine gland
In secondary hypofunction of an endocrine gland, a destructive
lesion in one organ, such as the pituitary, interferes with the secre-
tion of trophic hormone. This results in hypofunction of the
target endocrine glands. Large, endocrinologically inactive,
pituitary neoplasms in adult dogs, cats, and other animal
species may interfere with the secretion of the multiple pitu-
itary trophic hormones and result in clinically detectable
hypofunction of the adrenal cortex, follicular cells of the
thyroid, and gonads.
Target endocrine organs respond dramatically to a lack of
normal production of pituitary trophic hormones. The adrenal
glands of animals with large nonfunctional pituitary adenomas
are small and may be difficult to find at autopsy. The adrenals
consist primarily of medullary tissue surrounded by a narrow
zone of atrophic cortex. The adrenal cortex appears as a thin
273
yellow-brown rim composed of a moderately thickened
capsule and secretory cells of the outer (aldosterone-
producing) layer, the zona glomerulosa, which is under limited
ACTH control (see Fig. 3-19). The zonae fasciculata and
normal adrenal glands, secrete subnormal amounts of gluco-
corticoid hormones, and have a blunted increase in cortisol or
corticosterone following the administration of exogenous
ACTH. By comparison, thyroid glands in animals with large
pituitary adenomas disrupting normal trophic hormone (e.g.,
TSH) production are either near-normal size or only slightly
reduced in size to a much lesser degree than is the adrenal
flattened (atrophic) cuboidal follicular cells, and distended
Calcitonin-secreting thyroid C cells function normally because
they are not controlled by pituitary trophic hormones. Semi-
active spermatogenesis, and the ovarian cortex is devoid of
functional ovarian follicles.
Secondary hypofunction of an endocrine gland also occurs
when insufficient iodide ion is available for thyroid follicular
cells to synthesize adequate amounts of thyroid hormones to
meet the animal’s daily requirements. The thyroid gland
attempts to compensate by increasing the efficiency of iodide
trapping and by preferentially synthesizing more T3 than T4,
thereby saving a molecule of iodide for every molecule of
thyroid hormone produced. Dietary iodine deficiency resulting
in diffuse hyperplastic goiter (see Fig. 3-67) was common in
many areas of the world before the widespread addition of
iodized salt to animal diets and still occurs worldwide in
domestic animals and humans living in iodine-deficient areas.
Marginally iodine-deficient diets that contain goitrogenic
compounds may cause severe thyroid follicular cell hyperpla-
sia and goiter. Goitrogenic substances include thiouracil, sul-
fonamides, and a number of plants of the family Brassicaceae.
Offspring of females fed iodine-deficient diets are likely to
develop severe thyroidal follicular cell hyperplasia and have
clinical signs of hypothyroidism. The affected lobes are firm
and dark red because an extensive interfollicular capillary
network develops under the influence of long-term TSH stim-
ulation. Follicles are irregular in size and shape in hyperplastic
goiter because they contain various amounts of lightly eosino-
philic and vacuolated colloid. Some follicles collapse because
of the lack of colloid. Their lining epithelial cells are columnar
and have deeply eosinophilic cytoplasm and small hyperchro-
matic nuclei. The follicles are lined by single or multiple layers
of hyperplastic follicular cells that form papillary projections
into the lumens of some follicles.
Endocrine hyperactivity secondary to diseases of
other organs
A common example of endocrine hyperactivity secondary to
diseases of other organs in animals is the hyperparathyroidism
that develops secondary to chronic renal failure or nutritional
imbalances. In the renal form, there is retention of blood
phosphate and inadequate production of the active form of
vitamin D (1,25-dihydroxycholecalciferol; calcitriol) by the
renal tubules. This results in reduced negative feedback of the
parathyroid gland chief cells because of the lack of calcitriol
and persistent activation of the parathyroid hormone gene and
stimulation of chief cell proliferation. Some animals with
chronic renal disease may also have hypocalcemia, but this is
274 CHAPTER 3  •  Endocrine Glands
not a consistent finding. All parathyroid glands are affected.
They are enlarged initially because of organellar hypertrophy
and later chief cell hyperplasia. Although skeletal involvement
is generalized with hyperparathyroidism, it does not affect all
parts uniformly. Bone lesions include resorption of bone from
alveolar sockets and loss of lamina dura dentes that occur early
in the course of the disease. This results in loose teeth that
may be dislodged easily and interfere with mastication.
Because of the accelerated rate of resorption, cancellous bones
of the maxilla and mandible become weakened, are readily
pliable (“rubber jaw”), and the jaws fail to close properly.
Nutritional hyperparathyroidism develops in animals fed
abnormal diets that are low in calcium, high in phosphate or
oxalate, or deficient in vitamin D for certain nonhuman pri-
mates. Unsupplemented all-meat diets fed to carnivores fail
to supply the daily requirements for calcium, leading to pro-
gressive hypocalcemia that stimulates the parathyroid gland
to increased activity. After a carnivore is fed an imbalanced
diet for several weeks to months, its skeleton becomes severely
demineralized and predisposed to fractures. The cortices  D3 diets.
of long bones are thin and the medullary cavity widened 
because of intense osteoclastic resorption of bone that is stim-
ulated indirectly by the increased secretion of parathyroid
hormone.
Hypersecretion of hormones by
non-endocrine tumors
Certain neoplasms of non-endocrine tissues in both animals
and humans either secrete hormones or molecules that share
chemical and/or biological characteristics with the “native”
hormones secreted by an endocrine gland. Most of the humoral
substances secreted by non-endocrine tumors are peptides
rather than steroids, iodothyronines, or catecholamines, which
require more complex biosynthetic pathways. For example,
humoral hypercalcemia of malignancy (HHM) is a clinical
syndrome produced primarily by the autonomous secretion of
parathyroid hormone–related protein (PTHrP) by cancer
cells. PTHrP binds and activates the parathyroid hormone
(PTH) receptor in target cells (e.g., bone and kidney) with
equal potency to PTH and results in persistent, often life-
threatening, hypercalcemia.
Humoral hypercalcemia of malignancy is associated with
diverse malignant neoplasms in animal and human patients.
HHM occurs commonly in dogs with T-cell lymphoma and
adenocarcinomas derived from apocrine glands of the anal sac.
Characteristic findings in patients with HHM include hyper-
calcemia, hypophosphatemia, hypercalciuria (often with
decreased fractional calcium excretion), increased fractional
excretion of phosphate, and increased osteoclastic bone
resorption. The direct effects of PTHrP on bone and kidney, and
indirect effects on the intestine produce hypercalcemia. Increased
osteoclastic bone resorption is a consistent finding in HHM
with increased calcium release from bone. The kidney plays a
critical role in the pathogenesis of hypercalcemia and hypo-
phosphatemia, because renal calcium reabsorption is stimu-
lated by PTHrP and phosphate reabsorption is inhibited as  fetal hypothalamic-adenohypophyseal-adrenocortical axis in
a result of binding to and activation of the renal PTH recep-
tors. In some forms of HHM, there is increased serum 1,25-  placenta. Although the presence or absence of functional
dihydroxyvitamin D3 that may increase calcium absorption
from the intestine. Although excessive secretion of biologi-
cally active PTHrP plays a central role in the pathogenesis of
hypercalcemia in most forms of HHM, cytokines such as
interleukin-1, tumor necrosis factor-α, transforming growth
General Considerations
factors, and 1,25-dihydroxyvitamin D3 (calcitriol) may have
synergistic or cooperative actions with PTHrP.
Endocrine dysfunction resulting from failure of
target cell response
Endocrine dysfunction resulting from a failure of target cell
response has been recognized coincident with a more com-
plete understanding of how hormones convey their biological
message. Insulin resistance associated with obesity in both
animals and humans can result from nonresponsive receptors
on the surface of target cells. The absence of vitamin D recep-
tors results in vitamin D–dependent rickets, type II, also called
vitamin D–resistant rickets (VDRR). New World primates
have a relative end-organ resistance to calcitriol and require
high levels of vitamin D3 in their diet. The common marmoset
has been shown to represent a model of vitamin D–dependent
rickets, type II. Marmosets have increased serum calcitriol
concentrations compared to rhesus monkeys, and some mar-
mosets developed osteomalacia even when on high vitamin
Failure of fetal endocrine function
Subnormal function of the fetal endocrine system, especially in
ruminants, may disrupt normal fetal development and result in
prolongation of the gestation period. In Guernsey and Jersey
cattle, a genetic failure of development (aplasia) of the adeno-
hypophysis results in a lack of fetal pituitary trophic hormone
secretion during the last trimester and hypoplastic develop-
ment of target endocrine organs (e.g., adrenal cortex, thyroid
follicular cells, gonads). Fetal development is normal up to
approximately 7 months of gestation, but subsequently fetal
growth ceases regardless of how long the viable fetus is
retained in utero.
Prolongation of gestation also occurs in ewes that ingest
the plant Veratrum californicum early in gestation. Toxins in
the plant cause extensive malformations of the central nervous
system (CNS) and hypothalamus in lambs. Although the
adenohypophysis is present, it is unable to secrete normal
amounts of trophic hormones (e.g., ACTH) because it lacks
the necessary fine control derived from the releasing hor-
mones of the hypothalamus. Target endocrine organs in the
fetus are hypoplastic and the adrenal cortex does not differ-
entiate completely into the 3 distinctive zones that secrete
corticosteroid hormones. The plant contains potent steroidal
alkaloids that inhibit neural tube development when ingested
by the ewe between days 9 and 14 of gestation. Cyclopia and
extensive CNS malformations are found in lambs. Arhinen-
cephaly and lack of development of nasal bones accompany
the formation of a proboscis-like structure. The lambs retained
in the uterus continue to grow beyond the normal gestation
period.
The concepts that have emerged from the study of these
naturally occurring diseases are (1) fetal hormones are neces-
sary for final growth and development in utero in certain
animals and (2) normal parturition at term requires an intact
these species working in concert with trophoblasts of the
adenohypophyseal tissue determines whether the fetus con-
tinues to grow in utero, the pathogenesis of prolongation of
the gestational interval is similar in these 2 examples. The
subnormal development of the fetal adrenal cortex results in
inadequate secretion of cortisol and failure to induce the
 General Considerations
C
M Thyroid
Figure 3-2  Failure of fetal endocrine function. Adrenal cortical
hypoplasia in a calf with prolonged gestation. The adrenal cortex
(C) is markedly reduced in thickness, and the adrenal medulla
(M) is relatively more prominent. Bar = 1 cm. Note that the
adrenal cortex is darker than the medulla in cattle.
17-α-hydroxylase in the placenta that converts precursor mol-
ecules (e.g., progesterone) to estrogen. The fetal adrenal gland
is small, and there is incomplete development of the distinct
zones of the cortex (Fig. 3-2). The dam’s circulating proges-
terone is maintained near mid-gestational concentrations, and
there is a lack of the marked increase in estrogens that nor-
mally occurs near term and results in parturition by stimulat-
ing the local synthesis of prostaglandins in the uterus.
Endocrine dysfunction resulting from abnormal
degradation of hormone
Increased degradation of hormone. The long-term adminis-
tration of various xenobiotics (e.g., phenobarbital and others)
results in the induction of liver enzymes (e.g., T4–uridine
diphosphate [UDP]-glucuronyl transferase) that increases the
degradation of T4, especially in laboratory rats, and to a lesser
degree in dogs. Endocrine gland and target cell function are
normal. The chronic disruption of the thyroid-pituitary axis
and augmented TSH secretion in rodents, especially male rats,
often increases the development of thyroid follicular cell
tumors in chronic toxicity and oncogenicity studies with
certain drugs and chemicals. Hepatic microsomal enzymes
play an important role in thyroid hormone economy because
glucuronidation is the rate-limiting step in the biliary excre-
tion of T4 and sulfation, primarily by phenol sulfotransferase,
for the excretion of T3. Long-term exposure of rats to a wide
variety of different chemicals induces these enzyme pathways
and results in chronic stimulation of the thyroid by disrupting
the hypothalamic-pituitary-thyroid axis. The resulting chronic
stimulation of the thyroid by increased circulating levels of
TSH in rats often results in a greater risk of developing tumors
derived from follicular cells in chronic toxicity/carcinogenicity
studies with these compounds (Fig. 3-3). The chronic admin-
istration of phenylbutazone, a nonhormonal antipyretic com-
pound used in the medical management of inflammatory
conditions of the musculoskeletal system, especially in horses,
which is a hepatic microsomal enzyme inducer, often results
in moderate thyroid enlargement by a similar mechanism.
Decreased degradation of hormone. The rate of secretion
of hormone by an endocrine gland may be normal with this
275
Pituitary
TSH
(↓) T4-/T3
T4-/T3 Thyroid
hyperplasia/neoplasia
T4
Xenobiotic (↑) UDP-Glucuronyl transferase
chemical
Bile
T4-Glucuronide
T4-Glucuronide
Feces
Figure 3-3  Hepatic microsomal enzyme induction by the chronic
administration of xenobiotics (goitrogens) in rodents, leading to
thyroid follicular cell hyperplasia, and to neoplasia with use of
large doses of compound. T3, triiodothyronine; T4, thyroxine;
TSH, thyroid-stimulating hormone.
mechanism, but blood hormone levels are persistently ele-
vated, thereby simulating a syndrome of hypersecretion,
resulting from a decreased rate of hormone degradation. 
The classic example of this pathogenic mechanism is the
syndrome of feminization resulting from hyperestrogenism
associated with cirrhosis and decreased hepatic degradation of
estrogens.
Syndromes of iatrogenic hormone excess
Direct effects. The administration of hormone, either directly
or indirectly, influences the activity of target cells with this
mechanism and results in important functional disturbances.
It is well recognized that the administration of potent prepara-
tions of adrenocortical steroids at inappropriately high daily
doses for prolonged intervals in the symptomatic treatment of
various diseases can produce most of the functional distur-
bances associated with endogenous hypersecretion of cortisol.
Similarly, the administration of excessively large doses of
insulin can result in hypoglycemia, and an excess of exogenous
T4 or T3 may result in hyperthyroidism, especially in certain
species (e.g., cats) that have limited capacity to conjugate T4
with glucuronic acid and enhance biliary excretion.
Indirect effects. The administration of progestins to dogs
indirectly results in a syndrome of growth hormone excess.
The injection of medroxyprogesterone acetate for the preven-
tion of estrus in dogs stimulates expression of the growth
hormone gene in the mammary gland leading to an elevation
in circulating growth hormone levels, and results in the classic
clinical manifestations and lesions of acromegaly (e.g., exces-
sive skin folds, respiratory stridor resulting from increased soft
tissue in oropharyngeal region, expansion of interdental spaces,
and hyperglycemia) (see Fig. 3-16).
Further reading
Capen CC. Toxic responses of the endocrine system. In: Klaassen CD,
editor. Casarett and Doull’s Toxicology: The Basic Science of Poisons.
7th ed. New York: McGraw Hill; 2007. p. 807-879.
 275.e1

Further reading
Cooray SN, Clark AJL. Melanocortin receptors and their accessory
proteins. Mol Cell Endocrinol 2011;331:215-221.
Gayrard V, et al. Competitive binding to plasma thyroid hormone trans-
port proteins and thyroid dysfunction by phenylbutazone used as
a probe. Gen Comp Endocrinol 2011;174:225-231.
Gröne A, et al. Altered parathyroid hormone-related protein secretion
and mRNA expression in squamous cell carcinoma cells in vitro. Eur
J Endocrinol 1996;135:498-505.
Kooistra HS, et al. Progestin-induced growth hormone (GH) production
in the treatment of dogs with congenital GH deficiency. Domest
Anim Endocrinol 1998;15:93-102.
Kumar R, McEwan IJ. Allosteric modulators of steroid hormone
receptors: structural dynamics and gene regulation. Endocr Rev
2012;33:271-299.
Mol JA, et al. Progestin-induced mammary growth hormone produc-
tion. Adv Exp Med Biol 2000;480:71-76.
Morris DD, Garcia M. Thyroid-stimulating hormone response test in
healthy horses, and effect of phenylbutazone on equine thyroid
hormones. Am J Vet Res 1983;44:503-507.
Rijnberk A, et al. Acromegaly associated with transient overproduction
of growth hormone in a dog. J Am Vet Med Assoc 1980;177:534-
557.
Rosol TJ, Capen CC. Calcium-regulating hormones and diseases of
abnormal mineral (calcium, phosphorus, magnesium) metabolism.
In: Kaneko JJ, et al., editors. Clinical Biochemistry of Domestic
Animals. 5th ed. New York: Academic Press; 1997. p. 619-702.
Rosol TJ, et al. Parathyroid hormone (PTH)-related protein, PTH, and
1,25-dihydroxyvitamin D in dogs with cancer-associated hypercal-
cemia. Endocrinology 1992;131:1157-1164.
Spiegel AM. Inborn errors of signal transduction: mutations in G pro-
teins and G protein-coupled receptors as a cause of disease. J Inher
Metab Dis 1997;20:113-121.
Tennent BJ, Beamer WG. Ovarian tumors not induced by irradiation
and gonadotropins in hypogonadal (hpg) mice. Biol Reprod
1986;34:751-760.
Vilardaga J-P, et al. Molecular basis of parathyroid hormone receptor
signaling and trafficking: a family B GPCR paradigm. Cell Mol Life
Sci 2011;68:1-13.
Wettschureck N, Offermanns S. Mammalian G proteins and their cell
type specific functions. Physiol Rev 2005;85:1159-1204.
Winkler I, et al. Pseudovitamin D deficiency rickets in pigs: in vitro
measurements of renal 25-hydroxycholecalciferol-1-hydroxylase
activity. Zentralbl Veterinärmed [A] 1982;29:81-88.
276 CHAPTER 3  •  Endocrine Glands
Grammatopoulos DK. Insights into mechanisms of corticotropin-
releasing hormone receptor signal transduction. Br J Pharmacol
2011;166:85-97.
Groeneweg FL, et al. Mineralocorticoid and glucocorticoid receptors at
the neuronal membrane, regulators of nongenomic corticosteroid
signaling. Mol Cell Endocrinol 2012;350:299-309.
Rosol TJ, Capen CC. Biology of disease: mechanisms of cancer-induced
hypercalcemia. Lab Invest 1992;67:680-702.
Rosol TJ, et al. Endocrine system. In: Haschek WM, et al., editors.
Haschek and Rousseaux’s Handbook of Toxicologic Pathology.
Elsevier/Academic Press; 2013. p. 2391-2492.
Taylor CW, Tovey SC. From parathyroid hormone to cytosolic Ca2+
signals. Biochem Soc Trans 2012;40:147-152.
PITUITARY GLAND
Although the pituitary gland is partially derived from the
oropharyngeal ectoderm, it is completely separated from the
oral cavity in adult animals. It is situated in the sella turcica,
a concavity of the sphenoid bone, and enveloped by an  but they are considered supporting cells of the secretory
extension of dura mater. The pituitary gland (hypophysis)  cells and the source of follicles that occasionally form in
is subdivided anatomically into the adenohypophysis and
neurohypophysis.
Development, structure, and function
Embryologic development of the pituitary gland
The pituitary gland develops embryologically from a dorsal
evagination of oropharyngeal ectoderm (Rathke’s pouch) (Fig.
3-4) and a ventral downgrowth of diencephalic neuroecto-
derm. The rostral part of the adenohypophyseal vesicle pro-
liferates and forms the pars distalis and is responsible for the
secretion of multiple trophic hormones. The point of fusion
of the 2 primordia develops into the pars intermedia. The pars
nervosa originates from the neuroectoderm and is connected
to the overlying hypothalamus through the infundibular stalk.
Brain
Infundibulum
Rathke's pouch
Third ventricle Pars nervosa
Pars tuberalis
Central cavity
Pars distalis Pars intermedia
Figure 3-4  Embryologic development of the pituitary gland.
(From Villee CA, et al.: General Zoology, 2nd ed. Philadelphia,
1963, W.B. Saunders.)
Pituitary Gland
The pituitary gland has 2 preformed cavities, the residual
lumen of Rathke’s pouch (adenohypophyseal cleft, not present
in the horse) and the infundibular recess of the third ventricle
(central cavity). Separation of the developing adenohypophy-
sis from the oropharynx is completed by formation of the
sphenoid bone.
Structure of the adenohypophysis
The adenohypophysis consists of 3 parts: the pars distalis, pars
tuberalis, and pars intermedia. In many species, the adenohy-
pophysis completely surrounds the pars nervosa of the neu-
rohypophyseal system.
• The pars distalis is the largest region of the adenohypophy-
sis and contains the multiple populations of endocrine cells
that secrete the different pituitary trophic hormones. The
secretory cells are supplied with abundant capillaries that
have fenestrae in their peripheral cytoplasmic extensions
and are supported by the cytoplasmic processes of keratin-
positive folliculostellate (follicular or sustentacular) cells. The
functions of folliculostellate cells are still poorly defined,
the adenohypophysis. The stellate cells may be phagocytic,
especially for hormonal secretory granules, and serve as
dendritic cells. In addition, they possibly represent organ-
specific stem cells.
• The pars intermedia forms the junction between the pars
distalis and pars nervosa. It lines the residual lumen of
Rathke’s pouch and contains both secretory and stellate
cells.
• The pars tuberalis consists of dorsal projections of cells
along the infundibular stalk. It functions primarily as a
scaffold for the capillary network of the hypophyseal 
portal system during its course from the median eminence
to the pars distalis, but also contains secretory and 
stellate cells.
Functional cytology of the adenohypophysis
The multiple populations of endocrine cells in the pars distalis
originate from stem cells and develop, depending on the pres-
ence and absence of transcriptional activators and signaling
molecules. The development of somatotrophs (producing
growth hormone [GH]), lactotrophs (producing prolactin
[PRL]) and thyrotrophs (producing thyrotropin [TSH]) is
dependent on the transcription factor, Pit1 , followed by a
divergence between somatotrophs/lactotrophs and thyro-
trophs that is regulated by GATA2 (Fig. 3-5). The develop-
ment of corticotrophs (producing adrenocorticotropic
hormone, ACTH), melanotrophs (producing melanocyte-
stimulating hormone, MSH) and gonadotrophs (producing
luteinizing hormone [LH], and follicle-stimulating hormone
[FSH]) is Pit1 independent, and further division between
corticotrophs/melanotrophs and gonadotrophs is regulated by
transcription factors, including Tbx19 and Sf1 (see Fig. 3-5).
Corticotrophs and melanotrophs produce a common precur-
sor molecule, pro-opiomelanocortin (POMC) that is differen-
tially processed to ACTH, MSH, and additional peptides,
which is dependent on the presence of specific proteinases,
such as proconvertase 1 and 2.
The endocrine cells of the pars distalis can be identified by
immunohistochemical demonstration of hormones. Secretory
cells in the adenohypophysis are morphologically subdivided
into acidophils, basophils, and chromophobes based on the
 Pituitary Gland
Pit1 positive Pit1 negative
lineage lineage
Common precursor
Tbx19
GATA2
Sf1
TSH GH/PRL LH/FSH ACTH/MSH
Figure 3-5  Development of multiple endocrine cell populations
in the pars distalis. ACTH, adrenocorticotropic hormone; FSH,
follicle-stimulating hormone; GATA2, GH, growth hormone; LH,
luteinizing hormone; α-MSH, α-melanocyte-stimulating hormone;
Pit1, PRL, prolactin; Sf1; Tbx19, TSH, thyroid-stimulating hor­
mone. GATA2, Pit1, Sf1, and Tbx19 are transcription factors.
staining of their secretory granules with pH-dependent histo-
chemical stains. Cells that stain acidophilic include somato-
trophs and luteotrophs. Their granules contain hormones that
are simple proteins that stain with orange G, azocarmine, or
erythrosin. Cells that stain basophilic include gonadotrophs,
thyrotrophs, and corticotrophs. Secretory granules of basophils
contain glycoproteins that react with the periodic acid–Schiff
reagent. Cells that do not have obvious cytoplasmic secretory
granules on light microscopic evaluation stain as chromo-
phobes. They include cells that synthesize ACTH and α-MSH,
nonsecretory folliculostellate cells, degranulated chromophils
(acidophils and basophils), and undifferentiated embryonic
stem cells of the adenohypophysis.
Specific immunohistochemical staining of the adenohy-
pophysis has demonstrated that ACTH- and MSH-staining
cells are polyhedral to round, sparsely granulated, and most
numerous in the ventrocentral and rostral portions of the pars
distalis. They are less frequent in the dorsal and caudal regions
of the pars distalis and throughout the pars tuberalis. In the
pars intermedia of dogs, most cells demonstrate immunoreac-
tivity to either ACTH or α-MSH.
Thyrotrophs are large polyhedral cells situated singly or  and antidiuretic hormone (ADH; vasopressin), are synthesized
in small groups ventrocentrally in the paramedian plane in  in hypothalamic neurons, but are released into the blood-
the pars distalis of dogs. Gonadotrophs (cells reacting  stream in the pars nervosa. The infundibular stalk joins the
with antisera to FSH and/or LH) are oval to polyhedral and
distributed singly in the pars distalis, particularly in the dor-
socranial region and in the caudal extensions along the pars
intermedia.
Immunoreactive prolactin cells occur in small groups of
large polygonal cells with prominent granules in the ventro-
central and cranial portions of the canine pars distalis. A
diffuse increase in this population of cells occurs in females
near parturition. Growth hormone–secreting cells are present
singly along capillaries in the dorsal region of the pars distalis
near the pars intermedia. They are small, round to oval,  Oxytocin is produced predominantly by neurons in the para-
and have numerous cytoplasmic granules. Somatotrophs  ventricular nucleus of the hypothalamus, whereas ADH is
frequently undergo diffuse hyperplasia and hypertrophy in  synthesized by neurons in the supraoptic nucleus.
old dogs, especially females with mammary dysplasia or
neoplasia.
277
Hypothalamic control of the adenohypophysis
Each population of endocrine cells in the pars distalis is under
the control of a corresponding releasing hormone from the hypo-
thalamus (Fig. 3-6). The releasing hormones are small pep-
tides synthesized by neurons in the hypothalamus. Axonal
processes transport them to the median eminence, where 
they are released into capillaries and conveyed by the 
hypophyseal portal system to specific endocrine cells in the
adenohypophysis, where each stimulates the rapid release of
secretory granules containing a specific preformed trophic
hormone.
There are separate hypothalamic releasing hormones that
regulate the rate of secretion of each trophic hormone secreted
by the adenohypophysis. For most pituitary trophic hormones,
negative feedback control is accomplished by the blood concen-
tration of the hormone produced by the target endocrine gland,
for instance, thyroid gland, adrenal cortex, ovary, or testis. The
hormone produced by the endocrine glands exerts negative
feedback control either on the neurosecretory neurons in the
hypothalamus that synthesize the corresponding releasing
hormone or on trophic hormone–secreting cells in the adeno-
hypophysis or at both sites. ACTH secretion is inhibited by
glucocorticoids in the pars distalis, but not in the pars inter-
media. POMC synthesis is inhibited by dopamine originating
from the hypothalamus. GH, PRL, and MSH do not act on
target endocrine organs to stimulate secretion of a hormone.
Negative feedback control of these pituitary hormones is effected
by production of a corresponding release-inhibiting hormone by
neurons in the hypothalamus. The relative local concentrations
of the specific releasing hormone and release-inhibiting
hormone appear to govern the rate of release of GH, PRL,
and MSH from the adenohypophysis. Growth hormone–
release-inhibiting hormone (“somatostatin”), which controls
the release of GH, also is produced by endocrine cells in the
pancreatic islets. Dopamine is the principal release-inhibiting
hormone for PRL and MSH.
Structure and function of the neurohypophysis
The pars nervosa of the neurohypophysis represents the
distal component of the neurohypophyseal system. It is com-
posed of numerous capillaries that are supported by modified
glial cells (pituicytes). The capillaries in the pars nervosa are
termination sites for the nonmyelinated axonal processes of
neurosecretory neurons in the hypothalamus. Secretory gran-
ules that contain the neurohypophyseal hormones oxytocin
pars nervosa to the overlying hypothalamus and is composed
of nonmyelinated axonal processes from neurosecretory
neurons.
Neurosecretory neurons in the hypothalamus receive
neural input from higher centers and translate this into endo-
crine output in the form of hormonal secretion. In addition
to the usual structural features of neurons, they contain prom-
inent lamellar arrays of rough endoplasmic reticulum, large
Golgi apparatuses, and numerous membrane-limited neurose-
cretory granules in the cell body and axonal process (Fig. 3-7).
ADH and its corresponding transport protein neurophysin
are synthesized as part of a common larger biosynthetic
278 CHAPTER 3  •  Endocrine Glands Pituitary Gland

III ventricle
PRL-RH
TRH
PRL-RIF
CRH (Dopamine)

GHRH LH(FSH)-RH Mamillary

Optic GH-RIH body
chiasm

Median eminence

Rostral
hypophyseal
artery Pars tuberalis

Pars distalis

PRL-RH Pars
GH-RH PRL-RIF LH-RH
TRH CRH nervosa
GH-RIH (Dopamine) (FSH)

Acidophils Basophils Chromophobes

Corticotrophs
Somatotrophs Luteotrophs (POMC)
Gonadotrophs Thyrotrophs

STH Prolactin LH FSH TTH ACTH -end MSH

(GH) (LTH) (, )
Figure 3-6  Separate hypothalamic releasing hormones or factors control the secretion of each
trophic hormone by the adenohypophysis. Trophic hormones that do not act on a target endocrine
organ to release a final endocrine product (e.g., growth hormone [GH] and prolactin) also are
regulated by a hypothalamic release-inhibiting hormone (RIH) or factor (e.g., somatostatin for
GH, and dopamine for prolactin and melanocyte-stimulating hormone [MSH]). ACTH, adreno-
corticotropic hormone; CRH, corticotropin-releasing hormone; β-end, β-endorphin; FSH, follicle-
stimulating hormone; LH, luteinizing hormone; LTH, luteotrophic hormone, prolactin; POMC,
pro-opiomelanocortin; PRL, prolactin; RH, releasing hormone; RIF, release-inhibiting factor; STH,
somatotropic (growth) hormone; TRH, thyrotropin-releasing hormone; TTH, thyrotropin.

precursor molecule, termed propressophysin. The hormones
are packaged into membrane-limited neurosecretory granules
and transported to the pars nervosa by axonal processes of the
neurosecretory neurons. These axons terminate on fenestrated
capillaries in the pars nervosa and release ADH or oxytocin
into the circulation.
ADH is transported by the bloodstream to its site of action
in the kidney, where it binds to specific receptors on epithelial
cells in the distal part of the nephron and collecting ducts. The
overall effect of ADH on the kidney is to increase the active
renal tubular reabsorption of water from the glomerular
filtrate.
Blood supply to the pituitary gland
The neurohypophysis in most animals is supplied directly by
the caudal hypophyseal arteries that branch from the internal
carotid arteries. Branches of the rostral hypophyseal arteries
originate from the internal carotid arteries and form the
caudal communicating arteries of the circle of Willis.
Arteriolar branches penetrate the pars tuberalis, lose their
muscular coat, and form a capillary plexus near the median
eminence. These vessels subsequently drain into hypophyseal
portal veins that supply the pars distalis and transport the
hypothalamic releasing hormones to the pituitary. A small
artery that arises from the caudal hypophyseal artery may
provide a minor blood supply to the adenohypophysis.
Diseases of the pituitary gland
Hypophyseal changes associated with alterations in
target organs
In response to surgical removal or disease processes in a target
endocrine organ of the pituitary, there is a progressive decline
in the circulating concentration of hormone produced by the
target organ. This reduction in circulating hormone level is
detected by the hypothalamic-adenohypophyseal system and
results in structural changes in the specific trophic hormone–
secreting cell population in the pars distalis.
 Pituitary Gland
M displace the nucleus eccentrically, characteristic of cells in the
GA ER
N TSH as well as for GH, so-called thyroid-deficiency cells. Inhibi-
L stane caused increased plasma ACTH levels and hypertrophy
NT
A
NS
NS
Figure 3-7  Structural characteristics of a neurosecretory neuron.
Nerve cell body (N, nucleus) has dendritic and axonal (A) pro-
cesses, arrays of rough endoplasmic reticulum (ER), a prominent
Golgi apparatus (GA), and large mitochondria (M). Hormone-
containing, membrane-limited neurosecretory granules (NS) are
transported along the axon to the site of release in the pars
nervosa. L, lysosomes; NT, neural tubules.
The initial reaction is rapid release of storage granules
containing preformed trophic hormone from one population
of endocrine cells in the pars distalis. For example, only thy-
rotrophic basophils degranulate following thyroidectomy or
thyroid disease, corticotrophic chromophobes degranulate
after adrenalectomy, and gonadotrophic basophils release their
secretory granules in response to gonadectomy. After an inter-
val of several days following surgical ablation or extensive
destruction of a target endocrine organ, the corresponding
degranulated trophic hormone–secreting cell in the pars dis-
talis undergoes hypertrophy with expansion of the cytoplas-
mic area in response to the sustained increased demand for
the particular trophic hormone. The abundant cytoplasm con-
tains extensive organelles concerned with hormonal synthesis
(rough endoplasmic reticulum) and packaging into secretory
granules (Golgi apparatus) plus large mitochondria.
If the demand for trophic hormone secretion is sustained
for days or weeks, one specific population of endocrine  similar to those of the sellar adenohypophysis, usually extends
cells in the pars distalis undergoes hyperplasia. Groups of
hyperplastic trophic hormone–secreting cells are present, scat-
tered as small nests throughout an otherwise normal pars
distalis. In response to long-term (weeks to months) stimula-
tion, the hypertrophied cytoplasm of the cells becomes vacu-
olated because of the extensive distention of profiles of rough
endoplasmic reticulum with finely granular, moderately
279
electron-dense material. The multiple small cytoplasmic vacu-
oles coalesce subsequently to form a large vacuole that may
pituitary gland that degranulate following thyroidectomy,
adrenalectomy, or gonadectomy. In hypothyroid dogs, thyro-
troph hyperplasia is accompanied by a decrease in lactotrophs
and the presence of cells immunohistochemically positive for
tion of cortisol secretion in dogs that were treated with trilo-
and hyperplasia of pituitary corticotrophs.
Pituitary cysts
Cysts derived from the distal (“sellar”) end of the cranio-
pharyngeal duct.  Cysts may develop from remnants of the
distal craniopharyngeal duct, which normally disappears by
birth in most animal species. The cysts are lined by cuboidal
to columnar, often ciliated, epithelium and contain mucin. In
dogs, especially of the brachycephalic breeds, cysts from these
remnants are often found at the periphery of the pars tuberalis
and pars distalis. Cystic remnants of the craniopharyngeal duct
in one survey were found in about 50% of dogs of several
breeds.
Craniopharyngeal duct cysts occasionally become large
enough to exert pressure on the infundibular stalk and
hypophyseal portal system, median eminence, or pars distalis.
Structures adjacent to the cysts atrophy to variable degrees
because of compression and interference with the blood
supply. Disruption of a large cyst with escape of the protein-
aceous contents into adjacent tissues may incite local inflam-
mation with subsequent fibrosis that may interfere with
pituitary function. Clinical signs can include visual difficulties
resulting from pressure on the optic chiasm, diabetes insipi-
dus, obesity, and hypofunction of the adenohypophysis leading
to gonadal atrophy, decreased basal metabolic rate, and
hypoglycemia.
Cysts derived from the proximal end of the craniopharyn-
geal duct (pharyngeal hypophysis).  The proximal portion of
the adenohypophyseal anlage may persist in the dorsal aspect
of the oral cavity in adults as undifferentiated remnants of
cells along the craniopharyngeal canal or as differentiated cells
similar to those of the definitive adenohypophysis. These rem-
nants, called the pharyngeal hypophysis, have been described
in dogs, cats, other animal species, and humans. The pharyn-
geal hypophysis is physically separated from the sellar adeno-
hypophysis in dogs, but in cats, these structures may be
continuous because of persistence of the craniopharyngeal
canal.
The pharyngeal hypophysis is seen most often in brachyce-
phalic breeds of dogs. It is a tubular structure lined by ciliated
columnar epithelium, located on the midline of the nasophar-
ynx, and is frequently continuous with a multilocular cyst that
is lined by ciliated cuboidal or columnar epithelium. The cyst
contains colloid material and cellular debris. A mass of dif-
ferentiated acidophilic, basophilic, and chromophobic cells,
from the cyst wall.
Cysts (up to several centimeters in diameter) may be
derived from the oropharyngeal end of the craniopharyngeal
duct and project as a space-occupying mass into the nasophar-
ynx in dogs. The predominant clinical sign may be related to
respiratory distress resulting from ventral displacement of the
soft palate and occlusion of the caudal nares. The cyst wall
280 CHAPTER 3  •  Endocrine Glands Pituitary Gland

A B
Figure 3-8  Failure of oropharyngeal ectoderm to differentiate into trophic hormone–secreting
cells of the adenohypophysis in a German Shepherd dog with dwarfism. A. Sagittal section. Pars
nervosa compressed by mucin-filled cyst. B. Ventral view of cyst. Bars = 1 cm.

may be hard on palpation resulting from the presence of

partially mineralized woven bone. The contents of the cyst are
often yellow-gray and caseous because of the accumulation of
keratin and desquamated epithelial cells from the cyst lining.
The squamous epithelial lining of the cyst is derived from
metaplasia of the remnants of the primitive oropharyngeal
epithelium.
Cysts resulting from failure of differentiation of the oro-
pharyngeal ectoderm of Rathke’s pouch.  A proper orchestra-
tion of expression of transcription factors and signaling
molecules is essential for normal development of the pituitary.
A failure of the oropharyngeal ectoderm of Rathke’s pouch
to differentiate into trophic hormone–secreting cells of the
pars distalis results in the absence of an adenohypophysis,
often with a progressively enlarging, multiloculated cyst in the
sella turcica. The cyst is lined by pseudostratified, often cili-
ated, columnar epithelium with interspersed mucin-secreting
goblet cells. The mucin-filled cysts eventually occupy the
entire pituitary area in the sella turcica and severely compress Figure 3-9  Panhypopituitarism (“pituitary dwarfism”) in a
the pars nervosa and infundibular stalk (Fig. 3-8A, B). Only a 3-year-old German Shepherd dog.
few differentiated cells that immunohistochemically stain for
specific trophic hormones are present in the pituitary region. production in the liver and plasma activity is controlled 
An occasional small nest or rosette of poorly differentiated by GH) is low in dwarf dogs. Useful diagnostic aids for pitu-
epithelial cells is interspersed between the multiloculated itary dwarfs include comparison of height with littermates,
cysts, but the cytoplasm of these cells is usually devoid of radiographs of open epiphyseal lines, thyroid function tests,
hormone-containing secretory granules. skin biopsy, and determination of serum GH or IGF-1
Juvenile panhypopituitarism (pituitary dwarfism) occurs concentrations.
most frequently in dogs, but has also been seen cats and other The dwarf pups appear normal or are indistinguishable
species, such as a Eurasian badger (Meles meles). Most com- from littermates at birth and until ~2 months of age. Subse-
monly affected are German Shepherd dogs, but it has been quently, the slower growth rate than the littermates, retention
seen in other breeds, such as the Spitz, Toy Pinscher, Karelian of puppy hair, and lack of primary guard hairs gradually
Bear dogs, Saarloos, and Czechoslovakian Wolfdogs as well. A become evident in dwarf pups. German Shepherd dogs with
molecular defect in the LHX3 gene (deletion in exon 5) has pituitary dwarfism appear coyote- or fox-like, given their small
been reported to be the cause in German Shepherd dogs and size and soft woolly coat. Bilaterally symmetrical alopecia
other dogs. There is a deficiency in GH, TSH, prolactin, and develops gradually and often progresses to complete alopecia
the gonadotropins. ACTH may be normal or decreased. Pan- except for the head and tufts of hair on the legs (Fig. 3-9).
hypopituitarism in German Shepherd dogs often occurs in There is progressive hyperpigmentation of the skin until it is
littermates and related litters and has an autosomal recessive uniformly brown-black over most of the body. Adult German
mode of inheritance. The activity of insulin-like growth factor Shepherd dogs with panhypopituitarism vary in size from as
1 (IGF-1) (a cartilage growth-promoting peptide whose  small as 2 kg up to nearly half normal size, depending upon
 Pituitary Gland 281

whether the failure of formation of the adenohypophysis is

nearly complete or only partial. ( )
Permanent dentition is delayed or completely absent.
Closure of epiphyses is delayed as long as 4 years, depending

Cortisol

Cortisol
ACTH

ACTH
on the severity of hormonal insufficiency. There are few tra-
beculae in the primary and secondary spongiosa of the
metaphysis of long bones, and osteoblasts are decreased in
dwarf pups when compared with normal littermates. The
external genitalia usually remain infantile. The testes and penis Normal Adrenal cortical adenoma
are small, mineralization of the os penis is delayed or incom- or carcinoma
plete, and the penile sheath is flaccid. In females, the ovarian
cortex is hypoplastic and estrus irregular or absent. Cutaneous Adenoma Hypothalamus
lesions include hyperkeratosis, follicular keratosis, hyperpig- (?)
mentation, adnexal atrophy and loss of elastin fibers, and the

Cortisol

Cortisol
ACTH

ACTH
loose network of collagen fibers in the dermis. Hair shafts are
absent, and hair follicles are primarily in the telogen (resting)
phase of the growth cycle. The shortened life span in dogs
with pituitary dwarfism results not only from the panhypopi-
tuitarism but also from the resulting secondary endocrine
dysfunction, such as hypothyroidism and hypoadrenocorti- Corticotroph adenoma, Idiopathic cortical
cism. The variation in severity and onset of the lesions in adenohypophysis hyperplasia
pituitary dwarfism appears to be related to the degree of
penetrance of the defect. The degree to which the oropharyn-
( ) ( )
geal epithelium fails to differentiate is variable, as is the rapid-
ity with which the mucin-filled cysts enlarge and exert

Cortisol

Cortisol
ACTH

ACTH
pressure on adjacent structures. Lung
Cysts associated with pituitary dwarfism morphologically
are distinct from the cysts that develop following the abnor-
mal accumulation of colloid in the residual lumen of Rathke’s ACTH
pouch. The normally developed pars distalis and pars nervosa Iatrogenic + +
are compressed to various degrees by the abnormal accumula-
tion of colloid in a normal cavity of the pituitary. Ectopic ACTH secretion
Figure 3-10  Multiple pathogenic mechanisms of cortisol excess
Neoplastic diseases of the pituitary in dogs. ACTH, adrenocorticotropic hormone.
The consequences of pituitary neoplasms depend on their
functionality. Effects of hormone-producing neoplasms are
usually mediated via the target organs, whereas nonfunctional
neoplasms cause disturbances because of local effects, such as
compression and destruction of adjacent tissues. Most func-
tional tumors express only one hormone; however, plurihor-
monal tumors also occur.

Corticotroph (ACTH–secreting) adenoma

Functional tumors arising in the adenohypophysis may be
derived from corticotroph (ACTH-secreting) cells in either PI
the pars distalis or the pars intermedia. They are the most
common cause of the clinical syndrome of cortisol excess (pituitary-
dependent hyperadrenocorticism: Cushing’s disease) in dogs
(Fig. 3-10). These neoplasms are infrequent in other animal
species.
Corticotroph adenomas develop in adult-to-aged dogs and
Figure 3-11  Adenoma of the pars distalis (arrowheads) in a dog
have been reported in a number of breeds. Boxers, Boston
with hyperadrenocorticism. The adenoma has displaced much of
Terriers, and Dachshunds appear to have a higher incidence
the normal pars distalis, but there is minimal enlargement of the
of ACTH-secreting pituitary tumors than other breeds. The
pituitary gland. The pars intermedia (PI) is normal. Bar = 5 mm.
spectrum of clinical manifestations and lesions that develop is
primarily the result of long-term overproduction of cortisol by
hyperplastic adrenal cortices. These changes are the result of be directly related to the size of the neoplasm. Small cortico-
the combined gluconeogenic, lipolytic, protein catabolic, and troph adenomas are as likely to be endocrinologically active
anti-inflammatory actions of glucocorticoid hormones on as are larger neoplasms (Fig. 3-11). The larger adenomas are
many organ systems of the body. often firmly attached to the base of the sella turcica but
The pituitary gland is consistently enlarged in dogs with without evidence of erosion of the sphenoid bone. In the dog,
corticotroph adenomas of the pars distalis. Neither the occur- the diaphragma sellae is incomplete. Therefore the line of least
rence nor the severity of functional disturbances appears to resistance favors dorsal expansion of the gradually enlarging
282 CHAPTER 3  •  Endocrine Glands
pituitary mass and invagination into the infundibular cavity;
dilation of the infundibular recess and the third ventricle, with
eventual compression or replacement of the hypothalamus;
and possible extension of the tumor into the thalamus. In the
larger neoplasms, there are often focal areas of hemorrhage,
necrosis, liquefaction, and mineralization. Growth of the pitu-
itary tumor along the basilar aspects of the brain may result
in incorporation of the second, third, and fourth cranial nerves,
leading to disturbances of their function.
Bilateral enlargement of the adrenal glands occurs in dogs
with functional corticotroph adenomas (see Fig. 3-101D).
This enlargement often is striking and is due to increased
cortical parenchyma, primarily in the zonae fasciculata and
reticularis. Nodules of yellow-orange cortical tissue often are
found outside the capsule in the periadrenal fat, as well as
extending down into the adrenal medulla. The corticomedul-
lary junction is irregular, and the medulla is compressed.
Pituitary corticotroph adenomas are composed of well-
differentiated, large or small, cells supported by fine connective
tissue septa. They can be divided into sinusoidal and diffuse
types on the basis of the predominant pattern of cellular
architecture. The cytoplasm of the tumor cells usually is
devoid of secretory granules detectable by routine histochemi-
cal procedures used for pituitary cytology. However, pituitary
corticotroph adenomas arising in both the pars distalis and the
pars intermedia associated with the syndrome of cortisol
excess in dogs are composed of polyhedral cells that immu-
nohistochemically stain selectively for pro-opiomelanocortin
(POMC), ACTH, and MSH. POMC immunostaining of the
adenoma cells is usually the most robust. Nodules of focal
hyperplasia and microadenomas, composed of similar ACTH/
MSH cells, often are present in the adenohypophysis of older
dogs.
Although remnants of the pars distalis can be identified
near the periphery of corticotroph adenomas, the demarcation
between the neoplasm and pars distalis often is not distinct.
The pars distalis either is partly replaced by the neoplasm or
severely compressed. The pars nervosa and infundibular stalk
either are infiltrated and disrupted by tumor cells or com-
pletely incorporated within the larger neoplasms.
Hormone-containing secretory granules can be demonstrated
by electron microscopy in functional corticotroph adenomas of
dogs. The granules vary in number from cell to cell, are spheri-
cal, and are surrounded by a delicate limiting membrane. They
are small (mean diameter, 170 nm), electron dense, often situ-
ated peripherally in the cell, and may have a prominent  characterized by strong immunostaining for ACTH and weak-
submembranous space.
A number of distinctive clinical and functional alterations
develop in dogs with corticotroph (ACTH-secreting) adeno-
mas, resulting in the syndrome of hyperadrenocorticism. Cen-
tripetal redistribution of adipose tissue leads to prominent fat
pads on the dorsal midline of the neck, giving the neck and
shoulders a thick appearance. Appetite and intake of food
often are increased, either as a direct result of the hyperadre-
nocorticism or involvement of hypothalamic appetite control
centers by a large pituitary tumor. The muscles of the extremi-
ties and abdomen are weakened and atrophied. The loss of
abdominal muscles and muscles of the appendicular skeleton
results in gradual abdominal enlargement (“pot belly”), lordo-
sis, muscle trembling, and a straight-legged skeletal-braced
posture to support the body’s weight. Profound atrophy of
the temporal muscles may result in concave indentations  onagers (Equus hemionus onager). Adenomas of the pars inter-
and readily palpable prominences of underlying skull bones.
Pituitary Gland
Hepatomegaly resulting from increased fat and glycogen
deposition plus vacuolation of hepatocytes produces a dis-
tended, often pendulous, abdomen. Functional alterations of
the skin, muscle, lung, and other tissues are the direct effects
of elevated blood cortisol levels.
Adenomas of the pars intermedia in dogs result in only
moderate enlargement of the pituitary gland. Nonbrachyce-
phalic breeds of dogs develop adenomas in the pars intermedia
more often than brachycephalic breeds.
The pars distalis is readily identifiable and sharply demar-
cated from the rostral margin of the neoplasm. The tumor 
may extend across the residual hypophyseal lumen and 
result in compression atrophy, but usually does not invade the
parenchyma of the pars distalis (Fig. 3-12A). The neurohy-
pophysis is incorporated within the tumor, but the infundibu-
lar stalk is intact. Degenerative changes within the neoplasm
are minimal.
Adenomas of the pars intermedia in dogs appear to arise
from the lining epithelium of the residual hypophyseal lumen
covering the pars nervosa. They often are relatively small and
more strictly localized than corticotroph adenomas arising in
the pars distalis of dogs, but are not encapsulated. The histo-
logic appearance is different from corticotroph adenomas of
the pars distalis, in that there are numerous colloid-filled follicles
interspersed between nests of large neoplastic cells (Fig. 3-12B).
The follicles are lined by simple cuboidal to columnar epithe-
lium, which may be partly ciliated, and contain interspersed
mucin-secreting goblet cells. The follicular colloid is eosino-
philic to amphophilic and PAS positive. Endocrinologically
active (ACTH-secreting) adenomas of the pars intermedia 
in dogs have prominent groups of large corticotrophs with
abundant eosinophilic cytoplasm interspersed with variable
numbers of smaller, more basophilic cells and widely scattered
follicles. Dense bands of fibrous connective tissue are occa-
sionally interspersed between the follicles and nests of chro-
mophobic cells, particularly in the endocrinologically inactive
adenomas of the pars intermedia.
Adenomas of the pars intermedia in dogs either are endo-
crinologically inactive and associated with various degrees of
hypopituitarism and diabetes insipidus, or endocrinologically
active and secrete excessive ACTH, leading to bilateral adre-
nocortical hyperplasia and hyperadrenocorticism. The clinical
signs in the dogs with functional adenomas are similar to those
described for corticotroph adenomas of the pars distalis. Cor-
ticotroph adenomas associated with Cushing’s disease are
to-moderate immunostaining for α-MSH.
Corticotroph adenomas similar to those in dogs have been
reported in cats, although they are less common. Observed
differences in clinical presentation are most likely due to the
greater tolerance of cats to high levels of steroids. In the horse,
corticotroph adenomas are rarely reported in the pars
distalis.
Pars intermedia (melanotroph) adenoma
Adenomas derived from cells of the pars intermedia are the most
common type of pituitary tumor in horses, and produce various
POMC-derived peptides, and cause the clinical syndrome of
pituitary pars intermedia dysfunction (PPID). The adenomas
develop frequently in older horses, with females affected more
frequently than males. The tumor has also been reported in
media in horses can be large tumors that extend out of the
 A B

H
C
D

E F
Figure 3-12  A, B. Corticotroph adenoma of pars intermedia in a dog. A. Central neoplasm sharply
demarcated from pars distalis. Rathke’s pouch (right of tumor) is dilated and contains eosinophilic
fluid. The clear cleft between the adenoma and pars distalis (left) is an artifact. B. Pars intermedia
adenoma with colloid-filled follicles and infiltration and compression of the pars nervosa (top).
C-G. Adenomas and hyperplasia of pars intermedia in a horse. C. Note the large adenoma (large
arrowhead) compressing the pars nervosa (N); smaller adenomas (small arrowheads); and thick-
ened and hyperplastic region of the pars intermedia (H). The pars distalis is displaced cranially
(left) and caudally (right). D. Pars intermedia adenoma with polygonal to fusiform tumor cells
containing abundant eosinophilic cytoplasm. E. Macroscopic image of a multinodular pars inter-
media adenoma with infiltration of the pars nervosa (center). Compressed pars distalis is present
at left and ventral edges. F. Abundant expression of α-melanocyte-stimulating hormone (α-MSH)
in the pars intermedia adenoma. Immunohistochemistry. Continued
284 CHAPTER 3  •  Endocrine Glands
sella turcica and severely compress the overlying hypothala-
mus. The adenomas are yellow to white, multinodular, and
incorporate the pars nervosa (Fig. 3-12C). On sectioning of
the pituitary mass, the pars distalis usually can be identified
as a compressed subcapsular rim of tissue on the rostral margin
(see Fig. 3-12C). A sharp line of demarcation remains between
the neoplasm, which is partly encapsulated, and the com-
pressed and atrophic pars distalis. The tumors are subdivided
into nodules or compartments by fine septa of connective
tissue that contain numerous capillaries and rare inflammatory
cells. Tumor cells are large cylindrical, spindle shaped, or poly-
hedral, with an oval hyperchromatic nucleus (Fig. 3-12D).
The histologic pattern is often reminiscent of the prominent
pars intermedia of normal horses. Occasionally, cuboidal cells
form follicular structures that contain dense eosinophilic
colloid. In other areas, the spindle-shaped cells may assume a
G compression of the overlying hypothalamus. The hypothala-
Figure 3-12, cont’d  G. Restriction of adrenocorticotropic
hormone staining to non-neoplastic areas of the pars distalis
(arrowheads). Immunohistochemistry.
Figure 3-13  Hypertrichosis (“hirsutism”) in a horse, resulting from failure of the cyclic shedding
of hair, associated with an adenoma of the pars intermedia.
Pituitary Gland
more sarcomatous pattern and palisade around vessels. The
cytoplasm is lightly eosinophilic and granular. Electron micros-
copy of the large cells comprising adenomas of the pars inter-
media in horses reveals that the rough endoplasmic reticulum
and Golgi apparatus are particularly well developed, suggest-
ing they are synthesizing abundant POMC and packaging
considerable amounts of peptide hormones for secretion. The
neoplastic cells contain numerous membrane-limited secre-
tory granules in their cytoplasm with a mean diameter of
~300 nm that are surrounded by a closely applied limiting
membrane.
The clinical syndrome of PPID is characterized by polyuria,
polydipsia, laminitis, increased appetite, muscle weakness,
somnolence, intermittent hyperpyrexia, and generalized
hyperhidrosis. The most striking change is hypertrichosis (hir-
sutism) because of failure of the seasonal shedding of hair (Fig.
3-13). The hair over most of the trunk and extremities is long
(up to 9-10 cm), abnormally thick, wavy, and often matted.
Biopsy of skin reveals normal hair follicles uniformly in the
anagen phase, normal epidermis and dermal collagen, and
absence of the characteristic skin lesions observed in dogs with
Cushing’s disease caused by cortisol excess. Horses with larger
tumors may have hyperglycemia (insulin-resistant) and gly-
cosuria, most likely the result of downregulation of insulin
receptors on target cells induced by the chronic excessive
intake of food and hyperinsulinemia. The disturbances in
carbohydrate metabolism, ravenous appetite, hypertrichosis,
and hyperhidrosis are considered to be primarily a reflection of
deranged hypothalamic function caused by the compressive and
destructive effects of the large pituitary tumors. Adenomas of the
pars intermedia in horses often expand dorsally because of the
incomplete diaphragma sellae, and result in localized necrosis
of nuclei in this important regulatory center as a result of
mus is the primary autonomic center for homeostatic regula-
tion of body temperature, appetite, and cyclic shedding of hair,
among many other functions.
  Pituitary Gland 285

Pro-opiomelanocortin (pro-OMC)

() Dopaminergic
Pars Pars control
distalis intermedia
PD
ACTH α-MSH
β-LPH CLIP (/)
() γ-LPH β-MSH
β-Endorphin

[Plasma cortisol]
Figure 3-14  Post-translational processing of pro-
opiomelano­cortin (POMC) produced in pars distalis and pars A
intermedia. The plasma concentration of cortisol regulates pro-
cessing in the pars distalis, whereas the pars intermedia is primar-
ily under dopamine control. ACTH, adrenocorticotropic hormone;
CLIP, corticotropin-like intermediate lobe peptide; LPH, lipotro-
pin; α-MSH, α-melanocyte-stimulating hormone.

Tumor tissue and plasma from horses with adenomas of

the pars intermedia contain high concentrations of immuno-
reactive peptides (corticotropin-like intermediate lobe peptide
[CLIP], α- and β-MSH, and β-endorphin [β-END]) derived
from POMC and processed in the pars intermedia (see Fig.
3-12E-G). This biosynthetic precursor undergoes different
post-translational processing in the pars distalis and pars inter-
media, dependent on the activity of specific proteinases. In the
normal pars distalis, POMC is processed to ACTH, β-lipotropin
(β-LPH), and γ-LPH, whereas, in the normal pars intermedia,
the same precursor molecule is cleaved into α-MSH, CLIP,
β-MSH, and β-END (Fig. 3-14). Plasma cortisol strongly
inhibits ACTH secretion by the pars distalis, whereas peptide
secretion in the pars intermedia is under dopaminergic inhibi-
tory control. Selective post-translational processing of POMC
in neoplastic cells in a similar manner as the normal pars
intermedia results in highly elevated CLIP, α- and β-MSH, and
β-END levels. Measurement of serum α-MSH is useful for the
clinical diagnosis of PPID; however, horses normally have a
substantial increase in serum α-MSH and ACTH concentra-
tions in the autumn that needs to be taken into consideration.
Serum ACTH is normal or mildly increased horses with PPID.
Adrenal glands are normal in most horses with PPID, but a
subset of horses may have mild adrenocortical hyperplasia.
Immunohistochemical evaluation of adenomas of the pars
intermedia reveals a diffuse moderate to strong staining for
POMC, α-MSH (see Fig. 3-12F), and β-END. Although many
of the functional disturbances in horses with pituitary adeno-
mas (e.g., diabetes insipidus, polyphagia, hyperpyrexia, hyper-
hidrosis, hypertrichosis) appear to be the result of hypothalamic
or neurohypophyseal dysfunction, other signs (e.g., docility,
diminished responsiveness to painful stimuli) may be related
to the elevated plasma and cerebrospinal levels of β-END.
ACTH is weakly demonstrable in a few of the neoplastic cells
of the pars intermedia adenomas, but the staining intensity is
greater in the normal ACTH cells of the pars distalis (see Fig.
3-12G). The immunohistochemical staining pattern and clini-
cal endocrinology of the affected horses suggests that pars
intermedia adenomas produce a small amount of ACTH that
may partially or completely replace or mildly increase circu-
lating ACTH concentrations, and the normal pars distalis cor-
ticotrophs have inhibition of secretion of ACTH.
B
Figure 3-15  Acidophil adenoma. A. Ewe with severe compres-
sion of the pars distalis (PD) and overlying brain. Bar = 1 cm.
B. Histology from a feline tumor depicting the acidophil nature
of the neoplasm. Acid fuchsin–aniline blue stain.
The overall processing of peptides in adenomas in the pars
intermedia appears to be similar to that in the normal equine
pars intermedia. The clinical syndrome in horses with pituitary
tumors, leading to hypothalamic and neurohypophyseal derange-
ment as well as autonomous production of excess amounts of
POMC-derived peptides, should be called PPID and not equine
Cushing’s disease as it is distinctly different from Cushing’s
disease that occurs in dogs, cats, and human patients. In addition,
PPID is considered a primarily neurodegenerative disease
resulting from age-related decrease of dopaminergic inhibition
in the pars intermedia. This concept would also explain the
presence of PPID in horses with hyperplastic pars intermedia
but without adenomas.
Somatotroph adenomas
Although growth hormone (GH)-secreting acidophils
(somatotrophs) are one of the major cell types in the adeno-
hypophysis, development of functional adenomas from this popu-
lation of acidophils is infrequent in animals; they have been
reported in the cat, dog, and sheep. Functional somatotroph
adenomas may be underdiagnosed in cats, where they can
cause acromegaly and be a concurrent and predisposing condi-
tion to adult-onset diabetes mellitus.
Somatotroph adenomas enlarge the pituitary gland and
indent the overlying hypothalamus or extend into the overly-
ing brain to various degrees (Fig. 3-15A). The enlarged
hypophysis is composed of irregular columns of acidophils
286 CHAPTER 3  •  Endocrine Glands
Figure 3-16  Iatrogenic acromegaly in a Beagle. Note the coarse-
ness of facial features and marked thickening and folding of the
skin of the face. These characteristic changes are the result of the
protein anabolic effects of growth hormone, produced in excess
by hyperplastic mammary ductular epithelial cells that have been
stimulated by the exogenous administration of medroxyproges-
terone acetate. Inset: Note gingival hyperplasia, increased separa-
tion of the frontal incisors, and macroglossia.
interspersed between numerous blood-filled sinusoids. The
fibrous stroma is sparse. Although the degree of cytoplasmic
granulation of acidophils varies from cell to cell, the predomi-
nant type of neoplastic acidophil usually contains many sec-
retary granules. The nuclei of the densely granulated acidophils
are small, oval, and hyperchromatic. Sparsely granulated
(“chromophobic”) cells are interspersed between the densely
granulated acidophils. Their cytoplasm is more abundant and
lightly eosinophilic but contains only an occasional secretory
granule. Secretory granules of acidophils are bright red when
stained with acid fuchsin-aniline blue (Fig. 3-15B) and with
Crossman’s modification of Mallory’s trichrome. Orange-G
stains the granules an intense yellow-orange, but they are PAS
negative. Colloid-containing follicles lined by follicular cells are
found occasionally within acidophil adenomas in dogs. The
colloid is intensely PAS positive. Numerous sinusoids are dis-
tended with erythrocytes, detached neoplastic cells, and large
masses of fibrin. The pars nervosa and infundibular stalk are
infiltrated at the periphery by neoplastic cells, compressed,
and partly replaced by fibrous astrocytes.
Functional disturbances resulting from hypersecretion of
GH have been reported in cats and dogs. Acromegaly is a
disease characterized by an overgrowth of connective tissue,
increased appositional growth of bone, coarsening of facial
features, gingival hyperplasia and increased separation of
teeth, macroglossia, and enlargement of viscera resulting from
chronic excessive secretion of GH (Fig. 3-16). In dogs, this is
usually due to tumors from organs other than the pituitary,
such as the mammary gland, but in cats, somatotroph adenoma
is a common cause. Functional acidophil adenomas in cats
secrete excess GH, which results in downregulation of insulin
receptors and resistance to the action of insulin at the target
cell level. Somatotroph adenomas are considered to be a pre-
disposing cause of insulin-resistant diabetes mellitus in cats.
Tumor cells are immunohistochemically positive for GH. The
circulating GH and IGF-1 levels are severely elevated. Clinical
evidence of acromegaly includes an enlarged abdomen and
Pituitary Gland
Figure 3-17  Enlargement and deepening of sella turcica (arrow-
heads) in a ewe, associated with a large acidophil adenoma
(prolactin-secreting cells) of the pituitary gland that remained
confined to this region because of the complete diaphragma sellae.
prognathia inferior. In addition, it is associated with prolifera-
tion of joint cartilage, leading to degenerative arthropathy, and
kidney disease resulting from periglomerular fibrosis and
mesangial proliferation.
Acidophil adenomas in sheep may attain considerable size
(see Fig. 3-15A) and remain confined to the sella turcica
because sheep have a complete diaphragma sellae separating
the pituitary fossa from the brain. The remaining adenohy-
pophysis and neurohypophysis are compressed severely, and
the sella turcica is enlarged and deepened due to pressure-
induced osteolysis (Fig. 3-17).
Tumors arising from somatotrophs occur in young to
middle-aged budgerigars (Melopsittacus undulates). These are
usually adenomas, but metastasizing carcinomas are also
reported. The pituitary gland is replaced by the neoplasm that
often extends into adjacent structures. Neoplastic cells are
polygonal with presence of karyomegalic cells. Most neoplas-
tic cells stain positive for GH. Clinical signs include difficulties
flying, ataxia, and blindness, and are caused by local expansion
of the tumor.
Thyrotroph adenoma
Thyrotroph adenoma has been reported from a cynomolgus
monkey (Macaca fascicularis). Production of TSH by a
pituitary adenoma was present in combination with other
hormones, including FSH, prolactin (PRL), or ACTH in the
monkey. In dogs, reactive thyrotroph hyperplasia is seen 
in response to hypothyroidism. Basophil adenomas in 
people also may secrete TSH, resulting in bilateral enlarge-
ment of both thyroid lobes (“goiter”). Serum thyroxine,
triiodo­thyronine, and TSH are elevated and may be respon­
sive to thyrotropin-releasing hormone (TRH) from the
hypothalamus.
Lactotroph adenoma
Pituitary adenomas that produce PRL occur in cynomolgus
monkeys, rarely in small ruminants, and frequently in aged
rats. Tumors in the monkeys had polygonal cells arranged in
cords and nests with minimal anisocytosis and anisokaryosis
and few, if any, mitotic figures. Necrosis, hemorrhage, inflam-
mation, or acinar formation was absent. Goats with acidophil
 Pituitary Gland
A phic with vesicular nuclei and prominent nucleoli, and
B nosis of germ cell tumor was based on 3 criteria:
Figure 3-18  Suprasellar germ cell tumor (craniopharyngioma)
in a dog. A. The neoplasm is well demarcated, with complete
destruction of the pituitary gland and extension into the hypo-
thalamus and thalamus. The tumor cells produce waxy brown
keratin. There is hemorrhage and necrosis of the tumor. Bar =
1 cm. B. Cords of eosinophilic neoplastic cells with keratinization
and cytoplasmic vacuoles. Inset: The neoplastic cells are positive
for pancytokeratin by immunohistochemistry.
pituitary adenomas may have increased serum PRL levels and
inappropriate lactation.
Suprasellar germ cell tumor (craniopharyngioma)
This tumor occurs in young animals and is present in either a
suprasellar or infrasellar location (Fig. 3-18A). It is one cause
of panhypopituitarism and dwarfism in young dogs due to
subnormal secretion of somatotropin and other trophic hor-
mones beginning at an early age, prior to closure of the growth
plates. Pleomorphic tumors in the suprasellar region often are
large and grow along the ventral aspect of the brain, where
they can incorporate several cranial nerves. In addition, they
extend dorsally into the hypothalamus and thalamus. The
clinical signs resulting from this type of rapidly growing tumor
in the pituitary region often are a combination of:
1. Lack of secretion of pituitary trophic hormones, resulting
in trophic atrophy and subnormal function of the adrenal
cortex and thyroid, gonadal atrophy, and failure to attain
somatic maturation because of a lack of GH secretion.
2. Disturbances in water metabolism (polyuria, polydipsia,
low urine-specific gravity and osmolality) from interfer-
ence with the release and synthesis of antidiuretic hormone
(ADH) by the large tumor.
287
3. Deficits in cranial nerve function.
4. Central nervous system dysfunction caused by extension
into the overlying brain.
Histologically, the tumors have alternating solid and 
cystic areas. The solid areas are composed of nests of epithelial
cells (cuboidal, columnar, or squamous) with focal areas of
mineralization. The solid areas are composed of nests of 
epithelial cells (cuboidal, columnar, or squamous cells) with
prominent focal areas of keratinization and occasional miner-
alization that compress the overlying hypothalamus (Fig.
3-18B). The areas of keratinization are densely eosinophilic
and frequently are associated with fragments of nuclear chro-
matin. The neoplastic epithelial cells are large and pleomor-
frequently have discrete vacuoles in their cytoplasm (see Fig.
3-18B). There frequently is an admixture with smaller cuboi-
dal to polyhedral cells that have acidophilic secretory granules
staining positive for either prolactin or GH by immunocyto-
chemistry. The cystic spaces are lined by either columnar or
squamous cells and contain keratin debris and colloid. Colloid-
containing follicles may be formed that are lined either by
cuboidal or by columnar cells and contain variable amounts
of eosinophilic colloid.
A suprasellar germ cell tumor is a benign neoplasm that is
derived from epithelial remnants of the oropharyngeal ecto-
derm of the craniopharyngeal duct (Rathke’s pouch). However,
it has been proposed that some pleomorphic neoplasms in the
suprasellar region of younger dogs be classified as suprasellar
germ cell tumors rather than craniopharyngiomas. The diag-
1. Midline suprasellar location.
2. Presence within the tumor of several distinct cell types—
one population resembling a seminoma or dysgerminoma,
and others suggesting teratomatous differentiation into
secretory glandular and squamous elements.
3. Positive staining for α-fetoprotein.
This interpretation suggests that the secretory (glan­
dular) and squamous elements represent teratomatous
differentiation.
Hormonally inactive adenoma of the pars distalis
Nonfunctional pituitary tumors occur in dogs, cats, laboratory
rodents, and parakeets, but are uncommon in other species.
They are also called null-cell adenomas resulting from the lack
of hormones as demonstrated by immunohistochemistry.
Although these chromophobe adenomas appear to be hormonally
inactive, they may cause significant functional disturbances and
clinical signs by compression of adjacent portions of the pituitary
gland and dorsal extension into the overlying brain.
Nonfunctional pituitary adenomas result in clinical distur-
bances either by interfering with secretion of pituitary trophic
hormones and diminishing target organ function or dysfunc-
tion of the central nervous system. Affected animals often 
are depressed, have incoordination and other disturbances of
balance, are weak, and may collapse with exercise. In long-
standing cases, there may be evidence of blindness with dilated
and fixed pupils caused by compression and disruption of
optic nerves by dorsal extension of the pituitary tumor.
Animals with hormonally inactive pituitary adenomas
often have progressive loss of weight, with muscle atrophy
because of lack of the protein anabolic effects of GH. Com-
pression of the cells that secrete gonadotrophic hormones or
the corresponding hypothalamic releasing hormone(s) results
288 CHAPTER 3  •  Endocrine Glands
C F R M
Figure 3-19  Adrenal cortex from a dog with a large nonfunc-
tional pituitary adenoma. The inner zonae fasciculata (F) and
reticularis (R) are atrophic as a result of subnormal production of
adrenocorticotropic hormone. The outer zona glomerulosa
(arrow) is normal but relatively more prominent. C, adrenal
capsule; M, medulla.
in atrophy of the gonads, causing decreased libido or anestrus.
Affected animals appear dehydrated, as evidenced by a luster-
less dry hair coat, and they consume increased amounts of
water.
Hormonally inactive pituitary adenomas often attain con-
siderable size before they cause obvious signs or kill the
animal. The proliferating tumor cells incorporate the remain-
ing structures of the adenohypophysis and infundibular stalk.
The neoplasms attach firmly to the base of the sella turcica,
but cause no erosion of the sphenoid bone. An incomplete
diaphragma sellae permits dorsal growth of the adenoma
along lines of least resistance. The entire hypothalamus may
become compressed and replaced by the tumor.
The adrenal glands in animals with large nonfunctional
pituitary adenomas are small and consist primarily of medul-
lary tissue surrounded by a narrow zone of cortex. The adrenal
cortex appears as a thin yellow-brown rim composed of a
moderately thickened capsule and secretory cells of the outer
zona glomerulosa, which are not predominantly under the
control of ACTH. The zonae fasciculata and reticularis are
severely atrophied (Fig. 3-19). Thyroid glands in animals with
large pituitary adenomas are either normal size or smaller than
normal, although less atrophied than the adrenal cortex (Fig.
3-20A). Most of the atrophic thyroid follicles are large, lined
by flattened cuboidal epithelium (Fig. 3-20B). The thyroid
lesion is due to lack of TSH-induced endocytosis of colloid.
Seminiferous tubules of the testes are small and show little
evidence of active spermatogenesis.
The cells comprising nonfunctional pituitary adenomas are
cuboidal to polyhedral and either arranged in diffuse sheets
or subdivided into small packets by fine connective tissue
septa. Special histochemical techniques for pituitary cytology
fail to demonstrate specific secretory granules within the cyto-
plasm of tumor cells. The histogenesis of nonfunctional chro-
mophobe adenomas often is difficult to define precisely, but
they appear to be derived from less differentiated pituitary
cells that neither store nor secrete a specific hypophyseal
trophic hormone.
Pituitary Gland
B
Figure 3-20  Destruction of the pituitary by a nonfunctional
adenoma in a dog. A. Trophic atrophy of the adrenal cortex and
thyroid follicular cells. Bar = 1 cm. B. The thyroid follicular cells
have undergone trophic atrophy and are low cuboidal to flattened
because of a lack of thyroid-stimulating hormone. Accumulation
of colloid in involuted follicles prevents a marked reduction in
thyroid gland size.
Pituitary chromophobe carcinoma
Pituitary chromophobe carcinomas are uncommon compared
with pituitary adenomas, but have been seen in older dogs,
cows, and sheep. They are usually endocrinologically inactive
but may result in significant functional disturbances by
destruction of the pars distalis and neurohypophyseal system,
leading to panhypopituitarism and diabetes insipidus.
Pituitary carcinomas are large and extensively invade the
overlying brain (Fig. 3-21), along the ventral aspect of skull,
and into the sphenoid bone of the sella turcica, inducing
resorption of the bone. Metastases may occur to regional
lymph nodes or to distant sites, such as the spleen or liver.
Malignant tumors of pituitary chromophobes are highly
cellular and often have large areas of hemorrhage and necrosis.
Giant cells, nuclear pleomorphism, and mitotic figures are
encountered more frequently than in chromophobe adeno-
mas. A confirmed diagnosis of malignancy requires invasion
into the sphenoid bone or metastasis, whereas cases of local
invasion into surrounding brain or connective tissue structures
are considered to represent adenomas.
Tumors metastatic to the pituitary gland
The pituitary gland occasionally is either partially or com-
pletely destroyed by metastatic tumors from distant sites.
 Pituitary Gland
Figure 3-21  Nonfunctional chromophobe carcinoma destroying
the pituitary and invading the brain in a dog. Note the irregular
margins of the neoplasm. Bar = 1 cm.
Figure 3-22  Metastasis of a mammary carcinoma to the pars
distalis of the pituitary in a dog.
Examples include malignant lymphoma in cattle, dogs, and
cats; malignant melanoma in horses and dogs, transmissible
venereal tumor, and adenocarcinoma of the mammary gland
in dogs (Fig. 3-22). In addition, the pituitary may be com-
pressed or destroyed by local infiltration from osteosarcomas
of the sphenoid bone, ependymomas arising in the infundibu-
lar recess of the third ventricle, meningiomas, and gliomas
(“infundibulomas”) of the infundibular stalk.
Granular cell tumors of the pituitary
Granular cell tumors (GCT) are uncommon in most animal
species, but have been reported in dogs, horses, and cats. They
are encountered most commonly in the oral cavity; occasion-
ally in the heart, lymph nodes, brain, and skin, and rarely the
pituitary gland in a parasellar location. Granular cell tumors
may involve the pituitary, optic chiasm, and ventral pyriform
lobes, resulting in blindness, seizures, ataxia, weakness, and
behavioral changes.
The neoplastic cells in GCT have abundant eosinophilic
granular cytoplasm with round-to-oval eccentrically placed
nuclei. The cytoplasm stains diffusely positive with the PAS
reaction, but immunohistochemical staining for pancytokera-
tin, vimentin, S-100 protein, glial fibrillary acidic protein,
289
Figure 3-23  Granular cell tumor involving the pituitary gland
and ventral brain from a dog. Note the monomorphic population
of large cells with abundant granular, eosinophilic cytoplasm.
Neuropil of the ventral brain is on the left.
neuron-specific enolase, and synaptophysin is uniformly nega-
tive. Ultrastructurally, the neoplastic cells contain numerous
membrane-bound lysosomal bodies that displace the nucleus
to an eccentric location and obscure other cytoplasmic organ-
elles (Fig. 3-23).
Mechanisms of pituitary tumor induction
The cellular origin of neoplastic cells forming pituitary tumors
is uncertain. Most pituitary tumors are considered to be
monoclonal and originate from a stem cell, early progenitor
cell, or differentiated cell. It is still under debate whether
pituitary adenomas arise in areas of hyperplastic change or
following specific mutations in oncogenes or tumor suppressor
genes. The first model is supported by findings in laboratory
animals in which absence of negative feedback inhibition of
pituitary cells leads to unrestrained proliferation and hyper-
plastic change. Such an effect can be potentiated by the 
concurrent administration of ionizing radiation or chemical
carcinogens. The administration of estrogens is a reproducible
method for inducing pituitary tumors in certain experimental
animals. The effect of exogenous estrogen on the rat pituitary
includes stimulation of prolactin secretion and the induction
of prolactin-secreting tumors. However, many, if not most,
pituitary tumors are not associated with hyperplasia, indicat-
ing a de novo genetic event and leading to transformation of
pituitary cells.
Other diseases and inflammation of
the adenohypophysis
The pituitary is occasionally involved in systemic or regional
diseases. Bacterial septicemia, especially in ruminants, can
result in hypophysitis or a pituitary abscess. This occurs more
frequently in male animals, presumably resulting from trauma
originating from fights or dehorning. In many cases of hypoph-
ysitis, a purulent inflammatory process is present in an adja-
cent organ, such as the ethmoid turbinates, ventral brain, or
meninges (Fig. 3-24A, B). Bacterial thromboembolism can also
occur in the rete mirabile, particularly in ruminants. In cows
with systemic AA amyloidosis resulting from chronic disease,
amyloid deposits can be present in the pituitary.
290 CHAPTER 3  •  Endocrine Glands Pituitary Gland

Loss of pituitary cells in the anterior lobe accompanied by

atrophy of adrenal glands and sex glands was present in sheep
treated long-term with ammonium tetrathiomolybdate. This
chemical is used for treatment of chronic copper intoxication
in sheep. It is retained in the pituitary (and adrenal glands)
and interferes with release of trophic hormones resulting in
atrophy of endocrine organs.

Diseases of the neurohypophysis

A tion of normal or elevated circulating levels of ADH (nephro-
B nervosa with hypophyseal diabetes insipidus associated with
Figure 3-24  A. Suppurative hypophysitis (arrowhead) secondary
to streptococcal meningoencephalitis in a horse. B. Suppurative
meningitis destroying the pituitary gland (arrowhead) in a cat.
Bar = 1 cm.
Diabetes insipidus is a disorder in which inadequate antidi-
uretic hormone (ADH) is produced (hypophyseal form), or
target cells in the kidney are unable to respond to the secre-
genic form).
The hypophyseal form of diabetes insipidus develops as a
result of compression and destruction of the pars nervosa,
infundibular stalk, or supraoptic nucleus in the hypothalamus.
The lesions responsible for the disruption of ADH synthesis
or secretion include large pituitary neoplasms, dorsally expand-
ing cysts or granulomas, and traumatic injury to the skull with
hemorrhage and glial proliferation in the neurohypophyseal
system. This interrupts the nonmyelinated axons that trans-
port ADH from its site of production, primarily in the supra-
optic nucleus of the hypothalamus, to the site of release in
the capillary plexus of the pars nervosa. Compression of neu-
rosecretory neurons in the supraoptic nucleus of the hypo-
thalamus by the dorsally expanding neoplasm may also result
in decreased ADH synthesis. Axons in the compressed pars
pituitary neoplasms are depleted of ADH-containing, dense
neurosecretory granules, unlike those in normal animals (Fig.
3-25A, B). Sporadic cases of hypophyseal diabetes insipidus
may be the result of an inherited biochemical defect in the syn-
thesis of ADH and its corresponding neurophysin I, as has been
described in the Brattleboro strain of rat.

SG

A B
Figure 3-25  A. Cross-section of axonal process in pars nervosa of dog with hypophyseal diabetes
insipidus associated with a pituitary adenoma. Axonal swelling contains few neurosecretory gran-
ules with dense cores, but occasional irregularly shaped, empty vesicles (arrow). B. Cross-section
of axonal process in pars nervosa of normal dog, illustrating numerous membrane-bound, antidi-
uretic hormone–containing, neurosecretory granules (SG). Electron micrographs.
 Calcium-Regulating Hormones
Figure 3-26  Pituicytoma in a cat. The neoplastic cells resemble
astrocytes with fibrillary neurofilaments. Luxol fast blue stain.
In the nephrogenic form of diabetes insipidus, blood
levels of ADH are normal or elevated, but target cells in the
distal nephron and collecting ducts are unable to respond
because of a lack of adenylyl cyclase in the plasma
membrane.
Animals with diabetes insipidus excrete large volumes of
hypotonic urine, which in turn obliges them to take in equally
large amounts of water to prevent hyperosmolality of body
fluids and dehydration. Urine osmolality is decreased below
normal plasma osmolality (~300 mmol/L) in both hypophy-
seal and nephrogenic forms of diabetes insipidus. In response
to water deprivation, urine osmolality remains below that of
plasma in both forms in contrast to what is observed in normal
animals. The elevation of urine osmolality above that of plasma
in response to exogenous ADH in the hypophyseal form, but not
in nephrogenic diabetes insipidus, allows separation of these 2
forms of the disease.
Tumors of the neurohypophysis are called pituicytomas;
they are very rare in animals. Morphologically they resemble
astrocytomas (Fig. 3-26). Immunohistochemically, they are
positive for glial fibrillary acidic protein (GFAP).
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Fracassi F, et al. Pituitary macroadenoma in a cat with diabetes mellitus,
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291
Extracellular Ca
Ca Ca
 PTH
↓ Ca
Calcitriol
Ca
Ca
Calcitonin
Figure 3-27  Interrelations of parathyroid hormone (PTH),
calcitonin, and calcitriol (active form of vitamin D: 1,25- 
dihydroxycholecalciferol) in the hormonal regulation of calcium
in extracellular fluids.
Rosol TJ, et al. Endocrine system. In: Haschek WM, et al., editors.
Haschek and Rousseaux’s Handbook of Toxicologic Pathology. Else-
vier/ Academic Press; 2013. p. 2391-2492.
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CALCIUM-REGULATING HORMONES
Calcium ion plays a key role in many fundamental biological
processes, including muscle contraction, blood coagulation,
enzyme activity, neural excitability, hormone release, and
membrane permeability, in addition to being an essential
structural component of the skeleton. To maintain a constant
concentration of calcium, despite variations in intake and
excretion, endocrine control mechanisms have evolved that
primarily consist of the interactions of 3 major hormones (Fig.
3-27). Although the roles of parathyroid hormone, calcitonin,
calcitriol (the active form of vitamin D: 1,25-dihydroxyvitamin
D), and fibroblast growth factor-23 (FGF23) frequently are
emphasized in the control of blood calcium; other hormones,
such as adrenal corticosteroids, estrogen, thyroxine, somatotropin,
and glucagon, also contribute to the maintenance of calcium
homeostasis under certain conditions.
Calcium (Ca) serves 2 primary functions in the body: (1)
for structural integrity of bones and teeth, and (2) as a messenger
or regulatory ion. The 10,000-fold concentration gradient of
calcium ion (Ca2+) between the extracellular fluid (1.2 mmol/L)
and the cytoplasm (100 nmol/L) permits Ca2+ to function as
a signaling ion to activate intracellular processes. The lipid
bilayer of the cell membrane has a low permeability to Ca2+;
therefore influx of Ca2+ into the cytoplasm is controlled by a
heterogeneous group of Ca channels regulated by membrane
potential, cell membrane receptors, or intracellular secondary
messengers. Influx of Ca2+ into cells can (1) regulate cellular
function by interactions with Ca-binding proteins (e.g.,
calmodulin) and Ca-sensitive protein kinases, and (2) stimu-
late biologic responses, such as neurotransmitter release,

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292 CHAPTER 3  •  Endocrine Glands
contraction, and secretion. Ionized calcium (Ca2+) also plays an
important role in cell adhesion and blood coagulation. In addi-
tion, Ca2+ may regulate cellular function by binding to a
G-protein–linked Ca2+-sensing receptor in the cell membrane,
such as in parathyroid chief cells or renal epithelial cells.
It is critical for cells to maintain the normal low level of
intracellular Ca2+. If cellular calcium homeostasis fails because
of anoxia, an energy-deprived state, or perturbed membrane
integrity, cell viability is threatened because of uncontrolled
entry of Ca2+ through the plasma membrane or from intracel-
lular stores.
There are 2 sources of calcium in bone that can enter the
circulation: (1) readily mobilizable Ca salts in the extracellular
fluid, and (2) hydroxyapatite crystals that require digestion by
osteoclasts before Ca2+ can be released from bone. The nature
and regulation of the readily mobilizable Ca in bone is poorly
understood; however, it is present in small amounts and likely
plays a role in the fine regulation of serum Ca concentration.
If there is a significant need for Ca from bone, it must come
from osteoclastic resorption of hydroxyapatite crystals. In
adult animals, there is a stable balance between Ca deposition
associated with bone formation by osteoblasts and Ca release
associated with osteoclastic bone resorption. In young animals,
bone has a positive Ca balance, given the relative excess of
bone formation. Conditions that result in excessive bone
resorption (e.g., humoral hypercalcemia of malignancy, osteo-
lytic bone metastases, or primary hyperparathyroidism), can
release large amounts of Ca from bone and contribute to the
development of life-threatening hypercalcemia.
Parathyroid glands and parathyroid hormone
Development and structure
Parathyroids are of entodermal origin and derived from the
third and fourth pharyngeal pouches in close association with
the primordia of the thymus (Fig. 3-28). The anatomic loca-
tion of parathyroid glands varies in relation to thyroids and
related structures in various species of animals (Fig. 3-29).
The parathyroid glands contain a single basic type of secretory
cell, the chief cell, which is concerned with the elaboration of a
single hormone. Inactive chief cells are cuboidal and have simple
interdigitations between contiguous cells. The relatively electron-
transparent cytoplasm contains poorly developed organelles,
and secretory granules are sparse. The cytoplasm often has
Cranial
Foramen cecum
I signal sequence of 25 amino acid residues that facilitates the
II Thyroglossal duct
External parathyroid
gland (III) III
Internal parathyroid
IV
gland (IV)
V proPTH by the proteolytic cleavage of 25 amino acids from
Thymus Thymus
Ultimobranchial body
Left thyroid lobe Right thyroid lobe
Caudal
Figure 3-28  Embryologic development of thyroid and parathy-
roid glands.
Calcium-Regulating Hormones
either numerous lipid bodies and lipofuscin granules or aggre-
gations of glycogen. Active chief cells are in the minority in
the parathyroid glands of most species. The cytoplasm of
active chief cells has increased electron density because of the
close proximity of organelles and secretory granules, increased
density of the cytoplasmic matrix, and loss of glycogen par-
ticles and lipid bodies.
The second cell type in the parathyroid glands of certain
species, including humans, is the oxyphil cell. These cells are
absent in rats, chickens, and many species of lower animals.
Oxyphil cells tend to increase with age and occur either singly
or in small groups interspersed between chief cells. They are
larger than chief cells, and their abundant eosinophilic cyto-
plasm is filled with numerous large, often bizarre-shaped,
mitochondria (Fig. 3-30). Glycogen particles and free ribo-
somes are interspersed between the mitochondria. Granular
endoplasmic reticulum, Golgi apparatuses, and secretory 
granules are poorly developed in oxyphil cells of normal 
parathyroid glands. Oxyphil cells have a higher oxidative and
hydrolytic enzyme activity than chief cells, associated with the
marked increase in numbers of mitochondria. Oxyphil cells
are immunohistochemically positive for parathyroid hormone
(PTH), the calcium-sensing receptor (CaSR), vitamin D
receptor (VDR), and 1-α-hydroxylase. Expression of these
molecules, with the exception of VDR, is higher in oxyphil
cells than in chief cells. The functional consequences of these
findings are unclear; however, humans with chronic kidney
disease (CKD) have increased oxyphil cell numbers.
Cells are observed with cytoplasmic characteristics inter-
mediate between those of chief and oxyphil cells. These tran-
sitional oxyphil cells have numerous mitochondria, but other
organelles are also present, including rough endoplasmic retic-
ulum, Golgi apparatuses, and secretory granules. Oxyphil cells
are not altered in response to either short-term hypocalcemia
or hypercalcemia in animals. Therefore oxyphil cells do not
appear to be degenerate chief cells, but rather occur as a result
of aging or some other metabolic derangement.
Biosynthesis and secretion of parathyroid hormone
The principal product of the parathyroid gland is parathyroid
hormone (PTH). Together with other hormones, such as cal-
citriol, calcitonin, and FGF23, it plays a major role in calcium
and, indirectly, phosphate metabolism (Fig. 3-31). Much of
the current knowledge about the regulation of these hor-
mones has been acquired by investigating naturally occurring
diseases and genetically modified knock-out mouse models.
The production of PTH involves the biosynthesis of a large
precursor on ribosomes of the rough endoplasmic reticulum
in chief cells. This initial translation product is pre-proPTH.
It is composed of 115 amino acids and contains a hydrophobic
penetration and discharge of the nascent peptide into the
cisternal space of the rough endoplasmic reticulum. Pre-
proPTH is rapidly converted (within 1 minute or less) to
the NH2-terminal end. ProPTH is composed of 90 amino acids
and moves within the rough endoplasmic reticulum to the
Golgi apparatus. Enzymes within the Golgi apparatus cleave
a hexapeptide from the NH2-terminal (biologically active)
end of the molecule, forming active PTH, which is packaged
into membrane-limited, secretory granules in the Golgi appa-
ratus for subsequent storage in chief cells. Under certain 
conditions of increased demand, PTH may be released 
 Calcium-Regulating Hormones 293

Thymus
ePTG

PTG
(upper) iPTG
TG TG

Ovine
Thymus
ePTG

PTG (lower) iPTG

First rib TG
Bicarotid trunk
Equine Caprine

ePTG ePTG
iPTG iPTG
TG TG
Isthmus
Canine Feline
Thymus
PTG
ePTG

TG
iPTG

Common
carotid a. Common
carotid a.
Bovine Porcine
Figure 3-29  Anatomic location of parathyroids and thyroids in various species. a, artery, ePTG,
external parathyroid gland, iPTG, internal parathyroid gland, TG, thyroid gland. (Modified from
Grau H, Dellmann HD. Species differentiation of the parathyroid glands of our domestic animals
(German). Z Mikrosk Anat Forsch 1958;64:192-214.)

1-hydroxylase
calcitriol

 
 

PTH
FGF23


Figure 3-30  Focal oxyphil cell hyperplasia in an aged bovid. 

Note that oxyphil cells are enlarged with abundant eosinophilic
cytoplasm because of an accumulation of mitochondria. Normal
chief cells are present in the upper right corner.
Figure 3-31  Interaction and feedback control mechanisms
of parathyroid hormone (PTH), calcitriol (1,25-dihy-
droxycholecalciferol), and fibroblast growth factor-23 (FGF23) in
Ca2+ regulation.
294 CHAPTER 3  •  Endocrine Glands
directly from chief cells without being packaged into secretory
granules.
Biologically active PTH secreted by chief cells is a straight-
chain polypeptide consisting of 84 amino acid residues with
a molecular weight of 9,500. The molecule is rapidly cleaved
into amino-terminal and carboxyl-terminal fragments in the
peripheral circulation and especially in the liver. The purpose
of this fragmentation is uncertain because the biologically
active amino-terminal fragment (1-34) is no more active than
the entire (1-84) PTH molecule. The plasma half-life of the
N-terminal fragment is considerably shorter than that of the
biologically inactive carboxyl-terminal fragment of parathy-
roid hormone. The C-terminal portion of PTH is degraded
primarily in the kidney and accumulates in the circulation of
animals with chronic renal disease.
Chief cells synthesize and secrete another major protein,
termed chromogranin A. It has a higher molecular weight than
PTH, being composed of 430-448 amino acids, and is co-stored
and secreted with parathyroid hormone. A similar molecule has
been found in secretory granules of a wide variety of peptide–
hormone-secreting cells (e.g., thyroid C cells, pancreatic islets,
adrenal medulla, endocrine cells of the gastrointestinal tract),
and in neurotransmitter secretory vesicles of sympathetic
nerves. A proteolytic cleavage product of chromogranin A
inhibits PTH secretion from chief cells. These findings suggest
that one function of chromogranin A is to act locally in an
autocrine manner to inhibit the secretion of active hormone,
such as PTH, by endocrine cells.
Secretory cells in the parathyroids of most animals store
relatively small amounts of preformed hormone but are
capable of responding to minor fluctuations in Ca2+ concentra-
tion by rapidly altering the rate of hormonal secretion, and
more slowly by altering the rate of hormonal synthesis. The
parathyroids have a unique feedback control system based pri-
marily on the concentration of calcium (and to a lesser extent of
magnesium) ion in blood. If the blood calcium is elevated, then
circulating levels of parathyroid hormone rapidly and mark-
edly decrease, but a basal level of secretion is always main-
tained. Conversely, if the blood calcium is lowered, parathyroid
hormone levels increase. The concentration of blood phospho-
rus has no direct regulatory influence on the synthesis and
secretion of PTH; however, certain disease conditions with
hyperphosphatemia are associated clinically with secondary
hyperparathyroidism. An elevated blood phosphorus level
may lead indirectly to parathyroid stimulation by virtue of its
ability to lower blood calcium according to the mass-law
equation when the serum is saturated with these 2 ions.
Hyperphosphatemia also suppresses the rate of formation of
calcitriol in the kidney, which contributes to the development
of hypocalcemia and parathyroid stimulation.
Serum calcium ion (Ca2+) binds to a cell membrane calcium
ion receptor on the chief cell, which permits serum Ca2+ to regulate
chief cell function. The receptor is present on the plasma mem-
branes of parathyroid chief cells, renal epithelial cells, thyroid
C cells, and other cells that respond to extracellular Ca2+.
Mutations in one or both of the Ca2+-sensing receptor genes
in humans result in familial hypocalciuric hypercalcemia or
neonatal severe hypercalcemia, respectively. Interaction of
serum Ca2+ with its receptor on chief cells results in the for-
mation of an inverse sigmoidal relationship between serum
Ca2+ and PTH concentrations. The serum [Ca2+] that results
in half-maximal PTH secretion is defined as the serum
calcium “set-point” and is stable for an individual animal. The
Calcium-Regulating Hormones
sigmoidal relationship between serum [Ca2+] and PTH secre-
tion permits the chief cells to respond rapidly to a reduction
in serum Ca2+. The major inhibitors of PTH synthesis and secre-
tion are increased serum [Ca2+] and calcitriol. Inhibition of PTH
synthesis by calcitriol completes an important endocrine feed-
back loop between the parathyroid chief cells and the renal
epithelial cells, because PTH stimulates renal production of
calcitriol (see Fig. 3-31). A newly discovered hormone pro-
duced by osteocytes in bone is FGF23, which increases renal
phosphate excretion and decreases PTH mRNA expression
and secretion after binding to the FGF receptor 1 (FGFR1)
on renal epithelial and chief cells. The FGFR1 functions in
concert with the transmembrane protein Klotho.
Biological action of parathyroid hormone
Parathyroid hormone is the principal hormone involved in the
minute-to-minute, fine regulation of blood Ca2+. It exerts its
biologic actions by directly influencing the function of target
cells, primarily in bone and kidney, and indirectly in the intes-
tine. The action of PTH on bone is to mobilize calcium from
skeletal reserves into extracellular fluids.
The response of bone to parathyroid hormone is biphasic.
The immediate effects are the result of increasing the activity
of existing osteoclasts and osteocytes present in bone. This
results in an increased flow of calcium from deep in the bone
through the coordinated action of osteocytes and endosteal
lining cells (inactive osteoblasts). Osteoclasts are primarily
responsible for the long-term action of parathyroid hormone
on increasing bone resorption and overall bone remodeling. If
the increase in parathyroid hormone is sustained, the active
osteoclast pool in the bone is increased. A long-term increase
in PTH secretion, such as occurs with certain disease condi-
tions, may also result in the formation of greater numbers of
osteoblasts with a resultant increase in bone formation as well
as resorption. However, bone resorption usually is greater than
bone formation, leading to a net negative skeletal balance.
Osteoclasts are primarily responsible for the catabolic action
of PTH on bone by increasing resorption. PTH not only stimu-
lates increased activity of preformed osteoclasts, but increases
their differentiation from precursor cells of the osteoclast
lineage. However, receptors for PTH are present on osteo-
blasts, not on osteoclasts. Isolated osteoclasts respond to PTH
only in the presence of osteoblasts. Bone resorption is a
complex process that involves the activation of multiple genes
and the action of several hormones. The receptor ligand
(receptor activator of nuclear factor κB [NFκB] ligand
[RANKL]) is a member of the tumor necrosis factor (TNF)
superfamily and a membrane-bound protein on osteoblasts
that serves as a common mediator for osteoclastic bone
resorption. This ligand is produced by osteoblast lineage cells
and stimulates differentiation of cells of the osteoclast lineage,
enhances the functional activity of mature osteoclasts, and
prolongs osteoclast life by inhibiting apoptosis. Expression 
of RANKL in osteoblasts/stromal cells is upregulated by 
multiple osteotrophic factors, such as PTH, calcitriol, TNF,
interleukin-1 (IL-1), IL-6, and IL-11. RANKL is identical to
TNF-related activation-induced cytokine (TRANCE), which
stimulates T-cell growth and dendritic cell function.
The membrane receptor (RANK) for RANKL is on cells
of the osteoclast lineage. Binding of RANKL to its receptor
activates signaling pathways in osteoclasts that lead to
increased functional activity. Osteoclast precursors express
RANK, recognize RANKL through cell-to-cell interaction
 Calcium-Regulating Hormones
with osteoblasts/stromal cells, and differentiate into osteo-
clasts in the presence of macrophage-colony stimulating factor
(M-CSF). Mice made deficient in RANK by targeted deletion
of the gene develop severe osteopetrosis as a result of decreased
osteoclast function.
Osteoprotegerin (OPG) (“decoy receptor” for RANKL) is
a novel member of the TNF receptor superfamily produced
by cells of the osteoblast lineage/stromal cells and is a negative
regulator of bone resorption. When this soluble receptor binds
to RANKL, it prevents it from binding to its receptor, RANK.
Overexpression of this decoy receptor in transgenic mice leads
to osteopetrosis associated with decreased osteoclastic bone
resorption. In contrast, targeted gene ablation results in osteo-
porosis and arterial mineralization. Osteoclast formation
appears to be determined by the ratio of RANKL to OPG,
and alterations in this ratio may be a major cause of bone loss
in certain metabolic disorders, such as estrogen deficiency and
glucocorticoid excess.
Binding of PTH to the PTH1 receptors on bone cells results
in the activation of adenylyl cyclase in the plasma membrane,
which catalyzes the conversion of ATP to 3′,5′-adenosine
monophosphate (cAMP). PTH also induces an increase in
cytoplasmic Ca2+ and stimulates phosphatidylinositol turn-
over. Calcium concentration in the osteoblast may also be
increased by the activation of protein kinase C, resulting in
the production of inositol triphosphate and subsequent release
of calcium from the endoplasmic reticulum.
Parathyroid hormone has a rapid (5-10 minutes) and direct
effect on renal tubular function, leading to decreased reab-
sorption of phosphate and phosphaturia. The site where PTH
blocks tubular reabsorption of phosphate has been localized
to the proximal tubule of the nephron. PTH binds to the
PTH1 receptor on the basolateral aspect of renal epithelial
cells. The PTH1 receptor belongs to the family of G protein–
linked receptors with 7 transmembrane spanning domains
that activate adenylyl cyclase. PTH also increases the reab-
sorption of renal tubular calcium because of a direct action
on the distal convoluted tubule, which is also coupled to an
increase in intracellular cAMP.
The other important effect of parathyroid hormone  calcium-binding protein (CaBP, calbindin). CaBP is at the
is the regulation of the conversion of inactive 25-  luminal aspect of intestinal absorptive cells, where it com-
hydroxycholecalciferol to biologically active 1,25-  plexes with calcium ions for transport to the basolateral aspect
dihydroxycholecalciferol (calcitriol).
Cholecalciferol (vitamin D3)
Biosynthesis of 1,25-dihydroxycholecalciferol
(calcitriol)
The second major hormone involved in the regulation of
calcium metabolism and skeletal remodeling is the active form
of vitamin D, calcitriol.
Cholecalciferol is ingested in small amounts in the diet and
can be synthesized in the epidermis from precursor molecules.
This reaction is catalyzed by ultraviolet irradiation (wave-
lengths 290-320 nm) from the sun. A high-affinity vitamin
D–binding protein transports cholecalciferol in the blood.
Vitamin D must be metabolically activated before it can
produce its known physiologic functions. Endogenous chole-
calciferol synthesized in the skin from 7-dehydrocholesterol
also is protein-bound for transport to the liver. In the liver,
cholecalciferol is converted to 25-hydroxycholecalciferol by a
hepatic microsomal enzyme, cholecalciferol-25-hydroxylase,
which is associated with the endoplasmic reticulum in
295
hepatocytes. Serum 25-hydroxycholecalciferol concentration
is the best indicator of nutritional vitamin D adequacy in an
animal. Animals that have ingested excess vitamin D may have
serum 25-cholecalciferol up to 20-fold greater than normal.
The inactive metabolite, 25-hydroxycholecalciferol, 
is transported to the kidney and hydroxylated to 1,25- 
dihydroxycholecalciferol (calcitriol). This is catalyzed by 25-
hydroxycholecalciferol-1-α-hydroxylase (1-α-hydroxylase) in
mitochondria, primarily in cells of the proximal convoluted
tubule. The conversion of 25(OH)D3 to 1,25(OH)2D3 (cal-
citriol) is the rate-limiting step in vitamin D metabolism. The
control of this final step in the metabolic activation is complex
and is regulated in part by the plasma calcium concentration
and its influence on the rate of secretion of PTH. PTH stimu-
lates the activity of the 1-α-hydroxylase and the formation of
calcitriol. Low blood phosphate increases the formation of
calcitriol, whereas high blood phosphate suppresses the activ-
ity of the 1-α-hydroxylase. Serum calcitriol levels are influ-
enced by FGF23, which decreases the activity of the renal
1-α-hydroxylase. In addition, FGF23 increases the expression
of the 24-hydroxylases, which hydroxylates carbon 24 and
inactivates calcitriol.
Other hormones also may increase the activity of renal
1-α-hydroxylase and the formation of calcitriol under certain
conditions. Prolactin, estradiol, placental lactogen, and somato-
tropin all enhance 1-α-hydroxylase activity. Increased secre-
tion of these hormones, either alone or in combination,
appears to be important in the efficient adaptation to major
calcium demands, such as pregnancy, lactation, and growth.
Biological action of calcitriol
Calcitriol increases the absorption of calcium and phosphate
from the intestine. From a functional point of view, calcitriol
can be thought to bring about the retention of sufficient mineral
ions to ensure mineralization of bone matrix, whereas parathy-
roid hormone maintains the proper ratio of calcium to phosphate
in extracellular fluids.
Intestinal cells that transport calcium from the lumen to
the blood stream in response to calcitriol synthesize a specific
of the cell. Calcium-binding protein has also been isolated
from kidney, parathyroid gland, bone, cartilage, and the shell
gland of laying hens. The absorptive capacity of the intestine for
calcium is a direct function of the amount of CaBP present. The
physiologic function of CaBP may be to protect absorptive
cells against high cytosolic concentrations of Ca2+. At the
basilar aspect of intestinal absorptive cells, calcium is
exchanged for sodium and enters the extracellular fluids.
Calcitriol acts on bone both directly and indirectly. Cal-
citriol stimulates osteoclastic bone resorption by inducing
RANKL and increasing the number and activity of osteoclasts.
In contrast, calcitriol stimulates FGF23 expression by osteo-
cytes in bone, which inhibits PTH secretion, inhibits renal
1-α-hydroxylase, and increases renal phosphate excretion.
Small amounts of calcitriol are necessary to permit osteolytic
cells to respond to parathyroid hormone (“permissive effect”)
under physiologic conditions. Both 25-hydroxycholecalciferol
and calcitriol, in pharmacologic doses, stimulate osteoclastic
resorption of bone.
Less is known regarding the action of calcitriol on the
kidney, but it appears to stimulate the retention of calcium by
296 CHAPTER 3  •  Endocrine Glands
increasing renal tubular reabsorption, probably in the distal
part of the nephron.
Calcitriol has important effects on the parathyroid chief
cells, where it inhibits PTH synthesis and secretion and
increases of the expression of the VDR, CaSR, and Klotho.
Disorders of vitamin D metabolism
Lack of vitamin D causes rickets and osteomalacia in young
and mature animals, respectively (see Vol. 1, Bones and joints).
Deficiency of vitamin D results not only from simple dietary
lack or inadequate exposure to sunlight, but also from a defi-
ciency of the hydroxylase enzymes essential for metabolic
activation of precursor molecules. Vitamin D–dependent
rickets, type I, in both pigs and humans, is a familial disease
inherited as an autosomal recessive disorder. Newborn pigs
appear healthy and have normal blood calcium and phosphate
concentrations. At 4-6 weeks of age, blood Ca and P decrease,
serum alkaline phosphatase activity increases, and clinically
detectable rickets develops during the following 3-4 weeks.
The pigs develop deformities of bone in the axial and appen-
dicular skeleton, severe pain, and classic lesions of rickets.
Serum 25-cholecalciferol levels are markedly increased com-
pared to those of control pigs, whereas serum calcitriol levels
are depressed in rachitic pigs compared with normal pigs.
Homozygous animals have no renal 1-α-hydroxylase. Vitamin
D–dependent rickets caused by mutations in the CYP27B1
gene that encodes the renal 1-α-hydroxylase has been identi-
fied in individual cats.
Vitamin D–dependent rickets, type II, also called vitamin
D–resistant rickets (VDRR), is a group of disorders resulting
from defective VDRs. The disease is characterized by increased
serum calcitriol levels, hypocalcemia, secondary hyperpara-
thyroidism, and clinically by rickets or osteomalacia. New
World primates have a relative end-organ resistance to cal-
citriol and require high levels of vitamin D3 in their diet. The
common marmoset has been shown to represent a model of
vitamin D–dependent rickets, type II. Marmosets have
increased serum calcitriol concentrations compared to rhesus
monkeys, and some marmosets developed osteomalacia even
when on high vitamin D3 diets. Vitamin D–dependent rickets,
type II, has also been reported in individual cats.
Fibroblast growth factor-23 (FGF23)
Fibroblast growth factor-23 is a 32-kDa protein that is pro-
duced by osteocytes and osteoblasts. It belongs to the so-  tive for thyroglobulin), typical C cells, stellate cells that form
called endocrine FGFs and requires a cofactor to activate its
receptor FGFR1. The presence of the cofactor, the membrane-
spanning protein Klotho, defines the cells on which FGF23
can act. These include the parathyroid chief cells and proximal
renal tubules as well as tissues not primarily involved in
mineral metabolism, such as the choroid plexus and vascular
tissue.
FGF23 regulates serum phosphate by negative feedback
mechanisms involving the kidney and parathyroid. In the
kidney, FGF23 increases phosphate excretion in the proximal
tubules by inducing the expression of cotransporters in the
brush border. In addition, FGF23 suppresses calcitriol produc-
tion in the kidney by inhibiting the 1-α-hydroxylase and
promoting calcitriol catabolism by increasing 24-hydroxylase
activity. FGF23 decreases PTH mRNA expression and secre-
tion in chief cells. Production of FGF23 in the bone is stimu-
lated by calcitriol and PTH. In bone, FGF23 expression is
activated by the VDR/retinoic X receptor complex. Decreased
Calcium-Regulating Hormones
PTH results in reduced FGF23 concentrations and decreased
renal Klotho expression.
Diseases associated with mutations in either Klotho or
FGF23 are described in humans. Familial hyperphosphatemic
tumoral calcinosis is caused by inactivation of the FGF23 gene,
but also occurs with inactivation of Klotho. A gain-of-function
mutation of FGF23 leads to autosomal dominant hypophos-
phatemic rickets caused by renal loss of phosphate. FGF23
levels were analyzed in cats and appear to be elevated in cases
of CKD. Some mesenchymal tumors secrete excessive FGF23
and cause tumor-associated hypophosphatemia. The detection
of FGF23 and its mechanisms of action has propelled bone
from being viewed as mainly providing storage for calcium
and phosphate to being an active partner in the parathyroid
gland (PTG)-kidney-bone axis and function as an endocrine
organ.
Thyroid C cells and calcitonin
Development and structure of thyroid C cells
Another calcium-regulating hormone, calcitonin, which is
secreted by the thyroid C cells in response to hypercalcemia,
lowers plasma calcium. C cells are distinct from follicular 
cells. They are situated either within the follicular wall
between follicular cells or as small groups between follicles.
They do not border the follicular colloid directly, and their
secretory polarity is oriented toward the interfollicular
capillaries.
The ultimobranchial body (last, and usually fifth, pharyn-
geal pouch), which delivers the neural crest–derived C cells
to the postnatal thyroid gland, fuses with each thyroid lobe at
the hilus and distributes C cells throughout each lobe to
various degrees in different species. In submammalian species,
C cells and calcitonin activity remain segregated in the ulti-
mobranchial gland, which is anatomically distinct from both
the thyroid and the parathyroid glands.
In the dog and other species, nodular aggregates of C cells
frequently persist along the course of the blood vessels to the
hilus of the thyroid, which occasionally contain ultimobranchial-
derived, colloid-containing follicles. Islands of C cells, termed
C-cell complexes, are present in the thyroid glands (especially
prominent in dogs) often near the internal parathyroid gland
and should not be misinterpreted as areas of C-cell hyperpla-
sia. C-cell complexes contain follicular cells (that stain posi-
follicle-like structures (that stain positive for somatostatin),
and undifferentiated cells. The C-cell complex may be the
origin of the unique mixed thyroid carcinoma in human
patients or ultimobranchial thyroid neoplasms in bulls that are
composed of cells that have positive immunoreactivity for
both thyroglobulin and calcitonin. This suggests that the ulti-
mobranchial body may contribute to the formation of thyroid
follicles in certain areas of the thyroid lobes.
Cysts derived from remnants of the ultimobranchial body
can be observed in the postnatal thyroid and are lined by
squamous epithelium and contain keratin debris. Occasional
follicles derived from ultimobranchial primordia contain het-
erogeneous material and scattered ciliated epithelial cells in
the follicular wall.
The concentration of Ca2+ in plasma and extracellular fluids
is the principal physiologic stimulus for the secretion of calcitonin
by C cells. The rate of calcitonin secretion is increased greatly
in response to elevations in blood calcium. C cells have the
 Calcium-Regulating Hormones
same Ca2+-sensing membrane receptor as parathyroid chief
cells.
Biosynthesis and secretion of calcitonin
The 32–amino acid calcitonin peptide is transcribed from the
CALCA gene. Alternative splicing of CALCA mRNA results
in the formation of calcitonin or calcitonin gene–related gene
peptide (CGRP), depending on cell type. Calcitonin also
shares homology with amylin (isolated from pancreatic
amyloid deposits) and adrenomedullin, which belong to the
calcitonin family. The amino acid structure of calcitonin
differs between species; however, the amino terminus is
similar in all species and consists of a 7-membered ring
enclosed by an intrachain disulfide bridge. Salmon calcitonin
is more potent in lowering blood calcium than any of the
other calcitonins when administered to mammals, including
humans. The reason for the greater biological potency of
salmon calcitonin in mammals is uncertain, but probably is
related to an increased resistance to metabolic degradation or
a greater affinity for receptor sites.
C cells store abundant preformed hormone in cytoplasmic
secretory granules. Calcitonin secretion is increased in response
to a high-calcium meal, often before a significant rise in
plasma calcium can be detected. Certain gastrointestinal hor-
mones (such as gastrin) act as secretagogues for calcitonin
release from the thyroid gland. Hyperplasia of C cells occurs in
response to long-term hypercalcemia.
Biological actions of calcitonin
Calcitonin functions on targets cells primarily in bone and
kidney. The actions of parathyroid hormone and calcitonin are
antagonistic on bone resorption but synergistic on decreasing the
renal tubular reabsorption of phosphorus. The hypocalcemic
effects of calcitonin are primarily the result of transient inhibi-
tion of osteoclastic bone resorption. Osteoclasts have specific
receptors for calcitonin on their surfaces. Although calcitonin
can block bone resorption completely, the inhibition is a tran-
sient effect due to downregulation of receptor function. The
physiologic significance of calcitonin for calcium and phos-
phate regulation is significantly less compared to PTH. Lack
of calcitonin has little effect on calcium balance and bone
density.
Serum calcitonin is best measured by radioimmunoassay.
Because of the low degree of homology of calcitonin between
species, there is poor cross-reactivity of radioimmunoassays
(RIAs) for calcitonin. In veterinary medicine, the need to
measure circulating levels of calcitonin is associated with
calcitonin-secreting thyroid neoplasms and other clinical dis-
orders resulting from abnormal blood levels of calcitonin. In
humans, calcitonin RIA is useful to identify functional C-cell
(medullary) tumors of the thyroid gland. Measurement of
serum procalcitonin can be used as an early biomarker for
sepsis.
Calcitonin and parathyroid hormone, acting in concert,
provide a dual negative-feedback control mechanism to main-
tain the concentration of calcium in extracellular fluids within
narrow limits. Parathyroid hormone is the major factor
involved in the minute-to-minute regulation of blood calcium
under normal conditions. In mammals, calcitonin functions
more as an “emergency” hormone to prevent the development
of hypercalcemia during the rapid postprandial absorption of
calcium and to protect against excessive loss of calcium and
phosphorus from the maternal skeleton during pregnancy.
297
C
Figure 3-32  Kürsteiner’s cyst (C) next to a parathyroid gland
with hyperplastic chief cells from a dog with chronic renal failure.
Note the normal C-cell clusters (arrowheads).
Diseases of the parathyroid gland
Parathyroid and related cysts
Parathyroid (Kürsteiner’s) cysts are observed within the
parenchyma of the parathyroid or in the immediate vicinity
of the gland, frequently in dogs and occasionally in other
animal species (Fig. 3-32). Parathyroid cysts usually are small,
multiloculated, lined by cuboidal to columnar (often ciliated)
epithelium, and contain densely eosinophilic proteinaceous
material. Chief cells adjacent to larger cysts may be moder-
ately compressed.
Other cystic structures may occur in the thyroid-
parathyroid area. (1) Cysts derived from remnants of the
thyroglossal duct, which are lined by multilayered thyroido-
genic epithelium and colloid-containing follicles, and usually
are located on or near the midline from the base of the tongue
caudally into the mediastinum. (2) Ultimobranchial duct
cysts often are present in the parenchyma of the thyroid (near
the thyroid hilus) and have a keratinizing squamous epithelial
lining, which may be ciliated. The secretions are often muci-
nous or basophilic. There may be remnants of thymic lympho-
cytes, which should not be interpreted as inflammation. (3)
Branchial cysts are located lateral to the parathyroid-thyroid
area, often near the base of the ear and angle of mandible,
attached deeply to cervical structures, and clinically are
referred to as “lateral neck cysts.” They are lined by pseu-
dostratified columnar or squamous, partially ciliated, epithe-
lium that is derived from remnants of the second pharyngeal
pouch. (4) Salivary mucoceles may also be present in the
parathyroid-thyroid region.
Degenerative changes of the parathyroid gland
Parathyroid glands of dogs and rats may have multinucleated
syncytial giant cells (Fig. 3-33). They often are more numer-
ous near the periphery of the parathyroid gland, but this is
variable. The cytoplasm of syncytial cells is densely eosino-
philic and homogeneous, and the plasma membranes between
adjacent cells are indistinct. The nuclei are smaller, more
hyperchromatic and oval, than those in adjacent chief cells.
The significance of the syncytial cells is uncertain, and they
may represent an artifact of tissue collection or processing.
Amyloidosis can occur in the parathyroids of aged animals,
particularly aged cattle. There are 2 types of parathyroid
298 CHAPTER 3  •  Endocrine Glands
Figure 3-33  Parathyroid gland from a dog, with multinucleated
syncytial cells. The cytoplasm of syncytial cells is densely eosino-
philic, and the plasma membranes between adjacent cells are
indistinct. The nuclei are small, hyperchromatic, and oval.
A
Figure 3-34  Amyloidosis of the parathyroid gland of an aged cow.
The parathyroid chief cells are surrounded by homogeneous to
fibrillar eosinophilic amyloid. Inset: Parathyroid hormone (PTH)
immunohistochemistry. The chief cells stain intensely positive for
PTH (arrowhead). The amyloid (A) stains moderately positive for
PTH.
amyloidosis: (1) part of systemic inflammatory amyloidosis or
(2) parathyroid gland–specific amyloidosis that likely repre-
sents amyloid derived from secreted proteins of the chief cells.
The amyloid may be derived from PTH, because the amyloid
can stain immunohistochemically positive for PTH (Fig. 3-34).
Chemical-induced injury of parathyroid glands
Ozone. In response to exposure to ozone, many chief cells
undergo compensatory hypertrophy and hyperplasia with
areas of capillary endothelial cell proliferation, interstitial
edema, degeneration of vascular endothelium, formation of
platelet thrombi, leukocyte infiltration of the walls of larger
vessels in the gland, and disruption of basement membranes.
Aluminum. Evidence for a direct effect of aluminum on
the parathyroid was suggested from studies of patients with
chronic renal failure treated by hemodialysis with aluminum-
containing fluids or orally administered drugs containing  of parathyroids associated with long-term hypercalcemia. The
aluminum. These patients had a depressed response by the
Calcium-Regulating Hormones
Figure 3-35  Lymphocytic parathyroiditis in a dog with hypocal-
cemia. There is marked lymphoplasmacytic inflammation and no
normal chief cells remaining. There are multiple areas of nodular
regenerative hyperplasia of chief cells (arrowheads) with mild
inflammatory cell infiltration.
parathyroid gland to hypocalcemia. The inhibition of PTH
secretion by aluminum was reversible.
L-asparaginase. Rabbits administered L-asparaginase
developed severe hypocalcemia and tetany characterized by
muscle tremors, opisthotonos, carpopedal spasms, paralysis,
and coma. Parathyroid chief cells appeared to be selectively
destroyed by L-asparaginase. Chief cells were inactive and
degranulated, with large autophagic vacuoles. Rabbits devel-
oped hyperphosphatemia, hypomagnesemia, hyperkalemia,
and azotemia, in addition to acute hypocalcemia.
Lymphocytic parathyroiditis and hypoparathyroidism
Decreased secretion of parathyroid hormone by pathologic
parathyroid glands or inability of the hormone secreted to
interact normally with target cells results in hypoparathyroid-
ism. Hypoparathyroidism has been recognized in dogs, par-
ticularly in smaller breeds such as Schnauzers and Terriers, but
infrequently in other animal species. The functional distur-
bances of hypoparathyroidism primarily are the result of increased
neuromuscular excitability and tetany. Bone resorption is
decreased because of a lack of PTH and calcitriol, and blood
calcium levels consequently diminish progressively.
Several pathogenic mechanisms can result in inadequate
secretion of parathyroid hormone. Diffuse lymphocytic para-
thyroiditis, resulting in extensive degeneration of chief cells
and replacement by fibrous connective tissue, in adult dogs is
usually the cause of idiopathic hypoparathyroidism. In the
early stages, there is infiltration of the gland with lymphocytes
and plasma cells, and nodular regenerative hyperplasia of
remaining chief cells (Fig. 3-35). Later, the parathyroid gland
is completely replaced by lymphocytes, fibroblasts, and capil-
laries with few viable chief cells. Lymphocytic parathyroiditis
is most likely an immune-mediated disease. Similar lesions are
produced in dogs by injection of parathyroid tissue emulsions
and by repeated injections of parathyroid emulsions with
Freund’s adjuvant.
Other possible causes of hypoparathyroidism include inva-
sion and destruction of parathyroids by primary or metastatic
neoplasms in the cranial cervical region and trophic atrophy
parathyroid glands may be damaged or inadvertently removed
 Calcium-Regulating Hormones 299

during the course of surgery to remove thyroid tumors or Functional disturbances associated with hypocalcemia in
multifocal hyperplasia. Regeneration of adequate functional cows are related to paresis, whereas, in the bitch, they are
parenchyma and subsequent disappearance of clinical signs is primarily the result of neuromuscular tetany. The occurrence
generally possible, depending on the severity of damage to of either tetany or paresis in response to hypocalcemia appears to
parathyroid glands or their vascular supply. Agenesis of both be the result of basic physiologic differences in the function of the
pairs of parathyroids is a rare cause of congenital hypopara- neuromuscular junction of the cow and the bitch. The release of
thyroidism in pups. acetylcholine and transmission of nerve impulses across neu-
romuscular junctions are blocked by hypocalcemia in cows
Parathyroid stimulation associated with acute (but not in the bitch), leading to muscle paresis. Excitation-
hypocalcemia near parturition secretion coupling is maintained at the neuromuscular junc-
Parturient paresis is a complex metabolic disease characterized tion in the bitch with hypocalcemia, and tetany occurs as a
by the development of severe hypocalcemia and hypophosphate- result of spontaneous repetitive firing of motor nerve fibers.
mia near parturition and the initiation of lactation in dairy cattle.
Lactation requires high levels of calcium, exceeding the ani- Parathyroid hyperplasia
mal’s ability to mobilize sufficient calcium, and disease inci- Focal (nodular) hyperplasia. Chief cell hyperplasia may affect
dence is higher in older cows. In parturient paresis (also called the parathyroids in a distinctly focal or multifocal distribution
milk fever), the serum calcium (total and ionized) concentra- (Fig. 3-36A, B). In focal parathyroid hyperplasia, there are
tion falls to <50% of normal in spite of increased secretion of single or multiple nodules in one or both glands in which there
parathyroid hormone. The composition of the prepartum diet is an increased number of chief cells, often with an expanded
is a significant factor in the pathogenesis of parturient hypo- cytoplasmic area. The foci of chief cell hyperplasia are not
calcemia. High-calcium diets increase the incidence of the encapsulated and are poorly demarcated from adjacent
disease, and low-calcium diets or prepartum diets supple-
mented with pharmacologic doses of vitamin D reduce the
incidence of the disease. Calcium homeostasis in pregnant
cows fed a high-calcium diet appears to be maintained prin-
cipally by intestinal calcium absorption. This greater reliance
on intestinal absorption than on PTH-stimulated bone resorp-
tion is a significant factor in the more frequent development
of profound hypocalcemia near parturition. The parathyroid
glands respond to the acute hypocalcemia by increased syn-
thesis and secretion of PTH, and there are increased serum
PTH concentrations. The increased rate of hormone secretion
exceeds the rate of synthesis by the gland.
Cows fed a high-calcium diet have higher blood calcium levels
prepartum, but are less able to maintain serum calcium near the
critical time of parturition. Plasma PTH levels are lower pre-
partum than in cows fed a balanced diet, and decline further
at 48 hours postpartum. Inactive chief cells predominate in
cows fed high-calcium diets, whereas actively synthesizing A
chief cells are most numerous in parathyroids of cows fed
balanced prepartum diets. In response to the elevated blood
calcium in cows fed high-calcium prepartum diets, the C cells
are stimulated to secrete calcitonin, which decreases bone
turnover and osteoclast numbers prior to parturition.
Calcium homeostasis in cows fed balanced or relatively low-
calcium diets prepartum appears to be more under the fine control
of PTH secretion with the approach of parturition. The higher
levels of PTH secreted during the prepartum period by an
expanded population of actively synthesizing chief cells results
in a larger pool of active osteoclasts to fulfill the increased
needs for calcium mobilization at the critical time near par-
turition and the initiation of lactation.
Less is known about the development of hypocalcemic
syndromes in animal species other than in the cow. In dogs,
puerperal tetany (eclampsia) is most frequently encountered B
in the small, hyperexcitable breeds. The clinical course is rapid
and the bitch may proceed from premonitory signs of restless- Figure 3-36  Multinodular chief cell hyperplasia in a dog with
ness, panting, and nervousness to ataxia, trembling, muscular primary hyperparathyroidism. A. Note the multifocal, poorly
tetany, and convulsive seizures in 8-12 hours. There is no demarcated nodules of chief cell hyperplasia (arrowheads) that
evidence to suggest that puerperal tetany in heavily lactating are paler because of hypertrophy of the cytoplasm. B. Focal
bitches is the result of interference in PTH secretion. Supple- nodular hyperplasia (left), with hypertrophied chief cells contain-
mental dietary calcium and vitamin D have proven useful in ing abundant eosinophilic cytoplasm. The atrophied normal chief
preventing relapses in certain bitches with puerperal tetany. cells are on the right.
300 CHAPTER 3  •  Endocrine Glands
A
B
Figure 3-37  Diffuse chief cell hyperplasia. A. Enlargement of the
external and internal parathyroid glands in a cat with chronic
kidney disease. Bar = 5 mm. B. Hypertrophied and hyperplastic
chief cells from a dog are closely packed with narrow perivascular
spaces and abundant cytoplasm.
parenchyma. Chief cells within the nodules have a relatively
uniform composition with a high cytoplasm to nucleus ratio
and a slightly more hyperchromatic nucleus than adjacent
normal chief cells. There may be slight compression of adja-
cent chief cells around larger areas of focal hyperplasia. Focal
chief cell hyperplasia often is difficult to separate from a chief
cell adenoma by using only morphologic criteria. The presence
of multiple nodules of various sizes and uniform cellularity in one
or both parathyroids with minimal compression and no fibrous
encapsulation is more compatible with focal hyperplasia than
chief cell adenoma. Focal or multifocal nodular chief cell
hyperplasia is often associated with primary hyperparathy-
roidism and may require surgical removal of multiple or all
parathyroid glands to control the clinical syndrome.
Diffuse hyperplasia. Parathyroid hyperplasia, such as seen
with chronic renal failure and long-term dietary imbalances,
results in uniform enlargement of all parathyroid glands as a
result of both hypertrophy and hyperplasia of chief cells (Fig.
3-37A). There is not a peripheral rim of compressed atrophic
parathyroid parenchyma as occurs around a functional
adenoma, but rather a uniform population of hyperplastic chief
cells extending to the capsule of the gland. The chief cells often
are packed together with indistinct cell boundaries, and peri-
vascular spaces are narrow (Fig. 3-37B). The expanded cyto-
plasmic area of chronically stimulated chief cells is lightly
Calcium-Regulating Hormones
Chronic renal disease
↑ FGF23
↓ PO4
excretion
↑ PTH ↓ Calcitriol
Figure 3-38  In chronic renal disease, decreased phosphate excre-
tion and hyperphosphatemia result in increased secretion of fibro-
blast growth factor-23 (FGF23) from osteocytes and osteoblasts.
FGF23 from bone cells and loss of nephrons decreases renal cal-
citriol production. Decreased serum calcitriol stimulates parathy-
roid hormone (PTH) synthesis and secretion and subsequent chief
cell hypertrophy and hyperplasia. Hyperparathyroidism further
enhances FGF23 production by bone cells.
eosinophilic with occasional distinct vacuoles. A more promi-
nent fibrovascular stroma in some diffusely hyperplastic para-
thyroids may result in a lobulated appearance, and in others,
chief cells form distinct acinus-like structures.
Hyperparathyroidism secondary to renal disease
Secondary hyperparathyroidism as a complication of chronic
kidney disease (CKD) is characterized by excessive production
of PTH. When renal disease reaches the point at which there
is a significant reduction in glomerular filtration rate, phos-
phate is retained. Early increases in serum fibroblast growth
factor-23 (FGF23) concentrations from osteoblasts and osteo-
cytes are a compensatory reaction and often occur before
hyperphosphatemia develops (Fig. 3-38). Initially, elevated
blood FGF23 depresses the renal 1-α-hydroxylase activity. In
the later stage of CKD, there are also decreased numbers of
renal tubular epithelial cells that contain the 1-α-hydroxylase
to form the active form of vitamin D (calcitriol). Early stages
of chronic renal failure (CRF) are often associated with normal
concentrations of circulating calcitriol (even with the loss of
nephrons) resulting from the effects of increased PTH on
renal 1-α-hydroxylase to enhance renal tubular synthesis of
calcitriol. Animals with advanced CRF have decreased circu-
lating concentrations of calcitriol because of decreased renal
synthesis. Calcitriol is an important regulator of parathyroid
chief cell function and decreases PTH mRNA expression 
and increases expression of the vitamin D receptor (VDR).
Decreased circulating levels of calcitriol in animals with CKD
result in chief cell hyperplasia and increased secretion of intact
PTH. In an experimental model of CKD, anti-FGF23 antibod-
ies reversed these effects; however, this resulted in hyperphos-
phatemia. Although increased serum FGF23 is a potential
indicator of early renal disease, the presence of increased PTH
 Calcium-Regulating Hormones
with normal FGF23 suggests that other mechanisms resulting
in secondary hyperparathyroidism are present. As in humans,
FGF23 is increased in cats with CKD and predicts azotemia
in elderly cats. In advanced CKD, all 4 parathyroid glands
undergo marked chief cell hyperplasia (see Fig. 3-37B), and
the bones have various degrees of generalized fibrous osteo-
dystrophy (see Vol. 1, Bones and joints).
Hyperparathyroidism secondary to
nutritional imbalances
Nutritional secondary hyperparathyroidism occurs in cats,
dogs, certain nonhuman primates, horses, domestic, wild and
captive birds, and reptiles. The increased secretion of parathy-
roid hormone is a compensatory mechanism directed against
a disturbance in mineral homeostasis induced by diets with
either low calcium or excessive oxalate content, or high phosphate
with normal or low calcium content. Inadequate vitamin D3,
besides causing rickets, also causes lesions of secondary hyper-
parathyroidism in some species. The significant result of these
imbalances is hypocalcemia, which results in parathyroid
stimulation. In response to the diet-induced hypocalcemia,
chief cells undergo hypertrophy and eventually hyperplasia
(see Fig. 3-37A). The expanded cytoplasmic area is lightly
eosinophilic and vacuolated compared with chief cells in
normal animals. Perivascular spaces are narrow, and there are
few fat cells in the interstitium. The skeletal lesions of nutri-
tional hyperparathyroidism are discussed in Vol. 1, Bones and
joints.
Primary parathyroid hyperplasia
Primary parathyroid hyperplasia has been described in German
Shepherd pups associated with hypercalcemia, hypophospha-
temia, increased serum parathyroid hormone, and increased
fractional clearance of inorganic phosphate in the urine.  remarkably potent, with as little as 2 g being capable of pro-
Clinical signs included stunted growth, muscular weakness,
polyuria, polydipsia, and diffuse reduction in bone density.
Intravenous infusion of calcium failed to suppress the autono-
mous secretion of parathyroid hormone by the diffuse hyper-
plasia of chief cells in all parathyroids. Lesions included
nodular hyperplasia of thyroid C cells and widespread miner-
alization of lungs, kidney, and gastric mucosa. The disease is
inherited as an autosomal recessive trait.
Parathyroid suppression associated with
vitamin D intoxication from calcinogenic
plants and rodenticides
Livestock grazing on various calcinogenic plants develop a pro-
gressive debilitating disease with widespread mineralization of
soft tissues. Cestrum diurnum (day-blooming jessamine) in
Florida and elsewhere in the southern United States, and
Trisetum flavescens in the Bavarian and Austrian Alps cause
calcinosis in horses, cattle, and sheep. Solanum glaucophyllum
(formerly malacoxylon) in Argentina and Brazil produces the
disease enteque seco or espichamento in cattle, which is char-
acterized by the development of hypercalcemia, hyperphos-
phatemia, and severe soft tissue mineralization. Morphologically
similar diseases occur in Jamaica (Manchester wasting disease)
and Hawaii (Naalehu disease). Other plants that contain
calcitriol-like activity are Solanum torvum, S. verbascifolium,
Dactylis glomerata, and Medicago sativa. Sporadic cases of
extensive mineralization occur in cattle throughout the world.
The leaves of these calcinogenic plants contain a
substance(s) possessing calcitriol-like biologic activity. The
301
Figure 3-39  Vitamin D intoxication from Solanum glaucophyl-
lum (Enteque seco in Argentina). Contraction of tendons and
kyphosis in affected cow. Inset: Kneeling stance caused by inabil-
ity to straighten the front legs. (Courtesy E.J. Gimeno, La Plata
University, Argentina.)
dried leaves of Solanum glaucophyllum contain a steroid-
glycoside conjugate in which the steroidal component is iden-
tical to 1,25(OH)2D3. The leaves are not palatable when
green, but are eaten readily when dry. The calcinogenic plants
appear to produce disease only in herbivores after ingestion
of leaves. Intoxication produces rapid wasting and marked
elevations of the calcium and phosphate levels in the blood.
The patterns of these elevations of blood electrolytes as well as the
soft tissue mineralization are comparable to those produced by
intoxication by vitamin D. The leaves of S. glaucophyllum are
ducing elevations of calcium and phosphate in the blood of
adult cattle. The typical wasting syndrome is seen clinically
when animals are forced to eat large quantities of the leaves.
The animals develop kyphosis with contraction of the tendons
and ligaments, resulting in an inability to completely straighten
their front limbs and a kneeling posture (Fig. 3-39). Contrac-
tion of the abdominal aponeurosis gives a unique tucked-up
line to the abdomen, resulting in affected animals having a
racehorse-like appearance. Many animals develop severe vas-
cular and pulmonary disease as a result of irregular or occa-
sional exposure to the plant because of mineralization and
ossification of interalveolar septa in the lung.
Diseases associated with the ingestion of calcinogenic plants
are not restricted to cattle but also occur in goats, sheep, and
horses, although with lesser frequency and severity. Adult
animals are most commonly affected, usually producing pro-
gressive debility. The earliest signs are those of stiffness and
wasting. There is subtle progression to permanent lameness
resulting from contraction of the tendons. At this stage,
affected animals often are excitable, tire easily if made to
exercise, and may show signs of acute cardiac insufficiency. If
they are removed from affected areas, the stiffness and defor-
mity are not lessened, but the wasting is stopped, and the
animals gain weight if good pasture is available.
Autopsy reveals widespread mineralization of tissues, particu-
larly the aorta, heart, and lungs, often with areas of ossification
(Fig. 3-40A, B). Small mineralized blood vessels are encoun-
tered in the subcutis, and mineralized plaques are present on
the parietal and visceral pleura. Portions of the lungs fail to
302 CHAPTER 3  •  Endocrine Glands
A B
Figure 3-40  Mineralization in poisoning by Solanum glaucophyllum. A. Cow heart and aorta.
B. Goat aorta. (Courtesy E.J. Gimeno, La Plata University, Argentina).
collapse, and these represent areas of mineralization in which
the parenchyma is disrupted and emphysematous. The pul-
monary lesions primarily involve the caudal lobes and consist
of irregular thickening of alveolar septa resulting from miner-
alization and collagen deposition. The opened heart often
reveals mineralization of the right atrium but not of the right
ventricle. The endocardial mineralization is most severe in the
atrium and ventricle (chiefly the basal portion of the latter)
also involving the semilunar cusps, the bicuspid valve, and
chordae tendineae, and extending into the aorta. The aortic
mineralization in early cases is restricted to the areas around
orifices of large branches, but in advanced cases, it is more
diffuse. In advanced cases of intoxication, many small arteries,
especially the coronary and mesenteric arteries, are mineral-
ized severely but irregularly. The arterial mineralization begins
in the intima and, with continuous accretion, extends to the
media disrupting the elastic laminae of the vessels. Histologi-
cally, areas of mineralization are localized to the mucosa of
the abomasal fundus as well as in other fibroelastic tissues.
Mineralization of ligaments and of the fibrocartilaginous por-
tions of tendons is responsible for the stiffness, along with the
degenerative arthropathy that usually is present in affected
animals.
In chronic cases, the bones become extremely dense as new
trabeculae are formed in the marrow spaces. These trabeculae
appear to develop in an atypical basophilic matrix similar to
that deposited in vitamin D poisoning (see Vol. 1, Bones and
joints). Parathyroid chief cells appear initially to accumulate
secretory granules after feeding S. glaucophyllum and later to
undergo involution and atrophy.
The incidence of hypercalcemia resulting from vitamin D
intoxication in small animals has increased because of use of
vitamin D (cholecalciferol) as a pesticide and rodenticide. The
ingested vitamin D is converted to 25-hydroxyvitamin D in
the liver and is the major toxic metabolite. 25-Hydroxyvitamin
D has a much reduced binding affinity for the vitamin D
receptor (500- to 1,000-fold) than calcitriol, but is present  to the thyroids or infrequently within the thoracic cavity near
at such high concentrations that it stimulates hypercalcemia
by increasing intestinal absorption of calcium. Only small
Calcium-Regulating Hormones
amounts of the 25-hydroxyvitamin D are converted to cal-
citriol, which is present in the circulation at normal to 
subnormal levels. This is because of inhibition of renal 1-α-
hydroxylase by low serum PTH, hypercalcemia, hyperphos-
phatemia, and negative feedback from 25-hydroxyvitamin D
that binds to the vitamin D receptor. The hypercalcemia of
hypervitaminosis D is usually accompanied by hyperphospha-
temia (because vitamin D also increases intestinal absorption
of phosphate in addition to calcium) and normal serum alka-
line phosphatase activity. Skeletal disease is not a consistent
feature, because the increased concentrations of blood calcium
and phosphate are derived principally from augmented intes-
tinal absorption; however, widespread mineralization of soft
tissue occurs similar to animals ingesting calcinogenic plants.
Neoplasms of the parathyroid glands
Functional adenomas and carcinomas of parathyroid glands
secrete parathyroid hormone in excess of normal, causing a syn-
drome of primary hyperparathyroidism. The normal control
mechanism for parathyroid hormone is lost, and hormone
secretion is excessive in spite of an increased level of blood
calcium. Cells of the renal tubules are sensitive to alterations
in the amount of circulating parathyroid hormone. The 
excretion of phosphate and retention of calcium initially are
enhanced. A prolonged increased secretion of parathyroid
hormone accelerates osteoclastic bone resorption and results
in generalized fibrous osteodystrophy.
Adenomas of parathyroid glands are encountered in older
animals, particularly dogs, occasionally cats, and rarely in
horses. Keeshonds appear to have a genetic predisposition to
the development of chief cell adenomas. Tumors of parathy-
roid chief cells in animals are not sequelae of long-standing
secondary hyperparathyroidism of renal or nutritional origin.
Chief cell adenomas usually result in considerable enlarge-
ment of a single parathyroid gland (Fig. 3-41A). They are light
brown to red and are located either in the cervical region close
the base of the heart. Parathyroid neoplasms in the precardiac
mediastinum are derived from ectopic parathyroid tissue,
 Calcium-Regulating Hormones 303

A B

C D
Figure 3-41  Functional chief cell adenoma. A. Adenoma from a dog (left) that is well demarcated
and encapsulated. The thyroid gland is on the right. B. The chief cells of the adenoma (bottom)
are large with karyomegaly and abundant cytoplasm. There is a fibrous capsule with a dilated
venule. There is a thin rim of atrophied, normal chief cells with small nuclei and minimal cytoplasm
(top). C. The neoplastic chief cells have variable sized nuclei with karyomegaly. There are thin
bands of fibrous connective tissue that separate the chief cells. D. Adenoma from a horse with
primary hyperparathyroidism. The neoplasm is composed predominantly of water-clear chief cells.

displaced into the thorax with the expanding thymus during
embryonic development. Parathyroid adenomas are sharply
demarcated and encapsulated from the adjacent thyroid gland.
Multiple white foci may be seen in the thyroids of dogs with
functional parathyroid tumors. These represent areas of C-cell
hyperplasia in response to the long-term hypercalcemia. A
parathyroid adenoma will enlarge a single gland to a great
degree, and the remaining parathyroids will be atrophic. In
comparison, all 4 parathyroids are enlarged 2-5 times normal
size in secondary hyperparathyroidism. Histologic demonstra-
tion of a compressed rim of parathyroid parenchyma and a
partial-to-complete fibrous capsule in an enlarged gland points
to the diagnosis of adenoma rather than chief cell hyperplasia
(Fig. 3-41B).
Parathyroid adenomas are composed of closely packed
chief cells subdivided into small groups by fine connective
tissue septa with many capillaries. Neoplastic cells may pali-
sade around small blood vessels. The chief cells are cuboidal
or polyhedral, and the cytoplasm stains lightly eosinophilic
(Fig. 3-41B, C). Some neoplastic chief cells may have
karyomegaly, but this is not an indicator of malignancy. Occa-
sional oxyphil cells, water clear cells, and transitional forms
may be distributed throughout the adenoma. Some parathy-
roid adenomas are composed predominantly of large eosino-
philic oxyphil cells or water clear cells (Fig. 3-41D). Adipose
cells and mast cells often are present in the stroma of
adenomas.
Adenomas may compress the adjacent thyroid gland. A rim
of compressed and atrophic parathyroid parenchyma usually
is present outside the capsule of a small adenoma (see Fig.
3-40B). In an animal with a functional parathyroid adenoma,
the remaining, non-neoplastic parathyroid tissue is chronically
suppressed by the elevated serum calcium. The atrophic chief
cells are small, irregular in shape, have a small amount of
densely eosinophilic cytoplasm and basophilic nuclei, and may
contain cytoplasmic lipofuscin or lipid (see Fig. 3-41D). The
adenomas and the atrophied chief cells will stain immunohis-
tochemically positive for cytoplasmic PTH 1-34 or 1-84 and
chromogranin A.
Parathyroid adenomas usually are slow growing and can be
surgically excised without difficulty. Successful removal of a
functional parathyroid adenoma results in a rapid decrease in
circulating parathyroid hormone levels, because the half-life
of parathyroid hormone in plasma is short (~5 minutes).
304 CHAPTER 3  •  Endocrine Glands Calcium-Regulating Hormones

A B

C D
Figure 3-42  Parathyroid carcinoma in a cat. A. The carcinoma (in multiple nodules, at arrow-
heads) has invaded the thyroid gland and its capsule with formation of a large cyst (C). The thyroid
gland contains a central thyroid adenoma (T). The normal external parathyroid gland is also
present (arrow). B. The carcinoma is poorly demarcated and invasive into the normal thyroid
parenchyma. C. The parathyroid carcinoma and normal parathyroid gland (arrowhead) are immu-
nohistochemically positive for parathyroid hormone (PTH) 1-34. Note that some regions of the
carcinoma are negative for PTH. D. The parathyroid carcinoma is immunohistochemically negative
for thyroglobulin. The normal thyroid follicles and thyroid follicular adenoma are immunohisto-
chemically positive for thyroglobulin.

Plasma calcium levels in animals may decrease rapidly following
surgical removal and reach subnormal levels within 12-24
hours, resulting in life-threatening hypocalcemic tetany. Infu-
sion of calcium gluconate, feeding a high-calcium diet, and
supplemental vitamin D therapy will correct this postopera-
tive complication.
Parathyroid carcinomas are larger than adenomas and
invade the capsule and adjacent structures (e.g., thyroid glands
and cervical muscles) (Fig. 3-42A-D). Metastasis to regional
lymph nodes and lung is possible, but rare. Parathyroid carci-
nomas are uncommon in animals but have been observed in
dogs and cats. Parathyroid carcinomas are composed of chief
cells with a highly variable development of cytoplasmic organ-
elles, and the malignant chief cells may form follicles. Large
cystic spaces lined by cuboidal to flattened chief cells may be
seen in cats, which may be identified by ultrasound examina-
tion of the neoplasms prior to surgery (see Fig. 3-42A). Altera-
tions of the nuclear morphology are present. There is usually
a greater degree of cellular pleomorphism than in chief cell
adenomas with more frequent mitotic figures and microscopic
evidence of invasion into the adjacent parathyroid, thyroid, or
periglandular connective tissues. Parathyroid carcinomas will
stain immunohistochemically positive for PTH and chromo-
granin A and negative for thyroglobulin (Fig. 3-42C, D).
Primary hyperparathyroidism. The clinical disturbances
observed with functional parathyroid tumors primarily are 
the result of the persistent hypercalcemia and a weakening of
bones caused by excessive resorption. Hypercalcemia results
in anorexia, vomiting, constipation, depression, polyuria, 
polydipsia, and generalized muscular weakness because of
decreased neuromuscular excitability. Cortical bone in long-
standing cases is thinned as a result of increased resorption by
osteoclasts stimulated by the autonomous secretion of PTH.
Lameness caused by fractures of long bones may occur after
relatively minor physical trauma. Compression fractures of
vertebral bodies can exert pressure on the spinal cord and
nerves, resulting in motor or sensory dysfunction, or both.
Facial hyperostosis resulting from extensive osteoblastic pro-
liferation and deposition of poorly mineralized osteoid, and
loosening or loss of teeth from alveolar sockets, has been
observed in dogs with primary hyperparathyroidism (Fig.
3-43A, B). They usually have a history of multiple fractures
 Calcium-Regulating Hormones
A
B
Figure 3-43  Hyperostotic fibrous osteodystrophy in the maxilla
of a dog with primary hyperparathyroidism. A. Bony enlargement
of maxilla. B. Cross-sections showing encroachment on the nasal
cavity by extensive proliferation of woven bone.
associated with severe generalized skeletal demineralization
and normal renal function. Radiographic evaluation reveals
areas of subperiosteal cortical resorption, loss of lamina dura
around the teeth, soft tissue mineralization, bone cysts, and a
generalized decrease in bone density, with multiple fractures
in advanced cases.
Urinary excretion of calcium and phosphate is increased
and may predispose to the development of nephrocalcinosis
and urolithiasis. Repeated palpation of enlarged parathyroid
gland tumors may result in infarction because of vascular
thrombosis with extensive ischemic necrosis of tumor cells
and the rapid development of hypocalcemia similar to that
seen following surgical removal.
Hypercalcemia associated with neoplasms of
nonparathyroid origin
Hypercalcemia is a common disorder that affects animals and
has many causes. The most common cause of hypercalcemia in
animals and human beings is cancer-associated hypercalcemia.
There are 3 mechanisms (Fig. 3-44) of increased serum calcium
induced by neoplasms:
1. Humoral hypercalcemia of malignancy (HHM), or
pseudohyperparathyroidism.
2. Hypercalcemia induced by metastases of solid tumors to
bone.
3. Hematologic malignancies that are localized to bone.
305
Metastatic Hematologic
tumors malignancies
Ca
Ca
Cancer-associated
Ca hypercalcemia Ca
Humoral hypercalcemia
of malignancy
Ca
Tumor
Ca
Humoral factors
Figure 3-44  Humoral and local forms of cancer-associated hyper-
calcemia increase circulating concentrations of calcium by stimu-
lating osteoclastic bone resorption and increasing renal tubular
reabsorption of calcium. (Adapted from Rosol TJ, Capen CC. Lab
Invest 1992;67:680-702.)
Hypercalcemia results from an imbalance of calcium
released from bones, calcium excretion by the kidney, and/or
calcium absorption from the intestinal tract. The functional
disturbances of hypercalcemia are similar regardless of under-
lying cause and depend on the rapidity of onset and extent of
the increased serum ionized calcium levels. Animals with
serum calcium values >4.0 mmol/L (16.0 mg/dL) generally have
the most severe clinical signs. Exceptions to this rule occur, and
occasionally animals with severe hypercalcemia have mild
clinical signs, especially if the calcium is primarily protein
bound. Horses and rabbits have normal total serum calcium
concentrations greater than other domestic animals, which
should be considered before hypercalcemia is diagnosed in
these species.
Metabolic acidosis will enhance the severity of clinical
signs because it will result in an increase in the ionized fraction
of serum calcium. Increased serum ionized calcium will induce
clinical signs related to the gastrointestinal, neuromuscular,
cardiovascular, and renal systems. Decreased contractility of
the gastrointestinal smooth muscle may be associated with
anorexia, vomiting, or constipation. There may be generalized
motor weakness because of decreased neuromuscular excit-
ability. Polyuria and polydipsia are commonly encountered in
animals with hypercalcemia. Initially, polyuria and polydipsia
are because of impaired renal concentrating ability resulting
from an inhibition by the hypercalcemia of the antidiuretic
hormone-dependent resorption of NaCl in the diluting
segment of the nephron by decreasing adenylyl cyclase activ-
ity. Hypercalcemia also has a toxic effect on renal tubules
either directly or from ischemia induced by vasoconstriction.
Tubular epithelial cells undergo degeneration, with the col-
lecting system most severely affected.
Humoral hypercalcemia of malignancy (HHM) is one form
of cancer-associated hypercalcemia that is induced by the
secretion of humoral factors that have effects distant to the
site of the neoplasms. Some neoplasms that cause HHM may
metastasize to bone, but the primary mechanism of hypercal-
cemia involves the distant effects of humoral factors and not
the localized effects of bone metastases. Multiple humoral
factors have been associated with HHM, including parathyroid
hormone, parathyroid hormone–related protein (PTHrP),
cytokines, steroids such as 1,25(OH)2D, and prostaglandins
306 CHAPTER 3  •  Endocrine Glands Calcium-Regulating Hormones

(Fig. 3-45). Many of the humoral factors produced by tumor
cells that alter calcium metabolism and bone resorption can
also be produced by osteogenic cells, such as osteoblasts.
The clinical syndrome of HHM in animals mimics primary
hyperparathyroidism, and a term used previously to describe
HHM was “pseudohyperparathyroidism.” However, HHM does
not mimic hyperparathyroidism in all aspects, as there are
distinct differences in bone remodeling and vitamin D metab-
olism between patients with HHM or with primary hyper-
parathyroidism. The most consistent feature of HHM in animals
is increased osteoclastic bone resorption distant to the site of the
neoplasm (Fig. 3-46). Other features include hypercalciuria,
decreased fractional excretion of calcium, increased nephrog-
enous 3′,5′-cyclic adenosine monophosphate (cAMP), hypo-
phosphatemia, and hyperphosphaturia.
The similarities of these clinicopathologic alterations to
hyperparathyroidism initially led to the hypothesis that the
Humoral factors and HHM
Humoral factors Ca and horses (gastric squamous cell carcinoma). The dog is most
(ILs, TNFs, TGFs, etc.)
Ca
Synergy
Tumor or
additivity
PTHrP
Ca
Figure 3-45  Multiple humoral factors can act additively or syn-
ergistically to induce hypercalcemia associated with humoral
hypercalcemia of malignancy (HHM). ILs, interleukins; PTHrP,
parathyroid hormone–related protein; TGFs, transforming growth
factors; TNFs, tumor necrosis factor. (From Rosol TJ, Capen CC.
Lab Invest 1992;67:680-702.)
neoplasms secrete parathyroid hormone (PTH) or PTH-like
substances; however, native PTH is not produced by the vast
majority of neoplasms associated with HHM. Immunoreactive
PTH levels are normal or low in patients with HHM, and the
tumors do not produce PTH mRNA. There are well-validated
reports of ectopic production of PTH by some tumors, but
these occurrences are uncommon.
Purification of the responsible factor from neoplasms asso-
ciated with HHM resulted in the discovery of the hormone
PTHrP. PTHrP plays a central role in the pathogenesis of
HHM because it is a consistent feature of HHM and shares
most or all of the biological activities of PTH. PTHrP acts
alone in some forms of HHM but may act synergistically or
additively with other humoral factors in the pathogenesis of
hypercalcemia (see Fig. 3-45).
Humoral hypercalcemia of malignancy occurs as a sponta-
neous disease in domestic and laboratory animals. Malignant
neoplasms that are commonly associated with HHM in
animals include the adenocarcinoma derived from apocrine
glands of the anal sac in dogs (Fig. 3-47A-C), some T-cell lym-
phomas of dogs, multiple myeloma, and miscellaneous carcinomas
that sporadically induce HHM in various species, such as cats
often affected. HHM occurs in ~30% of dogs with T-cell lym-
phoma (usually thymic or multicentric forms) and in the
majority of dogs with adenocarcinomas derived from apocrine
glands of the anal sac. Cats also infrequently develop apocrine
gland carcinomas of the anal sac, but HHM does not occur.
Lymphoma is a relatively common tumor in older, large-breed
dogs, whereas the apocrine adenocarcinoma is less common.
There are 3 primary mechanisms by which humoral factors
can induce hypercalcemia:
1. Stimulation of osteoclastic bone resorption.
2. Increase in calcium reabsorption from the kidney.
3. Increase in calcium absorption from the intestine.
Increased osteoclastic bone resorption is a fundamental
component of the pathogenesis of hypercalcemia and is a
consistent feature of HHM. The kidney also plays a central

Hypercalcemia and HHM

Na Ca
GFR
Ca Ca cAMP

PTHrP () Ca

R PTHrP

Osteoblasts

Osteoclastic
bone resorption

(↑) Ca (↓) FCa

(↑) cAMP
Figure 3-46  Humoral hypercalcemia of malignancy (HHM) develops in animal and human
patients when neoplasms constitutively secrete parathyroid hormone–related protein (PTHrP).
PTHrP binds to the PTH1 receptors (R) on osteoblasts, which subsequently signal osteoclasts to
increase bone resorption and renal epithelial cells in the distal nephron to enhance calcium reab-
sorption (decreasing fractional [F] calcium [Ca2+] excretion), resulting in persistent hypercalcemia.
cAMP, cyclic adenosine monophosphate; GFR, glomerular filtration rate.
 Calcium-Regulating Hormones
A
B the PTH gene is simpler and has only 3 exons and encodes for
C stimulate PTH receptors. The biological actions of PTHrP in
Figure 3-47  Apocrine adenocarcinoma of anal sac in a dog.
A. Carcinoma arising from apocrine glands in the wall of the left
anal sac (arrowhead). B. Multiple early carcinomas (arrowheads)
arising from the apocrine glands of the anal sac (arrow). The colon
is on the right. Bar = 1 cm. C. Subgross image of carcinoma (left)
with normal anal sac on the right. Note the normal apocrine
glands surrounding the anal sac.
307
role in the induction of hypercalcemia. Increased osteoclastic
bone resorption would increase the flux of calcium into the
circulation, but this could be readily excreted by the kidney
under normal circumstances. In HHM, fractional excretion of
calcium often is reduced, which results in decreased excretion
and increased tubular reabsorption of calcium. Therefore bone
and renal mechanisms both appear to be responsible for
hypercalcemia in HHM. The role of intestinal absorption of
calcium in the pathogenesis of hypercalcemia has not been
well evaluated in domestic animals.
Most of the humoral factors implicated in the pathogenesis
of HHM are capable of stimulating osteoclastic bone resorp-
tion in vivo and in vitro. The humoral factors must be secreted
by the neoplasms in quantities large enough to increase circu-
lating concentrations and stimulate bone resorption alone or
by cooperative interactions with other humoral factors. None
of the humoral factors identified so far stimulates osteoclast
formation or activation directly. Most factors, including PTHrP
and cytokines, bind to receptors on osteoblasts, which are
responsible for coordinating the stimulation of osteoclastic
bone resorption.
Parathyroid hormone–related protein was initially purified
from human tumors associated with HHM; subsequently, the
cDNA and gene for PTHrP were isolated and sequenced. The
PTHrP gene is complex and contains at least 6 exons, 2
5′-untranslated regions each with its own promoter, a pre-
prohormone coding region, a main coding region, and 2 addi-
tional 3′ regions that have coding and noncoding regions.
There is alternative splicing of PTHrP mRNA so that 3 mature
peptides can be formed, composed of 139, 141, and 173
amino acid residues, respectively. The PTHrP gene is located
on the short arm of chromosome 12 in humans and is thought
to have evolved from the PTH gene on the short arm of chro-
mosome 11 through chromosome duplication. In comparison,
a protein of 84 amino acids. There is a high degree of sequence
homology in PTHrP between species. For example, only amino
acid 49 is different between canine and human PTHrP in the
first 112 amino acids, so human immunoassays for PTHrP can
be used for dogs, cats, horses, and other species, but not birds
and reptiles.
Parathyroid hormone–related protein binds to the PTH1
receptors in bone and kidney with similar affinity to PTH. The
first 34 N-terminal amino acids of PTHrP contain the PTH-
like biological activity. This is similar to PTH in which the first
34 N-terminal amino acids (of a total of 84) contain most of
the biological activities. There is 70% sequence homology of
the first 13 N-terminal amino acids of PTHrP and PTH, but
little homology after amino acid 13. The N-terminus is impor-
tant in the activation of the PTH receptor. Sequence homol-
ogy in this region is important for the ability of PTHrP to
bone and kidney are similar to PTH. Both PTHrP and PTH
induce their cellular actions in osteoblasts and renal cells by
stimulating pathways leading to increased cAMP and intracel-
lular calcium concentration. N-terminal PTHrP stimulates
osteoclastic bone resorption in vivo and in vitro with similar
potency to PTH.
Parathyroid hormone–related protein plays a central role
in the pathogenesis of HHM. It is produced by most tumors
and is present in the circulation at increased concentrations in
animals and humans with HHM. The administration of anti-
PTHrP antibodies to animal models of HHM decreases serum
308 CHAPTER 3  •  Endocrine Glands Calcium-Regulating Hormones

calcium levels and bone resorption. Increased circulating con-

centrations of PTHrP also have been detected in dogs with
spontaneous HHM as well as in experimental animal models
of HHM. Dogs with adenocarcinomas derived from apocrine
glands of the anal sac have markedly elevated concentrations
of PTHrP (10-100 pM), suggesting that PTHrP plays a primary
role in the pathogenesis of the hypercalcemia associated with
these tumors. In contrast, dogs with HHM and lymphoma
have PTHrP concentrations that range from undetectable to
17 pM. PTHrP appears not to be the sole humoral factor
responsible for the induction of hypercalcemia in dogs with
lymphoma, but may interact cooperatively with other humoral
factors.
The syndrome of HHM in elderly dogs is most frequently A
associated with adenocarcinomas derived from apocrine glands
of the anal sac (see Fig. 3-47A-C). They develop as firm masses
in the perirectal area, ventral-lateral to the anus, in close asso-
ciation with the anal sac, but are not attached to the overlying
skin. The tumor arises in the wall of the anal sac and projects
as a mass of variable size into its lumen. It forms glandular acini
with projections of apical cytoplasm extending into a lumen and
is histologically distinct from the more common perianal (circum-
anal) gland tumor in this region of dogs. Most neoplasms are B
histologically bimorphic with glandular and solid areas (Fig.
3-48A). The solid pattern of arrangement of neoplastic cells
is characterized by sheets, microlobules, and packets separated
by thin fibrovascular stroma. Pseudorosettes are common in
solid areas adjacent to small blood vessels. The neoplastic cells
immunohistochemically stain weakly positive for PTHrP, con-
sistent with minimal cytoplasmic storage of PTHrP; however,
they have abundant PTHrP mRNA. The neoplastic cells may
also stain variably positive for chromogranin A, which suggests
some cells have neuroendocrine differentiation. The carcino-
mas express the receptor tyrosine kinases vascular endothelial
growth factor receptor (VEGFR), platelet-derived growth
factor receptor α/β (PDGFR α/β), and phosphorylated RET,
which may play a role in the pathogenesis or treatment of the
tumors.
All tumors have histologic features of malignancy, and
most metastasize to iliac and sublumbar lymph nodes, and
occasionally to the lungs and spleen (Fig. 3-48B, C). Apocrine
carcinomas are poorly demarcated from adjacent normal C
tissues. They frequently extend projections of tumor cells
Figure 3-48  Apocrine adenocarcinoma of anal sac in a dog.
along connective tissue planes and early in the course of the
A. Glandular and solid pattern of carcinoma. The glands contain
disease invade thin-walled lymphatics and veins to form
apocrine secretion and sloughed necrotic cells. B. Metastasis
tumor cell emboli. Clinical signs are primarily the result of
to sublumbar lymph node (arrowheads). C. Multifocal lung
severe hypercalcemia, and they complicate the problems asso-
metastases.
ciated with the malignant neoplasm. Renal mineralization is
detected histologically in ~90% of dogs with HHM. Tubular
mineralization is most pronounced near the corticomedullary
junction but also is present in cortical and deep medullary hypercalcemia in tumor-bearing dogs, indicating a response to
tubules, Bowman’s capsules, and glomerular tufts. Mineraliza- circulating PTHrP.
tion is present less frequently in the fundic mucosa of the Physiologic role for parathyroid hormone–related protein.
stomach and endocardium. PTHrP was originally isolated from human and animal tumors
The parathyroid glands are small and difficult to locate or associated with humoral hypercalcemia of malignancy.
not visible macroscopically. Microscopically, they are charac- However, PTHrP is not strictly a calcium-regulating hormone
terized by narrow cords of inactive chief cells with abundant as it appears to have an important physiologic role in many
fibrous connective tissue stroma and widened perivascular normal tissues. PTHrP is widely produced in the body and acts
spaces, indicating atrophy as a response to persistent hyper- as a paracrine factor in the tissues in which it is produced.
calcemia (Fig. 3-49). Thyroid C cells respond to the persistent In contrast to parathyroid hormone, which is produced
elevation in blood calcium by undergoing diffuse or nodular only by the parathyroid gland, PTHrP is produced by many
hyperplasia. There is inappropriate serum concentration of normal tissues in adult animals, including stratified squamous
1,25-dihydroxycholecalciferol (calcitriol) for the degree of epithelium; endocrine glands (adrenal cortex and medulla,
 Calcium-Regulating Hormones
Figure 3-49  Atrophic parathyroid gland from a dog with humoral
hypercalcemia of malignancy. Narrow cords of atrophic chief cells
are separated by interstitial spaces with increased connective
tissue.
fetal and adult parathyroid glands, adenohypophysis, thyroid
C cells); skeletal, cardiac, and smooth muscle; kidney; bone;
lactating mammary gland; lymphocytes; macrophages; lung;
skin; brain; pancreatic islets; testis; prostate; urinary bladder;
gastrointestinal tract; blood vessels; ovary; uterus; placenta;
and avian oviduct. Present evidence suggests that PTHrP acts as
an autocrine or paracrine regulator in normal tissues, having an
important role in development, differentiation, and cell function.
PTHrP is involved in normal longitudinal bone growth and
tooth eruption in addition to its role of transferring calcium
across the placental membranes. PTHrP is expressed by renal
glomeruli, where it may influence blood flow, and overexpres-
sion plays a role in the development of renal hypertrophy.
PTHrP may be involved in the promotion of renal fibrosis as
a result of epithelial-mesenchymal transition. In humans with
diabetes mellitus type 2, serum PTHrP levels are increased,
but the physiologic significance is uncertain. PTHrP is impor-
tant in the embryonic development of the mammary glands,
lactation, and calcium levels in milk. Milk contains very high
concentrations of PTHrP (10-100 nM). PTHrP is produced by
keratinocytes and is necessary for normal hair follicle differ-
entiation. In general, PTHrP expression is increased when
smooth muscle is stretched, and PTHrP induces relaxation of
smooth muscle and attenuation of contraction.
Lymphoma is the most common neoplasm associated
with hypercalcemia in dogs and cats. Peripheral lymph node
enlargement may or may not be detected, but there usually is
evidence of cranial mediastinal or visceral involvement. Most
lymphomas associated with HHM in dogs are of the T-cell subset.
Most dogs with lymphoma and hypercalcemia have increased
circulating concentrations of PTHrP, but the concentrations
are not as high as those in dogs with HHM and apocrine
adenocarcinomas, and PTHrP does not correlate with serum
calcium concentration. Experimental evidence points to
PTHrP as the most consistent factor responsible for hypercal-
cemia in dogs with lymphoma, usually in concert with other
factors. Tumor necrosis factor-α and receptor activator of
NFκB ligand (RANKL) are also produced in some of these
tumors. Dogs with lymphoma in the bone marrow have
increased numbers of osteoclasts on trabecular bone surfaces
opposite a surface lined by osteoid and large columnar osteo-
blasts (Fig. 3-50).
309
Ob
Ob
Figure 3-50  Hypercalcemic dog with lymphoma of bone marrow
(von Kossa tetrachrome stain). Several osteoclasts are present in
lacunae (arrowheads). Hyperplastic osteoblasts (Ob) and promi-
nent osteoid seams (light blue) are present adjacent to eroded
trabecular surfaces. (From Meuten DJ, et al. Lab Invest
1983;49:553-562.)
Hypercalcemia with tumors metastatic to bone. Solid
tumors that metastasize widely to bone can produce hypercalce-
mia by the induction of local bone resorption associated with
tumor growth. This is not common in animals, but is an impor-
tant cause of cancer-associated hypercalcemia in human
beings. Tumors that often metastasize to bone and induce
hypercalcemia in human patients include breast and lung
carcinomas. The pathogenesis of enhanced bone resorption is
not completely understood, but the 2 primary mechanisms
include (1) secretion of cytokines or factors that stimulate
local bone resorption, and (2) indirect stimulation of bone
resorption by tumor-induced cytokine secretion from local
immune or bone cells. Cytokines or factors that may be
secreted by tumor cells and stimulate local bone resorption
include PTHrP, transforming growth factor-α and -β, and pros-
taglandins (especially PGE2). In some cases, bone-resorbing
activity (see Fig. 3-40) can be inhibited by indomethacin,
which suggests that prostaglandins are either directly or indi-
rectly associated with the stimulation of bone resorption. The
cytokines most often implicated in indirect stimulation of
bone resorption by local immune cells include interleukin-1
and tumor necrosis factor.
Further reading
Ardura JA, et al. Parathyroid hormone-related protein promotes
epithelial-mesenchymal transition. J Am Soc Nephrol 2010;21:
237-248.
Bienaime F, et al. Vitamin D metabolism and activity in the parathyroid
gland. Mol Cell Endocrinol 2011;347:30-41.
Brown EM. Calcium sensing by endocrine cells. Endocr Pathol 2004;
15:187-219.
Dittmer KE, Thompson KG. Vitamin D metabolism and rickets in
domestic animals: a review. Vet Pathol 2011;48:389-407.
Donate-Correa J, et al. FGF23/Klotho axis: phosphorus, mineral
metabolism and beyond. Cytokine Growth Factor Rev 2012;23:
37-46.
Finch NC, et al. Fibroblast growth factor 23 (FGF-23) concentrations in
cats with early nonazotemic chronic kidney disease (CKD) and in
healthy geriatric cats. J Vet Intern Med 2013;27:227-233.

Further reading
Bergwitz C, Jüppner H. FGF23 and syndromes of abnormal renal phos-
phate handling. Adv Exp Med Biol 2012;728:41-64.
Black HE, et al. Effect of a high calcium prepartal diet on calcium
homeostatic mechanisms in thyroid glands, bone, and intestine of
cows. Lab Invest 1973;29:437-448.
Capen CC, Rosol TJ. Recent advances in the structure and function of
the parathyroid gland in animals and the effects of xenobiotics.
Toxicol Pathol 1989;17:333-345.
Capen CC, et al. The pathology of hypervitaminosis D in cattle. Pathol
Vet 1966;3:350-378.
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THYROID GLAND
Development, structure, and function
Embryologic development of the thyroid gland
The thyroid gland originates as a thickened plate of epithe-
lium in the floor of the pharynx. It is intimately related to the
aortic sac in its development, and this association leads to the
frequent finding of accessory thyroid parenchyma in mediasti-
nal structures, especially in dogs. This accessory thyroid tissue
may undergo neoplastic transformation. Branched cell-cords
develop from the pharyngeal plate and migrate dorsolaterally
but remain attached to the pharyngeal area by the narrow
thyroglossal duct. The entodermal bud that forms the thyroid
gland arises on the midline at the level of the first pharyngeal
pouch (see Fig. 3-28). This gives rise to the thyroglossal duct,
which migrates caudally. The proliferation of cell cords at the
distal end of the thyroglossal duct forms the follicles of each
thyroid lobe. The area at the base of the tongue marking the
origin on the thyroid gland is referred to as the foramen cecum
linguae in postnatal life. Calcitonin-secreting C cells of pre-
sumed neural crest origin reach the postnatal thyroid gland by
migrating into the ultimobranchial body. This last pharyngeal
pouch moves caudally in mammals to fuse with the primordia
of the thyroid gland and distribute C cells into each thyroid
lobe. It appears that the ultimobranchial body retains some
ability to differentiate into thyroid follicular structures that
are not fully competent compared to the normal thyroid
gland.
Folliculogenesis is a complex process in the thyroid that
begins by the proliferation of irregularly arranged cell cords
derived from the entoderm of the thyroglossal duct on the
midline of the developing pharyngeal gut. The solid cell clus-
ters extend caudally into the primitive mesenchyme and
Thyroid Gland
Figure 3-51  Ectopic thyroid tissue (arrow) at the base of the
heart from a dog. Inset: Histology of ectopic tissue showing
normal follicles in adipose tissue with no C cells. Bar = 1 cm.
develop complex interdigitations of plasma membranes of
adjacent cells. Primitive follicles develop either by invagina-
tion of the plasma membrane of individual follicular cells to
form intracytoplasmic colloid-containing microfollicles that
subsequently coalesce to form larger follicles, or by the secre-
tion of colloid in the narrow intercellular spaces limited by
zonulae adherens and desmosomes. Thyroid follicles form in
the last third of gestation, and the follicles in the periphery of
the thyroid gland are larger than the central regions. Thyroid-
stimulating hormone (TSH) may not be required for the
formation of the initial primitive follicles, but final develop-
ment is dependent on TSH.
A portion of the thyroglossal duct may persist postnatally
and form a cyst. Thyroglossal duct cysts are present in the
ventral aspect of the cranial cervical region in dogs. Their
lining epithelium may undergo neoplastic transformation to
form papillary carcinomas.
Accessory thyroid tissue is common in the dog, and may be
located anywhere from the tongue to the diaphragm. About
50% of adult dogs have accessory thyroid tissue embedded in
the fat on the intrapericardial aorta. These nodules are usually
2-5 mm in dimension and may be multiple (Fig. 3-51). They
lack C cells, which secrete calcitonin, but their follicular struc-
ture and function (ability to concentrate iodine and iodinate
tyrosyl residues) are the same as that of the main thyroid
lobes. Attempts to induce hypothyroidism in the dog by surgi-
cal thyroidectomy are not consistently successful because the
follicular cells in the accessory thyroids readily respond to the
prompt increase in endogenous TSH and undergo hyperplasia
sufficient to sustain adequate hormone production.
Structure of the thyroid gland
The 2 thyroid lobes in most species are located on the lateral
surfaces of the trachea. In pigs, the main lobe of the thyroid is
in the midline in the caudal cervical region with dorsolateral
projections from each side (see Fig. 3-29).
 Thyroid Gland
The principal blood supply to each lobe in the dog is from
the cranial thyroid artery (a branch of common carotid), and
the major venous drainage is via the caudal thyroid vein that
enters the internal jugular vein. Lymph drainage from the
cranial pole of the thyroid lobes in dogs is to the retropharyn-
geal lymph nodes. Lymph flow from the caudal aspect of each
thyroid lobe is variable, but it often bypasses any lymph nodes
before entering the brachiocephalic trunk. Efferent lymphat-
ics usually enter directly into the cervical lymphatic trunk or
internal jugular vein. This explains the frequent occurrence of
pulmonary metastases from thyroid carcinoma in dogs prior to
development of secondary foci in regional lymph nodes. Small
efferent lymphatics may pass through the caudal cervical
lymph nodes along the ventral surface of the trachea before
entering the cranial mediastinum. These vascular arrange-
ments are significant for the spread of thyroid carcinomas.
The thyroid gland is the largest of the endocrine organs that
functions exclusively as an endocrine gland. The basic histologic
structure of the thyroid is unique for endocrine glands, con-
sisting of follicles of various sizes (20-250 µm) that contain
colloid produced by the follicular cells (thyrocytes). The fol-
licular cells are cuboidal to low columnar (under conditions
of normal iodine intake), and their secretory polarity is
directed toward the lumen of the follicles. An extensive
network of interfollicular capillaries provides the follicular
cells with an abundant blood supply. Follicular cells have
extensive profiles of rough endoplasmic reticulum and a large
Golgi apparatus in their cytoplasm for synthesis and packaging
substantial amounts of protein (e.g., thyroglobulin) that is
then transported into the follicular lumen. The interface
between the luminal side of follicular cells and the colloid is
modified by numerous microvilli.
Various numbers of lysosomes, which contain enzymes
such as acid phosphatase, are found in the apical portion of
follicular cells. Soon after stimulation of follicular cells by
TSH, intracellular droplets of ingested colloid (phagosomes),
corresponding to those demonstrated by light microscopy
with the PAS reaction, are more numerous than in the resting
state. Some of these form phagolysosomes in follicular cells
by fusion with lysosomes.
Biosynthesis of thyroid hormones
The synthesis of thyroid hormones is unique among endocrine
glands because the final assembly of hormone occurs extracellu-
larly within the follicular lumen. Essential raw materials, such
as iodide ion (I−), are trapped by follicular cells from plasma,
transported rapidly against a concentration gradient to the
lumen of the follicle, and oxidized by a peroxidase enzyme in
the microvillus membranes to iodine (I2).
The assembly of thyroid hormones within the follicular
lumen is made possible by a unique protein, thyroglobulin,
synthesized by follicular cells (Fig. 3-52). Thyroglobulin is a
high-molecular-weight glycoprotein synthesized in successive
subunits on the ribosomes of the endoplasmic reticulum in
follicular cells. The constituent amino acids (tyrosine and
others) and carbohydrates (mannose, fructose, galactose) are
derived from the circulation. Recently synthesized thyroglob-
ulin leaving the Golgi apparatus is packaged into apical vesi-
cles that are extruded into the follicular lumen.
The amino acid tyrosine, an essential component of thyroid
hormones, is incorporated within the molecular structure of
thyroglobulin. Iodine is bound to the tyrosyl residues in thy-
roglobulin at the apical surface of follicular cells to form
311
successively monoiodotyrosine (MIT) and diiodotyrosine
(DIT). These biologically inactive iodothyronines subse-
quently are coupled together under the influence of thyroper-
oxidase to form the 2 biologically active iodothyronines—
thyroxine (T4) and triiodothyronine (T3)—secreted by the
thyroid gland.
The functionally important thyroperoxidase enzyme in the
thyroid hormone synthetic pathway is present in the apical
plasma membrane and microvilli as well as in other membra-
nous structures of the follicular cells. Thyroperoxidase is a
membrane-bound, heme-containing glycoprotein composed
of 933 amino acids with a transmembrane domain. This
important enzyme oxidizes (in the presence of hydrogen per-
oxidase) iodide ion (I−) taken up by follicular cells through
the function of the sodium iodide symporter (NIS) into reac-
tive iodine (I2), which binds to the tyrosine residues in thyro-
globulin. Iodine is incorporated not only into newly synthesized
thyroglobulin recently delivered to the follicular lumen, but
also into molecules already stored in the lumen. Thyroperoxi-
dase also functions as a coupling enzyme to combine MIT and
DIT to form T3, or 2 DITs to form T4.
The mechanism of active transport of iodide has been
shown to be associated with a NIS present in the basolateral
membrane of thyroid follicular cells (Fig. 3-53). Transport of
iodide ion across the thyroid cell membrane is linked to the
transport of Na+. The ion gradient generated by the Na+-K+
ATPase is the driving force for the active cotransport of iodide.
The transporter protein is present in the basolateral mem-
brane of thyroid follicular cells and is a large protein contain-
ing 643 amino acids with 13 transmembrane domains.
Other tissues, such as salivary gland, gastric mucosa,
choroid plexus, ciliary body of the eye, and lactating mammary
gland, also have the capacity to actively transport iodide, albeit
at a much lower level than the thyroid. In the salivary glands,
NIS protein has been detected in ductal cells but not in acinar
cells. Only the thyroid follicular cells accumulate iodide in a
TSH-dependent manner. The NIS gene is complex (15 exons,
14 introns), and its expression in the thyroid is upregulated
by TSH. The functionally active iodine transport system in the
thyroid gland has important clinical applications in the evalua-
tion, diagnosis, and treatment of several thyroid disorders, includ-
ing cancer. The NIS and active transport of iodide can be
selectively inhibited by competitive anion inhibitors (e.g., per-
chlorate, thiocyanate), thereby effectively blocking the ability
of the gland to iodinate tyrosine residues in thyroglobulin and
synthesize thyroid hormones.
The ability of NIS to concentrate iodide holds clinical rele-
vance, in addition to its physiologic importance, by providing the
basis for using radioactive iodine in the treatment and manage-
ment of various thyroid diseases. Radioactive iodine is com-
monly used to destroy overactive thyrocytes in patients with
thyrotoxicosis (such as cats with hyperthyroidism), to ablate
normal and malignant thyroid tissues in patients who have
undergone total thyroidectomy for thyroid carcinoma, and to
perform whole-body scans for the detection of recurrent and
metastatic thyroid cancer.
Once within the thyrocyte, iodide ion is passively trans-
ported via pendrin into the follicular lumen. Pendrin, a
~86-kDa chloride/iodide transport protein, is located at the
apical membrane of thyrocytes, and is responsible for 
the transport of iodide ion into the follicular lumen. It is the
product of the gene responsible for Pendred syndrome, a
genetic disorder in human patients characterized clinically by
312 CHAPTER 3  •  Endocrine Glands Thyroid Gland

Thyroid follicular lumen

Thg Thg
T3
(19S) (17S) Thg
Colloid (Co) T4
I2
TPO Co Pseudopodia
(O) MV MV

I– Thg Mf Mf
AV (17S)
AV M
Mt CD CD

Mt
Ly Ly PL

GA CHO
Ly
Ly
Nucleus
DNA RNA Mt
Nucleus

mRNA 12S
Thg
mRNA M
cAMP T3,T4
Thg ATP

TSH-R
I– Carbohydrates (CHO) Amino acids TBG
– Glucose – Tyrosine T3,T4
TTR
– Mannose – Others
– Galactose
– Others ECF
Hormone synthesis Hormone secretion
Figure 3-52  Thyroid follicular cells illustrating 2-way traffic of molecules from capillaries to fol-
licular lumen. Raw materials, such as iodide ion (I−), are concentrated and rapidly transported into
the follicular lumen (left side of drawing). Amino acids (e.g., tyrosine) and sugars are assembled
by follicular cells into thyroglobulin (Thg), packaged into apical vesicles (AV), and released into
lumen. Iodination of tyrosyl residues occurs within the thyroglobulin molecule to form thyroid
hormones (iodothyronines) in the follicular lumen. Elongation of microvilli (MV) and endocytosis
of colloid by follicular cells occurs in response to thyroid-stimulating hormone (TSH) stimulation
(right side of drawing). Intracellular colloid droplets (CD) fuse with lysosomal bodies (Ly), and
active thyroid hormones (T4 and T3) are enzymatically cleaved from thyroglobulin, and free T4
and T3 are released into circulation. ECF, extracellular fluid GA, Golgi apparatus; M, mitochondria;
Mf, microfilaments; Mt, microtubules; PL, phagolysosome; T3, triiodothyronine; T4, thyroxine;
TBG, thyroxine-binding globulin; TSHR, thyroid-stimulating hormone receptor; TTR, transthyre-
tin. (Modified and redrawn from Good RA, et al. Molecular Pathology, Springfield, 1975, C.C.
Thomas Publishers.)

sensorineural hearing loss and goiter. Pendrin is closely related
to a family of sulfate transport proteins; however, pendrin does
not transport sulfate and unlike NIS does not require sodium
for its transport of iodide.
Thyroid hormone secretion
The secretion of thyroid hormones from stores within luminal
colloid is initiated by elongation of microvilli on follicular cells
and formation of pseudopodia. These elongated cytoplasmic
projections are increased by pituitary TSH, extend into the
follicular lumen, and phagocytize a portion of adjacent colloid.
Colloid droplets within follicular cells subsequently fuse with
lysosomes that contain proteolytic enzymes. Triiodothyronine
(T3) and thyroxine (T4) are released from the thyroglobulin
molecule and, because of their hydrophobic nature, diffuse
out of follicular cells into the adjacent capillaries. The
biologically inactive iodotyrosines (MIT, DIT), simultaneously
released from the colloid droplets, are deiodinated enzymati-
cally, and the iodide generated is either recycled to the follicu-
lar lumen to iodinate new tyrosyl residues or released into 
the circulation under normal conditions. Thyroxine is rapidly
bound in plasma to low-affinity albumin, moderate-affinity
prealbumin (transthyretin [TTR]), and high-affinity thyroxine-
binding globulin (TBG); T3 is bound to albumin and TBG in
dogs. TBG has a greater affinity for T4 than for T3.
Negative feedback control of thyroid hormone secretion is
accomplished by the coordinated response of the adenohypophysis
and specific hypothalamic nuclei to circulating levels of thyroxine,
which is converted to T3 in target cells. A decrease in thyroid
hormone concentration in plasma is sensed by groups of neu-
rosecretory neurons in the hypothalamus that synthesize and
secrete a small peptide (3 amino acids), thyrotropin-releasing
 Thyroid Gland
Blood Thyrocyte Colloid
vessel
2Na
2Na
NIS
I I I I
TG TG
TSH TSHR TG
TPO  H2O2
G I
cAMP TG-T3
L TG-T4
T3 (20%)
T3 T4 (80%)
T4
Figure 3-53  Sodium iodide symporter (NIS) and thyroid
hormone biosynthesis. Expression of NIS (in the basolateral
membrane of thyrocytes) is induced by thyroid-stimulating
hormone (TSH) and the secondary messenger cAMP, to stimulate
the rapid uptake and concentration of iodide ion (I−) from the
circulation. I− is passively transferred to the colloid with the
transporter pendrin, in the apical membrane. The enzyme thyro-
peroxidase (TPO) in microvilli on the luminal surface oxidizes
I− in the presence of H2O2 to reactive iodine, which subsequently
binds to tyrosyl residues in the thyroglobulin (TG) molecule of
the colloid. G, G-protein; L, lysosome; T3, triiodothyronine; T4,
thyroxine; TSHR, thyroid-stimulating hormone receptor.
hormone (TRH), into the hypophyseal portal circulation.
TSH or thyrotropin (TTH) is conveyed to thyroid follicular
cells, where it binds to the basilar aspect of the cell, activates
adenylyl cyclase, and increases the synthesis and secretion of
thyroid hormones (Fig. 3-54).
One of the initial responses by follicular cells to TSH is the
formation of numerous cytoplasmic pseudopodia, resulting in
increased endocytosis of colloid and release of preformed
thyroid hormones stored within the follicular lumen. If the
secretion of TSH is sustained (hours or days), thyroid follicu-
lar cells become more columnar, and follicular lumina become
smaller because of increased endocytosis of colloid. Numerous
PAS-positive colloid droplets are present in the luminal aspect
of the hypertrophied follicular cells. Thyroid follicles become
enlarged and distended with colloid because of decreased
TSH-mediated endocytosis of colloid. Follicular cells lining
involuted follicles are flattened to cuboidal.
There are differences in thyroid morphology and function
between canine breeds of European origin and the Basenji,
which originated in Africa. At the same level of iodine intake,
thyroidal turnover of iodine is 2-3 times faster in the Basenji
than in European breeds. The corresponding differences in
thyroid morphology in the Basenji include smaller follicles,
more widespread and uniform vacuolation of colloid, more
columnar follicular epithelium, and ultrastructural features of
follicular cells that more closely resemble those of the TSH-
stimulated thyroid in European breeds, such as the Beagle.
Action of thyroid hormones
Once released into the circulation, T4 and T3 act on many
different target cells in the body. The overall functions of the
hormones are similar, although much of the biological activity
313
Hypothalamus
T4 T3
TRH Somatostatin
Pituitary
T4 T3
TSH
T4
T3
Figure 3-54  Hypothalamic-pituitary-thyroid axis. Thyroid-
stimulating hormone (TSH) from the pituitary stimulates the
secretion of both thyroxine (thyroxine [T4] and triiodothyronine
[T3]). These act at the pituitary to control secretion of TSH by a
negative feedback mechanism. In addition, T4 is converted to T3
within the pituitary by a monodeiodinase. Secretion of TSH is
stimulated by thyrotropin-releasing hormone (TRH) from the
hypothalamus, and inhibited by somatostatin and to a lesser
extent by dopamine. Thyroid hormones act at the hypothalamus
to stimulate the secretion of somatostatin. T4 also is deiodinated
to T3 within the hypothalamus, and this conversion plays a role
in feedback regulation.
is the result of monodeiodination by 5′-deiodinase to 3,5,3′-
triiodothyronine (active T3) in target cells prior to interacting
with thyroid hormone receptors. Under certain conditions
(protein starvation, neonatal animals, liver and kidney disease,
febrile illness, etc.) or exposure to xenobiotics, thyroxine is
preferentially monodeiodinated by 5′-deiodinase to 3,3′,5′-
triiodothyronine (“reverse T3”). Because this form of T3 is
biologically inactive, monodeiodination to form reverse T3
provides a mechanism to attenuate the metabolic effects of
thyroid hormones in peripheral tissues.
The subcellular mechanism of action of thyroid hormones
resembles that for steroid hormones in that free hormone
enters target cells and binds loosely to cytosol-binding 
proteins. Free T3 initially binds to receptors on the inner
mitochondrial membrane to activate mitochondrial energy
metabolism, and subsequently binds to nuclear receptors and
increases transcription of target genes to facilitate new protein
synthesis (e.g., structural, enzymatic, and binding proteins).
Thyroid hormone functions in target cells are mediated 
by 3 nuclear receptors—T3Rα1, T3Rβ1, and T3R-β2—that are
encoded by 2 genes, namely, T3Rα and T3Rβ. Thyroid hor-
mones are essential for numerous postnatal developmental
processes, including growth and neurogenesis. The T3Rα gene
is widely expressed from early development, whereas the
T3Rβ gene is highly restricted and expressed later in develop-
ment. Mice with targeted disruption of the T3Rα gene have
markedly reduced production of both T4 and T3, associated
with growth arrest and delayed development of bones and
314 CHAPTER 3  •  Endocrine Glands
small intestine. By comparison, mice with targeted disruption
of the T3Rβ gene have overproduction of thyroid hormones
and impairment of auditory function but no developmental
defects.
The overall physiologic effects of thyroid hormones are to
increase the basal metabolic rate; make more glucose available
to meet the elevated metabolic demands by increasing gly-
colysis, gluconeogenesis, and glucose absorption from the
intestine; stimulate new protein synthesis; increase lipid
metabolism and conversion of cholesterol into bile acids and
other substances; activate lipoprotein lipase and increase sen-
sitivity of adipose tissue to lipolysis by other hormones; stimu-
late heart rate, cardiac output, and blood flow; and increase
neural transmission, cerebration, and neuronal development
in young animals.
Diseases of the thyroid gland
Developmental disturbances of the thyroid gland
Aplasia (athyreosis) and hypoplasia are rare and may be bilat-
eral (in species with paired thyroids) or unilateral. Primary
thyroid aplasia or hypoplasia is usually the result of thyroid
dysgenesis, which is associated with genetic mutations in
thyroid developmental transcription factors, such as thyroid
transcription factors-1 or -2, NKX2.1, FOXE1, and PAX-8.
Secondary thyroid hypoplasia is caused by nonresponsive or
deficient TSH receptors or a TSH deficiency or defect, and
may be associated with mutation of the TSH receptor (TSHR)
gene or TSH gene, respectively, or a developmental defect of
thyrotrophs in the adenohypophysis. Bilateral aplasia or hypo-
plasia of the thyroid in a young animal results in various
degrees of severity of congenital hypothyroidism. Clinical
signs include growth retardation (but normal birth weight),
disproportionate dwarfism, protruding tongue, epiphyseal  to the exterior. Their lining epithelium consists of multiple
dysgenesis, and impaired mental status. Older animals may
develop epiphyseal fractures and degenerative joint disease.
Primary thyroid hypoplasia with congenital hypothyroid-
ism has been reported in Scottish Deerhound pups and spo-
radically in dogs, cats, and other species. Thyroid glands in
Scottish Deerhound pups were smaller than normal and com-
posed of small follicles with little or no colloid compared to
age-matched normal pups. The pituitary gland was normal
macroscopically, but contained few granulated acidophils with
a high percentage of markedly vacuolated cells with few cyto-
plasmic granules, similar to thyroidectomy cells. Serum thy-
roxine levels were markedly decreased and did not increase  the colloid of thyroid follicles occurs frequently in adult-to-
in response to exogenous TSH. The affected puppies had
retarded growth, fine hair coat, weakness, difficulty in walking,
mental depression, and somnolence. Pups with thyroid hypo-
plasia were smaller than their littermates and had short limbs
and short broad heads. There was an absence of ossification of
epiphyses in the axial and appendicular skeleton. A deficiency
or defect in TSH with congenital hypothyroidism has been
reported sporadically in dogs, and mutations of the TSH
receptor resulting in TSH nonresponsiveness have been
reported in a dog and a cat. Secondary thyroid hypoplasia
occurs in animals with pituitary disorders and lack of secretion
of TSH, such as in German Shepherd dogs with pituitary
dwarfism or Guernsey cattle with head anomalies, prolonged
gestation, and abnormal development of the hypothalamic-
pituitary axis (Fig. 3-55).
Congenital hypothyroidism with dyshormonogenic goiter
occurs in animals with defects in the synthesis of thyroid
Thyroid Gland
Figure 3-55  Secondary thyroid hypoplasia as the result of lack
of thyroid-stimulating hormone in a Guernsey calf with a head
anomaly, prolonged gestation, and disruption of the hypothalamic-
pituitary axis. Note the lack of follicle development and small
follicles with little colloid.
hormones, which has been reported in dogs, cats, goats, sheep,
cattle, and other species. Lack of iodide or excess iodide is also
a cause of congenital hyperthyroidism with goiter.
Thyroglossal duct cysts develop most frequently in dogs
and pigs and occasionally other animals by persistence of por-
tions of the midline embryologic primordium of the thyroid
that migrates caudally from the floor of the primitive pharynx
to form the postnatal thyroid lobes. Thyroglossal duct cysts
are present in the ventral midline of the cervical region in dogs
as fluctuant masses that may rupture and form a fistulous tract
layers of follicular cells with occasional colloid-containing fol-
licles that may undergo neoplastic transformation and give rise
to papillary carcinomas (see Neoplasms of the thyroid gland).
Other cysts that develop in the thyroid region that must be
differentiated from thyroglossal duct cysts include parathyroid
cysts, branchial (“lateral neck”) cysts, ultimobranchial duct
cysts, follicular (“colloid”) cysts, and salivary mucoceles. These
are discussed under Parathyroid and related cysts.
Degenerative changes of the thyroid gland
The formation of densely basophilic spherules or granules in
aged dogs and occasionally in other species. These corpora
amylacea–like bodies appear to represent the precipitation of
mineral on aggregated colloid (possibly with abnormal chemi-
cal structure). Colloid mineralization develops in animals
with normal blood calcium and phosphorus levels, and does
not appear to be consistently associated with other diseases
(Fig. 3-56). It is distinctly different from the mineralization of
interfollicular capillaries associated with chronic renal failure.
The mineralization of colloid usually is not associated with
any interference with thyroid function, even though it affects
many follicles.
Accumulation of lipofuscin in follicular cells occurs in
many animals and accounts for the progressive darkening
(brown-red) of the thyroid with advancing age. The numerous
PAS-positive lipofuscin granules accumulate, particularly in
the luminal aspect of follicular cells, but do not appear signifi-
cantly to interfere with thyroid function.
 Thyroid Gland
Figure 3-56  Colloid mineralization in a dog.
Figure 3-57  Interstitial and perifollicular amyloidosis in an aged
bovid.
Deposition of amyloid in the interstitium between thyroid
follicles has been observed in dogs, cats (especially certain
breeds such as Abyssinian), cattle, and occasionally in other
animals (Fig. 3-57). Affected thyroids may be slightly enlarged,
pale, and firmer than normal. The interstitial accumulation of
amyloid may be extensive and compress adjacent follicles, but
usually not to a degree that interferes with thyroid function
clinically. Amyloid in the thyroid of dogs and cattle almost
always is part of generalized amyloidosis associated with a
chronic suppurative process elsewhere in the body.
Hypofunction of the thyroid gland
Hypothyroidism of adult onset is a well-recognized clinical
disease in dogs, but is encountered only occasionally in other
animals. Although hypothyroidism may occur in many adult
purebred and mixed-breed dogs, certain breeds (Golden  tively more prominent resulting from progressive loss of fol-
and Labrador Retrievers, Doberman Pinschers, Dachshunds,
Boxers, Bulldogs, Great Danes, among others) have been
reported to be more commonly affected. Hypothyroidism in
dogs usually is the result of primary lesions in the thyroid gland,
particularly lymphocytic thyroiditis and idiopathic follicular col-
lapse. Less common causes of hypothyroidism in dogs are
bilateral nonfunctional thyroid tumors or severe iodine-deficient
hyperplastic goiter. Hypothyroidism associated with long-
standing pituitary or hypothalamic lesions that prevent the
315
P
T
Figure 3-58  Idiopathic follicular atrophy in a dog. Thyroid (T)
is reduced in size compared to adjacent parathyroids (P) and
lighter in color because of increased adipose connective tissue.
Thyroid arteries (arrows) are thickened and prominent because
of atherosclerosis. Scale = 5 mm.
release of either TSH (secondary) or thyrotropin-releasing
hormone (TRH) (tertiary) is much less common in dogs. The
thyroid gland in secondary hypothyroidism is moderately
reduced in size and composed of colloid-distended “involuted”
follicles lined by flattened follicular cells.
Idiopathic follicular atrophy (“collapse”).  In follicular
atrophy, there is progressive loss of follicular epithelium and
replacement by adipose tissue, with minimal inflammatory
response. The gland usually is smaller and lighter in color than
normal (Fig. 3-58). The early lesion of follicular atrophy that
is seen in dogs with mild clinical signs of hypothyroidism
appears to be confined to one part of the thyroid. The affected
part of the thyroid gland contains small follicles lined by tall
columnar follicular cells, often with little colloid. Immediately
adjacent thyroid follicles are normal. Individual or small
groups of degenerate follicular cells with eosinophilic cyto-
plasm and pyknotic nuclei are present in the follicular wall,
colloid, and interstitium.
A more advanced form of follicular atrophy is seen in dogs
with clinical hypothyroidism and low circulating concentra-
tions of thyroid hormones. The thyroid gland is composed
predominantly of adipose tissue and C cells with only occa-
sional clusters of small follicles containing vacuolated or
clumped colloid (Fig. 3-59A-C). When the thyroid is reduced
markedly in size, it consists primarily of small follicles and
individual follicular cells with PAS-positive colloid in micro-
follicles in the cytoplasm. Small foci of lymphocytes and
plasma cells may be associated with disruption of thyroid fol-
licles and release of colloid. The mild increase of connective
tissue in the interstitium is the result of condensation of the
normal stroma. Focal aggregates of normal C cells appear rela-
licular cells (Fig. 3-59B). Occasionally, thyroid glands with
idiopathic follicular atrophy have either an encapsulated
microadenoma or a nonencapsulated area of nodular hyper-
plasia of follicular cells.
The earliest lesion of idiopathic follicular atrophy is degen-
eration of individual follicular cells lining thyroid follicles. The
advanced stage of follicular atrophy is characterized by a lack
of normal thyroid follicles and the presence of microfollicles
in the cytoplasm of individual follicular cells. The remaining
316 CHAPTER 3  •  Endocrine Glands
A high percentage of dogs with hypothyroidism. Laboratory
B of thyroiditis.
C 3-63). The basement membrane around thyroid follicles is
Figure 3-59  Idiopathic follicular atrophy in a dog. A. The thyroid
gland is composed predominantly of C cells and adipose tissue
with scattered follicles near the periphery of the gland. Parathy-
roid gland (arrowhead). B. Calcitonin immunohistochemistry
demonstrates the unaffected C cells. There is a focal ultimobran-
chial cyst (lower right). C. There is a lack of thyroid follicles, with
replacement by fat. The remaining follicles have degenerate fol-
licular cells with clumped colloid.
hypertrophic follicular cells form small nests and are arranged
closely along capillaries. Degenerate follicular cells are char-
acterized by poorly defined plasma membranes and an irregu-
larly shrunken nucleus (see Fig. 3-59C). Macrophages are
present near the degenerate follicular cells. The basement
membrane may be thickened around remaining follicular cells.
Idiopathic follicular atrophy (“collapse”) is a primary degen-
erative disease of the thyroid and differs distinctly from the trophic
atrophy of follicular cells secondary to diminished secretion of
TSH. Under the latter conditions, thyroid follicles undergo
involution, are lined by low cuboidal epithelium, and dis-
tended by uniformly dense PAS-positive colloid with little
evidence of endocytosis. Hypertrophy and hyperplasia of  thyroiditis. They contain abundant oxidative enzymes but
thyrotrophic basophils occurs in the pars distalis of dogs  sparse rough endoplasmic reticulum, suggesting an imbalance
with idiopathic follicular collapse and hypothyroidism (Fig.
3-60A, B).
Lymphocytic thyroiditis.  Lymphocytic thyroiditis in dogs,
an obese strain of chickens, nonhuman primates, and Buffalo
Thyroid Gland
rats closely resembles Hashimoto’s disease in humans.
Although the exact mechanism in the dog is not well estab-
lished, evidence suggests a polygenic pattern of inheritance
similar to that observed in the human disease. The immunologic
basis for the development of chronic lymphocytic thyroiditis in
both humans and dogs is through production of autoantibodies
directed against thyroglobulin, thyroperoxidase (a microsomal
antigen), the TSH receptor, or other thyroid follicular cell
antigens. Thyroglobulin autoantibodies have been found in a
Beagles with spontaneous lymphocytic thyroiditis also have
circulating thyroid autoantibodies, but the focal thyroiditis
usually is not associated with clinical hypothyroidism. 
Thyroiditis in laboratory Beagles is similar serologically to
human thyroiditis in that antibodies are present against thy-
roglobulin and thyroperoxidase; however, there is not a posi-
tive correlation between the occurrence or magnitude of the
thyroglobulin antibody titers and the occurrence or severity
Thyroid glands of dogs with lymphocytic thyroiditis may
be slightly enlarged and tan-white, normal, or reduced in size.
Histologic alterations include multifocal to diffuse infiltrates of
lymphocytes, plasma cells, and macrophages (Fig. 3-61A, B).
Lymphoid nodules are present occasionally. The remaining
follicles are small and lined by columnar epithelial cells. 
Lymphocytes, macrophages, and degenerate follicular cells
often are present in the colloid (Fig. 3-62A, B). Thyroid C
(parafollicular) cells are seen in small nests or nodules between
follicles and often are relatively more prominent than in
normal dogs.
Lymphocytic thyroiditis is characterized by lymphocytes,
plasma cells, and macrophages in the interstitium, migrating
through the follicular wall, and into the lumen, where they
are mixed with colloid and degenerate follicular cells (Fig.
thickened by electron-dense deposits that represent immune
complexes as seen in humans with Hashimoto’s thyroiditis.
The thyroid lesion of lymphocytic thyroiditis progresses to
replacement of the thyroid gland by mature fibrous connective
tissue with only a few remaining scattered foci of inflammatory
cells (see Fig. 3-61B). Thyroid follicles are small and widely
separated in the “end-stage” of thyroiditis and contain only a
small amount of vacuolated colloid. There is a marked increase
in collagen fibers surrounding small follicles or groups of fol-
licular cells.
Many of the follicular lesions with lymphocytic thyroiditis
are the result of lymphocytes and plasma cells migrating
between thyroid follicular cells. This migration causes separa-
tion of adjacent follicular cells from the basement membrane,
exfoliation of follicular cells, migration of lymphoid cells into
the lumen, and eventual destruction of the follicle. To com-
pensate for the progressive destruction of thyroid follicles by
inflammatory cells, follicular cells in the remaining follicles
often undergo hypertrophy, presumably in response to
increased secretion of TSH.
Oncocytes with abundant eosinophilic cytoplasm often
are seen in thyroids of dogs with long-standing lymphocytic
between the respiratory and synthesizing activities of the cell.
Thyroid hormone synthesis is compromised in these modified
follicular cells. The occurrence of oncocytes in thyroid glands
may be related to aging or overstimulation.
 Thyroid Gland 317

A B
Figure 3-60  Hypertrophy and hyperplasia of thyrotrophic basophils in the pars distalis. A. Region
of the pars distalis composed predominantly of hypertrophied and basophilic thyrotrophs, with
few acidophils and chromophobic pituitary cells. B. Adjacent region of the pars distalis with mostly
acidophils and chromophobes and few basophils.

A
A

B
Figure 3-61  Lymphoplasmacytic thyroiditis in the dog. A. Early-
stage thyroiditis with infiltration of the interstitium and follicles
with lymphocytes and plasma cells and formation of lymphoid
nodules. B. Late-stage thyroiditis with lack of thyroid follicles. The
thyroid gland is composed of fibrous tissue, C cells, and foci of
lymphoplasmacytic inflammation. The normal parathyroid glands
are present adjacent to the thyroid glands. B
Figure 3-62  Lymphoplasmacytic thyroiditis in the dog. A. Thy-
roiditis with infiltration of the interstitium and follicles with
lymphocytes and plasma cells. The thyroid follicles are indistinct,
with a lack of colloid and disruption of the follicular cells. B. The
remaining degenerate follicular cells still stain immunohistochem-
ically for thyroglobulin.
318 CHAPTER 3  •  Endocrine Glands
Figure 3-63  Lymphoplasmacytic thyroiditis in the dog. Infiltra-
tion of the interstitium with lymphocytes and plasma cells, fol-
licular atrophy, follicular cell degeneration, necrosis with pyknotic
nuclear debris, and perifollicular fibrosis.
Extrathyroidal lesions and functional disturbances in
hypothyroidism.  Many functional disturbances associated
with hypothyroidism result from a reduced basal metabolic
rate. A gain in body weight without a change in appetite may
occur. The weight gain varies from slight to striking, and
hypothyroid dogs are less active than normal.
Lesions in skin and hair coat occur in the majority of hypo-
thyroid dogs. Thyroxine stimulates the anagen or active phase
of hair growth, whereas reduced blood levels of thyroid hor-
mones favor the telogen or resting phase. Telogen hairs are
more easily dislodged from the hair follicles, resulting in thin-
ning of the hair coat and often a bilaterally symmetrical alo-
pecia. Areas affected initially by hair loss are those receiving
frictional wear, such as the tail and cervical area. The tail may
become almost completely bare in dogs with long-standing
hypothyroidism.
Hyperkeratosis is a consistent finding in hypothyroidism
and results in increased scaliness of the skin. It may become
severe and occur in circular scaling patches resulting in skin
lesions suggestive of seborrhea. Microscopic examination con-
sistently reveals marked hyperkeratosis that includes the
external root sheath. The excessive keratin formation and
accumulation within hair follicles often results in follicular
keratosis that may cause grossly observable distention of
follicles.
Hyperpigmentation occurs in many dogs with hypothy-
roidism, especially in localized areas of alopecia, such as the
dorsal aspect of the nose and distal portion of the tail. Increased
numbers of melanocytes are present in the basal layer of the
epidermis. Changes in the thickness of the epidermis are vari-
able in dogs with hypothyroidism. Epidermal atrophy is
reported in ~50% of hypothyroid dogs, normal thickness in
~20%, and mild to moderate epidermal thickening resulting
from a prominent stratum granulosum with an atrophic
stratum spinosum in the remaining 30% of dogs.
Myxedema may develop and produce a characteristic clini-
cal appearance in long-standing or severe hypothyroidism.
Mucin (neutral and acid glycosaminoglycans combined with
protein) accumulates in the dermis and subcutis. This material
binds considerable amounts of water and produces marked
Thyroid Gland
Figure 3-64  Hypothyroidism in a dog. Myxedema with thick-
ened facial skin folds and “tragic” facial expression.
thickening of the skin. This is most obvious around the face
and head, where accentuation of the normal skin folds causes
a “tragic” appearance (Fig. 3-64). The eyelids appear thick and
drooping, thus contributing to the sad facial expression. The
skin feels thick and doughy, but the characteristic pitting
observed with other types of edema does not occur with
myxedema. Histologically, mucin appears as a blue-purple,
granular or fibrillar material that disrupts the normal collagen
and elastin fibers on skin sections. Mucin is not well visualized
on skin sections stained with hematoxylin and eosin, but dis-
ruption of the normal pattern of collagen and elastin fibers is
evident in the dermis.
Abnormalities in reproduction are common in hypothy-
roidism. Lack of libido and reduction in sperm count may
occur in males, whereas abnormal or absent estrous cycles
with reduced conception rates may result in females. The
spermatogenic epithelium in the testis often is markedly atro-
phic in long-standing cases of hypothyroidism. Impaired joint
function with evidence of pain and joint effusion also can
result from severe or prolonged hypothyroidism.
Hypothyroidism in dogs is accompanied by reduced circu-
lating concentrations of thyroid hormones and decreased 131I
uptake by the thyroid gland. The occurrence of mild, nonre-
sponsive, normocytic, normochromic anemia is consistent
with a diagnosis of hypothyroidism.
The marked hypercholesterolemia seen with long-standing
and severe hypothyroidism results in a variety of secondary
extrathyroidal lesions, including atherosclerosis, hepatomegaly,
and renal glomerular, and corneal lipidosis. Hypercholesterol-
emia results from the decreased rate of lipid metabolism, with
diminished intestinal excretion of cholesterol and conversion
of lipids into bile acids and other compounds.
• Atherosclerosis of coronary, cerebral, and other vessels may
develop in dogs with severe hypothyroidism and long-
standing hyperlipidemia (Fig. 3-65, see Fig. 3-58,). This
occasionally results in hemorrhage and ischemic necrosis
of the myocardium caused by impingement on the vessel
 Thyroid Gland
Figure 3-65  Hypothyroidism in a dog. Coronary atherosclerosis
with lipid-filled macrophages in the intima and media (black-
stained cells) and cholesterol clefts. Osmium stain.
Figure 3-66  Glomerular lipidosis in a dog with severe and long-
standing hypothyroidism with marked hypercholesterolemia.
lumina by numerous lipid-laden macrophages in the tunica
media and adventitia.
• In dogs with markedly elevated plasma lipids, renal glom-
eruli may become plugged with lipid, resulting in progres-
sive renal failure. The lipid-filled glomeruli can be seen
macroscopically as small yellow-white foci throughout the
kidney cortex (Fig. 3-66).
• Accumulation of excessive lipid in the liver often results
in various degrees of hepatomegaly with abdominal disten-
tion and hepatic failure.
• Corneal lipidosis is observed occasionally in hypothyroid
dogs with hypercholesterolemia. This lesion often is uni-
lateral because the lipid is deposited in corneas that have
been previously injured and have a network of “ghost”
vessels from which the lipid diffuses into the connective
tissue stroma.
Evaluation of thyroid function
Serum cholesterol concentration is an indirect and valuable
index of the peripheral action of thyroid hormone. Two  canine TSH assays are relatively insensitive compared to the
thirds of dogs with spontaneous hypothyroidism have fasting
serum hypercholesterolemia concentration >7.75 mmol/L
(>300 mg/100 mL). Hypercholesterolemia is as dependent
upon the composition of the dog’s diet as the severity and
319
duration of hypothyroidism. Cholesterol values tend to be
lower in dogs maintained on commercially manufactured dry
dog foods. Hypercholesterolemia also occurs in some dogs
with cortisol excess, a disease that must be considered in the
differential diagnosis of hypothyroidism. Therefore the mea-
surement of serum cholesterol is not a specific test of thyroid
function.
The most sensitive and accurate method for evaluation 
of thyroid function is measurement of total blood thyroxine
(T4) and triiodothyronine (T3) levels by radioimmunoassay.
The normal blood level of total T4 in the dog is 13-51 nmol/L
(1.5-3.6 µg/dL) and 0.74-2.4 nmol/L (48-154 ng/dL) for
total T3. In dogs with hypothyroidism, the total T4 level usually
is <13 nmol/L (<1.0 µg/dL), and T3 is <0.77 nmol/L (<50 ng/
dL). When levels are borderline, clearer separation of dogs
with hypothyroidism from euthyroid dogs can be made by
injecting TSH. In euthyroid dogs, the T4 level will at least
double 8 hours after administration of TSH. In dogs with
hypothyroidism, T4 and T3 levels do not change significantly
after injection of TSH. The increase in serum T3 after TSH is
more variable in normal dogs than for T4.
Free T4 can be measured by equilibrium dialysis with tracer.
Other methods of measuring free T4 are technically less dif-
ficult but are less accurate. The range of serum free T4 in
normal dogs is 7-35 pmol/L (0.5-2.7 ng/dL). The advantages
of measuring free T4 over total T4 include (1) higher correlation
with thyroid secretory function, (2) less overlap of hypothy-
roid and euthyroid levels, and (3) slower decrease with non-
thyroidal illness.
Histologic examination of a thyroid biopsy is a useful aid in
the diagnosis of thyroid disease when either the results of
serum assays for T4 and T3 are equivocal or a nodule is pal-
pated in the thyroid area. The removal of the caudal one
fourth of either lobe of the thyroid for histologic examination
is a relatively simple surgical procedure without significant
risk, even when the dog is hypothyroid. In most cases of
hypothyroidism, there is either marked loss of thyroid follicles
with replacement by adipose connective tissue or multifocal
lymphocytic thyroiditis and interstitial fibrosis.
In the evaluation of clinically important thyroid diseases
and potential thyroid toxicity of various xenobiotics, an accu-
rate quantitation of circulating levels of thyroid-stimulating
hormone (TSH or thyrotropin) is important in the assessment
of thyroid function. TSH is the major regulator of the syn-
thetic and secretory processes of thyroid follicular cells.
However, the immunoassay for TSH is highly species specific,
with considerable interanimal and interassay variations. TSH
is a glycoprotein synthesized by thyrotrophic basophils in the
adenohypophysis and is composed of α and β subunits. The α
subunit is similar to that of several pituitary hormones of the
same family, but the β subunit is specific for TSH. The
hormone circulates primarily in the free (unbound) form and
has a short (~15 minutes) plasma half-life. Serum plasma
samples for TSH assay should be collected in the morning
before noon to minimize the effects of diurnal variation on
hormone levels. Immunoassays specific for serum canine TSH
are available. The circulating TSH levels in dogs are 10- to
20-fold lower than those in humans. Although the current
human TSH assays, an increased TSH level has been demon-
strated in some dogs with primary hypothyroidism. Also, a
peak increase in serum TSH occurs at 30 minutes postinjec-
tion of thyrotropin-releasing hormone (TRH).
320 CHAPTER 3  •  Endocrine Glands Thyroid Gland

Hyperplasia of the thyroid gland
Non-neoplastic and noninflammatory clinical enlargements
(“goiter”) of the thyroid develop in all domestic mammals,
birds, and submammalian vertebrates. The major pathogenic
mechanisms responsible for the development of thyroid
hyperplasia include iodine-deficient diets, goitrogenic compounds
that interfere with thyroid hormone synthesis, dietary iodide
excess, and genetic enzyme defects in the biosynthesis of thyroid
hormones (Fig. 3-67). All of these factors result in inadequate
thyroid hormone synthesis and decreased blood levels of T4
and T3. The low blood levels are detected by the hypothala-
mus and pituitary to increase the secretion of TSH, which
results in hypertrophy and hyperplasia of follicular cells.
Diffuse hyperplastic and colloid goiter.  Iodine deficiency
that resulted in diffuse thyroid hyperplasia was common in
many goitrogenic areas throughout the world before the wide-
spread addition of iodized salt to animal diets. Although
iodine-deficient goiter still occurs in large areas of the world

Mechanisms of goitrogenesis

Goitrogenic Deficient Excess Genetic defects

compounds dietary iodine dietary iodine "congenital goiter"

• Complex anions • Defective

KSCN thyroglobulin
KClO 4 synthesis (O,B,C)
TcO4 • Iodination defect (H)
• Thiouracil, PTU • Coupling defect
• Sulfonamides • (↓) I uptake (NIS)
• Plant goitrins O I (TPO)
• (↓) 2I → 2
Genus Brassica

Inadequate Thyroxine Synthesis or Release



Increased Decreased
Thyroxine Demand Blood T4/T3

• Young animal 
• Pregnancy
• Stress (↑) Hypothalamic TRH
• Severe infection (Releasing Hormone)
• Puberty 

(↑) Pituitary TSH

Defective
homeostasis LATS Thyroid gland -
(exophthalmic hypertrophy and hyperplasia
goiter) (H) of follicular cells

(↑) Thyroid hormone

synthesis & secretion

Hypothyroid Euthyroid Hyperthyroid

Clinical status

Figure 3-67  Mechanisms of goitrogenesis. Multiple pathogenic factors (goitrogenic compounds,

deficient or excessive dietary iodine intake, and genetic defects) result in inadequate thyroxine
(T4)/triiodothyronine (T3) synthesis and lead to long-term stimulation of thyroid follicular cells
(hypertrophy and hyperplasia) by increased secretion of pituitary thyroid-stimulating hormone
(TSH). B, bovine; C, caprine, H, human; KClO4−, potassium perchlorate; KSCN−, potassium thio-
cyanate; LATS, long-acting thyroid stimulator, an autoantibody that binds to the TSH receptor
and stimulates the synthetic and secretory activity of follicular cells; NIS, sodium iodide symporter;
O, ovine; PTU, propylthiouracil; TcO4−, pertechnetate; TPO, thyroperoxidase; TRH, thyrotropin-
releasing hormone. (From Capen CC. Tumors of the endocrine glands. In: Meuten DJ, ed. Tumors
of Domestic Animals. 4th ed. 2002, Wiley.)
 Thyroid Gland
Figure 3-68  Congenital goiter in a lamb. Note large thyroids
(within swollen neck, at arrowhead), poor development of wool,
and swollen tongue.
in domestic animals, the outbreaks are sporadic and fewer
animals are affected. Marginal iodine-deficient diets contain-
ing certain goitrogenic compounds may result in severe thyroid
hyperplasia and clinical evidence of goiter. These substances
include thiouracil, sulfonamides, anions of the Hofmeister
series, and a number of plants from the family Brassicaceae
(see Thyrotoxic effects of drugs and chemicals, later). Young
animals born to females on iodine-deficient diets are more
likely to develop severe thyroid hyperplasia and have clinical
signs of hypothyroidism (Fig. 3-68).
Although seemingly paradoxical, excess iodide in the diet
also can result in thyroid hyperplasia in animal and humans.
Foals of mares fed dry seaweed containing excessive iodide
may develop thyroid hyperplasia and clinically evident goiter.
The thyroid glands of the young are exposed to higher blood
iodide levels than the dam because of concentration of iodide,
first by the placenta, and second by the mammary gland. High
blood iodide interferes with one or more steps of thyroid
hormone synthesis and secretion, leading to lowered blood T4
and T3 levels, and a compensatory increase in pituitary TSH
secretion. Excess iodine appears to primarily block the release
of thyroid hormones by interfering with the fusion of colloid
droplets and lysosomal bodies, thereby disrupting the prote-
olysis of colloid and release of T4 and T3.
Iodine deficiency may be conditioned by other antithyroid
compounds present in animal feeds and be responsible, in
particular situations, for a high incidence of goiter. Prolonged
low-level exposure to thiocyanates, which are produced by
ruminal degradation of cyanogenic glycosides from plants,
such as white clover (Trifolium), couch grass (Cynoden),
and linseed meal, and by degradation of glucosinolates of  the thyroid enlargement may be sufficient to cause dystocia
the Brassica crops, is associated with congenital goiter in rumi-
nants. Goitrin (5-vinyl-oxazolidine-2-thione) derived from
the glucosinolates of Brassica spp. inhibits organification of
iodine. Leucaena leucocephala and other legumes of the genus
are native or cultivated in many subtropical areas and contain
the toxic amino acid mimosine. The effects of mimosine are
discussed in Vol. 1, Integumentary system. It is not directly
goitrogenic but is converted in the rumen to 3-hydroxy-
4(1H)-pyridone, which prevents organic binding of iodine by
the thyroid.
Goiter in adult animals usually is of little clinical signifi-
cance and, except for occasional local pressure influences,
general health is not impaired. However, it does continue to
be of significance as a disease of newborn animals.
321
Figure 3-69  Congenital hyperplastic goiter. Hypertrophy and
hyperplasia of thyroid follicular cells with a lack of colloid and
collapse of the follicles.
Congenital hypothyroidism caused by impaired thyroid
hormone production in domestic animals is associated with hyper-
plastic goiter, even though the dam may show no evidence of
thyroid dysfunction. Gestation often is prolonged, the larger
goiters may cause dystocia, and there is a tendency to retain
the fetal placenta. Affected foals show extreme weakness and
die within a few days after birth. The thyroids may be only
slightly enlarged. Calves are somewhat more resistant to the
effects of hypothyroidism. Although up to 70-80% may have
large goiters in endemic areas, the majority survive and thrive.
A few calves are partially or completely hairless, but these are
either born dead or die soon after birth. Newborn goitrous
pigs, goats, and lambs (see Fig. 3-68) frequently have myx-
edema and alopecia. The mortality rate is high, with the
majority being born dead or dying within a few hours of birth.
Enlarged thyroid glands are readily palpable or visible in kids
and lambs, but are not readily apparent in piglets because of
the combination of a short neck and the development of
myxedema. The tongue is swollen, and there is edematous
swelling of the fauces and larynx, which probably are con-
tributory factors to death of the animals. Asphyxiation may
result also from pressure by the enlarged thyroid gland on the
trachea and adjacent structures. Young, goitrous animals 
that are treated and survive usually do not show permanent
ill effects.
Congenital hyperplastic goiter with hypothyroidism is 
not a prominent feature of thyroid disease in domestic carni-
vores. However, degrees of follicular cell hyperplasia will be
found that parallel changes in the maternal gland. In puppies,
or asphyxiation. In the most severe form, death occurs 
shortly after birth, and those affected have poorly developed
coarse hair, anemia, and defective bone mineralization. Less
severe forms are more common, and affected pups often
recover spontaneously. They are characterized by dry, coarse,
and sparse hair coat; narrow palpebral fissures; and broad
skulls and legs, which are relatively thicker and heavier than
normal.
Both lobes of the thyroid are uniformly enlarged in young
animals with diffuse hyperplastic goiter as a result of extensive
follicular cell hypertrophy and hyperplasia with enhanced endo-
cytosis of colloid and collapse of follicles (Fig. 3-69). The enlarge-
ments may be extensive and result in palpable swellings in the
cranial cervical area. The affected lobes are firm and dark red
322 CHAPTER 3  •  Endocrine Glands
Figure 3-70  Colloid goiter with distended follicles lined by low
cuboidal and inactive follicular cells.
because an extensive interfollicular capillary network devel-
ops under the influence of long-term TSH stimulation.
Colloid goiter represents the involutionary phase of diffuse
hyperplastic goiter and is usually seen in young adult and adult
animals. The markedly hyperplastic follicular cells continue to
produce colloid, but endocytosis of colloid is decreased
because of diminished pituitary TSH levels in response to the
return of blood T4 and T3 to normal. Both thyroid lobes are
diffusely enlarged but are more translucent and lighter in color
than with hyperplastic goiter. The differences in macroscopic
appearance are the result of reduced vascularity in colloid
goiter and development of macrofollicles distended with
colloid (Fig. 3-70).
The changes in diffuse hyperplastic and colloid goiters are
consistent throughout the enlarged thyroid lobes. The follicles are
irregular in size and shape in hyperplastic goiter because of
variable amounts of lightly eosinophilic and vacuolated colloid
in the lumen. Some follicles are collapsed due to lack of
colloid (see Fig. 3-69). The lining epithelial cells are columnar
with a deeply eosinophilic cytoplasm and small hyperchro-
matic nuclei that often are situated in the basilar part of the
cell. The follicles are lined by single or multiple layers of
hyperplastic follicular cells, which in some follicles may form
papillary projections into the lumen. Similar proliferative
changes are present in ectopic thyroid parenchyma in the neck
or mediastinum.
Colloid goiter may develop either after sufficient amounts
of iodide have been added to the diet of animals with iodine-
deficient hyperplastic goiter or after the requirements for
thyroid hormones have diminished in an older animal. Blood
thyroid hormone levels return toward normal, and the secre-
tion of TSH by the pituitary gland is correspondingly
decreased. Follicles are progressively distended with densely
eosinophilic colloid because of diminished TSH-induced
endocytosis. The follicular cells lining the macrofollicles are
flattened and atrophic. The interface between the colloid and
luminal surface of follicular cells is smooth (see Fig. 3-70).
Some involuted follicles in colloid goiter have remnants of the
papillary projections of follicular cells extending into their
lumen.
Nodular hyperplasia.  Nodular hyperplasia (goiter) in
thyroid glands of old horses, cats, and dogs appears as multiple
white to tan nodules of variable size (Fig. 3-71). The affected
lobes are moderately enlarged and irregular in contour.
Thyroid Gland
Figure 3-71  Nodular goiter with multiple hyperplastic nodules
in a horse.
Nodular goiter in most animals is endocrinologically inactive and
encountered as an incidental lesion at autopsy; however, multi-
nodular follicular cell hyperplasia is typically functional in cats.
Nodular goiter consists of multiple foci of hyperplastic
follicular cells that are sharply demarcated, but not encapsu-
lated, and result in minimal compression of adjacent thyroid
parenchyma. The microscopic appearance within a nodule is
variable. Some hyperplastic cells form small follicles with little
or no colloid. Other nodules are formed by larger irregularly
shaped follicles lined by one or more layers of columnar cells
that form papillary projections into the lumen. Some of the
follicles are involuted and filled with densely eosinophilic
colloid. These changes appear to be the result of alternating
periods of hyperplasia and colloid involution. The areas of
nodular hyperplasia may be microscopic or grossly visible
causing enlargement of the thyroid, as in old horses (see 
Fig. 3-71).
There are no absolute morphologic criteria for distinguishing
hyperplastic nodules and adenomas derived from thyroid follicu-
lar cells. As a general rule, hyperplastic nodules are multiple,
poorly or not encapsulated, variable in their histologic struc-
ture, and do not cause compression of adjacent thyroid paren-
chyma. Adenomas tend to be well demarcated and partially
or fully encapsulated, uniform in histologic structure, and
cause compression of the surrounding parenchyma as a result
of expansile growth (Fig. 3-72). Endocrinologically active
thyroid adenomas result in colloid involution of follicles in the
rim of surrounding thyroid because of inhibition of TSH
secretion.
Inherited dyshormonogenic goiter.  An inability to synthe-
size and secrete adequate amounts of thyroid hormones begin-
ning before or at birth has been documented in human infants
and in several animal species. Congenital dyshormonogenic
goiter is inherited as an autosomal recessive trait in Corriedale,
Dorset Horn, Merino, and Romney sheep; Afrikaner cattle;
and Saanen dwarf goats. The subnormal growth rate, absence
of normal wool development or a rough sparse hair coat,
myxedematous swellings of the subcutis, weakness, and slug-
gish behavior indicate that the affected young are clinically
hypothyroid. Most lambs with congenital goiter either die
shortly after birth or are highly sensitive to the effects of
adverse environmental conditions.
Thyroid glands are symmetrically enlarged at birth because of
intense diffuse hyperplasia of follicular cells (Fig. 3-73A). Thyroid
 Thyroid Gland 323

Figure 3-72  Solitary thyroid follicular cell adenoma with a

fibrous capsule and compression of the adjacent thyroid tissue in
a horse.

follicles are lined by tall columnar cells, but often are collapsed A
because of lack of colloid resulting from the markedly
increased endocytotic activity and diminished ability to syn-
thesize thyroglobulin (Fig. 3-73B).
Although thyroidal uptake and turnover of 131I are greatly
increased, levels of circulating T4 and T3 are consistently low. The
absence of a defect in the iodide transport mechanism and
organification or dehalogenation, together with an absence of
normal 19-S thyroglobulin in goitrous thyroids is consistent
with impairment in thyroglobulin biosynthesis. A closely related
or similar defect occurs in inherited congenital goiter in sheep,
cattle, and goats, in which the protein-bound iodine levels are
markedly elevated. This appears to be the result of iodination
of albumin and other plasma proteins by the thyroid gland
under long-term TSH stimulation. Hypothyroid goats with
congenital goiter can be returned to a state of euthyroidism B
by the addition of iodide (1.0 mg/day) to the diet. Although
Figure 3-73  A. Congenital dyshormonogenic goiter in a Cor-
the goats remain unable to synthesize thyroglobulin, supple-
riedale lamb. B. Congenital goiter in a lamb with severe diffuse
mentation with excess iodide results in sufficient formation of
thyroid-stimulating hormone-mediated follicular cell hypertro-
T3 and T4 in the abnormal iodoproteins to make the animals
phy and hyperplasia. Thyroid follicles have collapsed and have
euthyroid. Although thyroglobulin mRNA is present in the
slit-like lumens, given a lack of colloid. Immunohistochemistry 
goitrous tissue, the concentration is reduced by 90-97% of
for thyroglobulin demonstrates minimal thyroglobulin (brown
normal, and the intracellular distribution is abnormal. The lack
material) in the follicular lumens, and lack of staining of the fol-
of thyroglobulin in these examples of congenital goiter in animals
licular cells resulting from the inability to effectively synthesize
appears to be the result of a defect in thyroglobulin mRNA,
thyroglobulin.
leading to aberrant processing of primary transcripts or trans-
port of the thyroglobulin mRNA from the nucleus to the
ribosomes of the endoplasmic reticulum.
In addition to defects in thyroglobulin processing, dyshor- Thyrotoxic effects of drugs and chemicals
monogenic goiter can occur by other mechanisms that impair Many of the significant physiologic and pathologic data in the
thyroid hormone synthesis, including impaired transport of literature on thyroid function and structure have come from
iodide, decreased or inactive TSH, decreased or impaired TSH studies in animals. Although the basic hypothalamic-pituitary-
receptor, decreased or impaired thyroperoxidase function, and thyroid axis functions in a similar manner in animals and
decreased deiodination of T4 to form T3. These are usually humans, there are differences between species in the response of
the result of sporadic debilitating mutations in the sodium the thyroid to chemical inhibition of hormone synthesis, which are
iodide symporter, TSH, TSH receptor, thyroperoxidase, or 5′- important when extrapolating animal data from toxicity and
deiodinase. Congenital goiter with hypomyelination has been carcinogenicity studies for human risk assessment. Long-term
reported in Rat Terrier dogs because of a mutation in the perturbations of the pituitary-thyroid axis by various xenobi-
thyroid peroxidase gene. Dyshormonogenic goiter with con- otics or physiologic alterations (e.g., iodine deficiency, partial
genital hyperthyroidism and goiter has been reported in indi- thyroidectomy) are more likely to predispose laboratory
vidual neonates or siblings (including dogs and cats) and likely animals to a higher incidence of proliferative lesions (e.g.,
occurs in all species, but is rare. hyperplasia and adenomas of follicular cells) than is the case
324 CHAPTER 3  •  Endocrine Glands Thyroid Gland

Influences from periphery via nervous system

Cerebral cortex
[T4 → T3] ()
Hypothalamus
TRH () 5' deiodinase (Type II)

Adenohypophysis [T4 → T3] ()

(thyrotrophs)

↑TSH ()

Thyroid gland Thyroperoxidase

Coupling
Thyro- Thyroglobulin
Extracellular peroxidase MIT  DIT→ T3
fluids I I I2  tyrosine ↓T4 ↓T3
(O) DIT  DIT→ T4
TBG TTR
NaI I I Binding
5' deiodinase (Type I)
symporter proteins

Deiodination

I- trapping Thyroperoxidase inhibition ↓ Proteolysis

↓ T4, T3 release

() ()
()
Goitrogenic • Thiocyanate • Thiourea, PTU • Iodide-excess
chemical • Perchlorate • Sulfonamides • Lithium
• Methimazole
• Aminotriazole
• Acetoacetamide
Figure 3-74  Mechanism of action of goitrogenic chemicals on thyroid hormone synthesis and
secretion. Chemicals can interfere with thyroid function by (1) blocking iodide ion trapping, (2)
inhibiting organic binding-coupling, or (3) disrupting proteolysis and release of T4 and T3 from
colloid. DIT, diiodotyrosine; MIT, monoiodotyrosine; PTU, propylthiouracil; T3, triiodothyronine;
T4, thyroxine; TBG, thyroxine-binding globulin; TRH, thyrotropin-releasing hormone; TSH,
thyroid-stimulating hormone; TTR, transthyretin.

in the human thyroid gland. This appears to be particularly
true in male rats, in which there are higher circulating levels
of TSH than in females. The greater sensitivity of the animal
thyroid to derangement by drugs, chemicals and physiologic
perturbations also is related to the shorter plasma half-life of
T4 (12-24 hours) than in humans (5-9 days), in part the result
of considerable differences among species in the transport
proteins for T4.
There also are marked species differences in the sensitivity
of the functionally important thyroperoxidase enzyme to inhi-
bition by xenobiotics. Thioamides (e.g., sulfonamides) and
other chemicals can selectively inhibit thyroperoxidase and
significantly interfere with the iodination of tyrosyl residues
incorporated in the thyroglobulin molecule, thereby disrupt-
ing the orderly synthesis of T4 and T3. Long-term administra-
tion of sulfonamides results in the development of thyroid
“nodules” (e.g., focal hyperplasias and adenomas) frequently
in the sensitive species (such as the rat, dog, and mice) but
not in species resistant (e.g., monkey, guinea pig, chicken, and
humans) to the inhibition of peroxidase in follicular cells.
The dog also is a species sensitive to the effects of sulfon-
amides, resulting in markedly decreased serum T4 and T3
levels, hyperplasia of thyrotrophic basophils in the pituitary
gland, and increased thyroid weights. By comparison, the thy-
roids of monkeys and human beings are resistant to the devel-
opment of changes that sulfonamides produce in the thyroid
gland.
In humans, primates, and dogs, circulating T4 is bound
primarily to thyroxine-binding globulin (TBG); however, this 
high-affinity binding protein is not present in rodents, 
birds, amphibians, or fish. T3 is transported bound to TBG and
albumin in human beings, monkey, and dog, but only to
albumin in mouse, rat, and chicken. In general, T3 is bound
less avidly to transport proteins than T4, resulting in a faster
turnover and shorter plasma half-life in most species.
Xenobiotics that disrupt thyroid hormone synthesis, 
secretion, or peripheral metabolism often result in prompt
increases in circulating TSH levels. Chemical disruption of
thyroid hormone synthesis and secretion in animals may occur
at a number of different steps in thyroxinogenesis (Fig. 3-74).
 Thyroid Gland
These include blockage of iodine uptake, organification
defects, blockage of hormone release, drug-induced thyroid
pigmentation, inhibition of 5′-deiodinase, and induction of
hepatic microsomal enzymes.
Blockage of iodine uptake.  The initial step in the biosynthe-
sis of thyroid hormones is the uptake of iodide from the circula-
tion, and transport against a gradient across follicular cells to the
lumen of the follicle. Various anions act as competitive inhibi-
tors of iodide transport in the thyroid, including perchlorate
(ClO4−), thiocyanate (SCNT−), and pertechnetate. Blockage
of the iodide-trapping mechanism has a disruptive effect on
the thyroid-pituitary axis similar to iodine deficiency. The
blood levels of T4 and T3 decrease, resulting in a compensatory
increase in the secretion of TSH by the pituitary gland (see
Fig. 3-74). The hypertrophy and hyperplasia of follicular  undergo hypertrophy and hyperplasia.
cells that follows sustained exposure results in increased
thyroid weight and the development of thyroid enlargement
or goiter.
Organification defect.  A wide variety of chemicals, drugs,
and other xenobiotics affect the second step in thyroid
hormone biosynthesis. The stepwise binding of iodide to  rosine is a red dye used widely as a color additive in foods,
the tyrosyl residues in thyroglobulin requires oxidation of
inorganic iodide (I−) to molecular (reactive) iodine (I2) by
thyroperoxidase present in the luminal aspect (microvillar
membranes and apical cytoplasm) of follicular cells and adja-
cent colloid. Classes of chemicals that inhibit the organifica-
tion of thyroglobulin include
1. Thioamides (e.g., thiourea, thiouracil, propylthiouracil,
methimazole, carbimazole, goitrin).
2. Aniline derivatives and related compounds (e.g., sulfon-
amides, para-aminobenzoic acid, para-aminosalicylic acid,
amphenone).
3. Substituted phenols (e.g., resorcinol, phloroglucinol,
2,4-dihydroxybenzoic acid).
4. Miscellaneous inhibitors (e.g., aminotriazole, tricyanoami­
nopropene, antipyrine and its iodinated derivative
[iodopyrine]).
These chemicals exert their action by inhibiting thyroper-
oxidase, which results in disruption both of the iodination of
tyrosyl residues in thyroglobulin but also the coupling reaction
of inactive iodotyrosines (MIT and DIT) to form active iodo-
thyronines (T3 and T4) (see Fig. 3-74).
Blockage of thyroid hormone release.  Relatively few
chemicals selectively inhibit the secretion of thyroid hormone
from the thyroid gland. Excess iodine inhibits secretion of
thyroid hormone and occasionally can result in goiter and
hypothyroidism. Several mechanisms have been suggested,
including a decrease in lysosomal protease activity, inhibition
of colloid droplet formation, and inhibition of TSH-mediated
increase in cAMP. Lithium also has a striking inhibitory effect
on thyroid hormone release. The widespread use of lithium
carbonate in the treatment of manic states occasionally  (2-AAF), N-methyl-N-nitrosourea (MNU), N-bis(2-hydroxy­
results in the development of thyroid enlargement with  propyl) nitrosamine (DHPN), methylcholanthrene, dichloro-
either euthyroidism or occasionally hypothyroidism in human
patients.
Drug-induced thyroid pigmentation.  The antibiotic mino-
cycline produces a striking black discoloration of the thyroid
lobes, with the formation of brown pigment granules within
follicular cells. These pigment granules stain similarly to
melanin and are best visualized with the Fontana-Masson
procedure. Electron-dense material first accumulates in
lysosome-like granules and in the rough endoplasmic reticu-
lum. The pigment appears to be a metabolic derivative of
325
minocycline, and administration of the antibiotic at high dose
may result in disruption of thyroid function and development
of goiter. The release of T4 is significantly decreased, but fol-
licular cells retain the ability to phagocytize colloid in response
to TSH.
Other chemicals (or their metabolites) selectively localize
in the thyroid colloid resulting in abnormal clumping and
increased basophilia to the colloid. Brown to black pigment
granules may be present in follicular cells, colloid, and mac-
rophages, resulting in macroscopic darkening of both thyroid
lobes. The physicochemically altered colloid in the lumina of
thyroid follicles is less able than normal colloid to support the
formation of thyroid hormones. Serum T4 and T3 are decreased,
serum TSH levels are increased, and thyroid follicular cells
Inhibition of 5′-deiodinase.  Erythrosine (FD&C red no. 3)
is one the best characterized chemicals that acts as a 5′-
deiodinase inhibitor and results in perturbations of thyroid
function. It is a tetraiodinated derivative of fluorescein, with
iodine accounting for ~58% of the molecular weight. Eryth-
cosmetics, and pharmaceuticals. Amiodarone is an organic
iodinated antiarrhythmic compound that also disrupts thyroid
hormone economy by inhibiting 5′-deiodinase. Iopanoic acid
and flavonoids also inhibit the enzyme in hepatocytes.
Erythrosine alters the peripheral metabolism of T4. Inhibi-
tion of 5′-deiodinase in the liver and kidney by erythrosine causes
lower circulating T3 levels. This results in accumulation of inac-
tive reverse T3. The lowered circulating levels of T3 causes
increased secretion of TSH from the pituitary and stimulation
of thyroid follicular cells.
Induction of hepatic microsomal enzymes.  Hepatic micro-
somal enzymes play an important role in thyroid hormone
economy because glucuronidation is the rate-limiting step in the
biliary excretion of T4, and sulfation, for the excretion of T3
by phenol sulfotransferase. Long-term exposure to many
chemicals may induce these enzyme pathways and result in
chronic stimulation of the thyroid by disrupting the
hypothalamic-pituitary-thyroid axis (Fig. 3-75). Xenobiotics
that induce liver microsomal enzymes (such as cytochrome
P450 isoenzymes and UDP-glucuronyl transferase) and disrupt
thyroid function include central nervous system drugs (e.g.,
phenobarbital, benzodiazepines), calcium channel blockers
(e.g., nicardipine, bepridil), steroids (spironolactone), reti-
noids, chlorinated hydrocarbons (chlordane, DDT, TCDD),
and polyhalogenated biphenyls (PCB, PBB).
In contrast to the previous categories of indirect-acting
thyrotoxic compounds, certain chemicals and irradiation have
a direct effect on the thyroid gland, resulting in genetic damage
that leads to cell transformation and tumor formation in animals.
Examples of thyroid initiators include 2-acetylaminofluorine
benzidine, and polycyclic hydrocarbons. Tumorigenicity of
these chemicals can be enhanced by iodine deficiency.
Understanding the mechanism of action of xenobiotics on
the thyroid gland provides a rational basis for extrapolation of
findings from long-term rodent studies for the assessment of
safety for humans (see Figs. 3-74, 3-75). Many nongenotoxic
chemicals and drugs disrupt one or more steps in the synthesis
and secretion of thyroid hormones, which results in subnormal
levels of T4 and T3 and compensatory increased secretion of
pituitary TSH. When tested in highly sensitive species, such
326 CHAPTER 3  •  Endocrine Glands Thyroid Gland

↑ UDP-glucuronyl
T4 transferase
Bile
Thyrotropic Hypothalamus
T4-glucuronide area
T4 → T3
T4-glucuronide TRH ()

() Pituitary gland

()
T4 → T3
Hypothalamus
rT3 Decreased T4/T3 pituitary-
synthesis/secretion thyroid axis
T4 T3 ↓ I uptake
↓ 5-Deiodinase ↓ Thyroperoxidase Pituitary-
- binding/coupling thyroid
↓ Proteolysis axis
TSH
[T4/T3]

xs TSH

Thyroid
Neoplasia Hyperplasia
gland
(late) (early)
Figure 3-75  Multiple sites of disruption of the hypothalamic-pituitary-thyroid axis by xenobiotics.
Chemicals can exert direct effects by disrupting thyroid hormone synthesis or secretion and indi-
rectly influence the thyroid through inhibition of 5′-deiodinase or by inducing hepatic microsomal
enzymes (e.g., T4-uridine diphosphate (UDP)-glucuronyl transferase). All of these mechanisms can
lower circulating levels of thyroid hormones (T4 and T3), resulting in release from negative feed-
back inhibition and increased secretion of thyroid-stimulating hormone (TSH) by the pituitary
gland. The chronic hypersecretion of TSH predisposes the sensitive rodent thyroid to develop an
increased incidence of focal hyperplastic and neoplastic (predominantly adenomas) lesions. T3,
triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; xs, excess. (From Capen CC.
Toxicol Pathol 1997;25:39-48.)

as rats and mice, these compounds result early on in follicular
cell hypertrophy/hyperplasia, and in long-term studies they
increase the incidence of thyroid tumors. Prolonged stimula-
tion of the human thyroid (and likely other species, such as
the dog or horse) by TSH will induce neoplasia only in excep-
tional circumstances, possibly by acting together with some
other genetic, metabolic, or immunologic abnormality. For
example, goiter, in adults is not associated with an increased
incidence of thyroid tumors.
Neoplasms of the thyroid gland
Most thyroid tumors are of follicular origin. They are common in
dogs and cats and distinctly rare in cattle, sheep, and swine.
Horses infrequently develop both thyroid follicular and C-cell
tumors. Tumors usually develop in animals that often are
permitted to live to an advanced age, such as dogs, cats, guinea
pigs, and horses. Guinea pigs occasionally develop thyroid
follicular adenomas or carcinomas.
Follicular cell adenoma
Adenomas are usually white to tan, relatively small, solid nodules
that are well demarcated from the adjacent thyroid parenchyma.
The affected thyroid lobe is only moderately enlarged and
distorted. A distinct white fibrous capsule of variable thickness
separates the adenoma from the compressed parenchyma.
Only a single adenoma usually is present in a thyroid lobe (see
Fig. 3-72). Other thyroid adenomas are composed of fluctuant
thin-walled cysts filled with yellow to red fluid. The external
surface of cystadenomas is smooth and covered by an exten-
sive network of blood vessels. Small masses of neoplastic tissue
remain in the wall and form rugose projections into the cyst
lumen. The thyroid parenchyma of the affected lobe may be
completely obliterated.
Adenomas are classified into follicular and papillary types.
They are sharply demarcated and encapsulated by a partial or
complete fibrous capsule of variable thickness. Adenomas
derived from follicular cells that retain the ability to form follicles,
according to one of several patterns, are considerably more
common than papillary adenomas in animals. Each follicular
adenoma tends to have a consistent growth pattern within
itself.
There are several different patterns of growth for follicles,
similar to those of the normal thyroid. Microfollicular adeno-
mas consist of tumor cells arranged in miniature follicles with
small amounts of colloid or an absence of colloid. Macrofollicu-
lar adenomas are comprised of irregularly shaped large follicles
that are greatly distended with colloid and lined by flattened
follicular cells. There often is extensive hemorrhage and des-
quamation of follicular cells into the lumina of the distended
follicles.
Cystic adenomas consist of 1 or 2 large cavities filled with
proteinaceous fluid, necrotic debris, and erythrocytes. Focal
 Thyroid Gland
accumulations of tumor cells, forming either follicles or solid
nests, are present in the capsule of dense fibrous connective
tissue. These adenomas may develop by progressive cystic
degeneration. Trabecular adenomas are the most poorly dif-
ferentiated of the follicular type. The tumor cells are small
and are arranged in narrow columns separated by an edema-
tous fibrous stroma. There is little evidence of follicle
formation.
Oxyphilic adenomas are composed (predominantly or
entirely) of large cells with densely eosinophilic granular cyto-
plasm arranged in indistinct follicles with little or no colloid
formation. Oxyphilic (Hürthle) cells appear to be metaboli-
cally altered follicular cells that accumulate abnormally large
numbers of mitochondria in their cytoplasm.
Papillary adenomas of thyroid origin are recognized infre-
quently in most animal species. Columnar or cuboidal follicu-
lar cells are arranged in a single layer about a thin vascular
connective tissue stalk. These papillary projections extend into
the lumina of cystic spaces of various sizes. The cysts contain
desquamated tumor cells, colloid, erythrocytes, and occasion-
ally laminated foci of mineralization resembling psammoma
bodies.
Hyperthyroidism associated with thyroid tumors
Multinodular hyperplasia and follicular cell adenomas are
common lesions in thyroid glands of adult-to-aged cats that
develop a clinical syndrome of hyperthyroidism. Follicular cell
adenomas often develop in a thyroid with multinodular
hyperplasia. Thyroid carcinomas are uncommon. Adenomas
and carcinomas are most likely to be encountered in aged cats,
whereas nodular hyperplasia can occur at any age. The mean
age of cats with benign tumors has been reported to be 12.4
years, and thyroid carcinomas as 15.8 years. Guinea pigs with
thyroid follicular adenomas or carcinomas can also develop
hyperthyroidism.
Since the late 1970s, there has been a dramatic increase in
the incidence of thyroid neoplasms and other focal proliferative
lesions in cats, resulting in hyperthyroidism, and at present, it is
one of the 2 most common endocrine diseases in adult cats, dia-
betes mellitus being the other. Prior to 1980, clinical hyper-
thyroidism was diagnosed infrequently in cats. The reason for
the apparent increased incidence is uncertain, but appears in
part to be related to (1) a larger population of older cats
seeking veterinary medical care since 1980, (2) improved
assays for thyroid hormones, and (3) detailed characterization
of the clinical syndrome and increased awareness of its
common occurrence in adult to aged cats by veterinary clini-
cians. In addition, there does appear to be a “real” increase in
the incidence of feline hyperthyroidism over the last 30 years.
Potential risk factors have been reported to include a predomi-
nantly indoor environment, regular treatment with flea
powders, exposures to herbicides and fertilizers, goitrogens in
commercial foods (such as bisphenol-A [BPA], which acts as
a thyroid receptor antagonist, or polyphenolic soy isoflavones
that inhibit conversion of T4 to T3), and non-Siamese breeds
(10 times greater occurrence). It has been suggested that wide
variations (excessive to inadequate) in dietary iodine intake
over prolonged periods may play a role in the pathogenesis of
thyroid disorders in cats.
This important thyroid disease in cats most closely resem-
bles toxic nodular goiter in humans. Hyperplastic and neoplastic
thyroid tissue from cats is transplantable into athymic (nude)
mice and continues to overproduce T4 and T3 in a subcuticular
327
location. Studies using primary cultures of follicles from
thyroid proliferative lesions from cats with hyperthyroidism
have reported that organification and 3H-thymidine labeling
continue in the absence of TSH, in contrast to follicles from
normal cat thyroids. These findings suggest that an intrinsic
alteration in follicular cell function occurs in thyroids of cats with
multinodular goiter, leading to autonomy of cell growth and per-
sistent overproduction of thyroid hormones. An overexpression
of the c-ras oncogene in areas of nodular hyperplasia and
adenomas derived from follicular cells in cats with hyperthy-
roidism was reported, which suggests activating mutations in
this oncogene may play a role in the pathogenesis of these
proliferative lesions. In addition, genetic mutations have been
found in the TSH receptor and the G protein (Gsα) in foci
of hyperplasia or adenomas (similar to humans with toxic
nodular goiter), which may be important, especially if the
TSH receptor is activated or there is increased cAMP pro-
duced by the modified cells. Point mutations in the human
thyrotropin receptor (TSHR) gene cause 2 forms of thyrotoxi-
cosis, namely, autonomously functioning toxic follicular ade-
nomas and hereditary (autosomal dominant) toxic thyroid
hyperplasia. The normal feline TSHR sequence between
codons 480 and 640 is highly homologous to that of other
mammalian TSHRs, with 95, 92, and 90% amino acid identity
between the feline, canine, human, and bovine TSHRs,
respectively.
The syndrome of hyperthyroidism in aged cats can be associ-
ated with adenomas, multinodular hyperplasia, or adenocarcino-
mas derived from follicular cells. The most common clinical sign
is weight loss, in spite of normal or increased appetite. Poly-
dipsia and polyuria, increased frequency of defecation,
increased volume of stools, and increased activity occur. A
common functional disturbance is tachycardia accompanied
by premature beats and/or a systolic murmur. Cardiomegaly
resulting from left ventricular hypertrophy may be evident on
radiographs or at autopsy.
Thyroid adenomas in cats usually appear as well-demarcated,
lobulated nodules that enlarge and distort the contour of the
affected lobe (Fig. 3-76). A thin, partial fibrous capsule sepa-
rates the adenoma from the adjacent, often compressed,
thyroid parenchyma. Functional thyroid adenomas are com-
posed of cuboidal to columnar follicular cells with occasional
papillary infoldings that form follicles containing variable
amounts of colloid (Fig. 3-77A,B). The follicles usually are
partially collapsed and contain little colloid because of the
intense endocytotic activity of neoplastic follicular cells. Long
cytoplasmic projections extend from the follicular cells into
the lumen to endocytose colloid (Fig. 3-78). As a result of the
P
A
Figure 3-76  Functional follicular cell adenoma (A) in a cat with
hyperthyroidism. The tumor is sharply demarcated from the
normal thyroid. The hilus of the thyroid (left) contains multiple
ultimobranchial cysts (arrowheads) and a small remnant of the
thymus (arrow). P, parathyroid gland.
328 CHAPTER 3  •  Endocrine Glands
A Figure 3-78  Functional follicular cell adenoma in a cat. Numer-
B
Figure 3-77  Functional follicular cell adenoma. A. The adenoma
is composed of follicles with little stored colloid as a result of
autonomous and excessive secretion of thyroid hormones. B. Fol-
licles in the normal thyroid tissue have undergone colloid involu-
tion and are distended with colloid and lined by low cuboidal
follicular cells as a morphologic response to suppressed thyroid-
stimulating hormone levels.
marked endocytotic activity, numerous colloid droplets are
present in the apical cytoplasm of follicular cells in close
proximity to the many lysosomal bodies. Follicles in the sur-
rounding suppressed thyroid are enlarged and distended by
colloid, a lesion referred to as “colloid involution.” The follicu-
lar cells are low cuboidal and atrophied with little evidence
of endocytotic activity in response to the elevated levels of
thyroid hormones produced by the adenoma, resulting in sup-
pressed levels of TSH (see Fig. 3-77B). Focal areas of necrosis,
mineralization, and cystic degeneration are present in larger
adenomas. Functional follicular adenomas often develop in
thyroids that have multinodular hyperplasia of follicular cells
in both lobes.
Hyperthyroidism in cats also occurs in association with bilat-
eral multinodular (“adenomatous”) hyperplasia. These multiple
areas of thyroid hyperplasia usually do not appreciably enlarge
the affected lobe(s) (Fig. 3-79). The hyperplastic nodules are
composed of irregularly shaped, colloid-filled follicles lined by
cuboidal follicular cells. The multiple nodules of follicular cell
hyperplasia eventually may coalesce or progress to form mac-
roscopically observable thyroid adenomas.
Thyroid Gland
ER
p
ous cytoplasmic processes (p) extend from the luminal surface of
neoplastic follicular cells to engulf colloid by endocytosis. Note
lysosomal (l) bodies associated with colloid droplets (c) and long
microvilli (arrow) on surfaces bordering colloid. Profiles of rough
endoplasmic reticulum (ER) are dilated by finely granular mate-
rial. Transmission electron micrograph.
P
Figure 3-79  Multinodular follicular cell hyperplasia and adeno-
mas in both thyroid lobes from a cat with hyperthyroidism. P,
parathyroid gland with mild hyperplasia. Bar = 5 mm.
Cats with hyperthyroidism usually have markedly elevated
serum thyroxine and triiodothyronine levels. Normal feline
serum levels of T4 measured by radioimmunoassay are
19-64 nmol/L (~1.5-5.0 µg/dL), and serum T3 levels are
0.9-3.1 nmol/L (60-200 ng/dL). The serum T4 levels in cats
with hyperthyroidism range from 64-640 nmol/L (5.0 to >50
µg/dL), and serum T3 levels range from 1.5-150 nmol/L (100-
1,000 ng/dL). Moderately increased liver-derived serum
enzyme levels, including aspartate aminotransferase (AST
[SGOT]), alanine aminotransferase (ALT [SGPT]), and espe-
cially alkaline phosphatase, occur in hyperthyroid cats.
The likelihood of developing clinical hyperthyroidism asso-
ciated with thyroid neoplasms in animals depends upon (1)
the capability of tumor cells to synthesize T4 and T3, and (2)
the degree of elevation of circulating levels of T4 and T3. For
example, dogs have a much more efficient enterohepatic excretory
mechanism for thyroid hormones than cats and infrequently have
clinical signs associated with functional thyroid tumors. Cats are
very sensitive to phenol and phenol derivatives, and have a
 Thyroid Gland
Figure 3-80  Chief cell hypertrophy and hyperplasia of the para-
thyroid gland from a cat with hyperthyroidism. Note the abun-
dant and partially vacuolated cytoplasm of the chief cells, which
is an indication of increased synthesis and secretion of parathyroid
hormone.
poor ability to conjugate phenolic compounds (such as T4)
with glucuronic acid and excrete the T4-glucuronide into the
bile. The capacity of conjugation of T3 with sulfate is limited
and easily overloaded. Therefore cats with relatively small func-
tional proliferative lesions of thyroid follicular cells often have
marked elevations in circulating levels of T4 and T3, with clinical
signs of hyperthyroidism, whereas dogs with functional thyroid
tumors have only slight elevations of serum T4 and T3 and less
frequently develop clinical hyperthyroidism.
Hyperthyroid cats often have disturbances of calcium homeo-
stasis and diffuse chief cell hypertrophy and hyperplasia in the
parathyroid glands (Fig. 3-80). Compared to reference inter-
vals, blood ionized (not total) calcium and plasma creatinine
concentrations often are significantly decreased, and plasma
phosphate and intact parathyroid hormone levels are increased.
Hyperparathyroidism occurred in 77% of hyperthyroid cats,
with parathyroid hormone levels elevated up to 19 times the
upper limit of the reference range. Hyperphosphatemia was
present in ~40% of hyperthyroid cats. The mechanisms for the
development of hyperphosphatemia in feline hyperthyroid-
ism are uncertain but may be related, in part, to polyphagia
with increased intestinal phosphate absorption, increased
catabolism of muscle proteins and release of phosphate
because of the gluconeogenic effects of the elevated thyroid
hormone levels, and increased bone resorption with release of
phosphate into the blood. Although the total calcium usually
is within the reference interval, the serum ionized calcium is
reduced in ~50% of cases. These findings suggest that hyper-
thyroid cats have altered bone metabolism; however, the bone
disease usually is not clinically significant in adult-to-aged cats
with hyperthyroidism.
Surgical excision of affected thyroid lobe(s), medical man-
agement by thyroid blocking drugs (e.g., methimazole, pro-
pylthiouracil), and radioactive iodine are effective treatments
available for cats with hyperthyroidism. Low iodide diets have
also been developed to treat hyperthyroidism. Bilateral thy-
roidectomy is necessary if both glands are abnormal in appear-
ance at surgery. At least one parathyroid gland should be left
with an intact blood supply if bilateral thyroidectomy is
329
performed. A thyroid-blocking agent, such as methimazole or
propylthiouracil, can be used before surgery to alleviate some
of the severe clinical effects (e.g., tachycardia, cardiomegaly)
of hyperthyroidism.
Follicular cell carcinoma
Thyroid carcinomas are palpable masses in the ventral cervical
region, and they may be unilateral or bilateral. Most thyroid
tumors are palpated near the larynx, but larger ones may
extend toward the thoracic inlet. The tumor may be firm or
soft. Respiratory distress occurs if the tumor encroaches upon
the larynx or trachea. Carcinomas become fixed in position
by extensive local invasion of adjacent structures, whereas
adenomas are freely movable under the skin.
In dogs, thyroid carcinomas occur more often than adenomas,
but in cats, carcinomas are uncommon to rare. No sex preva-
lence has been observed in dogs. Beagles, Boxers, Siberian
huskies, and Golden Retrievers have a significantly greater risk
for thyroid carcinoma than other breeds of dogs.
Adenocarcinomas of the thyroid are larger than adenomas,
are coarsely multinodular, and often have large central areas
of hemorrhage and necrosis. Unilateral involvement is about
twice as frequent in dogs as is involvement of both thyroid
lobes. Early carcinomas are often well demarcated with inva-
sion into the capsule and capsular vessels, but are amenable
to complete surgical excision (Fig. 3-81A-C). Later carcino-
mas with vascular invasion form large tumor cell thrombi (Fig.
3-82A, B) into branches of the cranial and caudal thyroid veins
with development of multiple pulmonary metastases, often
before involvement of the retropharyngeal and caudal cervical
lymph nodes. Advanced carcinomas may be poorly encapsu-
lated and invade locally into the wall of the trachea, cervical
muscles, esophagus, larynx, nerves, and vessels. Focal white
gritty areas of mineralization or bone formation are scattered
throughout some tumors (see Fig. 3-82B). Although carcino-
mas derived from follicular cells usually arise in the neck from
the thyroid lobes, they may develop from ectopic thyroid paren-
chyma in the mediastinum and must be included in the dif-
ferential diagnosis of “heart-base tumors” in dogs. Follicular
thyroid carcinomas also develop in the base of the tongue in
dogs and have a good prognosis with complete surgical
removal.
Malignant tumors of thyroid follicular cells are more highly
cellular and have a greater degree of cellular pleomorphism
than adenomas. On the basis of the predominant histologic
pattern of growth, differentiated thyroid adenocarcinomas are
subdivided into follicular, papillary, and compact cellular (solid)
types. In dogs, thyroid carcinomas usually have both a follicular
and compact cellular growth pattern, whereas papillary carci-
nomas are uncommon.
Follicular-compact cellular carcinoma is the most common
type of malignant thyroid tumor in dogs, having approximately
equal follicular and compact cellular growth patterns (see Fig.
3-81A, B). The follicles formed are variable in size and may
be smaller and contain little colloid, or they may be larger and
cystic. The tumor cells arranged in compact or solid areas
appear to be morphologically and functionally less differenti-
ated than those that form follicles and secrete colloid. Hemor-
rhage may occur into the follicles and cause their distention
with erythrocytes or plasma (see Fig. 3-81C).
In follicular adenocarcinomas, the majority of tumor cells
are arranged in a recognizable follicular pattern. It is possible to
subdivide follicular carcinomas further on the basis of size of
330 CHAPTER 3  •  Endocrine Glands
A
B
C (Fig. 3-83B).
Figure 3-81  Compact and follicular thyroid carcinoma in a dog.
A. Early invasion into capsular vessel (arrowhead). B. The carci-
noma is composed of solid regions and small to large neoplastic
follicles. C. Hemorrhage often occurs into and distends neoplastic
follicles.
follicles, as described for follicular adenomas, but this often is
difficult because of the admixture of growth patterns present
in any one tumor. Such subdivisions appear to be of little
prognostic value in animals with thyroid cancer. The tumor
cells are tall cuboidal to columnar, and form follicles of vari-
able size, shape, and colloid content. Mitotic activity in the
tumor cells is minimal. The colloid in follicular lumina occa-
sionally is clumped and extensively mineralized.
Thyroid Gland
A
B
Figure 3-82  Thyroid follicular carcinoma in a dog with invasion
in thyroid veins. A. Note the distention of the thyroid veins by
tumor emboli growing into and down the veins (arrows). Bar =
1 cm. B. Growth of a follicular cell carcinoma tumor embolus in
a distended vein. L, lumen of the vein.
In compact cellular carcinoma, tumor cells form aggrega-
tions or solid sheets of cells often separated by fibrous stroma
with little or no attempt at follicle formation and colloid
secretion (Fig. 3-83A). The polyhedral cells are closely apposed
and have eosinophilic cytoplasm that is finely granulated or
vacuolated. It may be challenging to differentiate compact
cellular carcinomas from C-cell carcinomas. Immunohisto-
chemistry can be used to stain the neoplastic cells for thyro-
globulin to confirm their origin from thyroid follicular cells
Papillary carcinomas in which tumor cells form papillae
extending into cystic spaces are uncommon in animals. Single
or multiple layers of cuboidal cells surround fibrovascular
stalks that project into cystic spaces. Their nuclei are vesicular
and pleomorphic with prominent nucleoli. The nuclear vacu-
oles seen by light microscopy have been shown to represent
cytoplasmic invaginations. Infiltration of tumor cells through
the fibrous connective tissue capsule and into adjacent tissues
may occur in thyroid adenocarcinomas.
Undifferentiated (anaplastic) thyroid carcinomas lack a
characteristic architectural pattern of arrangement of tumor cells.
They are an uncommon form of thyroid carcinoma in animals.
Small-cell carcinoma is one type of undifferentiated thyroid
carcinoma. They are composed of highly malignant follicular
cells with either a diffuse or compact pattern of growth. The
small tumor cells are uniform in appearance and are closely
 Thyroid Gland
B
Figure 3-83  Compact thyroid follicular carcinoma. A. Neoplastic
cells form solid sheets of cells separated by fibrous stroma. B.
Immunohistochemistry for thyroglobulin can be used to confirm
the diagnosis of compact follicular carcinoma.
packed within clusters separated by fibrous stroma. The scant
cytoplasm is eosinophilic, and the oval nucleus is densely
hyperchromatic. Mitotic figures are frequent.
Giant cell carcinoma is a highly malignant thyroid tumor
derived from poorly differentiated follicular cells. The anaplas-
tic tumor cells are large, pleomorphic, and often spindle shaped,
making differentiation from a fibrosarcoma difficult. Syncytial
cells may be prominent in some area of the carcinoma (Fig. 3-84).
The demonstration of identifiable epithelial structures may
require multiple sections from several areas of the tumor. Fol-
licular remnants of transitional forms suggest that giant cell
carcinomas are derived from thyroid follicular cells.
Malignant mixed thyroid tumors have been reported in the
dog. The tumors contain both malignant thyroid follicular
cells and mesenchymal elements, usually osteogenic or carti-
laginous (Fig. 3-85).
Thyroid carcinomas often grow rapidly, invading adjacent
structures, such as the trachea, esophagus, and larynx, and
usually are fixed in position. The earliest and most frequent site
of metastasis is the lung, because thyroid carcinomas tend to
invade branches of the thyroid vein. Tumor cords may be
palpated in the thyroid or jugular veins in some animals with
thyroid carcinoma. The retropharyngeal and caudal cervical
lymph nodes are less frequent sites of metastasis. Thyroid
331
Figure 3-84  Anaplastic giant cell thyroid carcinoma from a dog.
The neoplastic cells are poorly differentiated, somewhat spindle
shaped, and form large syncytial cells.
Figure 3-85  Malignant mixed thyroid carcinoma from a dog.
There are poorly differentiated thyroid follicular cells with 
formation of neoplastic bone with osteoid (O), osteoblasts, and
osteocytes.
carcinomas infrequently metastasize to bone and may be asso-
ciated with hypercalcemia.
Some thyroid tumors in the dog secrete sufficient thyroid
hormone to produce mild clinical signs of hyperthyroidism. It
is surprising that hyperthyroidism occurs even with functional
tumors because experimental induction of hyperthyroidism in
the dog requires daily administration of ~25 times the normal
replacement dose of desiccated thyroid or L-thyroxine. The
clinical signs of hyperthyroidism in dogs with functional
thyroid tumors include weight loss, polyphagia, polyuria, poly-
dipsia, weakness and fatigue with exercise, intolerance to heat,
and nervousness.
Thyroid carcinomas occur much less frequently in cats
than either adenomas or multinodular hyperplasia. They often
result in considerable enlargement of one or both thyroid
lobes and may invade adjacent structures. Thyroid carcinomas
are characterized by neoplastic invasion of vessels and connec-
tive tissue capsule. Metastases to regional lymph nodes (ret-
ropharyngeal, mandibular, deep cervical) and distant sites have
been reported infrequently in thyroid carcinomas of cats. The
well-differentiated thyroid adenocarcinomas are composed of
332 CHAPTER 3  •  Endocrine Glands
a uniform pattern of small follicles containing variable amounts
of colloid. Strands of dense connective tissue with an abun-
dant capillary network and foci of lymphocytes subdivide the
neoplastic cells into small lobules.
Thyroid carcinogenesis and radiation. Epidemiologic
investigations in humans and animal studies have indicated
that the risk of developing thyroid cancer is increased follow-
ing exposure to external (localized) X-rays (especially to the
cervical region) or to internal 131I irradiation.
Neoplasms of thyroglossal duct remnants
Tumors arising in cystic remnants of the thyroglossal duct are
rare in animals but have been reported in dogs. They appear
as well-circumscribed, fluctuant, movable enlargements
(2-4 cm diameter) on the ventral midline in the cranial cervi-
cal region. The clinical history usually indicates a slowly pro-
gressive expansion of the cervical mass. On cross-section,
multilocular cystic areas containing translucent proteinaceous
fluid alternate with white solid areas. The thyroid glands
appear to be normal in the few cases studied in dogs. These
tumors appear to develop from the epithelium of the thyro-
glossal duct and are not a cystic metastasis from a primary
carcinoma in the thyroid gland.
Neoplasms of thyroglossal duct remnants are well-differentiated
papillary carcinomas. Multiple papillary outgrowths covered
by multiple layers of tall cuboidal to columnar epithelial cells
extend from the cyst wall into the lumen (Fig. 3-86). The cyst
wall is composed of dense fibrous connective tissue with focal
areas of hemorrhage and cholesterol clefts. Aggregations of
thyroidogenic epithelium in the form of small follicles and cell
cords are present within the fibrous capsule and in surround-
ing connective tissue. These follicles are lined by low cuboidal
epithelium and contain variable amounts of colloid. Carcino-
mas of thyroglossal duct remnants appear to be well differen-
tiated and slow growing, with limited evidence of local tissue
invasion.
Thyroid C-cell (parafollicular) tumors
Tumors derived from C cells (parafollicular cells) of the
thyroid gland are most frequently encountered in adult-to-
aged bulls (ultimobranchial body origin), certain strains of
laboratory rats, adult-to-aged horses, but infrequently in dogs
and other species. A high percentage of aged bulls have been
Figure 3-86  Papillary cystadenocarcinoma derived from thyro-
glossal duct remnants in a dog. Note the normal thyroid follicles
in the wall of the neoplasm derived from the persistent thyroglos-
sal duct.
Thyroid Gland
reported to develop C-cell tumors (30%) or hyperplasia of C
cells and ultimobranchial derivatives (15-20%) when they
were fed diets with a high calcium content similar to that fed
to cows. These frequently occurring hyperplastic and neoplastic
lesions of C cells have been observed only in bulls and not in
cows. The incidence of C-cell tumors increases with advancing
age in bulls.
The syndrome of C-cell tumors in bulls shares many simi-
larities with medullary thyroid carcinoma in humans. Multiple
endocrine tumors, especially bilateral pheochromocytomas and
occasionally pituitary adenomas, are detected coincidentally
in bulls and human patients with C-cell tumors. This may
represent a simultaneous neoplastic transformation of multi-
ple endocrine cell populations of neural crest origin in the
same individual. A high frequency of thyroid C-cell tumors
and pheochromocytomas has been reported in a family of
Guernsey bulls, suggesting an autosomal dominant pattern of
inheritance. Diffuse or nodular hyperplasia of secretory cells
in the adrenal medulla appears to precede the development
of pheochromocytoma.
The calcitonin-producing C cells were described initially
in dogs as light or gray cells and are particularly prominent in
this species. Nodular aggregations of C cells (C-cell clusters)
in dogs are present either near the thyroid hilus in the peri-
thyroidal connective tissues, or within the thyroid lobes along
the course of the major branches of the thyroid artery. The
ultimobranchial body (last, usually fifth pharyngeal pouch)
that delivers the neural crest–derived C cells to the postnatal
thyroid gland fuses with each thyroid lobe at the hilus and
distributes C cells throughout each lobe to various degrees in
different species. In the dog, nodular aggregations of C cells
frequently persist along the course of the major vessels to the
thyroid; therefore C-cell hyperplasia in dogs should be diagnosed
only when there is a definite increase in C-cell numbers through-
out each thyroid lobe compared to age-matched controls. Both
thyroid lobes should be sectioned longitudinally in a consis-
tent manner for microscopic evaluation. This will minimize
the prominent regional differences of C cells in the thyroid
glands of normal dogs, which can result in the overinterpreta-
tion of these focal aggregations of C cells as a significant lesion.
The C cells in the focal aggregations have abundant, lightly
eosinophilic, finely granular, cytoplasm and a spherical-oval
nucleus. There are occasional ultimobranchial-derived, colloid-
containing follicles lined by more basophilic cells within the
focal accumulations of C cells along the course of vessels
within the thyroid lobe or in the connective tissues of the
thyroid hilus in dogs.
Focal (nodular) hyperplasia of C cells often precedes the
development of C-cell neoplasms in animal and humans. The
histologic distinction between focal hyperplasia and adenoma of
C cells often is difficult and somewhat arbitrary. The diagnosis
of C-cell hyperplasia refers to a focal or diffuse increase of C
cells between thyroid follicles and/or within the follicular
basement membrane. Focal C-cell hyperplasia is a preneoplas-
tic change that occurs sporadically and may be increased in
animals with chronic hypercalcemia. Diffuse C-cell hyperpla-
sia is a physiologic response to chronic hypercalcemia (Fig.
3-87A, B). The C cells appear normal, with abundant, lightly
eosinophilic, granular cytoplasm and a round-to-oval nucleus
with finely stippled chromatin. Cell boundaries often are
indistinct. Focal hyperplasia of C cells forms a nodule with 
an approximate diameter equal to or <5 average colloid-
containing thyroid follicles with minimal evidence of
 Thyroid Gland
A amyloid deposits may be found both in nodular hyperplasia
B vesicular nuclei are oval or elongate and have more frequent
Figure 3-87  C-cell hyperplasia in a dog with chronic humoral
hypercalcemia of malignancy. A. The hyperplastic C cells are
present in the thyroid follicles or between the follicles and have
characteristic amphophilic cytoplasm. B. The hyperplastic C cells
stain immunohistochemically positive for calcitonin. Note that
most C cells have light staining for calcitonin because of stimula-
tion of secretion by hypercalcemia. Scattered C cells have intense
cytoplasmic staining for calcitonin because they have more
numerous cytoplasmic storage granules similar to unstimulated  The etiology of the localized amyloid deposition in thyroid
C cells.
compression of adjacent follicles (guidelines for rat thyroids).
Hyperplastic C cells within the basement membrane may
compress individual thyroid follicles. Calcitonin immunoreac-
tivity is localized to the cytoplasm of hyperplastic C cells.
C-cell adenomas appear as discrete, single or multiple, gray
to tan nodules in one or both thyroid lobes (Fig. 3-88A, B).
Adenomas are smaller than carcinomas, and are separated
from the thyroid parenchyma by a thin, partial to complete,
fibrous connective tissue capsule. The adjacent thyroid is com-
pressed but not invaded by neoplastic C cells. In horses, C-cell
adenomas may result in a palpable enlargement in the cranial
cervical region. Larger C-cell adenomas incorporate most of
the thyroid lobe, but a rim of dark brown-red thyroid often is
present on one side. C-cell adenomas may be subdivided into
packets of cells by fine or coarse connective tissue septa and
capillaries (neuroendocrine pattern). The neoplastic C cells
are well differentiated and have abundant cytoplasm that is
lightly eosinophilic, amphophilic, or clear. The adenomas
usually contain multiple entrapped thyroid follicles, and should
333
not be interpreted as a thyroid follicular adenoma (Fig. 3-88C,
D). The follicular cells of entrapped follicles may be eventu-
ally replaced by C cells, but the colloid usually remains. Areas
of subendothelial growth of neoplastic C cells should not be
overinterpreted as vascular invasion and evidence of malig-
nancy. The well-differentiated cells comprising C-cell adeno-
mas have numerous membrane-limited secretory granules and
stain immunohistochemically positive for calcitonin (see 
Fig. 3-88D). Some C-cell adenomas are composed of larger
cells with amphophilic cytoplasm, large nuclei with coarsely
clumped chromatin, and prominent nucleoli. These cells bear
a histologic resemblance to ganglion cells and the potential of
primitive neuroectodermal cells that give rise to the adrenal
medulla to differentiate into either sympathetic ganglion 
cells or catecholamine-secreting endocrine cells. Occasional
and in adenomas.
Thyroid C-cell carcinomas result in more extensive multi-
nodular enlargements of one or both thyroid lobes. The pro-
liferating neoplastic tissue may incorporate the entire thyroid
gland. Multiple metastases in cranial cervical lymph nodes
may be large and have areas of necrosis and hemorrhage.
Pulmonary metastases are present infrequently and appear as
discrete tan nodules throughout all lobes of the lung. C-cell
carcinomas are more highly cellular, and the tumor cells are
more pleomorphic than are C-cell adenomas (Fig. 3-89A, B).
They often have evidence of intrathyroidal and/or extracap-
sular invasion, occasionally with metastasis to distant sites. The
neoplastic cells are polyhedral to spindle shaped with lightly
eosinophilic to amphophilic, finely granular cytoplasm. The
mitotic figures than do adenomas. Malignant C cells often are
subdivided into small groups by fine connective tissue septa
that contain small capillaries.
Thyroid C-cell tumors in bulls, other animals and humans
often are firm, and in some areas the stroma consists of dense
bands of fibrous connective tissue. In both adenomas and
carcinomas, there may be deposits of homogeneous eosino-
philic material that stains positively for amyloid and are
observed between the bundles of collagen fibers (Fig. 3-89C).
C-cell neoplasms is uncertain, but it is not associated with
chronic suppurative lesions in other organs, and the protein
likely originates from the neoplastic C cells.
Bioassay of C-cell adenomas and carcinomas from bulls has
demonstrated the presence of calcitonin in tumor tissue, and
calcitonin has been detected at higher than normal levels in
plasma of bulls by immunoassay. Calcium infusion to raise
serum calcium increases plasma calcitonin. Mean serum
calcium levels in bulls with calcitonin-secreting C-cell tumors
are normal or only slightly lower than in adult control bulls.
The near-normal serum calcium in animals with chronic
hypersecretion of calcitonin probably is a result of the low
turnover rate of bone and the expected downregulation of
calcitonin receptors on osteoclasts chronically exposed to
increased serum concentration of calcitonin.
The etiology of C-cells neoplasms is unknown, but chronic
hypercalcemia predisposes to both diffuse and focal C-cell
hyperplasia and eventual progression to C-cell adenoma 
and carcinoma. C-cell tumors are occasionally seen in dogs
with chronic humoral hypercalcemia of malignancy. A rela-
tionship has been suggested between the long-term dietary
intake of excessive calcium and the high incidence of these
334 CHAPTER 3  •  Endocrine Glands Thyroid Gland

A B

C D
Figure 3-88  Multinodular C-cell adenoma in a horse. A. The adenoma has multiple nodules that
compress the adjacent thyroid parenchyma and are surrounded by a fibrous capsule. Bar = 1 cm.
B. The adenoma is well demarcated and compresses adjacent thyroid follicles. C. The neoplastic
C cells are well differentiated and have abundant cytoplasm that is lightly eosinophilic or ampho-
philic. Note the multiple entrapped thyroid follicles that contain homogeneous or vacuolated
colloid present in the C-cell adenoma. D. Calcitonin immunohistochemistry demonstrates the
neoplastic C cells. Note that the follicular epithelial cells of the entrapped follicles are negative
for calcitonin.

tumors in bulls (Fig. 3-90A, B). Depending upon the feeding
regimen, adult bulls may ingest 3.5-6.0 times the amount of
calcium normally recommended for maintenance. The chronic
stimulation of C cells by high levels of calcium absorbed from the
digestive tract is related to the pathogenesis of C-cell neoplasms.
A significant decline in the incidence of C-cell tumors occurs
when bulls are switched from a high-calcium intake to a
reduced-calcium intake. Cows do not develop proliferative
lesions of C cells under similar dietary conditions, possibly
because of the high physiologic requirements for calcium
imposed by pregnancy and lactation. Familial or sporadic acti-
vation (gain-of-function) of the RET tyrosine kinase proto-
oncogene is important in humans with C-cell (medullary)
carcinoma or multiple endocrine neoplasia (involving both C
cells and chromaffin cells of the adrenal) and may play a role
in animals.
Ultimobranchial tumors in the thyroid glands of bulls
often have a more complex histologic structure than the
typical C-cell (medullary) neoplasms in human patients,
horses, dogs, and certain strains of laboratory rats. Focal areas
in the tumor are composed of more differentiated C cells  patients. This variant, designated as an intermediate type of
that have abundant lightly eosinophilic cytoplasm and are
located either in the wall of thyroid and ultimobranchial fol-
licles or as larger nodules with a solid histologic structure (Fig.
3-90C). This often is accompanied by multifocal hyperplasia
of C cells in other parts of the thyroid lobes and hilus. The
neoplastic C cells often are embedded in an increased amount
of hyalinized stroma that may contain amyloid. Other areas
of this unique thyroid neoplasm in bulls appear to be derived
from less differentiated ultimobranchial remnants and consist
of follicle-like structures, cysts, and tubules composed of
immature small basophilic cells. They closely resemble undif-
ferentiated or stem cells of the normal ultimobranchial body
in bulls and other species that have the potential to differenti-
ate into both C and follicular cells. Thyroid follicles and crib-
riform structures with colloid-like material formed by cells
resembling differentiated follicular cells often are present 
in the neoplasms in close association with these more primi-
tive ultimobranchial-derived structures. The heterogeneous 
histologic structure of ultimobranchial neoplasms in bulls
resembles an unusual type of thyroid carcinoma of human
 Thyroid Gland 335

B
B

C
Figure 3-89  C-cell carcinoma in a dog. A. The neoplastic cells
are polyhedral with amphophilic, finely granular cytoplasm, and C
are separated by bands of fibrous stroma. Note the 2 residual
Figure 3-90  C-cell carcinoma in a bull. A. Enlargement of the
thyroid follicles. Most of the follicular epithelial cells have been
ventral neck because of C-cell carcinoma in the thyroid gland and
replaced by C cells, but the colloid remains. B. Immunohisto-
metastasis to multiple cervical lymph nodes (arrowheads). 
chemistry for calcitonin reveals variable cytoplasmic staining for
B. C-cell carcinoma metastases to multiple cervical lymph nodes.
calcitonin. The lightly stained C cells secrete calcitonin in an
C. Neuroendocrine pattern of malignant C-cells with the forma-
unregulated manner, so they have little stored cytoplasmic calci-
tion of elongated cells with eosinophilic cytoplasm and nuclear
tonin. C. Homogeneous amyloid deposits may be seen between
palisading.
neoplastic cells in some C-cell carcinomas.
336 CHAPTER 3  •  Endocrine Glands
differentiated thyroid carcinoma, has structural and immuno-
histochemical characteristics of both medullary (C-cell) and
follicular carcinomas.
Further reading
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Campos M, et al. Immunohistochemical expression of potential
therapeutic targets in canine thyroid carcinoma. J Vet Intern Med
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Capen CC. Toxic responses of the endocrine system. In: Klaassen CD,
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Gaskill CL, et al. Changes in serum thyroxine and thyroid-stimulating
hormone concentrations in epileptic dogs receiving phenobarbital
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Hilderbran AC, et al. Nonthyroidal illness syndrome in adult horses. J
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Mooney CT. Canine hypothyroidism: a review of aetiology and diag-
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Ozmen O, Haligur M. Immunohistochemical observations on TSH
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J Vet Med A 2005;52:454-459.
Peeters ME, et al. Feline thyroid adenomas are in part associated with
mutations in the G(s alpha) gene and not with polymorphisms
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Ramos-Vara JA, et al. Immunohistochemical detection of thyroid tran-
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487.
Rosol TJ, et al. Endocrine System. In: Haschek WM, et al., editors.
Haschek and Rousseaux’s Handbook of Toxicologic Pathology.
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ADRENAL CORTEX
Development, structure, and function
Embryonic development of the adrenal gland
The adrenal glands of mammals consist of 2 distinct parts that
differ not only in morphology and function but also in origin.
Because of their close structural relationships, the outer cortex
and inner medulla of the adrenal gland usually have been
considered parts of one organ (Fig. 3-91). The adrenal cortex
Adrenal Cortex
Figure 3-91  Normal adrenal glands (top = right; bottom = left)
from a dog. The cortex is paler compared to the medulla because
of the presence of cytoplasmic lipid vacuoles. The cortical to
medullary ratio is approximately 1 : 1-2 : 1, depending on the area
of sectioning. The red areas are cortical congestion.
develops from cells of the celomic epithelium that are of
mesodermal origin and are related developmentally, anatomi-
cally, and physiologically with steroid-producing cells of 
the gonads. The coelomic epithelium transcription factors,
GATA-6 and GATA-4, direct differentiation of the steroid-
producing cells of the adrenal and ovaries, respectively. The
chromaffin tissue and sympathetic ganglion cells of the adrenal
medulla are derived from ectoderm of the neural crest. It is
not until relatively late in fetal development that a definitive
relationship between the 2 primordia occurs.
Structure of the adrenal gland
The adrenal glands are covered by a thin fibrous capsule and
are richly vascularized, receiving arterial branches either
directly from the aorta or from the phrenic, renal, and lumbar
arteries. The arteries form a vascular plexus in the capsule that
eventually supplies the entire adrenal gland through separate
channels to the capsule, cortex, and medulla. A sinusoidal
network is formed about the cell columns of the adrenal
cortex that empties into the venous tree at the periphery of
the medulla. The larger branches of the venous tree empty
into the adrenal vein.
The adrenal cortex classically is subdivided into 3 layers or
zones, although the demarcation between zones often is not
distinct.
• The zona glomerulosa (multiformis, arcuata) is composed
of columns of cells that have a sigmoid arrangement 
next to the capsule. It represents ~15% of the cortex 
and is responsible for the secretion of mineralocorticoid
hormones.
• The secretory cells of the zona fasciculata are arranged in
long anastomosing cords separated by numerous small cap-
illaries. This middle zone, which comprises ~70% of the
cortex, is composed of cells that contain abundant cyto-
plasmic lipid and are responsible for the secretion of the
glucocorticoid hormones.
• The zona reticularis accounts for the remaining 15% of the
cortex. The secretory cells are arranged in small groups
surrounded by capillaries. This inner layer is responsible for

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 Adrenal Cortex
the secretion of sex steroids by the adrenal gland. Cortical
cells may project for a short distance into the medulla.
Growth and replacement of adrenocortical cells follows a
distinct pattern of cell differentiation, proliferation, and migra-
tion. Adrenocortical stem cells (Sf1−, Gli1+) reside in the
adrenal capsule and migrate to the zona glomerulosa to form
small nests of proliferative progenitor cells (Sf1+). The pro-
genitor cells replace the both the zona glomerulosa and fas-
ciculata cells (Sf1+). As the zona fasciculata cells age, they
migrate centrally down the cords of the adrenal cortex and
eventually differentiate into reticularis cells. Cortical cells con-
tinue to migrate toward the cortical-medullary junction and
undergo apoptosis at that location. This is why pigment-laden
macrophages are often found at the cortical-medullary junc-
tion in older animals. The process of adrenocortical cell pro-
liferation and migration can be followed by in vivo labeling of
DNA synthesis, such as with bromodeoxyuridine (BrdU).
Biosynthesis and action of adrenal cortical hormones
Mineralocorticoids are adrenal steroids that have their principal
effects on ion transport by epithelial cells, resulting in a loss of
potassium and conservation of sodium. The most potent and
important naturally occurring mineralocorticoid is aldoste-
rone. The enzymatically controlled electrolyte “pumps” in
epithelial cells of the renal tubule and sweat glands respond
to mineralocorticoids by conserving sodium and chloride and
by excreting potassium. In the distal convoluted tubule of the
mammalian nephron, a cation exchange mechanism exists for
the resorption of sodium from the glomerular filtrate and
secretion of potassium into the lumen. These reactions are
accelerated by mineralocorticoids and proceed at a slower rate
in their absence. A lack of secretion of mineralocorticoids
(such as in idiopathic adrenal atrophy of dogs) may result in
a lethal retention of potassium and loss of sodium.
Glucocorticoid hormones secreted by the adrenal cortex
are involved with the intermediary metabolism of glucose.
Cortisol and lesser amounts of corticosterone are the most
important naturally occurring glucocorticoids secreted by the
adrenal gland in domestic animals. In general, the actions of
glucocorticoids on carbohydrate, protein, and lipid metabolism
result in sparing of glucose and a tendency to hyperglycemia and
increased glucose production. The acute effects of glucocorti-
coids are observed 15-30 minutes before the compensatory
effects of insulin become prominent. There is a decrease in
glucose uptake in adipose tissue, skin, fibroblasts, and lym-
phoid tissue, followed shortly by increased catabolism in these
tissues and muscle. This provides amino acids for gluconeo-
genesis, which is increased mainly in the liver. In addition,
glucocorticoids decrease lipogenesis and increase lipolysis in
adipose tissue, which results in release of glycerol and free
fatty acids.
Glucocorticoids also function to suppress inflammatory and
immunologic responses and thereby attenuate the associated
tissue destruction and fibroplasia. However, under the influ-
ence of high levels of glucocorticoids, there is enhancement
of the spread of infections and reduced resistance to a number
of bacterial, viral, and fungal diseases. Glucocorticoids may
impair the immunologic response at any stage from the initial
interaction and processing of antigens through the induction
and proliferation of immunocompetent lymphocytes and sub-
sequent antibody production. Inhibition of a number of lym-
phoid cell functions by glucocorticoids forms part of the basis
for suppression of the immunologic response.
337
Glucocorticoids also decrease the initial inflammatory reac-
tion and its classic manifestations of heat, swelling, and pain.
The degree of hyperemia, extravasation, cellular migration,
and infiltration at the site of injury is decreased. Especially
important are the effects of glucocorticoids on the vascular
responses of increased permeability, diapedesis, and extravasa-
tion. Capillary blood flow is decreased, and there is less endo-
thelial swelling. In addition, a number of phagocytic mechanisms
are inhibited by glucocorticoids, and clearance of particulate
substances from the blood and lymph is impaired. The accu-
mulation of engulfed antigens in macrophages probably is
related to the enhanced stability of lysosomal membranes caused
by glucocorticoids. There is a diminished capacity of lyso-
somes to interact with phagocytized material and release
hydrolytic enzymes.
Glucocorticoids exert a negative effect on wound healing.
Dogs receiving high therapeutic levels of adrenal corticoste-
roids or animal patients with hyperadrenocorticism may have
wound dehiscence following surgery. The basis mechanism
involved is inhibition of fibroblast proliferation and collagen
synthesis, leading to a decrease in scar tissue formation.
Secretion of adrenal sex hormones by cells of the zona
reticularis occurs under normal conditions but in minute
amounts that probably are of minor physiologic significance.
Secretory cells of the inner zone of the cortex synthesize
progesterone, estrogens, and androgens. Under pathologic con-
ditions, excessive secretion of adrenal sex steroids infrequently
may occur associated with an adrenocortical neoplasm. The
clinical manifestations of virilism, precocious sexual develop-
ment, or feminization depend upon which steroid is secreted
in excess, the sex of the patient, and the age of onset.
The renin-angiotensin system is the major regulator of
aldosterone production by the zona glomerulosa of the adrenal
cortex. Renin is an enzyme secreted into the circulation by
cells of the juxtaglomerular apparatus in the kidney. It acts to
cleave the plasma globulin angiotensinogen, to form angioten-
sin I. This decapeptide is further hydrolyzed to angiotensin II
by a converting enzyme. Angiotensin II is both a potent vaso-
constrictor and a trophic hormone for the zona glomerulosa
of the adrenal cortex, resulting in the synthesis and secretion
of aldosterone. It is a very labile peptide that is quickly inac-
tivated in plasma and tissues by angiotensinases.
A number of factors regulate renin secretion by the kidney.
The “short loop” of negative feedback control is the direct
inhibition exerted by circulating angiotensin II. The “long
loop” is exerted by an indirect feedback inhibition by aldoste-
rone on renin secretion. Renin release and eventually aldoste-
rone secretion are increased by conditions that compromise
blood flow and pressure to the kidney, severe dehydration that
results in decreased intravascular blood volume, and sodium
depletion.
Adrenocorticotropin (ACTH) secreted by the adenohy-
pophysis is the principal regulator of adrenal cortical growth
and secretory activity, particularly of cells in the zonae fascicu-
lata and reticularis. The adrenal cortex secretes physiologic
quantities of cortisol only in response to ACTH stimulation.
The zona glomerulosa (and its secretion of aldosterone) is
responsive to ACTH, but at a lower level compared to the
zonae fasciculata and reticularis. ACTH exerts its action on
target cells through the melanocortin 2 receptor and subse-
quent activation of adenylyl cyclase and generation of the
intracellular mediator, 3′,5′-adenosine monophosphate (cyclic
AMP). Cyclic AMP stimulates certain key enzymes (e.g.,
338 CHAPTER 3  •  Endocrine Glands Adrenal Cortex

protein kinases) to initiate the biochemical events leading to

the biosynthesis of corticosteroid hormones.
Control of the secretion of ACTH by the adenohypophysis
is governed by the hypothalamus largely through the secretion
of corticotropin-releasing hormone (CRH). This peptide is
secreted by neurons of the hypothalamus into capillaries that
form the hypothalamic-pituitary portal system and convey CRH
to corticotrophs of the pituitary. CRH acts by stimulating
cAMP formation within ACTH-secreting cells, resulting in the
rapid release of preformed secretory granules containing
ACTH. Arginine-vasopressin produced in neurons of the
hypothalamus may also play a role in regulation of secretion
of ACTH in some species.
A
Negative feedback control of ACTH secretion is exerted pri-
marily by the circulating level of cortisol acting on secretory cells
in the hypothalamus and adenohypophysis. When plasma cor-
tisol levels are elevated beyond the normal physiologic range
(as occurs following exogenous administration or with a
cortisol-producing adrenal tumor), ACTH secretion is sup-
pressed, secretory cells in the zonae fasciculata and reticularis
decrease the rate of synthesis and release of corticosteroid
hormones, and the adrenal cortex undergoes trophic atrophy.
Conversely, when cortisol levels are subnormal, there is
increased release of ACTH from the pituitary gland in an
attempt to increase cortisol secretion and return blood levels
toward normal.
B
Diseases of the adrenal cortex Figure 3-92  Adrenal glands from neonatal cloned calves.
Developmental disturbances of the adrenal cortex A. Normal adrenal gland from a male Japanese Black calf. B.
The adrenal glands are composed of steroid hormone–secreting Adrenal gland dysplasia from a stillborn female Holstein calf with
cells of mesodermal origin and catecholamine hormone– abnormal development and increased body weight. The adrenal
secreting cells of neural crest origin that become associated gland was enlarged with an irregular shape, irregular and inter-
anatomically to various degrees in different animals. The mingled cortical and medullary tissue, nodular hyperplasia of the
development of one component does not depend on the zona glomerulosa, and reduced development of zonae fasciculata
development of the other. and reticularis. (Courtesy M. Sato, National Institute for Animal
Unilateral agenesis of an adrenal gland occurs occasionally Health, Tsukuba, Japan.)
in dogs, most frequently on the left side. Total agenesis of the
adrenal cortex is fatal in all species because of the inability to
produce mineralocorticoids, but the medulla is not essential
for life. Developmental anomalies or diseases that decrease or
prevent the production or release of ACTH from the fetal
pituitary result in hypoplasia or atrophy of the zonae fascicu-
lata and reticularis but not the zona glomerulosa. Adrenal
gland dysplasia has been seen in cloned calves with increased
birth weight that were either stillborn or failed to thrive
because of multiple congenital defects. The adrenal glands of
normal neonatal cloned calves have a typical cortical-medullary
structure (Fig. 3-92A). The adrenal glands of neonatal cloned
calves that were stillborn or failed to thrive were enlarged
with an irregular shape, irregular and intermingled cortical and
medullary tissue, nodular hyperplasia of the zona glomerulosa
with multiple layers of cells, lack of the cord-like structure of
the zona fasciculata, and reduced development of the fascicu- Figure 3-93  Accessory adrenal cortical tissue in a cat, adjacent
lata and reticularis (Fig. 3-92B). The adrenal dysplasia was to the mesosalpinx. All 3 layers of the cortex (zona glomerulosa,
more severe in female calves. fasciculata, and reticularis) are present. No chromaffin or medul-
Accessory adrenal cortical tissue is frequent in many lary cells are present.
species. It may be found in the capsule of adrenal, in the
periadrenal or perirenal adipose tissue, and in the mesorchium Hypoplasia of the adrenal cortex is associated with malde-
or mesovarium. The accessory adrenal tissue does not contain velopment of the hypophysis associated with anencephaly, 
any chromaffin cells, but usually has all 3 layers of the adrenal in some cases of cyclopia, and in hypophyseal aplasia. The
cortex (Fig. 3-93). Accessory adrenocortical tissue is seen fre- adrenal cortices are small and histologically have nests of corti-
quently in the vicinity of the equine testis or ovary. cal cells without distinct zonal development, similar to the
 Adrenal Cortex
Figure 3-94  Adrenal subcapsular cysts from a dog, lined by
simple low cuboidal epithelium and filled with proteinaceous
fluid.
arrangement of the fetal adrenal cortex (see Fig. 3-2). The
adrenal medulla is normal.
Foci of hematopoietic cells are found incidentally in the
adrenal glands and usually are not associated with anemia or
other evidence of bone marrow depression or extramedullary
myelopoiesis. They are observed most commonly in cattle as
round white foci (up to 3-4 mm in diameter) and histologi-
cally are composed predominantly of eosinophils. Foci of lym-
phopoiesis are seen in the cortex of both sheep and cattle and
also may be present in the medulla.
Cysts occur uncommonly in the adrenal cortex. They are
usually located in the subcapsular region and are lined by a
single layer of cuboidal epithelial cells (Fig. 3-94).
Congenital enzyme defects of adrenal
cortical steroidogenesis
Several genetically determined enzyme defects in the adrenal
cortex of humans interfere with the synthesis of certain  cortisol levels in response to an apparent increased secretion
cortical steroids and lead to various degrees of hypoadreno-
corticism. For example, lack of 3-hydroxycorticosteroid dehy-
drogenase activity blocks the synthesis of cortisol, aldosterone,
and adrenal sex steroids. It is uncertain whether any of these
congenital enzyme defects occurs in domestic animals.
Rabbits (III VD/J strain) with a congenital (autosomal
recessive gene) deficiency of cholesterol-20α-hydroxylase in
the adrenal cortex and testis have marked adrenal cortical
hyperplasia and feminization at birth. This is a lethal trait and
results in death soon after birth. The blockage at an early stage
of steroidogenesis in the adrenal cortex interferes with the
ability to synthesize cortisol (and other steroids) and leads  Amyloid deposition begins around the sinusoids in the inner
to marked accumulation of cholesterol in cytoplasmic fat
vacuoles. Marked hyperplasia of the zonae fasciculata and
reticularis occurs in response to the elevated ACTH levels
stimulated by the low blood cortisol. The lack of cholesterol-
20α-hydroxylase in the testis interferes with the synthesis of
androgenic steroids. Inadequate androgen levels during devel-
opment result in failure of virilization of structures derived
from the urogenital sinus and account for the finding of female
external genitalia in ~80% of the rabbits.
Degenerative changes of the adrenal cortex
Swollen and vacuolated cortical cells with mineralization of
the adrenal glands occurs frequently in adult cats (Fig. 3-95).
A 30% incidence has been reported for cats compared with
339
Figure 3-95  Degeneration, necrosis, and mineralization of the
adrenal cortex in an aged cat. The cortical cells are hypertrophied
with small to large vacuoles. There are regions of coagulative
necrosis (N) and mineralization (M).
<6% for dogs. Mineralization also is common in adrenal glands
of monkeys. The cause is unknown. The mineral deposits,
although often bilateral and extensive, usually are not associ-
ated with clinical signs attributable to hypoadrenocorticism.
The mineralized adrenals may be detected at autopsy or
during routine radiographic evaluation of the abdomen.
Extensively mineralized adrenal glands are coarsely nodular,
firm and mottled with multiple yellow-white foci throughout
the cortex and extending into the medulla. They are gritty and
difficult to cut. Histologically, there are large areas of necrosis
with mineral deposition adjacent to areas of nodular regenera-
tive hyperplasia of remaining viable cortical cells. These
hypertrophic cortical cells have abundant lipid in their
expanded cytoplasmic area and maintain near normal blood
of ACTH.
Capsular sclerosis affects the adrenal glands of old cows
often with ovarian follicular cysts. The connective tissue
changes often proceed to collagenous and osseous metaplasia
in old bulls. There may be associated moderate reduction in
the width of the cortex.
Amyloid deposition in the adrenal glands usually involves
the cortex but not the medulla. It occurs in all species and is
regularly part of the syndrome of generalized amyloidosis in
cattle. Affected adrenal cortices often are widened, and the
amyloid deposits may be grossly visible as translucent areas.
portions of the zona fasciculata and often is largely confined
to this zone. Signs of adrenal cortical insufficiency usually do
not develop.
Hemorrhages in the adrenals occur in the newborn of
any species. They are presumed to be due to birth trauma.
Widespread hemorrhage and early degeneration occurs in 
the adrenal cortex as part of the exhaustion phase of the 
“stress response.” It is seen in wild animals that die suddenly
during restraint and horses that die from overexertion (e.g.,
struggling to free themselves from being trapped in a fence).
Toxemia (e.g., intestinal torsion in horses) and septicemia also
may injure the endothelial lining of adrenal sinusoids and
result in extensive cortical hemorrhage (Fig. 3-96) or the
formation of infarcts (Fig. 3-97A). Hemorrhagic adrenal
340 CHAPTER 3  •  Endocrine Glands
Figure 3-96  Severe adrenal cortical hemorrhage in a horse.
A Tuberculosis of the adrenal is encountered mainly in cattle
B sion bodies, necrosis, and hemorrhage in the cortex and
Figure 3-97  Infarction of the adrenal cortex. A. Infarct (arrow-
heads) in the adrenal cortex of a horse with toxemia. B. Dog with
sepsis. Low-power photomicrograph. H&E.
necrosis (Waterhouse-Friderichsen syndrome) is an expression
of disseminated intravascular coagulation in septicemic calves
(see Vol. 3, Cardiovascular system).
Telangiectasis of the adrenal cortex occurs in middle-aged
or older animals as single or multiple dark foci near the cor-
ticomedullary junction. These areas typically are depressed on
cut surfaces. Areas of telangiectasis appear to develop subse-
quent to degeneration and loss of cortical cells and ectasia of
adrenal sinusoids in the area. Persisting parenchymal cells in
these foci either may be hypertrophied and contain much
lipid or be small and atrophic.
Inflammation of the adrenal cortex (adrenalitis)
Infectious and parasitic agents frequently localize in the
adrenal gland and elicit various degrees of inflammation and
necrosis. The high local concentration of anti-inflammatory
Adrenal Cortex
Figure 3-98  Multifocal granulomatous adrenalitis in a dog. The
cortices are atrophied with multiple mineralized granulomas. 
Bar = 5 mm.
steroids in the adrenal cortex suppresses local cell-mediated
immunity and permits the preferential progressive growth of
certain fungi, protozoa, and bacteria in the adrenal gland. Focal
suppurative inflammation occurs in the course of bacterial
septicemia. The adrenal capsule provides an effective barrier
against direct invasion by inflammatory processes in adjacent
tissue. Gram-negative bacteria, especially coliforms, produce
suppurative inflammation with necrosis as part of septicemia
in many species (Fig. 3-97B). Emboli often lodge in the adrenal
sinusoids to produce focal necrosis and suppurative infection.
and humans. Toxoplasma gondii localizes in the adrenal cortex
of many animals and produces focal areas of necrosis with
minimal inflammation. Granulomatous inflammation caused
by Histoplasma capsulatum, Coccidioides immitis, or Cryptococ-
cus neoformans occasionally occurs in dogs and cats in areas
where these fungi are endemic. Multiple distinct granulomas
with central areas of necrosis and mineralization may nearly
destroy the entire cortex (Fig. 3-98). Small nodules of viable
hypertrophic cortical cells are present between the granulo-
mas. The reaction to Cryptococcus in the adrenal may vary
from no reaction to extensive infiltration by macrophages.
Several viruses affect the adrenals and focal lesions are
expected in herpesviral infections, such as pseudorabies. The
adrenal lesions are characterized by intranuclear viral inclu-
medulla. Lymphocytes and macrophages infiltrate the necrotic
and hemorrhagic foci in the later stages of the infection.
Inflammatory edema of the adrenal glands occurs in older
animals with acute infectious diseases. These conditions would
be more likely to cause cortical hemorrhages in young animals.
The glands are enlarged as a result of swelling of the cortex
from hyperemia and edema. The cortical cells are swollen,
granular, depleted of lipid, and dissociated by the inflamma-
tory edema.
Mechanisms of toxicity of the adrenal cortex
Adrenal cortical cells contain large stores of lipid used as
substrate for steroidogenesis. Many compounds that are toxic
for the adrenal cortex are lipophilic and accumulate in these
lipid-rich cells. Mechanisms of toxicity include:
• Impairment of steroidogenesis, which is an important
mechanism of toxicity in the adrenal cortex that can occur
by inhibition of cholesterol biosynthesis or metabolism,
and by disruption of cytochrome P450 enzymes. Both of
these mechanisms will lead to the accumulation of
increased cytoplasmic lipid droplets (Fig. 3-99).
 Adrenal Cortex 341

Lysosome
Endocytosis
SER
LDL Acetyl CoA
Steroidogenesis
Steroid
nCEH hormone
HDL Cholesterol Mitochondrion
ACAT Storage nCEH
pathway

Nucleus
A Lipid droplet CE

Lysosome
Endocytosis
SER
LDL Acetyl CoA
Steroidogenesis Steroid
nCEH hormone
HDL Cholesterol Mitochondrion
ACAT nCEH
Storage CE
pathway

CE Nucleus

B Lipid droplet CE

Figure 3-99  Cholesterol metabolism and steroid hormone biosynthesis in adrenocortical cells.
Cholesterol is the substrate for steroid hormone biosynthesis. Conversion of cholesterol to preg-
nenolone occurs in the mitochondria, and oxidative reactions catalyzed by cytochrome P450
enzymes occur in both the smooth endoplasmic reticulum (SER) and mitochondria. Sources of
cholesterol include lipoprotein (low-density lipoprotein [LDL] and high-density lipoprotein
[HDL]) uptake from serum, de novo synthesis from acetate via the acetyl coenzyme A pathway,
and hydrolysis of cholesteryl esters (CE) by neutral CE hydrolase (nCEH). The storage pool in
the form of lipid droplets is derived principally from the conversion of free cholesterol to CE,
catalyzed by acyl coenzyme A/cholesterol acyltransferase (ACAT). (From Latendresse JR, et al.
Toxicol Appl Pharmacol 1993;122:281-289.)

• Toxin activation by mitochondrial cytochrome P450
(CYP450) enzymes in the cortical cells. Activation of
toxins can result in the generation of reactive oxygen
metabolites, result in membrane damage, and produce
phospholipidosis in the cells.
• Exogenous steroids, which can disrupt normal function
and structure of the adrenal cortex. Agonists will induce
negative feedback inhibition of ACTH secretion by the
pituitary and will result in atrophy of the zonae fasciculata
and reticularis. Some steroids, such as the sex steroids, can
induce proliferative lesions in the adrenal cortex. Antago-
nists will block steroid hormone action, leading to increased
ACTH secretion and diffuse hyperplasia of the cortex.
• DNA damage, by agents such as carcinogens or radiation,
may induce neoplasia of the adrenal cortex.
There is considerable species variation in the response of
the adrenal cortex to exogenous chemicals. This is because of
both inherent differences in the sensitivity to certain drugs
and differences in the metabolic pathways of steroidogenesis.
An interesting example is o,p′-DDD (mitotane, a derivative
of DDT), which was originally developed to treat metastatic
adrenal cortical cancer in humans. However, humans are rela-
tively insensitive to the effects of o,p′-DDD, and the drug was
not effective in the treatment of adrenal cancer. In contrast,
dogs are considerably more sensitive to the effects of o,p′-
DDD, and it has been used effectively in a dose-dependent
manner in the medical management of pituitary-dependent
hyperadrenocorticism caused by autonomous secretion of
ACTH by pituitary (corticotroph) tumors. o,p′-DDD is a
selective toxin for the zonae fasciculata and reticularis; thereby
sparing the important life-sustaining functions of the zona
glomerulosa.
Adrenal lesions associated with hypoadrenocorticism
Idiopathic adrenocortical atrophy. The most frequently observed
lesion in dogs with hypoadrenocorticism is bilateral idiopathic
adrenocortical atrophy in which all layers of the cortex are mark-
edly reduced in thickness (Fig. 3-100A-C). There usually is
deficient production of all classes of corticosteroids (mineralo-
corticoids, glucocorticoids, and adrenal sex steroids). The
adrenal cortex is reduced to one tenth or less its normal thick-
ness and consists primarily of the adrenal capsule. The adrenal
medulla is relatively more prominent and, with the capsule,
makes up the bulk of the remaining adrenal glands. The patho-
genesis of idiopathic adrenocortical atrophy is unknown, but
it is likely that the lesion is the result of immune-mediated inflam-
mation similar to Addison’s disease in humans. Multiple foci
of lymphocytes and plasma cells are seen interspersed between
342 CHAPTER 3  •  Endocrine Glands Adrenal Cortex

A
B

C D
Figure 3-100  Idiopathic adrenal cortical atrophy in a dog. A. All 3 layers of the adrenal cortex
from both glands are markedly reduced in thickness because of atrophy as a sequela of immune-
mediated adrenalitis and destruction of parenchymal cells. The arrows mark the edges of the
medulla. Bar = 5 mm. B. Chronic adrenal cortical atrophy in a dog with hypoadrenocorticism.
The medulla lies between the arrowheads, and there is congestion in the thin cortical region. The
capsule is prominent. C. Severe adrenal cortical atrophy. The adrenal capsule (top) appears thick-
ened because of collapse of the layers of the cortex. The cortex is very thin (between arrowheads)
with a few remaining vacuolated cortical cells. There is scattered lymphocytic inflammation of the
capsule and cortex. The medulla (M) is along the bottom. D. Early phase of immune-mediated
adrenalitis in a dog with infiltration of lymphocytes and plasma cells in the zona fasciculata and
loss of cortical cells.

adrenal sinusoids and groups of fibroblasts in the earlier stages
of the disease (Fig. 3-100D). The entire 3 zones of the cortex
are nearly absent in dogs that die from untreated hypoadre-
nocorticism. The capsule appears thickened because of col-
lapse of the adrenal cortex plus fibroblastic proliferation.
No obvious pituitary lesions other than compensatory
hyperplasia of corticotrophs have been observed in dogs with
idiopathic adrenal cortical atrophy. All zones of the adrenal
cortex are involved, including the zona glomerulosa, which is
not under ACTH control. In comparison, trophic atrophy of
the adrenal cortex secondary to a destructive pituitary lesion
that decreases ACTH secretion is characterized by severe
atrophy only of the inner 2 cortical zones. These animals do
not have the characteristic electrolyte abnormalities present
in hypoadrenocorticism because the secretion of aldosterone
remains within normal limits.
Additional (less common) causes of adrenocortical insuffi-
ciency in the dog include granulomatous inflammation that
destroys the cortex, thrombosis of adrenal vessels with
infarction of the cortex, invasion and destruction of adrenal
cortex by metastatic neoplasms, hemorrhage and necrosis with
subsequent replacement by fibrous connective tissue, and
extensive amyloid deposition along adrenal sinusoids.
Many of the functional disturbances of hypoadrenocorticism
associated with chronic adrenal insufficiency are not specific
and include recurrent episodes of gastroenteritis, slowly pro-
gressive loss of body condition, and failure to respond appro-
priately in stressful situations, such as minor illnesses or
surgery. Less commonly, the dog is presented in a shock-like
coma with no history of previous illness. Although hypoadre-
nocorticism occurs in dogs of any breed or sex and at any age,
idiopathic adrenocortical insufficiency occurs more frequently
in young adult dogs. This may be related to the immune-
mediated pathogenesis with the generation of autoantibodies
against cortical cells, progressive degeneration of parenchymal
cells, and lymphoplasmacytic adrenalitis.
Reduction in the synthesis and secretion of mineralocorti-
coids, primarily aldosterone, results in marked alterations of
 Adrenal Cortex
serum potassium, sodium, and chloride levels. Less potassium
is excreted by the kidney, resulting in a progressive rise in
serum potassium levels and severe hyperkalemia. Less sodium
and chloride are reabsorbed from renal tubules, leading to
various degrees of hypernatriuria and hyperchloruria and a
corresponding decline in blood levels. The severe hyperkale-
mia frequently produces marked cardiovascular disturbances
that are reflected by changes in the electrocardiogram.
Although the development of clinical signs often is insidi-
ous and not readily apparent, the dog frequently is presented
with acute circulatory collapse and evidence of renal failure.
Progressive decrease in blood volume contributes to hypoten-
sion, weakness, and microcardia. Peripheral circulatory col-
lapse may result from progressive hemoconcentration.
Increased excretion of water by the kidney, resulting from
hyponatremia and hypochloremia, results in progressive dehy-
dration and hemoconcentration. Emesis, diarrhea, and anorexia
are common in dogs with hypoadrenocorticism, and they con-
tribute to the animal’s deterioration. Weight loss is frequently
severe.
Decreased production of glucocorticoids results in several
characteristic functional disturbances of hypoadrenocorticism.
Failure of gluconeogenesis and increased sensitivity to insulin
contribute to development of moderate hypoglycemia. Hyper-
pigmentation of the skin occurs in some dogs with long-
standing adrenocortical insufficiency. This change results from
lack of negative feedback on the pituitary gland, increased
release of ACTH, and binding to melanocyte-stimulating
hormone (MSH) receptors on melanocytes in the skin.
Peripheral lymph nodes may be moderately increased in
size as a result of lymphoid hyperplasia. Histologically, promi-
nent germinal centers are observed in lymph nodes, and sub-
stantial numbers of eosinophils may infiltrate the peripheral
lymph sinus. There often are increased numbers of eosinophils
and lymphocytes in the circulation as a result of the dimin-
ished cortisol levels.
Hematologic alterations that occur in hypoadrenocorticism
include hemoconcentration caused by dehydration and loss of
intravascular fluid volume. Blood urea and creatinine levels
begin to rise as renal perfusion and urine output decrease. The
serum glucose level ranges from low normal to moderately
subnormal in affected dogs, but this usually is not responsible
for functional disturbances.
Hypercalcemia occurs in ~30% of dogs with hypoadreno-
corticism. The elevated serum calcium concentration returns
to normal when the adrenal cortical disease is treated with
adequate corticosteroid replacement therapy. The mechanism
of hypercalcemia is not understood completely, but the
ionized fraction of serum calcium remains normal, whereas
the nonionized fraction increases, and there is inappropriate
hypocalciuria for the degree of hypercalcemia. Because the
ionized serum calcium concentration is not increased, the
hypercalcemia is not deleterious to the animal; however,  blood pressure all will increase aldosterone production by
some of the clinical signs of hypoadrenocorticism (vomiting,
anorexia, polyuria, polydipsia) are similar to those of
hypercalcemia.
Carbadox and related compounds (olaquindox and
cytadox) are antibiotics and growth promotants used in young
pigs. Chronic or high exposure has been associated with
lesions in the zona glomerulosa. There is disorganization of
the zona glomerulosa, with loss of distinction from the zona
fasciculata, hydropic degeneration, and eventually atrophy,
mild fibrosis, and mononuclear cell infiltrates in the zona
343
glomerulosa with fibrosis of the capsule, which consistently
contains cells with PAS-positive cytoplasmic granules. Depend-
ing on duration and severity of exposure, adrenal lesions may
persist following removal of the drug. Plasma aldosterone and
sodium levels are reduced after exposure to toxic levels of
carbadox, and potassium is increased.
Hyperplasia of the adrenal cortex
Accessory cortical nodules are common in the adrenal glands
of adult-to-aged animals and are found in the capsule, cortex,
and medulla. Many accessory cortical nodules either arise as
evaginations of the outer cortex into the capsule and sur-
rounding periadrenal fat, or invaginations of the cortex into
the medulla (Fig. 3-101A).
Nodular hyperplasia also is common in the adrenal as well-
defined spherical nodules in the cortex or attached to the
capsule. Hyperplastic nodules are usually multiple and bilat-
eral, yellow, and may involve any of the 3 zones of the cortex
or medulla (Fig. 3-101B). Histologically, the nodules near 
the capsule resemble zona glomerulosa, sometimes with areas
similar to zona fasciculata. The cells either are about the same
size as those of the adrenal cortex or hypertrophied. The lipid
content in these hyperplastic nodules is not depleted in cir-
cumstances that reduce the amount of lipid in the rest of the
cortex. Hyperplastic cortical nodules are most common in
older horses, dogs, and cats.
Nodular hyperplasia of the zona reticularis may appear as
discrete foci of cortical parenchyma extending into the
medulla and result in an irregular corticomedullary junction
(Fig. 3-101C). This adrenal lesion has been seen in animals
with functional disturbances suggesting androgen excess (e.g.,
greater muscle mass, well-developed crest, hypertrophy of
clitoris, and involution of mammary glands).
Diffuse cortical hyperplasia results in uniform, usually
bilateral, enlargement of the adrenal cortex (Fig. 3-101D).
There is a marked hypertrophy and hyperplasia of cells in the
zonae fasciculata and reticularis in response to autonomous
hypersecretion of ACTH by a corticotroph adenoma of the
pituitary. The hyperplastic cells in the zona fasciculata are
vacuolated (lipid rich) and arranged in straight columns sepa-
rated by sinusoids. Cells in the outer zona glomerulosa often
are compressed by the expanded inner 2 zones. The cortico-
medullary junction is irregular in diffuse hyperplasia, and pro-
jections of cortical cells often extend into the medulla. Areas
of discrete nodular hyperplasia may be present in a diffusely
hyperplastic cortex.
Hyperplasia of zona glomerulosa occurs as part of the
compensatory mechanism of the body to a variety of factors
that stimulate long-term release of renin from the juxtaglo-
merular apparatus of the kidney (Fig. 3-101E). Chronic
sodium depletion or potassium excess, decreased blood
volume to the kidney, or a sustained reduction in systemic
stimulating renin release. Renin results in the formation of
angiotensin II, a trophic hormone for the zona glomerulosa of
the adrenal cortex.
Neoplasms of the adrenal cortex
Myelolipoma
This is a benign lesion encountered in the adrenals of cattle,
nonhuman primates, and infrequently in other animals. It is
composed of accumulations of well-differentiated adipose
344 CHAPTER 3  •  Endocrine Glands Adrenal Cortex

C D

E
Figure 3-101  Adrenal cortical hyperplasia. A. Discrete accessory adrenal cortical nodules in the
capsule and medulla in a dog. Bar = 5 mm. B. Multifocal nodular cortical hyperplasia (arrows) in
a dog. Well-demarcated cortical adenoma (A). Bar = 5 mm. C. Multifocal cortical hyperplasia
of the zona reticularis in a bovid. Bar = 5 mm. D. Bilateral diffuse adrenal cortical hyperplasia in
a dog with a functional pars distalis chromophobe adenoma that secreted adrenocorticotropic
hormone. Bar = 1 cm. E. Hypertrophy and hyperplasia of the zona glomerulosa in a dog. Note
the enlarged and columnar zona glomerulosa cells forming prominent arches.

connective tissue cells and hematopoietic tissue, including Cortical adenoma

both myeloid and lymphoid elements. Focal areas of bone
formation occur in the tumor. Although the origin of these
nodular aggregations of fat, bone, and myeloid cells is uncer-
tain, they appear to develop by metaplastic transformation of
cells in the adrenal cortex.
Adenomas of the adrenal cortex are seen most frequently in
old dogs (8 years and older) and sporadically in horses, cattle,
and sheep. They usually are encountered as incidental findings
at autopsy. Castrated male goats are reported to have a higher
incidence of cortical adenomas than intact males.
 Adrenal Cortex 345

Cortical adenomas are well demarcated, usually single,

nodules in one adrenal gland, but may be bilateral. Larger
cortical adenomas are yellow to red, distort the external
contour of the affected gland, and are partially or completely
C
encapsulated. Adjacent cortical parenchyma is compressed,
and the tumor may extend into the medulla.
Discrete cortical adenomas often develop in an adrenal
with multiple areas of nodular hyperplasia (see Fig. 3-101B).
Smaller cortical adenomas are more yellow and similar in
color to the normal adrenal cortex because of the high lipid
content. They are surrounded on all sides by mildly com-
pressed cortex with attempts at encapsulation, and may be
difficult to distinguish from nodular cortical hyperplasia in old
dogs. However, nodular hyperplasia consists of multiple small
foci, usually in both adrenals, with no evidence of encapsula-
tion and often is associated with extracapsular nodules of
hyperplastic cortical tissue.
Cortical adenomas are composed of well-differentiated A
cells that resemble secretory cells of the normal zonae fascicu-
lata or reticularis. Tumor cells are arranged in broad trabeculae
or nests separated by small vascular spaces. The abundant
cytoplasmic area of tumor cells is lightly eosinophilic, often
vacuolated, and filled with many lipid droplets. Adenomas are
partially or completely surrounded by a fibrous connective
tissue capsule of variable thickness and a rim of compressed
cortical parenchyma. The tumors may have prominent dilated
thin-walled sinusoids filled with blood (telangiectasis) with
chronic hemorrhage, hemosiderosis, and fibrosis that mimic
hemangiomas (Fig. 3-102A-C). Focal areas of mineralization,
hematopoiesis, and accumulations of fat cells may be found
in cortical adenomas.

Cortical carcinoma
Adrenal cortical carcinomas occur less often than adenomas
and have been reported most often in cattle and older dogs, but B
infrequently in other species. Carcinomas develop in adult to
older individuals, and there is no apparent breed or sex pre-
disposition. Activation of the PI3 kinase by insulin growth
factor-1 (IGF-1) may be important in the pathogenesis of
adrenal cortical carcinoma in humans and dogs.
Adrenal carcinomas are larger than adenomas and more
likely to be bilateral. In dogs, they are composed of variegated,
yellow-red, friable tissue that incorporates the affected adrenal
gland (Fig. 3-103A). They are often fixed in location because
of extensive invasion of surrounding tissues with extension into
the caudal vena cava, forming large tumor-cell thrombi. Car-
cinomas may attain considerable size in cattle (≥10 cm in
diameter) and have multiple areas of mineralization or
ossification.
Carcinomas are composed of more highly pleomorphic
cortical cells than adenomas, and are subdivided into small C
groups by fibrovascular stroma of variable thickness. The
architecture of the affected adrenal usually is completely Figure 3-102  Adrenal cortical adenoma in a dog with telangiec-
obliterated by the carcinoma. The pattern of growth varies tasis. A. Well-demarcated adenoma (between arrowheads) in the
between individual tumors and within the same carcinoma. adrenal cortex. The adenoma has large dilated sinusoids (telangi-
Tumor cells usually are large and polyhedral with prominent ectasis) with chronic hemorrhage. Normal cortex (C). B. Adrenal
nuclei and densely eosinophilic or vacuolated cytoplasm, but cortical adenoma composed of thickened cords of well differenti-
the tumor may also contain smaller cells (Fig. 3-103B). Areas ated cells. Note the clusters of hemosiderin-laden macrophages.
of hemorrhage within the tumors are common because of C. Cords of adrenal cortical adenoma cells are separated by large
rupture of thin-walled sinusoids. Metastasis occurs most fre- dilated sinusoids that mimic hemangioma.
quently to the liver and lungs. The normal adrenal cortex can
be immunohistochemically stained for steroidogenic factor-1,
calreticulin, α-inhibin, melan-A, and S-100 protein, and
346 CHAPTER 3  •  Endocrine Glands
A many organs. The course of the disease is insidious and slowly
B
Figure 3-103  Functional adrenocortical carcinoma in a dog. A.
Adrenocortical carcinoma with destruction of the normal adrenal
gland (left) and invasion of the caudal portal vein with formation
of a tumor thrombus (right). The contralateral adrenal gland
(lower) has cortical atrophy secondary to hyperadrenocorticism.
Bar = 1 cm. B. Large, polyhedral cortical carcinoma cells forming
clusters with lack of the typical narrow cord formation seen in
the normal adrenal cortex. There are also small carcinoma cells
present.
adenomas and carcinomas will be variably positive for the
same antigens.
Carcinomas and adenomas of the adrenal cortex in dogs
occasionally are functional and secrete excessive amounts of
hormone, usually cortisol. Approximately 15% of dogs with
hyperadrenocorticism (Cushing’s disease) are due to func-
tional adrenal tumors, whereas 85% of dogs have pituitary
tumors that secrete ACTH. The clinical picture of adrenal
cortical carcinoma may be complicated by compression of
adjacent organs by the large tumor, invasion into the aorta or
caudal vena cava leading to intra-abdominal hemorrhage, and
metastases to distant sites.
Functional cortical adenomas and carcinomas are associ-
ated with atrophy of the contralateral cortex because of nega-
tive feedback inhibition of pituitary ACTH secretion by the
elevated blood cortisol levels. The atrophic cortex consists
primarily of the adrenal capsule and zona glomerulosa. Few
secretory cells remain in the zonae fasciculata and reticularis.
Similar atrophy may be present in the remnants of com-
pressed adrenal cortex around functional adenomas. The
adrenal medulla in the contralateral gland may appear
expanded and more conspicuous because of the lack of corti-
cal parenchyma.
Adrenal Cortex
Aldosterone-secreting adenomas and carcinomas occur
infrequently, and are most often reported in cats. Primary
hyperaldosteronism leads to hypokalemia and systemic hyper-
tension (Conn syndrome).
Hyperadrenocorticism
The manifestations and lesions associated with hyperadreno-
corticism (Cushing’s syndrome), mainly in dogs, result from
long-term overproduction of cortisol by hyperactive adrenal
cortices. As a result of the cortisol excess, affected dogs develop
a spectrum of functional disturbances and lesions from the
combined gluconeogenic, lipolytic, protein catabolic, and 
anti-inflammatory effects of the glucocorticoid hormones on
progressive. Cortisol excess is one of the most frequent endocri-
nopathies in adult-to-aged dogs, occurs occasionally in cats,
but is encountered infrequently in other species of domestic
animals.
The elevation in circulating cortisol levels in dogs with
hyperadrenocorticism may result from one of several different
pathogenic mechanisms. The most common mechanism (85%
of cases) is a functional corticotroph (ACTH-secreting) adenoma
of the pituitary gland (pars distalis or pars intermedia in dogs)
that causes bilateral adrenal cortical hypertrophy and hyper-
plasia (see Fig. 3-101D). Hyperadrenocorticism associated
with adrenal cortical hyperplasia occurs most frequently in
small-breed dogs, such as Poodles and other breeds.
Functional adrenal neoplasms are infrequent (15% of
cases) causes of the syndrome of cortisol excess (Cushing’s
syndrome) in the dog. One third of dogs with hyperadre­
nocorticism caused by an adrenal tumor have activating 
mutations in the stimulatory G protein α-subunit associated
with the ACTH receptor (melanocortin 2 receptor [MC2R]),
which may allow the functional tumors to be independent of
ACTH stimulation for secretion of cortisol. Many of the clini-
cal signs and lesions of naturally occurring hyperadrenocorti-
cism can be induced by the long-term, daily administration of
large doses of corticosteroids for the treatment of other
diseases.
The appetite and intake of food often are increased as a
direct result of either the hyperadrenocorticism or the destruc-
tion of hypothalamic centers that control appetite by a dor-
sally expanding pituitary tumor. The muscles of the extremities
and abdomen are weakened and atrophied. The loss in tone
of the abdominal muscles and muscles of the appendicular
skeleton results in gradual abdominal enlargement, lordosis,
muscle trembling, and a straight-legged, skeletal-braced
posture (Fig. 3-104). Profound atrophy of the temporal
muscles may result in obvious concave indentations and
readily palpable prominences of underlying skull bones. Hepa-
tomegaly resulting from increased fat and glycogen deposition
may contribute to the development of the distended, often
pendulous, abdomen. The muscular asthenia and wasting is
the result of increased catabolism of structural proteins, com-
bined with diminished protein synthesis, under the influence
of long-term cortisol excess.
Skin lesions occur in a high percentage of dogs with hyper-
adrenocorticism. The initial changes in the skin often are
observed over points of wear, such as neck, flanks, behind the
ears, and over bony prominences. These initial skin changes
spread in a bilaterally symmetrical pattern to involve a signifi-
cant percentage of the body surface. The basic skin lesion 
of cortisol is atrophy of the epidermis and pilosebaceous 
 Adrenal Cortex
Figure 3-104  Hyperadrenocorticism (Cushing’s disease) in a
dog. Hyperadrenocorticism with alopecia extending over most of
the body. The skin is thin, wrinkled, and hyperpigmented. Muscle
asthenia is evident from the pendulous abdomen and swayed
back.
Figure 3-105.  Hyperadrenocorticism in a dog. Severe mineraliza-
tion of the skin. Note empty hair follicles and mineral crystals
protruding through atrophic epidermis.
apparatus, combined with loss of collagen and elastin fibers  the 2 inner zones. The cortex becomes markedly thinned and
in the dermis and subcutis. The skin is of fine texture and  consists of an intact zona glomerulosa surrounded by a fibrous
often paper thin. Cats with chronic hyperadrenocorticism
(with or without the concurrence of diabetes mellitus) can
develop skin fragility syndrome resulting from epidermal and
dermal atrophy, leading to spontaneous tearing of the skin.
Most of the hair follicles are inactive and in the telogen phase.
However, the stratum corneum is considerably thickened
because of the accumulation of multiple layers of keratin on
the surface.
Cutaneous mineralization (calcinosis cutis) is a characteristic
lesion in dogs with hyperadrenocorticism, but occurs only in
long-standing cases. Although mineral deposition may occur
in any region of the body, the dorsal midline, ventral abdomen,
and inguinal region are frequently affected sites. Numerous
mineral crystals are deposited along collagen and elastin fibers
in the dermis and may protrude through the atrophic and
thinned epidermis (Fig. 3-105). The epidermis remains intact
in less severe cases and appears irregularly elevated by the
opaque white deposits of mineral. Foreign-body granuloma-
tous inflammation often surrounds the areas of mineralization.
The mineral deposits occur in dogs with normal blood calcium
and phosphorus levels. The pathogenesis of this manifestation
of hyperadrenocorticism most likely is related to the gluco-
neogenic and protein catabolic action of cortisol, resulting in
the rearrangement of the molecular structure of proteins, such
347
as collagen and elastin, and the formation of an organic matrix
that attracts and binds calcium.
Severe mineralization also occurs in several other tissues. The
lungs are most frequently affected (>90%), but active skeletal
muscles and the wall of the stomach also may have extensive
areas of mineralization. Pulmonary function may be compro-
mised when mineralization is extensive.
The syndrome of long-term cortisol excess often is 
complicated by increased susceptibility to bacterial infections.
Multifocal areas of suppurative folliculitis and dermatitis
develop near the lip folds and footpads and elsewhere in 
the skin. Suppurative bronchopneumonia frequently is a
serious, life-threatening complication because it develops 
in lungs whose function is already partially impaired by 
extensive mineralization of alveolar walls and terminal
bronchioles.
Laboratory confirmation of the syndrome of cortisol excess is
accomplished by a combination of suppression and stimulation
tests of the hypothalamic-pituitary-adrenocortical axis. Low
doses of dexamethasone (15 µg/kg) suppress ACTH produc-
tion and subsequently plasma cortisol levels in normal dogs,
but do not suppress cortisol levels in dogs with pituitary-
dependent hyperadrenocorticism or functional adrenal corti-
cal neoplasms. High doses of dexamethasone (1.0 mg/kg)
usually suppress plasma cortisol levels in dogs with pituitary-
dependent hyperadrenocorticism but do not significantly
influence levels in dogs with cortisol-producing adrenal 
cortical neoplasms. Assays for plasma ACTH are useful in
differentiating pituitary-dependent (elevated) and adrenal- 
dependent (suppressed) causes of the syndrome of cortisol
excess.
Dogs with the syndrome of cortisol excess caused by
diffuse cortical hyperplasia (corticotroph adenoma of pitu-
itary, or idiopathic adrenal hyperplasia) can be managed 
medically by the oral administration of mitotane (o,p′-DDD)
or trilostane. Mitotane is cytotoxic to the zonae fasciculata
and reticularis and results in necrosis, followed by collapse of
capsule. Withdrawal of mitotane results in recovery of the
zonae fasciculata and reticularis in a diffuse or nodular pattern.
Trilostane is an inhibitor of 3β-hydroxysteroid dehydrogenase,
which is necessary for the synthesis of steroid hormones,
including cortisol. Trilostane induces the accumulation of
cytoplasmic lipid vacuoles, apoptosis, necrosis, and hemor-
rhage of the adrenal cortex in dogs. A small subset of dogs
may develop hypoadrenocorticism after treatment with trilo-
stane because of extensive adrenocortical necrosis, hemor-
rhage, and fibrosis.
Adrenal tumors in ferrets
Adrenal tumors are recognized in ferrets that are kept as
household pets and live to an advanced age. The adrenal
enlargements are either bilateral because of diffuse or nodular
hyperplasia, or unilateral because of adrenal cortical carci-
noma (more common) or cortical adenoma. Clinical signs in
ferrets with adrenal cortical tumors include vulvar enlarge-
ment; bilaterally symmetrical alopecia, especially on the ventral
abdomen and medial aspects of the rear legs; polyuria; poly-
dipsia; and the presence of a palpable mass at the cranial pole
of the kidney (left side has a greater frequency than the right).
Other functional disturbances, including anemia, thrombocy-
topenia, pyometra, endometrial hyperplasia, and prostate
348 CHAPTER 3  •  Endocrine Glands
squamous metaplasia, are consistent with an overproduction of
estrogenic steroids by the adrenal tumors. About 13 of ferrets
with adrenal cortical tumors also have neoplasms derived
from the insulin-producing β-cells of the pancreatic islets that
can be associated with hypoglycemia and elevated levels of
serum insulin, resulting in seizures, episodic lethargy, ptyalism,
ataxia, and hind leg weakness.
The most consistent endocrinologic change in ferrets with
adrenal tumors is elevation of plasma levels of estradiol-17β. It
is presumed that the estradiol-17β is produced by the tumor
directly, but an alternative possibility would be that the
adrenal tumors secrete androgenic steroids that are aroma-
tized elsewhere to estrogenic steroids. There is no increase in
circulating estradiol-17β levels in response to exogenous
ACTH, but plasma levels decrease following adrenalectomy.
Plasma cortisol and corticosterone levels in ferrets with adrenal
tumors either are in the range of normal or below, and do not
show an exaggerated increase in response to exogenous ACTH.
There is not a decrease in plasma cortisol following unilateral
adrenalectomy, and the contralateral adrenal cortex is not
atrophic, as would be expected if the adrenal tumor were
secreting excess cortisol. However, the urinary cortisol to cre-
atinine ratio is increased in ferrets with adrenal cortical tumors.
The clinical signs in ferrets with adrenal cortical tumors can
be effectively reversed by adrenalectomy, but not by chemo-
therapy with o,p′-DDD.
Adrenal tumors develop in adult ferrets with females more
frequently affected than males. The history frequently indi-
cates the ferrets were gonadectomized at an early age. Gonad-
ectomy results in high levels of circulating luteinizing hormone
(LH) because of a lack of negative feedback on the hypothala-
mus and pituitary gland from sex steroids. LH induces prolif-
eration of adrenocortical stem cells and differentiation into
sex steroid–producing cells (particularly in ferrets), which
may represent the cells of origin of adrenocortical tumors in
these animals. Gonadectomy also increases the incidence of
adrenal tumors in goats and mice. Adrenocortical tumors that
occur in gonadectomized animals often have expression of LH
receptors and GATA4, which is a transcription factor specific
for sex steroid–producing cells.
Nodular hyperplasia usually consists of multiple foci of
various sizes in both adrenals. Cortical adenomas usually are
well-demarcated single nodules in one adrenal gland, but they
may be bilateral. They are surrounded by mildly compressed
cortex and may be difficult to distinguish from adjacent areas
of nodular cortical hyperplasia (Fig. 3-106A).
Adrenal adenomas and carcinomas in ferrets are typically
pleomorphic with small undifferentiated cells, larger well-
differentiated cortical cells with cytoplasmic lipid vacuoles,
and variable degrees of spindle cell differentiation (Fig.
3-106A, B). It is often difficult to accurately differentiate foci
of hyperplasia and the nodules of adenomas or carcinomas in
the same gland because of the intermingling of the lesions.
The neoplastic spindle cells may also differentiate to smooth
muscle–like cells and stain immunohistochemically positive
for α-smooth muscle actin and desmin (see Fig. 3-106B).
Immunohistochemical markers for the tumor cells include
vimentin, α-inhibin, synaptophysin, estrogen receptor, and
GATA-4. Carcinomas of the adrenal cortex are larger, locally
invasive, and metastasize to distant sites, especially the liver
(Fig. 3-106C). Some carcinomas develop myxoid differentia-
tion with lumen-like spaces containing alcian blue–positive
acid glycosaminoglycans (Fig. 3-106D).
Adrenal Medulla
ADRENAL MEDULLA
Development, structure, and function
Embryonic development and structure
The adrenal medulla has a different embryonic derivation
than the cortical portion of the adrenal gland. It is derived
from neuroectoderm of the neural crest. Secretory cells in the
adrenal medulla are involved in biosynthesis of the catechol-
amine hormones (epinephrine and norepinephrine).
The medulla is completely surrounded by the adrenal
cortex in mammals, and venous drainage from the cortex
bathes the medullary cells with blood containing the highest
concentration of corticosteroids of any fluid in the body. This
close anatomic association between the adrenal cortex and
medulla in mammals is not fortuitous; the N-methylating
enzyme (phenylethanolamine-N-methyl transferase, PNMT),
which converts norepinephrine to epinephrine, is corticoste-
roid hormone dependent.
A variety of techniques may be used for the demonstration
of catecholamines in tissue sections. The chromaffin reaction is
the oxidation of catecholamines by potassium dichromate
solutions and results in the formation of a brown to yellow
pigment in medullary tissue. The chromaffin reaction as tra-
ditionally performed has a low level of sensitivity and should
not be used for the definitive demonstration of the presence
of catecholamines in tissues. Fluorescence techniques using
formaldehyde or glyoxylic acid can be used to demonstrate
catecholamines at the cellular level. These aldehydes form
highly fluorescent derivatives with catecholamines, which can
be visualized by ultraviolet microscopy. Immunohistochemistry
provides an alternative approach for the identification of chro-
maffin cells. Both epinephrine- and norepinephrine-producing
chromaffin cells are positively stained for chromogranin A
(which is a nonspecific marker for peptide- or amino acid
hormone–producing cells), tyrosine hydroxylase, or dopamine
β-hydroxylase. Antibodies to PNMT will specifically label only
the epinephrine-producing chromaffin cells.
Biosynthesis of catecholamine hormones
The main biosynthetic pathway for catecholamines in
mammals starts with tyrosine derived either from the diet
or formed through hydroxylation of phenylalanine in the 
liver. Tyrosine is first converted to 1-dihydroxyphenylalanine
(DOPA) by tyrosine hydroxylase, and DOPA is then decar-
boxylated to 1-dihydroxyphenylethylamine (dopamine) by
l–amino acid decarboxylase, which subsequently undergoes 
β-hydroxylation by dopamine β-hydroxylase to norepinephrine
(Fig. 3-107).
Although the adrenal medulla is not absolutely essential
for life, there are a number of physiologic conditions (e.g.,
sudden hypoglycemia, acute stress) in which release of epi-
nephrine from the medulla is beneficial. Stimulation by pre-
ganglionic sympathetic fibers that synapse on secretory cells
of the adrenal medulla also increases the output of catechol-
amines, primarily by increasing tyrosine hydroxylase and
dopamine β-hydroxylase activity.
Catecholamines are degraded in peripheral tissues by
catechol-O-methyl transferase and monoamine oxidase to
several metabolites, such as vanillylmandelic acid, metaneph-
rine, and normetanephrine that are excreted in the urine.
Measurement of the urinary excretion of these metabolites
plus the relatively small amount of free catecholamines
excreted in the urine is useful in the diagnosis of
 Adrenal Medulla 349

B
A

C D
Figure 3-106  Adrenal hyperplasia and tumors in a ferret. A. Adrenal cortical adenoma. Note that
the adenoma consists of well differentiated, polyhedral cells with fat vacuoles and spindle-shaped
cells. Inset: Multifocal adrenocortical hyperplasia with a focal adenoma (arrowhead) replacing the
normal adrenal cortex and medulla. B. The spindle-shaped cells of the adrenal adenoma stain
immunohistochemically positive (brown cytoplasmic staining) for desmin. C. Adrenocortical
carcinoma with replacement of the normal adrenal gland, capsular invasion, and vascular invasion
(arrowhead). D. Adrenocortical carcinoma with small polyhedral cells containing small fat vacuoles
and a region of myxoid differentiation with formation of glands filled with basophilic mucin.

certain disorders characterized by overproduction of adrenal
medullary hormones. This is best done on urine samples col-
lected over a 24-hour period as catecholamine overproduction
often is episodic rather than continuous.
Neoplasms of adrenal medullary secretory cells
Pheochromocytoma and malignant
pheochromocytoma
Pheochromocytomas are the most common neoplasms arising in
the adrenal medulla of animals. They develop most often in
cattle and dogs, and infrequently in other domestic animals.
In bulls and humans, pheochromocytomas may develop con-
currently with calcitonin-secreting C-cell tumors of the
thyroid gland. In some animals, this appears to represent neo-
plastic transformation of multiple types of endocrine cells of
neuroectodermal origin in the same individual. Malignant
pheochromocytoma is used to designate medullary tumors that
invade through the adrenal capsule and into adjacent struc-
tures or that metastasize to distant sites.
Pheochromocytomas are tumors of chromaffin cells and are
almost always located in the adrenal gland of animals. They can
be either unilateral or bilateral (Fig. 3-108A-C). Although size
varies considerably, they often are large (≥10 cm diameter)
and incorporate the majority of the affected adrenal gland. A
small remnant of the adrenal gland often can be found at one
pole (see Fig. 3-108B). Smaller tumors are completely sur-
rounded by a thin compressed rim of adrenal cortex. Large
pheochromocytomas are multilobular and variegated light
brown to yellow-red as a result of areas of hemorrhage and
necrosis. A useful aid in macroscopic diagnosis of pheochro-
mocytoma is the Henle chromaffin reaction with either potas-
sium dichromate or iodate. Application of Zenker’s solution
to the flat-cut surface of a freshly resected tumor results in
oxidation of catecholamines, forming a dark brown pigment
within 20 minutes (see Fig. 3-108C).
Tumor cells in pheochromocytomas vary from small 
cuboidal or polyhedral cells to large pleomorphic cells with
multiple hyperchromatic nuclei (Fig. 3-109). The cytoplasmic
area is lightly eosinophilic, finely granular, and plasma
350 CHAPTER 3  •  Endocrine Glands Adrenal Medulla

Tyrosine OH
NH2
HO
Tyrosine  Neural input
hydroxylase  ACTH

O
Dihydroxy- HO
phenylalanine OH
(DOPA) NH2
HO
Aromatic L-amino acid
decarboxylase

HO NH2
Dopamine
HO
Dopamine  Neural input
-hydroxylase  Adrenal corticoids

OH
HO NH2
Norepinephrine
HO
Phenylethanolamine  Adrenal
N-methyl transferase corticoids
(PNMT)
OH H
HO N
CH3
Epinephrine
HO
Figure 3-107  Synthesis of norepinephrine and epinephrine in chromaffin cells of the adrenal
medulla. Tyrosine hydroxylase is the rate-limiting enzyme. Enzymatic conversion of tyrosine to
L-dihydroxyphenylalanine (DOPA) and dopamine occurs in the cytoplasm. Synthesis of norepi-
nephrine occurs in the secretory granule, which is the site of dopamine β-hydroxylase. Norepi-
nephrine leaves the secretory granules and is converted to epinephrine in the cytoplasm by
phenylethanolamine-N-methyltransferase (PNMT) and then re-enters the secretory granules.
ACTH, adrenocorticotropic hormone. (From Rosol TJ, et al. Toxicol Pathol 2001;29:41-48.)

Figure 3-108  Pheochromocytoma. A. Well-demarcated pheo-

chromocytoma in a horse. Bar = 1 cm. B. Large pheochromo-
cytoma in a dog with remnant of adrenal medulla (M) at top
right. C. Bilateral pheochromocytomas in a bovid. Lower panel
represents a positive chromaffin reaction in the tumors and
small region of normal adrenal medulla (right side of the
C
smaller adrenal gland).
 Adrenal Medulla 351

membranes often are indistinct because of early onset of
autolysis in adrenal medullary tissue. Tumor cells are charac-
teristically subdivided into small lobules by fine connective
tissue septa and capillaries.
Pheochromocytomas are composed of epinephrine-secreting
cells, norepinephrine-secreting cells, or both. The principal distin-
guishing morphologic feature of these 2 populations of cells is in
the fine structure of their secretory granules. Pheochromocyto-
mas from which norepinephrine is the principal catechol-
amine are composed of cells with secretory granules that have
an eccentrically situated electron-dense core surrounded by a
wide submembranous space (Fig. 3-110). When epinephrine
is the principal catecholamine, the secretion granules in tumor
cells have a coarsely granular internal core of lower density
and a narrow submembranous space (see Fig. 3-110).
Small pheochromocytomas are well encapsulated and
remain confined to the affected adrenal gland. Larger malig-
nant pheochromocytomas may exert pressure on and invade
adjacent tissues, particularly the caudal vena cava and aorta
(Fig. 3-111A). Tumor cells often invade the capsule and pen-
etrate through the wall of the caudal vena cava, forming a
large thrombus that partially occludes the venous return from
the caudal extremities (Fig. 3-112B). Metastasis occurs to the
liver, regional lymph nodes, spleen, and lungs in ~50% of dogs
with malignant pheochromocytomas. Growth of tumor cells
in a subendothelial location along vascular sinusoids and arti-
factual displacement of clusters of tumor cells into the lumen
of thin-walled veins during sectioning and forced through the
capsule should not be misinterpreted as evidence of malig-
nancy in adrenal medullary neoplasms.
Functional pheochromocytomas with clinical signs related to
catecholamine overproduction occur infrequently in animals.
Tachycardia, edema, and cardiac hypertrophy observed in
dogs and horses with pheochromocytomas have been attrib-
uted to excessive catecholamine secretion. Arteriolar sclerosis
and widespread medial hyperplasia of arterioles have been
reported in dogs with pheochromocytomas that were associ-
ated with clinical signs suggestive of paroxysmal hypertension.
The catecholamine content in pheochromocytomas from
bulls with concurrent C-cell tumors of the thyroid gland is
higher than in the normal bovine adrenal medulla. Urinary
excretion of vanillylmandelic acid and free unconjugated cat-
echolamines is elevated in bulls with pheochromocytomas.

Figure 3-109  Pheochromocytoma in a dog. The neoplastic chro- Mechanisms of adrenal medullary tumor
maffin cells are polyhedral with finely granular cytoplasm and development
form cords or packets separated by fine connective tissue stroma. The cause of pheochromocytomas in domestic animals 
The neoplastic cells are similar to normal chromaffin cells. is unknown. Most tumors are sporadic, but a familial 

Figure 3-110  Pheochromocytomas from a bull. Left panel: Pheochromocytoma composed pre-
dominantly of cells with ultrastructural characteristics of epinephrine-secreting cells of the adrenal
medulla. Medullary cells contain many secretory granules(s) of low electron density and a narrow
submembranous space. Right panel: Pheochromocytoma composed predominantly of cells with
norepinephrine-secreting cells of the adrenal medulla. Secretory granules(s) have an eccentric
electron-dense core surrounded by a prominent submembranous space.
352 CHAPTER 3  •  Endocrine Glands
B
Figure 3-111  Malignant pheochromocytoma in dogs. A. The
malignant pheochromocytoma has invaded through the adrenal
capsule (arrowheads) into the surrounding tissues and around
major regional arteries. Bar = 5 mm. B. A malignant pheochromo-
cytoma (top) has invaded through the caudal vena cava to form
a large intravascular tumor embolus. Bar = 1 cm.
predisposition may occur, especially in cattle, given that pheo-
chromocytomas have been seen in combination with C-cell
and pituitary tumors. Two main molecular pathways have
been identified in humans. These include the activation of the
hypoxic pathway and the mitogen-activated protein (MAP)
kinase/mammalian target of rapamycin (mTOR) pathways. In
addition, hypermethylation or mutation of the succinate
dehydrogenase (SDHx) genes has been associated with pheo-
chromocytomas. Succinate appears to act as an oncogenic
metabolite. The genetic pathogenesis appears to be similar for
both pheochromocytoma and paragangliomas in humans.
Some strains of rats have a high incidence of pheochromocy-
toma, which suggests a genetic or familial predisposition
occurs. Chronic stimulation of the adrenal medulla in rats
from stress and hypercalcemia will increase the incidence of
pheochromocytoma.
Adrenal medullary hyperplasia
Diffuse or nodular adrenal medullary hyperplasia appears to
precede the development of pheochromocytoma in bulls and
laboratory rats, and humans with C-cell tumors of the thyroid
gland. Diffuse proliferation of chromaffin cells is nonencapsu-
lated but compresses the surrounding adrenal cortex (Fig.
3-112A). The hyperplastic cells are columnar to cuboidal and
have a lightly basophilic cytoplasm (Fig. 3-112B). Bulls with
prominent diffuse medullary hyperplasia often have a few
small foci of intense nodular (focal) proliferation of medullary
cells. Medullary hyperplasia is detected by increased total
Adrenal Medulla
B
Figure 3-112  Diffuse hyperplasia of the adrenal medulla from a
bull. A. The adrenal medulla is enlarged as a result of chromaffin
cell hyperplasia, and there is compression of the adrenal cortex
with a reduced corticomedullary ratio. Bar = 1 cm. B. The hyper-
plastic chromaffin cells form cords composed of hypertrophic and
columnar cells with finely granular amphophilic cytoplasm. The
size of the enlarged chromaffin cells can be compared to cells of
the zona reticularis (ZR).
adrenal weight, a decrease in the corticomedullary ratio
because of an increase in the size and number of medullary
cells, and the presence of frequent mitotic figures in the
adrenal medulla.
Neoplasms of cells of the sympathetic nervous
system in adrenal medulla
Neuroblastoma
Neuroblastomas arise from primitive neuroectodermal cells, often
in younger animals, and form a large intra-abdominal mass.
They are differentiated from pheochromocytomas by being
composed of small tumor cells with hyperchromatic nuclei
and scant amounts of cytoplasm that often resemble lympho-
cytes and tend to form pseudorosettes (Fig. 3-113A,B).
 Adrenal Medulla
A strated in neuroblastomas. The tumor cells are immunohisto-
B Secondary foci of neoplastic growth in the adrenal glands are
C gastric, and pancreatic carcinomas, and melanoma had the
Figure 3-113  Neuroblastoma in a canine adrenal gland. A. The
tumor cells have invaded the adrenal cortex and have small hyper-
chromatic nuclei with poorly defined cytoplasm. B. Neuroblas-
toma cells are small and undifferentiated, but in some areas, they
form pseudorosettes (arrowheads). C. The tumor cells stain
immunohistochemically positive for chromogranin A. The adrenal
cortex is at the top of the image and is unstained.
353
Figure 3-114  Compact thyroid follicular carcinoma metastatic
to the adrenal medulla in a dog. The adrenal cortex is on the left.
Neurofibrils or unmyelinated nerve fibers can be demon-
chemically positive for chromogranin A (Fig. 3-113C).
Ganglioneuroma
Ganglioneuromas are benign tumors in the medulla composed of
multipolar ganglion cells and neurofibrils with a prominent
fibrous connective tissue stroma. They usually are well-
differentiated small tumors that, in cattle, often contain
melanin pigment. The surrounding adrenal cortex is com-
pressed to various degrees, depending upon the size of the
tumors. Neoplastic cells in medullary tumors occasionally may
differentiate in 2 directions, resulting in adjacent pheochro-
mocytomas and ganglioneuromas in the same adrenal gland.
Tumors metastatic to the adrenal medulla
common in cases of disseminated neoplasia and originate pri-
marily as tumor cell emboli. The metastases usually are bilat-
eral, and the medulla is an early site of tumor growth as a
result of the low-pressure venous blood supply (Fig. 3-114).
Direct invasion of the adrenal glands may occur from primary
or secondary tumors of contiguous structures; however, direct
invasion is uncommon because of the adrenal capsule.
Involvement of the adrenal glands by certain malignancies
may be extensive, and both adrenals are likely to be affected.
Tumor emboli lodge in sinusoids of the adrenal medulla and
may grow to an extent that they compress the surrounding
adrenal cortex. The average rate of adrenal involvement in
metastatic cancer was 21% in dogs, 15% in cats, 27% in horses,
and 31% in cattle. In dogs, pulmonary, mammary, prostatic,
highest rates of metastasis; hemangiosarcoma and melanoma
had high rates of adrenal involvement in horses; and lym-
phoma was most common in cats and cattle.
Further reading
Ash RA, et al. Primary hyperaldosteronism in the cat: a series of 13
cases. J Feline Med Surg 2005;7:173-182.
Behrend EN, et al. Diagnosis of spontaneous canine hyperadrenocorti-
cism: 2012 ACVIM consensus statement (small animal). J Vet Intern
Med 2013;27:1292-1304.

Further reading
Altman NH, et al. Castration and its relationship to tumors of the
adrenal gland in the goat. Am J Vet Res 1969;30:583-589.
Bielinska M, et al. Gonadectomy-induced adrenocortical neoplasia in
the domestic ferret (Mustela putorius furo) and laboratory mouse.
Vet Pathol 2006;43:97-117.
Couëtil L, et al. Plasma adrenocorticotropin concentration in healthy
horses and in horses with clinical signs of hyperadrenocorticism. J
Vet Intern Med 1996;10:1-6.
Doss JC, et al. Immunohistochemical localization of chromogranin A in
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354 CHAPTER 3  •  Endocrine Glands Paragangliomas (Chemodectomas)

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between the ascending aorta and pulmonary artery near the
left coronary artery, and scattered in the wall of the pulmonary
artery. Although chemoreceptor tissue appears to be widely
distributed in the body, tumors develop principally in the aortic
and carotid bodies of animals. The genetic pathogenesis of
paragangliomas is similar to pheochromocytoma (see Pheo-
chromocytoma and malignant pheochromocytoma).
Aortic body adenoma and carcinoma
Aortic body neoplasms are encountered more frequently than
neoplasms of the carotid body in animals, but the reverse is
true for humans. These tumors develop primarily in dogs, and
infrequently in cats and cattle. Brachycephalic breeds of dogs,
such as the Boxer and Boston Terrier, are highly predisposed
to develop tumors of the aortic and carotid bodies.
Aortic body tumors appear most frequently either as single
masses or as multiple nodules within the pericardial sac near the
base of the heart (Fig. 3-115A). They vary considerably in size
(0.5-12 cm) with carcinomas, in general, being larger than
adenomas. Solitary small aortic body adenomas either are
attached to the adventitia of the pulmonary artery and ascend-
ing aorta or are embedded in the adipose connective tissue
a

PARAGANGLIOMAS (CHEMODECTOMAS)
Development, structure, and function
Paragangliomas are neuroendocrine tumors derived from cells
of the neural crest and occur in association with sympathetic
or parasympathetic ganglia in the body (head, neck, thorax,
and abdomen). Synonyms include chemodectoma and glomus
tumors. They usually are benign. In domestic animals, most A
paragangliomas occur in dogs and are derived from the che-
moreceptor organs (nonchromaffin extra-adrenal paraganglia),
which are sensitive to changes in the blood carbon dioxide
content, pH, and oxygen tension, thereby aiding in the regula-
tion of respiration and circulation. Carotid and aortic bodies
can initiate an increase in the depth, minute volume, and rate
of respiration by way of parasympathetic nerves, and result in
an increased heart rate and elevated arterial blood pressure by
way of the sympathetic nervous system. They are composed
normally of parenchymal (chemoreceptor, glomus) cells and stel-
late (sustentacular) cells. Nerve endings with synaptic vesicles
as well as nerve fibers are seen in close association with the
chemoreceptor cells.
Chemoreceptor tissue is present at several sites in the body,
including the carotid body, aortic bodies, nodose ganglion of B
the vagus nerve, ciliary ganglion in the orbit, pancreas, bodies
on the internal jugular vein below the middle ear, and glomus Figure 3-115  Aortic body tumor in dogs. A. Aortic body tumor
jugulare along the recurrent branch of the glossopharyngeal (arrowheads) at the base of the heart of a dog, adjacent to the
nerve. Aortic bodies of dogs normally consist of clusters of aorta (a). Bar = 1 cm. B. Aortic body tumors consist of sheets or
cells embedded in adventitia at multiple sites, including the clusters of polyhedral cells with eosinophilic or vacuolated cyto-
innominate artery immediately below the origin of the right plasm separated by fine fibrous stroma. Most tumors contain
subclavian artery, on the cranial surface of the aortic arch, scattered hypertrophic giant cells with lobulated karyomegalic
beneath the arch between the aorta and pulmonary artery, nuclei (arrow).
 Paragangliomas (Chemodectomas)
between these major vascular trunks. They have a smooth
external surface and on cross-section are white, mottled  tumors.
with red to brown areas. Larger adenomas may indent the atria
or displace the trachea, are multilobular, and partially sur-
round the major arterial trunks at the base of the heart.
Although the vessels may be completely surrounded by neo-
plastic tissue, there usually is little evidence of vascular
constriction.
Aortic body carcinomas occur less frequently in dogs than
adenomas. Carcinomas may infiltrate the wall of the pulmo-
nary artery to form papillary projections into the lumen or
invade through the wall into the lumen of the atria. Although
tumor cells often invade blood vessels, metastases to the lung
and liver occur infrequently.
Aortic body tumors in animals tend to be more benign than
tumors of the carotid body. They grow slowly by expansion
and exert pressure on the vena cava and atria. Aortic body
carcinomas may invade locally into the atria, pericardium, and
adjacent large thin-walled vessels. When they metastasize, sec-
ondary foci of growth are found most frequently in the lung
and liver.
Tumors of the aortic bodies in animals are not functional
(i.e., they do not secrete excess hormone into the circulation),
but may result in a variety of functional disturbances as space-
occupying lesions. These include manifestations of cardiac
decompensation caused by pressure on the atria, vena cava, or
both, associated with larger aortic body adenomas and carci-
nomas. There may be dyspnea, coughing, vomiting, cyanosis,
hydrothorax, hydropericardium, ascites, edema of the subcu-
taneous tissue (involving head, neck, and forelimbs), and
passive congestion of the liver. The accumulation of serous,
often blood-tinged, fluid in the pericardial sac, results from
the invasion of tumor cells into lymphatics at the base of the
heart or the compression of small pericardial veins.
Carotid body adenoma and carcinoma
Carotid body neoplasms arise near the bifurcation of the common
carotid artery in the cranial cervical area. They usually appear
as a unilateral slow-growing mass and only rarely develop on
both sides in the same animal.
Carotid body adenomas are well encapsulated, have a
smooth external surface, and are 1-4 cm in diameter. The
bifurcation of the carotid artery is incorporated in the mass,
and tumor cells adhere firmly to the tunica adventitia. A
branch of the glossopharyngeal nerve may be traced into the
capsule of the tumor by careful dissection. Adenomas are firm,
white with scattered areas of hemorrhage, and extremely vas-
cular. Complete surgical excision or biopsy often is difficult
due to the high degree of vascularity and intimate relationship
with major arterial trunks in the neck.
Carotid body carcinomas are larger (up to 12 cm in diam-
eter) and more coarsely multinodular than adenomas.
Although malignant carotid body tumors appear to be encap-
sulated, tumor cells invade the capsule and penetrate into the
walls of adjacent vessels and lymphatics. The external jugular
vein and several cranial nerves (in addition to the carotid
bifurcation) may be incorporated by the neoplasm. Larger
tumors can result in extensive dorsolateral deviation of the
trachea. Metastases of carotid body tumors occur in about 13
of cases and have been found in the lung, bronchial and medi-
astinal lymph nodes, liver, pancreas, and kidney. Multicentric
neoplastic transformation of chemoreceptor tissue occurs fre-
quently in brachycephalic breeds of dogs. About 2 3 of the
355
reported cases of carotid body tumors also had aortic body
The histologic characteristics of chemoreceptor tumors
(“chemodectomas”) are essentially similar whether they are
derived from the carotid or aortic body. The neoplastic che-
moreceptor cells are subdivided into lobules by prominent
branching trabeculae of connective tissue that originate from
the fibrous capsule. They are further subdivided into small
compartments by fine septa that contain collagen and reticulin
fibers plus small capillaries. Tumor cells are commonly aligned
along and around small capillaries. Most tumors contain a
variable number of large hypertrophied giant cells with irregu-
lar or lobated karyomegalic nuclei (Fig. 3-115B).
The tumor cells of chemodectomas are discrete, cuboidal
to polyhedral, and closely packed. The cytoplasm is lightly
eosinophilic, finely granular, and often vacuolated. Cells 
comprising chemodectomas rapidly undergo autolysis. Cell
boundaries become indistinct, and the cytoplasm appears
clear if the postmortem interval is prolonged. Chromaffin gran-
ules cannot be demonstrated in the cytoplasm of cells comprising
chemodectomas, in contrast to pheochromocytomas of the
adrenal medulla. However, the tumor cells contain variable
numbers of endocrine secretory granules that can be demon-
strated by electron microscopy and will stain immunohisto-
chemically positive for chromogranin A. The tumor cells may
also be positive for neuron-specific enolase, synaptophysin,
and S-100 protein, but not all cases will be positive for these
markers.
Cells of aortic and carotid body tumors in the dog resemble
those in normal chemoreceptor tissue, but lack the normal
relationship to sustentacular, neural, and vascular elements.
The large polyhedral chemoreceptor or parenchymal cells are
arranged in small clusters. The cytoplasmic density of the
neoplastic cell varies from light to dark, depending on the
development of secretory organelles and numbers of storage
granules.
Carotid body tumors are very vascular and have numerous
muscular arterioles, large thin-walled veins, and an abundant
network of capillaries in the connective tissue septa. There are
focal areas of hemorrhage from disruption of thin-walled
vessels and areas of coagulative necrosis. Several layers of
tumor cells may radiate along fine connective tissue septa
from the thin-walled vessels. Tumor cells frequently invade
blood vessels and lymphatics with the formation of emboli.
Carcinomas have evidence of tumor cell invasion through the
capsule and into the walls of large muscular arteries and adja-
cent structures.
Dogs with carotid body tumors usually are presented with
a palpable, slowly enlarging mass in the craniolateral cervical
region near the angle of the mandible. Larger neoplasms inter-
fere with swallowing because of pressure on the esophagus
and result in circulatory disturbances from compression of the
larger veins in the neck. Other functional disturbances may
be related to the presence of an aortic body tumor in the same
animal.
Carotid body tumors tend to be more malignant than aortic
body tumors, and metastases are present in about 13 of reported
cases. The presence of tumor cell emboli in vascular or lym-
phatic spaces in a biopsy of a primary chemodectoma does
not necessarily indicate that metastases are present in distant
organs.
The etiology of carotid and aortic body tumors is unknown,
but it appears that a genetic predisposition aggravated by chronic
356 CHAPTER 3  •  Endocrine Glands
hypoxia may account for the higher risk of certain brachyce-
phalic breeds, such as the Boxer and Boston Terrier. Carotid
bodies of several mammalian species, including dogs, undergo
hyperplasia when subjected to chronic hypoxia by living in a
high-altitude environment. People and cattle living at high
altitudes have a higher frequency of chemodectomas com-
pared to those living at sea level.
Heart-base tumors derived from
ectopic thyroid
Adenomas and carcinomas derived from ectopic thyroid tissue
account for ~5-10% of “heart-base” tumors in dogs. They often
compress or invade structures in the cranial mediastinum near
the base of the heart. Areas of ectopic thyroid tumors with a
compact cellular (solid) pattern of arrangement are difficult
to distinguish histologically from aortic body tumors. Cells
comprising ectopic thyroid tumors generally are smaller than in
aortic body tumors, with more hyperchromatic nuclei and eosino-
philic cytoplasm.
Neoplastic thyroid follicular cells are not consistently sub-
divided into small packets by fine strands of connective tissue.
Tumor giant cells are infrequent in ectopic thyroid tumors,
and the stroma is less prominent. Multiple sections usually
reveal the formation of primitive follicular structures or colloid-
containing follicles by neoplastic follicular cells in ectopic
thyroid tumors but not in aortic body tumors. Thyroglobulin
immunohistochemistry can be used to confirm a diagnosis of
ectopic thyroid tumor if typical follicle structures and colloid
are not present. Ectopic thyroid carcinomas arising at the base
of the heart in dogs either remain localized and enlarge in the
cranial mediastinum or occasionally metastasize to extratho-
racic sites.
Extra-adrenal paragangliomas
Benign and malignant extra-adrenal paragangliomas in the
mediastinum or retroperitoneum are occasionally reported in
the horse, dog, cat, or other species. The tumors originate from
chromaffin or nonchromaffin paraganglia. The chromaffin
paraganglia are ganglia of the sympathetic truck, such as the
aortic-sympathetic ganglion (organ of Zuckerkandl) near the
adrenal gland. Tumors of chromaffin paraganglia are con­
sidered extra-adrenal pheochromocytomas. The tumor cell  C-cell carcinoma in humans.
morphology and pattern of paragangliomas are typical of neu-
roendocrine tumors or chemodectomas and may stain immu-
nohistochemically positive for chromogranin A, neuron-specific
enolase, or synaptophysin. Metastases of the malignant neo-
plasms are reported to occur to the brain, lung, kidney, spleen,
or thyroid gland.
Orbital (extra-adrenal) paragangliomas
A unique extra-adrenal paraganglioma occurs in horses, result-
ing primarily in clinical signs related to exophthalmos. The
lesion appears to be derived from cells of neural crest origin,
most likely nonchromaffin paraganglia near the ciliary gan-
glion. The neoplastic cells usually invade locally in the retro-
bulbar space but may infiltrate more aggressively through the
optic canal into the cranial vault, resulting in lysis of bone and
extension into the nasal cavity.
The tumors are densely cellular with nests or packets of
neoplastic cells subdivided by a fine fibrovascular (reticulin-
positive) stroma characteristic of neuroectodermal-derived
tumors. The cytoplasmic area is abundant, lightly eosinophilic,
Multiple Endocrine Neoplasia (MEN)
and finely granular, often with indistinct individual cell bound-
aries. The neoplastic cells stain positive by immunohistochem-
ical methods for chromogranin A and neuron-specific enolase.
Ultrastructurally, neoplastic cells of orbital paragangliomas in
horses are similar to those in canine aortic and carotid body
tumors, with typical membrane-bound secretory granules and
prominent arrays of rough endoplasmic reticulum.
Surgical removal of the tumors by transpalpebral orbital
exenteration has been performed with variable success,
depending upon the degree of local tissue invasion of the
tumor beyond the orbit. Manipulation of the tumors during
surgery may result in hypotension.
Further reading
Aupperle H, et al. Primary and secondary heart tumours in dogs and
cats. J Comp Pathol 2007;136:18-26.
Brown PJ, et al. Immunohistochemical characteristics of canine aortic
and carotid body tumours. J Vet Med A Physiol Pathol Clin Med
2003;50:140-144.
Ilha MRS, Styer EL. Extra-adrenal retroperitoneal paraganglioma in a
dog. J Vet Diagn Invest 2013;25:803-806.
Miesner T, et al. Extra-adrenal paraganglioma of the equine orbit: six
cases. Vet Ophthalmol 2009;12:263-268.
Paltrinieri S, et al. Pathologic and immunohistochemical findings in a
feline aortic body tumor. Vet Pathol 2004;41:195-198.
Rizzo SA, et al. Malignant mediastinal extra-adrenal paraganglioma
with spinal cord invasion in a dog. J Vet Diagn Invest 2008;20:272-
275.
Uchida K, et al. Glomus tumor in the digit of a cat. Vet Pathol
2002;39:590-592.
MULTIPLE ENDOCRINE NEOPLASIA (MEN)
Multiple endocrine neoplasia (MEN) occurs in humans who
have a genetic predisposition to developing endocrine tumors
in multiple organs. There are different subtypes of MEN,
depending on the genetic pathogenesis, which include MEN1,
MEN2A, MEN2B, and familial medullary thyroid carcinoma
(FMTC). Medullary thyroid carcinoma is the term used for
• MEN1 patients have islet cell tumors, pituitary adenoma,
and parathyroid hyperplasia caused by mutation of the
MEN1 gene that encodes for menin, which is a tumor
suppressor.
• MEN2A patients have parathyroid hyperplasia, C-cell
tumors or hyperplasia, and pheochromocytoma as the
result of a gain-of-function rearrangement of the RET
proto-oncogene, which is a cell membrane tyrosine kinase.
• MEN2B patients have C-cell tumor or hyperplasia, and
pheochromocytoma, also because of activation of RET.
• FMTC patients have familial C-cell tumors caused by acti-
vation of RET and the NTRK gene (receptor tyrosine
kinase for nerve growth factor).
Sporadic MEN has been reported in animals, such as dogs,
cats, horses, cattle, and rarely in other species. The genetic
pathogenesis has not been discovered in most cases, which
may differ from the conditions described in humans, because
the spectrum of neoplasia is variable. Rats have a high back-
ground incidence of C-cell tumors, but it appears that the RET
proto-oncogene does not play a role in the pathogenesis.
 356.e1

Further reading
Arias-Stella J, Bustos F. Chronic hypoxia and chemodectomas in bovines
at high altitudes. Arch Pathol Lab Med 1976;12:636-639.
Cheville NF. Ultrastructure of canine carotid body and aortic body
tumors: comparison with tissues of thyroid and parathyroid origin.
Vet Pathol 1972;9:166-189.
Cho K-O, et al. Metastatic intracavitary cardiac aortic body tumor in a
dog. J Vet Med Sci 1998;60:1251-1253.
Chou C-L, et al. Electrophysiological and immunocytological demon-
stration of cell-type specific responses to hypoxia in the adult cat
carotid body. Brain Res 1998;789:229-238.
Edwards C, et al. The carotid body in animals at high altitude. J Pathol
1971;104:231-238.
Hardcastle MR, et al. Carotid and aortic body carcinomas (chemodec-
tomas) in a dog. J Am Vet Med Assoc 2013;242:175-177.
Hayes HM, Sass B. Chemoreceptor neoplasia: a study of the epidemio-
logical features of 357 canine cases. J Vet Med (A) 1988;35:401-
408.
Herbach N, et al. Metastatic extra-adrenal sympathetic paraganglioma
in a horse. J Comp Pathol 2010;143:199-202.
Hoglund R. An ultrastructural study of the carotid body of horse and
dog. Z Zellforsch Mikrosk Anat 1967;76:568-576.
Kameda Y. The accessory thyroid glands of the dog around the intra-
pericardial aorta. Arch Histol Jpn 1972;34:375-391.
Kumamoto K, et al. Malignant aortic body tumor in a Holstein cow.
J Vet Med Sci 1997;59:383-385.
Levy M, et al. Chemodectoma in a horse. Can Vet J 1990;31:776-777.
Obradovich JE, et al. Carotid body tumors in the dog. Eleven cases
(1978-1988). J Vet Intern Med 1992;6:96-101.
Patnaik AK, et al. Extra-adrenal pheochromocytoma (paraganglioma)
in a cat. J Am Vet Med Assoc 1990;197:104-106.
Sander CH, Whitenack DI. Canine malignant carotid body tumor. J Am
Vet Med Assoc 1970;156:606-610.
Shinya K, et al. Glomus tumor in a dog. J Vet Med Sci 1997;59:949-
950.
Smith P, et al. The earliest histopathological response to hypobaric
hypoxia in rabbits in the Rifugio Torino (3370 M) on Monte Bianco.
J Pathol 1993;170:485-491.
van Maanen C, et al. Three cases of carcinoid in the equine nasal cavity
and maxillary sinuses: histologic and immunohistochemical fea-
tures. Vet Pathol 1996;33:92-95.
van Nes JJ, et al. Glomus jugulare tumour in a dog; a case report.
Tijdschr Diergeneeskd 1978;103:1091-1098.
Willis R, et al. Aortic body chemodectoma causing pulmonary oedema
in a cat. J Small Anim Pract 2001;42:20-23.
Yates WDG, et al. Chemoreceptor tumors diagnosed at the Western
College of Veterinary Medicine 1967-1979. Can Vet J 1980;21:
124-129.
 Multiple Endocrine Neoplasia (MEN) 357

Roccabianca P, et al. Multiple endocrine neoplasia type-I-like syndrome

Further reading
Germann SE, et al. Multiple endocrine neoplasia-like syndrome in a
horse. Vet Rec 2006;159:530-532.
Proverbio D, et al. Potential variant of multiple endocrine neoplasia in
a dog. J Am Anim Hosp Assoc 2012;48:132-138.
in two cats. Vet Pathol 2006;43:345-352.
For more information, please visit the companion site:
PathologyofDomesticAnimals.com.
 357.e1

Further reading
De Cock HEV, MacLachlan NJ. Simultaneous occurrence of multiple
neoplasms and hyperplasias in the adrenal and thyroid gland of
the horse resembling multiple endocrine neoplasia syndrome: case
report and retrospective identification of additional cases. Vet
Pathol 1999;36:633-636.
Kiupel M, et al. Multiple endocrine neoplasia in a dog. J Comp Pathol
2000;123:210-217.
Walker MC, et al. Multiple endocrine neoplasia type 1 in a crossbred
dog. J Small Anim Pract 2000;41:67-70.
CHAP TER 4 
Female Genital System
Donald H. Schlafer  •  Robert A. Foster
PATHOLOGY OF THE GENITAL SYSTEM OF THE
NONGRAVID FEMALE 359
GENERAL INTRODUCTION 359
Unique challenges presented by the female
reproductive system 359
DISORDERS OF SEXUAL DEVELOPMENT 360
Normal sexual differentiation 360
Establishment of sex chromosomes 360
Establishment of gonad phenotype 360
Phenotypic sexual development 360
Development of the tubular genitalia 360
Abnormal sexual development 361
Sex chromosome disorders of sexual development 363
XY disorders of sexual development 365
XX disorders of sexual development 365
Ovary—developmental anomalies 366
Cysts arising from remnants of developmental structures. 366
Arrested development of the paramesonephric duct 367
Vaginal anomalies 369
PATHOLOGY OF THE OVARY (NONDEVELOPMENTAL-RELATED
CONDITIONS) 370
Miscellaneous lesions 370
Age-related degenerative changes 371
Equine ovarian varicosities 371
Ovarian cysts 371
Germinal inclusion cysts of the mare 372
Cystic follicular disease 372
Cystic ovarian disease in cows 372
Luteinized cyst 373
Extra-ovarian lesions associated with cystic ovarian
degeneration in cows 373
Cystic ovarian degeneration in other species 374
NEOPLASTIC CONDITIONS OF THE OVARY 375
Sex cord–stromal tumors 375
Tumors of the surface celomic epithelium 377
Tumors of germ cells 377
Tumors of nongonadal tissues 378
Metastatic tumors 378
Vascular hamartomas 378
PATHOLOGY OF THE UTERINE (FALLOPIAN) TUBES 379
Hydrosalpinx 379
Salpingitis 380
Pyosalpinx 380
PATHOLOGY OF THE UTERUS 380
Abnormalities of position or location 380
Circulatory disturbances 381
PATHOLOGY OF THE ENDOMETRIUM 382
Irregularities of endometrial growth 382
Atrophy 382
Hyperplastic conditions of the endometrium 382
Adenomyosis 385
Endometrial polyp 385
Uterine accumulation of secretory or
inflammatory exudates 386
Hydrometra and mucometra 386
Serosal inclusion cysts 386
358
INFLAMMATORY DISEASES OF THE UTERUS 387
General considerations 387
Endometritis 388
Metritis 389
Chronic endometritis 389
Uterine abscess 390
Parametritis and perimetritis 390
Pyometra 390
PATHOLOGY OF THE GRAVID UTERUS, PLACENTA,
AND FETUS 393
General considerations 393
Embryonic death 395
Fetal death 395
Mummification of fetus 395
Fetal maceration and emphysema 396
Embryonic death with persistence of membranes (cystic
placental mole) 396
Adventitial placentation (semiplacenta diffusa) 396
Hydramnios and hydrallantois 397
Amniotic plaques, placental mineralization, and avascular
chorion 397
Prolonged gestation 397
ABORTION AND STILLBIRTH 398
Diagnosing the infectious causes of abortion 399
Bacterial causes of abortion 402
Brucellosis 402
Campylobacter infections of the genital tract in sheep
and cattle 406
Flexispira rappini infections 408
Listeriosis 408
Leptospira infections causing abortion in cattle 409
Leptospira infections of the pregnant uterus in swine 410
Leptospira infections causing abortion or stillbirth in horses 411
Leptospira infections causing abortion in sheep 411
Ureaplasma diversum infection 411
Trueperella pyogenes as a cause of abortion in cattle
and sheep 412
Salmonella as a cause of abortion in sheep and cattle 412
Yersinia pseudotuberculosis as a cause of abortion
in cattle, sheep, and goats 413
Histophilus somni infections of the pregnant bovine uterus 414
Chlamydophila (Chlamydia) infections causing abortions 414
Abortion in sheep, goats, and cattle caused by
Coxiella burnetii 416
Mare reproductive loss syndrome and late-term abortions 417
Nocardioform placentitis in mares 417
Miscellaneous infections causing abortion in mares 417
Mycotic abortion in cattle 418
Epizootic bovine abortion 419
Protozoan infections causing abortions 420
Toxoplasmosis 420
Neospora infections causing reproductive failure in cattle,
sheep, dogs, and cats 421
Sarcocystis species causing abortion in cattle, goats,
sheep, and pigs 423
Genital tritrichomoniasis 423
Pathology of the Genital System of the Nongravid Female
Viral infections of the pregnant uterus 424
Porcine reproductive and respiratory syndrome (PRRS) 424
Classical swine fever virus infection of the pregnant
uterus in sows 424
Bovine viral diarrhea virus infection of the pregnant uterus 425
Border disease virus infection in sheep and goats 426
Equine arteritis virus infection of the pregnant uterus
in mares 427
Wesselsbron virus infection of the pregnant uterus in
sheep and cattle 428
Porcine parvovirus infection of the pregnant uterus 429
Bovine parvovirus infection of the pregnant uterus in cattle 429
Canine minute virus infection 430
Bluetongue virus infections of pregnant sheep and cattle 430
Epizootic hemorrhagic disease virus infection of the
pregnant uterus in cattle, sheep, and white-tailed deer 431
Chuzan disease of cattle 431
Canine herpesvirus infection in pups and pregnant bitches 431
Suid herpesvirus 1 infection causing abortion in swine 432
Suid herpesvirus 2 (cytomegalovirus) infection of the
pregnant uterus of the pig 433
Bovine herpesvirus infections of the pregnant uterus
in cattle, goats, sheep, and pigs 433
Bovine herpesvirus 4 (cytomegalovirus) infection of
the pregnant uterus in cattle 435
Equid herpesvirus 1 abortion in horses 435
Akabane virus infection of the pregnant uterus 437
Schmallenberg virus infection of cattle, sheep, and goats 438
Aino virus infection in cattle 438
Cache Valley virus infection of sheep 438
Rift Valley fever virus infection of cattle and sheep 439
Circovirus postweaning multisystemic wasting syndrome 440
MISCELLANEOUS LESIONS OF THE POSTPARTUM UTERUS 440
PATHOLOGY OF THE CERVIX, VAGINA, AND VULVA 441
PATHOLOGY OF THE CERVIX 441
PATHOLOGY OF THE VAGINA AND VULVA 442
Swelling of the vulva 442
Inflammatory diseases of the vagina and vulva 443
Granular vulvitis 443
ACKNOWLEDGEMENTS
We gratefully acknowledge contributions made to this chapter by
authors of earlier editions: Dr. Richard B. Miller and Dr. Peter
C. Kennedy.
PATHOLOGY OF THE GENITAL SYSTEM OF
THE NONGRAVID FEMALE
GENERAL INTRODUCTION
Unique challenges presented by the female
reproductive system
In no other system does one commonly encounter so great a
variety of gross and microscopic changes in “normal” tissues
as those that are routinely encountered in reproductive organs
in the normal cycling and gravid female. The complex physi-
ologic events that are associated within the estrus cycle, in
pregnancy, or during the postpartum periods are accompanied
by dramatic tissue changes in the gonads, tubular, and external
genitalia, such as marked hyperplasia, atrophy, necrosis, hem-
orrhage, and tissue invasion. These are changes that patholo-
gists usually associate with pathologic processes. Consequently,
General Introduction 359
Infectious bovine cervicovaginitis and
epididymitis (“epivag”) 443
Infectious pustular vulvovaginitis of cattle 443
Contagious equine metritis 445
Necrotic vaginitis and vulvitis 445
Dourine 445
NEOPLASTIC CONDITIONS OF THE TUBULAR GENITALIA 447
Smooth muscle tumors (leiomyoma, leiomyosarcoma) 447
Canine transmissible venereal tumor 448
Fibropapilloma of the vulva 449
Transmissible genital papilloma of the pig 449
Carcinoma of the endometrium and cervix 449
Lymphosarcoma 450
Metastatic tumors 450
PATHOLOGY OF THE MAMMAE 451
Developmental biology 451
Inflammatory disease of the mammary glands 451
Mechanical injury 451
Innate and acquired resistance of mammae 451
Bovine Mastitis 452
Staphylococcal mastitis 452
Coliform mastitis 454
Streptococcal mastitis 455
Summer mastitis 455
Mycoplasma mastitis 456
Miscellaneous infections 456
Mastitis in swine 457
Mastitis in horses 457
Mastitis in sheep and goats 457
Mastitis in dogs and cats 458
Mastitis in camelids 458
MAMMARY MASSES INCLUDING NEOPLASIA 459
Non-neoplastic mammary enlargement and masses 459
Mammary neoplasia in dogs 460
Prognosis and grading of mammary neoplasia 460
Benign mammary neoplasms 460
Mammary carcinomas 460
Mammary sarcomas 463
Mammary neoplasia in cats 463
Mammary neoplasia in other species 464
when presented with reproductive tissues, an examining
pathologist must start with a firm understanding of the normal
embryology, anatomy, and reproductive physiology of the
species under study. Additionally, the reproductive tract
co-opts cytokines, immunologic and inflammatory compo-
nents for physiologic functions complicating interpretation.
Awareness of these is essential.
Remarkable species variations exist, which limits the useful-
ness of broad generalizations and makes casual extrapolations
fraught with error. A good clinical history that includes stage
of cycle, prior reproductive status, and supporting endocrinol-
ogy is especially important; if not provided, it should be
aggressively sought!
It must also be appreciated that, to a significant extent, the
commercial value of individual animals can depend on the
pathologist’s report (e.g., endometrial biopsy from a brood-
mare). Not only do the descriptive and diagnostic sections of
the report have to be accurate and precise, clinicians and
owners will likely place great weight on the pathologist’s
interpretation and assessment of clinical significance. This part
of the report must be carefully formulated.
Pathology of the reproductive system is unquestionably
both fascinating and challenging.
360 CHAPTER 4  •  Female Genital System
DISORDERS OF SEXUAL DEVELOPMENT
Disorders of sexual development are common and affect all
domestic animal species. Most are incidental, of a minor
nature, and do not affect reproductive performance. Some are
confused with serious disease during clinical examinations
(e.g., detection of cysts in or near the ovary during ultrasound
examination) and during routine surgery or postmortem
examinations. Basic knowledge of the normal process of sexual
development, including a full appreciation of the anatomic
changes that occur, is essential for the pathologist. The first
section of this chapter provides a brief overview of normal
sexual development. This is followed by a discussion of fre-
quently encountered lesions and anomalies of the reproduc-
tive organs.
Normal sexual differentiation
Knowledge of the essential elements of the developmental
biology of the reproductive organs is important for apprecia-
tion of the anatomy and histology of the gonads—tubular and
external genitalia of the female—and is essential for compre-
hension and interpretation of anomalies, the phenotype of
neoplasms, or the pathogenesis of many diseases.
There are 3 sequential series of events that occur during
normal sexual development:
1. The initial establishment of sex chromosomes (at
fertilization).
2. The subsequent modeling of embryonic gonadal tissue as
ovarian tissue, thereby establishing gonadal type.
3. Controlled, programmed regression and growth of differ-
ent parts of the indifferent tubular and external genital
tissues of the early embryo to form those definitive struc-
tures of the normal female reproductive pattern (the
female phenotype). This is referred to as the establishment
of sex phenotype.
Establishment of sex chromosomes
The determination of sex chromosomes is fixed at the time
of fertilization when egg and sperm unite. The expression of
genes imposes on the primitive bipotent gonad developmental
changes that will result in formation of the definitive gonadal
type (ovary or testis), a key step in control of subsequent
stages in sexual development.
Each normal embryo will have either XX (in females) or
XY (in males) sex chromosomes. Aberrations in the multiple
genes of sexual development can lead to a broad variety of
developmental anomalies. Knowledge gained through study
of spontaneous cases of abnormal sexual development in
animals and humans has greatly expanded through work
using engineered mutations in mice. However, the precise
mechanisms through which genes control each aspect of
sexual development are complex and only superficially
understood.
When the sex chromosomes are XX, there is no SRY and
therefore no testis-determining factors (for detailed develop-
ment of the male, see Vol. 3, Male genital system). The gonads
await activation of female specific genes. Upregulation of
many genes occurs early in female development and at the
same time or before SRY is expressed in males. WNT4 is an
important gene in ovarian and therefore female development.
It is active in the primitive bipotent gonad and is downregu-
lated in males. WNT4 upregulates the folistatin (FST) gene.
Nuclear receptor subfamily 0, group B, member 1 (NROB1),
Disorders of Sexual Development
also known as DAX1, is an important gene in the development
of females, and it is female specific. It is upregulated by WNT4,
and it is inhibited by SRY. It inhibits SOX9, the gene that is
important in male development. It is not, by itself, an ovary-
determining gene, however. Forkhead/winged helix transcrip-
tion factor 2 (FOXL2) is also female specific, like NROB1
(DAX1). In combination with bone morphogenetic protein 2
gene (BMP2), it upregulates FST expression.
Establishment of gonad phenotype
Growth and development of the gonads require a complex
series of steps. The ovary arises from paired primordial primi-
tive bipotent gonads called the genital ridges, located between
the mesonephros and attachment of the mesentery. Primordial
germ cells migrate to the developing indifferent gonad in
vessels of the wall of the yolk sac and the mesentery to the
sex cords. These sex cords go on later to organize as follicles
containing the germ cells.
In a normal XX female embryo, the outer cortical layer of
the primitive bipotent gonad becomes the ovary, whereas the
medullary region develops as the testis in normal male (XY)
embryos. The typical ovotestis has ovary at the periphery and
testis in the medulla. Gonadal factors control subsequent dif-
ferentiation of the rest of the reproductive organs. Hormones
produced by Sertoli cells and interstitial endocrine cells in
males act to promote male and inhibit female tubular and
external genitalia. Female sexual differentiation does not
require products from the fetal ovary, but does require activa-
tion of genes such as WNT4, DAX1, and SF1.
Phenotypic sexual development
Female tubular and external genital development progresses
in genetic female embryos only in the absence of hormones,
whereas in the male, anti-Müllerian hormone (AMH) and tes-
tosterone function to develop male structures. These hormones
influence the regression of female embryonic tubular struc-
tures and support the formation of male tubular organs (epi-
didymis, deferent duct, accessory genital glands) and stimulate
the progressive development of the genital tubercle to become
the penis, the genital folds to close as the prepuce, and the
genital sinus to differentiate into the pelvic structures.
Modeling of the tubular genitalia involves growth, fusion,
and extension of the embryonic paramesonephric ducts to
form the internal female tubular organs (uterus, cervix, and
cranial vagina) and changes in the urogenital recess, genital
tubercle, and genital folds to form the vulva, clitoris, vestibule,
and caudal vagina. The presence of androgens, either endog-
enous (from testicular tissue, e.g., in individuals with ovotes-
tes) or from exogenous sources (androgens administered
during pregnancy) can influence this development, leading to
partially masculinized females.
Development of the tubular genitalia
Even as the primitive bipotent gonads are developing from
the genital ridge, in embryos destined to become females,
cylindric (ductal and tubular) elements are forming in the
abdomen that will further differentiate into the tubular
genitalia.
During the early stages, male embryos and female embryos
contain the same structures and cannot be differentiated.
Paired mesonephric (Wolffian) ducts and paired parameso-
nephric (Müllerian) ducts form de novo from longitudinal
folds along the lateral inner abdominal wall (Fig. 4-1).
Pathology of the Genital System of the Nongravid Female
Mesonephric
tubules
Developing
gonad
Paramesonephric Mesonephric
duct duct
Figure 4-1  Embryonic development of the female genital system.
Initial development of the indifferent ducts, tubules, and external
genitalia is the same in male and female embryos. Anatomically,
the internal organs in the “indifferent” stage consist of 2 bilaterally
symmetrical ductal systems—the mesonephric (Wolffian; male)
and paramesonephric (Müllerian; female) ducts—and the devel-
oping, but uncommitted, gonad. Additionally, the mesonephric
duct develops tubular extensions at its cranial end that extend
into the hilar area of the gonad. Although the uterine tubes,
uterine horns, body, cervix, and cranial vagina develop from the
paramesonephric duct, the mesonephric tubes become the rete
and contribute to the sex cords of the ovary. Normally the ducts
of the opposite sex regress; however, their embryonic remnants
are frequently encountered in otherwise normal adult animals,
appearing as grossly detectable cystic structures in or near the
ovary, uterus, cervix, or vagina. (Illustration prepared with the
help of Michael Simmons.)
Mesonephric tubules branching from the cranial segment of
the mesonephric ducts contribute to development of the rete
and sex cords.
The mesonephric and paramesonephric ducts run parallel
to one another. Both ductal systems are symmetrically paired
and extend caudally toward the urogenital sinus. The cranial
ends of the developing paramesonephric ducts do not close
and open directly into the peritoneal cavity, corresponding to
the tissue that will become the fimbrial part of the uterine
tube. In domestic animals, the paramesonephric ducts fuse at
their caudal ends to form the body of the uterus, the cervix,
and the cranial vagina, each with a single lumen.
Abnormal sexual development
Disorders of sexual development (DSD) occur in all domestic
species. They result from abnormalities of sex chromosome
origin or inappropriate product; hormone; or receptor upregu-
lation, downregulation, or exposure. The mechanisms involved
in the production of many abnormalities are not known, and
a condition cannot often be classified precisely. The classifica-
tion of DSD is now based on as complete a description of the
underlying abnormality as possible, beginning with the sex
chromosome type, presence of SRY, gonad type, tubular genitalia,
and external genital phenotype. As sex chromosome typing
Disorders of Sexual Development 361
Figure 4-2  Abnormal external genitalia of a horse with a disor-
der of sexual development. There is clitoromegaly and partial
fusion of the vulvar lips. The external female genitalia were par-
tially masculinized from exposure to testosterone released from
testicular tissue (interstitial cells) present in its ovotestes during
embryonic development.
becomes more readily available, complete classification
becomes possible.
The main categories begin with the sex chromosome com-
plement. Disorders are therefore either sex chromosome, XX,
or XY DSD. The presence of the SRY gene is listed next. The
gonadal type (ovary, testis, ovotestis, or dysgenesis) follows.
The tubular genitalia and the external appearance are listed.
In completion, a specific syndrome is included. Terms such as
intersex, ambiguous development, hermaphrodite, or pseudo-
hermaphrodite are therefore avoided.
Abnormal sexual development commonly results in abnormal-
appearing external genitalia. As demonstrated in Figure 4-2, a
photograph of a mare with bilateral ovotestes, the external
genitalia have features that are partially female and partially
male. Testosterone produced by testicular tissues (interstitial
endocrine cells) of her ovotestes masculinized her external
genitalia. The vulva is located more ventrally than in a normal
female, the vulvar lips are variably fused, and there is clitoro-
megaly. Clitoral enlargement is an important indicator of an
underlying disorder. The spectrum of changes ranges from
nearly normal-appearing females, with grossly normal ovaries
and uteri, to males with small genitalia, perhaps hypospadias,
and gonads contained in scrotal sacs that look like testes with
epididymides, but histologically containing ovarian tissue. It is
not uncommon to find normal-appearing testes attached to
complete and well-formed uterine horns (Fig. 4-3).
Classification of gonads can be challenging, and patholo-
gists often have difficulty in identifying ovotestes. Ovotestes
contain both ovarian and testicular tissues (Fig. 4-4). Careful
examination of the connective tissue of the outer part of the
gonad for ovarian structures is required. Follicles can develop
here and can ovulate, and there may be corpora lutea in
362 CHAPTER 4  •  Female Genital System
Figure 4-3  Abnormal internal reproductive organs from a bitch,
revealing a near-normally formed, but hypoplastic, uterus
(paramesonephric duct derived). There are bilateral ovotestes
that are predominantly testicular and an attached epididymis
(derived from mesonephric tubules).
Figure 4-4  Section of an ovotestis from a bitch. The gonad is
contained within a bursa (visible on the left) and has both ovarian
tissue (with primary and antral follicles on the left) and lobules
of hypoplastic testicular tissue in the medullary area (on the right)
containing seminiferous tubules. Even relatively small areas of
testicular tissue in ovotestes produce sufficient amounts of
2 hormones: testosterone from the interstitial cells and anti-
Müllerian hormone from Sertoli cells, which act during early
gestation to masculinize the developing mesonephric and parame-
sonephric ducts, tubules, and the external genitalia.
gonads that also contain male (seminiferous and interstitial
endocrine) tissue. Ovotestes will vary greatly in both their
gross and microscopic appearance, depending on the relative
amounts of ovarian and testicular tissue present (Fig. 4-5).
Ovotestes composed predominantly of ovarian tissues are
usually contained in a bursa. There may be identifiable epi-
didymal tissues at the caudal pole, near the attachment of the
Disorders of Sexual Development
B
C
Figure 4-5  Ovotestes from bitches. These 3 subgross photo-
graphs show the variability in amounts of ovarian and testicular
tissue that occur in ovotestes. Microscopically, ovarian tissues are
found in the cortex, and testicular tissues develop in the medulla.
A. The ovotestis on the left is mostly ovarian, with only a few
lobules of hypoplastic seminiferous tubules in the medulla. B. The
ovotestis is mostly testicular tissue (seminiferous tubules forming
a lobular pattern), but also note the presence of tertiary follicles
in the ovarian tissue at the left pole. C. The ovotestis is nearly
entirely testicular and has a large epididymis attached.
proper ligament of the ovary. Ovotestes composed of mostly
testicular tissue will look like hypoplastic testes, have large
epididymides, and may be near or in the inguinal canal or
scrotal sac. They will, however, be attached to uterine horns.
In dogs, ovotestes are commonly contained within a bursa
(Fig. 4-6). Associated developmental changes involving the
tubular genitalia include persistence of variable amounts of
Pathology of the Genital System of the Nongravid Female
Figure 4-6  Gonadal tissues from a bitch. Although this ovotestis
is mostly testicular, it is enclosed in a bursa. Sections of the uterus
are shown in Figure 4-7.
Figure 4-7  Subgross picture of a section of one uterine horn from
the bitch in Figure 4-6. Note the presence of derivatives of both
the paramesonephric and mesonephric ductal systems (uterine
horn on right and deferent duct on left, respectively). Hypoplastic
deferent ductal tissues also located on the side of the broad liga-
ment (mesometrium).
mesonephric ductal tissues that are found as either cysts or
linear segments of the mesonephric duct(s) (Fig. 4-7).
Sex chromosome disorders of sexual development
An abnormal number or structure of sex chromosomes leads
to inadequate gene expression and subsequent disorders.
These disorders are divided into 2 groups: those with aneu-
ploidy and those with chimerism and mosaicism. Examples
of aneuploidy include X_ (a Turner-like syndrome), XXX, and
XXY (Kleinfelter-like syndrome). These mimic the human
equivalent of these syndromes. Chimerism and mosaics is
most commonly seen as freemartinism, where there is an XX/
XY sex chromosome combination. Chimerism, known as free-
martinism, occurs most commonly in cattle. The bovine freemar-
tin is a genetic female born co-twin with a male (twinning
occurs in 1-2% of pregnancies in cattle). The twinning is
Disorders of Sexual Development 363
Figure 4-8  Twin bovine embryos contained within their amnions.
Note the fusion of branches of their umbilical arteries causing
shared circulation of blood and establishment of chimerism.
When the twins are of opposite sexes, development of the female’s
reproductive organs will be altered and partially masculinized.
The constellation of changes that occur in her developing repro-
ductive organs is known as freemartinism.
dizygotic in most cases; anastomoses develop between the
placental vascular systems of the 2 fetuses (Fig. 4-8). Normal
development of the gonads, tubular, and external genitalia of
the female embryo is dramatically altered by hormones and
cells received through the common circulation with her male
twin. If anastomoses fail to develop, the female is not affected,
but almost all male-female twinning in cattle results in the female
becoming a freemartin.
The effect on the male is always minimal. In the female
the gonads are small and frequently contain hypoplastic semi-
niferous tubules (ovotestes). The uterine horns are hypoplas-
tic, or may be nearly completely absent or lack communication
with the vagina (Fig. 4-9). Some parts of the mesonephric
ducts are commonly present. The external genitalia commonly
have enlargement of the clitoris, a small vulva, and a promi-
nent tuft of hair (Fig. 4-10A). A consistent feature (and therefore
a key diagnostic feature) is the presence of poorly developed
vesicular glands attached to the lower fused segment of the
paramesonephric ducts (Fig. 4-10B). The vagina is short and
nonpatent.
A critical step in freemartinism is when blood of the twins
is exchanged and leads to permanent colonization by hematopoi-
etic cells, with the result that each twin develops an acquired
tolerance for the blood cells of the other. This condition
appears to be confined to hematopoietic cells. The allantoic
fusion in bovine twin pregnancies occurs at about the 10-mm
crown rump–length stage of development. Approximately
90% of females born co-twin with males are freemartins and
sterile. Freemartins occur in bovine triplets, quadruplets, and
quintuplets as well as twins.
Exchange of nonhematopoietic cells does not appear to
take place in freemartinism. It is believed that the male fetus
sterilizes the female by testis-determining factors carried by the
bloodstream via the placental anastomoses to the female gonad,
where it inhibits ovarian development. This inhibition is mani-
fest first functionally; estrogen production by the freemartin
ovary is reduced, and androstenedione is elevated as early as
40 days of gestation. This is well before morphologic evidence
of damage is recognized.
364 CHAPTER 4  •  Female Genital System
B is the presence of paired hypoplastic vesicular glands, seen in this
Figure 4-9  A, B. Reproductive organs of a newborn freemartin
calf. Note the markedly hypoplastic uterine horns, failure of the
paramesonephric ducts to fuse to form a single uterine body,
presence of paired vesicular glands, and abnormal gonads. In panel
A, note that the gonads in this case are also hypoplastic and are
sometimes ovotestes.
The gonad of a freemartin is usually a cordlike thickening
in the cranial border of the ovarian ligament. The rete is well
developed, but other ovarian structures may be absent. Alter-
natively, greatly reduced ovarian tissue can be present, but it
lacks the normal germ cell complement. The variation of the
tubular genitalia is directly linked to the degree of gonadal
development. When the gonad is predominantly ovary, there
is no epididymis and the deferent duct is poorly developed.
With increasing differentiation towards a testis, the deferent
duct and epididymis become better developed. The uterus
and uterine tube, of paramesonephric duct origin, may vary
Disorders of Sexual Development
B
Figure 4-10  A. Abnormal vulva from a freemartin heifer (same
animals as in Figure 4-9). Comparison of the external genitalia of
a normal newborn freemartin calf on the right and the prominent
clitoris and a long tuft of hair attached ventrally to the freemartin
calf’s vulva on the left. The vagina is shortened and not patent in
freemartins. B. A key diagnostic feature of the freemartin condition
photograph as paired structures extending from the nonpatent
vagina in the middle of the photograph.
from cordlike structures without a lumen to well-developed
uterine horns with lumen and endometrial glands. Communi-
cation with the vagina is always absent, no matter how well
developed the uterus may be.
Vestigial vesicular glands are always present, the vagina is
hypoplastic or nonpatent with a complete hymen, the vulva
and vestibule are hypoplastic, and the clitoris is enlarged.
Many freemartins have a prominent fold of skin on the median
plane of the body, extending from a position ventral to the
vulva to an area near the umbilicus. Mammary glands fail to
develop.
Twin ovulation is relatively common in horses. Most twins
do not survive to term, but vascular anastomoses with hema-
topoietic chimerism occur in equine twins, although freemar-
tinism is not proven. Large anastomoses occur between
chorionic sacs in swine, and freemartinism results. Because of
Pathology of the Genital System of the Nongravid Female Disorders of Sexual Development 365

the large litter size, it is difficult to identify the neighbor of

affected piglets, and proof is lacking. In sheep, dizygotic twin-
ning is common and freemartinism does occur, but it is much
less common; only 1% of male female co-twins are freemar-
tins. Large-caliber interplacental anastomoses develop infre-
quently. Freemartinism does occur in goats, complete with
hematopoietic chimerism, but is rare because, as in sheep,
large anastomoses between fetuses are rare. Freemartinism
occurs in camelids also, but is not reported in dogs or cats.

XY disorders of sexual development

Any congenital disorder of the genital system in an animal
with XY sex chromosomes is called an XY DSD. They are
subdivided into those with or without an SRY gene (XY SRY+
and XY SRY− DSD). The most extreme is the XY SRY+
ovarian DSD with female internal genitalia and phenotype. Figure 4-11  Retained ovotestis in a young mare that had mascu-
Individual examples of all species of domestic mammals linized external genitalia. The retained gonads have gross features
with XY sex chromosomes and female phenotype are reported. of hypoplastic testes and nearly normal-appearing epididymes.
The majority are XY, SRY+, testicular DSD with a female
phenotype. These were called XY sex reversal syndrome,
androgen insensitivity, or testicular feminization syndrome.
Horses have an inherited autosomal sex-limited dominant
trait with a Y chromosome mutation with variable expression.
There is a considerable range of phenotypic expression in this
syndrome. Affected individuals vary from phenotypically
normal but sterile mares with inactive ovaries and normal
tubular genitalia, to individuals with streak gonads or ovotes-
tes and severely hypoplastic or aplastic tubular genitalia. A
family of horses with an XY, SRY+ DSD that is an X-linked
trait, based on pedigree analysis, is reported. Affected animals
were phenotypically normal mares but had hypoplastic testes
and uteri.
An XY SRY+, testicular DSD, and female phenotype is
especially recognized in humans, mice, rats, horses, cattle, and
cats. This inherited syndrome has a controlling mutation identi-
fied as TFM. Affected individuals have XY chromosomes and
have testosterone-producing testes. The external genitalia are Figure 4-12  Photomicrograph of gonadal tissues from the mare
female in type. The TFM mutation produces a deficiency of in Figure 4-11 demonstrating the presence of many hypoplastic
intracellular androgen receptors, rendering all cells insensitive seminiferous tubules and interstitial cells.
to androgens. AMH is still produced by the testes of affected
animals, and therefore paramesonephric duct derivatives are
absent because of their sensitivity to this hormone. Horses XX disorders of sexual development
with this syndrome have normal-appearing female external Mammals with XX sex chromosomes and abnormal sexual
genitalia. The vagina ends in a blind sac, with no cervix, uterus, development are myriad. The majority are normal females
or uterine tubes being present. The gonads are small and with a minor anomaly, such as cystic remnants of ducts or
clearly testicular, but present in the normal ovarian position tubules. These are the XX SRY−ovarian DSD. There are no
(Fig. 4-11). The seminiferous tubules are small and lined by reports documenting an XX, SRY+ DSD in domestic mammals.
inactive Sertoli cells (Fig. 4-12). Rare spermatogonia can be An extreme XX SRY− DSD is complete sexual reversal
found, but spermatogenesis does not occur. Well-differentiated (XXSR), where the sex chromosomes are XX and the phe-
interstitial endocrine cells are present (see Fig. 4-12). notype is male. Much of what is known about this condition
Horses with the syndrome have no detectable male acces- is from mice that have an autosomal dominant gene, Sxr,
sory genital glands. Cattle with this syndrome have rudimen- which acts like a Y chromosome. Thus XX mice that carry
tary vesicular glands and ampullae. Both cattle and horses that the Sxr gene develop testes and male tubular genitalia. A
lack androgen receptors have normally formed female similar condition occurs in dogs, pigs, and goats, although in
mammae. Horses are unique as affected individuals show male these species the autosome-associated gene with the Y action
behavior patterns. This syndrome is distinguished from others functions as a recessive gene.
by assaying the androgen receptors on target cells, such as XX ovotesticular female DSD (XX sex reversal) is common
fibroblasts from the genital skin. Labial tissue must be used in pigs. The mode of inheritance is unknown, and some cases
because receptor activity is sharply reduced in nongenital skin. are confused with freemartinism. The masculinizing effect is
Occasional mammals with XY SRY+ DSD and gonadal dys- incomplete. The gonads in affected individuals are often ovo-
genesis are reported. They are phenotypically female. Those testes and, although the testicular tissue lacks germ cells, ovu-
phenotypically male animals that are XY SRY+ but have lation and pregnancy are reported. Hematopoietic chimerism
anomalies are discussed in Vol. 3, Male genital system. does not exist, as would occur in freemartinism.
366 CHAPTER 4  •  Female Genital System Disorders of Sexual Development

This condition is studied in goats with the polled intersex

syndrome (PIS). Affected goats have an XX testicular or XX
ovotesticular disorder of sexual development because they
have a deletion of the 11.7 kb PIS region of chromosome 1.
The PIS region is a normal region that is 300 kb upstream of
and regulates the function of FOXL2, an ovary determining
gene in goats. FOXL2 normally inhibits DMRT1 that regulates
the testis-determining gene SOX9. Deletion of the PIS locus
results in an inactive FOXL2 and a male goat with XX chro-
mosomes. The autosomal gene with the testis-determining
region is on the chromosome that controls polling or is closely
linked to it. The polled gene is a dominant autosome, a single
copy of which produces hornlessness without affecting sexual
differentiation. In the homozygous condition, however, there
is apparent translocation of a subcritical portion of the testis-
A
determining gene to the autosome that contains the gene for
polling, producing the recessive mode of sex determination.
There is a considerable range of masculinization. The affected
individuals may have largely female appearance with only an
enlarged clitoris and abdominal testes. Other animals have the
appearance of near-normal, although sterile, males.
XX SRY− males caused by male differentiating genes on
the X chromosomes are reported in >15 breeds of dogs. The
American Cocker Spaniel breed is particularly prone. XX
SRY− testicular and XX SRY− ovotesticular DSD are described.
Some XX SRY−ovotesticular female DSD are fertile and give
birth to pups. The male components of the gonads lack germ
cells. The condition has an autosomal recessive inheritance.
Genes other than SRY are implicated, possibly SOX9, in ini-
tiating male differentiation in XX female canine embryos.
B
Ovary—developmental anomalies
Abnormal development of genital components is described in Figure 4-13  Duplication of the ovaries occurs very rarely. A. The
the context of normal sex chromosomes (XX for females). gonads in this newborn calf were each divided, giving the impres-
The majority are XX SRY− ovarian DSD. sion that 2 separate gonads had formed. An isthmus attaches the
Agenesis of one or both ovaries is rare, but is observed in ovaries on the right. B. The 2 separated left gonads are shown
ruminants, swine, and dogs. In bilateral agenesis, the tubular more clearly in this photograph.
genitalia may be absent as part of the defect or, if present, are
infantile or underdeveloped. with neoplasms, they are described in the section on ovarian
Duplication of ovarian tissues is very rare. Although there tumors.
are no controlled studies, duplication may just be splitting of Hypoplasia of the ovaries is studied primarily in cattle, but
ovarian tissue. Ovaries from a young calf with ovarian duplica- occurs in other species. It is usually bilateral but varies consider-
tion are shown in Figure 4-13. ably in its severity and symmetry so that “severe hypoplasia” or
Ovarian remnants. Interest in the occurrence of anomalous “partial hypoplasia” may be applicable to one or both ovaries.
ovarian duplication commonly arises when either cats or dogs, In severe hypoplasia, the defective gonad varies in size from
supposedly surgically neutered, exhibit signs of estrus. This is a cordlike thickening in the cranial border of the mesovarium
ovarian remnant syndrome. In the bitch, the effects of circulat- to a flat, smooth, firm, bean-shaped structure in the normal
ing estrogen are easily detected by serial vaginal cytology. position. There are neither follicles nor luteal scars and, micro-
Hormonal studies are confirmatory, and ultrasonographic and scopically, the ovary is largely composed of medullary connec-
exploratory surgical examinations are also done. This is best tive tissues and blood vessels.
done when the animal is in estrus and has large follicles or Ectopic adrenal tissue is usually found incidentally during
during the luteal phase of the cycle, when corpora lutea would histopathology. These small nodules are composed of adrenal
also make ovarian tissue easily identified. Although proposed, cortex and are most commonly found with the capsule of the
there is little information about whether small pieces of ovary of mares or with the ovarian suspensory ligament of the
ovarian tissue inadvertently released during canine or feline ovary of queens (Fig. 4-14).
surgery might implant on the peritoneal surface in the
abdomen. In some countries, parts of ovaries are surgically Cysts arising from remnants of
placed in the spleen and these subsequently develop ovarian developmental structures
neoplasia. Although frequently discussed, there is little evi- Cystic structures in and near the ovary and uterine tubes are
dence that congenital ectopic ovarian tissues occur in any of common, especially in the mare. Figure 4-15 demonstrates the
the domestic animal species. embryonic origin of the most common of these cysts. Cystic
Vascular hamartomas of the ovary are described in horses, remnants are more common and can become large, especially
swine, cattle, and dogs. Because they are often confused in the mare (Fig. 4-16).
Pathology of the Genital System of the Nongravid Female Disorders of Sexual Development 367

Cysts arising from either the cranial or caudal segments of
the mesonephric tubules are thin-walled, movable cysts at
either the cranial or caudal pole of the ovary and are called
cystic epoophoron or paroophoron, respectively, or just cystic
mesonephric tubule remnants. Cystic rete are common in the
cat and dog and arise from the rete ovarii, which are also
derived from the mesonephric tubules. These arise in the hilar
area of the ovary. All cystic remnants of the mesonephric
tubules have smooth muscle in their walls, whereas the cystic
rete do not. The epithelial lining is cuboidal in small cysts,
tends to become squamous in slightly larger cysts, and is often
absent due to pressure atrophy in larger cysts. Only the cystic
rete progress to compress ovarian tissues and compromise
ovarian function. Hyperplasia of the rete epithelium is com­
mon, and cystic adenomas occur, most commonly in the bitch.
Cystic apical segments of the paramesonephric duct or fim-
brial cysts are common in mares. They are 1 or 2 thin-walled
cysts, up to 1 cm in diameter, attached to the fimbria of the
uterine tube (Fig. 4-17). They may be detected by palpation
or by ultrasonography, but do not reduce fertility. The dif-
ferential diagnosis is a cystic remnant of the mesonephric
duct, but these are found adjacent to the uterine tube or along
the lateral border of the uterine tube, uterine body, or in the
cervix or vagina.
Mesonephric duct remnants are frequently found as small
cysts lying along the lateral side of the uterine tubes, uterine
horns, uterine body, cervix, or cranial vagina. They are in or
near the attachment of the mesosalpinx or mesometrium of
the uterine tube and uterine horns, but those found in the
uterine body and cervix tend to be found within the myome-
trium, and those in the vagina are commonly multiple or
linear cystic structures in the submucosa. Animals with disor-
ders of sexual development and a female phenotype often
have remnants of mesonephric ducts located in the attach-
ment of the mesometrium and run parallel with the uterine
horns (Fig. 4-18). These have the microscopic appearance of
the deferent duct of the male and have a lumen lined by
epithelial cells and a relatively prominent smooth muscle wall.
Cystic mesonephric duct remnants are common in the cow.
The fluid they contain is usually clear, but may be opaque
(Fig. 4-19).
Duplication of the paramesonephric duct is occasionally
seen in dogs. These have a more complex endometrial type
lining, and the cells become vacuolated in the diestral phase
of the estrus cycle.

Arrested development of the

Figure 4-14  Ectopic adrenal tissue is most commonly found
adjacent to, or attached to, the tunic of the ovary of the queen
and mare. A nodule of ectopic adrenal tissue (upper right) is in
the suspensory ligament adjacent to the ovary in this feline tissue.
Cross-sections of a uterine tube and ovary are also present.
paramesonephric duct
There are 3 patterns of defect:
1. Failure of segments of the paramesonephric ducts to
develop.
2. Failure of the caudal parts of the 2 paramesonephric ducts
to fuse appropriately and develop a single lumen.
3. Failure of the caudal ends of the fused paramesonephric
ducts to fuse with the invaginated urogenital sinus, leading

Cystic epoophoron

Fimbrial cyst hydatid

of Morgagni

Developing
gonad

Mesonephric duct cyst

Cystic paroophoron
Paramesonephric Mesonephric
duct duct

Figure 4-15  Cysts in or near the ovary and along the uterus are common, but usually incidental
findings. The embryonic origin of several common cysts is shown in this drawing. Details are
provided in the text, and examples of some of these cysts as they occur in different species are
shown in the following figures. (Michael Simmon, illustrator.)
368 CHAPTER 4  •  Female Genital System
Figure 4-16  A large cystic epoophoron extends from the proxi-
mal pole of the ovary of a mare. These cysts arise from remnants
of the cranial mesonephric tubules, and although they can become
large, do not reduce fertility. They are moveable over the surface
of the ovary, are frequently palpable per rectum, and can be seen
during ovarian ultrasonography.
Figure 4-17  Paramesonephric duct cyst (fimbrial cyst) extending
from the fimbria of the uterine tube of a young filly. These are
very common.
Figure 4-18  Cross-section of uterine horns at their bifurcation,
with a unilaterally persistent mesonephric duct (corresponding
to the deferent duct) in the mesometrial attachment on the right
side.
Disorders of Sexual Development
Figure 4-19  Cystic remnant of a mesonephric duct adjacent to
the uterine tube in a cow.
to failure of the lumen of the fused ducts to become con-
tinuous with the caudal vagina.
Segmental aplasia of the paramesonephric duct is found as
either failure of short or long segments of the uterine horn to
develop (Fig. 4-20). This was commonly found in white Short-
horn cattle and gave rise to the name “white heifer disease”
for the syndrome, but no breed is exempt from the condition.
The arrested development is thought to be autosomal reces-
sive. Complete absence of an entire horn is called uterus
unicornis. Within the isolated segments of uterus, secretions
and sloughed epithelial cells accumulate and become inspis-
sated to form soft tan concretions within the distended iso-
lated lumen of the uterine horn proximal to the area of
segmental aplasia (Fig. 4-21).
Failure of the paramesonephric ducts to fuse is most com-
monly found in the cow and usually involves the cervix, and
less commonly the uterine body. Partial failure of the parame-
sonephric ducts to fuse with loss of the joining wall to form
a single lumen is more common than complete failure to fuse.
An example of the more common appearance is shown in the
tissues in Figure 4-22. The uterine body and cranial cervix
have developed normally, but there is a persistent median
septum in the cervix, leaving 2 cervical canals and the appear-
ance of 2 cervices. The apparent septum is the medial walls
of the 2 paramesonephric ducts that failed to regress.
Less commonly, there may be failure of the caudal aspects
of the paramesonephric ducts to fuse. This occurs in the cow
and bitch and results in a longitudinal median band of tissue
extending from the mid-dorsal to the mid-ventral walls of the
vagina cranial to the urethral orifice.
Failure of fusion of the paramesonephric ducts with the
urogenital sinus results in persistence of a tissue band running
across the vagina just cranial to the opening of the urethra.
This tissue forms an imperforate hymen that is complete or,
more commonly, is only a small piece of the wall (Fig. 4-23).
The remainder of the genital tract may be normal, but if the
hymen is complete, in time and with the accumulation of
secretions (there may be 10 L or more), the vagina, cervix,
Pathology of the Genital System of the Nongravid Female
Figure 4-20  Segmental aplasia of the left uterine horn of a heifer
caused by failure of a segment of the paramesonephric duct of
this side to develop normally. Also note the hydrosalpinx.
Figure 4-21  Segmental aplasia of the left uterine horn of an adult
cow. The uterine wall has been opened revealing soft tan concre-
tions formed from accumulated uterine secretions and sloughed
cells.
and uterus become distended and atonic, and severe dilation
leads to atrophy and permanent loss of tone of the walls. If
the hymen is perforated and the distension relieved early, the
genital tract may function normally. If the hymen is complete,
secretions may accumulate and subsequent bacterial infection
of the contents can produce pyometra. In cows, moderate
hypoplasia of the cervix, in which some rugae are absent and
the canal widely patent, may prevent closure of the canal and
predispose to persistent invasion of the uterus and chronic
endometritis. Occasionally, the cervical canal is irregular in its
course or even tortuous. Although this may not interfere with
conception following natural breeding, insertion of an insemi-
nating catheter may be difficult or impossible. Repeated
attempts to pass a pipette can lead to cervical trauma, occa-
sionally complicated by formation of traumatic inclusion cysts
or abscesses.
Disorders of Sexual Development 369
B
Figure 4-22  Double external cervical os. A. As viewed from the
vagina—caused by failure of the medial wall of the mesonephric
ducts to join and dissipate during embryonic development. B. This
defect is demonstrated in the dissected bovine cervix. The uterine
body is normally formed as a result of fusion of the 2 parameso-
nephric ducts); however, 2 separate cervical canals (demonstrated
by the probes), are present in the distal cervix as a result of failure
of the medial wall of the joined paramesonephric ducts to fuse
and dissipate. Complete division of both the uterine body and
cervix is less common and when present is called uterus
didelphys.
Dilations and diverticula of the cervix are a cause of infer-
tility in heifers. The malformations occur at the level of the
third and fourth rugae, and the cervical canal is constricted
caudal to the defect. The dilated areas are usually spherical
and located near the internal os. Diverticula are dorsal or
dorsolateral and eventually become filled with tenacious
mucus. The cause of the condition is unknown, but is assumed
to be developmental.
Vaginal anomalies
Vaginal stenosis is uncommon in most species, but occurs to
variable degrees in bitches. It may be congenital or acquired.
The stenosis in Figure 4-24 was complete and had caused
dilation of the proximal vagina.
370 CHAPTER 4  •  Female Genital System
Figure 4-23  Incomplete hymen in the caudal vagina of a young
heifer. The hymen is a membrane that forms as a tissue band at
the point where the invaginating urogenital sinus that will form
the caudal vagina meets the caudal aspects of the descending
paramesonephric ducts, which will form the cranial vagina. Com-
plete or partial hymens are commonly found in young calves. The
vaginal lumen cranial to the hymen will accumulate mucus and
cellular debris.
Figure 4-24  Segmental stenosis of the tubular genitalia is uncom-
mon. The middle region of the vagina of this bitch was completely
occluded, and the lumen of the cranial vagina was distended with
tan fluids. (From Romagnoli S, Schlafer DH. Disorders of sexual
differentiation in puppies and kittens: a diagnostic and clinical
approach. Vet Clin North Am Small Anim Pract 2006;36:
573-606.)
Further reading
Elzaiat M, et al. High-throughput sequencing analyses of XX genital
ridges lacking FOXL2 reveal DMRT1 up-regulation before SOX9
expression during the sex-reversal process in goats. Biol Reprod
2014;91:153.
Hughes IA. Disorders of sex development: a new definition and clas-
sification. Best Pract Res Clin Endocrinol Metab 2008;22:119-134.
Meyers-Wallen VN. Review and update: genomic and molecular
advances in sex determination and differentiation in small animals.
Reprod Domest Anim 2009;44:40-46.
Meyers-Wallen VN. Gonadal and sex differentiation abnormalities of
dogs and cats. Sexual Develop 2012;6:46-60.
Poth T, Breuer W, et al. Disorders of sex development in the dog: adop-
tion of a new nomenclature and reclassification of reported cases.
Anim Reprod Sci 2010;121:197-207.
Schlafer DH, et al. A case of SRY-positive 38, XY true hermaphroditism
(XY sex reversal) in a cat. Vet Pathol 2011;48:817-822.
Pathology of the Ovary
Smith KC, et al. Morphological, histological and histochemical
studies of the gonads of ovine freemartins. Vet Rec 2003;152:
164-169.
PATHOLOGY OF THE OVARY
(NONDEVELOPMENTAL-RELATED
CONDITIONS)
Reproductive organs of sexually mature animals normally
undergo dramatic changes during the estrous cycle. These
morphologic changes associated with follicular development,
ovulation, luteinization, and regression of the corpus luteum
are referred to as the ovarian cycle. Species variations exist
that can potentially be very confusing, both during gross and
microscopic examination. Albeit beyond the scope of this
chapter, the importance of acquiring basic information from
the relevant literature, including basic texts on animal repro-
duction and theriogenology, cannot be overemphasized.
Miscellaneous lesions
Intrafollicular hemorrhage occurs commonly in calves and is
also found in follicular cysts in the bitch and occasionally in
atretic follicles of cows. Hemorrhage occurs during ovulation
in all species of domestic animals, but is usually minimal and
largely confined to the cavity of the collapsed follicle. However,
it can be severe and occasionally even lethal in the mare. In
the mare in the autumn (fall transition), hemorrhage occurs
in anovulatory follicles (hemorrhagic anovulatory or “autumn”
follicles).
Focal areas of serositis develop adjacent to corpora lutea,
indicating that they occur following ovulation. The recently
formed strands of tissue, which are referred to as ovulation
tags, are composed of fibrin, proliferating capillaries, and slight
infiltrates of leukocytes. As the lesion regresses, neutrophils
are replaced by lymphocytes, macrophages, and plasma cells,
and mesothelial cells cover the tags. Fine bursal adhesions may
result, but they are too delicate to interfere with ovulation or
the passage of ova into the uterine tube. Ovulation tags occur
in all species, but most frequently in the cow and mare. Scars
that form on the surface of the ovary are small and of no
consequence.
A significant form of ovarian hemorrhage is that which
follows the older clinical practice of manual enucleation of
corpora lutea in cattle. The blood loss may vary from 0.5 L to
several liters and cause death. Hemorrhage is more profuse in
pregnant cows and those with pyometra than in normally
cycling cattle. In cases of pyometra and salpingitis, the release
of inflammatory detritus into the bursa often results in the
formation of extensive adhesions between the uterine tube
and ovary. The expressed mass of luteal tissue persists indefi-
nitely as a roughly spherical, flattened soft mass. The mass
develops a fibrous capsule enclosing the necrotic luteal cells
and can be differentiated from a lipoma.
Postparturient vascular lesions occur frequently in the
bovine ovary. The changes consist of intimal proliferation of
mucoid tissue in ovarian arteries and hyalinization of the walls
of arteries and arterioles. Some of the more severely affected
vessels occasionally undergo thrombosis. Degeneration of arte-
rioles also occurs in rapidly regressing corpora lutea associated
with abnormally short estrous cycles.
Oophoritis is relatively rare and, when it occurs, it is
usually pyogenic (Fig. 4-25). Some cases of lymphocytic
 370.e1

Further reading
Campos M, et al. Sry-negative XX sex reversal in a French Bulldog.
Reprod Domest Anim 2011;46:185-188.
Cotinot C, et al. Molecular genetics of sex determination. Semin
Reprod Med 2002;20:157-167.
Ennis S, et al. The diagnosis of freemartinism in cattle using sex-specific
DNA sequences. Res Vet Sci 1999;67:111-112.
Kieffer NM. Male pseudohermaphroditism of the testicular feminizing
type of a horse. Equine Vet J 1976;8:38-41.
Koopman P. Sry and Sox9: mammalian testis-determining genes. Cell
Mol Life Sci 1999;55:839-856.
Koopman P, et al. Male development of chromosomally female mice
transgenic for Sry. Nature 1991;351:117-121.
Lillie FR. The freemartin; a study of the action of sex hormones in the
foetal life of cattle. J Exp Zool 1917;23:371-452.
MacLaughlin DT, Donahoe PK. Sex determination and differentiation.
N Engl J Med 2004;350:367-378.
Nielsen TD, et al. Ovarian cysts in guinea pigs: influence of age and
reproductive status on prevalence and size. J Small Anim Pract
2003;44:257-260.
O’Connor CL, et al. Trisomy-X with estrous cycle anomalies in two
female dogs. Theriogenol 2011;76:374-380.
Rota A, et al. Age dependent changes in plasma anti-Müllerian
hormone concentrations in the bovine male, female, and freemar-
tin from birth to puberty: relationship between testosterone pro-
duction and influence on sex differentiation. Gen Comp Endocrinol
2002;129:39-44.
Rota A, et al. The case of an Sry-negative XX male Pug with an inguinal
gonad. Reprod Domest Anim 2010;45:743-745.
Veitia RA, et al. Testis determination in mammals: more questions than
answers. Mol Cell Endocrinol 2001;179:3-16.
Wilker CE, et al. XX sex reversal in a llama. J Am Vet Med Assoc
1994;204:112-115.
Pathology of the Genital System of the Nongravid Female
Figure 4-25  Purulent oophoritis has destroyed the ovary of this
cow. This cow also had suppurative salpingitis and metritis. The
uterotubal junction usually prevents ascending infection from an
infected uterus.
oophoritis are reported in dogs as a potential cause of ovarian
and ovulatory failure.
Ovarian abscesses may follow enucleation of the corpus
luteum in cows with pyometra or from oocyte retrieval using
needle aspiration. Serosal granulomas on the ovary occur in
bovine peritoneal tuberculosis and in brucellosis, visible mac-
roscopically as small red nodules or tags. Similar lesions are
usually visible on adjacent serosal surfaces of the genital
organs and adnexa. These infective granulomas remain local-
ized to the surface of the ovary and do not penetrate its
substance.
Perioophoritis occurs in cats with feline infectious perito-
nitis and secondary to salpingitis. The characteristic lesions of
feline infectious peritonitis should include a plasma cell–rich
inflammatory process; confirmation of the presence of the
feline coronavirus is by immunohistochemistry.
Age-related degenerative changes
Equine ovarian varicosities
The surface of the equine ovary is richly endowed with veins
that, with age, commonly become varicose. Thrombi may
form, and if extensive can lead to infarction or ischemic
damage to the ovary. Ovarian varicosities are rare in other
species. They appear as dark, nearly black serpentine, fluid-
filled tissue on the surface of the ovary (Fig. 4-26A, B).
Ovarian cysts
Cysts arise either within or adjacent to the ovary. Several dif-
ferent types of cysts develop from embryonic structures,
including cysts of the mesonephric duct, mesonephric tubules,
and paramesonephric duct (see Fig. 4-15). These cysts are
discussed briefly in this section.
There are 3 types of cysts that develop from mesonephric
tubules: cystic rete, cystic epoophoron, and cystic paroopho-
ron. A cystic epoophoron (see Fig. 4-16) develops from the
cranial mesonephric tubules, whereas a cystic paroophoron
occurs less commonly and is found on the caudal surface of
the ovary. Because these cysts are found near the ovary, they
are casually referred to as paraovarian cysts. More precise
identification can be achieved through closer examination
(the location relative to the ovary is very helpful) or by his-
topathology. Cysts of the epoophoron and paroophoron are
movable cysts on the cranial surface of the ovary and have a
thin wall of connective tissue and muscle fibers, are lined by
Pathology of the Ovary 371
A
B
Figure 4-26  A. Varices on the surface of the ovary of an older
mare. B. Subgross photograph showing the distended veins on the
surface of this ovary. These vessels commonly thrombose.
low columnar epithelium with clear cytoplasm, and have a
basement membrane. Follicles may protrude from the surface
of the ovary, but are not movable.
Cystic rete (Fig. 4-27) develop from mesonephric tubules
that form the rete ovarii within the ovary. Less commonly,
cystic extraovarian rete are found. Cystic rete tubules have
been observed in the bitch, queen, and cow. Those in the cow
seldom attain significant size, but those of the bitch and queen
occur commonly and can become large enough to be confused
with cystic follicles, cyst adenomas, or cyst adenocarcinomas.
Cystic rete are differentiated from cystic remnants of the
mesonephric duct by the absence of smooth muscle in their
wall. Cystadenomas of the ovary may arise focally in these
cysts, but these are exceptionally rare.
Cysts of paramesonephric duct origin are very common in
the mare. They are located on the fimbria of the oviduct and
are called fimbrial cysts, hydatids of Morgagni, or accessory
oviducts.
Cystic subsurface epithelial structures (cystic SES) of the
bitch. The modified peritoneal cells covering the surface of
the ovary of the bitch normally extend into the ovary a short
distance, where they are arranged as small, single, epithelial-
lined cavities called “subsurface epithelial structures” or SES.
Their importance is 2-fold. They frequently give rise to single,
or more commonly, multiple cysts extending along the ovarian
surface, and SES often undergo papillary hyperplasia and neo-
plastic transformation. Neoplasms of the SES are usually
adenomas, but carcinomas do occur. These tumors tend to
372 CHAPTER 4  •  Female Genital System
Figure 4-27  Cystic rete ovarii have compressed ovarian tissue in
this cat. Cyst rete are common in the ovaries of queens and fre-
quently occur in bitches. They develop in the hilar area of the
ovary. They can be single or multiple.
form cysts and have a folded, papillary pattern. They are often
multifocal.
The incidence of cysts of the SES increases with age. They
are small, seldom larger than 5 mm in diameter, and can be
located anywhere within the ovary, but their relationship to
the surface is usually obvious. These cysts are lined by cuboi-
dal epithelium. They do not appear to have any effect on
fertility, but because the SES are hormonally sensitive, cyst
formation may be associated with hormonal dysfunction. The
lining of the cysts, like the surface epithelium and the SES,
expresses cytokeratin, and this allows differentiation from
atretic follicular cysts.
Germinal inclusion cysts of the mare
Entrapment of small segments of peritoneum is associated
with ovulation, and in the mare leads to the development of
inclusion cysts that are found near the ovulation fossa (Fig.
4-28). They are also referred to as fossa cysts. Although rather
commonly encountered as one or a few small cysts lined by
epithelial cells (small follicles are lined by granulosa cells) near
the ovulation fossa, they are rarely numerous or large enough
to interfere with ovulation. Occasionally, their expansion can
lead to atrophy of compressed ovarian tissue with loss of
function.
Cystic follicular disease
Anovulatory cystic ovarian disease occurs in most, if not all,
species. Its importance as a disease entity varies greatly among
species; in domestic species, it is only a serious problem in cows
and sows. Cystic ovarian disease occurs infrequently in the
bitch and queen and rarely in the mare, ewe, doe, and
camelids.
Diagnosis depends in part on differentiating anovulatory
cystic follicles from normal antral or tertiary follicles. An
important criterion for this differentiation is size. Follicles
larger than they should normally be at ovulation, persistence,
and possible associated signs of hyperestrogenism are features
of cystic follicular disease.
Tertiary ovarian follicles vary greatly in size between
species, ranging from about 3 mm in the queen up to 7 cm in
the mare! Normal follicular diameters near ovulation are
approximately 2 cm in the cow, 1 cm in the sheep and pig,
and 0.75 cm in the dog. Knowledge of the stage of the cycle
Pathology of the Ovary
Figure 4-28  Inclusion cysts of various sizes in the ovarian stroma
adjacent to the ovulation fossa in a mare. The cysts form from
small pieces of surface epithelium (modified peritoneum) that
become entrapped after the surface is disrupted at ovulation.
They are usually multiple. These persist for long periods of time
and slowly increase in size, with resultant atrophy of the ovary
when they become very large. Their location adjacent to the
ovulation fossa and persistence and slow increase in size are char-
acteristic features of germinal inclusion cysts in the ovary of
mares.
is also helpful, but disappointingly is provided inconsistently
in the histories accompanying clinical case submissions. The
examining pathologist should persist and insist on receiving as
complete a reproductive history as possible.
It is only in cattle that the condition has received detailed
study. Accordingly, the major consideration here is of the
bovine disease.
Cystic ovarian disease in cows
A well-known feature of anovulatory follicular cysts is their
relation to nymphomania, but most ovarian cysts are not associ-
ated with signs of persistent estrus. The behavior of cows with
cystic ovaries is variable. The majority of cows with ovarian
cysts are anestrous. The disease arises from the failure of
mature follicles to ovulate. It occurs most often before the first
postpartum ovulation. Approximately 45-60% of animals that
develop anovulatory follicular cysts will re-establish normal
ovarian cycles spontaneously. Cystic follicles may also develop
after postpartum ovarian cycles have been established, and
these cysts are more likely to persist if effective treatment is
not instituted.
The cause of cystic ovarian disease is not understood in any
species. The disease in cattle occurs more frequently after
parturient or postparturient disease, and there is evidence that
intrauterine infections play a role in the pathogenesis of the
disease. There is clearly a genetic predisposition to the disease
in certain families. The daughters of cows that have had cystic
ovaries have a substantially increased risk of developing the
disease as compared to the general population. The disease
tends to involve primarily dairy cows, but it can occur in cattle
Pathology of the Genital System of the Nongravid Female
of any breed if they are withheld from breeding for a pro-
longed period of time. One of the factors that has made the
understanding of the disease difficult is the definition of the
disease itself. Follicular cysts in cattle are usually defined as fol-
licles >2.5 cm in diameter that fail to ovulate and may persist.
By the time a follicle can meet the criteria to be defined as
cystic, the conditions that led to its formation have passed and
are not available for study. To offset this difficulty, anovulatory
ovarian disease has been produced by a variety of experimen-
tal techniques. Unfortunately, it is not known whether any, or
all, of the experimental manipulations induces anovulatory
cystic disease by the mechanisms that operate in the natural
disease.
The most widely held theory of the origin of cystic ovarian
disease has involved aberration of the preovulatory surge of
luteinizing hormone, either the absence of the surge or the
mistiming of the surge. This hypothesis, or some modification
of it, is still the most attractive. Cows that develop cystic
ovaries as the result of estrogen and progesterone treatment
have an increased mean basal concentration of luteinizing
hormone secretion, with increase in the frequency and ampli-
tude of pulses, but the characteristic preovulatory luteinizing
hormone surge is deficient. This increase in luteinizing
hormone secretion is thought to be due to aberrant hypotha-
lamic function altered experimentally by steroids or naturally
by ovarian secretion.
The cysts may be single (Fig. 4-29) or multiple on one or
both ovaries. These cysts may persist, but during the course
of the disease, additional cysts may be recruited, and some
cysts undergo atresia. Patches of luteal tissue can be seen
grossly in the wall of some of the cysts and can be recognized
histologically in about a quarter of them. The walls of the cysts
show the same type of degeneration that occurs in normal
atresia. Degeneration of the granulosa cells takes place first,
the cells undergoing pyknosis and karyorrhexis and sloughing
Figure 4-29  Cystic follicle in the ovary of a cow. This condition
is thought to be due to inadequate luteinizing hormone release,
resulting in development of an anovulatory follicle, the lining of
which may luteinize to form a luteinized follicular cyst.
Pathology of the Ovary 373
into the cyst lumen. The oocyte also undergoes degeneration.
The changes of the theca interna are variable. The theca is
partially luteinized in some cases, whereas in others it degen-
erates and is infiltrated by fibrous tissue. The luteal tissue may
occur in patches or form a crescent of variable thickness.
Luteinized cyst
This type of cyst develops when ovulation fails to occur and the
theca undergoes luteinization. There is no ovulation papilla, and
the luteal mass is smooth and rounded (Fig. 4-30). The cavity
of the cyst is spherical and lined by a layer of fibrous tissue
adjacent to the zone of luteinized cells. Luteinized cysts occur
more frequently in cattle and swine than in other species of
domestic animals. Partial luteinization of the wall of follicular
cysts is a common feature in the bitch. In cattle they usually
occur as single cysts. Single luteinized cysts may occur in
pregnant sows, but multiple cysts are associated with
infertility.
Anovulatory luteinized cysts should not be confused with cystic
corpora lutea. A cystic corpus luteum is a corpus luteum that
has formed after ovulation and in which a central cavity has
persisted in a mass of developing luteal tissue. Cystic corpora
lutea are not evidence of ovarian malfunction. They form after
ovulation, and they do not affect the length of the estrous
cycle. If the cow has been successfully bred, the cavity will
slowly become obliterated. Large central cysts may occasion-
ally persist for 30-40 days after conception. Cystic corpora
lutea can be distinguished from luteinized cysts by the ovulation
papilla that distorts the outline of the cyst at the point of ovula-
tion. Additionally, their size is greater reflecting their develop-
ment from cystic follicles.
Ovarian epidermoid cysts have been recognized in cattle.
These are reported to be multiple and small and have a squa-
mous epithelial lining that forms keratin.
Extra-ovarian lesions associated with cystic ovarian
degeneration in cows
Changes in other organs develop only if the ovarian cysts
persist. Because most cases are responsive to treatment,
Figure 4-30  Luteinized follicular cyst from a cow. Note the
uniform layer of luteinized cells that line the transected cyst.
Because these develop from follicles that have not ovulated, there
is no ovulation papilla.
374 CHAPTER 4  •  Female Genital System
Figure 4-31  Mucometra in the uterus of a cow. The endome-
trium undergoes hyperplasia caused by the long-term release of
estrogens usually in cows with follicular cysts. In cases where the
accumulated secretions are less viscous, the condition is call hydro-
metra. If the accumulations are large, the resulting pressure will
lead to atrophy of the endometrium.
this is now the exception. It has been shown that in cystic
ovarian disease the hormone limits are within normal concen-
trations; however, the toxicity of ovarian hormones depends
not on the absolute levels, but in the loss of cyclicity and on
persistence.
In established cases of cystic ovarian disease, the uterus is
usually altered, the differences in degree being related to the
duration of the condition. In association with functionally
active follicular cysts, the uterus is enlarged and the wall is
edematous (Fig. 4-31).
The cervix is enlarged, the external os patent, and the plicae
edematous. The endometrium may appear grossly normal,
being smooth, semitransparent, gray-pink, and moist. There
may be some degree of cystic endometrial hyperplasia detect-
able by the naked eye as tiny gray-white elevated blisters in
the surface of the endometrium, which is overlain by a thin
layer of clear viscous mucus. The accumulation of mucus
(mucometra) and the development of cystic endometrial
hyperplasia progress with time and are most striking in those
animals that have been affected long enough for atrophy of
the ovarian cysts to have occurred and the animal to have
become anestrous. By then, the endometrium has become
very cystic and the volume of mucus accumulated to 100-
1,000 mL or more.
The cervix may be hypertrophic or atrophic, as described
previously. It usually contains thick, viscid, gray-white, and
cellular mucus. The epithelium undergoes squamous nonke-
ratinizing metaplasia of mild degree. The vagina is edematous
when the cysts are active, but otherwise the most striking
change is the formation of cysts in Gartner’s ducts. These
mesonephric duct vestiges that lie in the wall of the vagina,
one on each side of its floor, are normally visible only micro-
scopically as continuous or discontinuous ducts lined by a
Pathology of the Ovary
simple cuboidal epithelium. When chronically stimulated by
estrogen, the epithelium becomes squamous and the ducts
cystic and visible, or palpable, as a series of blebs or as tubules
up to 1 cm in diameter on the floor of the vagina.
Cystic Gartner’s ducts are usually accompanied by cystic
Bartholin’s glands. Either may become abscessed. Bartholin’s
glands, one on each side of the floor of the vulva, undergo
cyclic secretory changes during the estrous cycle, and a squa-
mous epithelium on the ducts is normal in estrus. Exaggera-
tion of this change following long-term exposure to estrogens
causes occlusion of the ducts and the formation of retention
cysts. The vulva may be edematous when the cysts are active,
and the clitoris may be enlarged in long-standing cases.
Cystic ovarian degeneration in other species
In swine, cystic ovaries are common and are an important cause
of infertility. Failure of a single follicle to ovulate need not
interfere with pregnancy and single large cysts, 2-3 cm in
diameter, may be found in pregnant animals. They are pre-
sumed to represent mature follicles that did not ovulate, but
single anovulatory cysts may also be associated with irregular-
ity of the estrous cycle. The association is more clearly mani-
fested with multiple cysts. The cysts vary in type from
follicular, which are lined by normal granulosa cells, to lutein-
ized cysts. Multiple luteinized cysts, with some cysts up to
5 cm in diameter, are a distinctive feature of cystic ovarian
disease in swine. The luteal tissue may form a complete rim
or be present in patches. The endometrium in cases of mul-
tiple luteal cysts shows hyperplasia of progestational type, and
in long-standing cases the clitoris is enlarged.
Cystic degeneration of the ovarian follicle, with loss of
cyclicity and infertility comparable to that of the cow and the
sow, does not appear to occur in the mare, but the matter is
not clear because anovulatory follicular cysts do develop
during the winter anestrous period, and some of these mares
will show irregular signs of estrus. The number and size of
these anovulatory cysts vary considerably. There is no evidence
that development of these cysts, regardless of their size, is
indicative of reproductive disease.
In the bitch, anovulatory cysts of both follicular and lutein-
ized type tend to occur in older age groups. Grossly, they tend
to be multiple and commonly have partial luteinization of cyst
walls (Fig. 4-32). The incidence of cystic ovarian disease is low
in the bitch, but there is some confusion on this point because
cystic rete tubules, cysts of SES, paraovarian cysts, and cystad-
enomas have been confused with follicular cysts.
Polycystic ovarian disease in the bitch is rare, but because
it can cause hyperestrogenism, it carries a special risk in the
dog because of the species’ sensitivity to either endogenous
or exogenous estrogen, which can induce lethal bone marrow
suppression. The condition can involve either one or both
ovaries, the affected ovary being greatly enlarged by multiple,
thin-walled cysts that vary from 1-12 mm in diameter (see
Fig. 4-32). The disease develops in mature animals that may
be either nulliparous or multiparous. If clinical signs occur,
they are apt to be associated with hyperestrogenism and include
persistent estrus with cornification of the vagina and swelling
of the mammary glands or the toxic effects of hyperestrogen-
ism on the bone marrow, with resultant pancytopenia. This
pancytopenia can result in anemia, thrombocytopenia with
bleeding, most often occurring as epistaxis, or neutropenia
with increased susceptibility to infection. The mechanism of
the inhibitory action of estrogen on the hematopoietic tissues
Pathology of the Genital System of the Nongravid Female
Figure 4-32  Multiple follicular cysts in a bitch. Externally, many
of the nodular structures have the appearance of corpora lutea.
Others have thin clear walls and look like enlarged follicles that
contain clear fluid. These anovulatory follicles are lined by granu-
losa cells that frequently undergo partial luteinization. The
amount of luteinization accounts for the difference in appearance.
This is analogous to the luteinization that occurs in cattle with
the persistent anovulatory follicles shown in Figure 4-30.
in estrogen-sensitive species is not known. Estrogen appears
to inhibit the differentiation of pluripotent stem cells while
stimulating the differentiation and maturation of committed
stem cells.
Most of the cysts are obviously of follicular origin but in
various stages of atresia. Degenerating oocytes can be identi-
fied in some of the cysts, but the disease is not just one of
anovulation because in some cases hundreds of follicles have
been recruited. The granulosa and theca lining of the cysts is
attenuated in the larger ones. Patchy areas of luteinization
form in the walls of some of the cysts. This luteinization may
involve individual cells or sheets of cells and either the theca
or the granulosa.
Further reading
Schlafer DH. Non-neoplastic ovarian lesions in the mare. Equine Reprod
2010;2:2697-2706.
Silvia WJ, et al. Ovarian follicular cysts in dairy cows: an abnormality in
folliculogenesis. Domest Anim Endocrinol 2002;23:167-177.
Sun Y-L, et al. Relationship between apoptosis and proliferation in
granulosa and theca cells of cystic follicles in sows. Reprod Domest
Anim 2012;47:601-608.
NEOPLASTIC CONDITIONS OF THE OVARY
The differential diagnoses for enlargement of the ovary include
a number of non-neoplastic conditions:
• Normal cyclical changes (tertiary follicles, developing
corpora lutea)
• Anovulatory follicles
• Ovarian hematoma
• Oophoritis
• Ovotestes
• Cystic conditions of ovarian structures
The types of ovarian cysts vary between species. For
example, common ovarian cysts found in the ovaries of bitches
include cystic rete and cysts arising from the subsurface
Neoplastic Conditions of the Ovary 375
epithelial structures; cysts found in the equine ovary include
epithelial inclusion cysts arising in the area of the ovulation
fossa and hemorrhagic anovulatory follicular (HAF) cysts.
These conditions must be differentiated from primary ovarian
neoplasms that occur with variable frequency in all species of
domestic animals.
In general, ovarian neoplasms tend to occur in mature or
older animals and may be associated with behavioral changes
or changes in target tissues if the tumor is endocrinologically
functional (e.g., stallion-like behavior in mares with granulosa
cell tumors that are producing androgens). Although rare,
metastases from neoplasms in other sites may also be found
in ovaries (in cattle, lymphosarcoma can be found within
corpora lutea; in dogs, mammary gland carcinomas can metas-
tasize to many organs, including the ovaries).
Tumors with a phenotype of specifically ovarian tissue can be
divided into 3 broad categories: tumors of the surface celomic
epithelium, tumors of the sex cords and gonadal stroma, and
tumors of germ cells. Tumors developing from nongonadal
supporting tissues of the ovary can be of the usual variety of
fibroblastic, smooth muscle, and vascular tumors, but are, in
fact, uncommon in domestic animals.
• Sex cord–stromal tumors
• Granulosa-theca cell tumors
• Thecoma or luteoma
• Tumors of the surface epithelium and the SES
• Papillary and cystic adenomas
• Papillary adenocarcinomas
• Germ cell tumors
• Dysgerminoma
• Teratoma
Primary ovarian tumors occur most frequently in the bitch,
mare, and cow. In the bitch, they are often bilateral, especially
those arising from the surface epithelium and the SES. In
the cow, ewe, and mare, they are usually unilateral and of the
gonadal-stromal type. In cows, there is a tendency for the
tumor to occur in the daughters of affected dams and, in these
animals, removal of the affected ovary may be followed by the
development of a tumor in the other ovary. Very few ovarian
neoplasms have been reported in the feline and porcine
species. The tumors of the cat are similar to those of the bitch.
Sex cord–stromal tumors
These are commonly tumors of granulosa and theca cells and
their luteinized counterparts. The vast majority are mixtures
of phenotypes with granulosa cells and theca cells predominat-
ing and often coexisting in the same tumor (e.g., granulosa-theca
cell tumors). Some tumors histologically resemble testicular
tumors of the Sertoli cell and interstitial endocrine cell types.
This group of tumors frequently produces hormones.
The granulosa-theca cell tumor is the most common tumor
in this group. They are generally unilateral, usually nonmalig-
nant tumors in any species. Although they may be observed in
young animals, the incidence increases with age. Part of their
interest lies in the production of steroids by these tumors.
In mares, in which species the tumors are common and
have been studied most carefully, 3 behavioral patterns have
been recognized: anestrous, continuous or intermittent estrus,
and male behavior. Surprisingly, testosterone levels in the
peripheral plasma are elevated in most cases. Male behavior
is usually only seen in those cases in which the testosterone
levels are >100 pg/mL plasma. Some mares with granulosa-
theca cell tumors also have elevated estrogen levels, but these
 375.e1

Further reading
Bogh IB, et al. Ovarian function and morphology in the mare after
multiple follicular punctures. Equine Vet J 2003;35:575-580.
Cook DL, et al. Secretory patterns of LH and FSH during development
and hypothalamic and hypophysial characteristics following devel-
opment of steroid-induced ovarian follicular cysts in dairy cattle.
J Reprod Fertil 1991;91:19-28.
Edwards JE. Three cases of ovarian epidermoid cysts in cattle. Vet
Pathol 2002;39:744-746.
Gumen A, et al. A GnRH/LH surge without subsequent progesterone
exposure can induce development of follicular cysts. J Dairy Sci
2002;85:43-50.
McCue PM, Squires EL. Persistent anovulatory follicles in the mare.
Theriogenol 2002;58:541-543.
376 CHAPTER 4  •  Female Genital System Neoplastic Conditions of the Ovary

Figure 4-33  Enlarged ovary from a mare that has been nearly
completely replaced by a large expanding granulosa cell tumor.
The red tissue on the surface of the mass in the center is the
displaced congested fimbria. The ovulation fossa is lost due to
expansion of the tumor.
Figure 4-34  Granulosa cell tumor from a mare. The tumor has
been bisected and reveals a very characteristic gross appearance.
Neoplastic granulosa cells form follicle-like cavities lined by neo-
plastic granulosa cells. Solid forms of this tumor occur less
commonly.

elevations are less clearly related to behavioral patterns. Even

in cases in which hormone production associated with the
tumor is low, atrophy of the opposite ovary usually occurs. The
cause of this atrophy has not been determined. It was thought
to be the result of testosterone production by the tumor, but
convincing association between testosterone levels and ovarian
atrophy has not been established, and androgen production
by tumors other than the granulosa-theca group has not
caused atrophy of the contralateral ovary. Granulosa cells
produce the peptide hormone, inhibin, which inhibits release
of follicle-stimulating hormone. This hormone has been dem-
onstrated to be elevated in granulosa cell tumors, and it may
be that the production of inhibin produces the characteristic
ovarian atrophy seen in this disease. Use of serum anti-Mül-
lerian hormone has recently been shown to be a sensitive
indicator for diagnosis of granulosa cell tumors in cows and
mares.
Normal function of the atrophic ovary usually returns Figure 4-35  Photomicrograph showing characteristic aggregates
within a year of removal of the tumor. In bitches with sex of neoplastic granulosa cells surrounding protein globules (Call-
cord–stromal tumors, cystic endometrial hyperplasia and pyo- Exner bodies) in an equine granulosa cell tumor.
metra are common. Vaginal changes can be used to monitor
estrogenic influences.
The surface of the granulosa-theca cell tumor is smooth or parts of tumors, a pseudoalveolar pattern, depending on the
(Fig. 4-33), and the cut surface may be solid or cystic (Figs. disposition of the stroma. There is a tendency for some
4-34, 4-35). The solid portions of the tumor are white or granulosa-theca cell tumors to develop a tubular pattern
yellow, depending on the lipid content. The cells in these similar to that of the Sertoli cell tumor of the testis (see Fig.
tumors resemble their counterparts in normal follicles, but 4-35). The stroma consists of broad irregular bands of dense
their histologic arrangement is quite varied. These tumors collagen. Cyst formation and hemorrhage are common. The
commonly contain areas with characteristic gland-like or more thecomatous portions of such tumors may resemble
rosette patterns of abortive follicles, some of which may normal theca cells and, at the other extreme, be distinguish-
contain a secretory globule resembling an ovum and called a able from plump fibroblasts only by the demonstration of
Call-Exner body. sudanophilic droplets in the cytoplasm or by histochemical
This type of differentiation is frequently observed in the techniques for steroids.
early stages of development of bovine neoplasms, but is less The cysts that often make up the bulk of the tumor are
common in other species and in large tumors. Instead, the lined by granulosa cells that are surrounded by a variable
arrangement of cells is usually diffuse with, in some tumors population of thecal cells (Fig. 4-36). In some equine tumors,
Pathology of the Genital System of the Nongravid Female
Figure 4-36  Photomicrograph of a granulosa cell tumor from a
mare. Neoplastic cells are aligned perpendicular to the fibrous
septa.
particularly those associated with high testosterone levels,
embedded in the thecal cell layer are large polyhedral eosino-
philic cells resembling the testosterone-producing Leydig
cells. Ancillary diagnostic testing includes endocrinology. Tes-
tosterone and estradiol concentrations tend to be variable, but
α-inhibin concentrations have been shown to correlate to
tumor mass and to be more consistently elevated.
Tumors composed only of theca cells, thecoma or luteoma,
are much less common in all domestic animals than those
arising from granulosa cells or containing a mixture of theca
and granulosa cells. The few tumors reported have been firm,
white-to-orange, and composed of streaming oval or spindle
cells that resembled the cells of the theca interna. The dem-
onstration of lipid in the cytoplasm allows differentiation from
fibromas.
Sex cord–stromal tumors often develop within ovarian
remnants.
Tumors of the surface celomic epithelium
Neoplasms arising from the epithelium covering the surface
of the ovary are very important tumors in women, but in
nonhuman mammals, they occur commonly only in the bitch
as papillary cystadenomas and cystadenocarcinomas. It appears
that the tumor, irrespective of type, may occasionally stimu-
late the ovarian stroma, with concomitant production of
steroid hormones.
Grossly, the papillary structures, when extending from the
surface of the ovary, produce a cauliflower-like appearance
(Fig. 4-37). Once free of the bursa, peritoneal implantation
occurs readily. Papillary cystadenocarcinomas should be con-
sidered in the differential diagnosis of ascites in adult entire
bitches. The ascites develops from obstruction of the dia-
phragmatic lymphatics by permeating tumor fragments, with
perhaps a contribution by secretion by the tumor epithelium.
Histologically, the epithelium varies from low cuboidal to
columnar, with stratification in some areas, and mitotic figures
are scant, even in the malignant form. The tumor appears to
develop from the surface and from tubular structures (cortical
tubes, SES) of the ovarian cortex. Many of the tubules are
continuous with the surface epithelium and responsive to
estrogenic stimulation.
Neoplastic Conditions of the Ovary 377
Figure 4-37  Papillary cystadenocarcinoma of the ovary of a
bitch. The ovary is enlarged, and its surface is very irregular. In
adenocarcinomas, neoplastic cells frequently penetrate the surface
of the ovary and metastasize to the lining of the bursa and
throughout the abdomen. Papillary cystadenomas are quite
common in older bitches, tend to develop multifocally, and
usually develop in both ovaries.
Papillary tumors have been induced in the bitch by pro-
longed administration of diethylstilbestrol. The experimen-
tally induced tumors regress following withdrawal of hormone
treatment. Tumors of the surface epithelium can occur in associa-
tion with sex cord–stromal tumors, possibly by hormonal induc-
tion by the granulosa-theca tumors. The separate identification
of the 2 tumors can be difficult, particularly in areas where the
tumors join, but is aided by immunohistochemical staining. Cyto-
keratin intermediate filaments, especially CK7, are expressed
in the surface epithelium and the SES. On the basis of limited
investigation, it appears that this specificity has been con-
served during tumor development and aids in easy differentia-
tion of the above from CK7-negative tumors of the sex
cord–stromal group.
Tumors of germ cells
Germ cell tumors of the ovary, like their testicular counter-
parts, arise from germ cells and are usually divided into 2 main
categories in domestic animals: the dysgerminoma and the
teratoma.
The dysgerminoma is composed of cells that show morpho-
logic similarity to primordial germ cells and resemble their testicu-
lar homolog, the seminoma. These are relatively rare. It is usually
unilateral and has been observed in the bitch, queen, cow, mare,
and sow. Grossly, the tumor is smooth, or nearly so, and rela-
tively soft. The cut surface is gray and may have areas of
hemorrhage or yellow patches of necrosis. It is composed of
a uniform population of large rounded cells with large central
chromatic nuclei. Mitotic figures and giant cells are frequent.
The pattern of growth is diffuse; the stroma is always scanty.
Just as in the canine testicular seminoma, accumulations of
lymphocytes are present within the tumors.
In teratomas, totipotential germ cells have undergone somatic
differentiation, giving rise to 2 or more germinal layers with a
variety of tissues present in the tumors.
Ovarian germ cell tumors are rare in domestic species. In
addition to the germ cell tumors that show no somatic dif-
ferentiation (dysgerminomas) and tumors that have extensive
378 CHAPTER 4  •  Female Genital System
A Figure 4-39  Photomicrograph of a typical teratoma with multi-
B bursa of the dog. Pathologists unfamiliar with the appearance
Figure 4-38  A. Teratoma in the ovary of a bitch. The ovary is
enlarged, effaced and contains hard areas (bone and cartilage) and
cystic spaces. B. Equine ovarian teratoma. The large cystic mass
containing mats of hair. A variety of tissues can often be identified
in these tumors, including bone, teeth, nervous tissue, intestine,
and muscle.
differentiation into tissues of multiple germinal layers (tera-
tomas), there are reports of other rare tumors such as endo-
dermal sinus tumors (yolk sac tumors), choriocarcinomas,
embryonal carcinomas, and tumors from single germ layers
(epidermoid cyst). This variability is to be expected in tumors
arising from pluripotential germ cells.
Teratomas usually have solid and cystic areas containing
sebaceous material and hair (Fig. 4-38). Various other tissues
are often present, including neural tissue, adipose tissue, bone,
teeth, and respiratory epithelium (Fig. 4-39).
There were several theories on the histogenesis of terato-
mas, but it is now believed that the benign cystic ovarian tera-
tomas are parthenogenic tumors that develop from a single
germ cell that has completed its first meiotic division, but not
its second. The evidence for this has come from a series of
Neoplastic Conditions of the Ovary
ple tissue types.
elegant cytogenetic and biochemical studies that have shown
that tissues from ovarian teratomas are unique in that they
are XX diploid cells, but are homozygous at chromosomal loci
for which the host is heterozygous. This lack of heterozygosity
is most reasonably explained as being the result of meiotic
division.
Tumors of nongonadal tissues
Ovarian hemangioma is rare in all domestic animals except
the pig. Ovarian hemangiomas are globular, well circum-
scribed, and tan to red-brown. Their surface is smooth and
glistening and contains prominent vessels. The tumors arise in
the ovarian cortex, and they are occasionally bilateral. The
tumor is composed of well-differentiated endothelial cells that
line vascular clefts and spaces.
Ovarian tumors of other supporting tissues are very infre-
quent. Leiomyomas developing from the smooth muscle in
the mesovarium have been reported in the bitch, queen, and
sow. Lipomas, fibromas, and rhabdomyosarcoma occur in the
of the ovarian stroma, particularly in the mare, sometimes
mistake normal tissue for fibroma or leiomyoma. Lymphoma
can affect the ovary of cattle, dogs, and cats. In cattle neoplas-
tic foci tend to develop within corpora lutea (Fig. 4-40).
Metastatic tumors
Secondary tumors of the ovary are probably not less rare than
primary ones, the relatively high incidence largely being attrib-
utable to secondary deposits of lymphomas. Mammary carci-
nomas, endometrial carcinoma and canine transmissible
venereal tumor in the bitch, and intestinal carcinomas in the
cow may metastasize to the ovary and apparently have an
affinity for corpora lutea.
Vascular hamartomas
Vascular hamartomas of the ovary are included with tumors
because they may be confused with neoplasms and because
granulosa-theca cell tumors occasionally occur in the same
gonad. Hamartomas are tumor-like malformations that may be
present at birth and cease to grow after the animal reaches
maturity unless the mass is subjected to trauma, infection, or
vascular embarrassment. They have been observed in the cow,
mare, sow, and bitch. The mass of malformed vessels may vary
Pathology of the Genital System of the Nongravid FemalePathology of the Uterine (Fallopian) Tubes
Figure 4-40  Bovine ovarian lymphosarcoma. Several soft pale
masses of neoplastic lymphocytes are present within a corpus
luteum. Although the uterus is a predilection site for bovine
lymphosarcoma, ovarian tissues, especially corpora lutea, are fre-
quently involved.
in size from those barely visible on gross examination to those
weighing several kilograms. The smaller hamartomas are com-
posed principally of mature-appearing, tortuous arteries and
veins with relatively little intervascular connective tissue. In
the mature individual, the increase in size of the hamartoma
is due to thrombosis, with subsequent edema, hemorrhage,
and necrosis, followed by proliferation of fibrous connective
tissue. Small hamartomas are clearly demarcated from the
adjacent ovarian tissue, but the ovary is gradually replaced as
the mass enlarges. The distinction between hemangiomas and
vascular hamartomas is a difficult one, and it may be that some
of the reported ovarian hemangiomas are, in fact, vascular
hamartomas.
Further reading
Bailey MT, et al. Inhibin concentrations in mares with granulosa cell
tumors. Theriogenology 2002;57:1885-1895.
Ball BA, et al. Determination of serum anti-Müllerian hormone concen-
trations for the diagnosis of granulosa-cell tumours in mares.
Equine Vet J 2013;45:199-203.
Crabtree J. Review of seven cases of granulosa cell tumour of the
equine ovary. Vet Rec 2011;169:251.
Kitahara G, et al. Anti-Müllerian hormone profiles as a novel biomarker
to diagnose granulosa-theca cell tumors in cattle. J Reprod Dev
2012;58:98-104.
Kennedy PC, et al. Histological Classification of Tumors of the Genital
System of Domestic Animals. Washington, DC: Armed Forces Insti-
tute of Pathology, American Registry of Pathology, and The World
Health Organization Collaborating Center for Worldwide Reference
on Comparative Oncology; 1998. p. 2
Riccardi E, et al. Immunohistochemical diagnosis of canine ovarian
epithelial and granulosa cell tumors. J Vet Diagn Invest 2007;
19:431-435.
PATHOLOGY OF THE UTERINE
(FALLOPIAN) TUBES
Primary lesions in the uterine tubes are uncommon. Hydro-
salpinx, pyosalpinx, and salpingitis are most important, and
these are usually secondary to disease of the uterus or to
379
Figure 4-41  Bilateral hydrosalpinx in a sheep. Also note the small
cluster of serosal inclusion cysts on the surface of the uterine
horns at the top of the photograph.
manual manipulation of the ovary. As regards incidence of
salpingeal lesions, the only agreement is that they are much
more common than is their diagnosis. They are recognized to
be important in the cow and sow, but not in other species.
Hydrosalpinx
Hydrosalpinx is so called because the uterine tube is dis-
tended, uniformly or irregularly, up to 1.5 cm or so, with clear
watery mucus that fluctuates. The tube appears to be increased
in length and tortuosity and is thin walled. Histologically,
there may be extensive multilocular cyst formation in the
mucosa with obliteration of the lumen, and in some chroni-
cally inflamed uterine tubes, there is extensive interstitial
fibrosis.
Distension of the uterine tube by fluid follows loss of
patency of the lumen (Fig. 4-41). The obstruction may have a
congenital or inflammatory basis. Congenital anomalies involv-
ing the tubes are very rare except in freemartins, but second-
ary hydrosalpinx can be associated with obstructions and
segmental aplasias of the uterine horns. In the latter instances,
the apex of the horn is usually distended with fluid also. Acute
septic inflammations are more likely to produce pyosalpinx;
chronic infective inflammations tend to produce loculations
and stenosis of the lumen with secondary hydrosalpinx. As
almost all infections are of ascending type from coexisting
uterine inflammation, the most severe changes and the
obstruction in such cases are usually at or near the uterine end
of the tube.
A common form of inflammation that results in hydrosal-
pinx in cattle is at least in part traumatic in origin, following
manual manipulation of the ovary. Uterine irrigations are some-
what less important, but in either event, it is the adhesion
between the tube and adnexa (usually the ovary with partial
or complete obliteration of the bursal cavity) that causes
obstruction of the abdominal ostium and secondary hydrosal-
pinx. Squashing of the normal diestrual corpus luteum (there
 379.e1

Further reading
Ellenberger C, et al. Histomorphological and immunohistochemical
characterization of equine granulosa cell tumours. J Comp Pathol
2007;136:167-176.
Hsu FS. Ovarian hemangioma in swine. Vet Pathol 1983;20:401-409.
Lappohn RE, et al. Inhibin as a marker for granulosa-cell tumors. N Engl
J Med 1989;321:790-793.
Patnaik AK, Greenlee PG. Canine ovarian neoplasms: a clinicopatho-
logic study of 71 cases including histology of 12 granulosa cell
tumors. Vet Pathol 1987;24:509-514.
Scully RE. Ovarian tumors: a review. Am J Pathol 1977;87:686-720.
380 CHAPTER 4  •  Female Genital System
is at best only partial expression of the body) is not difficult,
but because of its vascularity, there is always some hemor-
rhage, varying in extent from very slight to fatal. Small clots,
which are usually retained in the bursa, can be completely
resorbed. Larger clots must be organized, and this results in
the formation of adhesions within the bursa and the fimbri-
ated portion of the tube. With more extensive hemorrhage,
adhesions may form to adjacent abdominal viscera and other
genital tissues.
Salpingitis
The uterine tube is a rather simple structure histologically, but
even minor inflammatory changes, evidenced by slight conges-
tion or the presence of a few plasma cells, appear to be
important because of the readiness with which the epithelial
cells desquamate or lose their cilia. The proper function of the
living epithelium is necessary for the propulsion of the ovum,
for the dissolution of the cumulus oophorus prior to fertiliza-
tion, and for the maintenance of a luminal environment suit-
able to survival of the ovum. The salpingeal mucosa has much
less capacity for restitution than does the endometrium.
Inflammation of the uterine (fallopian) tubes without signifi-
cant enlargement is the most common and most important tubal
lesion. It is usually bilateral; is usually not detectable macro-
scopically; and may show serous, catarrhal, or fibrinous inflam-
mation. In the mildest forms of salpingitis, the mucosa alone
is affected, and changes of functional significance may be
slight enough to be overlooked histologically. Congestion of
the mucosal vessels, mononuclear cell infiltration, loss of epi-
thelial cilia, and some desquamation of epithelium may be the
only changes detectable. With more severe infections, catarrhal
exudate collects in the lumen, the mucosal folds are thickened
by cellular infiltration and congestion, and the epithelium is
in large part destroyed. Loss of epithelium occurs first in the
free edges of the mucosal folds, and these denuded areas tend
to fuse and adhere to produce intramucosal cysts. Alterna-
tively, in chronic catarrhal salpingitis, the mucosa is virtually
destroyed and replaced by proliferated connective tissue and
cellular infiltrations with partial or complete occlusion of the
lumen.
Salpingitis is a common lesion in animals, with both Myco-
plasma and Ureaplasma infections. Nonspecific infections
causing salpingitis almost invariably do so following spread
from the uterus. There is probably 70-75% association between
uterine and salpingeal inflammation when diagnosis of the
latter is based on histologic evidence. In some cases there will
be perimetritis with adhesions, pyosalpinx, or bursal abscess.
Adhesions of the infundibulum of the mare are very common.
The cause of these adhesions is unknown. Some are associated
with perimetritis, but most are not. It has been suggested that
they may develop as a result of ovulatory hemorrhage.
However, this explanation does not easily account for the
substantial predominance of adhesions of the right
infundibulum.
Granulomatous salpingitis is uncommon. When it does
occur, the uterine tube will be firm and distended.
Pyosalpinx
This is less common than hydrosalpinx and typically follows
metritis in the same manner as do other forms of salpingitis.
The significant anatomic difference is the accumulation of pus in
the tube following obstruction of the lumen. The obstruction may
be produced by inspissated exudate, inflammatory thickening,
Pathology of the Uterus
and fusion of the mucosal folds, or chronic granulation tissue.
The length of the tube is usually not uniformly involved
by the inflammatory process; rather, there are segments in
which the reaction is more acute or more advanced so that
the obstruction tends to involve irregular segments with the
intervening portions distended with exudate.
The entire thickness of the wall of the duct is infiltrated
with neutrophils, lymphocytes, and plasma cells, and the same
cells collect in the lumen and in the mucosal cysts formed by
adhesions between the denuded epithelial folds. Surviving
epithelium may be partly squamous. Eventually, the bacteria
will be destroyed and the exudate converted to a watery fluid
(hydrosalpinx). Frequently, accompanying pyosalpinx are the
bursal adhesions and local peritonitis described earlier.
Among the organisms that may be found in inflammatory
diseases of the uterine tube are streptococci, staphylococci,
Escherichia coli, and Trueperella pyogenes, with the latter as the
most common and important. Brucella suis in swine and Myco-
bacterium tuberculosis in cattle are responsible for specific
forms of salpingitis; the lesions are as described for these infec-
tions in the uterus.
Miscellaneous uncommon diseases of the uterine tubes
such as neoplasms are reported, for instance, leiomyoma,
fibroadenoma, adenoma, and adenocarcinoma. Metastases
from ovarian neoplasms also implant within the uterine tubes.
Cystic remnants of mesonephric and paramesonephric duct
occur.
PATHOLOGY OF THE UTERUS
Abnormalities of position or location
Torsion of the uterus is uncommon except in the cow and mare.
In almost all cases, such twisted uteri are pregnant (Figs. 4-42,
4-43), but torsion may also occur with pyometra, hydrometra,
endometrial polyps, and endometrial neoplasia. The torsion is
of the same nature as an intestinal volvulus and occurs about the
transverse axis of the organ, with the mesovarium as one fixed
point. In uniparous species (cow) in which a well-developed
intercornual ligament does not permit much independent
movement of the horns, the entire organ is involved in the
torsion, which is about the mesovarium and vagina or cervix
as fixed points. In multiparous species (bitch, cat) with long
horns and no intercornual ligament, the torsion will involve
part of one horn or the entire horn, the fixed points in the
latter instance being the mesovarium and the site of
Figure 4-42  Torsion of a gravid bovine uterus.
Pathology of the Genital System of the Nongravid Female
Figure 4-43  Torsion of one gravid uterine horn in a cat.
attachment of the horn to the uterine body. There seem to be
no rules governing the direction of the twist. Minor degrees
of torsion (up to 90°) are fairly common in cows and appar-
ently resolve themselves. The condition becomes of importance
only when the torsion is 180°or more and results in dystocia. Any
twist in excess of 180° may also result in local circulatory
embarrassment. The thinner-walled veins are obstructed
before the arteries, and the uterus becomes congested and
edematous, with edema of the placenta and death of the fetus.
The devitalized uterine wall becomes friable and susceptible
to rupture or, if cesarean section is performed, the friability of
the wall makes suturing difficult. Death of the fetus may
be followed by mummification if the cervix remains closed; if
air and bacteria enter the uterus, the fetus putrefies. In the
bitch and cat, transverse rupture of the twisted segment near
parturition can release the dead fetuses into the peritoneal
cavity, which can be misdiagnosed as evidence of ectopic
pregnancy.
The fetuses within the peritoneal cavity (sometimes called
ectopic pregnancy) undergo mummification; attach to the
omentum, liver, or intestine; and become covered by a rather
thin membrane. Occasionally a fetus becomes dismembered,
and fetal bones may be scattered throughout the omentum.
In some cases the mummified fetuses remain in the peritoneal
cavity for months or years without causing clinical signs of
disease. If the horn does not rupture, the fetus may die,
become mummified, and the uterus will shrink.
Prolapse of the vagina, cervix, and/or uterus occurs commonly
in ruminants and pigs and exceptionally in other species. Pre-
disposing causes in the cow are essentially those that cause,
or are associated with, uterine hypotony and probably also
with dysrhythmia of involutionary contractions. Among the
most common associations in the cow are prolonged dystocia
relieved by forced traction, retained placenta, and postparturient
hypocalcemia. Probably the same sorts of influences operate in
ewes, and in addition, uterine prolapse after parturition is a
common complication of the hyperestrogenism that results
from the ingestion of legumes with a high content of
estrogens.
In any species, usually only the previously gravid horn
prolapses. In the cow and ewe, the nongravid horn, and
sometimes intestine and bladder also, may be present within
the everted horn. The pathologic sequelae of prolapse
are comparable to those of intestinal intussusception, with
Pathology of the Uterus 381
Figure 4-44  Uterine artery rupture in a mare. The resulting
hematoma can dissect along fascial planes in the broad ligament
or extend into the abdominal cavity, where they continue to bleed
and frequently lead to exsanguination.
the added factor of trauma. Congestion and edema are fol-
lowed by hemorrhage, necrosis, and sepsis. Gangrene may
supervene.
Rupture of the uterus may occur spontaneously, but is
usually a result of obstetrical manipulations. Most ruptures
occur in the body of the uterus adjacent to the pelvic brim as
irregular tears that may involve the full width of the wall or
only the mucosa. Mucosal ruptures are of little consequence.
Complete ruptures are often fatal either by virtue of hemor-
rhage, spread of uterine inflammation to the peritoneum, or
displacement of retained membranes into the abdominal
cavity. The majority of ruptures occur in uteri that are devital-
ized as a result of torsion or prolonged dystocia.
Rupture may also follow acute distension of the uterus
produced by infusion fluids. This is not an uncommon acci-
dent. The rupture occurs on the lesser curvature along the line
of attachment of the mesometrium, and the irrigating fluids
spread into the ligament.
Circulatory disturbances
Endometrial hyperemia and edema occur normally at estrus
and reach the greatest relative development in the bitch in
proestrus. The resulting diapedesis and endometrial exfolia-
tion account for the uterine hemorrhage at proestrus in this
species. A small amount of mucosal hemorrhage is common
in heifers, less common in older cows, and occurs immediately
after estrus. The source of the hemorrhage is the endometrial
capillary bed immediately cranial to the cervix. It is probably
an estrogen withdrawal effect and the nearest thing to men-
struation in domestic animals. Punctate hemorrhages occur in
the uterine serosa in heifers in estrus.
Hemorrhage of importance follows torsion and eversion, by
obvious mechanisms. Perhaps the most common association
of abnormal bleeding is endometrial hyperplasia in the bitch,
especially if there is superimposed infection. Subinvolution of
placental sites also produces uterine hemorrhage. A less
common cause in this species is uterine neoplasia. Vaginal
hemorrhage from uterine leiomyosarcomas was a fairly
common clinical feature in Saanen goats.
Rupture of the uterine artery with hemorrhage into the
broad ligament, with or without extension into the abdominal
cavity, occurs in the mare and rarely in other species. The latter
situation commonly results in the death of the mare from
exsanguination. The uterine artery near the rupture com-
monly contains pre-existing chronic degenerative changes
(Fig. 4-44).
382 CHAPTER 4  •  Female Genital System Pathology of the Endometrium

Further reading
Azawi OI, et al. Pathological and bacteriological studies of hydrosalpinx
in buffaloes. Reprod Domest Anim 2010;45:416-420.
Beltman M. A novel twist to uterine torsion and abomasal displace-
ment in dairy cows. Vet J 2013;196:284-285.
Marino G, et al. Adenoma of the uterine tube in the bitch: two case
reports. Vet Res Commun 2007;31:173-175.
Palmieri C, et al. Congenital and acquired pathology of ovary and
tubular genital organs in ewes: a review. Theriogenol 2011;75:393-
410.
Ueno T, et al. Pathology of lethal peripartum broad ligament haema-
toma in 31 Thoroughbred mares. Equine Vet J 2010;42:529-533. A

PATHOLOGY OF THE ENDOMETRIUM

Irregularities of endometrial growth
Atrophy
Atrophy of the endometrium results from loss of trophic ovarian
function. Senile atrophy is not important in large domestic
animals. Atrophy is common after ovariectomy, may reflect
hypopituitarism of chronic inanition or wasting disease, or a
primary hypophyseal lesion. The more superficial portions of
the endometrium are the more atrophic, and in advanced
atrophy, the lining mucosa covers a thin layer of condensed
stroma in the depths of which are the inactive glandular rem- B
nants that are sometimes cystic.
The endometrium of those species that have a seasonal
period of anestrus undergoes a normal atrophic change. In
mares, in which these changes have been studied by endome-
trial biopsies, the luminal and glandular epithelium becomes
cuboidal, and the glands are straight during the winter anes-
trous period, but there is considerable individual variation in
the degree of atrophy mares develop.

Hyperplastic conditions of the endometrium

General considerations.  Endometrial hyperplasia in the
bitch is common and usually involves cystic distension of
endometrial glands. There are 2 discrete patterns: generalized
cystic endometrial hyperplasia (CEH) and pseudoplacentational
endometrial hyperplasia (PEH) or localized endometrial hyper-
plasia of pseudopregnancy. Both frequently result in accumu-
lation within the uterine lumen of endometrial secretions. In
PEH, cellular debris from associated superficial endometrial
necrosis will also be present, which causes the distended
uterus to have features that can be confused as being pyome-
tra. In either CEH or PEH, infection of the uterus may follow.
This association between development of endometrial
hyperplasia and subsequent infection has been recognized for
many years and is known as the cystic endometrial hyperplasia–
pyometra syndrome. Bacteria might also provide appropriate
stimulation that could drive the endometrium to undergo
hyperplasia and hypertrophy. An alternative plausible patho-
genesis for cystic endometrial hyperplasia–pyometra is that an
initial event is the establishment of a low-grade, subclinical
infection that, during the luteal phase (also referred to as the
secretory or progestational phase), causes the endometrium
to proliferate. Changes in the uterine environment, accumula-
tion of secretions, and other progestational effects could then
lead to massive proliferation of bacteria and inflammatory cell
within the endometrium and accumulation of purulent
exudate in the uterine lumen.
C
Figure 4-45  Cystic endometrial hyperplasia (CEH) in uterine
sections from 3 bitches. The hyperplasia can involve many glands,
as in A, or involve only one or a few glandular units, as in B.
Occasionally, the entire endometrium is involved. The hyperplas-
tic endometrium in the latter cases tends to secrete large amounts
of fluid. CEH predisposes the bitch to development of endome-
tritis and pyometra. C. The darker areas in the endometrium are
mononuclear cellular infiltrates that will change to become pre-
dominantly neutrophilic when bacteria proliferate and will result
in pyometra.
Cystic endometrial hyperplasia can involve a single or a
few glands, or endometrial glands extending along segments
of endometrium (Fig. 4-45). Sometimes the entire endome-
trial surface is involved. Individual endometrial glandular cysts
can become quite large, up to 1 cm. More diffuse involvement
can leave the endometrium thickened and, on cross-section,
effaced by variably dilated glands (see Fig. 4-45).
Endometrial hyperplasia can also be attributed in some
species to excessive and prolonged estrogenic stimulation. Sources
of estrogen can be endogenous, for example, from sex cord–
stromal tumors, such as granulosa cell tumor; exogenous, as in
ingestion of certain plants; or iatrogenic, from inadvertent
exposure to creams containing estrogens. Secretions from a
 382.e1

Further reading
Aubry P, et al. A study of 55 field cases of uterine torsion in dairy cattle.
Can Vet J 2008;49:366-372.
Ellington JE, Schlafer DH. Uterine tube disease in cattle. J Am Vet Med
Assoc 1993;202:450-454.
Gelberg HB, McEntee K. Pathology of the canine and feline uterine
tube. Vet Pathol 1986;23:770-775.
Miesner MD, Anderson DE. Management of uterine and vaginal pro-
lapse in the bovine. Vet Clin North Am Food Anim Pract 2008;24:
409-419.
Pathology of the Genital System of the Nongravid Female
Figure 4-46  Mucometra distending the uterus of a bitch. The
physical pressure placed on the endometrium leads to endome-
trial atrophy over time.
markedly chronically stimulated endometrium can lead to
gross accumulation of mucoid fluid in the uterus, a condition
called mucometra (Fig. 4-46).
Progesterone plays the major role in the induction of endo-
metrial hyperplasia in the dog and cat, but even here the
endometrial response to progesterone depends upon estrogen
priming. Estrogens act by binding to the estrogen receptors
that are present in the endometrial cells and act on these
susceptible cells to induce the synthesis of intracellular recep-
tors for progesterone. The progestational effect of conversion
of the endometrium to its secretory mode depends on this
estrogenic priming, and it is likely that in some cases the
disturbances of endometrial growth giving rise to endometrial
hyperplasia are to be found in the disturbances of the timing
and duration of the priming, although cystic endometrial
hyperplasia can be produced in the bitch in the normal early
diestral uterus by mild trauma (see also Pyometra, in the bitch
and queen, later). Many cases of cystic hyperplasia of the
endometrium have developed following the use of long-acting
progestational compounds to delay the onset of estrus in
bitches and queens. Cystic endometrial hyperplasia in the cow
is associated with ovarian follicular cysts or granulosa cell
tumors, both of which can produce prolonged hyperestrogen-
ism. Cystic endometrial hyperplasia is very uncommon in the
mare and camelids. It has not been associated with granulosa-
theca cell tumors in these species.
Ovarian tumors, especially sex cord–stromal tumors and
papillary cystadenocarcinomas, are present in some cases of
endometrial hyperplasia of the bitch, but in the majority of
clinically recognizable cases, the ovaries contain apparently
normal corpora lutea. The hyperplasia develops during the
long luteal phase that is normal in the bitch. Often paraovar-
ian cysts are present in cases of endometrial hyperplasia.
Noncystic endometrial hyperplasia is not recognizable
macroscopically except as an equivocal thickening of the
endometrium. The thickening is due to increased size and
number of glands, which are irregular in their distribution and
course, the normal parallel alignment being lost. The stroma
is not hyperplastic but is edematous. The glands may show
both proliferative and secretory activity. In the bitch, the
glands are tortuous and secretory; the mucosal epithelial cells
are typically progestational, being hypertrophied with clear
cytoplasm; the glands of the basal endometrium are also
active; and there is little evidence of the normal partitioning
of the endometrium into layers. There is usually some degree
Pathology of the Endometrium 383
of adenomyosis. Cystic hyperplasia, the so-called “Swiss-
cheese” endometrium, is the histologic extreme of the condi-
tion and is irreversible. It is probable that endometrial hyperplasia
is but an exaggeration of the normal proliferative activity of the
endometrium in response to ovarian hormones.
Endometrial hyperplasia is a significant precancerous lesion
in women. In domestic animals, this is not so. Endometrial
hyperplasia is very common in the bitch, but uterine cancer
is extremely rare.
Canine pseudoplacentational endometrial hyperpla-
sia.  The endometrium of the bitch occasionally undergoes an
unusual, but very characteristic, endometrial segmental hyper-
plasia consisting of localized proliferation of the endometrium
that closely resembles pregnancy implantation sites (Fig. 4-47).
Pseudoplacentational endometrial hyperplasia (PEH) is a fre-
quent component of pseudopregnancy. The unopened uterus
may have one or more ovoid distended areas that may resem-
ble pregnancy sites. Prior to opening the uterus, other differ-
ential diagnoses would include endometrial polyp, chronic
pyometra, leiomyoma, or fetal mummification.
The pathogenesis of this very specific form of endometrial
hyperplasia has been investigated. Experimental studies have
shown that a variety of sterile substances, such as sterile silk or
autogenous tissue, when placed in the lumen of the uterus of
a bitch in the luteal phase of the estrous cycle, will result in
dramatic endometrial proliferation and remodeling. These
studies demonstrated how sensitive and responsive the canine
endometrium is during the period of the estrous cycle, when
it would be an intimate part of placental structures if the bitch
were pregnant.
Segmental endometrial hyperplasia can occur in virgin
bitches and is part of pseudopregnancy. Similar segmental
areas of hyperplasia have been experimentally produced by
placing various sterile materials in the lumen of bitches that
are in the luteal phase of their cycles. It has been suggested
that these are florid decidual reactions and have been referred
to as deciduomas, but use of this term is discouraged.
The microscopic features of PEH are characteristic (Fig.
4-48). The hyperplastic endometrium may appear as a broad-
based polypoid mass extending into the uterine lumen (see
Fig. 4-47) or may form a continuous band of protruding tissue
(see Fig. 4-48A, B). The endometrium is organized in 3 dis-
crete layers, corresponding to the deep glandular zone, con-
densed connective tissue band, and folded luminal epithelial
junctional zones. The luminal surface is almost always necrotic,
and no fetal placental tissues are present.
Estrogenic plants.  Pasture legumes as sources of estrogenic
activity have claimed attention as a cause of a spectacular
syndrome of infertility in sheep, and as a cause of less obvious
depression of fertility in sheep. Although many estrogenic
substances are known to occur in plants, pasture plants that
have been found to produce estrogenic effects are mainly
some varieties of Trifolium subterraneum, T. pratense, Medicago
sativa, and M. truncatula. The estrogens of the clover species
are usually isoflavones; alfalfa and the barrel medic contain
coumestans.
Extensive metabolism of phytoestrogens occurs in the
rumen. During such metabolism, compounds of very different
estrogenic potency from those in the plant can be produced.
Among the isoflavones, formononetin, a compound with little
estrogenic activity in itself, is the main compound producing
histologic effects in sheep after its conversion in the rumen to
the potent estrogenic metabolite, equol.
384 CHAPTER 4  •  Female Genital System
B areas of endometrial glands (the deep glandular zone). The
Figure 4-47  Pseudoplacentational endometrial hyperplasia
(PEH) in a bitch. A less common form of endometrial hyperplasia
occurs during the luteal phase in some bitches. A. The endome-
trium undergoes dramatic highly organized hyperplasia that
replicates the endometrial tissue growth and remodeling that
occurs at placentation sites during normal pregnancy. The uterine
horn is distended and, frequently when opened, the proliferative
band of endometrial tissue protrudes from the endometrial
surface. B. PEH involving the uterus of another bitch. The cross-
section of a uterine horn in the area of segmental enlargement
with dramatic endometrial hyperplasia is shown. (Also note the
presence of several serosal inclusion cysts on the surface of the
uterus.)
There is variation in estrogenic potency between strains of
clover and also with the season or stage of growth, activity
being greatest in winter and early spring. Potency is dimin-
ished if the clover is allowed to wilt and dry or if it is made
into hay, but the activity is retained if the clover is artificially
dried.
Pathology of the Endometrium
Figure 4-48  Pseudoplacentational endometrial hyperplasia
(PEH) in the bitch. Note the uniform distention of the deeper
luminal epithelium has many thin folds, lined by secretory epi-
thelial cells (equivalent of the junctional zone in a normal preg-
nancy site). The luminal ends of these folds usually undergo
coagulative necrosis. Necrotic debris is usually found admixed
with mucoid endometrial secretions. A. The subgross photograph
in A corresponds to the tissues in Figure 4-47B. B. Higher
magnification.
Estrogenic pastures grazed during the breeding season may
temporarily impair fertility, and ewes so affected may have a
very low lambing rate and a high incidence of dystocia and
uterine prolapse. Wethers on such pastures develop enlarge-
ment of the bulbourethral glands (see Vol. 3, Male genital
system). The fertility of affected ewes returns after removal
from the offending pastures if the exposure is short, but infer-
tility can be permanent if there is prolonged exposure. The
infertility is in large part attributable to failure of transport of
sperm through the cervix because of changes in the cervical
mucus. Estral cycles are normal, and normal ovulation appar-
ently occurs. The dystocia that is common is attributed to
Pathology of the Genital System of the Nongravid Female Pathology of the Endometrium 385

reduced myometrial tone at parturition; it results in a high

rate of maternal and neonatal death. Uterine prolapse occurs
in maiden and nonpregnant ewes as well as postpartum ewes;
mammary development and lactation occur in nonpregnant
ewes.
The principal morphologic changes in the cervices of
affected ewes consist of greater glandular development, so it
is more like uterus; reduced numbers of goblet cells; and a
reduced amount of stratified epithelium. These changes are
associated with an increased incidence of cervicitis. The endo-
metrium is hyperplastic, and macroscopic cysts are often
present. Hydrometra and pyometra are occasionally seen.
These are the signs and lesions that were described in the
original reports of infertility in ewes caused by estrogenic Figure 4-49  Canine adenomyosis. Adenomyosis can occur as
plants, commonly known as clover disease. single small endometrial glands within the myometrium. They can
The development of varieties of clover low in formonone- become more extensive, as demonstrated in this subgross section.
tin has made it possible through changes in management and The epithelial lining of these ectopic glands ranges from normal
agronomic measures to control the most severe forms of the appearing to attenuated in the larger cysts.
disease. But, as the original syndrome has been brought under
control, a much more insidious form of estrogenic infertility in
ewes has emerged as the result of chronic or repeated ingestion of
low levels of phytoestrogens. This syndrome causes less severe
reproductive losses, but the infertility tends to be permanent.
Its anatomic basis consists primarily of subtle cervical changes
that also impair sperm transport. The cervical lesions are those
of blunting of the cervical folds, with a reduction of the
number of folds and crypts associated with an increase in the
stroma of the lamina propria. There is an increase in coiled
tubular glands of the endometrial type in the cervical lamina
propria. This change is most severe at the cranial end of the
cervix. This glandular induction is the reason the disease has
been referred to by the awkward name of estrogen-induced
transdifferentiation. The persistent effects of estrogen also
bring about modification of sexual behavior; some ewes
develop a more male behavior, clitoromegaly, and fusion of
the ventral labia. These changes are mild, and the disease can
be best identified by careful cervical histologic examination,
Figure 4-50  Photomicrograph of canine adenomyosis. These
determining the number of folds, and quantifying the area of
slightly irregular endometrial glands are present within the
the lamina propria. Because this is unknown territory for most
myometrium.
pathologists, adequate control material is essential.
The effects of estrogenic pastures or of the various isofla-
vones on cows have not been conclusively examined, but there segmental aplasia. It may also be present as a malformation of
is little doubt from information accrued in Israel and Tasmania the tips of the uterine horns in cows.
that the effects are important; alfalfa (lucerne) and the clovers Adenomyosis as seen in domestic animals shares features
listed previously have been blamed. The principal features of with endometriosis of menstruating primates only when the
the syndromes reported are similar to those produced by aberrant site is within the myometrium; in this site the 2
cystic follicles. The infertility rate is high and is associated with conditions are histologically similar.
persistent cystic ovaries, aberrations of the estrous cycle with
abnormally long estrus; swelling of the vulva independent of Endometrial polyp
estrus; and sometimes enlargement of the clitoris, increase in This lesion is seen most commonly in the bitch and queen and
size of the uterus and cervix with cystic endometrial hyper- is striking when the polyps are large (Fig. 4-51). Segmental
plasia, and enlargement and function of the virgin mammary distension of the uterine horn(s) can be confused with tumors
gland. of the myometrium (leiomyomas and leiomyomatosis),
chronic pyometra, pregnancy or sites of fetal resorption, or
Adenomyosis segmental cystic endometrial hyperplasia. In contrast to the
This term applies to the presence of endometrial glands and polypoid form of endometrial hyperplasia, the true polyp con-
stroma between the muscle bundles of myometrium (Figs. tains substantial connective tissue stroma in addition to dilated
4-49, 4-50). glands and is pedunculated (Fig. 4-52). Polyps may be multiple
In some cases it is a malformation, and in others it arises or isolated, and their shape is molded to the uterine lumen.
by hyperplastic overgrowth of the endometrium. It is not a Polyps may provide sufficient mass that uterine contrac-
common lesion in any domestic species, but is seen in the tions can mechanically force prolapse of the affected horn.
bitch with cystic endometrial hyperplasia. Adenomyosis is Endometrial polyps may be observed protruding through the
occasionally observed in cows as part of the local disarray of cervix into, and sometimes even from, the vagina.
386 CHAPTER 4  •  Female Genital System
Figure 4-51  Multiple endometrial polyps in a queen. This queen
had several firm segmental enlargements involving both uterine
horns. Endometrial polyps can be single or multiple and occur
most commonly in older queens and bitches.
Figure 4-52  Canine endometrial polyp extending into the uterine
lumen. Note the cystic spaces that are dilated endometrial glands.
These polyps contain fibrous connective tissue bands and progress
from locally extensive areas of cystic hyperplasia that become
fibrotic. Larger polyps assume the shape of the lumen.
Uterine accumulation of secretory or
inflammatory exudates
Hydrometra and mucometra
The 2 conditions are considered together as the difference is
probably only in physical properties and depends on the
degree of hydration of the mucin, which in turn may be
related to the relative activity of estrogenic hormones. The
accumulation of thin or viscid fluid in the uterus is concurrent
with the development of endometrial hyperplasia or is proximal
to an obstruction of the lumen of the uterus, cervix, or vagina.
Grossly, there is uniform or segmental distension of the uterus
(Fig. 4-53). If hydrometra or mucometra persists for a long
time, the endometrium becomes markedly attenuated and will
atrophy (Fig. 4-54).
In cases of congenital or acquired obstruction of the lumen
of the tubular genitalia, the volume of fluid that accumulates
proximal to the obstruction depends on the site of the obstruc-
tion. In uterus unicornis in cattle, there may be 500 mL; in
imperforate hymen, there may be 10 L or more. The fluid is
slightly cloudy and watery, but in some cases of segmental
aplasia where the volume of retained secretion is not great, it
may be very viscid, ocher colored, and sometimes inspissated
to rubbery masses of mucin and cellular detritus. In these cows
Pathology of the Endometrium
Figure 4-53  Hydrometra in a goat. The uterine wall becomes
thinner as fluids accumulate. The accumulation of viscous fluid
within the uterus is called mucometra.
B
Figure 4-54  A. Subgross photograph of a cross-section of a
uterine horn from a normal bitch for comparison to B, the dis-
tended uterine lumen from a bitch with hydrometra. Long-
standing hydrometra or mucometra can lead to atrophy of the
endometrium.
the ovaries are normal. If affected uteri become infected,
intractable pyometra results. An abnormally long and tortuous
cervix may result in a form of mucometra caused by the reten-
tion of uterine secretions.
Serosal inclusion cysts
Uterine serosal inclusion cysts are thought to arise by pinch-
ing off of surface epithelial indentations. They are occasionally
observed in the aged pluriparous bitch and less commonly in
ruminants, and appear as thin-walled cysts containing clear
watery fluid. Serosal inclusion cysts form from small folds of
peritoneum that adhere and form entrapped pieces of serosal
epithelium that slowly accumulate secreted fluids. They tend
to occur either during uterine involution or in association with
perimetritis; however, inflammatory cellular infiltrates are not
usually present in or near these cysts.
Pathology of the Genital System of the Nongravid Female
A useful index of the severity of reaction and of the pathogen-
B at least temporarily, to infection, and more and more is being
Figure 4-55  A. Serosal inclusion cysts on the surface of a canine
uterus. These cysts develop following adhesion of the serosa to
itself in areas of linear folds. B. Subgross photomicrograph reveal-
ing both the superficial location and very thin walls that are key
features of this condition.
The gross appearance of these cysts can be striking. Most
appear to lie on the surface of the uterus (Fig. 4-55). They
contain clear fluid and have thin translucent walls. They may
vary from a few millimeters to 2 cm or more in diameter.
Serosal inclusion cysts can be distinguished from paraovarian
cysts by their location. Similarly, although a differential diag-
nosis would also include mesonephric duct cyst, the latter are
located along the mesometrium, tend not to be multiple, are
not as superficially located, and microscopically would have
smooth muscle in their wall.
Further reading
Chambers B, et al. Unilateral uterine torsion secondary to an inflam-
matory endometrial polyp in the bitch. Aust Vet J 2011;89:380-
384.
Gifford AT, et al. Histopathologic findings in uterine biopsy samples
from subfertile bitches: 399 cases (1990-2005). J Am Vet Med
Assoc 2014;244:180-186.
Marino G, et al. Endometrial polyps in the bitch: a retrospective study
of 21 cases. J Comp Pathol 2013;149:410-416.
Mir F, et al. Findings in uterine biopsies obtained by laparotomy from
bitches with unexplained infertility or pregnancy loss: an observa-
tional study. Theriogenol 2013;79:312-322.
Nomura K, Funahashi H. Histological characteristics of canine decidu-
oma induced by intrauterine inoculation of E. coli suspension. J Vet
Med Sci 1999;61:433-438.
Schlafer D, Gifford AT. Cystic endometrial hyperplasia, pseudo-
placentational endometrial hyperplasia, and other cystic conditions
of the canine and feline uterus. Theriogenol 2008;70:349-358.
Inflammatory Diseases of the Uterus 387
Sontas BH, et al. Inguinal herniation with hydrometra/mucometra in a
poodle bitch. Can Vet J 2013;54:840-844.
INFLAMMATORY DISEASES OF
THE UTERUS
General considerations
Inflammation limited in extent to the endometrium is termed
endometritis; involvement of the entire thickness of the wall
is metritis; of the serosa, perimetritis; and of the mesome-
trium, parametritis. The classification is to some extent a
esis. The great majority of inflammatory conditions of the
uterus begin in the endometrium and are in some manner
associated with the reproductive process. The predisposing
factors are to be sought then at either end of the gestation
period.
The normal nonpregnant uterus is endowed with a high degree
of resistance to infection, and even in the case of the specific
genital diseases, brucellosis, trichomoniasis, and campylobac-
teriosis, is incapable of supporting bacterial growth or even
the persistence of bacteria for any extended period. Some-
thing is known of factors that render the uterus susceptible,
discovered about innate mechanisms of resistance. The self-
limiting nature of most infections, other than those associated
with pyometra, has long been recognized and formed the basis
for the recommendation of a period of sexual rest for animals
with uterine infections. Even the specific genital infections are
self-limited in duration; active infection of a uterus with Cam-
pylobacter fetus or Tritrichomonas foetus, in the absence of
pregnancy, survives only for 2-3 estrus cycles. Brucella abortus
causes infection of the pregnant uterus but does not persist
well in the nonpregnant uterus, although it is apparently
capable of persisting in the mammary gland and lymph nodes
of infected cows.
Uterine resistance varies during the estrous cycle, susceptibility
being greatest during the luteal phase of the cycle. Several factors
may be involved. Uterine motility is increased during estrus,
and this aids in the physical clearance of microorganisms.
Innate immune mechanisms, including pathogen-associated
molecular patterns such as Toll-like receptors and defensins,
operate in the endometrium. The epithelium has a cytokine
profile that varies with the cycle and exposure to infectious
agents. Adaptive immune mechanisms include uterine synthesis
and secretion of immunoglobulin G (IgG) and IgA; these vary
during the cycle, but the variations are not great, and the
timing varies between species. The functional activity of the
neutrophils migrating into the uterus may also be affected by
the stage of the cycle, being more active during estrus than
diestrus, but much of the reduced uterine resistance during
diestrus and pregnancy is related to secretion into the uterine
lumen of progesterone-induced immunosuppressants that are
capable of inhibiting lymphocyte proliferation. It has been
well demonstrated that the uterus that is under the influence of
progesterone (which includes the pregnant uterus) is very suscep-
tible to many nonspecific bacteria and that a uterus not under
the influence of progesterone is remarkably resistant to the
same organism, even when its expulsion is prevented by liga-
tion of the cervix. This comparison can be carried a step
further to show that even greater susceptibility to infection is
present at the implantation sites in the pregnant uterus. The
 387.e1

Further reading
Adams NR. Pathological changes in the tissues of infertile ewes with
clover disease. J Comp Pathol 1976;86:29-35.
Adams NR. Measurement of histologic changes in the cervix of ewes
after prolonged exposure to oestrogenic clover or oestradiol-17β.
Aust Vet J 1986;63:279-282.
Bellenger CR, Chen JC. Effect of megestrol acetate on the endome-
trium of pre-pubertaly ovariectomised kitten. Res Vet Sci 1990;
48:112-118.
Brodey RS, Fidler IJ. Clinical and pathological findings in bitches treated
with progestational compounds. J Am Vet Med Assoc
1966;149:1406-1415.
Lightfoot RJ, Adams NR. Changes in cervical histology in ewes follow-
ing prolonged grazing on oestrogenic subterranean clover. J Comp
Pathol 1979;89:367-373.
Schlafer D, et al. Theriogenology question of the month: canine endo-
metrial polyp. J Am Vet Med Assoc 1997;210:759-761.
388 CHAPTER 4  •  Female Genital System Inflammatory Diseases of the Uterus

uterus after ovariectomy is resistant to infection but does not Mild endometritis may not be overtly evident clinically. A
clear infections as promptly as does the uterus under the influ- slight opacity of the normally crystal-clear estral mucus may
ence of estrogens. These factors of susceptibility and resistance be all that is seen. Histologically, the changes are not striking
provide some insight into the pathogenesis of postcoital and consist for the most part of a diffuse but light infiltration
uterine infections and pyometra in the dog and cat. of neutrophils with slight desquamation of the superficial
A different set of influences operates on the puerperium. epithelium and no significant vascular changes. Involvement
It is well recognized that uterine infections are likely to follow any of the glands is minimal. The significance of a few leukocytes
abnormal parturition, such as an abortion, retained placenta, in the stroma is always equivocal in cattle; they follow within
twin births, dystocia, and traumatic lacerations of the genital 2-3 days of parturition and are present during estrus. However,
canal. Of the specific abortive agents in the cow, C. fetus the presence of neutrophils in the stroma of the endometrium
and T. foetus typically cause early death of the conceptus is evidence of inflammation in the mare. The best indication of
that is not complicated by placental retention or metritis. But endometritis in all species consists of accumulations of plasma
with other causes, B. abortus especially, abortion may occur cells and foci of lymphocytes in the stroma. Resolution of this
later in pregnancy, at which time the well-developed and type of endometritis may occur with no more residue than a
manifold interdigitations of the cotyledons favor retention of few cystic glands with periglandular fibrosis (Fig. 4-56),
the placenta and the development of acute metritis. But in although during its course, it may be responsible for early
these instances, much of the uterine disease is the result of embryonic mortality. If the endometritis is more severe or
secondary invasion by bacteria that gain access to the uterus persists for a longer time, the cumulative damage to the endo-
as the result of an abnormal delivery of a dead or diseased metrium may render the mare sterile.
fetus. Contagious equine metritis is a venereal disease of mares
Some cases of postpartum metritis are a continuation and caused by T. equigenitalis, a gram-negative, microaerophilic
exaggeration of a gestational uterine infection, but most puer- coccobacillus. The disease produced by this organism does not
peral infections of the uterus can be viewed as analogous to wound appear to be significantly different from other common infect-
infections, with the organisms entering via the cervix. Probably ing organisms of the mare’s genitalia. The interest in this
all mares have uterine infections by streptococci within 1-3 disease stems from its apparently abrupt appearance in
days of parturition, but these do not persist for more than 2-3
days. In the cow, too, it has been observed that 25-30% are
infected in the normal puerperium but that most recover
spontaneously from these infections with T. pyogenes, E. coli,
and other bacteria. Clearly, the outcome will be determined
as much by the number and virulence of invading organisms
as by the environment within the uterus. The recognized
predisposing causes outlined previously will all be associated
with retarded uterine involution, as will most cases of metritis.
With the more virulent anaerobic bacteria, such predisposi-
tion is not essential.
The period necessary for normal involution varies with the
species and is determined by the nature of placentation (depth
and nature of invasion—deciduate versus adeciduate) and the
rate of endometrial repair. It is well advanced in the mare
within 9 days, as judged by the capacity for fertile mating at
that time, in contrast to the involutionary process in the bitch,
which involves deposition of material and extensive, slowly A
progressive remodeling. In the latter case, abnormalities of
involution are common and termed subinvolution of placental
sites. Most of these are probably never recognized clinically
and spontaneously regress.

Endometritis
In endometritis, the endometrium or uterine mucosa is mainly
involved. Almost all uterine infections begin as endometritis,
and many such cases progress to involve the myometrium,
becoming metritis. The mildest forms are seen postcoitus. In
the mare, semen is ejaculated directly into the uterus and
induces a transient postcoital endometritis. Such postmating
endometritis is recognized in most species. Infectious agents
tropic for the uterus include T. foetus and C. fetus or pyogenic B
cocci and coliforms of low pathogenicity.
Uterine infection by α-hemolytic streptococci, Klebsiella Figure 4-56  A. Endometrial tissue from a mare with marked
pneumoniae, E. coli, and Taylorella equigenitalis (the contagious lymphocytic endometritis. B. Glandular nesting caused by peri-
equine metritis organism) frequently occurs in mares both glandular fibrosis. Inflammation, gland loss, lymphatic distention,
following foaling and after coitus. The endometritis is usually and fibrosis are histologic features assessed during evaluation of
mild, but the impact on fertility can be substantial. equine endometrial biopsies for categorization.
Pathology of the Genital System of the Nongravid Female
horse-breeding establishments in England in 1977 and its
rapid spread to equine studs around the world. Strict control
measures seem to have limited its spread, and the clinical
disease is now rare.
The disease causes temporary infertility in mares and a
mucopurulent discharge that lasts 2-3 weeks. The organism
can persist in infected mares for several months, and recovered
mares represent an important reservoir of infection. Stallions
transmit the organism by genital contact but do not develop
clinical disease.
The temporary infertility that is the clinical hallmark of the
disease is the result of mild to moderate inflammation of the
endometrium and adjacent structures. After experimental intro-
duction of the organism into the uterus, and presumably after
natural infection, the bacteria can be regularly demonstrated
in the uterine tubes, endometrium, cervix, and vagina for a
2-3 week period, during which time the organism elicits a
mild to moderate inflammatory response. The endometrial
folds are turgid and swollen and covered by a small amount
of cloudy viscid exudate. At this stage, the endometrium is
edematous and the inflammatory infiltrate consists mainly of
neutrophils. As the reaction subsides, the edema disappears
and plasma cells predominate. Changes in the cervix parallel
those of the endometrium. Salpingitis develops in some cases
but is a less regular feature of the infection. Infection produces
no gross changes in the vagina or vaginal vestibule, and histo-
logic changes are mild. No lesions develop in the clitoral fossa
or sinus, but the organism can be recovered from these sites
after it has disappeared elsewhere.
More severe grades of endometritis are common to the puer-
perium in cattle. Nothing of significance may be visible on the
serosal surface, but the organ is enlarged and flabby, and col-
lapsed rather than firm and contracted. The lumen contains
chocolate-colored lochia that is slightly tenacious and often
without foul odor. With the admixture of inflammatory
exudate and placental detritus, the uterine content becomes
progressively dirty gray-yellow. The endometrium is red and
swollen, and the intercotyledonary areas are ragged and tat-
tered with shreds of mucosa free in the lumen. Small hemor-
rhages are common in the mucosa, and neutrophils are
prominent at the surface involving all mucosal elements,
including the glands. Where suppuration and superficial
necrosis produce the tattered mucosa, the surface is compa-
rable to a pyogenic membrane. The remainder of the genital
canal may show nothing more than the traumatic lesions
incident to parturition. If the uterus is paretic, there may be
no discharge in the vagina.
Sporadic outbreaks of suppurative endometritis associated
with bovine herpesvirus 4 have been reported. The histopa-
thology is typical for herpesvirus infections, with focal necro-
sis, ulceration, and common secondary bacterial infections.
Intranuclear viral inclusion bodies are found in endometrial
epithelial and endothelial cells.
Metritis
The distinction drawn here between endometritis and metritis
for purposes of description is that, in metritis, all layers of the
uterine wall show evidence of acute inflammation. The uterus is
paretic, and there may be little or no vaginal discharge. The
wall of the uterus is thickened with suffused blood and edema
fluid and is very friable. The serosa is dull and finely granular
with “paintbrush” hemorrhages and a thin deposition of fibrin,
or the subserosal vessels may be very prominent. Other than
Inflammatory Diseases of the Uterus 389
traumatic rupture, perforation with secondary peritonitis is
not common except in anaerobic infections; death in untreated
cases usually occurs first from toxemia or septicemia.
The secretion may be scant or abundant, is fetid, and is
dirty yellow to red-black. The microscopic picture is that of
purulent inflammation. Subserosal connective tissues are
edematous and filled with neutrophils, and the same process
surrounds the blood vessels of the myometrium and perme-
ates bundles of, and individual, muscle fibers, which them-
selves undergo granular degeneration. In metritis, as in acute
endometritis, neutrophils are in large numbers on the mucosal
surface, and there is extensive hemorrhage, necrosis, and
sloughing. Invasion of blood vessels, both arteriolar and venous,
intensifies the lesion. Thrombosis may extend to the vessels
of mesometrium with the usual sequelae of hemorrhage and
infarction.
Chronic endometritis
Recovery from the acute phase of the infection often results
in chronic endometrial involvement. With greater or lesser
degrees of endometrial destruction and replacement by granu-
lation and scar tissue, the uterus takes on the nature of a fis-
tulous tract. The changes depend on the duration and severity
of the inflammation, but consist essentially of productive fibrosis
and leukocytosis in which lymphocytes and plasma cells predomi-
nate. Thickening of the endometrium is by inflammatory
tissue; the glands are depleted; those that survive are atrophic,
flattened, and attenuated, or cystic because of periglandular
fibrosis. The lining mucosa may be intact, denuded in places,
or show foci of polypoid hyperplasia or squamous metaplasia,
as do any chronically irritated mucous membranes. The
exudate in the lumen is not copious and may be serous,
catarrhal, or frankly purulent. Much of the endometrial
stroma, especially that of caruncles, may be replaced by scar
tissue, and dystrophic mineralization of necrotic portions of
the endometrium may sometimes be extensive enough that
the lining of the uterus feels gritty.
It is estimated that 20% of cows with generalized tubercu-
losis and 4% of all tuberculous cows have involvement of the
endometrium. There are 3 routes of infection, namely, hema-
togenous, via the uterine (fallopian) tubes from the perito-
neum, and coital; of these, the last is exceptional. As in
tuberculous lesions generally in cattle, there are 2 anatomic
forms of the lesion—miliary tuberculosis and diffuse caseating
tuberculosis, although transitional forms do exist. It is generally
accepted that the disseminated miliary lesion is of hematog-
enous origin during the phase of early dissemination.
In miliary tuberculosis, the uterus may appear normal exter-
nally. In the early stages, there may be no exudate in the
lumen, but later, as the granulomas enlarge and ulcerate, the
uterus will contain yellow purulent exudate. The granulomas
are visible as few or many nodules in the mucosa, usually the
more superficial portions, and microscopically are of typical
tuberculoid structure. A common site is near the bifurcation
of the uterus or in the caruncles of the pregnant uterus.
Caseous tuberculosis causes thickening and rigidity of the
horns with serofibrinous or purulent fluid in the lumen. The
endometrium is thickened, dry, and extensively caseous (see
Fig. 4-59). There may be intense leukocytic infiltration and
marked exudation. The caseated area is usually demarcated by
a zone of epithelioid cells from a margin of connective tissue.
In association with the uterine lesion in tuberculosis, there
is often involvement of other portions of the genital tract.
390 CHAPTER 4  •  Female Genital System Inflammatory Diseases of the Uterus

There may be multiple red granulomas on the surface of the

ovary and its ligaments, or there may be enlargement of the
ovaries with parenchymal tubercles. Tuberculous salpingitis or
pyosalpinx is probably the rule when the uterine tubes are the
portal of uterine infection. Similar lesions may be found infre-
quently in the lower genital tract. Infection of cows with
atypical mycobacteria also produces tuberculous metritis and
placentitis with multiple small endometrial granulomas.

Uterine abscess
The formation of single or multiple abscesses is not common.
The localization of an infection to one part of the uterine wall
is thought to follow severe metritis, localized traumatic injury
to the infected endometrium, or adenomyosis. Such an abscess
may reach 15 cm in diameter and is usually well encapsulated,
although there may be some perimetrial adhesion and, in a
few instances, rupture into the peritoneal cavity or an adjacent
hollow viscus.
Uterine abscesses are observed more frequently in cattle
than in other species. There appears to be a relationship
between the frequency of abscesses and uterine manipulations
involving the use of instruments. In cattle, most large abscesses
are located in the dorsal wall of the uterine body. This is the area Figure 4-57  Perimetritis of the uterus of a cow with postparturi-
most subject to trauma during the passage of insemination ent metritis.
pipettes and uterine catheters. Abscesses that develop follow-
ing severe metritis or pyometra are usually small (1-3 cm) and
do not have preferential sites.

Parametritis and perimetritis

Chronic adhesive peritonitis involving the genital tract does
not usually result from septic metritis because the uterine
serosa offers an efficient barrier to the spread of infection, and
spontaneous rupture of an infected uterus is not common.
Few virulent infections spread to the supporting ligaments.
Excluding an origin from an extragenital focus, perimetritis and
parametritis in cattle usually follow manual manipulation of the
ovary, pyosalpinx, pyometra, obstetrical operation, removal of
retained placenta, or uterine irrigation. In each of the latter 3
circumstances, there may be accidental perforation or rupture
of the uterus. The extent of the adhesion may vary from a few
fibrous bands (Fig. 4-57) to dense connective tissue that
obscures the contour of the organs and fixes them to adjacent
viscera. Abscesses may form in the adhesions of the ovarian
bursa and the rectovaginal pouch.

Pyometra
Pyometra is acute or chronic suppurative infection of the uterus
with accumulation of pus in the uterine lumen. The escape of
the pus is usually prevented by a functionally closed cervix.
Drainage from the uterus may also be prevented by an
acquired or congenital cervical stenosis, and in mares the
gravitational pull of the flaccid, distended uterus over the brim
of the pelvis may limit the discharge of pus. Pyometra may
occur as a sequel to uterine infections of the types described
in the previous sections, but as it is a pathologic entity with
a number of factors unique in its pathogenesis, it is considered
separately here. Pyometra is an uncommon condition in the
sow, ewe, and camelids. It is relatively common in the bitch and
cow, but less so in the mare and queen. Circumstances under
which the disease develops in these species vary.
Pyometra in the bitch and queen.  Pyometra in the bitch
is a disease that characteristically affects older animals, espe-
cially those that are not bred. The condition most often develops
Figure 4-58  Pyometra in a bitch. Note the spiraling of the uterine
horns, a change that occurs when the canine uterus is under the
influence of progesterone. Both horns are mildly distended by
purulent exudate. Cystic endometrial hyperplasia is a common
pre-existing lesion.
a few weeks after estrus. Affected animals may be depressed
and anorexic, frequently vomit, and have polyuria and poly-
dipsia, usually accompanied by a vaginal discharge. The patho-
logic findings vary with the stage of the disease. In less
advanced cases, the uterus may be only slightly enlarged, with
mild endometrial hyperplasia and inflammation (Fig. 4-58). In
the more advanced stages, there is a remarkable distension of
the uterine horns (Fig. 4-59), which may occupy most of the
Pathology of the Genital System of the Nongravid Female
Figure 4-59  Pyometra in a queen.
Figure 4-60  Suppurative endometritis and pyometra in a cow.
This condition develops most commonly secondary to retained
placenta.
peritoneal cavity. In contrast, pyometra in cattle most com-
monly develops in the postpartum period and is frequently
associated with retention of fetal membranes (Fig. 4-60). If
the purulent exudate does not drain from the uterus, it can
become dehydrated with time, and the inspissated material is
found as soft concretions in the uterine lumen (Fig. 4-61).
Distension of the cornua may be symmetric or asymmetric,
uniform or ampulla-like dilations, as in the uterus of mid-
pregnancy. The cervix is completely or almost completely
closed as a functional response to luteal hormones. The serosal
surface of the uterus is dark, and the vessels are prominent.
The wall is friable, and either rupture or perforation with
secondary peritonitis is common. There may be obvious
inflammation of the peritoneal serosa and mesometrium, but
this is unusual. The nature of the uterine content is variable.
In the more severe cases, usually those infected with E. coli
and Proteus spp., the exudate is thick, viscid, tenacious, opaque,
red-brown, and with a characteristic fetid odor. In other cases,
usually those infected with streptococci and staphylococci,
the exudate is more typically suppurative. The mucosa is
irregular in thickness, necrotic, and ulcerated in portions with
irregular superficial hemorrhages, and in other portions
Inflammatory Diseases of the Uterus 391
Figure 4-61  Chronic pyometra in a cow. The white material is
inspissated purulent exudate.
Figure 4-62  Marked cystic endometrial hyperplasia in a bitch.
This uterine horn is opened, exposing the endometrial surface.
The endometrium is thickened, and there is massive uniform
cystic distention of endometrial gland lumens.
obviously hyperplastic, dull-white, and dry in appearance,
with small cysts visible in these hyperplastic areas.
Microscopically, the most significant feature is the remarkable
endometrial hyperplasia and progestational proliferation in
almost all cases (Figs. 4-62, 4-63). The cells of such progesta-
tional epithelium are enlarged, columnar, vacuolated, and have
small pyknotic nuclei. In some cases the normal single layer
of cells piles up to produce pseudostratification or localized
papillary proliferations. Whatever remains of the endometrial
lining may show this development, or it may be patchy and
alternating with normal epithelium.
These changes are produced by the luteal hormones that
inevitably pave the way for the development of this disease.
The histologic changes caused by infection vary with the bacterial
cause and time. Masses of neutrophils collect in the uterine
lumen and in the glands, although there is relative sparing of
392 CHAPTER 4  •  Female Genital System
Figure 4-63  A typical case of cystic endometrial hyperplasia
involving the endometrium of a bitch.
the glands unless they are cystic. Neutrophils collect near the
surface and then penetrate the epithelium. Some cases, sur-
prisingly, are dominated by cells resembling eosinophils. This
form is not studied. In milder cases there may be a few neu-
trophils in the endometrial stroma, but they are not many
when compared with the numerous plasma cells and lympho-
cytes. There may not be much vascular reaction over and
above that of hormonal origin, although perivascular reaction
and leukocytosis of lymphatic vessels are almost constant in
the myometrium. Sometimes the reaction is much more
severe than that just described, and in the endometrial stroma,
there are all the exudative phenomena of acute inflammation
accompanied by the early reparative response of granulation
tissue. The blood vessels are very congested and some show
thrombosis, and about others, there is diapedesis or larger
hemorrhage. The stroma is edematous, and bullae often lift off
the overlying epithelium. Numerous neutrophils infiltrate the
stroma and collect in the lumen. There is little formation of
fibrin, and rarely are there microabscesses in the mucosa.
It is clear that most cases of pyometra in the bitch are associ-
ated with endometrial hyperplasia. It is usually a disease of the
diestral (metestrus) period, a time at which corpora lutea are
present and progesterone concentration is high, and because
the condition has been produced both experimentally and
accidentally by the administration of progestins, it is clear that
progesterone is an essential feature in the pathogenesis.
Because cystic endometrial hyperplasia had been produced
in dogs by administration of high levels of progesterone for
extended periods of time, and because cystic endometrial
hyperplasia was a hallmark of canine pyometra, it was pre-
sumed that cystic endometrial hyperplasia induced by abnor-
mal progesterone secretion or response preceded and paved
the way for the bacterial component. Some doubts concerning
the validity of this view were generated when hormonal
abnormalities could not be demonstrated in cases of pyometra.
Now it has been shown that cystic endometrial hyperplasia
can be produced in the normal, early diestral uterus by mild
trauma to the endometrium. The investigators scratched the
endometrium with a thin wire, but endometrial biopsy has
caused the same lesion. More to the point, inoculation of
appropriate strains of E. coli into the uterine lumen, if given
1-2 weeks after estrus, causes a pyometra that has all the
Inflammatory Diseases of the Uterus
features of the natural disease, including cystic endometrial
hyperplasia.
It appears that an appropriate stimulus applied to the
progesterone-primed endometrium produces cystic endome-
trial hyperplasia and that one such stimulus can be a bacterial
infection. Accordingly, rather than pyometra in the bitch
occurring as the result of bacterial infection being superim-
posed on an abnormal endometrium, it appears that the bacte-
rial infection of the progesterone-primed endometrium produces
both the pyometra and the cystic endometrial hyperplasia.
The bacterium most commonly present in pyometra in the
bitch is E. coli, and uterine E. coli isolates are typically identical
or very similar to isolates from feces of the same bitch.
Most of the strains involved are urinary tract pathogens and
possess uropathogenic virulence factors, including P fimbriae,
α-hemolysin, and cytotoxic necrotizing factor 1, that probably
enhance the pathogenicity of the strain in the canine genital
tract and may facilitate the colonization of the progesterone-
primed endometrium. Urinary tract infections are common in
bitches with pyometra, and the strains of bacteria infecting
both are often identical. It seems probable that the urinary
infection predisposes to pyometra and that the uterus is
infected at the stage that suitable receptors are developed in
the endometrium in response to hormone stimulation. This
explanation of the bacterial infection can be only a partial one
as not all bitches with pyometra have urinary tract infection
and not all infecting organisms are urinary pathogens. In some
cases of pyometra, bacteria cannot be recovered.
The clinical signs and extragenital lesions associated with
pyometra in the bitch are due to severe toxemia and probably
also intermittent bacteremia. Renal signs and lesions are
common. Profound hypotension may reduce renal perfusion
and lead to prerenal uremia. This is worsened by membrano-
proliferative glomerulonephritis that often develops as a result
of immune complex deposition. Polyuria, which is such a
common feature of the disease, is due to impaired tubular
ability to concentrate urine. The mechanisms involved in this
are not completely understood, but they are thought to be
brought about by E. coli antigen and have an immunologic
basis. Most animals have profound leukocytosis, reflected in
the bone marrow as an increased granulocyte to erythroid
ratio. There is granulocytic hyperplasia in bone marrow and
extramedullary granulopoiesis in liver, spleen, lymph nodes,
and adrenals.
Pyometra in the queen is roughly comparable to the disease
in the bitch, but there are differences, some of which are
related to the differences in the estrous cycle of the 2 species.
Cats are induced ovulators and usually, if not bred, have
repeated estrous periods. However, pyometra develops most
often 2-5 weeks after estrus and usually after spontaneous ovu-
lation and presumably corpora lutea formation. Unlike the
bitch, many queens with pyometra do not have corpora lutea
present in their ovaries at death or surgery, but approximately
half do, and there is an obvious correlation between the presence
of corpora lutea and the development of pyometra in queens. The
correlation with endometrial hyperplasia is less clear. Most
queens with pyometra do have some degree of cystic endo-
metrial hyperplasia, but this change is very common in the
age group affected.
Pyometra in the cow.  Pyometra in the cow is associated
with corpus luteum activity in the ovary. However, in contrast
to the situation in the bitch in which the high progesterone
levels of early diestrum predisposes to uterine infection, in the
Pathology of the Genital System of the Nongravid Female
cow, uterine disease causes the corpus luteum to persist and
maintain a high progesterone level. The retention of the corpus
luteum appears to be due to a reduction in or inhibition of
the synthesis and release of the luteolytic factor prostaglandin
F2α (PGF2α) by the diseased endometrium.
Broadly, there are 2 periods in which a uterine infection
can lead to retention of a corpus luteum with the accompany-
ing hormonal effects that convert endometritis to pyometra.
They are during the early postpartum period—following dysto-
cia, retained placenta, and metritis—and at various times after
breeding, as a result of venereal infections, with early embry-
onic death. Insemination during the luteal phase of the cycle
or similar operations that can introduce contamination into
the uterus during the luteal phase can mimic venereal
infection.
The role of retained luteal tissue in the pathogenesis of
pyometra appears clear. The secreted progesterone endows
the uterus with a high degree of susceptibility to infection,
maintains functional closure of the cervix, and inhibits myo-
metrial contractility.
The amount of pus retained in the uterus of a cow with
pyometra varies from a few milliliters to more than several
liters and is thick, rather mucinous, and cream or gray-green
colored. The cervix has no seal of mucus, so although con-
tracted, there is usually escape of a small amount of pus into
the cranial vagina. The wall of the uterus is thick, doughy,
and flaccid, but in long-standing cases, especially as complica-
tions of mucometra, the walls are thin or fibrosed. The histo-
logic changes do not differ significantly from those of
endometritis of comparable duration and severity. The organ-
isms involved are hemolytic streptococci, staphylococci, coli-
forms, T. pyogenes, and Pseudomonas. The venereally transmitted
protozoan, T. foetus, can be the cause of pyometra after
breeding.
Rarely, the anomalous developments of the uterus that
were described earlier can lead to pyometra. In the segmental
aplasias and with imperforate hymen, the lumen proximal to
the site of obstruction becomes distended with mucus and
cellular detritus. These closed cavities provide a satisfactory
environment for bacterial growth, but this is not a frequent
complication. When it does occur, the source of infecting
organisms is probably hematogenous. Pyometras seldom
resolve spontaneously, and although the condition is not
usually life threatening, as it is in bitches, the condition will
persist unless cyclic activity can be reinstituted.
Pyometra in the mare.  Pyometra in the mare differs from
the disease in the bitch and the cow in several particulars.
Although some cases develop following difficult parturitions
with infections, as they do in cattle, many do not. Remarkably,
most mares continue to cycle during the disease, and the
hormonal influences that are so marked in the bitch, queen,
and cow are much less important in the mare.
In some mares, cervical adhesions and closure may lead to
pyometra, but in most instances the purulent material collects
without demonstrable cervical closure, and in some cases the
cervix is fully dilated. Copious amounts of pus can be dis-
charged under such circumstances, particularly during estrus.
Pyometra in the mare seldom leads to evidence of systemic disease,
although some mares develop mild anemia.
The length of the estrous cycle appears to be related to the
severity of the endometrial damage. In rare cases, where the
endometrial damage is severe, the cycles are prolonged with
long luteal phases resulting from delayed or inadequate PGF2α
Pathology of the Gravid Uterus 393
release. Mares with less severe endometritis have normal or
shortened cycles.
A variety of organisms may be present in pyometra in the
mare: Streptococcus zooepidemicus is the most common, but E.
coli, Actinomyces spp., Pasteurella spp., and Pseudomonas are
often present.
Endometrial biopsy.  Endometrial biopsy is most firmly
established in equine theriogenology. The evaluation system is
based on identification and scoring of 4 microscopic lesions
plus consideration of the mare’s reproductive history. The
microscopic features evaluated include stage of cycle, inflam-
mation, presence of fibrosis, dilation of lymphatics, and loss of
glands.
Only a small amount of information has been published
on endometrial biopsy in other species. Pathologists are asked
to evaluate endometrial biopsies for cattle, bitches, and cam-
elids, and as more information is gathered and evaluated,
recommendations for scoring will be followed by further vali-
dation of their prognostic value.
Further reading
Christensen BW, et al. Diagnostic value of transcervical endometrial
biopsies in domestic dogs compared with full-thickness uterine
sections. Reprod Domest Anim 2012;47(Suppl. 6):342-346.
Gibson A, et al. A retrospective study of pyometra at five RSPCA hos-
pitals in the UK: 1728 cases from 2006 to 2011. Vet Rec
2013;173:396.
Kenney RM. Cyclic and pathologic changes of the mare endometrium
as detected by biopsy, with a note on early embryonic death. J Am
Vet Med Assoc 1978;172:241-262.
Mateus L, et al. Virulence genotypes of Escherichia coli canine isolates
from pyometra, cystitis and fecal origin. Vet Microbiol 2013;166:590-
594.
Schlafer DH, Gifford AT. Cystic endometrial hyperplasia, pseudo-
placentational endometrial hyperplasia, and other cystic conditions
of the canine and feline uterus. Theriogenology 2008;70:349-358.
Schlafer DH. Diseases of the canine uterus. Reprod Domest Anim
2013;47(Suppl. 6):318-322.
Smith FO. Canine pyometra. Theriogenol 2006;66:610-612.
PATHOLOGY OF THE GRAVID UTERUS,
PLACENTA, AND FETUS
General considerations
It is difficult to generalize on the subject of diseases of preg-
nancy because of the remarkable variation in the reproductive
affairs of the various species. Because the mechanisms by
which the gestation period is initiated, the pregnancy main-
tained, and the delivery triggered have such profound effects
on how diseases of the conceptus will be manifest, some
review of the special features of reproductive patterns in the
various domestic species is given here.
For a pregnancy to proceed, the normal cyclic lysis of the corpus
luteum must be prevented. This is achieved in cattle by secretion
by the blastocyst of interferon-γ, which inhibits synthesis and
release of PGF2α from the endometrium. This spares the
corpus luteum and allows it to serve as the corpus luteum of
pregnancy, and it then provides part or all of the hormonal
support of the pregnancy. In cattle, up to 40% of total embry-
onic loss probably occurs between days 8 and 17 of pregnancy.
Early embryonic death will permit release of PGF2α and lysis
 393.e1

Further reading
Chen YM, et al. Uropathogenic virulence factors in isolates of Esche-
richia coli from clinical cases of canine pyometra and feces of
healthy bitches. Vet Microbiol 2003;94:57-69.
Frazier K, et al. Endometritis in postparturient cattle associated with
bovine herpesvirus-4 infection: 15 cases. J Vet Diagn Invest 2001;
13:502-508.
Garoussi MT, et al. Mycoflora of cervicovaginal fluids in dairy cows with
or without reproductive disorders. Mycopathologia 2007;164:97-
100.
Gifford AT, et al. Histopathologic findings in uterine biopsy samples
from subfertile bitches: 399 cases (1990-2005). J Am Vet Med
Assoc 2014;244:180-186.
Keskin A, et al. Pathological abnormalities after long-term administra-
tion of medroxyprogesterone acetate in a queen. J Feline Med Surg
2009;11:518-521.
Maddens B, et al. Escherichia coli pyometra induces transient glo-
merular and tubular dysfunction in dogs. J Vet Intern Med
2010;24:1263-1270.
Mir F, et al. Findings in uterine biopsies obtained by laparotomy from
bitches with unexplained infertility or pregnancy loss: an observa-
tional study. Theriogenol 2013;79:312-322.
Nomura K, et al. Histological observations of canine cystic endometrial
hyperplasia induced by intrauterine scratching. Jpn J Vet Sci
1990;52:979-983.
Petit T, et al. Prevalence of potentially pathogenic bacteria as genital
pathogens in dairy cattle. Reprod Domest Anim 2009;44:88-91.
Potter K, et al. Clinical and pathologic features of endometrial hyper-
plasia, pyometra, and endometritis in cats: 79 cases (1980-1985).
J Am Vet Med Assoc 1991;198:1427-1431.
Zaragoza C, et al. Canine pyometra: a study of the urinary proteins by
SDS-PAGE and Western blot. Theriogenol 2004;61:1259-1272.
394 CHAPTER 4  •  Female Genital System
of the corpus luteum and subsequent reinstitution of the estral
cycles in these species. The delay between death of the con-
ceptus and the return of the dam to estrus is usually sufficient
to allow complete or near-complete autolysis and dissolution
of the fragile embryo. As a result, the early diseased products
of conception are rarely available for study. Venereal infections
cause some of the early losses, but on the basis of the few
studies that have been done, and on the experience in other
species, it is presumed that chromosomal abnormalities account
for most of these early losses. In monotocous species, embryos
that die undergo prompt dissolution, the products are expelled,
and the disease is recognized only as infertility with slightly
prolonged estral cycles. The death of a single embryo, or even
several, does not interrupt the pregnancy in swine, and dead
embryos are resorbed or mummified. Rarely, the death of the
conceptus may be caused by organisms that convert the preg-
nancy to a pyometra, the active infection preventing the lysis
of the corpus luteum. Trichomoniasis of cattle is an example
of a venereal infection that can lead to pyometra.
In the mare, gonadotropic hormone (equine chorionic
gonadotropin) is produced in linear, slightly dome-shaped
structures within the endometrium, the endometrial cups (Fig.
4-64). These structures form early in pregnancy. Originally
thought to be maternal in origin, “cup” cells are fetal in origin
and arise from a band of specialized trophoblast cells that
form the chorionic girdle on the expanded blastocyst. These
cells become detached from the fetal chorion on about day
35 of gestation and burrow into the stroma of the endome-
trium. There the cells enlarge and appear as large binucleated
cells.
The cup tissue becomes visible at about day 40 of gestation
as a horseshoe or ring-shaped band in the endometrium of the
pregnant horn (see Fig. 4-64). The cups increase in size until
day 60 of gestation, at which time their hormone production
is at a maximum. Hormone concentration falls after day 60,
and the cups become pale and slough between days 75 and
100 of gestation. The degeneration of the cups resembles graft
rejection. The cells of the fetal chorion are surrounded by an
intense maternal accumulation of lymphocytes and undergo
prompt coagulative necrosis. The necrotic slough is detached
Figure 4-64  Endometrial cups in the endometrium of a mare.
These transplanted trophoblast cells produce the hormone equine
chorionic gonadotropin. This tissue dies and becomes necrotic
about 100-120 days of gestation as a result of a marked maternal
lymphocytic response.
Pathology of the Gravid Uterus
and lies free between the endometrium and chorion, and then
the necrotic cup cells become contained in a pouch formed
by the enclosure in an area of chorioallantois. These are called
chorioallantoic pouches and appear as teardrop-shaped small
extensions from the allantoic surface on the inner surface of
the chorioallantoic membrane near where the umbilical cord
attaches.
This potent chorionic gonadotropin in mares stimulates
ovarian corpora lutea to develop, and these maintain the
pregnancy until approximately 126-140 days, when the fetal
chorion takes over the production of progesterone. If the
conceptus dies after day 35 of gestation, the cups persist
and continue to secrete chorionic gonadotropin, accessory
corpora lutea are produced, and the mare fails to return
to estrus and continues for a variable period in a state of
pseudopregnancy.
Domestic carnivores that are pregnant have corpora lutea
that persist during the gestation period. Prolonged luteal pres-
ence is also a feature of the relatively long luteal phase of the
cycle in bitches and queens. Corpora lutea develop after ovu-
lation, spontaneously in the case of the bitch and induced by
coitus in the cat. Once formed, their lifespan appears to be
inherent and the hormone production by them to be indepen-
dent of a pregnancy until the last stages of gestation. As a
result, death of the embryos or death or sickness of the fetuses
shortens the length of the gestation period only slightly. Fetal
death before the terminal stage does not usually lead to pre-
mature delivery; rather, the process of autolysis and resorption
or mummification begins, and the products are expelled at or
near term. As a consequence, it is very rare to obtain diseased
fetuses from these species in a satisfactory state for study. Most
studies of fetal diseases in carnivores have been based on
experimental investigation.
The corpus luteum is essential for the maintenance of
pregnancy during the entire gestation period in swine and
goats, as it is in dogs and cats, before term. The corpus luteum
is only essential during the first half of pregnancy in the mare
and ewe, and during all but the end of pregnancy in the cow.
During this time, the effects of fetal death are unpredictable.
In some cases the corpus luteum may undergo luteolysis, and
the dead fetus or fetuses are expelled, usually severely autol-
ysed, but in some cases the corpus luteum will not be lysed
and will persist, and the fetus will be resorbed or more likely
expelled. If the fetus is older, and particularly in cattle, it may
be mummified. During the last third of gestation in these
species, the pregnancy requires hormonal support from the
fetus, and fetal death at this stage leads to expulsion within a
few days. Even a few days allow time for autolysis to be
evident; the fetal tissues are pale, the red cells lysed, and
pleural and peritoneal cavities are filled with hemoglobin-
stained fluid.
The mechanisms by which dead fetuses are expelled in
cattle and sheep are not known, but it is probable that they
share features with normal parturition. They must involve
PGF2α release, cervical compliance, and coordinated myome-
trial contraction. Chronic fetal disease in cattle and sheep
results in premature delivery of live but diseased fetuses.
Because fetal stress activates the same hypothalamic-pituitary-
adrenal endocrine chain used to initiate normal parturition, it
is probable that chronic fetal disease operates through the
same chain to cause abortions of live fetuses. Equid herpesviral
infection regularly produces abortion of live, diseased, equine
fetuses.
Pathology of the Genital System of the Nongravid Female
Embryonic death
There is little that can be said with profit of the pathology of
the ovum, zygote, or early embryo, but a brief consideration
is included here for purposes of orientation.
When fertilized ova die, they undergo progressive cytolysis
within the zona pellucida, which often remains intact after
death. The whole structure then disintegrates and is resorbed
or discharged at the next estrus. It is rare to recover abnormal
ova from the bovine uterine tube during the first 72 hours
postestrus. Presumably, in those cases in which estrus occurs
after a normal cycle, the ova die most commonly between days
4 and 10 of the cycle. Most embryonic deaths in cows, however,
are associated with prolongation of the interestral period.
In the embryonic stage, the embryonic tissue proper disap-
pears first, and the trophoblast remains for a while before
degenerating.
The incidence of zygotic and embryonic mortality is remark-
ably high in the species that have been studied and probably is
in all species. Humans and the domestic species studied suffer
a zygotic loss of 15-30%. The causes are presumably diverse
and may vary somewhat from species to species. However, the
demonstration of abnormal karyotypes in early bovine and
porcine zygotes and in a high percentage of unselected spon-
taneous human abortions suggest that chromosomal or other
genetic abnormalities are an important cause of this mortality.
The frequency with which chromosomal abnormalities are
found varies with the stage of pregnancy; they are most
common in the early stages of pregnancy. This is the pattern
one would anticipate because some of the most severe anoma-
lies are not compatible with attachment or implantation. Most
of these chromosomal abnormalities represent numerical
changes such as monosomy, polysomy, polyploidy, and mixo-
ploidy. Only a small percentage is structural. The monosomies
and polysomies are the result of nondysjunction during meiosis
or early cleavage stages. Triploidy can be caused either by 2
sperm fertilizing one egg or by the suppression of the second
polar body and one sperm fertilizing a diploid egg; both pos-
sibilities increase with increased age of the gametes. Tetra-
ploidy occurs as a result of suppression of the first cleavage
division of the zygote. Mixoploids develop as a consequence
of mitotic error during cleavage division of the zygote. Struc-
tural anomalies are caused by spontaneous breakage and
reunion. Viruses, drugs, and radiation are known to cause this
type of chromosome damage.
Fetal death
A degenerate zygote or early embryo may be resorbed or
expelled from the uterus. At a later stage in development, the
dead fetus may be mummified, macerated, or aborted; an
abortion is defined as the expulsion of a fetus prior to the time
of expected viability. A dead fetus delivered within the period
of expected viability is arbitrarily referred to as stillborn.
Perinatal mortality is a natural extension and refers to death
from causes at or about the time of birth. It should be appreci-
ated that these different terms might be applied to fetuses
suffering from the same basic disease.
In uniparous domestic animals, death of the fetus in late
pregnancy is usually followed by abortion. In multiparous
species, if most of the fetuses die at the same time, all are
likely to be aborted, but it is more usual for one or several
dead fetuses to be retained with the remaining viable ones and
delivered at parturition. It is often apparent that the deaths
Pathology of the Gravid Uterus 395
Figure 4-65  A mummified bovine fetus. Fetal and placental
tissues undergo necrosis and dehydration in the absence of
bacteria.
have occurred at different ages, the dead fetuses being of dif-
ferent sizes and degrees of mummification or maceration.
Mummification of fetus
Mummification of a dead fetus is seen occasionally in any, but
usually multiparous, species and most commonly in the sow.
In the mare, it is typically one of twin fetuses that is mummi-
fied. Mummification may also occur in mares receiving pro-
gesterone in the early stages of gestation to prevent abortion
associated with failure of endometrial cup development and
subsequent failure of accessory corpora lutea formation and
thereby progesterone production. The exogenously adminis-
tered progesterone inhibits contractions of the uterus and, if
the fetus dies, prevents abortion, so the fetus mummifies. A
prerequisite for mummification is that bacterial infection is not
present.
The fluids are resorbed, and the membranes become closely
applied to the desiccated fetus. The whole mass becomes
brown or black and rather leathery, moist on the surface with
sticky mucus, but without odor or exudate (Fig. 4-65). The
time required for complete mummification will depend to
some extent on the size of the fetus. Dehydration is advanced
by 7 days in sheep fetuses; however, complete mummification
probably requires as long as 6-8 months in the case of a
6-month bovine fetus. All stages may be observed—from the
earliest, of beginning separation of the placenta with hemo-
globin staining of the tissues, to the latest, when all that
remains is a firm and shrunken remnant consisting almost
wholly of dried skin and bones. Until the time of expulsion,
which on occasion occurs spontaneously, or parturition in
multipara that still carry some viable fetuses, the cervix
remains closed and sealed. In uniparous animals, the mummi-
fied fetus may be retained indefinitely. Animals that have had
and delivered a mummified fetus usually breed normally on
subsequent occasions, so there cannot be any serious uterine
lesion accompanying the fetal death. Genetic diseases (both
inherited and chromosomal abnormalities), viral and proto-
zoan infections, and placental insufficiencies have been pro-
posed as the causes of fetal death leading to mummification,
but the cause is rarely firmly established in any particular case.
Very likely all the proposed causes and others can produce
fetal death at an appropriate time, and mummification can
396 CHAPTER 4  •  Female Genital System
result. The critical features for mummification appear to be the
retention of the dead fetus within the uterus through the action
of a functional corpus luteum and fetal skin mature enough to
resist autolysis.
Fetal maceration and emphysema
Maceration and emphysema of the fetus require the presence of
an infection in the uterus. If the early embryo succumbs to
uterine or embryonic infection, maceration is usually followed
by resorption within the uterus or expulsion along with a
small amount of purulent exudate. This is the usual course of
events in venereal infections by Campylobacter fetus and Trit-
richomonas foetus in cows, but is also to be expected with any
sort of nonspecific endometrial infection. The causes of infec-
tious death of the conceptus during the period of the fetus
are the same as previously, but the consequences, pyometra
or acute endometritis, are usually more severe because of the
presence of decomposing fetal remnants. The differences
between pyometra and endometritis are as discussed earlier;
in pyometra the corpus luteum may persist, the cervix remains
sealed, and the uterus withholds its contents. If the corpus
luteum and cervical seal break down, there is purulent dis-
charge of the contents, and except for the presence of fetal
remnants, this endometritis does not differ much from that of
the puerperium. After about the third month of pregnancy in
the cow, complete fetal maceration does not occur. Fetal
bones, and to a degree, fetal hair resist maceration (Fig. 4-66).
They may be discharged or retained in the purulent exudate
(pyometra) or remain in the uterine lumen indefinitely. The
uterine pus is usually intensely fetid until maceration is
complete.
The usual infectious causes of fetal death and endometritis
are not potent gas-formers; the development of fetal emphy-
sema almost invariably depends on patency of the cervix and
on invasion of the uterus and dead fetus by putrefactive organ-
isms from the vagina. There are 2 common antecedents to
emphysema: dystocia at or near term, and incomplete abor-
tion. In incomplete abortion, the cervix is open but not com-
pletely dilated, and the fetus may be delivered into the cervix
or cranial vagina, or because of malpresentation, uterine
Figure 4-66  A macerated bovine fetus. The presence of bacteria
causes putrefaction of fetal and placental tissues. Soft tissues
slowly undergo fetid disintegration, which leads to loss of all soft
tissues, and only fetal bones remain.
Pathology of the Gravid Uterus
inertia, or inadequate dilation of the cervix, it may be retained
in the uterus. The fetus putrefies, becomes distended with foul
gas, and crepitates. If the fetus is small, the dam may survive
the initial acute episode of fetal emphysema, after which
maceration occurs in a chronic, foul purulent metritis. The
cervix is not sealed, but because of uterine paresis, the pus is
retained in the flaccid, dependent organ.
Advanced uterine lesions accompany the macerated fetus.
The uterine wall is thickened, and the reaction within it varies
from the acute exudative inflammation of pyometra to more-
or-less complete sclerosis and replacement by granulation
tissue in long-standing cases. In these the uterus closes firmly
about the bones, and the bones may cause perforation.
Fetal emphysema, at or near term, complicating dystocia is
fatal unless treated, and maceration is not an expected sequel.
In some cases of uterine torsion, however, the twisted cervix
and vagina produce an adequate seal against bacterial invasion
of the dead fetus, and mummification, rather than maceration
or emphysema, results.
A special form of fetal emphysema occurs in ewes, caused
by Clostridium chauvoei, the organism responsible for blackleg.
It affects fetuses near full term, causing acute tympanitic
distension of the uterus, typical hemorrhagic and necrotizing
lesions of the fetus, and the accumulation of dark thin dis-
charge in small amounts in the uterus. The pathogenesis of
this special infection is not entirely clear, but there is usually
a relation to rough handling, such as at shearing.
Embryonic death with persistence of
membranes (cystic placental mole)
This is an uncommon development that can follow embryonic
death. In the period of the embryo, the fetal membranes are
in volume and mass the greater part of the products of con-
ception, and it is possible for the embryo to die and to be resorbed
while the membranes persist and continue to grow. The remaining
empty cyst has been referred to as a cystic placental mole. Most
empty placental cysts correspond in size to fetal membranes
at 3-4 months of gestation. There is usually no patent lumen
to the cyst. It is filled with a mass of clear-gelled fluid together
with placental stroma. In those cases with placentary develop-
ment, the allantoic and amniotic epithelia may be present. The
condition may become infected and converted to a pyometra
or undergo necrosis and be discharged. Infections that result
in rapid death of the fetus (e.g., bovine herpesvirus, Trueperella
pyogenes, Histophilus somni) usually result in a severely autol-
ysed fetus, as time is required for the corpus luteum to lyse,
the cervix to dilate, and for prostaglandin to contract the
uterus and expel the fetus. In infections that are chronic and
take time to kill the fetus (e.g., B. abortus, most mycotic abor-
tions, Yersinia pseudotuberculosis), the preparations for abor-
tion may be complete by the time the fetus dies, and therefore
the fetus will be aborted in a relatively well-preserved condi-
tion. In infections that are largely confined to the amnion, such
as Ureaplasma diversum, the probable mechanism involves
macrophage activation, resulting in cytokine-induced produc-
tion of prostaglandin by the endometrium, lysis of the corpus
luteum, and premature delivery of a well-preserved or slightly
autolysed fetus, depending on how quickly death follows the
infection.
Adventitial placentation (semiplacenta diffusa)
The development of intercotyledonary placentation in cattle is
a mechanism of compensation for inadequate development
Pathology of the Genital System of the Nongravid Female
of placentomes. The inadequate number of placentomes is
primarily endometrial and may be congenital or acquired.
There are normally 75-120 caruncles in the cow and 40-125
in the ewe and goat. Not all of them are fully used in a normal
single pregnancy. Occasionally, the numbers are much less
as a congenital disorder of endometrial organization; more
commonly, the reduction in number is acquired by inflamma-
tory destruction of portions of the endometrium. Compensa-
tion consists of a great increase in the size of remaining
caruncles during pregnancy, many of which may fuse, and by
the development of a more primitive villus placentation
between the placentomes. The adventitious placenta tissues
usually develop first adjacent to the placentomes; the process
may remain localized or involve virtually the entire intercoty-
ledonary placenta, chiefly along the floor of the uterus. In the
latter instances, pregnancy is insecure and may not proceed
beyond midterm. Hydrallantois is a complication. Adventitial
placentation has not been observed in the sheep or goat
placenta.
Hydramnios and hydrallantois
Excessive accumulations of fluid in the amniotic and allantoic
sacs are infrequent diseases of pregnancy. They occur most
often in cattle and are rare in other species. Excess fluid may
accumulate in both sacs, but this is the exception. The source,
nature, and control of the fluid in the 2 sacs are different, and
the conditions that give rise to excess fluid in each sac tend
to be different. The total amount of fetal fluid increases pro-
gressively throughout pregnancy, and the volume at term in
cattle is between 15 and 20 liters. This represents a 5-fold
increase during the last 4 months of gestation. The relative
quantity of fluid in each sac varies during the gestation period.
During the first and third trimesters, the amount of allantoic
fluid is greater. The nature of the fluid in each sac varies during
gestation. At term, the amniotic fluid is glary, slightly viscous,
and consists largely of fetal salivary secretion, the volume
being largely controlled by fetal swallowing. The allantoic
fluid is thin and watery and is derived from the fetal kidney
via the urachus, but regulation of the quantity of fluid is by
the membranes themselves.
Hydramnios, or hydrops of the amnion, is usually associated
with malformation of the fetus. The malformations may be
either inherited or acquired. A variety of inherited diseases
can cause hydramnios. There is a high incidence of the condi-
tion: in bison-cattle hybrids, in association with chondrodys-
trophic and muscle contracture malformations of bovine and
ovine fetuses, as well as in other types of fetal malformation,
particularly those involving gross facial anomalies.
Hydrallantois in cattle is most often associated with uterine
disease with inadequate numbers of caruncles and the develop-
ment of adventitial placentation. It also occurs with increased
frequency in cows bearing twins and in pregnancy of cloned
embryos. The quantity of excess allantoic fluid may be as
much as 170 L, but it is not notably different in quality
from normal. The fetal membranes are only slightly thickened,
but may be tough and rupture with difficulty. Dystocia
with uterine paresis, retention of placenta, and metritis are
sequelae of those few cases that do not abort earlier in gesta-
tion. The fetuses are usually dead when aborted or delivered
at term and small for their age, but may have anasarca
and ascites.
The disease occurs but rarely in mares. The conditions that
predispose in this species are not known.
Pathology of the Gravid Uterus 397
Amniotic plaques, placental mineralization,
and avascular chorion
In cattle these are normal grossly apparent features, and their
inclusion here is warranted only to avoid confusion to anyone
seeing them for the first time. Amniotic plaques are foci of
squamous epithelium on the internal surface of the amnion. They
may or may not be keratinized. They are ~2-4 mm in diam-
eter, flat, and resemble lesions of the poxes. They are especially
concentrated on the umbilical stump, where they are taller,
cylindrical, or papilliform. They seem to be constantly present
on the bovine amnion during the middle trimester, and they
do also occur in other species but have not received much
attention.
Deposits of mineral are visible in some chorioallantoic mem-
branes as white streaks and spots. These occur from about the
end of the first to the middle of the second trimester. The
degree of mineral deposition is quite variable and is more
extensive in the allantois than in the amnion.
Metaplastic ossification complete with large multinucleated
osteoclast-like cells occurs commonly in the placenta of sows
and goats giving birth to normal litters but is rarely seen in
other species.
In ruminants and pigs, it is common to find areas of necrotic
chorioallantois, commonly called the “necrotic tips,” at the
apical tips of both horns. It is almost invariably present from
the period of elongation to term. Sometimes the region may
extend for several centimeters.
Prolonged gestation
Syndromes characterized by abnormally long gestation periods
occur in cattle and sheep. Some of these syndromes have been
only partially defined, but in all cases adequately documented,
evidence of fetal anomaly, either anatomic or functional, has been
present. Two of the syndromes in cattle have a genetic basis,
the trait being governed by autosomal recessive genes, the
defective fetus being homozygous.
• The first of these, which is most common in the Holstein
and Ayrshire breeds, produces a nonviable large calf
after a gestation period that is approximately 2 months
longer than normal. The parturition is abnormal; the
maternal preparations of relaxation of the pelvic ligaments
and filling of the udder are minimal, and assistance is
usually necessary. The calves are large, but of nearly normal
proportions. They suffer from severe respiratory distress.
Death is due to either these respiratory difficulties or
uncontrollable hypoglycemia. The adrenals are hypoplastic,
and this is thought to be the lethal defect in the
syndrome.
• In the second type of inherited prolonged gestation, which
is seen in Guernsey, Jersey, and Swedish Red and White
breeds, fetal monsters are common. Many of these animals
have severe head anomalies of the cyclopian type, but in
some the defect is discrete and consists only of the absence
of the pituitary. Adenohypophyseal aplasia is common to all
of them. These fetuses fail to develop after approximately
the seventh month of gestation, and the length of gestation
appears to be determined by the viability of the fetus.
Some gestation periods last 17 months; at this time, pre-
sumably, the placenta can no longer adequately provide for
the fetus, and the dead fetus, still developmentally imma-
ture, is expelled.
Not all syndromes of prolonged gestation in cattle fit this
pattern either genetically or anatomically, and sporadic
398 CHAPTER 4  •  Female Genital System
examples of fetuses unable to terminate their gestation occur.
These are usually grossly deformed giants with severe brain
anomalies; these animals regularly die in utero.
Prolonged gestation occurs in sheep as a result of chemi-
cally induced teratogenesis. If ewes ingest Veratrum californi-
cum on or about day 14 of pregnancy, they may fail to begin
labor at term. Pregnancy then continues for weeks beyond
term, leading ultimately to rupture of pelvic ligaments and
maternal death. The fetuses damaged by the plant toxin cyclo-
pamine have holoprosencephaly and cyclopian deformities
and can attain giant proportions. Originally, the pituitaries
were thought to be absent. It appears that in most cases the
gland is displaced in the malformed head.
The functional defects that prevent the various types of
fetuses from making their timely contribution to their delivery
can now be interpreted in the light of experimental studies.
These indicate that, for a fetal lamb to initiate parturition, the
fetal hypothalamus, its connection to the pituitary, the pitu-
itary, and the adrenals must be functionally competent. If any
of these links is defective, prolonged gestation results. Only
hypophyseal absence, however, leads to fetal dwarfism.
An additional syndrome of prolonged gestation has
been recognized in ewes that are fed the African shrub
Salsola tuberculata. The mechanisms by which this plant poi-
soning interferes with parturition are unknown. They appear
to be different from previously reported ones in that the
effects of the plant are not teratogenic, and the intoxication
prevents parturition when fed during the last 50 days of gesta-
tion. The plant may inhibit fetal hypothalamic-releasing
factors.
S. tuberculata is drought-resistant, and the disease occurs
when other feed is lacking. The Karakul breed of sheep is the
breed raised where the plant is common and is the breed most
often affected, but other breeds are susceptible to the toxic
effects of the plant. The affected ewes fail to develop normal
preparturient udder enlargement, but show no other signs of
intoxication.
The fetuses continue to grow and usually initiate parturi-
tion 10-20 days past term. At delivery, the affected fetuses are
large, lethargic, and suffer a high mortality rate. The pelts are
overgrown and worthless, the hooves long, and the teeth
erupted. The adrenals of fetuses are hypoplastic and the pitu-
itaries are small, and normal granulation of the cells of the
adenohypophysis is lacking.
Prolonged gestation also occurs with exposure to ergot
alkaloids (ergopeptines) in fescue endophyte toxicosis in
horses and in exposure of ruminants to ergot alkaloids.
Further reading
Cornillie P, et al. Prolonged gestation in two Belgian blue cows due to
inherited adenohypophyseal hypoplasia in the fetuses. Vet Rec
2007;161:388-391.
Drost M. Complications during gestation in the cow. Theriogenol
2007;68:487-491.
Flaminio MJ, Antczak DF. Inhibition of lymphocyte proliferation and
activation: a mechanism used by equine invasive trophoblast
o escape the maternal immune response. Placenta 2005;26:
148-159.
Welch KD, et al. Cyclopamine-induced synophthalmia in sheep: defin-
ing a critical window and toxicokinetic evaluation. J Appl Toxicol
2009;29:414-421.
Abortion and Stillbirth
ABORTION AND STILLBIRTH
It will be apparent from the foregoing discussion that diseases
of the conceptus may result in death with resorption, fetal mum-
mification, abortion, or stillbirth, depending on the age of the
conceptus and the species involved, but not all fetal infections
result in fetal death. Some viral infections appear to cause little
harm to fetuses, at least during certain stages of gestation, and
in some the effects are subtle. Many fetal diseases, such as
brucellosis of cattle and sheep, epizootic bovine abortion, U.
diversum, and mycotic fetal infections in cattle are chronic and
may lead to the premature delivery of small-for-gestational-
age and diseased fetuses.
The list of bacterial and mycotic infections known to
produce sporadic abortion is so long as to be nearly valueless
because any bacteremia or systemic fungal infection occurring
during pregnancy carries with it a great risk of bacterial or
mycotic colonization of the fetomaternal interface. The entire
basis of this susceptibility is not known; however, factors
within the conceptus, such as isolation from the maternal
immune system, decreased oxygen concentration, elevated
temperature, sluggish inflammatory and immune responses,
and the provision of preferred nutrients for many organisms,
must be important. The organisms involved in fetal infection
are the same irrespective of the period of gestation. The
effects vary greatly and overall, fetal resistance increases with
age. There is some evidence suggesting that bacterial coloniza-
tion of the fetal membranes does not occur as readily before
embryo attachment.
Bacterial and mycotic fetal infections are most common in
cattle and horses. There are, however, important differences in
the pathogenesis of the infections in the 2 species. Except for the
venereal infections early in gestation, bacterial fetal infections
in cattle are probably hematogenous in origin. Leptospira and
Ureaplasma infections of cattle, however, may reside on the
zona pellucida of the ovum and in the uterine tube and move
to the placenta during pregnancy. Bacterial infections of the
equine placenta may arise hematogenously, by direct penetra-
tion with setae of ingested processionary caterpillars, or infect
the fetal membranes through the less protective cervix. The
route of the infection can usually be determined by examina-
tion of the placenta. Transcervical infection, the most common
route, involves the chorion adjacent to the internal os of the
cervix.
The fetal effects of viral infection depend on the virus and the
age of the fetus. Where the effects are known in detail, the
pattern is that infections early in gestation are more likely to
kill or produce serious teratologic effects; later in gestation,
the effects are less severe. There are important exceptions, and
the details are not known for most viral infections. Frequent
mention is made throughout these volumes to abortion in
relation to specific viral diseases. The fact that no mention is
made of fetal disease should not be implied to mean that the
virus in question is incapable of reaching the fetus or harming
it. And, alternatively, the fact that fetal disease is associated
with a specific viral disease should not be construed to mean
that fetal disease is produced at all stages of gestation, or if it
is, the resultant fetal lesions are the same throughout the
gestation period.
Toxic, nutritional, genetic, and physical diseases are also
important causes of reproductive failure and some mention is
made of them elsewhere, but often the details are not avail-
able. Selected here for description are those infections that
 398.e1

Further reading
Basson PA, et al. “Grootlamsiekte,” a specific syndrome of prolonged
gestation in sheep caused by a shrub Salsola tuberculata (Fenzl ex
Moq) Schinz var. tomentosa C. A. Smith ex Aellen. Onderstepoort
J Vet Res 1969;36:59-103.
Buczinski S, et al. Prolonged gestation in two Holstein cows: transab-
dominal ultrasonographic findings in late pregnancy and pathologic
findings in the fetuses. J Vet Med A Physiol Pathol Clin Med
2007;54:624-626.
Evans TJ. The endocrine disruptive effects of ergopeptine alkaloids on
pregnant mares. Vet Clin North Am Equine Pract 2011;27:
165-173.
Wintour EM, et al. Anatomy, physiology and pathology of the amniotic
and allantoic compartments in the sheep and cow. Aust Vet J
1986;63:216-221.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 399

BOX • 4-1 
Infectious causes of abortion

Bacterial Family Flaviviridae

Actinomycetes—Crossiella equi, Streptomyces, Amycolatopsis • Genus Flavivirus—Wesselsbron virus (WESSV)
Brucella spp.—B. abortus, B. suis, B. ovis, B. melitensis, B. canis • Genus Pestivirus—Border disease virus (BDV), Bovine viral
Campylobacter spp.—C. fetus subsp. venerealis, C. fetus subsp. diarrhea virus (BVDV), Classical swine fever virus (CSFV,
fetus, C. jejuni hog cholera virus)
Chlamydophila spp. Family Parvoviridae
Coxiella burnetii • Genus Bocavirus—Bovine parvovirus (BPV), Canine
Deltaproteobacterium minute virus (CnMV)
Flexispira rappini • Genus Parvovirus—Porcine parvovirus (PPV)
Histophilus somni Family Reoviridae
Leptospira spp. • Genus Orbivirus—Bluetongue virus (BTV), Chuzan virus
Listeria spp.—L. monocytogenes, L. ivanovii (CHUV, Palyam virus), Epizootic hemorrhagic disease
Salmonella spp. virus (EHDV), Ibaraki virus (IBAV)
Trueperella pyogenes Family Herpesviridae
Ureaplasma diversum • Genus Cytomegalovirus—Suid herpesvirus 2 (SuHV-2,
Yersinia pseudotuberculosis swine cytomegalovirus)
Miscellaneous—β-hemolytic streptococci, Escherichia coli, • Genus Rhadinovirus—Bovine herpesvirus 4 (BoHV-4,
Pseudomonas, Staphylococcus aureus, Klebsiella Movar virus)
pneumoniae, Actinobacillus equuli, Rhodococcus equi, • Genus Varicellovirus—Bovine herpesvirus 1 (BoHV-1;
Encephalitozoon cuniculi infectious bovine rhinotracheitis virus [IBRV]; infectious
pustular vulvovaginitis virus [IPVV]); Canid herpesvirus 1,
Mycotic (CaHV-1, canine herpesvirus); Equid herpesvirus 1
Aspergillus fumigatus (EHV-1, equine abortion virus); Suid herpesvirus 1
Pseudallescheria boydii (SuHV-1, pseudorabies virus, Aujeszky’s disease virus)
Yeast—Candida, Torulopsis Family Bunyaviridae
Zygomycetes—Lichtheimia (Absidia), Mortierella, Rhizomucor, • Genus Orthobunyavirus, Bunyamwera serogroup—Cache
Rhizopus Valley virus (CVV, Bunyamwera virus)
• Genus Orthobunyavirus, Simbu serogroup—Aino virus
Protozoan (AINOV, Shuni virus), Akabane virus (AKAV),
Neospora—N. caninum, N. hughesi Schmallenberg virus (SBV)
Sarcocystis spp. • Genus Phlebovirus—Rift Valley fever virus (RVFV)
Toxoplasma gondii Family Circoviridae
Tritrichomonas foetus • Genus Circovirus—Porcine circovirus 2 (PCV-2)

Viral
Family Arteriviridae, genus Arterivirus—Equine arteritis virus
(EAV), Porcine reproductive and respiratory syndrome virus
(PRRSV)

characteristically result in abortion as a major manifestation
(Box 4-1).
Diagnosing the infectious causes of abortion
The diagnostic rate on the causes of abortion, based on exami-
nation of samples submitted to veterinary laboratories
throughout the world, varies from 5-90%, depending on the
species and geographic location. The proportion of abortions
that are caused by infection in most species, with the excep-
tion of the horse, is not known; however, ~90% of those abor-
tions in which the cause is determined are assigned to
infection.
Not all of the infectious causes can be recognized by the
examination of fetuses and placentas. The effects of infectious
and noninfectious causes may be manifest indirectly through
the dam or directly through the placenta and fetus. Conditions
in the dam affecting the fetus and placenta and which may result
in abortion include hemoconcentration, circulatory failure,
anemia, fever, endotoxemia, and respiratory disease. With these
conditions, no lesion of diagnostic value will be found in the
fetus or placenta.
Pregnant animals may contact infectious agents by many
routes: through the respiratory tract, vagina, mouth, or, if
insect-derived, through the circulation. Some agents may be
carried into the reproductive tract with the semen or embryo
transfer fluids. In cattle, U. diversum, bovine herpesvirus 1
(BoHV-1), and bovine viral diarrhea virus (BVDV) may con-
taminate either of these, and being preserved by freezing and
resistant to the antibiotics commonly used, they survive there.
In addition, it appears that some agents, such as Leptospira
hardjo, may be maintained in the uterus or uterine tube over
the open period and infect the conceptus as it develops. The
role of the changing hormonal influence in the reproductive
tract on the multiplication of organisms may be substantial.
Campylobacter fetus moves from the vagina to the uterus as
400 CHAPTER 4  •  Female Genital System
pregnancy advances, and the hormonal influence is altered.
Some organisms may multiply in the conceptus for a very long
period before abortion. U. diversum, for example, may remain
in amniotic fluid for up to 117 days before abortion occurs.
Similarly, Aspergillus fumigatus may multiply in the placenta
for at least 25 days before producing abortion, and it is sus-
pected that BoHV-1 remains in the placenta for a prolonged
period before invading the fetus.
Cooperation among all parties involved (owner, clinician,
pathologist, bacteriologist, virologist, molecular biologist) is often
necessary to reach a diagnosis. Eventually, other specialists,
including nutritionists, toxicologists, botanists, and epidemi-
ologists, may be consulted.
Because the act of abortion rarely points to a definite cause,
it is important to collect all information at the first contact.
Although the history seldom points directly to the cause of
abortion, clues may be found that will indicate what needs to
be done to determine the diagnosis. Abortion may occur
sometime after the initiating illness, and therefore health,
performance, and travel records become important in suggest-
ing the diagnosis.
As the dam, placenta, and fetus may equally be involved, each
should be examined and sampled. In addition, and perhaps
more important, a representative portion of the remaining
animals that have not aborted should be examined.
• Samples should include serum from the dam and herd
(flock, or kennel), swabs, or samples from the uterus (the
caruncle in cattle may be useful), placenta, and fetus.
• If the placenta and fetus cannot be quickly and suitably
transported in their entirety, samples may be removed and
one portion placed in fixative and others in plastic bags on
ice for culture and molecular techniques.
• Tissues may, in addition, be frozen for future culture or
testing for agents by using one of the many immunologi-
cally based techniques presently available.
• Samples from the conceptus for culture should include
placenta, stomach content, lung, and kidney.
• Tissues essential for histology are a sample of the endome-
trium (caruncle), placenta, brain, eyelid (with conjunctiva),
thyroid, thymus, lung, heart, liver, spleen, kidney, adrenal,
and intestine. To be most useful, tissues for histology must
be properly fixed or chilled (not frozen) if transport is to
exceed 3 hours.
As with the history, it is important to maximize sample collec-
tion initially, thereby permitting the use of all the necessary diag-
nostic aids as the cause is gradually revealed. Samples not
required are easily discarded later. The results of serology are
more easily interpreted on a herd basis than on an individual
animal and may be particularly useful when samples are col-
lected before pregnancy or at the time of pregnancy diagnosis
and again at the time of abortion. This technique has proven
very useful in the diagnosis of leptospirosis. Only a representa-
tive portion of the group need be sampled to establish a
baseline titer. Two samples from a dam that has just aborted
may contribute little useful information as many agents that
subsequently cause abortion have initiated production of a
high antibody titer long before abortion occurs. Serum anti-
body titers are often within the “normal” range at the time of
abortion. Interpretation of the significance of antibody titers
may be further complicated in that many animals may not
respond to the agent with the production of antibody, and yet
the animal may be carrying the organism and abort because
of it. Up to 22% of cows aborting because of Leptospira hardjo
Abortion and Stillbirth
may not have a significant titer (microscopic agglutination
test) at the time of abortion.
It is important not to eliminate a disease from the list of
possibilities because of a history of vaccination. Many disease
agents may cause abortion in spite of previous vaccination, for
instance, BVDV, BoHV-1, and equid herpesvirus 1 (EHV-1),
and of course, vaccination with certain live vaccines during
pregnancy may cause abortion. Vaccination titers may be dif-
ficult to distinguish from titers resulting from infection, par-
ticularly if exposure has followed inoculation of even a single
dose of vaccine. Baseline values need to be established.
Frequently, lesions pointing to the diagnosis may only be
present in the placenta. As the placenta is a very large organ,
and much of it may be normal, the more of the placenta that
can be examined, the more accurate assessment of it is likely to
be. It rates in importance for examination equal to both the
alimentary and respiratory tracts of an animal after birth.
Unless the entire placenta is expelled, at least part of the
portion retained internally should be examined as it often has
the most severe lesion and is less contaminated by bacteria
from the environment. If the placenta cannot be found, endome-
trial samples become more crucial and should be requested.
Samples may be divided in 4 and used for bacterial culture
and histology, a portion frozen for virology, and for molecular
techniques, according to the submission guide of the diagnos-
tic laboratory. The optimal submission includes the fetus and
placenta plus serum from the dam. Serum is best collected at
pregnancy diagnosis and then resampled at time of abortion.
This method has been found of particular use in the diagnosis
of leptospirosis in dairy cows on drylot, where the fetus is
often not discovered until trampled. Examination of a “fresh”
fetus is 53 times more likely to contribute a diagnosis than an
autolysed one. Submissions including the entire fetus, pla-
centa, and serum are 4.28 times more likely to result in a
diagnosis than where pieces only of the fetus are submitted.
Titers of fetal antibody may also be useful in diagnosis of
BVDV, Neospora, or leptospiral infections.
Some lesions and normal findings that may be confusing
will be described briefly. To examine the caruncle, it should
be cut sagittally and the cut surface examined for infarction
or suppuration. Infarction is most commonly recognized in
mycotic infections but may be caused by a variety of bacteria,
including Brucella and Salmonella. Infarction frequently results
in retention of caruncular material by the cotyledon. A variety
of bacteria, including T. pyogenes, may cause suppurative pla-
centitis. Occasionally, fibrosis of caruncles is seen and may
represent normal caruncular maturation or be the result of a
chronic infection caused by organisms such as Yersinia
pseudotuberculosis.
To examine the chorioallantoic membranes, they should
be completely spread out and inspected carefully for lesions
on both surfaces. Lesions in the bovine placenta are commonly
observed toward the tip of the pregnant horn and should not
be confused with the normal avascular chorion in this site. On
histologic examination of H&E-stained sections of the chori-
onic villus, a blue finely granular to amorphous material may
be observed in the interstitium. This may be glycosaminogly-
cans, mineral, bacteria, or DNA, and special stains and even
close examination will differentiate it. Glycosaminoglycans
are considered normal, as is mineral in the early stages of
gestation. In the later stages, however, mineral is commonly
observed in areas of necrosis and feels gritty on gross
palpation.
Pathology of the Genital System of the Nongravid Female
Trophoblasts should be thoroughly examined on high
power as a variety of bacteria may be phagocytosed, or at least
contained, by them. The erythrophagocytic trophoblast has
been shown to phagocytose Brucella, and the organism has
been seen by electron microscopy in the rough endoplasmic
reticulum. Coxiella burnetii is also found in the trophoblast
and can usually be distinguished from Chlamydophila and
other bacteria in that the cytoplasm of the cell appears foamy
compared to the finely granular appearance of bacteria.
Lesions of variable intensity are usually seen in vessels of
the placenta. Discrete necrotizing vasculitis of the endothelial
cells in small vessels of the villi regularly occurs with BoHV-1
infection. Mycotic infections cause very severe vasculitis,
resulting in thrombosis and infarction of the caruncle and
cotyledon. H. somni, although perhaps uncommon as a cause
of abortion, may cause a similar lesion. Chlamydophila infec-
tions of the placenta may also cause severe vasculitis, but
usually without thrombosis. The bacteria-packed vessels in
Salmonella placentitis are so near the surface that they are
easily mistaken for phagocytosed bacteria in trophoblasts.
Microthrombi may be present also.
Lesions of hemorrhage, necrosis, mineralization, and fibro-
sis may also be observed on the chorionic and allantoic sur-
faces and are commonly seen with a variety of fungi and
bacteria, including U. diversum.
The inner surface of the amnion may be severely stained
with meconium, particularly in chronic progressive infections
of the chorion. It is frequently the site of lesions associated
with U. diversum infection and is there characterized by mul-
tifocal to confluent areas of necrosis, mineralization, and fibro-
sis, with marked thickening and mild vasculitis being most
common. Mycotic and Mycoplasma infections may penetrate
the chorion and allantois to the amnion and result in a similar
lesion.
Discrimination must be used in interpreting the results of
cultures derived from samples of fetus, placenta, or even the
stomach contents, as organisms may move or be carried from
the vagina to the conceptus when the cervix dilates during an
impending abortion resulting from another cause. These
organisms may rapidly contaminate the placenta, grow in the
fetal fluids, and may even be swallowed by a viable fetus,
thereby appearing in the stomach contents. To avoid confusion,
vaginal samples should be taken as soon as a vulvar discharge
is seen or impending abortion is suspected. Vaginal discharges
from animals with impending abortions are much less likely
to be contaminated by extraneous organisms than are samples
from an animal that has aborted several days previously.
Observing the relative state of preservation of the fetus
may contribute information about the cause. Acute infections,
such as those caused by BoHV-1, usually result in the dis-
charge of a severely autolysed fetus, as the fetus is killed
rapidly. Chronic infections, (such as U. diversum, B. abortus, Y.
pseudotuberculosis, or A. fumigatus), or other persistent stresses,
however, allow the fetus to prepare itself for delivery, and
hence it is discharged in a fresh state, perhaps small for ges-
tational age, and sometimes alive. Evidence of the significance
of an isolate may only be obtained by histologic examination of
certain tissues.
A few of the less commonly examined tissues that may be
useful in making the overall decision about the cause of abor-
tion will be briefly considered. Microscopic examination of
the eyelid (surface and palpebral conjunctiva) will reveal
lesions in about 2/3 of the bovine fetuses aborted because of
Abortion and Stillbirth 401
infectious causes. Lesions are most frequently observed on the
conjunctival surface and vary from a slight infiltrate of mono-
nuclear cells to a severe necrotizing reaction. As in other areas,
the cellular infiltrate may be determined by the duration of
the infection before death of the fetus. In cattle, Yersinia spp.,
Ureaplasma, and mycotic infections are commonly associated
with a heavy focal mononuclear cell infiltrate just under the
conjunctiva, whereas T. pyogenes infection may result in com-
plete loss of conjunctival epithelium, and the accumulation of
large numbers of bacteria, but few inflammatory cells, on the
surface. Many bacteria, including T. pyogenes and Listeria, con-
tinue to multiply after the death of the animal. BVDV infec-
tion may initiate perivascular lymphocytes and cause injury
to hair follicles. The pattern of follicular hair growth when
compared to the age of the fetus may determine the time of
infection. Mycotic infections cause folliculitis; however, the
lesion is very variable, not only as to its presence but also its
severity, and although intracorneal pustules may be seen, fre-
quently either no lesion is observed, or traces of inflammation
and fungi are only found in the outer sloughing keratinized
debris. This material may be lost unless care is taken in
sectioning.
Examination of the brain, particularly with the discovery
of the importance of protozoan infections as a cause of abor-
tion in ruminants, is an essential part of any postmortem
examination. Many viral infections manifest their effects in
the brain. Although the brain often appears soft and unworthy
of fixation, and some are literally poured into the fixative,
interesting and informative lesions are often found only in
this site.
The lung ranks among the most common organs in which to
see lesions. Aspiration of meconium into airways, with or
without evidence of an agent, is seen in the terminal phases
of many bacterial, and less commonly in mycotic infections,
and is probably related to the rapidity of the development of
the lesion and the degree of impairment of placental function.
Frequently, there will be no local reaction in the lung to the
agent, and in these the exudate present probably represents
aspiration of the agent and inflammatory cells from a placen-
titis. Many of the inflammatory cells may be maternal in
origin. In U. diversum and bovine parainfluenza virus 3 infec-
tions in bovine fetuses, airways may remain relatively clear,
and alveolar ducts become thickened and the lumina pave-
mented with many macrophages and a few neutrophils. Severe
necrotizing bronchitis may be seen with EHV-1 infection in
horses, whereas BoHV-1 in cattle usually produces only mul-
tifocal necrosis and no visible pneumonia.
Examination of the intestine contributes much informa-
tion in some specimens. Sections should be removed from
the small and large intestine, with care taken to preserve the
content intact. Bacteria may be seen colonizing the luminal
content and are used as an indicator of whether or not the
bacterial isolate is significant. Terminal swallowing of an agent
may transport it to the stomach; however, finding the agent
in the intestinal lumen is evidence that it has been in the
animal for at least several hours. The fetus swallows amniotic
fluid beginning at a very early age, and bacteria and fungi
can be easily seen in meconium. In one survey, lesions
were observed in association with a variety of agents in 32%
of 50 bovine fetuses examined. Lesions varied from mild
with A. fumigatus to focal areas of necrosis in the mucosa
with BoHV-1, diffuse necrotizing colitis with Listeria,
cryptal necrosis and Peyer’s patch lymphocyte hyperplasia
402 CHAPTER 4  •  Female Genital System
with Bacillus spp., loss of crypts, and large numbers of
lamina proprial lymphocytes and plasma cells with Y.
pseudotuberculosis.
Isolation of different organisms concurrently from the products
of abortion makes interpretation difficult. BVDV is commonly
detected along with other organisms also considered to be
causes of abortion, and in one study was found in 3 of 16
fetuses with Bacillus sp., 6 of 30 with T. pyogenes, and 17 of
45 with fungal infection. In these animals, immunosuppres-
sion associated with BVDV infection may permit the organ-
ism to circulate in the dam and localize in the placenta, or it
may be that, as just stated, the animal was aborting because
of BVDV infection and the other organisms were contami-
nants. In contrast, abortion may occasionally be classified as
infectious because of histologic lesions observed, but where
no organism is identified. Failure to grow the organism may
be due to improper handling of the samples or destruction of
the organism in severely autolysed fetuses.
Portions of chilled kidney are useful for the fluorescent
antibody detection of BoHV-1, BVDV, and Leptospira. Stomach
content is useful for bacterial or fungal culture and direct
examination for bacteria (including Coxiella) and fungi. In
some diagnostic laboratories, all samples of stomach content
and impression smears of placenta are examined using a modi-
fied acid-fast stain. Using this stain and others, an experienced
microbiologist can distinguish a variety of organisms. Certain
organisms are extremely fragile, and care in handling samples
becomes very important. Samples to be cultured for U. diver-
sum, for example, should be collected aseptically, chilled to 4°
C, and delivered to the laboratory immediately. Leptospires
may be equally fragile.
Fetal serum or thoracic fluid samples for antibody detec-
tion may be collected, but the antibody titers, as in the dam,
must be interpreted with caution. The fetus is capable of
responding to a variety of agents with antibody production
relatively early in gestation, and the presence of specific
antibody in fetal fluids may be considered evidence of fetal
infection. It has been shown, however, at least in sheep,
that placental vascular damage may allow antibodies to
cross the placenta from the dam to the fetus, thereby making
interpretation difficult. When antibody passage occurs, con-
centrations in the fetus will presumably be lower than in the
dam. Fetal antibody detection has been useful in diagnosing
fetal BVDV and leptospiral infections in third-trimester
fetuses.
Further reading
Boger LA, Hattel AL. Additional evaluation of undiagnosed bovine
abortion cases may reveal fetal neosporosis. Vet Parasitol 2003;
113:1-6.
Lamm CG, Njaa BL. Clinical approach to abortion, stillbirth, and neo-
natal death in dogs and cats. Vet Clin North Am Small Anim Pract
2012;42:501-513.
Njaa BL, editor. Kirkbride’s Diagnosis of Abortion and Neonatal Loss in
Animals. Oxford, UK: Wiley-Blackwell; 2012.
Schlafer DH. Canine and feline abortion diagnostics. Theriogenol
2008;70:327-331.
Schlafer DH. Examination of the equine placenta. In: McKinnon A,
et al., editors. Equine Reproduction. 2nd ed. Ames, Iowa: Wiley-
Blackwell; 2010. p. 99-110.
Tibary A, et al. Infectious causes of reproductive loss in camelids. The-
riogenol 2006;66:633-647.
Abortion and Stillbirth
Yorke EH, et al. Uterine torsion in mares. Compend Contin Educ Vet
2012;34:E2.
Bacterial causes of abortion
There are many different bacteria that infect the placenta. In
general, the response to infection is similar and stereotyped,
with some variation between species. The archetype bacterial
cause of a placentitis is Brucella, which will be described first.
Brucellosis
Bacteria of the genus Brucella are small, gram-negative bacilli
or coccobacilli that are strictly parasitic, prefer the intracel-
lular habitat, and produce in animals chronic infections with
persistent or recurrent bacteremias typically manifested by
abortion.
Three classic species of Brucella were described and defined
originally largely on the basis of host of origin—B. melitensis,
goats; B. abortus, cattle; and B. suis, swine—but now by bio-
chemical and serologic reactions. The differences between the
species are slight and quantitative rather than qualitative, and
the number of biotypes within each species is large. The bio-
logical similarities among the various species and biotypes of
Brucella are in keeping with the remarkable similarities in the
diseases produced in the different hosts by the various strains
of the organism. Infections are initially systemic, and relapsing
bacteremic phases are well-established events in the persisting
infections. Localization and persistence of infection may occur
in many organs, perhaps to a greater extent with B. suis than
with the other species. Some organs, however, notably the
genitalia and placenta, develop intense persistent foci of
infection.
Bovine brucellosis caused by Brucella abortus.  Brucellosis
occurs in cattle in most parts of the world. In some countries the
incidence of the disease is low, either because of measures
taken to prevent its entry or to eradicate it, but where the
disease is endemic and uncontrolled, the incidence may
approach 20-30%.
The usual source of infection for cattle is an aborted fetus or
placenta, or contaminated uterine discharges, and the usual route
of infection is alimentary. Infection can also occur per vaginam,
via the conjunctiva, or through the broken or unbroken skin.
The relative importance of these latter routes is not known.
Coital infection can occur but is uncommon, especially if
genital infection in the male is long standing, possibly because
fewer organisms are excreted in semen from chronic lesions.
Infection can be transmitted at artificial insemination if semen
from infected bulls is used. Irrespective of the route of infec-
tion, the development and establishment of infection are
probably comparable and will depend on the age and repro-
ductive status of the animal, its inherent resistance, and on the
dose and virulence of the infecting strain of the organism.
Young cattle are relatively resistant up to about the age of
puberty. They can be infected by the usual routes and means,
including the ingestion of milk in which the organisms are
intermittently excreted. Calves normally eliminate infection
in a few months.
Once infection is established in sexually mature animals,
females especially, it tends to persist indefinitely. Some,
perhaps many, will recover completely, but which ones will,
and when they will, cannot be predicted. The organisms
extend quickly to the lymph nodes regional to the point of
entry, and there they provoke acute lymphadenitis. The
 402.e1

Further reading
Ali H, et al. Common, emerging, vector-borne and infrequent aborto-
genic virus infections of cattle. Transbound Emerg Dis 2012;59:11-
25.
Decaro N, et al. Viral reproductive pathogens of dogs and cats. Vet
Clin North Am Small Anim Pract 2012;42:583-598.
Holler LD. Ruminant abortion diagnostics. Vet Clin North Am Food
Anim Pract 2012;28:407-418.
Jamaluddin AA, et al. Dairy cattle abortion in California: evaluation of
diagnostic laboratory data. J Vet Diagn Invest 1996;8:210-218.
Miller RB, Quinn PJ. Observations on abortions in cattle: a comparison
of pathological, microbiological and immunological findings in
aborted fetuses and fetuses collected at abattoirs. Can J Comp Med
1975;39:270-290.
Ortega-Pacheco A, et al. Common lesions in the female reproductive
tract of dogs and cats. Vet Clin North Am Small Anim Pract
2012;42:547-559.
Pretzer SD. Bacterial and protozoal causes of pregnancy loss in the
bitch and queen. Theriogenol 2008;70:320-326.
Pathology of the Genital System of the Nongravid Female
inflamed nodes are enlarged, often much so; hyperplastic with
no clear corticomedullary distinction; and frequently bear
small or large medullary hemorrhages. The sinuses are infil-
trated with neutrophils and eosinophils, germinal centers and
proliferative activity become obvious, and there is slow but
remarkable accumulation of plasma cells in the medullary
sinuses. The changes in the regional nodes take some weeks
to develop fully, and they persist for a prolonged period. There
is no fibrosis or necrosis in the nodes.
The infection may be overcome in the regional nodes, but
once established, it is expected to spread during the phase of
acute regional lymphadenitis. Spread is chiefly hematogenous,
and bacteremia may persist for several months, the duration
of persistence apparently depending on the susceptibility or
resistance of the host. As the infection becomes chronic, bac-
teremia becomes intermittent, ceases in some animals, and
recurs irregularly for at least 2 years in 5-10% of animals. Also,
it tends to recur at parturition. It might be expected that the
bacteremic episodes would result in localization and persis-
tence of the organism in many tissues, but curiously, localiza-
tion is largely restricted to the spleen; mammary glands;
mammary lymph nodes; pregnant uterus of the female; and
to the lymphoid tissues, testis, and accessory glands in the
male, and such localizations occur in the early bacteremic
phases. The organism has little or no predilection for the
kidney (although microscopic interstitial nephritis may be
present), ovary, bone marrow, or mesenteric lymph nodes and
appears not to be excreted in the urine or feces. Localization
does occasionally occur in synovial structures to produce
purulent tenosynovitis, arthritis, or bursitis, but whether local-
ization and persistence occur in synovium that is healthy is
not clear; some pre-existing inflammatory changes may be
necessary.
Infected animals, almost without exception, excrete B.
abortus in the colostrum. Thereafter excretion of the organism
in milk may cease, but frequently it continues, although inter-
mittently, throughout the period of lactation. Organisms
excreted in milk are an important source of infection for
children and also for calves, but they recover without signifi-
cant effect. It is still not clear whether, and to what extent, B.
abortus causes anatomic changes in the mammary glands. This
must be expected, but they must also be mild and difficult to
distinguish from the focal inflammatory reactions commonly
present in mammary glands. Dense infiltrations of the inter-
stitial tissue by plasma cells, lymphocytes, and histiocytes, and
exudation of neutrophils in acini, probably constitute the
usual changes. The mastitis is focal and not attended by gross
changes. The cellular content of milk is increased.
B. abortus has special affinity for the pregnant endometrium
and fetal placenta, to which it spreads hematogenously during the
initial or later bacteremia. Experiments using B. abortus in goats
have shown that the organism is carried by the bloodstream
to the periphery of the caruncle, where at the extremities of
the maternal villi, capillaries leak into the narrow space
(hemophagous organ) adjacent to the fetal erythrophagocytic
trophoblast of the chorion. Cells of the erythrophagocytic
chorionic trophoblast either phagocytose the Brucella organ-
isms or they invade; regardless, they multiply and spread, via
the uterine lumen and endocytosis or by cell-to-cell transfer,
to the rough endoplasmic reticulum of the adjacent chorionic
trophoblast cells. They multiply here and spread to the fetus
following ulceration of the trophoblast and invasion of the
fetal chorionic villi. The process may be similar in the bovine
Abortion and Stillbirth 403
caruncle, where hematomas appear at the ends of maternal
septa late in gestation.
Gross lesions in the placenta are characteristic but not
pathognomonic; similar lesions of lesser or equal severity may
be caused by other bacterial infections, and fungi produce
similar lesions, usually of greater severity. There is considerable
variation in the severity of the placental lesions, and this is
reflected to some extent in the course of the local infection.
If the lesion is severe, abortion or premature birth is the likely
outcome, and if the lesion is of minor severity, the calf may
be delivered normally at term and be viable or nonviable. The
intrauterine lesions apparently progress very slowly, because
an interval of many months may elapse between infection and
abortion or normal birth. Abortion occurs most often in the
seventh and eighth months of gestation. Once the infection
localizes in a pregnant uterus, it almost certainly remains there
and remains active until the fetus and placenta are delivered
and for some time thereafter. The nonpregnant uterus is not
particularly susceptible to B. abortus, and following abortion
or parturition, the organism is cleared from the uterus in a
few weeks, or longer in some cases.
The external appearance of an infected pregnant uterus is
normal. Sometimes the placenta is normal. Typically, between
the endometrium and chorion in the intercotyledonary area, there
is more or less abundant exudate that is odorless, dirty yellow,
slightly viscid and slimy, and which contains gray-yellow,
pulpy floccules of detritus. The fetal membranes and the
umbilical cord are saturated with clear edema fluid, and the
membranes may be 1.0 cm or more thick. The fetal fluids are
usually normal, although occasionally fluid in the amnion is
viscid and stained with meconium as the lesion extends.
The placental lesions are not uniform; some cotyledons may
appear more or less normal, and others will be extensively
necrotic, whereas still others are diseased to intermediate
degrees. Similarly, the intercotyledonary placenta varies in the
extent to which it is changed, lesions being most prominent
adjacent to the cotyledons. Affected areas of intercotyledonary
placenta are thickened with yellow gelatinous fluid, opaque
and tough, and the normal smooth glistening surface takes on
an appearance resembling yellow-to-gray Morocco leather
with, on the surface, a patchy coagulum of inflammatory
exudate and desquamated, degenerate epithelial cells. Affected
cotyledons or portions of them are necrotic, soft, yellow-gray,
and may be covered with the sticky, odorless, brown exudate.
Histologically, the lesions produced within placental
tissues by Brucella bacterial infection is very similar between
species. The chorionic epithelial cells are stuffed with bacteria
(Fig. 4-67), and many of them, with their inhabitants, desqua-
mate into the intercotyledonary space. Edematous placental
stroma contains increased numbers of leukocytes, largely
mononuclear but with some neutrophils. The organisms in
intact trophoblasts are cocci, but free in the exudates; they
assume a more elongate form even while still contained within
the ghosts of dead trophoblasts. Within placentomes, the same
sort of placentitis is present, but the infection is not so exten-
sive in the trophoblasts covering the cotyledonary villi except
at their base, or in the trophoblasts lining the caruncular
crypts, although many of the syncytial trophoblastic cells may
be necrotic. The intervillus portions of the placenta, the
so-called placental arcades, are quite severely affected, and
exudate accumulates between the arcades and the expanded
outer extremities of the maternal septa. There is normally
some placental exudate and minor hemorrhage in these
404 CHAPTER 4  •  Female Genital System
Figure 4-67  Massive proliferation of Brucella canis bacteria
within the cytoplasm of trophoblast cells, along the deep edge of
a canine placental labyrinth. Vasculitis and neutrophilic placenti-
tis also are features of canine brucellosis.
spaces, but this is greatly exaggerated in placentitis and con-
tains infiltrated leukocytes, epithelial debris, and bacteria. The
maternal portions of the placentome are not much involved
except for the expanded ends of the maternal septa where
these are bathed in the exudate of the placental arcades, and
in consequence, become denuded and superficially necrotic.
Beneath the necrotic tips of the maternal septa, there are
dense aggregates of neutrophils, with granulation and fibrosis
extending along the sides of the septa. Inflammatory enlarge-
ment of the terminal portions of the maternal septa produces
an increased degree of placental interlocking and probably
contributes to retention of the placenta. Adhesions, in the
usual sense of connective-tissue fusion, between placenta and
uterus do not occur. The endometrium is relatively unscathed
in the early infections. The zona basalis shows some increase
in lymphocytes and plasma cells, and there may be scattered
microscopic granulomas of epithelioid cells. Even the interca-
runcular epithelium may not be overly disturbed. Later there
is severe endometritis.
The fetus is usually autolysed and somewhat edematous
with blood-tinged subcutaneous fluid. The same fluid is
present in excess in the body cavities and the dorsal retroperi-
toneum. The normal abomasal content of a fetus is clear,
translucent, thick, and viscid; in brucellosis, it often becomes
very turbid, of a lemon-yellow color, and flaky. The important
fetal lesion in brucellosis is pneumonia, which is present to some
degree in most fetuses aborted in the last half of pregnancy. The
lungs may appear grossly normal, but histologic examination
reveals scattered microscopic foci of bronchitis and broncho-
pneumonia. When severely affected, the lungs are enlarged
and shaped to the thoracic contour, firm on palpation, red-
dened on the pleural surface or hemorrhagic, and with fine
yellow-white strands of fibrin on the pleura.
Microscopically, there may be any stage from the minor
changes mentioned through a well-developed catarrhal bron-
chopneumonia to the fibrinous variety. The predominant
inflammatory cells are mononuclear, although many immature
and mature neutrophils may be present in some areas. The
septa may be edematous and with perivascular leukocytes. An
Abortion and Stillbirth
Figure 4-68  Fetal pneumonia in a bovine fetus aborted because
of in utero infection with Trueperella pyogenes. Fetus and placenta
infected with Trueperella typically contain large numbers of bac-
teria. The arrow points to an alveolar macrophage with its cyto-
plasm distended with bacteria.
important differential diagnosis is Trueperella abortion, which
also produces suppurative placentitis and fetal lung lesions.
The pneumonia found in fetuses aborted by Trueperella infec-
tion is usually accompanied by large colonies of bacteria
within airways and alveolar spaces (Fig. 4-68).
In bovine brucellosis, by the time the placentitis has advanced
to an extent where abortion is inevitable, acute diffuse endome-
tritis, without histologic specificity, has developed. Variable lesions
in the fetus include necrotizing arteritis, especially of pulmo-
nary vessels; focal areas of necrosis; and granulomas with giant
cell formation in lymph nodes, liver, spleen, and kidney. The
organism may be identified by culture, immunofluorescence,
or immunohistochemistry.
Brucellosis in swine, caused by Brucella suis.  Pigs are
susceptible to B. melitensis and slightly susceptible to B.
abortus. The disease is usually caused by B. suis, and this organ-
ism presents important problems in many countries. There are
some differences in the diseases produced by B. suis and B.
abortus, and these depend largely on the frequency with which
B. suis in swine produces focal granulomatous lesions with
coagulative necrosis, the affinity of this organism for the skel-
eton and joints, and its tendency to remain in granulomatous
foci in the nonpregnant endometrium.
The early stages of the pathogenesis of the infection are
comparable with the early stages of bovine brucellosis. Infec-
tion can occur by the same variety of routes, but in swine,
brucellosis is chiefly transmitted by coitus. Boars are as readily
infected as sows, and most infected boars develop lesions in
the testes or accessory genitalia, from which the organisms are
shed in the semen, often for life. They may also be shed in the
urine from a focus of infection in the bladder. Infected females
may discharge the organism from the uterus for up to 2.5
years. Suckling piglets can be infected, although they are less
susceptible than weaners or adults, and although most infected
piglets eliminate infection, a few carry the bacterium into
adulthood.
With the development of lymphadenitis regional to the
point of entry, the infection becomes bacteremic. The bacte-
remia may be transient or persist for many months or even
Pathology of the Genital System of the Nongravid Female
for some years. Localization may occur in many organs, but
especially in the male and female genitalia; the skeleton,
including the vertebral column; synovial structures; mammary
glands; lymph nodes; spleen; liver; kidney; bladder; and even
in the brain.
B. suis can grow and multiply in phagocytes, and the typical
granulomatous lesion begins with the accumulation of histio-
cytes and epithelioid cells. Perhaps as a response to developing
hypersensitivity to the organisms, as the lesion enlarges,
caseous necrosis occurs centrally and fibrous tissue forms a
capsule. The granulomas enlarge progressively, and the necrotic
tissue attracts neutrophils. Giant cells are absent or scarce.
Mineral may be deposited in the necrotic foci.
Articular lesions caused by B. suis are quite common. They
begin as synovitis and chiefly affect the compound and large
joints of the limbs. The reaction is purulent or fibrinopurulent.
Osteomyelitis in this disease is typically vertebral (or usually
observed there). As with other causes of osteomyelitis, local-
ization is typically in the vertebral epiphyses of the lumbar
region. There is, however, an unusual tendency to involve and
destroy the intervertebral cartilages. The smaller bony lesions
are typically granulomatous with dry caseation necrosis, but
the necrotic cores of larger lesions may liquefy, and the sup-
purative reaction extends to the meninges or fistulae to
produce paravertebral abscesses.
In the uterus and uterine tubes, there are often conspicuous
and characteristic lesions, which are not dependent on an
association with pregnancy. They have been referred to as
miliary uterine brucellosis and, as the name infers, there are
few or very many pale yellow nodules with an average diam-
eter of 2-3 mm seeded in the mucosa. When the nodules are
numerous, they may coalesce to form irregular plaques and
then are associated with thickening of the uterine wall and
stricture of the lumen. The same lesion is usually also present
in the uterine tubes, where obstruction results in pyosalpinx.
Incised, a small quantity of caseous exudate can be expressed
from the nodules. Small, red, flat, and irregular granulomas are
often scattered over the surface of the supporting ligaments;
grossly, they resemble fetal fat and are easily overlooked.
There is some stromal fibrosis and diffuse cellularity in the
tubes and endometrium because of plasma cells and lympho-
cytes. In addition, well-developed and multiple hyperplastic
lymphocytic nodules are evident. There are few neutrophils
in the stroma, but with the mononuclear cells, they can be
seen moving through the epithelium to collect in abundance
in the lumen of the uterus and tube and in the more superfi-
cial glands. The glands are dilated and neutrophils are
enmeshed in strands of mucin and mixed with amorphous
globs of mucus. The deeper glands are cystically dilated with
attenuated epithelium, serous or thin mucinous content, and
few, if any, inflammatory cells. The epithelium lining the
lumen and superficial glands is in part retained, in part des-
quamated, and in part shows the development of a remarkable
degree of squamous metaplasia, even to the development of
rete pegs and intercellular bridges. The organism is not visible
in the lumen.
Abortion usually occurs between the second and third month
of pregnancy, but the incidence of abortion is relatively less
than in the bovine disease; there is also a high incidence of
stillborn and weak piglets born at term, and probably also a high
incidence of early undetected embryonic deaths. The placenta
may be retained. The specific uterine lesions of porcine bru-
cellosis are described previously. Apparently, the miliary
Abortion and Stillbirth 405
lesions may develop during pregnancy to a superimposed
diffuse catarrhal type of endometritis with patchy congestion,
hemorrhage, and edema and a small amount of creamy-pink
catarrhal exudate that contains large numbers of organisms.
The fetal placenta may not show conspicuous changes, but as
a rule, it is congested with small hemorrhages and patchy
edema. Usually too, there is a thin layer of exudate that is
slimy, gray-yellow, or gray-brown, like mucopus. It is more
copious than the secretion normally present in the interpla-
cental space, and smears from it show numerous free organ-
isms and many epithelioid cells, presumably chorionic, that
contain clumps of bacteria. The fetus shows autolysis with
subcutaneous edema and blood-stained fluid within body
cavities. The stomach contents may appear normal or be slimy,
turbid, or yellowish and may contain small flakes like curd.
Brucellosis in sheep, caused by Brucella ovis.  A Brucella
mutant, B. ovis, causes a specific form of epididymitis in rams
in most parts of the world in which sheep are raised. The
organism also causes placentitis in pregnant ewes, but epididy-
mitis is the more common and important manifestation of the
infection, and the main discussion of the disease is included
in Vol. 3, Male genital system.
There are probably as many modes of transmission as there
are for the Brucella in general, but in this disease, the coital
route is important; infected rams excrete large numbers of the
organism in the semen. There is bacteremia, but no systemic
disease. The organism is not very virulent. Even the epididy-
mitis of rams is largely an indirect effect. The epididymal
lesion produced by the organism is modest, but it does pre-
dispose to spermiostasis and extravasation, which produce the
characteristic spermatic granulomas by which the disease is
recognized. In contrast to the organism’s nonpathogenic
nature in the nonpregnant ewe, the organism readily parasit-
izes the placenta and produces abortion; this is not common,
although it may be important in individual flocks. Although
the manifestations of infection in both ewes and rams are
solely genital, the organism can be cultured in large numbers
from other organs in which it does not, however, produce
lesions.
The placenta is grossly edematous, being thickened to
2-5 cm by gelatinous fluid. Periarteritis and arteritis are fea-
tures, as in most forms of placentitis. The intercotyledonary
placenta has plaque-like thickenings that may coalesce to
resemble yellow-white chamois leather (Fig. 4-69). Diseased
cotyledons may become partially detached; they are firmer
Figure 4-69  Placentitis caused by Brucella ovis in a sheep.
406 CHAPTER 4  •  Female Genital System
than normal, enlarged, and pale yellow. There is extensive
necrosis of the epithelial elements of the cotyledons, with
edema and cellular infiltration of the stroma. Organisms in
abundance inhabit the epithelial cells of the chorion.
Most lambs are alive at the commencement of parturition,
but mummification or progressive autolysis is also common.
As usual, the fetus tends to be autolysed with blood-stained
fluid within body cavities. Some may contain flecks or strands
of fibrin. When present, mineralized plaques on the walls,
soles, or both, of the hooves and accessory digits occur, but
these are not pathognomonic. The fetus shows little histologic
evidence of systemic infection, even though the gastric contents
may be heavily infected. Mild pneumonia and lymphadenitis
of the tracheobronchial lymph nodes may be present together
with the development of germinal centers and plasma cells in
other nodes and spleen. Acute interstitial nephritis, particu-
larly about the corticomedullary junction, and inflammatory
infiltrates in portal triads are common.
The nonpregnant uterus is not affected by the infection. Infec-
tion of the fetus may be produced experimentally at any stage,
but following systemic exposure, as per conjunctiva, the
period of greatest susceptibility to intrauterine localization is
from ~21-90 days of pregnancy.
Following artificial exposure, there is a lag of 2-3 weeks
before bacteremia develops, and the bacteremic phase, in rams
and probably in ewes, lasts about 2 weeks. Breeding ewes to
rams with open epididymal infection is more likely to result
in infertility than abortion. The routes of natural exposure of
pregnant ewes are not known. Placental localization is fol-
lowed by slow development of the intrauterine infection, and
the pregnancy may survive for 2-3 months after first being
infected.
Brucellosis in sheep and goats, caused by Brucella meli-
tensis.  B. melitensis is the principal cause of brucellosis in
sheep and goats, although natural infections with B. abortus
occur occasionally. Brucellosis in goats and sheep is prevalent
in countries bordering the Mediterranean, in the Near East,
and in South America.
In most respects, the caprine disease resembles bovine brucel-
losis, but the disease in sheep is usually less protracted, and
spontaneous recovery is fairly common in a few weeks or
months. In the early bacteremic phases, goats may suffer
severe illness and even die, but many infections are asymp-
tomatic. The early signs of the disease may be referable to
acute mastitis with palpable nodules in the gland and a secre-
tion that is clotted and watery. The organism is excreted in
the milk, usually only for a few weeks in sheep, but often for
several months or even some years in goats.
As is usual for ruminants, abortion may be the only sign
observed, and it tends to occur late in pregnancy. The uterine
and vaginal discharges after pregnancy or parturition contain
large numbers of organisms. Abortion or stillbirth may termi-
nate successive pregnancies.
Brucellosis in dogs, caused by Brucella canis.  B. canis was
first isolated and recognized as a cause of abortion and epi-
didymitis in dogs in 1966. The disease was identified in Beagle
colonies in North America at that time. Since then, it has been
found in many parts of the world and in a variety of breeds.
However, accurate incidence rates are not available; in the
United States, where the infection is widespread, the reported
incidence rates are 0.5-5%.
The disease is caused by a mucoid strain of Brucella that
shares biochemical features with B. suis. Because of the
Abortion and Stillbirth
mucoid nature of the organism, it does not possess the smooth
(O) antigens of B. abortus or B. melitensis. As a consequence,
the conventional brucellosis test antigens that are used for
diagnosis of the disease in other domestic species are ineffec-
tive in the diagnosis of B. canis infections.
Transmission of the disease can be by ingestion of infected
vaginal discharge after abortion or venereally by infected
seminal fluids. The seminal fluids may remain infected for
months. Pregnant bitches may abort after 30 days of gestation,
but most abortions occur after 50 days. Testicular degeneration
and epididymitis are the usual manifestations of the disease in
male dogs. Affected dogs frequently lick the scrotal skin, pro-
ducing severe ulceration. Persistent bacteremias are common
in many dogs that show no signs of disease. Bacteria have been
recovered from the blood for periods as long as a year, even
though high agglutinating titers were maintained throughout
the bacteremic period. The nongenital lesions consist initially
of nonspecific enlargement of the retropharyngeal and man-
dibular lymph nodes. Later the lymph nodes throughout the
body may be enlarged because of diffuse hyperplasia of lym-
phocytes and macrophages. The aborted fetuses may be dead
or alive when expelled, but live fetuses usually die within a
few hours or days. Pneumonia, endocarditis, and hepatitis are
observed in the infected fetuses.
Focal necrosis is prominent in the chorionic villi and many
of the trophoblastic epithelial cells are laden with bacteria (see
Fig. 4-67). In the bitch, serosanguineous to gray-green vaginal
discharge may be evident for 1-6 weeks following abortion
and provides a source of infection for other dogs.
Brucellosis in other domestic species.  Brucella abortus or
B. suis is regularly found in the bursal lesions described else-
where as poll evil and fistulous withers (see Vol. 1, Bones and
joints). There are other isolated reports of suppurative skeletal
or synovial lesions in horses caused by these organisms.
Whereas cats are resistant to natural infection with Brucella
spp., dogs are relatively resistant to the classic strains of Bru-
cella, but natural infections caused by all 3 species of the
organism do occur. The majority of such infections are asymp-
tomatic and detected serologically. Orchitis and epididymitis
have been observed. Other lesions described in dogs with
brucellosis, chiefly minute granulomas in liver, kidney, and
lymph nodes, are neither specific nor necessarily related to the
infection.
Further reading
Anderson ML. Infectious causes of bovine abortion during mid- to
late-gestation. Theriogenol 2007;68:474-486.
Carvalho Neta AV, et al. Pathogenesis of bovine brucellosis. Vet J
2010;184:146-155.
Godfroid J, et al. Diagnosis of brucellosis in livestock and wildlife. Croat
Med J 2010;51:296-305.
Graham EM, Taylor DJ. Bacterial reproductive pathogens of cats and
dogs. Vet Clin North Am Small Anim Pract 2012;42:561-582.
Xavier MN, et al. Pathological, immunohistochemical and bacteriologi-
cal study of tissues and milk of cows and fetuses experimentally
infected with Brucella abortus. J Comp Pathol 2009;140:
149-157.
Campylobacter infections of the genital tract in
sheep and cattle
Infections caused by Campylobacter spp. are common and
widespread in humans, cattle, sheep, swine, and chickens and
 406.e1

Further reading
Díaz Aparicio E. Epidemiology of brucellosis in domestic animals caused
by Brucella melitensis, Brucella suis and Brucella abortus. Rev Sci
Tech 2013;32:43-51.
Gyuranecz M, et al. Detection of Brucella canis-induced reproductive
diseases in a kennel. J Vet Diagn Invest 2011;23:143-147.
Minten MA, et al. Effects of fertility on gene expression and function
of the bovine endometrium. PLoS ONE 2013;8:e69444.
Poester FP, et al. Pathogenesis and pathobiology of brucellosis in live-
stock. Rev Sci Tech 2013;32:105-115.
Roop RM, et al. Survival of the fittest: how Brucella strains adapt to
their intracellular niche in the host. Med Microbiol Immunol
2009;198:221-238.
Pathology of the Genital System of the Nongravid Female
also occur occasionally in dogs. In sheep and cattle, diseases
caused by these organisms were previously grouped under the
title of “vibriosis,” given their classification in the genus Vibrio
at that time. The principal patterns of disease are genital,
characterized by infertility or abortion, or intestinal, character-
ized by enteritis and diarrhea.
• C. fetus subsp. venerealis causes a true genital infection
and is an important cause of infertility in cattle and can
cause abortion in cattle and sheep.
• C. fetus subsp. fetus is a common resident of the ovine and
bovine intestine and can cause abortion in both species but
does so more commonly in sheep.
• C. jejuni is a common inhabitant of the intestinal tract in
sheep and cattle and may cause enteritis in humans and
occasionally animals. It frequently causes abortion in sheep
and less often in cattle, although heavy losses in individual
cattle herds do occur.
Genital infection of cattle caused by Campylobacter fetus
subsp. venerealis.  The disease in cattle caused by C. fetus
subsp. venerealis is a specific venereal disease transmitted by
coitus. Infected bulls may carry the organism indefinitely in
the preputial cavity, although some recover spontaneously.
Bulls do not become permanent carriers until they are at least
4 years of age, and most do not become readily infected until
they are 5-6 years of age. Epithelial crypts are more prominent
in the penile mucosa with advancing age and provide a favor-
able habitat for the bacteria. This also appears to be the
natural habitat for these organisms, and once the infection is
established in these older animals, it tends to be retained
permanently as a locally innocuous surface contaminant
together with the nonpathogenic C. sputorum subsp. bubulus.
The organism may also survive for long periods without
producing lesions on the surface of the bovine vagina, but not
in the uterus. Infected cows develop immunity and control
the infection. The outstanding feature seen with the infection is
not abortion but temporary sterility or repeat breeding with pro-
longation of the interestral periods. It is probable that the
delayed return to estrus is the consequence of early embryonic
death following fertilization and embryo attachment. Detect-
able abortions occur at any time but chiefly about the fourth
to sixth month of gestation. The placenta is not usually
retained.
The endometrial lesions in cows that are repeat breeders
are mild and consist of lymphocytic inflammation with
nodules and scattered cystic glands. Aborted placentas are
often autolysed, indicating that fetal death occurs before
expulsion. Placental lesions resemble those in brucellosis but are
less severe. The intercotyledonary placenta is edematous,
opaque, and may be leathery; there is diffuse inflammation,
mainly histiocytic. Diseased cotyledons are yellow and pulpy;
many have yellow necrotic villi at the margins, and in others
these are scattered throughout. There may be dense accumu-
lations of neutrophils among the denuded villi and in the
stroma. The degree of placentitis is quite variable and may be
inconspicuous. The parasitism of the chorionic epithelium
that is characteristic of Brucella occurs but is less evident in
placentitis caused by C. fetus subsp. venerealis. Lesions in the
fetus are nonspecific. Blood-stained fluid in the subcutis and
body cavities is common, and there may also be fibrin on the
serous membranes. The normal colorless thick viscid fluid of
the stomach content becomes yellow, very turbid, and flaky.
Genital infection of sheep and cattle caused by Campylo-
bacter jejuni or Campylobacter fetus subsp. fetus.  The chief
Abortion and Stillbirth 407
manifestations of these Campylobacter infections in sheep are
late abortion, premature birth, and the birth of weak lambs.
There is not usually retention of the placenta or sterility.
Occasional maternal deaths occur as a result of metritis. Infec-
tion is not synonymous with abortion, as infected ewes may
deliver infected but clinically normal lambs. The incubation
period is 7-60 days, and abortion occurs at any stage of preg-
nancy. The infection cycles through the flock throughout the
season.
Transmission of C. jejuni most often occurs by the oral
route, and fecal contamination of water supplies is relatively
frequent. The organism is carried in the intestinal tract of
poultry, and it is a commensal of cattle, sheep, and swine. The
organism is also a frequent inhabitant of the intestine in dogs
and cats and many rodents.
When strains of C. fetus subsp. fetus isolated from feces or
bile are given orally to susceptible sheep, there is transient
bacteremia followed by localization in the gut and bile, and
the infection can spread by contact between sheep. In preg-
nant, nonimmune ewes, localization also occurs in the uterus.
Surface (S)-layer proteins appear to be essential for coloniza-
tion and/or translocation of C. fetus subsp. fetus to the pla-
centa. With both of these Campylobacter spp., the genital
infection is primarily an intestinal infection; transmission is by
ingestion, and uterine localization is an accidental outcome of a
brief bacteremic phase in a nonimmune sheep. The incidence of
abortion will depend on the number of ewes pregnant more
than 1 month and on their experience with the infecting
strain. Immunity following infection or abortion usually lasts
for 2 years; however, if other strains are introduced, they may
cause abortion, as cross-protection between strains is incom-
plete. This also applies to vaccination strains.
The abortion rate in natural outbreaks varies from 5-70%
but is usually ~25%. Aborted fetuses may have only nonspecific
edematous changes; however, some have rather specific hepatic
lesions. Affected livers have few or many light tan areas, from
1 mm up to 2 cm in diameter, and randomly distributed (Fig.
4-70). Frequently, they have a “target pattern” with a more or
less distinct, slightly raised white outer rim and a depressed
tan inner zone. The abdomen is frequently distended with
fluid, fibrin, and the enlarged liver. If the lamb has lived a
while before succumbing, these lesions must be differentiated
from the focal necrobacillary hepatitis of umbilical origin.
Histologically, the lesion is multifocal necrotizing hepatitis, the
necrotic region represented by the tan area and the outer rim
by cellular infiltrate and necrosis. There is frequently broncho-
pneumonia with large numbers of neutrophils in major
airways and alveolar ducts. Small renal cortical hemorrhages
may also be present.
The cotyledons are enlarged, pale yellow to tan, dull and
pulpy, and covered with brown exudate. The chorionic stroma
is edematous and infiltrated with leukocytes, which are mainly
histiocytes. There is frequently vasculitis. There is mild or
acute endometritis with rather more prominent inflammatory
exudation in the caruncular septa. The placental lesions are
more severe over the placentomes than in the intercotyledon-
ary areas and are qualitatively similar to the lesions described
in the placenta in bovine brucellosis.
Diagnosis is based on the typical hepatic lesions and demon-
stration of the organism. Distinctive organisms may be observed
in smears of abomasal content or of affected cotyledons and
show up well with special stains. Darkfield or phase-contrast
microscopy may be used to see the characteristic darting
408 CHAPTER 4  •  Female Genital System
Figure 4-70  Focal hepatitis in a fetal lamb caused by Campylo-
bacter fetus. These umbilicated hepatic lesions are very charac-
teristic lesions of this infection.
motility. Discrimination of the species may be made by culture
or application of specific fluorescent antibody or molecular
techniques such as PCR tests.
Further reading
Bidewell CA, et al. Campylobacter fetus subspecies fetus abortion in
alpacas (Vicugna pacos). Vet Rec 2010;167:457-458.
Hazlett MJ, et al. A prospective study of sheep and goat abortion using
real-time polymerase chain reaction and cut point estimation shows
Coxiella burnetii and Chlamydophila abortus infection concurrently
with other major pathogens. J Vet Diagn Invest 2013;25:359-368.
Mshelia GD, et al. Epidemiology of bovine venereal campylobacteriosis:
geographic distribution and recent advances in molecular diagnos-
tic techniques. Reprod Domest Anim 2010;45:221-230.
Flexispira rappini infections
Flexispira rappini is a highly motile, anaerobic, rod-shaped
bacterium with multiple flagella at both of its tapered ends.
Although F. rappini is the generally accepted name, it has not
been firmly classified. The organism is closely related to organ-
isms in the genus Helicobacter but is distinguished from them
by its unusual spiral grooves visible on electron microscopic
examination. Comparable organisms are frequently found in
feces of dogs and pigs and in the stomachs and intestines of a
variety of other species.
Flexispira rappini infections in pregnant ewes result in fetal
mummification, abortion, and the birth of infected lambs born
weak. It is not considered to be the cause of epizootics of
abortion, and because the lesions closely resemble those
occurring in abortion caused by Campylobacter spp. (which do
cause epizootics), it is important that it be differentiated.
Naturally or experimentally infected ewes usually abort in
the last trimester of pregnancy. The fetus is usually well pre-
served; however, if it is retained in the uterus, it decomposes
Abortion and Stillbirth
rapidly, and the liver may be liquefied. An infected lamb may
be born alive, and occasionally only one lamb of a twin may
be affected.
Gross and microscopic lesions may be completely absent
but, when present, are in the placenta and liver. In the pla-
centa, they consist of a light covering of brown-to-gray exudate
on the chorionic surface. In the abdomen, there may be fibrin-
ous peritonitis, with a thin, loosely attached layer covering the
liver. The liver may be congested and enlarged or tan and soft.
Multifocal to coalescing pale, brown-to-gray, clearly demar-
cated, irregularly shaped areas (0.5 to several centimeters
across) are often visible on the surface and extend into the
parenchyma. In both the placenta and liver, lesions not visible
grossly may be obvious on microscopic examination. In the
placenta, foci of necrosis with accumulations of neutrophils
and mononuclear cells may be present on chorionic epithe-
lium. There is heavy infiltration of neutrophils and macro-
phages in the villus stroma, and severe neutrophil-rich
vasculitis may be present in the placental vessels. Capillaries
in the villus stroma may be distended with organisms. In the
liver, there are multiple, sometimes connecting, foci of necrotic
hepatocytes surrounded by large numbers of degenerating
neutrophils, macrophages, and lymphocytes.
The condition should be suspected when these lesions are
present and Campylobacter cannot be isolated. The organism
can be seen on dark-field or phase-microscopic examination
of a drop of stomach content. It stains weakly gram-negative
and is more easily visualized using Giemsa or crystal violet.
Special conditions are needed for culture. It is readily identi-
fied with 16S rDNA sequencing. The organism also produces
abortion in guinea pigs.
Further reading
Crawshaw TR, Fuller HE. Flexispira rappini suspected in ovine abortion.
Vet Rec 1994;134:507.
Listeriosis
Infections by Listeria monocytogenes occur worldwide and in
a variety of animals, including humans. In ruminants, infec-
tions are traditionally associated with cerebral localization and
encephalitis (for general discussion of the diseases associated
with this organism, see Vol. 1, Nervous system). However,
localization also occurs in the pregnant uterus, and abortion or
stillbirth is then the common sign. The syndromes of encepha-
litis and abortion may occur together in a herd or flock, but
rather surprisingly, this is the exception. More commonly, one
or the other syndrome occurs exclusively. L. monocytogenes
varies greatly antigenically; serovars 1 and 4b are commonly
isolated from cattle and serovars 4b and 5 from sheep. Serovar
5 (L. ivanovii) seems particularly pathogenic for sheep. L.
ivanovii as a cause of abortion in sheep and cattle occurs less
frequently than L. monocytogenes and rarely causes other
conditions.
L. monocytogenes is shed in the feces of normal carriers and
clinically affected animals alike and has been reported to
survive in some soils for as long as 2 years. It is most often
spread by ingestion of food or water contaminated by feces,
urine, placenta, or vaginal discharges from aborting animals.
Infection by the oral and other routes has been shown experi-
mentally to produce abortion. Silage is often the source of the
organism in severe outbreaks of the infection. The aerobic
 408.e1

Further reading
Bulgin MS, et al. Abortion in the dog due to Campylobacter species.
Am J Vet Res 1984;45:555-556.
Chaban B, et al. Evaluation of a Campylobacter fetus subspecies vene-
realis real-time quantitative polymerase chain reaction for direct
analysis of bovine preputial samples. Can J Vet Res 2012;76:166-
173.
Grogono-Thomas R, et al. Roles of the surface layer proteins of Cam-
pylobacter fetus subsp. fetus in ovine abortion. Infect Immun
2000;68:1687-1691.
Kirkbride CA. Diagnoses in 1784 ovine abortions and stillbirths. J Vet
Diagn Invest 1993;5:398-402.
Morrell EL, et al. Histopathological, immunohistochemical, lectinhisto-
chemical and molecular findings in spontaneous bovine abortions
by Campylobacter fetus. Reprod Domest Anim 2011;46:309-315.
408.e2

Further reading
Kirkbride CA, et al. Abortion in sheep caused by a nonclassified,
anaerobic flagellated bacterium. Am J Vet Res 1986;48:259-262.
Pathology of the Genital System of the Nongravid Female
A nonsuppurative cerebrospinal meningitis in which the organ-
B therapy; however, pregnant animals may still abort.
Figure 4-71  A. Marked focal hepatitis in a fetal calf caused by
infection by Listeria monocytogenes. B. Photomicrograph of a
focal area of hepatic necrosis and inflammation caused by Listeria
infection that would correspond to the hepatic foci evident in A.
Note the characteristic presence of Listeria bacteria associated
with areas of necrotizing hepatitis.
environment just beneath the surface of a silage bale provides
conditions for productive growth of the bacteria. L. monocy-
togenes can multiply in poorly preserved silage with a high pH
(6-7.8) but dies at a pH lower than 5.5.
The gravid uterus is highly susceptible to infection, and abor-
tion is experimentally induced by the intravenous injection of
pregnant ewes rather than by ingestion. Fetal infection is
considered to be by hematogenous spread from the placenta,
with an incubation period of about 5-12 days. Abortions in
both cattle and sheep caused by Listeria occur during the last
trimester of pregnancy. The percentage of pregnant animals
that abort within any group is variable; usually the abortions
produced are sporadic, but sometimes 50% of pregnant
animals may abort. If uterine infection develops during the
early part of the last trimester, the organism quickly invades
the placenta, and the fetus dies as a result of septicemia. The
dead fetus is expelled in approximately 5 days; by this time
autolytic changes mask minor gross lesions produced by the
organism, and all organs teem with bacteria, which continue
to multiply after death of the fetus. Abortions at this stage are
not usually accompanied by severe systemic disease in the
Abortion and Stillbirth 409
dam. The placenta is typically retained as a result of a mild
metritis, but the organisms and associated inflammation are
quickly cleared from the nonpregnant uterus.
If the fetus is near term when the infection develops,
abnormal parturition is instituted in which dystocia is the rule,
severe metritis and septicemia being the most common com-
plications. Lesions in the fetuses and placentas in this group
are less likely to be obscured by autolytic changes. Gross
lesions consist of tiny pinpoint yellow foci in the liver (Fig. 4-71).
Bacteria are typically present within these foci of hepatitis and
hepatic necrosis. Similar foci, but usually only visible micro-
scopically, are present in the lung, myocardium, kidney,
adrenal, spleen, and brain. These foci have a central area of
necrosis in which the organism can be visualized along with
small numbers of degenerating neutrophils and mononuclear
cells. If the fetus is near term, there may be severe diffuse
ism can also be seen. In the bovine fetus, in spite of marked
autolysis, the most dramatic and distinguishing lesion may be
in the mucosa of the colon, where severe necrotizing colitis with
clusters of colonizing gram-positive bacteria can be seen. The
jejunum is autolysed but otherwise normal. Grossly and
microscopically, the placental lesion is severe. The necrotic
tips of the cotyledonary villi are covered by purulent exudate
in which many bacteria are present. There is also focal-to-
diffuse red-to-brown exudative intercotyledonary placentitis.
Recovery of the organism is sometimes difficult and is
probably associated with the advanced autolysis or contamina-
tion of some samples. These difficulties can frequently be
overcome by refrigerating the specimen (4° C) and recultur-
ing after a period of storage using enriched or selective media.
Clinically affected animals respond well to antibiotic
Further reading
Gitter M, et al. Experimental infection of pregnant ewes with Listeria
monocytogenes. Vet Rec 1986;118:575-578.
van den Brom R, et al. Abortion in small ruminants in the Netherlands
between 2006 and 2011. Tijdschr Diergeneeskd 2012;137:
450-457.
Leptospira infections causing abortion in cattle
Leptospirosis is a zoonotic disease, widespread throughout the
world, and is an important cause of abortion and infertility in
cattle. Leptospirosis in cattle is caused most commonly by
serovar hardjo, which occurs as 2 species: Leptospira borg-
petersenii serovar hardjo type hardjo-bovis and Leptospira
interrogans serovar hardjo type hardjoprajitno. Type hard-
jobovis is distributed widely and is the only type isolated from
cattle in North America. Type hardjoprajitno is a highly viru-
lent type of Leptospira and has not been isolated in North
America but has mainly been associated with cattle in Europe.
Both hardjobovis and hardjoprajitno are spread by urine, post-
abortion discharges, infected placenta, and sexual contact, or
by in utero infection to the fetus. L. interrogans serovar
pomona is maintained by swine and some other animals and
is a common cause of incidental leptospirosis in cattle.
Exposure of nonvaccinated dairy cows to L borgpetersenii
serovar hardjo type hardjo-bovis has been shown to be associ-
ated with increased breedings required per conception. Diag-
nosis may be confirmed using immunologically based tests to
 409.e1

Further reading
Ladds PW, et al. Pathology of listeric infection in domestic animals. Vet
Bull 1974;44:67-74.
Navarro JA, et al. Diagnosis of placental pathogens in small ruminants
by immunohistochemistry and PCR on paraffin-embedded samples.
Vet Rec 2009;165:175-178.
Rowe JH, et al. Listeria monocytogenes cytoplasmic entry induces fetal
wastage by disrupting maternal Foxp3+ regulatory T cell-sustained
fetal tolerance. PLoS Pathog 2012;8:e1002873.
Silva AP, et al. Transcription of pattern recognition receptors and abor-
tive agents induced chemokines in the bovine pregnant uterus. Vet
Immunol Immunopathol 2012;145:248-256.
410 CHAPTER 4  •  Female Genital System
reveal and identify the organism and routine testing of fetal
cavity fluids for antibody. It has become a relatively common
diagnosis (0-40% of bovine fetuses submitted), depending on
the geographic location. Infection of cattle by either L inter-
rogans serovar hardjo or L interrogans serovar pomona results
in bacteremia, followed by damage in various parenchymal
organs (especially in the young) and eventually excretion of
organisms in milk and urine. Antibody titers develop by 4-6
weeks and may stay up for a year or more. Leptospires then
may localize in the proximal renal tubules. Persistence and
intensity vary with the organism and the host. L interrogans
serovar hardjo excretion in urine is usually high for 4-6 weeks
but may persist at a lower intensity for 6-12 months or life.
Cessation is usually associated with a marked increase in
urinary antileptospiral IgG and IgA antibodies. L interrogations
serovar hardjo may localize in the uterine tube and descend
into the uterus and placenta during pregnancy. Systemic infec-
tion may produce a febrile response and “flaccid agalactia”
with the udder secretion becoming scant, yellow, and thick.
The organism may also localize in the placenta and, in some
animals, produces fetal disease and abortion.
Most of the abortions caused by Leptospira occur in the last
trimester of pregnancy and often follow acute infection of the
dam by 1-6 weeks (serovar pomona) or 4-12 weeks (serovar
hardjo). L interrogans serovar autumnalis usually causes abor-
tion in the second trimester. L. hardjo may cause early embry-
onic death. Fetal infection is not invariably fatal, and weak
calves may be born with a substantial antibody titer. Fetuses
that die in utero because of Leptospira infection are usually
expelled in an autolysed state. Abortion rates with L interrogans
serovar pomona may be as high as 50%, whereas with L.
hardjo, they are generally around 3-10%, and infertility is a
common observation in infected herds.
Gross and histologic lesions in the fetus and placenta are
nonspecific; however, the presence of Leptospira-like organisms
in trophoblast cells, nonsuppurative meningitis, and nephritis war-
rants further testing.
The placenta may be edematous, but inflammatory changes
are modest in spite of the fact that there may be clumps of
leptospires in the chorionic epithelium. The fetus is often
autolysed, and calves in which leptospiral antigen is detected
in the placenta weigh 6-10 kg less than calves with no antigen
in the placenta. Histologically, multifocal necrotizing tubular
necrosis or interstitial inflammatory infiltrates, usually with
plasma cells, can be found in the kidneys of some of the
fetuses. Occasionally, the fetus will have nonsuppurative
meningitis.
The organism may be demonstrated in smears of homog-
enates of fetal kidney, lung, liver, and placenta; in fetal aqueous
humor by the indirect fluorescent antibody test; or by culture.
The organism can also be demonstrated in sections of fixed
fetal kidney by immunohistochemistry or in frozen sections
by using the fluorescent antibody technique. In stillborn
calves, the adrenal glands, lung, and placenta are the most
useful organs to examine for leptospiral antigen. Cultures of
fetuses can often be misleading. Calves infected with Lepto-
spira spp. have been found to be more likely infected by T.
pyogenes or Bacillus spp.; the latter is probably an incidental
finding, but more easily demonstrated than the Leptospira.
Cultures of specimens can be productive but are time con-
suming and cumbersome, with a long delay before results.
Fetuses that die when the infection is generalized may not
have formed antibody, but antibody is frequently present in
Abortion and Stillbirth
cavity fluids by the time the organism has localized in the fetal
kidneys. Cows aborting fetuses infected with L interrogans
serovar hardjo may have high microscopic agglutination titers,
but up to 40% are reported as not having a significant titer,
and more than half of those may have no detectable titer.
Prospective serology on a herd basis has been reported to be
of considerable value in sorting out titers resulting from vac-
cination and either previous or present infections.
Leptospira infections of the pregnant uterus
in swine
Abortion is often the only evidence of leptospiral infection in a
swine herd. There may be no relationship between return to
estrus and leptospirosis. Several serovars of Leptospira inter-
rogans regularly infect swine: canicola, grippotyphosa, ictero-
haemorrhagiae, sejroe, pomona, and tarassovi. The latter 2
serovars, which are adapted to spread in swine, are most com-
monly associated with fetal disease and abortion. Serologic
testing has indicated that infection by serovar bratislava, or a
closely related serovar, is also widespread; and abortions, still-
born, and weak liveborn piglets may have the organism and
antibodies to it. Serovar bratislava has also been associated
with infertility without abortions. In one report, L. bratislava
was detected in samples of the uterine tube by means of
immunofluorescence. Some of the serum samples from these
animals were positive for antibodies, whereas others were
negative. In one study, where many animals had a positive titer
to Leptospira, failure to identify L interrogans serovar bratislava
by immunofluorescence was believed to be associated with
transient infections early in life.
Leptospires are passed in the urine, and the organisms can
enter through mucous membranes or breaks in the skin. Poor
management of effluent from piggeries may result in contami-
nation of drinking water, resulting in transmission of the
organism to swine and other animals, inducing leptospirosis in
cattle, sheep, horses, and dogs. Infected swine develop bacte-
remia before the leptospires localize in the kidneys and uterus,
where they may persist and can be shed for months. Systemic
signs, if they occur at all, develop during the stage of lepto-
spiremia. It is also during this stage that the organism invades
the placenta and infects the fetus. Most of the abortions result-
ing from leptospirosis occur late in gestation, but stillbirths, some-
times with a few partially mummified fetuses, and births of live
but weak pigs are also part of the pattern. Seropositive dams
may have a greater risk of having weak newborn piglets and
also of having more weak newborn piglets per litter. Infected
fetuses often die in utero and undergo autolysis, which
obscures any lesions. Some aborted fetuses have elevated
immunoglobulin levels.
The placentas of infected pigs may be edematous, but the
most severe lesions are seen in those piglets delivered alive,
but sick, at or near term. Some of these will be icteric, have
patchy hepatic necrosis, fluid, and fibrin in the peritoneal
cavity and inflammatory changes in multiple organs. Focal
aggregations of lymphocytes in the renal cortex, medulla, and
pelvis are characteristic but inconstant. Leptospires can be
demonstrated in the kidneys or lungs on section by using a
silver stain. Special stains are much more useful on tissue sec-
tions taken from swine than cattle; however, the fluorescent
antibody test for the organism on kidney, lung, and placenta
homogenates gives a more definitive answer and allows visu-
alization of the lesion with the antigen. In addition, leptospires
may frequently be demonstrated by darkfield microscopy,
Pathology of the Genital System of the Nongravid Female
specific fluorescent antibody test, or detection of leptospiral
DNA in the urine of the dam up to 2 weeks after abortion
and occasionally in fetal cavity fluids from fresh or autolysed
fetuses.
Leptospires are rarely recognized in fluids from fetuses that
have been frozen or in fetuses in any condition when aborted
because of serovar bratislava. Fetal cavity fluids and maternal
serum may contain specific antibodies and, along with fluo-
rescent antibody and PCR testing of fetal tissues for antigen,
makes a practical diagnostic procedure. As in cattle, maternal
antibodies may only be useful in diagnosis if examined on a
herd basis.
Leptospira infections causing abortion or
stillbirth in horses
Until recently, leptospires have not generally been considered
to be a major cause of reproductive failure in horses. In Ireland,
where tissues from 22 aborted equine fetuses were cultured
and examined for leptospires, 9 fetuses were found to contain
organisms representing 4 serogroups: Australis, Hebdomadis,
Icterohaemorrhagiae, and Pomona. Serovars bratislava, ken-
newicki, and pomona are considered to be of major impor-
tance in horses, and in one large group of horses tested in
Ireland, 89% were found to carry antibody to serovar bratislava.
The horse is considered to be the maintenance host for serovar
bratislava.
Foals are usually aborted in the last trimester of pregnancy or
stillborn, and gross and microscopic lesions are seldom present.
Gross lesions occasionally observed in aborted foals include
icterus, yellow mottled liver, mild hepatomegaly, and petechial
hemorrhages on mucous membranes. Histopathology may
reveal dissociation of hepatocytes, disruption of hepatic cords,
multifocal hepatic necrosis, large multinucleated hepatocytes,
and renal tubular necrosis. Cerebral perivascular hemorrhage,
thrombosis, and severe meningitis with heavy neutrophil and
macrophage infiltrates have been observed. Leptospires were
identified as the cause of abortion in 4 aborted foals with giant
cell hepatitis. For diagnosis, high titers of fetal antibody
have been detected in fetal fluid by the microscopic agglutina-
tion test, and the organism has been identified in impression
smears or histologic sections of kidney and placenta by
immunofluorescence.
Leptospira infections causing abortion in sheep
A variety of serovars, including Leptospira interrogans
serovars bratislava, ballum, and pomona, will cause abortion
and stillbirths in sheep; however, the major serovar is hardjo,
and with this serovar, there seems to be a sheep reservoir that
does not include cattle. Sheep seem somewhat resistant to
leptospirosis but have a vulnerable period for 2 weeks before
lambing and 1 week after. Available evidence suggests that,
with different serovars, sheep are usually infected from an
environment contaminated by other animals. Feeding newborn
lambs with colostrum from Leptospira-infected cows is
believed to cause death in the lamb. Research has also led to
the speculation that leptospirosis is generally less common in
sheep than in horses, cattle, and pigs; however, under conditions
of intensive management, leptospirosis can cause severe losses in
the last 2 weeks of gestation and early postpartum period. Losses
include abortion, stillbirth, and birth of weak lambs. The
grazing lands for sheep are usually arid and therefore do not
support leptospires, and the drinking habits of sheep are more
fastidious in that they do not normally drink out of puddles.
Abortion and Stillbirth 411
Further reading
Grooms DL. Reproductive losses caused by bovine viral diarrhea virus
and leptospirosis. Theriogenol 2006;66:624-628.
Hamond C, et al. The role of leptospirosis in reproductive disorders in
horses. Trop Anim Health Prod 2014;46:1-10.
Martins G, Lilenbaum W. Leptospirosis in sheep and goats under trop-
ical conditions. Trop Anim Health Prod 2014;46:11-17.
Poonacha KB, et al. Leptospirosis in equine fetuses, stillborn foals, and
placentas. Vet Pathol 1993;30:362-369.
Saglam YS, et al. Detection of leptospiral antigens in kidney
and liver of cattle. Dtsch Tierarztl Wochenschr 2003;110:
75-77.
Zuerner RL, et al. Restriction fragment length polymorphisms distin-
guish Leptospira borgpetersenii serovar hardjo type hardjo-bovis
isolates from different geographical locations. J Clin Microbiol
1993;31:578-583.
Ureaplasma diversum infection
Ureaplasma diversum is a cause of reproductive failure in cattle.
The true prevalence of abortion caused by this organism is
unknown, however, as few laboratories attempt detection of
the organism. U. diversum is a bacterium in the family Myco-
plasmataceae. The organism is frequently present on the
mucous membranes of the nasal passages, vulva, and vagina of
the cow, the prepuce of bulls, and in semen and embryo
transfer fluids. It remains in these sites in the animal for long
periods and can be found in urine, and vaginal and nasal dis-
charges. It may be transmitted to cows (or bulls) during breed-
ing, and as the organism is preserved by freezing, it remains
viable in diluted frozen semen.
Virulent strains of U. diversum may produce vulvitis, embry-
onic death, abortion, or the birth of dead or weak calves at term.
Epidemics of abortion are rare in chronically infected herds,
but may occur where large groups of naïve animals are con-
gregated. Abortion usually occurs in the last trimester of gesta-
tion, or infection may manifest as premature delivery, with
the birth of weak or dead calves near term. The fetal mem-
branes may be retained. On gross examination, the amnion is
frequently the most severely affected portion of the placenta. It
has patchy thickening with fibrosis and, in addition, may have
foci of necrosis, hemorrhage, fibrin exudation, mineralization,
and areas that are stained with meconium. The chorioallantois
may be similarly affected, and if so, the lesion is often more
severe on the allantoic surface. On histologic examination of
the placenta, fibrosis and ongoing interstitial necrosis are
extensive. The inflammatory cell component is mainly mono-
nuclear, with macrophages and plasma cells predominating
(Fig. 4-72). Mild arteritis is also present.
The fetus is usually well preserved and may be stained with
meconium. The lungs are firm and, even if the calf is born
alive, are poorly aerated. There is an erosive conjunctivitis
with prominent goblet-cell formation of the palpebral con-
junctiva. Foci of lymphocytes, including plasma cells, are
present in the lamina propria. The lungs have nonsuppurative
alveolitis, and periairway lymphocytic mononuclear cell infil-
trates may be prominent. The lesions in the amnion, chorioal-
lantois, and lung are characteristic, but not pathognomonic, and
require validation by identification by either culture or DNA
detection techniques, from placenta, stomach contents,
or lung.
 411.e1

Further reading
Bolin CA, et al. Reproductive failure associated with Leptospira inter-
rogans serovar bratislava infection of swine. J Vet Diagn Invest
1991;3:152-154.
Rinehart CL, et al. Efficacy of vaccination of cattle with the Leptospira
interrogans serovar hardjo type hardjoprajitno component of a
pentavalent Leptospira bacterin against experimental challenge
with Leptospira borgpetersenii serovar hardjo type hardjo-bovis.
Am J Vet Res 2012;73:735-740.
Sebastian M, et al. Funisitis associated with leptospiral abortion in an
equine placenta. Vet Pathol 2005;42:659-662.
Shanahan LM, Slovis NM. Leptospira interrogans associated with
hydrallantois in 2 pluriparous Thoroughbred mares. J Vet Intern
Med 2011;25:158-161.
Smyth JA, et al. Stillbirth/perinatal weak calf syndrome: a study of
calves infected with Leptospira. Vet Rec 1999;145:539-542.
Whitwell KE, et al. Two cases of equine pregnancy loss associated with
Leptospira infection in England. Vet Rec 2009;165:377-378.
Wilkie IW, et al. Giant cell hepatitis in four aborted foals: a possible
leptospiral infection. Can Vet J 1988;29:1003-1004.
412 CHAPTER 4  •  Female Genital System
Figure 4-72  Ureaplasma diversum chronic necrotizing amnion-
itis in the placenta of a bovine fetus.
Further reading
Miller R, et al. Ureaplasma diversum as a cause of reproductive disease
in cattle. Vet Clin North Am Food Anim Pract 1994;10:479-490.
Watson P, et al. Laboratory diagnosis of Mycoplasma/Ureaplasma abor-
tion in cattle. Vet Rec 2012;170:82-84.
Trueperella pyogenes as a cause of abortion in
cattle and sheep
Trueperella (Arcanobacterium, Actinomyces, Corynebacterium)
pyogenes is widespread throughout the world as a common
cause of pyogenic infection in a variety of domestic animals.
The organism is commonly isolated from aborted fetuses and
is fairly consistently diagnosed in 1-15% of bovine fetuses
submitted. It also causes abortion in sheep, but this is consid-
ered less frequent. It is believed to be a primary pathogen in the
cause of abortion.
The organism is a common contaminant on the mucous
membranes and is found in the tonsils and vagina of healthy
cattle. As to the pathogenesis of abortion, it is suspected the
organism may penetrate the bloodstream from a mucosal
surface, resulting in transient bacteremia, which, in a pregnant
animal, results in placental localization and abortion. Abortion
is usually a single event in a herd or flock but is occasionally
multiple. Abortion may occur at any stage of gestation but is
usually in the last trimester. Dams may be ill following abor-
tion, and some die with suppurative endometritis, arthritis, or
mastitis.
The fetus may be severely autolysed or well preserved, and
gross lesions are visible in the placenta, trachea, and lung. The
placenta is often retained and when submitted may be heavily
contaminated. Gross examination of portions submitted
reveals marked autolysis and suppurative placentitis with
yellow-to-brown exudate over swollen edematous cotyledons.
In some fetuses, a hemorrhagic cast is present in the trachea.
On gross examination of the lung, it is dark red and swollen
with minute yellow foci visible on the surface.
On microscopic examination of the placenta and fetus,
lesions may be modest (with large numbers of bacteria but no
inflammatory cells in placenta and lung) (see Fig. 4-68) or
excessive (with a severe necrotizing, suppurative placentitis
and acute fibrinous bronchopneumonia). In addition, bacteria
may colonize in vessels, on the skin surface, and on the con-
junctiva, with destruction of the epithelium.
The diagnosis may be made based on the typical lesions and
isolating the organism, preferably from the placenta, lung, and
stomach contents. In the absence of lesions, the diagnosis can
Abortion and Stillbirth
be made with less confidence by culture only. It has been sug-
gested that the young fetus may be unable to respond to the
organism.
Salmonella as a cause of abortion in
sheep and cattle
The bacterium Salmonella is in the family Enterobacteriaceae.
It is a facultative anaerobe, a gram-negative rod, and usually
motile. There are >1,300 serotypes in the genus Salmonella.
Some of these are auxotrophic and have an affinity for just
one host, whereas others are ubiquitous and found in many
animals. Salmonella enterica ssp. enterica serovar Typhimurium
is ubiquitous, whereas S. enterica serovar Abortusovis is most
prevalent in sheep and therefore considered auxotrophic.
Many of the serotypes causing abortion in livestock are ubiq-
uitous. Salmonellosis is of worldwide concern as a human
disease and causes major losses in calves. It is also an important
cause of abortion in both cattle and sheep and, in some situ-
ations, in mares.
Clinically normal hosts may carry Salmonella. It is carried
by all domestic mammals and birds and is excreted in the
saliva, milk, feces, and urine and in the fluids discharged when
animals abort. Animals may become infected through their
feed, water, bedding, or the equipment used in feeding, han-
dling, and cleaning. Abortions are often precipitated by a stressful
event such as transport, change in diet, or feeding spoiled feed.
It is not completely defined how these events precipitate
increased multiplication of the organism, but it may partly be
due to disturbance of the normal intestinal flora. Although
specific nutrients in the placenta that enhance the growth of
Salmonella have not been demonstrated, in vivo experiments
have shown marked growth enhancement of Salmonella fol-
lowing inoculation of whole placental extracts into mice.
The organism may stay in a herd for several years, and
abortions may be sporadic or epizootic, usually occurring in late
gestation. Abortion can occur without illness in the dam or
may follow within a week of clinical signs. Cattle may suffer
with a variety of clinical manifestations, and in one report, the
main manifestations exhibited by S. enterica serovar Dublin
infection varied from pneumonia, to abortion and enteritis, to
polyarthritis, in successive years. Signs of enteritis and abortion
appear to be commonly associated. Sheep may have fever and
anorexia shortly before aborting.
The following pathogenesis of placental infection has been
proposed. The organism first localizes in the intestine of the
dam, and this is followed by a brief bacteremia with localiza-
tion in the lymph nodes, spleen, and lung. After a further
period of growth, a second bacteremia occurs in which the
placentome becomes infected. Excessive growth of the organ-
ism leads to almost complete destruction of the fetal villi,
which is followed by abortion and may occur without invasion
of the fetus. If S enterica serovar Dublin infection occurs
within a month of term, the calf may be born alive, carrying
the organism.
Following abortion, the placenta is often retained and the
fetus is usually autolysed. On gross examination, the chorioal-
lantois is found to be thickened with amber fibrin-containing
fluid, the chorionic surface is diffusely gray to red, and there
is yellow exudate on the variably tan and red cotyledons. Por-
tions of the caruncle may remain adherent to the cotyledon.
Histologically, there is mineralization of individual trophoblast
cells, interstitium of the villi, and chorioallantoic arcade. When
the chorion is severely affected, mineralization may also be
 412.e1

Further reading
Argue B, et al. Presence of Ureaplasma diversum in the Australian cattle
population. Aust Vet J 2013;91:99-101.
Ruhnke HL, et al. Bovine abortion and neonatal death associated with
Ureaplasma diversum. Theriogenology 1984;21:295-301.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 413

extensive on the allantoic surface. Accompanying the mineral,

exuberant bacterial growth expands the villi. In some villi, a
heavy infiltrate of neutrophils is present and, if the caruncle
remains attached to the cotyledon, there is a clear line of
demarcation between the affected villus within the maternal
crypt and the near-normal maternal septum. Dilated capillar-
ies, immediately under the sloughed trophoblasts in the arcade
zone, are filled with bacteria and in cross-section resemble
large rounded trophoblasts filled with bacteria. In spite of the
severe placentitis, there may be no lesions in the lung; however,
when present, lesions consist of a moderate to light accumula-
tion of neutrophils in bronchi, and bacteria may be seen colo-
nizing airway epithelium. In the liver, there can be multifocal
suppurative hepatitis.
Diagnosis is based on recovering the organism from pla-
centa and stomach content. Tissues in the fetus are sometimes
negative on culture in spite of marked placentitis. Nearly pure
cultures may be obtained from samples of vaginal discharge
taken just before abortion. Animals have a remarkable increase
in titer following abortion, but this is not a commonly used
test for diagnosis.

Yersinia pseudotuberculosis as a cause of abortion in Figure 4-73  Yersinia pseudotuberculosis bovine abortion. Chronic
cattle, sheep, and goats suppurative cotyledonary placentitis and pericotyledonary fibrin.
Yersinia pseudotuberculosis is a gram-negative coccobacillus in
the family Enterobacteriaceae. The DNA of Y. pestis, the cause
of human plague, and Y. pseudotuberculosis are at least 90%
interrelated. Six serogroups of Y. pseudotuberculosis are recog-
nized based on immunoreactivity of the O antigens. Y. pseu-
dotuberculosis causes ileitis, lymphadenitis, and abscessation in
humans, and infects a wide variety of domestic, laboratory, and
native animals and birds throughout the world. The organism
is frequently isolated from the feces of normal cattle, and from
abortions in sheep, goats, and cattle. In sheep, the organism
also causes abdominal abscessation and inflammation in the
testis and epididymis.
The pathogenesis of abortion probably follows invasion of
the intestinal epithelium, transient bacteremia, and localiza-
tion in the maternal caruncle, followed by passage to the
chorioallantois and fetus. It is revealing that in the description
of the experimental production of disease in sheep that
follows, uterine, and specifically caruncular, disease was
present as in naturally occurring abortion. It is possible that
nutrients in the caruncle favor localization and growth of
Yersinia that is followed by villus infarction and invasion of
the chorion.
Lesions reported are based on limited observations that are
generally similar in aborted fetuses and stillborns from sheep,
goats, and cattle. The aborted conceptus is usually well pre-
served and contains a variety of lesions. Placentitis is largely Figure 4-74  Yersinia pseudotuberculosis infection. Nonsuppura-
confined to the cotyledons. Cotyledons are red or tan, thick- tive conjunctivitis in an aborted calf.
ened and relatively devoid of exudate on the surface. Portions
of the caruncle may remain attached. The intercotyledonary
region is usually translucent, but a frosting of fibrin and some accompanied by mononuclear cell and neutrophil infiltrates.
fibrosis may closely surround the affected cotyledons (Fig. Lesions in the attached portions of caruncle consist of throm-
4-73). The thoracic and abdominal cavities contain excess bosis of septal vessels, hemorrhage, and necrosis, with a heavy
amber fluid with some fibrin. In the fetal liver, there may be diffuse infiltration of neutrophils and mononuclear cells. In
pale tan focal areas of necrosis ranging in size from 0.1-1 cm. the lamina propria of the conjunctiva, there are focal infiltra-
No other gross lesions are observed. tions of mononuclear cells, plasma cells, and a few neutrophils
Histologically in the placenta, there is necrosis of villi and (Fig. 4-74). In the lung, there are a few mononuclear cells in
moderate infiltration of granulocytes, macrophages, and mono- airways. Hepatic lesions consist of focal areas of necrosis infil-
nuclear cells in the interstitium of the chorioallantoic arcade. trated by granulocytes and mononuclear cells. Similar foci are
In placental vessels, there is fibrinoid necrosis of the media visible on microscopic examination of myocardium and lymph
414 CHAPTER 4  •  Female Genital System
nodes. Peyer’s patches are precociously cellular. The lamina
propria and submucosa of the colon are heavily populated by
plasma cells and mononuclear cells, and within the lumen,
colonies of the organism and scattered inflammatory cells can
be seen in the meconium.
Extensive lesions in the uterus follow the experimental
production of abortion in sheep. They consist of thrombosis
of septal vessels, necrosis of septa, and heavy infiltrations of
granulocytes in caruncles and intercaruncular regions.
Diagnosis is based on identification of the organism or its
DNA from placenta, stomach content, or lung, and the lesions
described.
Histophilus somni infections of the pregnant
bovine uterus
Histophilus somni is the only species of the genus Histophilus,
family Pasteurellaceae, and encompasses bacteria isolated from
cattle and previously described as Haemophilus somnus, as well
as ovine isolates formerly referred to as Histophilus ovis and
Haemophilus agni. H. somni is a fastidious gram-negative coc-
cobacillus that is considered normal flora of the male and
female bovine genital tract. There are marked differences in
the ability of different isolates from the reproductive tract to
produce central nervous system (CNS) disease. Preliminary
experiments have not shown the reverse to be true.
H. somni is best known for its association with CNS disease
and pneumonia in cattle, and these are discussed under those
sections. The organism is often associated with vaginitis, infertil-
ity, abortion, and occasionally with fatal endometritis. Usually
abortions induced by H. somni involve solitary animals;
however, occasionally an entire herd will develop reproductive
disease, including vaginitis and infertility attributed to this
organism. When this occurs, predisposing factors, in the form
of malnutrition, concurrent virus infection, or stress, should
be considered.
The organism is commonly resident in the vagina of cows
(3-76% of animals sampled), and in the prepuce of bulls
(>75% positive). Natural breeding therefore easily spreads it.
Most strains of the organism are sensitive to the antibiotics
used in the preparation of frozen semen. Sampling of a natu-
rally infected herd revealed >50% of calves infected by 7
months of age. The presence of the organism in the vagina
does not imply clinical disease.
The pathogenesis of abortion has not been clarified. The
organism shows some ability to penetrate the cervical area to
infect the placenta; however, lesions in the placenta are usually
in cotyledons, which suggests a hematogenous route. Bactere-
mia following a vaginal or respiratory infection is likely. Death
of the fetus after infection is usually rapid, resulting in the abor-
tion of a severely autolysed fetus.
Lesions in the placenta are primarily confined to the cotyledon
and consist of acute necrotic placentitis, which does not appear
to penetrate to either the amnion or allantoic surface. On
histologic examination, the most distinctive lesion in the pla-
centa consists of severe fibrinoid necrosis and thrombosis of
large and small arteries. The cellular infiltrate in vessel walls
and adjacent villi is mainly macrophages with some neutro-
phils. There is sparing of veins and capillaries. Colonies of
bacteria are visible next to the trophoblast cells. Lesions in the
fetus are usually sparse; however, acute fibrinous broncho-
pneumonia is occasionally observed. On histology, airways are
seen to contain degenerating mononuclear cells, macrophages,
but few neutrophils. Bacteria are frequently observed adjacent
Abortion and Stillbirth
to the epithelium of alveolar ducts, and swirling (oat-type)
macrophages are numerous in these areas. Fibrin often fills
lymphatics, distending interlobular septa.
Diagnosis is based on observing the characteristic lesions in
the placenta and lung, and isolation of the organism from the
stomach content or placenta.
Further reading
Barkallah M, et al. Survey of infectious etiologies of bovine abortion
during mid- to late gestation in dairy herds. PLoS ONE 2014;
9:e91549.
Madoz LV, et al. Endometrial cytology, biopsy, and bacteriology for the
diagnosis of subclinical endometritis in grazing dairy cows. J Dairy
Sci 2014;97:195-201.
Welsh RD, Stair EL. Yersinia pseudotuberculosis bovine abortion. J Vet
Diagn Invest 1993;5:109-111.
Chlamydophila (Chlamydia) infections
causing abortions
Chlamydophilae (chlamydiae) are obligate intracellular para-
sites that multiply in membrane-bound vacuoles in a variety
of cells. They have 2 distinct forms, the reticulate body, which
is not infectious, and the elementary body, which is infectious
and released from the cytoplasm by a mechanism not fully
understood but which involves disruption of the cell. The
inclusions, which can be seen on light microscopy, consist of
hundreds of gram-negative Chlamydophila cells bound by a
membrane in a cytoplasmic vacuole. Based on DNA sequence
analysis, the family Chlamydiaceae is divided into 2 genera:
Chlamydophila and Chlamydia. The species of Chlamydophila
and Chlamydia of veterinary interest include the redesignated
forms of Chlamydia psittaci, namely, Chlamydophila abortus
(former ovine serovar [immunotype] 1), C. psittaci (former
avian serovar), C. felis (feline serovar), C. caviae (guinea pig
serovar); plus C. pecorum (mammals), and Chlamydia suis
(former porcine serovar of C. trachomatis). C. suis, C. pecorum,
and C. abortus have all been associated with reproductive
failure and abortion. Chlamydiae have also been associated
with abortion in horses. Of significance as human pathogens
are C. psittaci, C. pneumoniae, and C. trachomatis.
Chlamydophila abortion in sheep, goats, and cattle.  Chla-
mydophila abortus is an important cause of in utero infections
in sheep and goats, resulting in abortion, stillbirth, and the
birth of weak offspring, and can cause abortion in women in
close contact with these aborting ruminants. The disease in
sheep has been known as “ovine enzootic abortion” and “enzo-
otic abortion of ewes” but will be referred to here as Chla-
mydophila abortion. C. pecorum, a fecal organism, may cause
sporadic abortion, but this is rare.
The products of abortion, uterine discharge, vaginal fluids,
and semen are potential sources of the organism. On exposure
of oral, conjunctival or reproductive mucosae, sheep and goats
develop chlamydophilemia and may develop interstitial pneu-
monia or focal hepatitis. Weeks or months later, the organism
appears in mononuclear cells of the pregnant uterus and then
is found in trophoblasts; the rest of the placenta and the fetus
may become infected. Naïve animals, including newly intro-
duced sheep and females pregnant for the first time, are most
vulnerable. The incubation period is 50-90 days. If infected in
the early part of gestation, the ewe may abort in the final trimester
of pregnancy, or infection may manifest as stillbirths or weak
 414.e1

Further reading
Angen O, et al. Proposal of Histophilus somni gen. nov., sp. nov. for
the three species incertae sedis “Haemophilus somnus”, “Hae-
mophilus agni” and “Histophilus ovis”. Int J Syst Evol Microbiol
2003;53:1449-1456.
Giannitti F, et al. Yersinia pseudotuberculosis infections in goats and
other animals diagnosed at the California Animal Health and Food
Safety Laboratory System: 1990-2012. J Vet Diagn Invest 2014;
26:88-95.
Headley SA, et al. Histophilus somni-induced infections in cattle from
southern Brazil. Trop Anim Health Prod 2013;45:1579-1588.
Kaneko K, et al. Influence of Trueperella pyogenes in uterus on corpus
luteum lifespan in cycling cows. Theriogenol 2013;79:803-808.
Metzner M, et al. Trueperella abortisuis, an emerging pathogen iso-
lated from pigs in Germany. Berl Munch Tierarztl Wochenschr
2013;126:423-426.
Radke BR, et al. Salmonella Muenster infection in a dairy herd. Can
Vet J 2002;43:443-453.
Pathology of the Genital System of the Nongravid Female
Figure 4-75  Pericotyledonary pattern found in placentitis caused
by Chlamydophila abortus in a sheep.
lambs. If she is infected in the later part of pregnancy, abortion
will occur in the next pregnancy. A ewe that aborts will not
abort again, but can carry the organism for several years.
Extensive losses (75%) may occur on introduction of the
organism to a flock, and yearly abortion rates of 5% are
common when it exists in the enzootic form.
Retention of fetal membranes may occur in some animals,
and aborting females may occasionally be ill. The placenta
resembles that seen in bovine brucellosis, and there is patchy,
almost equal involvement of cotyledons and intercotyledonary
regions. Affected cotyledons are a dull-clay or dark-red color,
firm, and matted with a dirty-red exudate (Fig. 4-75). The
intercotyledonary region is red to brown and has irregular
patches of edema amidst a dry, leathery thickening of the
chorioallantois. These thickenings are often concentrated in
ridges, which on histology are seen to consist of medium to
large vessels prominent because of marked vasculitis. The vas-
culitis is characterized by fibrinoid necrosis of the media with
a moderate to heavy infiltrate of neutrophils and some mono-
nuclear cells (Fig. 4-76). In the chorion, there is superficial
necrosis, and characteristic inclusions can be seen in the cyto-
plasm of trophoblast cells. Abortion is likely the result of
several factors, including tissue destruction by C. abortus, vas-
culitis, thrombosis, and a fetal inflammatory response. Produc-
tion of tumor necrosis factor-α (TNF-α) by fetal macrophages
that express major histocompatibility complex II molecules
may be significant in the pathogenesis of abortion.
The fetus is usually well preserved but may have few gross
lesions. These consist of scattered hemorrhages in the subcutis,
thymus, lymph nodes, and muscles. The liver is sometimes
swollen and has pinpoint yellow foci on the surface. Histologic
lesions in the fetus are minimal. There may be focal areas of
coagulative necrosis in the liver and spleen. These foci consist
of as few as 5 cells, stain pale pink, and are variably surrounded
by scant mononuclear cells. Throughout the liver and concen-
trated in portal areas, there may be an increase in mononuclear
cells. In the lung, alveolar septa are thickened by mononuclear
cells. Mild meningoencephalitis with vasculitis and hemor-
rhage has also been reported.
Cattle do carry C. pecorum in the intestine, as do sheep,
and the organism in the intestine can produce abortion. Abor-
tions in cattle are usually sporadic, occurring throughout the
year, with occasional outbreaks in isolated herds. Fetal lesions
Abortion and Stillbirth 415
Figure 4-76  Placentitis with severe inflammation of the chori-
onic surface and deeper vasculitis in Chlamydophila abortus abor-
tion in a ewe.
are similar to those in lambs. Waddlia chondrophila, another
member of the order Chlamydiales, is also responsible for
abortion in cattle. Chlamydiaceae may be an under-recognized
cause of reproductive failure in swine.
To establish Chlamydophila as the cause of an abortion in
cattle or sheep, the organism should be demonstrated in a
smear (preferably of placenta) stained by a modified Ziehl-
Neelsen, Gimenez, or Giemsa method. The organism can also
be demonstrated in sections from the diseased placenta by
using a specific fluorescent antibody test or immunohisto-
chemistry. The presence of specific antibody in the fetus is
confirmative, but antibody is not always present.
Demonstration of antibody in the dam is of little use as a
large proportion of cattle and sheep have been exposed and
test positive. Specific monoclonal antibodies are available to
detect antigens of known pathogenic strains of Chlamydophila,
but detection of chlamydial DNA is now widely available. The
organism can be grown on appropriate cell lines on coverslips,
fixed, stained, and examined within 3 days.
Further reading
Buxton D, et al. Ovine chlamydial abortion: characterization of the
inflammatory immune response in placental tissues. J Comp Pathol
2002;127:133-141.
Navarro JA, et al. Diagnosis of placental pathogens in small ruminants
by immunohistochemistry and PCR on paraffin-embedded samples.
Vet Rec 2009;165:175-178.
Pospischil A, et al. Abortion in cattle caused by Chlamydia psittaci.
Schweiz Arch Tierheilkd 2002;144:467-472.
Schautteet K, Vanrompay D. Chlamydiaceae infections in pig. Vet Res
2011;42:29.
Wheelhouse N, et al. Novel chlamydia-like organisms as cause of
bovine abortions, UK. Emerg Infect Dis 2010;16:1323-1324.
 415.e1

Further reading
Henning K, et al. Demonstration of Chlamydia from an equine abor-
tion. Dtsch Tierarztl Wochenschr 2000;107:49-52.
Henning K, et al. Neospora caninum and Waddlia chondrophila strain
2032/99 in a septic stillborn calf. Vet Microbiol 2002;85:285-292.
Longbottom D, et al. Intranasal infection with Chlamydia abortus
induces dose-dependent latency and abortion in sheep. PLoS ONE
2013;8:e57950.
Rodolakis A, et al. Chlamydia psittaci experimental abortion in goats.
Am J Vet Res 1984;45:2086-2089.
Schiller I, et al. Mixed infections with porcine Chlamydia trachomatis/
pecorum and infections with ruminant Chlamydia psittaci serovar
1 associated with abortions in swine. Vet Microbiol 1997;58:251-
260.
Thoma R, et al. Chlamydiae in porcine abortion. Vet Pathol
1997;34:467-479.
416 CHAPTER 4  •  Female Genital System
Figure 4-77  Caprine Coxiella burnetii abortion. Suppurative pla-
centitis primarily involving the intercotyledonary areas of the
chorioallantois is shown.
Abortion in sheep, goats, and cattle caused by
Coxiella burnetii
Coxiella burnetii is in the family Rickettsiaceae and is the only
member of the genus Coxiella. The organism is well known
as the cause of Q (query) fever in humans. It is an obligate
intracytoplasmic parasite. Dairy cows, goats, and sheep are the
common reservoirs of the organism, and cats and wildlife may
also carry it. Human and domestic animal infection occurs
when contaminated dust is inhaled; however, massive con-
tamination of a paddock or pasture facilitates oral transmis-
sion. Infection apparently persists indefinitely in sheep and
cattle, and organisms are shed at parturition and in the milk
and feces. Abortion usually follows initial exposure and may
be unusual in endemically infected flocks.
Abortion tends to occur late in the gestation period, and
weak lambs and kids may be born during an outbreak. The
aborted fetus may be well preserved or autolysed. Gross
lesions are confined to the placenta, which is thickened and leath-
ery, with multifocal to confluent areas of mineralization. The
exudate is copious, off-white, and most obvious in the inter-
cotyledonary region. If the cotyledon is involved, the early
lesion appears as a white outer ring with flecks of white scat-
tered in the central region.
Histologically, there is trophoblast hyperplasia and or acute
diffuse suppurative placentitis (Fig. 4-77) and extensive
necrosis of cotyledonary villi and intercotyledonary tropho-
blasts (Fig. 4-78). In contrast, the inflammatory cells in the
interstitium of the chorioallantoic arcade are largely mono-
nuclear, with a predominance of plasma cells. The lesion,
which on gross section appears to be largely confined to the
intercotyledonary region, is frequently found on histology to
be also extensive in the cotyledons, especially at the periphery.
The vasculitis that develops with Chlamydophila infections is
not usually a feature of placentitis caused by Coxiella. Smears
of placental exudate contain large numbers of organisms, which
can be stained by the modified Ziehl-Neelsen or Macchiavello
stain. The organism produces microcolonies within tropho-
blasts, which distend the cytoplasm (see Fig. 4-78). These
Abortion and Stillbirth
Figure 4-78  Ovine Coxiella burnetii abortion. Microcolonies of
Coxiella burnetii distend the cytoplasm of trophoblasts.
microcolonies can be seen in conventionally stained sections,
but must be distinguished from similar colonies formed by
Chlamydophila organisms. With H&E stains, Chlamydophila
inclusions tend to stain poorly and appear more homogeneous,
whereas cells containing Coxiella frequently have a character-
istic foamy appearance with multiple unstained vacuoles
within a pale blue cytoplasm. The nucleus, if visible, is usually
pushed against the cell wall and assumes a crescent shape.
The histologic lesions in affected fetuses are usually modest.
Granulomatous hepatitis and nonsuppurative pneumonia
with occasional focal lymphoid accumulations around bron-
chioles have been described. A few lymphocytes and macro-
phages may infiltrate the renal medulla and surround the
portal vessels of the liver.
Bovine fetuses may also be aborted as a result of Coxiella
infections. The lesion in the placenta is characteristic and
similar to that observed in sheep and goats. Care must be
taken in attributing the simple presence of Coxiella as suffi-
cient evidence for the cause of abortion. Animals may carry
the organism for a prolonged period and, although they appear
to abort only once, there may be large numbers of organisms
in the placenta in subsequent pregnancies. Assessment of the
extent of the placental lesion may be helpful.
Diagnosis is routinely based on the characteristic placental
lesions and the appearance of the organism in impression
smears stained by a modified acid-fast technique. More defini-
tive methods using direct or indirect fluorescent antibody
techniques and tests to detect Coxiella DNA are available.
Co-infection with Chlamydophila and Toxoplasma is common
in sheep and goats. Cutoff points may assist in determining if
the infection is relevant to abortion, but correlation with
lesions is always advised.
Further reading
Agerholm JS. Coxiella burnetii associated reproductive disorders
in domestic animals—a critical review. Acta Vet Scand 2013;
55:13.
 416.e1

Further reading
Berri M, et al. Shedding of Coxiella burnetii in ewes in two pregnancies
following an episode of Coxiella abortion in a sheep flock. Vet
Microbiol 2002;85:55-60.
Moore JD, et al. Pathology and diagnosis of Coxiella burnetii infection
in a goat herd. Vet Pathol 1991;28:82-84.
Roest HJ, et al. Q fever in pregnant goats: pathogenesis and excretion
of Coxiella burnetii. PLoS ONE 2012;7:e48949.
Roest HI, et al. Q fever diagnosis and control in domestic ruminants.
Dev Biol (Basel) 2013;135:183-189.
Pathology of the Genital System of the Nongravid Female
Hazlett MJ, et al. A prospective study of sheep and goat abortion
using real-time polymerase chain reaction and cut point estimation
shows Coxiella burnetii and Chlamydophila abortus infection
concurrently with other major pathogens. J Vet Diagn Invest
2013;25:359-368.
Muskens J, et al. Prevalence of Coxiella burnetii infections in aborted
fetuses and stillborn calves. Vet Rec 2012;170:260.
Mare reproductive loss syndrome and
late-term abortions
A syndrome of abortion reached epidemic proportions in the
spring of 2001 and to a lesser extent in 2002. It is of major
concern to the equine industry in various states but especially
in Kentucky. Several hundred late-term fetuses were exam-
ined. Most were aborted or stillborn at term or several weeks
before term, well preserved, and enclosed within the placenta.
There were few or no premonitory signs of illness in the mares.
Lesions observed in the fetus included hyphema and little or
no inflation in the lungs. Hemorrhages were frequently
observed on the chorion, amnion and amniotic segment of the
umbilical cord, pleura, and heart. The surface of the amniotic
segment of the cord was dull gray to yellow, roughened, and
thickened by stromal edema. On microscopic examination,
the amniotic portion of the umbilical cord had bacteria on the
surface, and where there was loss of epithelium, there were
light to heavy infiltrations of neutrophils and macrophages.
Similar light infiltrates were seen in the stroma of the
chorioallantois.
Cultures of the fetus and placenta yielded non–β-hemolytic
Streptococcus spp. and/or Actinobacillus spp. in 50% and 20%
of the specimens cultured, respectively. Similar bacteria were
also cultured from lung, stomach content, and placental mem-
branes. Microscopic lesions included funisitis, amnionitis,
pneumonia, fetal bacteremia, and sometimes chorionitis.
Further investigations supported unusually warm weather and
rate of change from cool to warm as major factors, which
correlated with increased bacterial growth and eastern tent
caterpillar (ETC) development. In a controlled study, investi-
gations involving the feeding of ETC to pigs caused abortion.
A similar study in mares revealed that abortion occurred only
on feeding of the insect exoskeleton and that hair remnants
resembling ETC setae were embedded in the submucosa of
the digestive tract of aborting gilts and of an aborting mare.
Studies of a similar disease caused by processionary caterpil-
lars show that the setae penetrate the intestine after ingestion and
subsequently migrate to the pregnant uterus by direct penetration.
With them go bacteria that induce infection of the pregnant
uterus and fetus and placenta.
Further reading
Cawdell-Smith AJ, et al. Equine amnionitis and fetal loss: mare abortion
following experimental exposure to processionary caterpillars
(Ochrogaster lunifer). Equine Vet J 2012;44:282-288.
McDowell KJ, et al. Invited review: the role of caterpillars in mare
reproductive loss syndrome: a model for environmental causes of
abortion. J Anim Sci 2010;88:1379-1387.
Todhunter KH, et al. Processionary caterpillar setae and equine
fetal loss: 2. Histopathology of the fetal-placental unit from
experimentally exposed mares. Vet Pathol 2014;doi:10.1177
/0300985813516639.
Abortion and Stillbirth 417
Nocardioform placentitis in mares
This disease, caused by actinomycete bacteria, is found sporadi-
cally throughout the world. All ages and breeds of mares are
affected. The mare shows no outward signs of illness except,
as with other near-term abortions, premature development of
the mammary gland and lactation may occur. Infection is
cleared early, and rebreeding has not been accompanied by
problems. The bacteria involved are gram-positive branching
filamentous organisms and include at least 3 different genera
of bacteria: Crossiella equi, Streptomyces, and 3 species of
Amycolatopsis. No risk factors have been identified, nor has
the condition been reproduced.
The lesion in the placenta is somewhat unique in that
infection does not seem to start at, nor communicate with,
the cervical star. The chorionic surface of the most cranial
portion of the body and entrance to the uterine horns is
covered with thick brown exudate containing sloughed cho-
rionic cells, neutrophils, and bacteria. The bacteria invade the
chorionic epithelium but have not been identified in fetal
fluids and organs.
Further reading
Erol E, et al. An investigation of a recent outbreak of nocardioform
placentitis caused abortions in horses. Vet Microbiol 2012;158:425-
430.
Giles RC, et al. Causes of abortion, stillbirth, and perinatal death in
horses: 3,527 cases (1986-1991). J Am Vet Med Assoc 1993;
203:1170-1175.
Labeda DP, et al. Amycolatopsis kentuckyensis sp. nov., Amycolatopsis
lexingtonensis sp. nov., and Amycolatopsis pretoriensis sp. nov.,
isolated from equine placentas. Int J Syst Evol Microbiol 2003;
53:1601-1605.
Miscellaneous infections causing abortion
in mares
The bacterial infections in foals that produce the syndromes
variously known as joint ill, navel ill, foal septicemia, and
pyosepticemia neonatorum can also produce abortions and
stillbirths. The implication is that these diseases of the newborn
can be continuations of intrauterine disease. The organisms
involved, in approximately the order of frequency, are:
β-hemolytic streptococci, E. coli, Pseudomonas, Staphylococcus
aureus, Klebsiella pneumoniae, and Actinobacillus equuli. These
organisms may occasionally reach the chorion by way of the
bloodstream of the dam, but most ascend through a patent
cervix (Fig. 4-79). This produces inflammatory thickening of
the cervical star region of placenta adjacent to and radiating
from the internal os of the cervix.
Aspergillus fumigatus is the most commonly isolated fungus,
but Lichtheimia (Absidia) corymbifera and other Aspergillus
spp. have been recovered.
Actinobacillus equuli is an important cause of neonatal
death of foals in most countries. Foals may become infected
in utero and be aborted, as discussed previously; they may die
of septicemia in the early neonatal period; or they may survive
for several days and develop foci of localization in many
tissues. It is probable that some of these infections are acquired
during or after parturition. Aborted foals and those dying
acutely of septicemia do not have distinctive lesions. After a
course of 3 or 4 days or more, localization of the infection
with miliary microabscesses and polyarthritis develops. The
 417.e1

Further reading
Cohen ND, et al. Descriptive epidemiology of late-term abortions
associated with the mare reproductive loss syndrome in central
Kentucky. J Vet Diagn Invest 2003;15:295-297.
Sebastian MM, et al. Review paper: mare reproductive loss syndrome.
Vet Pathol 2008;45:710-722.
Volkmann D, et al. Hormone profiles of mares affected by the mare
reproductive loss syndrome. Reprod Domest Anim 2008;43:
578-583.
417.e2

Further reading
Donahue JM, et al. Crossiella equi sp. nov., isolated from equine pla-
centas. Int J Syst Evol Microbiol 2002;52:2169-2173.
Volkmann DH, et al. The first reported case of equine nocardioform
placentitis in South Africa. J S Afr Vet Assoc 2001;72:235-238.
418 CHAPTER 4  •  Female Genital System
Figure 4-79  Ascending placentitis following transcervical infec-
tion by Streptococcus sp. in a horse.
microabscesses, which are embolic in origin, may be found in
many organs, and they are readily visible to the naked eye in
the renal cortices. The renal abscesses are small, being only
1-3 mm in diameter, and numerous. Histologically, bacterial
colonies are obvious in the glomeruli and intertubular capil-
laries and are enclosed in foci of intense suppuration. The
arthritis is fibrinopurulent.
There is little information on the epidemiology and patho-
genesis of actinobacillosis. Mares, which are caused to abort
by this infection, are not ill, and the organism does not persist
for long in the uterus after abortion. However, the same mare
may abort successive pregnancies, a fact which suggests that
the uterus can be reinfected from some endogenous asymp-
tomatic focus. A. equuli can occasionally be found in the
intestine and tissues of healthy animals and also as an oppor-
tunist in pathologic tissues such as verminous thromboses. It
is, however, seldom of significance in adult animals, although
septicemia has been observed.
Rhodococcus equi is an important cause of pneumonia and
colitis in foals <6 months of age, and a rare cause of placentitis
and abortion. The fetus may be expelled within the mem-
branes. The cervical star and surrounding region may be red;
the lungs are pale and fail to float. R. equi may be isolated in
pure culture from the placenta, lungs, liver, and stomach
content. The lesion in the placenta consists of a perivascular
macrophage infiltrate with a few lymphocytes and neutro-
phils. The macrophages contain numerous gram-positive coc-
cobacilli. Inflammation is most extensive on the allantoic
surface. On microscopic examination, there is multifocal
hypertrophy and hyperplasia of allantoic epithelial cells, and
small numbers of neutrophils and large macrophages are
loosely scattered within the amnion. Pulmonary alveoli
contain a few granulocytes and many macrophages, some of
which are multinucleated.
Encephalitozoon cuniculi is a microsporidial organism that
is a rare cause of placentitis and abortion in a wide range of
animals, including horses. A Quarter Horse mare aborted a
fetus and placenta 6 weeks before term; viscous yellow
exudate was scattered over the chorionic surface of the pla-
cental body and both horns. In addition, the joints of the foal
were swollen and contained tan to red gelatinous material. On
microscopic examination, there was necrotizing placentitis,
and trophoblasts contained large numbers of intracytoplasmic
Abortion and Stillbirth
Figure 4-80  Mycotic abortion in a cow with mycotic dermatitis
in the aborted calf.
vacuoles that were filled with elongated gram-positive organ-
isms. These were positively identified by PCR and electron
microscopy as E. cuniculi. No organisms were identified in the
joints.
Further reading
Donahue JM, et al. Classification of Actinobacillus spp isolates from
horses involved in mare reproductive loss syndrome. Am J Vet Res
2006;67:1426-1432.
Patterson-Kane JC, et al. Placentitis, fetal pneumonia, and abortion due
to Rhodococcus equi infection in a Thoroughbred. J Vet Diagn
Invest 2002;14:157-159.
Patterson-Kane JC, et al. Encephalitozoon cuniculi placentitis and
abortion in a quarterhorse mare. J Vet Diagn Invest 2003;15:
57-59.
Williams N. Mare reproductive loss syndrome. Equine Q 2002;
10:4-7.
Mycotic abortion in cattle
Sporadic cases of bovine abortion result from infection with
a variety of fungal species, with Aspergillus fumigatus the most
frequent isolate in North America. Zygomycetes (Lichtheimia
[Absidia], Mortierella, Rhizomucor, Rhizopus) are also com-
monly responsible. Mixed fungal infections are relatively
common, in which case both septate and nonseptate hyphae
may be observed in the placenta. A small number of abortions
result from Pseudallescheria boydii and yeast (Candida, Toru-
lopsis) infections. The portal of entry is not known, but the
initial development of lesions in placentomes indicates hema-
togenous arrival. Extension from either respiratory or rumen
infections is possible. With the exception of Rhizopus, these
organisms are well-known secondary pathogens. Abortion
occurs late in gestation, between the sixth and eighth month,
and the placenta is often firmly retained.
The fetus may appear normal, but often there are character-
istic cutaneous lesions in the form of irregular elevated plaques
resembling ichthyosis or extensive ringworm. These lesions are
seen most commonly about the periorbit, occiput, shoulders,
back, and sides (Fig. 4-80). Affected areas are slightly elevated,
gray, and irregular in outline and tend to coalesce. Histologi-
cally, the infection is seen to be superficial, involving the
 418.e1

Further reading
Hong CB, et al. Etiology and pathology of equine placentitis. J Vet
Diagn Invest 1999;5:56-63.
Mohan K, et al. Strains of Actinobacillus spp. from diseases of animals
and ostriches in Zimbabwe. Onderstepoort J Vet Res 1997;64:195-
199.
Monga DP, et al. Mycotic abortions in equines. Mykosen 1983;26:612-
614.
Morehead JP, et al. Evaluation of early fetal losses on four equine farms
in central Kentucky: 73 cases. J Am Vet Med Assoc 2003;220:1828-
1830.
Piancastelli C, et al. Isolation and characterization of a strain of Lich-
theimia corymbifera (ex Absidia corymbifera) from a case of bovine
abortion. Reprod Biol Endocrinol 2009;7:138.
Platt H. Infection of the horse fetus. J Reprod Fertil Suppl 1975;23:605-
610.
Prickett ME. Abortion and placental lesions in the mare. J Am Vet Med
Assoc 1979;157:1465-1470.
Swerczek TW. Equine fetal diseases. In: Morrow DA, editor. Current
Therapy in Theriogenology. Philadelphia: WB Saunders; 1986.
p. 699-704
Takai S. Epidemiology of Rhodococcus equi infections: a review. Vet
Microbiol 1997;56:167-176.
Wolfsdorf KE, et al. Theriogenology question of the month. J Am Vet
Med Assoc 2000;216:1915-1916.
Zink MC, et al. Corynebacterium equi infections in horses, 1958-1984:
a review of 131 cases. Can Vet J 1986;27:213-217.
Pathology of the Genital System of the Nongravid Female
Figure 4-81  Mycotic placentitis primarily involving the cervical
star area of an equine placenta.
Figure 4-82  Mycotic placentitis in a bovine placenta.
epidermis mainly, with parakeratosis, and edema and inflam-
matory cell infiltration of the underlying dermis. Sometimes
the fungus invades the hair follicles and dermis but, with
the exception of an occasional case of bronchopneumonia,
there are no lesions in the internal organs. The fungus can
be isolated from the stomach contents. The placental lesions
are remarkable. The gross appearance resembles that seen
in brucellosis but is often much more severe. The chorioal-
lantois is then leathery with extensive superficial necrosis.
Compare the characteristic gross appearance of equine
and bovine mycotic placentitis (Figs. 4-81, 4-82). In bovine
mycotic placentitis, cotyledons are greatly enlarged and
necrotic with swollen margins (“cupping”), and the interca-
runcular areas are typically thickened and opaque. The infect-
ing organisms are readily demonstrated in the necrotic tissue,
and typically extend along the blood vessels to produce nec-
rotizing vasculitis. They frequently can be demonstrated on
cytology using periodic acid–Schiff or Gomori methenamine
silver stains.
In contrast to the ascending route of infection of the pla-
centa in mares (see Fig. 4-81), the infection in cattle is hema-
togenous and begins in the placentomes, with later spread to
the intercotyledonary space. In cases with milder placentitis,
Abortion and Stillbirth 419
there are usually no cutaneous lesions in the fetus, although
the fungi can be found in the gastric contents. The endome-
trial lesions are less severe than those in the placenta. Second-
ary infections may follow retention of the placenta. The
majority of cows recover sufficiently after abortion to allow
subsequent pregnancies to be carried to term, but in some,
endometrial destruction is severe.
Further reading
Johnson CT, et al. The bovine placentome in bacterial and mycotic
abortions. Vet Rec 1994;134:263-266.
Knudtson WU, Kirkbride CA. Fungi associated with bovine abortion in
the northern plains states (USA). J Vet Diagn Invest 1992;4:181-
185.
Piancastelli C, et al. Isolation and characterization of a strain of Lich-
theimia corymbifera (ex Absidia corymbifera) from a case of bovine
abortion. Reprod Biol Endocrinol 2009;7:138.
Epizootic bovine abortion
This disease is a tick-borne infection of cattle that produces
chronic fetal disease and abortion. The name is a misnomer, as
epizootic bovine abortion (EBA) is actually provincial and
endemic and also was the original common name for bovine
brucellosis. Its distribution is apparently limited by that of the
vector, the argasid tick Ornithodoros coriaceus. The precise
geographic range of the tick is not known. It is known to
inhabit brushy foothills of California and adjacent areas of
Nevada, Oregon, and northern Mexico, hence the other
common name—foothills abortion. The most common hosts
of the tick are cattle and deer. The tick is presumed to transmit
an agent from the deer to cattle, as the infection remains
endemic in ranges on which no cattle have been grazed. The
cause of EBA is a novel deltaproteobacterium detected in sali-
vary glands and other tissues, in a high percentage of adult O.
coriaceus ticks in areas endemic for EBA.
Cattle exposed to the ticks for the first time are primarily
at risk. The infection produces no recognizable clinical signs
in cattle of any age, but if the animals are pregnant, especially
at 2-6 months, the infection is passed to their fetuses, wherein
a chronic disease develops. The fetus at this stage of gestation
has not fully developed a functional immune system. This,
coupled with a cow that has not been previously exposed to
the agent, allows the agent to cross the placenta to the fetus
and initiate chronic infection. There is a 3-month or longer
incubation period between the exposure of the dam to ticks,
development of the entire spectrum of lesions, and death and
abortion of the fetus. Because the lesions gain their specificity
only during the latter part of this prolonged period, the disease
can only be confidently diagnosed in those animals exposed
before the last trimester.
Not all diseased fetuses are aborted. The fetus is likely to
have developed a functional immune system by 7-8 months
of gestation and may not be aborted if infected by the agent
in that time period. Instead, the calf may not die from the
infection but be born weak. Weak calves are often seen associ-
ated with outbreaks of abortion in this disease. Cows that
abort because of the disease are not usually ill, and the pla-
centa is shed without difficulty. Cattle develop immunity and
do not abort even if they are re-exposed to the ticks and the
agent they carry. If there is little movement of animals,
 419.e1

Further reading
Cordes DO, et al. Mycotic pneumonia and placentitis caused by Mor-
tierella wolfii. Vet Pathol 1972;9:190-201.
Hill MW, et al. Pathogenesis of experimental bovine mycotic placentitis
produced by Aspergillus fumigatus. Vet Pathol 1971;8:175-192.
Jensen HE, et al. Bovine mycotic abortion—a comparative study of
diagnostic methods. Zentralbl Veterinarmed B 1991;38:33-40.
420 CHAPTER 4  •  Female Genital System
abortions may be rare in endemic areas. The disease becomes
a major cause of abortion in a herd only when pregnant non-
immune animals are moved into an area where the infection
is endemic.
The fetuses affected by the disease are most often aborted
during the last trimester. Most trigger their own deliveries and
die either during delivery or shortly thereafter. Only rarely do
they die in utero and undergo autolysis. Many, but not all,
affected fetuses have characteristic abdominal distension
resulting from ascites, which is a striking, but inconstant,
lesion. Lymph nodes throughout the carcass are enlarged,
usually impressively so. The normal superficial cervical lymph
node of a term bovine fetus weighs 3.5-7.0 g. Fetuses aborted
in this disease have superficial cervical lymph nodes that
weigh 16 g or more, making the node easy to see beneath the
skin immediately in front of the scapula. The spleens of
affected fetuses are similarly enlarged; the thymus, in contrast,
is reduced in size.
Petechial hemorrhages are regularly seen in the conjuncti-
val and oral mucosa as well as in the mucosa of the trachea.
The thymus is often embedded in massive hemorrhages and
edema. These hemorrhages are, at least in part, traumatic,
developing during parturition, the portion of the thymus
within the thoracic cavity being spared. The enlarged, coarsely
nodular liver is, when present, an impressive gross change in
fetuses affected by EBA. However, the lesion is not present in
all diseased fetuses, and similar hepatic congestion with ascites
occurs in fetuses with cardiac disease. Small gray foci of
inflammation can be seen in a variety of tissues, but are most
conspicuous in organs such as kidney and heart, which provide
a dark background.
The changes that develop in the lymphoid organs are the
most specific and diagnostic. The most distinctive fetal lesion
is a remarkable thymic inflammatory change. The cortical
mantle of thymocytes is greatly reduced, and macrophages
diffusely infiltrate both the medulla and the septa of the gland.
The enlargement of lymph nodes and spleen consists of remark-
able lymphoid and mononuclear cell hyperplasia. Well-defined
secondary follicles develop in the cortical and paracortical
regions of the lymph nodes. The sinuses are filled with mac-
rophages that form sheets in the medullary areas. The spleen
shows a similar hyperplastic response involving lymphocytes
of the follicles and periarteriolar lymphoid sheaths; there is
also widespread infiltration of macrophages.
The central veins of the liver are distended and the liver
plates thinned. Mononuclear cells are present around portal
vessels. Foci may be 100 µm in diameter and are often granu-
lomatous in appearance. Affected fetuses may have vasculitis
involving small- and large-caliber vessels. Lesions that are par-
ticularly useful in establishing the diagnosis are regularly
present in the lung and brain. The alveolar walls of the lung
are thickened, and histiocytic inflammatory foci are present
in the septa. In the brain, foci of vasculitis are scattered
throughout and the meninges are thickened by histiocytic
inflammation.
Lesions do develop in the placenta but are usually mild
and involve the loose connective tissue. They contrast with
the acute severe inflammatory reaction of the chorionic
surface seen in bacterial and fungal infections.
Diagnosis of EBA is based on a combination of gross and
histologic findings in an aborted fetus in the geographic area
endemic for O. coriaceus ticks. Identification of the 16S RNA
of the deltaproteobacteria is confirmatory.
Abortion and Stillbirth
Further reading
Anderson ML, et al. Histochemical and immunohistochemical evidence
of a bacterium associated with lesions of epizootic bovine abortion.
J Vet Diagn Invest 2006;18:76-80.
Brooks RS, et al. Quantitative duplex TaqMan real-time polymerase
chain reaction for the assessment of the etiologic agent of epizootic
bovine abortion. J Vet Diagn Invest 2011;23:1153-1159.
Protozoan infections causing abortions
Toxoplasmosis
Infection with Toxoplasma gondii appears to be very common
in many species, but the disease toxoplasmosis is much less
common, and its diagnosis is still somewhat of an event. The
present discussion is limited to genital manifestations. A more
complete discussion of the disease is given with coccidial
disease of the intestine (see Vol. 2, Alimentary system).
Toxoplasma gondii is an important abortifacient in sheep
and goats; it may occur simultaneously with Coxiella and
Chlamydophila in the same abortion outbreak. Animals that
are particularly at risk of Toxoplasma abortion are those moved
late in pregnancy to areas heavily contaminated with cat feces.
This occurs most often when ewes are housed in barns. Under
such circumstances abortion rates can be high. Although T.
gondii can cause abortion, congenital transmission from ewe
to lamb also occurs in a high percentage of normal healthy
lambings.
The ewes and does show no signs of infection. The aborted
lambs and kids show no significant gross lesions; in only a few
are lesions and parasites demonstrable histologically in myo-
cardium, lung, and brain. Irregular small or large foci of leu-
komalacia are common in the cerebral white matter. The fetal
cotyledons of the placenta have characteristic lesions. The coty-
ledons are bright to dark red compared with a normal deep
purple color; scattered among the fetal villi are numerous white
flecks or small soft white nodules 1-3 mm in diameter (Figs.
4-83, 4-84A). Histologically the villi are edematous, and there
is focal necrosis and desquamation of trophoblastic epithe-
lium. In some there may be caseous and mineralized cotyle-
donary nodules (Fig. 4-84B). The organism is identified either
free or in cysts. The intercotyledonary placenta shows edema
only. Encysted organisms can frequently be found in the endo-
metrium. It may be assumed that placental infection can occur
Figure 4-83  Aborted fetal lamb with focal placental necrosis
caused by Toxoplasma.
 420.e1

Further reading
Stott JL, et al. Experimental transmission of epizootic bovine abortion
(foothill abortion). Vet Microbiol 2002;88:161-173.
Pathology of the Genital System of the Nongravid Female
A
B
Figure 4-84  A. Closer view of an affected cotyledon from aborted
lamb in Figure 4-83 showing the discrete foci of necrosis and
associated placentitis characteristic of Toxoplasma gondii infec-
tion. B. Subgross photomicrograph showing intense foci of necro-
sis and mineralization.
at any time the infection is active and the organism is in the
proliferative phase.
Cattle rarely, if ever, abort because of toxoplasmosis.
Although the organism may be present in cattle, it does not
appear to cause disease. Toxoplasma has been reported to
cause abortion in swine, with fetal lesions, but this appears to
be an uncommon event.
Further reading
Castano P, et al. Placental thrombosis in acute phase abortions
during experimental Toxoplasma gondii infection in sheep. Vet Res
2014;45:9.
Dubey JP. Toxoplasmosis in sheep—the last 20 years. Vet Parasitol
2009;163:1-14.
Neospora infections causing reproductive failure in
cattle, sheep, dogs, and cats
Neospora caninum is a protozoan parasite belonging to the
class Apicomplexa. N. caninum was first isolated from a litter
of puppies, and domestic dogs are the only recognized defini-
tive hosts of the parasite. It is a major cause of abortion in both
dairy and beef cattle throughout the world. Although observed
in tissues from aborted bovine fetuses for many years, the
organism was first associated, and in 1987 identified, as the
cause of an abortion storm in cattle in New Mexico. It differs
morphologically and antigenically from Toxoplasma and
Sarcocystis spp.
Abortion and Stillbirth 421
The organism can cause severe neuromuscular paralytic
disease in dogs and cats. Experimentally induced infections in
pregnant dogs and cats lead to in utero death and birth of
infected offspring, some of which die, whereas others remain
normal. Orally induced infection in nonpregnant cats subse-
quently bred results in clinically normal young, born infected
with the parasite.
In cattle, the natural route of infection is probably by con-
sumption of oocysts excreted in the feces of dogs and other
canids, or by vertical transmission. Eating infected carcasses or
placentas from infected fetuses may infect canids. Most reports
of abortion involve dairy cattle and particularly cows on
drylot. This is believed to be associated with the density of
population and methods of feed storage, providing increased
opportunity for contamination, transmission, and spread of
the organism. However, beef cows also abort. Conception
does not seem to be affected; however, animals have been
reported to abort with N. caninum in 3 sequential pregnancies.
Abortion storms, where fresh or autolysed fetuses are aborted,
may be followed by the birth of mummified fetuses for several
months. Animals aborting in one year may or may not abort
in the next gestation. Herd investigations have shown that
23% of pregnant cows and heifers abort during the first
year of infection. Although protective immunity develops
in infected cows, this immunity does not prevent transplacen-
tal infection, and seropositive cows are more likely to abort
than are seronegative cows. Seronegative cows probably
always produce seronegative calves. Most Neospora-induced
abortions occur at 5-6 months of gestation; this mid-gestation
abortion frequency is distinctive from other kinds of abortion
in dairy cattle. Pregnancy-induced immunosuppression is
a possible, but unproven, cause of reactivation of latent
Neospora infections. The economic impact of N. caninum
infection in dairy cattle extends beyond that from abortion
to include premature culling resulting from the diminished
milk production that occurs in seropositive cows. Cows
infected with N. caninum are usually not clinically ill, nor do
they have an increased risk of dying compared to seronegative
cows.
Congenitally infected full-term calves may not show signs
of disease, but still have a high titer to the organism. Neospora-
infected calves may be born small-for-gestational-age, unable
to rise, ataxic, or have no clinical signs. Fore- and hindlimbs
may be flexed or hyperextended; there may be loss of con-
scious proprioception.
On postmortem, there are often no useful identifying gross
lesions. Bovine fetuses are often expelled in the second or third
trimester and may be fresh, autolysed, or in early stages of
mummification. In the placenta, the cotyledons are necrotic
and the intercotyledonary region is normal. Rarely, there are
scattered tan-to-gray soft foci visible in the brain, brainstem
(Fig. 4-85), skeletal muscle, and heart. These consist of necro-
sis, mononuclear and glial cells, perivascular cuffing, and some-
times mineralization. Cysts may be difficult to find or
conspicuous, and are probably more common in spinal cord
than brain. N. caninum invades many different cell types and
tissues in the fetus (Fig. 4-86). The zoites proliferate intracel-
lularly by endodyogeny; massive proliferation leads to host cell
lysis, and newly formed parasites are released to invade neigh-
boring cells.
N. caninum tachyzoites may be identified in focal brain
lesions; however, free protozoa are difficult to recognize and are
most easily identified using immunohistochemistry. Intracellular
 421.e1

Further reading
Edwards JF, Dubey JP. Toxoplasma gondii abortion storm in sheep on
a Texas farm and isolation of mouse virulent atypical genotype T.
gondii from an aborted lamb from a chronically infected ewe. Vet
Parasitol 2001;192:129-136.
Hazlett MJ, et al. A prospective study of sheep and goat abortion using
real-time polymerase chain reaction and cut point estimation shows
Coxiella burnetii and Chlamydophila abortus infection concurrently
with other major pathogens. J Vet Diagn Invest 2013;25:359-368.
Kim JH, et al. Porcine abortion outbreak associated with Toxoplasma
gondii in Jeju Island, Korea. J Vet Sci 2009;10:147-151.
Wiengchareon J, et al. Transplacental transmission in cattle: is Toxo-
plasma gondii less potent than Neospora caninum? Parasitol Res
2011;108:1235-1241.
422 CHAPTER 4  •  Female Genital System
zoites may be seen in myocytes and Purkinje fibers in myo-
cardium. Less consistent lesions include multifocal hepatic
necrosis, focal nonsuppurative interstitial nephritis, interstitial
pneumonia, and adrenalitis. Large numbers of N. caninum–like
zoites are rarely observed in poorly defined cysts within
Figure 4-85  Neospora-like organism in bovine abortion. Focal
necrosis is surrounded by a narrow zone of glial cells in brain.
B
A
C
Figure 4-86  Neospora-like organisms in brain. A. Clusters of zoites in vessel. B. Clusters of zoites
in endothelial cell. C. Clusters of zoites lying free in parenchyma. D. Cluster of zoites in paren-
chyma surrounded by cyst-like wall.
Abortion and Stillbirth
trophoblasts, and more often no significant lesions are seen in
the placenta. Mononuclear cells are found in areas of focal
necrosis in the cotyledons. Neospora, although rarely identified
in placenta by immunohistochemistry, may be positive on
PCR.
On light microscopy, N. caninum can be distinguished from
cysts of Toxoplasma and Sarcocystis, as the cyst wall is slightly
thicker. All stages can be differentiated from other protozoans
using immunohistochemistry, which is used successfully to
demonstrate protozoa in brain (Fig. 4-87), spinal cord, lung,
kidney, heart, and skeletal muscle of fresh or autolysed fetuses
and also, but with more difficulty, in mummified fetuses. Isola-
tion of N. caninum from autolysed tissues in cell cultures is
rarely successful because of the effects of autolysis. Tissue
cysts may be rare in in utero–infected fetuses; however, serol-
ogy on fetuses aborted at >5 months of gestation has proved
useful in detecting antibodies to N. caninum. Maternal anti-
bodies to Neospora may also be detected but decline within
2-5 months of abortion.
N. caninum has also been identified as a cause of abortion
in sheep and possibly in goats. Lesions appear to be similar in
bovine and ovine aborted fetuses, and clinically affected
bovine, ovine, canine, and feline neonates. The role of Neos-
pora spp. (N. caninum or N. hughesi) in equine abortions is
under investigation.
Pathology of the Genital System of the Nongravid Female
Figure 4-87  Immunohistochemically stained Neospora zoites.
Further reading
Almería S, López-Gatius F. Bovine neosporosis: clinical and practical
aspects. Res Vet Sci 2013;95:303-309.
Dubey JP, Schares G. Neosporosis in animals—the last five years. Vet
Parasitol 2011;180:90-108.
Leon A, et al. Molecular detection of Coxiella burnetii and Neospora
caninum in equine aborted foetuses and neonates. Prev Vet Med
2012;104:179-183.
Wouda W. Diagnosis and epidemiology of bovine neosporosis:
a review. Vet Q 2000;22:71-74.
Sarcocystis species causing abortion in cattle, goats,
sheep, and pigs
Sarcocystis spp. cause abortion, stillbirth, and neonatal deaths
in cattle, goats, sheep, and pigs. In contrast to some of the other
protozoa, they are usually specific for their intermediate host.
Transmission, pathogenesis, lesions, and diagnosis are similar
in all intermediates, and only lesions observed in cattle will be
described. Ingesting food or water contaminated by feces con-
taining oocysts, which are immediately infective to the inter-
mediate host, infects the animal. Definitive hosts include the
dog, coyote, wolf, red fox, and raccoon for the pathogenic
organism S. cruzi.
The pathogenesis of Sarcocystis-induced abortion is uncer-
tain, but may involve anemia in the dam, leading to fetal
hypoxia and death, premature induction of parturition
through release of PGF2α from damaged endothelial cells,
fever, or direct infection of the fetus. Infection in the dam may
result in acute necrotizing endometritis, followed by multiple
foci of necrosis in the soft tissues of the fetus. Why the organ-
ism is sometimes visible only in the dam but at other times
also in the fetus is not known. In the dam, the zoite-containing
cysts may be observed in the endometrium or caruncle fol-
lowing abortion, but if it passes to the fetus, in spite of autoly-
sis and near absence of gross lesions, extensive lesions are
evident microscopically. In the brain and meninges, there are
multifocal areas of necrosis surrounded by undifferentiated
mononuclear cells and lymphocytes. Cardiac muscle, kidney,
liver, lung, and chorioallantoic membranes may have similar
lesions, some of which are mineralized and undergoing fibro-
sis. Endothelial cells in several soft tissues may contain thin-
walled cysts that bulge into the lumen (Fig. 4-88) of the
frequently thrombosed vessel. The cysts, packed with elongate
Abortion and Stillbirth 423
Figure 4-88  Sarcocyst in endothelium of small vessel of the
Peyer’s patch in an aborted bovine fetus.
zoites, although often difficult to find, are most easily distin-
guished in nervous tissue, maternal caruncle, and endome-
trium away from the site of inflammation.
Diagnosis is based on finding typical lesions of nonsuppura-
tive meningoencephalitis, multifocal necrosis in soft tissues,
and the presence of cysts containing zoites with a tropism for
endothelium. If the organism cannot be found on routine
sectioning, it can readily be located using specific fluorescent
antibody or immunohistochemistry.
Further reading
Dubey JP, Lindsay DS. Neosporosis, toxoplasmosis, and sarcocystosis
in ruminants. Vet Clin North Am Food Anim Pract 2006;22:
645-671.
Genital tritrichomoniasis
This is a specific contagious venereal disease of cattle caused
by the flagellated protozoan Tritrichomonas foetus and trans-
mitted at coitus or artificially via contaminated semen.
Infection in the bull remains in the preputial cavity and
must be considered, in the absence of effective treatment, as
permanent. In early infections, there is balanoposthitis of
moderate severity, with preputial swelling and a slight puru-
lent discharge. As the infection becomes chronic, the inflam-
matory reaction disappears and the organisms become fewer
in number. There is a tendency for them to concentrate on
the head of the penis and adjacent areas of the prepuce, and
they may be detected by culture or PCR testing of preputial
washings.
Females are not readily infected, if at all, except by service
or experimentally by placing a culture of the organism in the
vagina. A few days after infection, acute vaginitis with swelling
of the vulva develops, and there is a moderate amount of
mucoid floccular discharge in the vagina. The protozoa may
 423.e1

Further reading
Anderson M, et al. Neosporosis in dairy cattle. Jpn J Vet Res
2012;60(Suppl.):S51-S54.
Goodswen SJ, et al. A review of the infection, genetics, and evolution
of Neospora caninum: from the past to the present. Infect Genet
Evol 2013;13:133-150.
Williams DJ, et al. Endogenous and exogenous transplacental transmis-
sion of Neospora caninum—how the route of transmission impacts
on epidemiology and control of disease. Parasitol 2009;136:
1895-1900.
423.e2

Further reading
Anderson ML, et al. Protozoal causes of reproductive failure in domes-
tic ruminants. Vet Clin North Am Food Anim Pract 1994;10:439-
461.
Buxton D. Protozoan infections (Toxoplasma gondii, Neospora caninum
and Sarcocystis spp.) in sheep and goats: recent advances. Vet Res
1998;29:289-310.
424 CHAPTER 4  •  Female Genital System
be easy or impossible to find in this exudate. The vaginitis
resolves quickly, and the infection localizes in the uterus and
cervix. Immediately prior to the estrus, which follows the
infective service, large numbers of organisms can usually be
found in exudate aspirated from the cervix, but as estrus
advances, the number of protozoa is greatly reduced.
The manifestations of established trichomoniasis in females
are cervicitis and endometritis that result in repeat breeding,
abortion, or pyometra. The inflammatory changes in the endo-
metrium and cervix are relatively mild and nonspecific,
although the mucopurulent exudate may be rather copious.
Discharge of exudate into the vagina may be more or less
continuous or intermittent, and the numbers and activity of
the trichomonads in the discharge vary considerably over
short periods. The discharge may not be apparent at the vulva.
The pattern of repeat breeding in tritrichomoniasis is the
same as that in venereal Campylobacter infections. Return to
service occurs at irregular intervals, a fact that indicates that
fertilization and implantation are followed by embryonic
death. When the embryo or fetus dies, it may be resorbed,
aborted, or retained with the development of pyometra.
Trichomonad abortions may occur at any time, but mainly in
the first half of pregnancy. There are no specific fetal lesions, but
large numbers of protozoa may be found in the fetal fluids and
stomach. The placenta is not severely altered as in brucellosis;
it may be covered by white or yellow flocculent exudate in
small amounts, thickened, and slightly tough; hemorrhage
without much necrosis may be evident on the cotyledons.
Pyometra is one of the remarkable changes of trichomoniasis,
but it is a relatively uncommon complication. Its pathogenesis
follows the scheme outlined earlier, and its character is
remarkable only for the copiousness of the exudate; any
volume up to 4 L or more may be present. The exudate may
be watery with floccules, colostrum-like, or brown and sticky.
It is without odor and swarms with trichomonads.
Further reading
Rae DO, Crews JE. Tritrichomonas foetus. Vet Clin North Am Food
Anim Pract 2006;22:595-611.
Viral infections of the pregnant uterus
Porcine reproductive and respiratory syndrome
(PRRS)
The syndrome is caused by species Porcine reproductive and
respiratory syndrome virus (PRRSV), family Arteriviridae,
genus Arterivirus, a positive-strand RNA virus. All ages of
nonimmune pigs are affected. Death rates can be high in
piglets born with pneumonia or infected before or after
weaning. Deaths in piglets are also associated with secondary
bacterial infections, including Salmonella choleraesuis, Strepto-
coccus suis, Actinobacillus pleuropneumoniae, and Haemophilus
parasuis. These secondary infections often account for major
reproductive losses. Viremia and circulating antibodies may
coexist. Strain differences may account for some of the rein-
fections. Nonimmune animals vaccinated with modified-live
PRRSV vaccines may experience increased abortions, still-
births, and high mortality in newborns.
The effects of PRRSV on reproductive performance are
variable between strains, and even though a gilt develops
antibodies to one strain, she may be susceptible to another.
Similar differences in pathogenicity occur in respiratory
Abortion and Stillbirth
disease. Effects also vary greatly depending on the stage of
gestation and may result in early farrowing of stillbirths and
mummified fetuses.
Initial clinical findings in infected pregnant gilts are
anorexia, lethargy, depression, and mild fever; cyanosis of the
snout, ears, tails, vulva, and abdomen occurred commonly in
European outbreaks but are rarely observed in North America.
This is commonly followed by a sudden increase in early far-
rowing, late-term abortions, stillbirths, mummified fetuses, infertil-
ity, and sometimes death. Live piglets with respiratory signs,
muscle tremors, and splayleg also occur. Transplacental passage
may result in fetal antibody production. After an outbreak of
reproductive failure, previous levels of reproductive perfor-
mance may not be achieved. Variable degrees of endometritis
and myometritis may be present.
Gross and microscopic lesions in piglets are variable to absent
and often obscured by autolysis. “Paintbrush” hemorrhages have
been observed on the placenta, and petechial hemorrhages
and necrosis occur on umbilical vessels, skin, and renal cortex.
Microscopic lesions include lymphoplasmacytic and histio-
cytic infiltrates within and around small capillaries at the
periphery of the tunica adventitia of umbilical arteries. Mild
to moderate, multifocal to diffuse, histiocytic and proliferative
interstitial pneumonia characterized by mononuclear cell
septal infiltration is commonly observed. Hypertrophy and
hyperplasia of type 2 pneumocytes is occasionally present.
Mild segmental necrotizing and lymphohistiocytic arteritis has
been seen in lungs. Mild segmental necrotizing and lympho-
histiocytic, suppurative and, less often, eosinophilic hepatitis
may be present. Mild multifocal perivascular lymphohistio-
cytic myocarditis and, rarely, multifocal myocardial hemor-
rhages are present.
The diagnosis is established by isolating the PRRSV, PCR
assay, or by in situ hybridization or immunohistochemical
(IHC) detection of the virus in formalin-fixed tissues. The
virus is rapidly inactivated in aborted, stillborn, or mummified
fetuses, and isolation is therefore inconsistent. PCR becomes
valuable in diagnosis as there are no consistent gross or micro-
scopic lesions of this syndrome in fetuses, and PCR testing
modalities are impacted the least by the adverse effects of
autolysis.
Further reading
Karniychuk UU, Nauwynck HJ. Pathogenesis and prevention of placen-
tal and transplacental porcine reproductive and respiratory syn-
drome virus infection. Vet Res 2013;44:95.
Snijder EJ, et al. Arterivirus molecular biology and pathogenesis. J Gen
Virol 2013;94:2141-2163.
Classical swine fever virus infection of the pregnant
uterus in sows
Species Classical swine fever virus (CSFV, syn. hog cholera
virus), family Flaviviridae, genus Pestivirus, (single-stranded,
positive-sense RNA genome), causes a serious and contagious
viral disease of swine; fortunately it has been eradicated from
many countries. Pestiviruses include CSFV, border disease virus
(BDV) of sheep, and bovine viral diarrhea virus (BVDV). Infec-
tion by any of these 3 viruses can have similar results, namely,
early embryonic losses resulting from in utero transmission to
the fetus, severe congenital abnormalities, and, particularly
with BVDV, lifelong persistent infections.
 424.e1

Further reading
Guerra AG, et al. Use of pooled protozoal cultures of preputial scrap-
ing samples obtained from bulls for the detection of Tritrichomonas
foetus by means of a real-time polymerase chain reaction assay.
J Am Vet Med Assoc 2014;244:352-356.
Mukhufhi N, et al. Evaluation of a PCR test for the diagnosis of Trit-
richomonas foetus infection in bulls: effects of sample collection
method, storage and transport medium on the test. Theriogenol
2003;60:1269-1278.
Rhyan JC, et al. Fetal and placental lesions in bovine abortion due to
Tritrichomonas foetus. Vet Pathol 1988;25:350-355.
424.e2

Further reading
Cheon DS, Chae C. Comparison of virus isolation, reverse transcription-
polymerase chain reaction, immunohistochemistry, and in situ
hybridization for the detection of porcine reproductive and respira-
tory syndrome virus from naturally aborted fetuses and stillborn
piglets. J Vet Diagn Invest 2000;12:582-587.
Rossow KD. Porcine reproductive and respiratory syndrome. Vet Pathol
1998;35:1-20.
Scruggs DW, Sorden SD. Proliferative vasculopathy and cutaneous
hemorrhages in porcine neonates infected with the porcine repro-
ductive and respiratory syndrome virus. Vet Pathol 2001;38:
339-342.
Pathology of the Genital System of the Nongravid Female
The virulence of CSFV varies from avirulent to highly viru-
lent. Pigs infected with highly virulent CSFV may have a high
fever, depression, incoordination, reddening of the skin, diar-
rhea, respiratory distress, and death with widespread hemor-
rhage resulting from severe necrotizing vasculitis. Moderately
virulent and virulent strains of CSFV cause subacute and
chronic disease with similar but milder signs. During an inap-
parent viremic phase in a pregnant sow, the virus may be
carried to the fetus and result in embryonic death, malforma-
tions, mummification, stillbirth, or birth of live clinically normal
pigs or pigs with tremors. Persistently infected (PI) piglets may
be born at term and appear clinically normal or weak but, in
either circumstance, eventually succumb to the effects of the
virus.
The virus can be transmitted from carrier or clinically
affected pigs through their secretions and excretions or
through the ingestion of contaminated wastes. Birds, parasites,
and fomites have also been identified as the source of virus in
outbreaks. At one time, the use of vaccines containing CSFV
of low virulence was the cause of severe losses caused by in
utero infections in pigs.
After exposure of a pregnant sow, the virus multiplies in
the tonsils and spreads to other lymphoid organs, eventually
reaching the fetus between 13 and 18 days. During the viremic
stage, the virus crosses the uteroplacental interface, infecting
all or only some fetuses. In the latter situation, the virus may
continue to pass from fetus to fetus in utero, eventually infect-
ing many.
Lesions produced in a fetus following in utero infection are
variable and depend on the virulence of the infecting virus,
the stage of gestation when the infection occurs, and an appar-
ent variation in the development time of immune competence
to CSFV in fetal piglets. In general, and with many exceptions,
early infections result in embryonic or fetal death or persistent
infections. Early to mid-gestation infections result in malfor-
mations, including pulmonary hypoplasia, pulmonary artery
malformation, micrognathia, arthrogryposis, and CNS malfor-
mations (including cerebellar hypoplasia, microcephaly, and
defective myelination in brain and spinal cord). Infections
during the last trimester may produce no abnormalities, or
may result in mummification or stillbirths.
Persistent infections in piglets most commonly follow expo-
sure to the virus from 22-70 days of gestation and, rarely, up
to 100 days. These fetuses may or may not die in utero and
often show retarded development and runting. Many show no
signs until sometime after birth, and PI pigs living to 11
months have been reported. The latter commonly have
marked depletion of lymphocytes (especially in the thymic
cortex), and B-cell–dependent regions of lymph nodes and
spleen. Lesions are also observed in heart (degeneration of
endothelium and valvular fibrosis), liver (portal fibrosis), intes-
tine (villus atrophy and ulceration), lungs (interstitial pneu-
monia), skin (necrosis and degeneration of epithelial cells),
and CNS (neuronal degeneration and hydranencephaly).
Many PI piglets are born alive with a congenital tremor and
CNS dysgenesis, cerebellar hypoplasia, and hypomyelination.
Piglets with tremor, which survive for long periods, have
reduced clinical signs but continue to excrete CSFV. The
similarity of this to the syndrome in border disease virus–
infected “shaker lambs” suggests a similar pathogenesis.
Many fetal piglets show some ability to respond immuno-
logically to CSFV between 70 and 90 days of gestation with
an immunoglobulin of low specificity and avidity. In
Abortion and Stillbirth 425
accordance with this, fetuses collected from sows infected
during this period may show general lymphoid hyperplasia
and development of primary follicles. Kidney and brain
may have mild lesions with scattered focal mononuclear
cells, and spleen and kidney may have foci of necrosis and
hemorrhage.
For diagnosis, CSFV can be isolated from a variety of fetal
tissues, including the placenta and from the serum of PI swine,
or detected by various PCR tests. Fetal antibody may be
present in late-gestation fetuses, but carrier sows may or may
not have antibody. In addition, the virus may be identified by
the fluorescent antibody technique in tissue sections. In some
laboratories, CSFV is routinely differentiated from BVDV and
BDV infections and, in some instances, CSFV vaccine strains
from field strains. This may be very important in large eradica-
tion and control programs.
Further reading
Dewulf J, et al. An experimental infection with classical swine fever
virus in pregnant sows: transmission of the virus, course of the
disease, antibody response and effect on gestation. J Vet Med B
Infect Dis Vet Public Health 2001;48:583-591.
Haines FJ, et al. Development and validation of a multiplex, real-time
RT PCR assay for the simultaneous detection of classical and African
swine fever viruses. PLoS ONE 2013;8:e71019.
Bovine viral diarrhea virus infection of
the pregnant uterus
Species Bovine viral diarrhea virus (BVDV), genus Pestivirus,
family Flaviviridae, is closely related to Border disease virus of
sheep and less closely to Classical swine fever virus. For further
discussion, see the section on border disease virus infection in
sheep and goats, later. These 3 viruses have been shown to cross
infect naturally between species. The various strains of BVDV,
although similar, differ in virulence and can be distinguished
antigenically. Two biotypes exist, one that is cytopathic for cell
cultures (cp-BVDV = CB, cytopathic biotype) and one that is
not cytopathic (ncp-BVDV = NCB, noncytopathic biotype).
Both cause disease in cattle. In addition, there is type 2 BVDV,
which can infect fetuses and exists in cytopathic and noncy-
topathic forms as well.
BVDV and Akabane virus are probably the most important
viral pathogens of the bovine fetus. BVDV is distributed
worldwide, and persistently infected (PI) cattle are reported
to make up about 1% of the general population. They do not
develop antibody to the homologous strain to which they are
infected, but may respond to heterologous strains used in vac-
cines. Cattle persistently infected with ncp-BVDV or tempo-
rarily infected with cp-BVDV may excrete virus in feces,
semen, urine, milk, nasal, ocular, and uterine secretions. Sus-
ceptible animals can acquire the virus by inhalation, ingestion
or when bred with contaminated semen. Cows may also
become infected from contaminated embryo transfer fluids
where serum from carrier animals is used. Cytopathic BVDV
is derived from mutations of ncp-BVDV. The ncp biotype may
persistently infect the immunologically incapable fetus. There is
no report of a cytopathic biotype being isolated from an
infected animal without the noncytopathic biotype also being
present; the cp form has no means of maintaining itself in the
population of animals without the ncp form.
 425.e1

Further reading
Choi C, Chae C. Localization of classical swine fever virus from chron-
ically infected pigs by in situ hybridization and immunohistochem-
istry. Vet Pathol 2003;40:107-113.
Elbers AR, et al. Assessment of the use of gross lesions at post-mortem
to detect outbreaks of classical swine fever. Vet Microbiol
2003;96:345-356.
Gomez-Villamandos JC, et al. African swine fever and classical swine
fever: a review of the pathogenesis. Dtsch Tierarztl Wochenschr
2003;110:165-169.
Penrith ML, et al. Classical swine fever (hog cholera): review of aspects
relevant to control. Transbound Emerg Dis 2011;58:187-196.
426 CHAPTER 4  •  Female Genital System
Reproductive disease in cattle induced by BVDV includes
oophoritis, fertilization failure, embryonic death, absorption or
abortion, mummification, stillbirth, birth of calves small for ges-
tational age or with congenital defects, and weak calves or near–
normal-looking calves born PI with ncp-BVDV. Abortion storms
can occur, and occasionally severe losses resulting from BVDV
may follow superovulation and embryo transfer. This may be
related to the creation of a population of fetuses of the same
gestational age (and therefore equally susceptible to the infec-
tion) or contamination of transfer fluids by BVDV. Present
evidence suggests that ncp-BVDV infects the bovine fetus
following oronasal exposure of the dam and only causes
embryo injury when it mutates to the cp form of fetal
infection.
Fertilization failure may occur when the virus is introduced
in utero to seronegative cows. Conception and pregnancy rates
in animals viremic at or shortly after insemination were
approximately half of noninfected controls at gestation day
77. Surviving embryos were not infected. These data strongly
support BVDV infection as being detrimental to early embryo
development. Acutely infected bulls shed the virus in their
semen for at least 14 days and may have abnormal semen for
several months. Spread of the virus is more likely to occur
with natural service than with artificial insemination. Carrier
and newly infected cows infect the fetus through the
placenta.
In the period from 45 to 125 days gestation, the ncp
biotype will probably not cause fetal loss, but if it changes to
the cp form, it may result in intrauterine growth retardation.
Only the ncp biotype can cause persistent infection. If born
alive, these PI animals constitute the main source of virus for
other animals. CNS malformations follow infections with
BVDV between 80 and 150 days of gestation. This is probably
associated with the stepwise development of immune capabil-
ity in the fetus, along with the corresponding gradual develop-
ment of its nervous system. Abnormalities attributed to BVDV
include microencephaly, cerebellar hypoplasia, hydranenceph-
aly, secondary hydrocephalus, hypomyelinogenesis, myelina-
tion defects, microphthalmia, cataracts, retinal degeneration,
optic neuritis, brachygnathism, thymic aplasia, hypotrichosis,
alopecia, pulmonary hypoplasia, and growth retardation with
growth-arrest lines in long bones. Porencephaly, hydranen-
cephaly, and secondary hydrocephalus have been described,
but the association with BVDV is less clearly documented. It
is believed by some that only the cp biotype causes abnormali-
ties. Cerebellar hypoplasia may be inapparent or severe.
Normal and severely affected folia may be adjacent. Early
lesions consist mainly of edema, hemorrhage, and necrosis of
external germinal cells. Remnants of severely affected folia
consist of fluid-filled cavities lined by flattened astrocytes sur-
rounded by a thin layer of neuropil containing many
hemosiderin-laden macrophages. Some folia have only reduced
myelin content. Purkinje cells may be reduced in number and
with a disorderly or absent external germinal cell layer. Peri-
vascular mononuclear cells and a few neutrophils may be
present in neural parenchyma and meninges in cerebrum and
cerebellum. Spongiform alterations of brainstem white matter
have been recorded, along with spongiform alteration and
liquefactive necrosis of ventral funicular white matter in the
spinal cord. Focal malacia of the ventral horns occurs follow-
ing degeneration of ventral horn neurons along with glial satel-
litosis. Cataracts and retinal atrophy may be present in the
eye, and the latter is presumed to follow focal-to-diffuse
Abortion and Stillbirth
necrotizing, nonsuppurative retinitis and usually accompanies
the cerebellar lesions. Microphthalmia and optic neuritis with
subsequent atrophy also occur.
Other lesions associated with BVDV infections in the fetus
include thymic cortical atrophy (with only epithelial stroma
and macrophages persisting in the cortex), multifocal myocar-
ditis, peribronchiolar lymphoid hyperplasia, pulmonary hypo-
plasia, multifocal perivascular dermatitis, and hypotrichosis.
Cellular accumulations are usually mononuclear, lymphocytic,
and plasma cell rich. Plasmablasts, plasma cells, and lympho-
blasts may be prominent in lymphoid tissues.
Antibody in fetal fluids, culture of virus from fluid and
tissues, and PCR-based tests are sensitive methods to deter-
mine if fetal infection has occurred. The presence of specific
antibody in an aborted fetus only indicates the fetus was
infected in utero. Fluorescent antibody and immunohisto-
chemical detection of virus are frequently used to indicate the
association of the virus with a lesion.
Naturally occurring BVDV infections in pregnant sows and
goats have been reported to pass to the fetus, causing stillbirth
and neonatal death similar to chronic swine fever and border
disease. Piglets infected in utero can either carry the virus
(without antibody), develop antibody later, or become clini-
cally affected and develop intestinal lesions, depending on the
stage of gestation when infection occurs. On postmortem,
infected piglets may also have nonsuppurative meningitis and
choroiditis. Swine fetuses dying early in gestation from in
utero infections with BVDV may also be absorbed.
Further reading
Byers SR, et al. The effects of exposure of susceptible alpacas to alpacas
persistently infected with bovine viral diarrhea virus. Can Vet J
2011;52:263-271.
Lanyon SR, et al. Bovine viral diarrhoea: pathogenesis and diagnosis.
Vet J 2014;199:201-209.
Webb BT, et al. Effects of in utero pestivirus infection on bovine fetal
bone geometry, biomechanical properties and composition. Vet J
2013;198:376-381.
Border disease virus infection in sheep and goats
Species Border disease virus (BDV), Classical swine fever virus
(CSFV), and Bovine viral diarrhea virus (BVDV) are in the
family Flaviviridae, genus Pestivirus. All are related antigeni-
cally and cause significant disease in animals. BDV and BVDV
are closely related, whereas CSFV is distinct. Some strains of
BDV appear to be more closely related to certain strains of
BVDV than to other strains of BDV, whereas others cannot
be differentiated from each other. BDV, BVDV, and CSFV
have been shown to cross infect between species, and this may
occur naturally. Border disease is the result of in utero infec-
tion of pregnant sheep or goats by BDV; prevalence of BDV
is variable in sheep and rare in goats. Infection can result in
embryonic or fetal death, abortion, mummification, dysmorpho-
genesis, early postnatal death, and birth of weak or clinically
normal young. Clinically normal kids or lambs can be persis-
tently infected (PI). Infection in the nonpregnant adult animal
may result in fever and leukopenia, but clinical signs are
usually absent.
Transmission of BDV is believed to occur mainly between
sheep; however, natural and experimental infections of
BVDV from cattle to sheep have been reported and can
 426.e1

Further reading
Harding MJ, et al. Role of bovine viral diarrhea virus biotype in the
establishment of fetal infections. Am J Vet Res 2002;63:1455-1463.
Kelling CL, Topliff CL. Bovine maternal, fetal and neonatal responses
to bovine viral diarrhea virus infections. Biologicals 2013;41:20-25.
Porter BF, et al. Hypomyelination associated with bovine viral diarrhea
virus type 2 infection in a longhorn calf. Vet Pathol 2010;47:658-
663.
Terpstra C, Wensvoort G. A congenital persistent infection of bovine
virus diarrhoea virus in pigs: clinical, virological and immunological
observations. Vet Q 1997;19:97-101.
Pathology of the Genital System of the Nongravid Female
cause BDV-like outbreaks. BDV can be transmitted by oral,
conjunctival, intranasal, and genital routes. As congenitally
infected sheep can have lifelong viremia, they are probably the
main reservoir for the virus. PI ewes can transmit the virus to
their fetus through the placenta (over several pregnancies),
and in rams, the virus has been observed in the seminiferous
tubules of the testes and can be transmitted in the semen.
BDV has been demonstrated in the germinal cells of the
ovaries of sheep; the significance of this site in the transmission
of the virus is not known.
A wide variety of fetal tissues are affected by BDV infec-
tion, and the name hairy shaker was coined because of the
frequently observed hairy appearance of the wool and the
tremor associated with hypomyelinogenesis. Abnormalities
induced in the fetus, as in cattle, depend mainly on the stage
of gestation and reflect the stepwise development of fetal
immunocompetence to the virus. Strains of the virus also vary
in virulence, as does the susceptibility of breeds of sheep to
the effects of the agent. As the ovine and caprine fetus
becomes immunocompetent to BDV by about 90 days, most
injury follows infections occurring before this time.
CNS lesions include hypoplasia and dysplasia of the cere-
bellum, microcephaly, porencephaly, hydranencephaly, leuko-
encephalomalacia, and reduced weight and length of the
spinal cord. The most consistent lesion is dysmyelination or
hypomyelination, which usually occurs without signs of
inflammation.
The mechanisms responsible for hypomyelination have not
been completely defined. It has been suggested that BDV has
a specific affinity for oligodendrocytes; however, evidence sup-
porting this is lacking. There is strong evidence that the hypo-
myelination seen in the brain and spinal cord in BD may be
due to lowered activity of oligodendrocytes with subnormal
thyroxine production. In the tested lambs with BDV, there
were significantly decreased concentrations of serum triiodo-
thyronine and thyroxine, and many of the thyroid follicle cells
contained BDV. As in many other tissues occupied by BDV
in PI animals, little cell death or associated inflammation was
present. Further support for the hormonal theory of hypomy-
elinogenesis came on finding significantly lower concentra-
tions of the thyroid hormone–dependent enzyme 2′,3′-cyclic
nucleotide-3′-phosphodiesterase (CNP) in oligodendrocytes
from affected animals. CNP is normally found in oligodendro-
cytes, and its activity, which is dependent on the presence of
both thyroxine and growth hormone, increases with myelina-
tion. Work in congenitally hypothyroid mice and thyroidecto-
mized rats has shown that growth hormone and thyroxine are
necessary for normal myelination of nerve fibers.
Abnormalities in the fleece are commonly seen in fetuses
following in utero infections with BDV. In smooth-coated
ewes and nannies infected between 50 and 85 days of gesta-
tion, the fleece of the fetus may become hairlike and curly.
The hairiness is associated with enlargement of primary fol-
licles, increased size of fiber, increased proportion of fibers
with a central medulla, and increased diameter of the medulla.
Around 90 days of gestation, animals become immunocom-
petent to the virus, and infection at that time may result in
only a diminished number of secondary follicles. The reduc-
tion has been suggested to be the result of reduced fetal
nutrition because of placentitis. In pigmented breeds, there
may be large patches of abnormally pigmented black or brown
fleece, especially along the neck. Exactly why these changes
are induced has not been determined. However, using
Abortion and Stillbirth 427
immunofluorescence, BDV antigen has been demonstrated in
skin follicles of fetuses infected at 45 days of gestation, starting
at 40 days postinoculation and continuing in lambs up to 5
months of age.
Intrauterine growth retardation commonly occurs with BDV
infection in goats and sheep and was reported to be of similar
degree to that seen in fetal starvation, cardiac anomalies, and
placentitis, except for lung and brain, which were more
severely affected. Growth-arrest lines (unmodelled metaphy-
seal trabeculae) are commonly observed in the long bones of
BDV-infected fetuses and lambs. Arthrogryposis and kypho-
scoliosis occur infrequently in conjunction with hydranen-
cephaly, cerebellar dysmorphogenesis, and hypoplasia in
BDV-infected fetuses.
BDV infection in sheep and goats causes placentitis and
endometritis that are particularly evident when infection
occurs during the first trimester of gestation. Early in the
infection, multiple white 1-2 mm foci of necrosis appear in
the caruncles at the base of the crypts. These may fuse into a
continuous band of necrosis, which may become mineralized
and infiltrated with connective tissue and a few macrophages,
or the entire base of the caruncle may be infarcted, necrotic,
and infiltrated with neutrophils. The lesion is believed to be
associated with endothelial swelling and thrombosis of capil-
laries in the endometrium and adjacent caruncle. The tropho-
blast does not usually undergo necrosis but may atrophy.
Definitive diagnostic tests can be selected with confidence
when several kids or lambs show typical signs of BDV infec-
tion. However, diagnosis may be difficult when BDV occurs
only as reproductive failure with embryo or fetal death, fol-
lowed by absorption, abortion, or mummification. Frequently
in goats, abortion may be the principal sign. In aborted fetuses
with congenital abnormalities, diagnosis requires the detection
of the virus, virus-specific antigens, fetal antibodies against the
virus, or PCR-based tests in or of cavity fluids. The cotyledons,
or preferably the caruncles, are the best source of virus. It is
variably recovered from aborted fetuses and almost never
from those that are mummified. Although isolates are usually
noncytopathic, viral antigen can be demonstrated by direct or
indirect immunofluorescence, and immunohistochemistry of
selected tissues from affected lambs or the caruncle following
abortion.
Sheep have been reported to retain BVDV in the uterus
from one estrus to the next and to produce PI offspring when
naturally bred or artificially inseminated by semen collected
from PI rams.
Further reading
Nettleton PF, et al. Border disease of sheep and goats. Vet Res
1998;29:327-340.
Toplu N, et al. Neuropathologic study of border disease virus in natu-
rally infected fetal and neonatal small ruminants and its association
with apoptosis. Vet Pathol 2011;48:576-583.
Equine arteritis virus infection of the pregnant
uterus in mares
Equine viral arteritis (EVA) is a disease of horses caused by
species Equine arteritis virus (EAV), a positive-stranded RNA
virus, family Arteriviridae, genus Arterivirus. Genetic diversity
of the virus is generated in the course of persistent infection
of the carrier stallion, and the genetic changes that maintain
 427.e1

Further reading
Pratelli A, et al. Genomic characterization of pestiviruses isolated from
lambs and kids in southern Italy. J Virol Methods 2001;94:81-85.
Thur B, et al. Immunohistochemical diagnosis of pestivirus infection
associated with bovine and ovine abortion and perinatal death. Am
J Vet Res 1997;58:1371-1375.
428 CHAPTER 4  •  Female Genital System
EVA in the stallion’s reproductive tract likely affect pheno-
typic properties of the virus, such as virulence. Strains of the
virus vary greatly in virulence. Consequences of infection
range from subclinical to mild fever; ocular and nasal dis-
charges; edema around the eyes, legs, and scrotum; skin rash;
and, in severe forms, diarrhea, respiratory distress, and rarely
death. Embryonic death and resorption rates are permanently
increased, and 40-80% of pregnant animals abort or deliver a
stillborn foal. Abortion usually occurs 1-4 weeks after the
onset of fever and is probably the most grievous manifestation
of the disease, although in some outbreaks, severe interstitial
pneumonia and necrotizing enteritis may occur in foals.
The virus is spread by aerosolization of respiratory secre-
tions among closely associated animals. Stallions are probably
the most important means of spread, as they shed the organism
in semen for a short or very long period, even for life, and
transmit the disease sexually. There are minimal consequences
of sexually acquired infection, with little effects on conception
rate, unless a mare is infected in the late stages of gestation,
in which case she may abort. Stallions that are shedding the
organism should not be used for breeding unless they are bred
to seropositive mares that have received the organism from
either vaccination or natural infection. In contrast, although
mares may spread the virus during their illness or shortly after,
they generally do not remain carriers, and after recovery,
neither mares nor stallions shed the virus in nasal passage
secretions, urine, or blood. Most horses develop long-term
immunity to EAV after natural infection of the virus.
Aborted fetuses are usually well preserved, but gross and
microscopic lesions are rarely observed as the virus seldom pro-
duces active infection in the fetus. In foals surviving for more
than 24 hours, fever, leukopenia, and/or thrombocytopenia are
sometimes observed. Widespread inflammatory lesions in sec-
tions of the brain, liver, and spleen have been recorded. On
microscopic examination, findings include interstitial pneu-
monia, lymphocytic periarteritis with fibrinoid necrosis of the
tunica media, and renal tubular necrosis. Moderate arteritis
with necrosis and mononuclear cell myocarditis has been
reported of a few fetuses. In the uterus of the mare, however,
there may be acute multifocal necrotizing myometritis and
replication of the virus in smooth muscle cells. Uterine infec-
tion might be the critical process contributing to abortion.
In the live mare and stallion during the early stages of
disease, the presence of EAV may be determined by culture
or PCR assay of swabs taken from nasopharynx and conjunc-
tiva, from white blood cells, or from semen. The virus may be
recovered from semen or revealed by breeding unexposed
mares, which may then develop a fever or become clinically
ill. Serologic tests are available to detect previously infected
animals. Samples for culture from the conceptus should
include placenta, lung, and spleen. Diagnosis can also be
obtained by immunohistochemistry, virus isolation, and PCR-
based tests.
Further reading
Balasuriya UB, et al. Equine arteritis virus. Vet Microbiol 2013;167:93-
122.
Holyoak GR, et al. Equine viral arteritis: current status and prevention.
Theriogenol 2008;70:403-414.
Snijder EJ, et al. Arterivirus molecular biology and pathogenesis. J Gen
Virol 2013;94:2141-2163.
Abortion and Stillbirth
Wesselsbron virus infection of the pregnant uterus
in sheep and cattle
Species Wesselsbron virus (WESSV) is in the family Flaviviri-
dae, genus Flavivirus, in the yellow fever virus group. It is
spread primarily by mosquitoes. Infection is often fatal in the
ovine and bovine fetus, in newborn lambs, and pregnant sheep.
It may also produce congenital anomalies in bovine and ovine
fetuses. Human illness is not fatal and is characterized by fever,
chills, muscle pain, hyperesthesia, and a skin rash. Information
is largely incomplete with regard to the pathogenesis and
pathology of this infection in pregnant animals.
The disease is widespread in the southern and western parts
of Africa in sheep and cattle; however, in spite of a high preva-
lence and high annual infection rate, mortality is low. In a
naïve flock of sheep, however, mortality in newborn lambs and
pregnant ewes may be high. Pregnant ewes may die before or
after abortion, whereas nonpregnant ewes, wethers, and year-
lings usually show no signs of illness. Changes in the liver
caused by WESSV infection may precipitate acute copper toxicity,
thereby inflating the perceived mortality directly caused by
this virus.
Pregnant sheep infected with WESSV develop a fever asso-
ciated with initial viremia and often abort at this stage because
of the systemic effects of the virus on the dam. Under these
circumstances, neither virus nor antibody is detected in the
fetus. If the ewe does not abort during the primary viremia,
the virus can invade the placenta and fetus in association with
a second growth phase and result in death of the fetus. The
fetus may be absorbed, mummified, aborted, or carried to
term and be delivered dead. The death rate for lambs infected
in utero approaches 100%, and even those born alive die soon
after. Both wild and attenuated strains of WESSV have been
shown to cause nonsuppurative meningoencephalitis, hydran-
encephaly, arthrogryposis, and hydrops amnii in fetal sheep;
however, this is probably infrequent under field conditions.
In pregnant cattle, WESSV probably only crosses the pla-
centa and infects the fetus in a low percentage of animals,
even in the face of prolonged maternal viremia. When the
virus does infect the fetus, abortion may occur or the calf may
be born weak and die shortly after. These calves have typical
liver lesions and precolostral antibody to WESSV. However,
virus may not be recovered. Many pregnant cows, even after
prolonged viremia, give birth to normal live calves that show
no serologic or virologic evidence of infection. In cattle, as
described in sheep, certain strains of the virus occasionally
produce nonsuppurative meningoencephalomyelitis, poren-
cephaly, and cerebellar hypoplasia in the fetus.
Gross and microscopic descriptions of findings in aborted
fetuses, or stillborn lambs and calves, are limited. Experimen-
tally infected newborn lambs have a slight to moderately
enlarged, yellow to orange, variably congested liver. On micro-
scopic examination, hepatocyte necrosis is slight to extensive,
but is usually single cell and generalized. Eosinophilic, intra-
nuclear inclusion bodies of various shapes are frequently present.
Separated, individual hepatocytes may be round, shrunken,
and have intensely pink-staining cytoplasm and nuclear lysis
(Councilman-like bodies). Kupffer cell hyperplasia is promi-
nent, particularly in the central vein region, and Kupffer cells
filled with yellow or pink granular material often bulge into
sinusoids. The sinusoids also contain large numbers of mono-
nuclear cells and degenerating neutrophils. Bile ducts and
canaliculi are frequently distended with bile. In portal areas,
there is bile duct hyperplasia, moderate numbers of
 428.e1

Further reading
Del Piero F. Equine viral arteritis. Vet Pathol 2000;37:287-296.
Eichhorn W, et al. Equine viral arteritis with abortions: serological and
virological evidence in Germany. J Vet Med Ser B 1995;42:
573-576.
Pathology of the Genital System of the Nongravid Female
macrophages, and some neutrophils and plasma cells. There
are petechial and ecchymotic hemorrhages on the mucosal
surface of the abomasum, and the content is dark brown.
Other nonspecific lesions, consistent with a viremia, are also
described.
The diagnosis of WESSV infection in pregnant animals is
based on clinical findings, histology, and culture from liver and
brain. The lesions produced by Rift Valley fever virus infection
may easily be confused with Wesselsbron disease, and, although
the liver lesions tend to be different, complications resulting
from precipitation of copper toxicity may make the differen-
tiation difficult.
Further reading
Ali H, et al. Common, emerging, vector-borne and infrequent aborto-
genic virus infections of cattle. Transbound Emerg Dis 2012;
59:11-25.
Porcine parvovirus infection of
the pregnant uterus
Species Porcine parvovirus (PPV), family Parvoviridae, subfam-
ily Parvovirinae, genus Parvovirus, is an important and common
cause of reproductive failure in pigs, and manifests as embry-
onic death with reabsorption, mummification, stillbirths, and
reduced litter size. Farrow-to-finish farms are affected nearly
twice as often as feeder pig farms, probably because of the
maintenance of a continual reservoir of PPV in the finishing
pigs. The virus is most commonly spread by the ingestion of
contaminated feces and will adhere to the zona pellucida of
embryos. Viremia develops in susceptible pigs, and in pregnant
pigs the virus enters the placenta and passes to the embryo or
fetus 23-32 days following oral inoculation. Up to a fetal age
of 70 days, the virus may cause death of the embryo (with
absorption) or fetus (with mummification); however, the
porcine fetus becomes increasingly resistant to the effects of
the virus after 36 days and is immunocompetent by about 70
days. Death of the fetus may be due to the total effect of the
virus on rapidly dividing cells, including neurons and capillary
endothelium of the cortical laminae in cerebellum and cere-
brum, and in cells in the lung, liver, pancreas, and chorioal-
lantois. Movement of virus from one fetus to another may be
affected by development of maternal antibody, increasing
resistance of fetuses with advancing age, and the variability of
the circulation and contact between the placental membranes
of adjacent fetuses.
When PPV is introduced by the uterine route, it causes
inflammation in the ovaries and degeneration of uterine epi-
thelium, both of which may contribute to reproductive failure
but do not otherwise cause clinical signs. Uterine changes may
include marked variation in surface epithelial cell height, epi-
thelial cell basophilia, degeneration, and ulceration. Light infil-
tration of neutrophils, eosinophils, and lymphocytes may be
present throughout the endometrium. Corpora lutea contain
foci of mononuclear cells, many of which are lymphoplasma-
cytic. In the fetus, lesions are most commonly observed in older
fetuses and may be present in kidney, liver, brain, and placenta.
In the cerebrum, which is the most dependable site, perive-
nous accumulations of plasma cells and other mononuclear
cells occur in white and gray matter and in meninges. Similar
accumulations are observed in the renal interstitium, hepatic
portal regions, and in the chorioallantois.
Abortion and Stillbirth 429
For diagnosis, viral antigen is demonstrable by the fluores-
cent antibody test in affected tissues of embryos and mum-
mified and stillborn fetuses, and a highly sensitive DNA probe,
specific for PPV-infected cells, is available. Identification of
specific antibody, particularly IgM, in fetal fluids indicates fetal
infection, and with other appropriate findings, it is supportive
evidence for the cause of reproductive failure. When the only
manifestations are small litters or pigs that recycle, the causal
relationship of these signs with PPV is difficult to establish,
and knowledge of titers of antibody against PPV in the gilt or
sow before and after the event may be the only incriminating
evidence. Various tests, including an ELISA, have been devel-
oped for this purpose.
Further reading
Krakowka S, et al. Viral wasting syndrome of swine: experimental
reproduction of postweaning multisystemic wasting syndrome in
gnotobiotic swine by coinfection with porcine circovirus 2 and
porcine parvovirus. Vet Pathol 2000;37:254-263.
Wolf VH, et al. Molecular basis for porcine parvovirus detection in dead
fetuses. Genet Mol Res 2008;7:509-517.
Bovine parvovirus infection of the pregnant
uterus in cattle
Species bovine parvovirus (BPV), family Parvoviridae, subfam-
ily Parvovirinae, genus Bocavirus. It is widely distributed in
cattle populations throughout the world. It is reported to cause
enteritis and diarrhea in young calves and abortion and birth of
weak calves when infections occur in naïve pregnant cows.
The organism is not considered a major cause of abortion, but
this may be because it is not looked for consistently in submis-
sions. Anywhere from 10-100% of the cattle in a population
will have antibody to parvovirus, and work in the United
States suggests that when reproductive problems, including
repeat breeding, embryonic mortality, and abortion, are con-
sidered, animals with antibody to BPV had about 3 times as
many of these problems as compared to control seronegative
animals.
BPV is excreted in the feces of affected and normal animals,
and the oral route is important in transmission. Inoculation of
parvovirus into pregnant cows can cause in utero fetal death
and abortion in the early stages of gestation. Some calves
may be born with cerebellar hypoplasia because of lysis associ-
ated with the multiplication of BPV in cells of the external
granular layer. Cerebellar hypoplasia is believed to follow
infection occurring in the period of rapid cell multiplication
(107-150 days of gestation) in the cerebellum. Intranuclear
inclusions are seen in external granular cells, hepatocytes,
adrenal cortical cells, and intestinal crypt cells associated with
areas of necrosis. Bovine fetuses are capable of forming IgM
antibody to the virus by 93 days of gestation; infections in the
third trimester usually only result in antibody formation with
no abortion.
For diagnosis, BPV may be recovered in a variety of
tissues, including placenta, amniotic fluid, adrenal glands, and
liver. When infection occurs in midgestation, detection of spe-
cific antibody in fetal serum may be used as putative evidence
of the cause of abortion. The presence of antibody may inter-
fere with recovery of the virus but probably will not com-
pletely prevent isolation, as the virus is frequently cell
associated.
 429.e1

Further reading
Hubalek Z, et al. Arboviruses pathogenic for domestic and wild animals.
Adv Virus Res 2014;89:201-275.
Mushi EZ, et al. Wesselsbron disease virus associated with abortions in
goats in Botswana. J Vet Diagn Invest 1998;10:191.
429.e2

Further reading
Mengeling WL, et al. The effect of porcine parvovirus and porcine
reproductive and respiratory syndrome virus on porcine reproduc-
tive performance. Anim Reprod Sci 2000;60-61:199-210.
430 CHAPTER 4  •  Female Genital System
Further reading
Kirkbride CA. Viral agents and associated lesions detected in a 10-year
study of bovine abortions and stillbirths. J Vet Diagn Invest
1992;4:374-379.
Manteufel J, Truyen U. Animal bocaviruses: a brief review. Intervirol
2008;51:328-334.
Canine minute virus infection
Species Canine minute virus (CnMV) is a species distinct from
Canine parvovirus 2 and Feline panleukopenia virus in the
family Parvoviridae, subfamily Parvovirinae, genus Bocavirus,
and antibody to it is widespread among dogs. It may occasion-
ally cause mild diarrhea in pups, but its significance is poorly
defined. Experimental oral-nasal infection is clinically inap-
parent, but it may produce inclusion bodies in the cells of the
duodenal villi. Transient lymphocytolysis in the cortex of
lymph nodes, thymus, and in gut-associated lymphoid tissue
has been reported.
The virus seems capable of transplacental transmission
to the fetus, and exposure of pregnant dogs has been associ-
ated with fetal resorption or birth of dead or weak pups,
depending on gestational stage at exposure. Anasarca and
myocarditis are reported in dead or weak puppies. Spontane-
ous reproductive failure associated with CnMV is not
reported.
The pathogenesis of CnMV and its clinical significance are
not yet known, but preliminary findings suggest it may be
responsible for a portion of deaths in pups <4 weeks of age,
and it may cause reproductive failure. Virus isolation is diffi-
cult, possibly because of antibodies in infected dams at the
time they resorb their fetuses; however, histologic examina-
tion of tissues from dead pups may reveal viral inclusion
bodies in small intestinal villus epithelial cells or bronchial
epithelial cells. Much more information is necessary to ascer-
tain the role of this virus in canine disease. Reports of deaths
and abortions suggest it is more common than currently
recognized.
Diagnosis can be confirmed by virus isolation, PCR, immu-
nofluorescence, or immunohistochemistry.
Further reading
Carmichael LE, et al. Pathogenicity of minute virus of canines (MVC)
for the canine fetus. Cornell Vet 1991;81:151-171.
Manteufel J, Truyen U. Animal bocaviruses: a brief review. Intervirol
2008;51:328-334.
Bluetongue virus infections of pregnant sheep
and cattle
Species Bluetongue virus (BTV), family Reoviridae, the proto-
type virus for the genus Orbivirus, causes a nearly worldwide
viral infection of sheep and other ruminants. The virus distri-
bution is expanding with expansion of the range of insect
vectors. In sheep and, with much less severity and frequency
in cattle, the disease is characterized by fever, erosive to ulcer-
ative lesions of the upper gastrointestinal mucosa, and focal
hemorrhage and necrosis of smooth, skeletal, and cardiac
muscles. BTV infections can be fatal, and in cattle, most infec-
tions are subclinical. Infections occurring during pregnancy,
however, can cause heavy losses because of early in utero death
Abortion and Stillbirth
and absorption, abortion, mummification, or stillbirth with severe
fetal growth retardation and multiple congenital anomalies.
There are several serotypes of BTV, and they vary greatly
in virulence. The virus is mainly spread by, and can multiply
in, various species of biting insects in the genus Culicoides.
With many serotypes of BTV, viremia exists for a longer
period in cattle than in sheep, and in both, antibody and virus
may coexist for several days. The prolonged viremia seen in
cattle has led some investigators to designate them as the
reservoir host for this virus. The virus has been found in the
semen of a few bulls; however, it is usually transient
and therefore of less importance than arthropods in
transmission.
When an animal becomes infected, primary virus replica-
tion occurs in the lymph nodes draining the site of inoculation.
This is followed by extension through the lymphatics and
bloodstream to the spleen and lymph nodes, where the virus
propagates and is carried via the blood to a variety of tissues.
The organism appears to be closely associated with erythro-
cytes during viremia. Species-specific differences in the pro-
duction and activities of endothelial cell-derived inflammatory
and vasoactive mediators appear to contribute to the greater
sensitivity of sheep than cattle to BTV-induced microvascular
injury.
The consequences of infection during pregnancy depend
on the stage of gestation when infection occurs and on the
serotype of virus. Infections in sheep up to approximately 50
days of pregnancy may result in death of the conceptus and
absorption or abortion. Between 50 and 80 days of gestation,
necrotizing encephalopathy occurs; and in the last third of gesta-
tion, as immunocompetence increases, there may be no
obvious disease. On the other hand, infections of near-term
and newborn lambs can result in a sluggish immune response,
possibly associated with the rise in fetal cortisol at parturition
and the ingestion of colostrum, both of which may suppress
the active immune response.
Lesions in the brain of the ovine fetus infected during the
50-70 day period consist of many mononuclear cells in the
meninges and necrosis of the cerebral cortex. The meninges
and areas of necrosis gradually become filled with macro-
phages and, unless the fetus is expelled early, appear as
variably sized fluid-filled cavities (porencephaly and hydran-
encephaly), frequently accompanied by some degree of sec-
ondary hydrocephalus in the new or stillborn lamb. Cerebellar
dysgenesis, retarded development, and skeletal growth-
retardation lines have also been described in fetuses inocu-
lated with BTV. The lungs in fetuses inoculated with virus at
80-100 days become infiltrated with large mononuclear cells
within the interstitium of small arterioles. These accumula-
tions eventually form continuous overlapping nodules of large
mononuclear cells that have abundant cytoplasm and indented
nuclei. Similar lesions are occasionally seen in the renal
medulla and hepatic portal areas. Cortical regions of lymph
nodes are enlarged by large numbers of primary and secondary
lymphoid follicles that contain numerous plasma cells. In the
spleen, small white nodules are visible on the cut surface.
These consist of greatly expanded periarteriolar lymphoid
tissue.
Lesions in the bovine fetus develop similarly, and up to 70
days of gestation, BTV infection may result in in utero death
and absorption or abortion of the conceptus. Between 70 and
130 days of gestation, serotypes 10, 11, 13, and 17 can cause
hydranencephaly and death of the fetus. Two distinct
 430.e1

Further reading
Liggitt HD, et al. Immunologic responses of the bovine fetus to parvo-
virus infection. Am J Vet Res 1982;43:1355-1359.
Storz J, et al. Parvovirus infection of the bovine fetus: distribution of
infection, antibody response, and age-related susceptibility. Am J
Vet Res 1978;39:1099-1102.
430.e2

Further reading
Decaro N, et al. Molecular characterization of canine minute virus
associated with neonatal mortality in a litter of Jack Russell terrier
dogs. J Vet Diagn Invest 2012;24:755-758.
Schwartz D, et al. The canine minute virus (minute virus of canines) is
a distinct parvovirus that is most similar to bovine parvovirus. Virol
2002;302:219-223.
Pathology of the Genital System of the Nongravid Female
processes may be involved in the development of CNS lesions
caused by BTV infections in bovine fetuses: Infarction, from
viral-induced vascular injury, is probably responsible for the
large areas of necrosis and cavitation occurring in the rostral
regions of the cerebrum, whereas viral destruction of clusters
of individual cells, including glial cell precursors, results in foci
of necrosis and accounts for microcavitation. Collapse of these
cavities may facilitate dilation of the lateral ventricles and
secondary hydrocephalus. Death of calves with hydranen-
cephaly pre-empts them spreading the virus by an arthropod
vector, even if they are viremic. The earliest evidence of anti-
body activity against BTV group antigen in bovine fetuses
occurs at around 145 days of gestation; by 200 days, there is
significant neutralizing antibody activity; therefore no virus is
detectable at birth.
Diagnosis of in utero infections in cattle and sheep is based
on finding the typical lesions and specific fetal antibody to
BTV in cavity fluid or blood. Virus isolation after fetal immu-
nocompetence to BTV is unlikely but not invariable. Maternal
precipitating antibody (agar gel immunodiffusion test) may
be absent at term, whereas neutralizing antibody may be more
persistent. The c-ELISA for specific neutralizing antibody is
more specific and sensitive. To culture the virus from blood,
animal inoculation or washed erythrocytes may need to be
used because the organism is closely associated with red cells.
BTV and epizootic hemorrhagic disease virus (EHDV) can be
detected and differentiated by multiplex RT-PCR.
Epizootic hemorrhagic disease virus infection of
the pregnant uterus in cattle, sheep, and
white-tailed deer
Species Epizootic hemorrhagic disease virus (EHDV) is an
arthropod-borne virus in the family Reoviridae, genus Orbivi-
rus. It exists as at least 2 serotypes, 1 and 2, and is present in
Africa, Australia, North America, and Japan. Ibaraki virus
(IBAV), first isolated in Japan, is a serotype 2 strain. EHDV is
spread by Culicoides spp. and causes fatal hemorrhagic disease
of white-tailed deer. In cattle, the Ibaraki strain can cause severe
ulceration of the mucosa of the mouth, tongue, and esophagus,
with necrosis of esophageal musculature and marked pain on
swallowing. Many animals die. In many respects the disease is
similar to BTV infection in sheep, but, in contrast to BTV,
EHDV has very low pathogenicity for sheep. Although EHDV
cross reacts with BTV in some serologic tests, it is considered
to represent a separate population of viruses. Experimental
inoculation of BTV has been reported to cause abortion and
mummification in white-tailed deer. EHDV, particularly the
IBAV strain, can cause abortion and stillbirths in cattle.
Further reading
Coetzee P, et al. A review of experimental infections with bluetongue
virus in the mammalian host. Virus Res 2014;182:21-34.
Dubovi EJ, et al. Isolation of bluetongue virus from canine abortions.
J Vet Diagn Invest 2013;25:490-492.
Maclachlan NJ, et al. The pathology and pathogenesis of bluetongue.
J Comp Pathol 2009;141:1-16.
Chuzan disease of cattle
Species Chuzan virus (CHUV, syn. Palyam virus) has been
isolated from cattle and the midge Culicoides oxystoma. The
virus is in the family Reoviridae, genus Orbivirus, Palyam
Abortion and Stillbirth 431
serogroup, and is most closely related to African horsesickness
virus within the orbiviruses. CHUV has been incriminated as
the cause of an epizootic in the Kyushu district of Japan,
wherein 2,463 calves, mostly beef breeds, were affected. A
high percentage of newborn calves were born with hydranen-
cephaly and cerebellar hypoplasia. A subsequent seroepidemio-
logic investigation revealed evidence to suggest the virus had
been spread from the most southerly island of Japan to the
mainland in the north. Cattle in the region did not have anti-
body to the virus previous to this epizootic.
Calves involved in the epizootic were born alive and were
normal in size and weight. Clinical signs and congenital abnor-
malities included corneal opacity, blindness, nystagmus, cere-
bellar ataxia, tremor, and opisthotonos. Postmortem lesions
included hydranencephaly, secondary hydrocephalus, micro-
cephaly, and cerebellar hypoplasia. No lesions were seen in
other organs, and no virus was isolated from any of the calves;
however, 44 of 49 precolostral serum samples checked for
neutralizing antibody to CHUV were positive. Experimental
infection of 15 cows at 89-150 days of gestation resulted in
14 normal calves and one calf with severe hydranencephaly
and cerebellar hypoplasia.
For diagnosis, CHUV can be recovered from blood for up
to 56 days after inoculation. It is closely associated with red
blood cells, even in the presence of antibody. Demonstration
of specific antibody in the serum of precolostral calves will be
incriminating.
Further reading
Miura Y, et al. Hydranencephaly-cerebellar hypoplasia in a newborn
calf after infection of its dam with Chuzan virus. Nippon Juigaku
Zasshi 1990;52:689-694.
Canine herpesvirus infection in pups
and pregnant bitches
Canine herpesvirus (Canid herpesvirus 1, CaHV-1), family
Herpesviridae, subfamily Alphaherpesvirinae, is in the genus
Varicellovirus. In adults or weaned puppies, CaHV-1 may
produce mild upper respiratory infection, and inapparent
infections are common. Infection of the neonate is possible by
various routes. It may be transmitted from maternal lesions of
genital infection to the pup as it traverses the birth canal, from
initial maternal infection, or by recrudescence of existing
latent virus. Viral recrudescence can be induced in recovered
animals by corticosteroids. There is considerable homology
between endonuclease fragments of CaHV-1 and felid herpes-
virus 1.
Canine herpesvirus infection is regularly fatal for newborn
puppies. Resistance to the disease is sharply age related; pups
exposed after 2 weeks but up to 8 weeks of age will not
develop severe illness. The disease has an incubation period of
3-7 days, after which the affected puppies rapidly sicken and
die, usually within 2 days. The clinical signs lack specificity.
Affected animals are not usually febrile; most vomit and
refuse food. Their breathing becomes shallow and rapid, and
shortly before death, the pups give evidence of abdominal
pain.
At autopsy, there is usually pleural and peritoneal effusion
that may be blood tinged. Petechial and ecchymotic hemorrhages
are scattered throughout the subserosal tissue, usually repre-
senting the most impressive gross feature of the disease. Large
 431.e1

Further reading
Falconi C, et al. BTV infection in wild ruminants, with emphasis on red
deer: a review. Vet Microbiol 2011;151:209-219.
Ohashi S, et al. Identification and PCR-restriction fragment length
polymorphism analysis of a variant of the Ibaraki virus from natu-
rally infected cattle and aborted fetuses in Japan. J Clin Microbiol
1999;37:3800-3803.
Rasmussen LD, et al. Transplacental transmission of field and rescued
strains of BTV-2 and BTV-8 in experimentally infected sheep. Vet
Res 2013;44:75.
van der Sluijs MT, et al. Transplacental transmission of bluetongue virus
serotype 1 and serotype 8 in sheep: virological and pathological
findings. PLoS ONE 2013;8.
Wouda W, et al. Epizootic congenital hydranencephaly and abortion
in cattle due to bluetongue virus serotype 8 in the Netherlands.
Tijdschr Diergeneeskd 2009;134:422-427.
431.e2

Further reading
Yamaguchi R, et al. Encephalopathy in suckling mice infected with
Kasba (Chuzan) virus. J Comp Pathol 1999;120:247-256.
Yamakawa M, Furuuchi S. Expression and antigenic characterization of
the major core protein VP7 of Chuzan virus, a member of the
Palyam serogroup orbiviruses. Vet Microbiol 2001;83:333-341.
432 CHAPTER 4  •  Female Genital System
Figure 4-89  Renal hemorrhages in a newborn pup. This lesion is
very characteristic for canine herpesvirus infection.
Figure 4-90  Photomicrograph of the renal lesion in Figure 4-89
showing necrosis and hemorrhage caused by canine herpesvirus.
Herpesviral infections are typically cytolytic, and microscopic
lesions in fetal tissues of all species are very characteristic and
similar, as shown in Figures 4-91 to 4-94.
hemorrhages are regularly seen in the kidney (Fig. 4-89). The
lungs are wet, and frothy fluid fills the bronchi and bronchi-
oles. Lymph nodes are enlarged and reddened, and spleno-
megaly is present. Tiny red foci, determined microscopically
to be foci of necrosis, are occasionally seen in the liver. Foci of
necrosis are characteristic of the disease and may occur in any
organ. Lung, heart, kidney, intestine, pancreas, adrenal, and
spleen are common sites (Fig. 4-90). The inflammatory
response associated with these disseminated focal areas of
necrosis is slight or absent. Viral inclusion bodies are not
numerous, but can best be seen adjacent to the areas of necro-
sis in the liver or lung, or in the kidney. The inclusion bodies
are intranuclear; most are basophilic, but some are faintly
acidophilic.
Discrete microscopic lesions are present in the brains of
the pup as early as 72 hours after experimental infection.
These increase in severity as the disease progresses. They
consist of nonsuppurative meningoencephalomyelitis, with
destruction of gray and white matter; the gray matter is
Abortion and Stillbirth
somewhat more severely involved. There are focal and seg-
mental areas of destruction of the cerebral cortices with con-
current microgliosis. Vascular changes vary from endothelial
swelling to mononuclear cuffing. Diffuse pial meningitis with
infiltrates of mononuclear cells and neutrophils is frequent, as
is ganglioneuritis of the Gasserian ganglia.
Canine herpesvirus can cause abortion, stillbirth, and infertil-
ity. Depending on the time of gestation, inoculation of bitches
with CaHV-1 has been reported to result in death and expul-
sion of fetuses, mummification, or premature delivery of live
puppies. Focal areas of necrosis with intranuclear inclusions
were variably observed in liver, spleen, kidney, placental laby-
rinth, and heart. Endothelium and trophoblast were com-
monly involved. Virus was recovered from many of the
fetuses.
Further reading
Ström Holst B, et al. Canine herpesvirus during pregnancy and non-
pregnant luteal phase. Reprod Domest Anim 2012;47(Suppl.
6):362-365.
Suid herpesvirus 1 infection causing abortion
in swine
Species Suid herpesvirus 1 (SuHV-1, pseudorabies virus,
Aujeszky’s disease virus) is in the family Herpesviridae, sub-
family Alphaherpesvirinae, genus Varicellovirus. SuHV-1 is
capable of causing reduced fertility in boars and sows, fetal
resorption, mummification, abortion, and stillbirth in sows, and
fatal meningoencephalitis in young pigs, sheep, cattle, and
dogs. Strains of SuHV-1 vary in their ability to invade the
placenta and fetus; however, abortion without invasion of the
conceptus may occur secondary to fever and nervous disease
in the sow. When the virus does invade the placenta and fetus,
characteristic gross and microscopic lesions are produced.
There is a strong correlation between the ability of strains to
cause syncytial formation in cell culture and their ability to
produce disease in pigs and cattle.
The disease has an almost worldwide distribution, and the
carrier sow is the most important source of the virus. Recrudes-
cence and shedding through nasal mucus may occur following
stress, and there is some evidence for long-distance airborne
transmission, although this would appear not to be a major
threat. Boars may carry SuHV-1, spreading it through nasal
mucus and semen. The virus can survive in a pen for up to
2 weeks.
The virus enters the nasal passages of the susceptible pig
and passes via the pharyngeal and olfactory nerves to the
brain, where it rapidly spreads to the rest of the brain, causing
nonsuppurative meningoencephalitis. It has affinity for the
respiratory tract, and may induce severe rhinitis, tonsillitis, and
pneumonia.
Abortion usually occurs about 10 days after the onset of
clinical illness in the sow. If the placenta and fetus are invaded,
lesions consist of multifocal coagulative necrosis of chorionic
villi and focal coagulative necrosis in many organs, including
liver, adrenal, and spleen. Intranuclear inclusions have been
observed in trophoblast and interstitial cells and hepatocytes
around areas of necrosis.
Virus may be demonstrated in nasal or vaginal swabs and
fetal tissues by isolation and fluorescent antibody or ELISAs;
PCR assays are also available.
 432.e1

Further reading
Decaro N, et al. Canine adenoviruses and herpesvirus. Vet Clin North
Am Small Anim Pract 2008;38:799-814.
Evermann JF, et al. Canine reproductive, respiratory, and ocular diseases
due to canine herpesvirus. Vet Clin North Am Small Anim Pract
2011;41:1097-1120.
Schulze C, Baumgartner W. Nested polymerase chain reaction and in
situ hybridization for diagnosis of canine herpesvirus infection in
puppies. Vet Pathol 1998;35:209-217.
Pathology of the Genital System of the Nongravid Female
Further reading
Pedersen K, et al. Pseudorabies in feral swine in the United States,
2009-2012. J Wildl Dis 2013;49:709-713.
Shibata I, et al. Experimental dual infection of specific pathogen-free
pigs with porcine reproductive and respiratory syndrome virus and
pseudorabies virus. J Vet Med B Infect Dis Vet Public Health
2003;50:14-19.
Suid herpesvirus 2 (cytomegalovirus) infection of
the pregnant uterus of the pig
Species Suid herpesvirus 2 (SuHV-2, swine cytomegalovirus)
is in the family Herpesviridae, subfamily Betaherpesvirinae,
genus Cytomegalovirus. Infection by this virus is normally con-
fined to pigs and was first described in England in 1955 as
inclusion body rhinitis and, subsequently, as a transplacental
infection of fetal pigs, in 1961 in Australia.
In neonates, SuHV-2 causes mild to severe nonsuppurative
necrotizing rhinitis characterized by the presence of large baso-
philic intranuclear inclusions in the epithelium of the mucous
glands and ducts in the nasal mucosa. The virus usually affects
young pigs (<4 weeks of age) but in naïve herds may cause
death in pigs of 4-12 weeks. The virus occasionally causes
severe systemic disease in mature pigs. When infection occurs
in pregnant sows, they may deliver small litters, mummified
fetuses, or stillborn or weak piglets either before or on the due date.
Pigs infected in utero may be born alive, small for gestational
age, and may develop systemic signs and die. Subsequent
reproductive performance in infected sows may be reduced
and manifested as decreased conception rates and decreased
litter size.
Surveys of pig herds for serum antibody to SuHV-2 indi-
cate infection to be widespread globally. Transmission occurs
when newly infected pigs excrete the virus in nasal and ocular
secretions and urine. Boars may also excrete it in semen and
sows in vaginal discharges. The virus has the capacity to
remain latent in macrophages and other cells of the monocyte-
macrophage system. Animals with latent virus may also
excrete it, even in the face of serum antibody, following
administration of corticosteroid and probably following
periods of stress. Heavy losses are infrequent in commercial
herds; however, in gnotobiotic pigs or minimal-disease herds
in which pigs have had no previous experience with the virus,
the introduction of actively or latently infected animals may
prove disastrous.
When a sow is infected with SuHV-2, multiplication
occurs first in the nasal mucosa. This is followed by viremia
and dissemination of virus to many body organs, including the
placenta in pregnant sows. The virus seems to pass through
the placenta without inducing injury; experimentally, the
virus has not been isolated from the placenta, even when the
fetus that has just died is positive. Neither has antibody been
detected in piglets that become infected in utero. Fetuses die
4-6 weeks after inoculation of the sow, and the time is inde-
pendent of the stage of gestation. Casualties of infection are
scattered randomly throughout the uterus in various stages of
decomposition and mummification, much as with porcine
parvovirus infection. Following experimental infection, no
gross lesions were seen on autopsy of the autolysed fetuses.
However, on microscopic examination there was cytomegaly,
and intranuclear inclusions were observed in liver and lung. In
a natural outbreak of SuHV-2 infection, pigs born alive with
Abortion and Stillbirth 433
a congenital SuHV-2 infection usually died within a week.
Gross lesions in these consisted of pulmonary edema and
congestion, hydrothorax and hydropericardium, and multiple
firm gray foci in the most ventral portions of the lungs. Medi-
astinal lymph nodes were enlarged, and petechial hemor-
rhages were visible on the heart, lungs, intestine, and kidneys.
Histologically, there was pulmonary edema and hemorrhage;
alveolar septa were thickened, mainly by macrophages, but
lymphocytes and neutrophils were also present. Large baso-
philic intranuclear inclusions were present in capillary endo-
thelial cells and macrophages. Similar inclusions were present
in capillaries of the renal medulla and tubular epithelium. Two
types of inclusion have been observed: the usual large baso-
philic type found in pulmonary macrophages and glands and
ducts of the nasal mucosa and renal tubular epithelium, and
a small herpesvirus-like inclusion found mainly in monocyte-
macrophage cells. Nonsuppurative meningoencephalitis has
been reported in some pigs, and the lesions are perivascular
lymphocytic cuffs and gliosis in the choroid plexus and men-
ingeal vessels outside the cerebral cortex.
Experimental infection of piglets in utero or newborns <2
weeks of age have shown them to be very susceptible and to
develop severe debilitating disease, with death a common
sequel. This severe infection has been related to viral infection
in the cells of the monocyte-macrophage system. This results
in disseminated hemorrhage and edema in the lung, kidney,
adrenal, liver, and lymph nodes, all of which is related to viral
destruction of macrophages and capillary endothelial cells. In
the less severe and nonfatal forms of the disease, there is inva-
sion of the mucus-producing cells of the nasal mucosa; the
cells of the renal tubules and, less frequently, the epithelium
of the salivary glands; Harderian and lacrimal glands; seminif-
erous epithelium; epithelium of the epididymal duct; mucous
glands of the esophagus; duodenum; jejunum; and hepato-
cytes. Invasion of macrophages into the endothelium or epi-
thelium is not completely exclusive, and both occur often.
The cytomegalovirus inclusions seen on histology, when cor-
related with appropriate signs, are diagnostic of SuHV-2 infection
in pigs. Infection in a herd may be revealed by detecting anti-
body in the maternal serum by using an indirect immunofluo-
rescent (IIF) antibody test on infected pulmonary macrophages.
To detect virus, samples of nasal mucosa, lung, and kidney
can be cultured directly on pulmonary macrophages. Viral
antigen may be detected in frozen sections of affected lung or
kidney by using the IIF test. As stated previously, the organism
is not found or seen in the placenta, and antibody is not
present in the fetus but may be present in piglets infected
after birth.
Further reading
Liu X, et al. Molecular epidemiology of porcine cytomegalovirus (PCMV)
in Sichuan province, China: 2010-2012. PLoS ONE 2013;8:
e64648.
Smith KC. Herpesviral abortion in domestic animals. Vet J 1997;153:
253-268.
Bovine herpesvirus infections of the pregnant uterus
in cattle, goats, sheep, and pigs
Bovine herpesviruses cause a wide variety of diseases in several
species, including cattle, sheep, goats, wildebeest, and other
wild ruminants. They are divided into 6 different groups,
 433.e1

Further reading
Gortazar C, et al. Natural Aujeszky’s disease in a Spanish wild boar
population. Ann N Y Acad Sci 2002;969:210-212.
Hsu FS, et al. Placental lesions caused by pseudorabies virus in pregnant
sows. J Am Vet Med Assoc 1980;177:636-641.
433.e2

Further reading
Edington N, et al. Porcine cytomegalovirus (PCMV) in early gestation.
Vet Microbiol 1988;17:117-128.
Narita M, et al. Morphologic study of inclusions in tissues from pigs
inoculated with cytomegalovirus. Am J Vet Res 1987;48:
1398-1402.
434 CHAPTER 4  •  Female Genital System Abortion and Stillbirth

designated BoHV-1 to BoHV-6. The infections of the pregnant

uterus caused by bovine herpesviruses that will be discussed
in this section include BoHV-1 (infectious bovine rhinotrache-
itis virus, IBRV; infectious pustular vulvovaginitis virus, IPVV),
and BoHV-4 (Movar virus, a cytomegalovirus).
Species Bovine herpesvirus 1 is in the family Herpesviridae,
subfamily Alphaherpesvirinae, genus Varicellovirus. Based on
restriction endonuclease analysis and cross-hybridization,
BoHV-1 is subdivided into 3 antigenic variants or subgroups:
subgroup 1: IBRV; subgroup 2: IPVV; and subgroup 3: neuro-
pathogenic. IBRV and IPVV both cause abortion. IBRV is con-
sidered to be more virulent than IPVV and, in addition to
abortion, causes severe upper respiratory disease, endometri-
tis, oophoritis, mammillitis, dermatitis, and fatal diarrhea of
young calves. IPVV primarily causes inflammation of the penis
and prepuce in bulls, inflammation in the vagina and vulva in
cows, and abortion in cows.
BoHV-1 is distributed worldwide. Cattle-to-cattle trans- Figure 4-91  Caprine herpesvirus 1 infection. Focal hepatic
mission is the principal method of spread, and virus is easily necrosis is present in an aborted kid.
dispatched from naturally infected or vaccinated cattle to
susceptible animals through respiratory, ocular, or vaginal dis-
charges. All BoHV-1 strains, including thermosensitive and
thymidine kinase–negative strains, are capable of becoming
latent and therefore undergoing recrudescence and shedding
from mucous membranes. Virus is more abundant in excre-
tions from primary than from recrudescent infections; however,
transmission may occur from either. Live vaccine viruses may
become latent, and none of the vaccines can prevent latency
by a superinfecting challenge virus, but, if the antibody titer
is high in the vaccinate, the incidence of latent superinfection
and amount of virus excreted may be lowered. Recrudescence
may be induced by superinfections, corticosteroids, transport,
parturition, and other stressful situations. Semen may also be
an important source of the virus and embryo transfer fluids
less so.
Sheep, goats, and pigs often have antibody titers to BoHV-1
and may occasionally show clinical signs of disease. Infection
may manifest as an upper respiratory disease, which usually Figure 4-92  Bovine herpesvirus 1 infection. Necrotizing vasculi-
goes unnoticed; however, sheep may develop pneumonia. tis in the placenta from an aborted bovine fetus.
Abortions, from which BoHV-1 has been recovered, have been
described in sheep and pigs. Sheep, goats, pigs, and wild rumi-
nants are rarely the source of BoHV-1 virus for other animals; autolysis. Rarely, fetal death coincides with the time of normal
it is more likely that cattle transmit the virus to them, and delivery, and the fetus is discharged well preserved. Vaccina-
disease is an infrequent event. tion of pregnant cattle with a live vaccine will replicate natural
When the virus enters the mucosa of the respiratory or disease.
genital tract in pregnant animals, it multiplies at that site and Gross lesions in the fetus are usually absent or masked by
is carried to the rest of the body in infected leukocytes and autolysis, but, when visible, include white to tan, 1-3 mm
blood to the uterus. It has been postulated that, on reaching diameter foci of necrosis under the liver capsule and, more
the caruncle, the virus passes though the endothelium to the rarely, on the surface of the lung. Perivascular renal hemor-
interstitium of the villus, therein infecting endothelium, mes- rhage may be present in addition to focal hemorrhages at the
enchyme, and then trophoblast. Death is due to tissue destruc- corticomedullary junction in the kidney.
tion in the fetus and the placenta. Early hatched embryos are On microscopic examination, foci of necrosis with minimal
also susceptible to IBRV infection. cellular infiltrate can be seen in many tissues, including liver,
Abortion rates in a herd of cattle may reach 25%; however, adrenal, kidney, intestine, lymph node, lung, and spleen. Iden-
the prevalence of abortion in a region declines with a reduc- tical lesions are also found in caprine herpes (CpHV-1) abor-
tion in the naïve population. Most cows infected with BoHV-1 tions (Fig. 4-91). As autolysis advances, inclusion bodies are
do not abort until 3-6 weeks following the initial infection, difficult to distinguish but are most profitably sought in the
and a significantly greater number of cows abort between 5 adrenal within the more normal cells surrounding a focus of
and 8 months of gestation than earlier. It is speculated the necrosis. Necrotizing vasculitis is consistently present in the
virus can stay in the placenta for a prolonged period before small vessels of placental villi (Fig. 4-92).
invading the fetus. As the virus invades, the fetus dies quickly To confirm the diagnosis, the immunoperoxidase test using
with no preparation for delivery. Expulsion occurs 3-5 days monoclonal antibodies for BoHV-1 antigen is specific, highly
following fetal death, and the carcass is in a state of advanced sensitive, can be done on fixed tissue sections, and requires no
Pathology of the Genital System of the Nongravid Female
tissue cultures. Results are also available quickly. Fluorescent
antibody techniques on frozen tissue sections of kidney, liver,
or placenta and tissue cultures of these samples can be used
for detection of virus. Viral DNA may also be detected by
PCR. To identify antibodies to BoHV-1, the ELISA has a
higher validity in differentiating a negative from a positive
sample than the serum neutralization test. With BoHV-1,
cows abort such a long time after initial infection that most
animals have very low titers to the virus at that time. On an
individual basis, therefore, antibody titers are of little value in
diagnosis. Also, as the fetus dies quickly, there is usually no
evidence of fetal antibody production.
Further reading
Gould S, et al. An evaluation of the prevalence of bovine herpesvirus
1 abortions based on diagnostic submissions to five U.S.-based
veterinary diagnostic laboratories. J Vet Diagn Invest 2013;25:243-
247.
Nandi S, et al. Bovine herpes virus infections in cattle. Anim Health Res
Rev 2009;10:85-98.
Bovine herpesvirus 4 (cytomegalovirus) infection of
the pregnant uterus in cattle
Species Bovine herpesvirus 4 (BoHV-4, bovine cytomegalovi-
rus, Movar virus) is in the family Herpesviridae, subfamily
Gammaherpesvirinae (cell-associated herpesviruses), genus
Rhadinovirus. It has worldwide distribution in cattle and has
been associated with a wide variety of clinical conditions,
including pneumonia, enteritis, metritis, mammillitis, and the
disease syndrome “epivag.” Epivag is characterized by vaginitis,
salpingitis, and oophoritis, or epididymitis.
BoHV-4 is considered an important cause of abortion in
cattle; however, experimental evidence confirming a causal
relationship is incomplete. The virus is less virulent than
BoHV-1, and concurrent infections of BoHV-4 with other
pathogens are frequent (up to 75%). It has been suggested
that the virus is immunosuppressive and thereby intensifies
the effects of other agents. BoHV-4 has been isolated along
with bovine viral diarrhea virus and border disease virus from
abortions, and with Mycobacterium paratuberculosis from
animals with Johne’s disease.
As the virus is carried within mononuclear cells in blood,
grows on mucosal surfaces, and is also considered a poor
immunogen, it elicits a low level of neutralizing antibody that
is also of low avidity. It is transmitted from cow to cow in oral
and nasal secretions and, during viremia, is carried to the
placenta, where it multiplies and invades the fetus. The virus
may remain latent in mononuclear blood cells and in the
trigeminal nerve ganglion. Recrudescence can be induced with
dexamethasone. Herds tested for BoHV-4 antibodies vary
greatly in the proportion of cattle with antibody to the virus.
Mummification and birth of weak pigs have also been
reported in association with BoHV-4 infections in sows. Fetal
pigs are capable of developing antibody to the virus by 74
days of gestation. Recrudescence induced by dexamethasone
has been reported in sheep and pigs, with spread of virus to
other animals.
Descriptions of the lesions seen in the aborted bovine fetus
are limited. In one report, no gross lesions were observed in
the fetus, but on histologic examination, there was thickening
of alveolar septa in the lungs, where many large intranuclear
Abortion and Stillbirth 435
inclusions were observed in large alveolar cells. Similar inclu-
sions were also seen in cells of bile duct epithelium, myocar-
dium, spleen, and epithelium of renal tubules. The virus was
not isolated from this animal, but the inclusions seen on light
and electron microscopy were typical of cytomegaloviruses.
To confirm the diagnosis, fetal lung, liver, and kidney should
be cultured for the virus, and fluorescent antibody techniques
may also be used to demonstrate its presence. A nested duplex
PCR assay has been used to detect BoHV-1 and BoHV-4 in
lymph nodes and peripheral blood leukocytes. The virus has
been demonstrated in aborted fetuses by in situ hybridization.
Neutralization tests are usually unsatisfactory for the detec-
tion of antibody as the virus elicits a low antibody response.
The ELISA and an IIF test have been found to be more sensi-
tive and may have value on a herd basis. Antibodies may also
be detected in cavity fluid of aborted fetuses and are evidence
at least of fetal infection.
Further reading
Chastant-Maillard S. Impact of bovine herpesvirus 4 (BoHV-4) on repro-
duction. Transbound Emerg Dis 2013;doi:10.1111/tbed.12155;
[Epub ahead of print].
Deim Z1, et al. Detection of bovine herpesvirus 4 DNA in aborted
bovine fetuses. Can J Vet Res 2007;71:226-229.
Equid herpesvirus 1 abortion in horses
Species Equid herpesvirus 1 (EHV-1, equine abortion virus) is
in the family Herpesviridae, subfamily Alphaherpesvirinae,
genus Varicellovirus. It is widespread throughout the world
and causes respiratory, neurologic, and generalized neonatal
disease, as well as abortion. The virus can be separated into 2
distinct subtypes (1 and 2) on the basis of restriction endo-
nuclease cleavage of the viral DNA. Both subtypes cause
respiratory disease, abortion, and neonatal disease. Subtype 1,
however, causes a more severe (but less frequently encoun-
tered) respiratory disease than subtype 2 and is the more
frequent isolate from aborted foals and neonatal disease. Also,
it is probably the only type causing neurologic disease. Subtype
2 is commonly isolated from mild upper respiratory disease
in horses and less so from abortion. Respiratory disease caused
by EHV-1 is common in some areas, whereas abortion is rare;
this may be explained to some extent by the presence of a
subtype less likely to produce abortion but capable of produc-
ing respiratory disease.
EHV-1 is very widespread, and first exposure usually
occurs before the foal is 1 year of age. Mild to severe upper
respiratory disease is produced, and secondary bacterial infec-
tion, frequently with Streptococcus zooepidemicus or other
streptococci, is common. Because the virus is so widespread
and contact so likely at an early age, abortion usually occurs
in an animal that has had previous experience with the virus.
As with herpesviruses generally, the level of immunity is low,
and the virus is transported in leukocytes through the blood-
stream to the placenta and hence the fetus. Death of the fetus
does not occur until the onset of the usually prompt and
uncomplicated abortion. The dam shows no premonitory
signs, and the fetus is aborted in a fresh state. The time from
exposure, whether by recrudescence of latent virus or reinfec-
tion, until abortion varies from 9 days to several months.
Respiratory disease in the mare is usually not observed follow-
ing the infection that results in abortion. It is reported that
 435.e1

Further reading
Kirkbride CA. Viral agents and associated lesions detected in a 10-year
study of bovine abortions and stillbirths. J Vet Diagn Invest
1992;4:374-379.
Muylkens B, et al. Bovine herpesvirus 1 infection and infectious bovine
rhinotracheitis. Vet Res 2007;38:181-209.
435.e2

Further reading
Sheldon IM, et al. Uterine diseases in cattle after parturition. Vet J
2008;176:115-121.
436 CHAPTER 4  •  Female Genital System
Figure 4-93  Equid herpesvirus 1 pulmonary lesions in an aborted
foal. Note the interlobular pulmonary edema and the fibrin cast
in the trachea.
Figure 4-94  Equid herpesvirus 1 abortion. Acute necrotizing
bronchiolitis in an aborted equine fetus.
95% of the abortions caused by EHV-1 occur in the last 3
months of pregnancy, and naturally acquired infection has not
been observed to produce abortion before 5 months of gesta-
tion. Exactly where the virus is, and in what state, during the
protracted incubation period has not been determined. Abor-
tion follows endothelial necrosis of the vessels of the endome-
trium of the pregnant uterus.
The aborted fetuses may show characteristic and diagnostic
lesions that are variable in their development and may be
modest. Edema of the subcutis and fascia and accumulated
amber fluid in the body cavities are common in aborted
fetuses. There may be slight general icteric discoloration and
meconium staining of the eponychia and amnion. The most
consistent gross lesion is severe pulmonary edema. The lungs
are heavy and rubbery, show the impressions of the ribs, and
exhibit a pitting response to pressure (Fig. 4-93). There is also
edema of the interlobular septa. Their color may be darker or
lighter than normal, and tan-to-white foci of necrosis (2-4 mm
in diameter) and petechial hemorrhages may be visible on the
surface. The bronchial and bronchiolar epithelia are usually
necrotic and frequently contain intranuclear inclusion bodies
(Fig. 4-94). Casts of fibrin containing sloughed cells are present
Abortion and Stillbirth
Figure 4-95  Equid herpesvirus 1 infection. Intranuclear inclu-
sions (arrow) and necrosis in intestinal crypts in a 2-day-old foal.
and can occasionally be seen grossly in the bronchi and, rarely,
in the trachea (see Fig. 4-93). Beneath the capsule of the liver
there are, in about 50% of aborted fetuses, gray-to-white foci
of necrosis varying in size from minute up to 5.0 mm in
diameter. Such foci may be few or numerous. Petechial or
ecchymotic hemorrhages may occur anywhere, but chiefly in
the upper respiratory mucosae. Occasionally, there is hemor-
rhagic necrosis of the renal cortices.
Histologically, the pulmonary interlobular septa are edem-
atous and infiltrated with mononuclear inflammatory cells.
The edema and spotty necrosis and hemorrhage involve the
whole organ uniformly; there is fibrinous alveolar exudation
and necrosis of bronchial and alveolar epithelial cells (see Fig.
4-94). The acidophilic inclusion bodies found in the nuclei of the
bronchial and alveolar epithelium are specific. The foci of
hepatic necrosis are not so common as the changes in the
lungs: They are often minute and may be missed in a section.
Acidophilic inclusion bodies also form in the nuclei of hepatic
parenchymal cells, but they are not constant and are never
numerous. If present, they can usually be found around the
areas of focal necrosis. There is edema of the liver, and leuko-
cytes in the necrotic foci and portal triads are common. Rarely,
there is a diffuse hepatitis without focal necrosis. Lesions of
fetal stress, including necrosis of germinal centers, occurs in
the splenic follicles and other lymphocytic tissues, including
thymus. Intranuclear inclusion bodies may be found in the
cells in such foci. There are focal hemorrhages in the splenic
white pulp. The placenta is normal.
Foals infected with this virus in utero may be born alive
at, or near, term. Whether any survive is not known. Many of
them die in the first few days with severe interstitial pneumo-
nia and secondary bacteremia. Focal hepatic necroses are, as a
rule, not present in these animals; however, focal necrosis of
crypt epithelium with hemorrhage in the intestine is some-
times observed (Fig. 4-95).
The diagnosis of abortion can be made on observing typical
microscopic lesions, including the presence of inclusions. The
demonstration of EHV-1 on cell cultures from samples of
Pathology of the Genital System of the Nongravid Female
lung, liver, spleen, or thymus or by immunohistochemistry on
placenta is definitive. Determination of the specific subtype
may be accomplished using monoclonal antibodies and PCR-
based tests. Serologic examination for antibody is of little use
in the diagnosis of abortion because most animals are exposed
to the virus at several intervals in their life, and abortion may
occur too long after the last exposure, making interpretation
impossible, even on the basis of paired samples.
Equid herpesvirus 4 causes a similar disease, but is less
common and is sporadic.
Further reading
Gardiner DW, et al. Strain impact on equine herpesvirus type 1 (EHV-1)
abortion models: Viral loads in fetal and placental tissues and foals.
Vaccine 2012;30:6564-6572.
Szeredi L, et al. Detection of equine herpesvirus-1 in the fetal mem-
branes of aborted equine fetuses by immunohistochemical
and in-situ hybridization techniques. J Comp Pathol 2003;129:
147-153.
Akabane virus infection of the pregnant uterus
Species Akabane virus (AKAV) is in the family Bunyaviridae,
genus Orthobunyavirus, Simbu serogroup. In Australia, the
Simbu serogroup includes Akabane, Tinaroo, Peaton, Aino,
Douglas, Thimiri, and Facey’s Paddock viruses; Akabane and
Tinaroo viruses are naturally occurring reassortants. Akabane
disease, commonly known as enzootic bovine arthrogryposis and
hydranencephaly (ag/he), occurs in Australia, Japan, Korea,
Israel, and Kenya. Evidence of disease in postnatal cattle,
sheep, and goats is minimal; only slight leukopenia in goats
and mild keratoconjunctivitis in cattle have been reported,
plus one report of encephalomyelitis in cows. In contrast,
infection of nonimmune pregnant sheep, goats, and cows has
resulted in extensive losses in Japan, Israel, and Australia.
AKAV is transmitted by various insects, including the
hematophagous midge Culicoides brevitarsis in Australia and
various species of mosquitoes, including Aedes vexans, Culex
tritaeniorhynchus, and C. pipiens. Losses are seasonal and con-
fined geographically by the range of the insect. Animals
beyond this range constitute a naïve population, and if for
some reason infected insects invade this area, extensive losses
may occur.
Infections by AKAV before 30 days of gestation can produce
multiple congenital abnormalities and can result in normal or
malformed fetuses that may be aborted; mummified; or delivered
alive or stillborn, early, on due date, or late. Many are delivered
with difficulty because of the congenital malformations.
Anomalies observed include microcephaly, porencephaly,
hydranencephaly, hydromyelia, arthrogryposis, kyphosis, lor-
dosis, scoliosis, brachygnathia, and muscle atrophy. Additional
abnormalities reported in lambs include spina bifida, cyclops,
Arnold-Chiari syndrome, and anal atresia. When the fetus is
infected between 41 and 50 days of gestation, thick perivas-
cular cuffing of macrophages, lymphocytes, and plasma cells
is observed, coupled with very prominent glial nodules. The
large variety of CNS malformations caused by AKAV is attrib-
uted to differences in the fetal age at infection, the vulnerabil-
ity of neurons to direct injury, and the nature of tissue response
to such injury. Affected lambs are reported to weigh signifi-
cantly less than normal lambs, even though gestation length
overall is slightly extended. Infection of the fetus after 90 days
Abortion and Stillbirth 437
of gestation is less severe; however, there are inflammatory
lesions without malformation in the brainstem.
AKAV is carried by a midge or mosquito from a viremic
to a susceptible animal, and at no time does the dam show
clinical signs of infection. Viremia lasts for about 4 days,
during which time the virus invades the placenta, replicates
in trophoblastic cells, and finally crosses the placenta and
infects the fetus. If AKAV is inoculated immediately after the
integration of the placental cotyledon with the maternal car-
uncle, viral invasion of the chorioallantoic membrane occurs
rapidly. Lesions in the brain and possibly in muscle are prob-
ably due to the direct cytopathic effect of the virus on devel-
oping neurons. A regular sequence of events follows the
primary insult of polioencephalitis; focal necrosis in the brain
may progress to malacia and, depending on the extent of
the injury and time, to porencephaly and hydranencephaly.
Neuronal death in brain and ventral spinal cord motor
neurons is followed by denervation atrophy of muscle and
arthrogryposis.
Autopsy findings in affected species are similar. In the brain,
gross lesions have a broad range, including microcephaly, poren-
cephaly, and hydranencephaly. Cystic cavities vary from being
visible only microscopically to having almost complete loss of
parenchyma. The cerebellum may be normal to markedly
atrophic. Microscopically, there is encephalitis with macro-
phages, plasma cells, and lymphocytes within areas of necrosis
and around vessels. Lesions are sometimes most prominent in
the brainstem and spinal cord. The cerebral cortex may have
multifocal areas of necrosis with gliosis and perivascular
mononuclear cells. In the cerebellum, there may be loss and
malpositioning of Purkinje cells and reduced size of molecular
and granular layers.
Lesions induced in the brain early in gestation, because of
extensive destruction of cells, may proceed to hydranenceph-
aly with subsequent arthrogryposis. Lesions produced late in
the first trimester usually consist of multifocal encephalitis
and proceed only to porencephaly. Infections late in the
second trimester may produce lesions consisting of multifocal
necrosis and gliosis with less development of cavities.
Lesions in the spinal cord can be bilateral or unilateral and
consist of mineralization of meninges, atrophy of the cord, and
hydromyelia. Necrosis and depletion of ventral horn motor
neurons may proceed to cavitation. Light or heavy accumula-
tions of perivascular lymphocytes may be present throughout
the cord with decreased numbers of axons and hypomyelin-
ation in the lateral and ventral tracts.
Joints of the front legs are more commonly affected than
those of the hind, and both may be fixed in either flexion or
extension. There is slight to marked atrophy of skeletal muscle
groups in affected limbs. The muscles are edematous, pale, and
flabby to firm. On microscopic examination of muscle, sarco-
plasmic nuclei are either swollen or pyknotic. Loss of stria-
tions, hypereosinophilia, and empty sarcolemmic cylinders
may be present. Replacement of muscle by connective tissue
and fat occurs finally. Well-preserved fibers may be present
adjacent to areas of complete loss of muscle mass. Polymyo-
sitis, from which the virus can be isolated, has been reported
in some infected fetuses.
The diagnosis of AKAV infection may be made by demon-
strating virus or antibody in affected animals. Virus may be
recovered from various fetal tissues and fluids, including
brain, spinal cord, cerebral fluid, skeletal muscle, chorioallan-
tois, and amnion. It may be grown on hamster lung cells
 437.e1

Further reading
Gerst S, et al. Detection of EHV-1 and EHV-4 in placental sections of
naturally occurring EHV-1- and EHV-4-related abortions in the UK:
use of the placenta in diagnosis. Equine Vet J 2003;35:430-433.
Léon A, et al. Detection of equine herpesviruses in aborted foetuses
by consensus PCR. Vet Microbiol 2008;126:20-29.
Schlafer DH. Examination of the equine placenta. In: McKinnon A,
et al., editors. Equine Reproduction. 2nd ed. Ames, Iowa: Wiley-
Blackwell; 2010. p. 99-110.
van Maanen C. Equine herpesvirus 1 and 4 infections: an update. Vet
Q 2002;24:58-78.
438 CHAPTER 4  •  Female Genital System
and can cause reduced litter size, transplacental infection
of the fetus, and birth of live, weak young. AKAV can also
grow in the brain of intracranially inoculated suckling mice.
As the fetus is capable of producing antibody from an early
stage of gestation, inferred evidence of the cause of malforma-
tion and abortion may be determined by finding specific anti-
body to AKAV in fetal cavity fluids, including fluids from
stored tissues or precolostral blood samples from affected
newborn animals.
Further reading
Jun Q1, et al. A serological survey of Akabane virus infection in cattle
and sheep in northwest China. Trop Anim Health Prod 2012;44:1817-
1820.
Kirkland PD. Akabane and bovine ephemeral fever virus infections. Vet
Clin North Am Food Anim Pract 2002;18:501-514.
Noda Y, et al. Demonstration of Akabane virus antigen using immuno-
histochemistry in naturally infected newborn calves. Vet Pathol
2001;38:216-218.
Schmallenberg virus infection of cattle, sheep,
and goats
During the summer and fall of 2011, cattle in northwestern
Germany and in the Netherlands became ill with a febrile
condition that was associated with drop in milk production,
hypothermia, and watery diarrhea. Later in the fall, some
cattle in these and other European countries aborted or gave
birth to calves with neurologic disease and skeletal anomalies.
Aborted fetuses had abnormally developed heads, spines, and
limbs. Laboratorians were able to identify a novel orthobun-
yavirus that had the molecular structure of the Shamonda
viruses. This virus was named the “Schmallenberg virus” (SBV)
after a town in Germany near which a farm had a sick cow
from which this virus was isolated. SBV is in the family
Bunyaviridae, genus Orthobunyavirus, Simbu serogroup, and
is a reassortant of Sathuperi and Shamonda viruses. An
RT-qPCR test was developed which was subsequently used to
identify the agent, conduct epidemiologic studies, and to
examine the pathogenesis of the disease. Transmission of
SBV is associated with exposure to biting midges, mosquitoes,
and sandflies. SBV can be transmitted via the semen of
infected bulls.
Schmallenberg virus infection of pregnant sheep also
results in similar teratogenic lesions, and significant losses have
been reported in Europe. Experimental inoculation of preg-
nant sheep causes subclinical infections in most animals. Infec-
tion was established in only about half the ewes inoculated.
Affected fetuses and offspring of infected ewes or cows, have
hydranencephaly, scoliosis, and/or arthrogryposis—a spectrum
of lesions similar to those of other Simbu group bunyaviruses,
such as Akabane virus.
Amniotic fluid collected from fetal stomachs, and samples
of fetal cerebrum and fetal spinal cords have proven to be
good samples from which SBV nucleic acids can be identified
by RT-qPCR. ELISAs have been developed for antibody detec-
tion, and serologic surveys have been conducted.
Further reading
Hubálek Z1, et al. Arboviruses pathogenic for domestic and wild
animals. Adv Virus Res 2014;89:201-275.
Abortion and Stillbirth
van den Brom R, et al. Epizootic of ovine congenital malformations
associated with Schmallenberg virus infection. Tijdschr Dierge-
neeskd 2012;137:106-111.
Veldhuis AM, et al. Schmallenberg virus in Dutch dairy herds: potential
risk factors for high within-herd seroprevalence and malformations
in calves, and its impact on productivity. Vet Microbiol 2014;
168:281-293.
Aino virus infection in cattle
Aino virus (AINOV, syn. Shuni virus) is closely related to
Akabane virus, and is similarly in the family Bunyaviridae,
genus Orthobunyavirus, Simbu serogroup. As with AKAV,
AINOV is mainly transmitted by the midge Culicoides brevi-
tarsis but has also been isolated from mosquitoes, including
Culex tritaeniorhynchus and a mixture of C. pipiens and C.
pseudovishnui. The range of the organism, as determined by
serum antibody titers, extends along the northern and eastern
coasts of Australia (from just within Western Australia to
central New South Wales) and is well within the range of C.
brevitarsis. The virus is also present in Japan. Using antibody
titers as evidence of previous infection, fewer species overall
and fewer animals within affected species appear to be
infected with AINOV compared to AKAV.
Cattle that are infected do not have clinical signs; however,
insofar as precolostral antibodies to the organism are found in
deformed newborns, the organism is capable of crossing the
bovine placenta and causing abortion. Lesions consist of placen-
tal edema and necrosis, renal tubular necrosis with interstitial
lymphoplasmacytic infiltrates, nonsuppurative meningitis, and
interstitial pneumonia with mononuclear cells and some neu-
trophils. Experiments conducted with sheep indicate that,
although the virus can infect the fetus after direct inoculation,
it does not cross the placenta after inoculation into the preg-
nant ewe.
Lesions induced in young calves following intracerebral
inoculation of AINOV and AKAV are reported to be different.
With AINOV, nonsuppurative encephalomyelitis developed
first in the cerebrum adjacent to the ventricles and spread to
the medulla and the brainstem, but remained mild in the
spinal cord. Using animals inoculated with AKAV as controls,
nonsuppurative encephalomyelitis was produced in the brain-
stem and spinal cord only. Intravenous inoculation of virus
into susceptible pregnant cows at various stages of gestation
may give a more valuable comparison.
Diagnosis is based on immunohistochemistry or fluorescent
antibody testing on frozen sections or smears of homogenates
of fetal kidney, lung, and liver. Prospective serology on
cows at pregnancy diagnosis and at abortion may be useful.
Aino and Akabane bunyaviruses can be differentiated by
nested PCR.
Further reading
Ali H, et al. Common, emerging, vector-borne and infrequent aborto-
genic virus infections of cattle. Transbound Emerg Dis 2012;
59:11-25.
Cache Valley virus infection of sheep
Cache Valley virus (CVV, syn. Bunyamwera virus) is in the
family Bunyaviridae, genus Orthobunyavirus, is a serotype of
species Bunyamwera virus, and is widely distributed in North
 438.e1

Further reading
Buxton D, Henderson D. Infectious abortion in sheep. In Pract
1999;21:360-368.
Charles JA. Akabane virus. Vet Clin North Am Food Anim Pract
1994;10:525-546.
Jagoe S, et al. An outbreak of Akabane virus-induced abnormalities in
calves after agistment in an endemic region. Aust Vet J 1993;70:56.
Parsonson IM, et al. Transmission of Akabane virus from the ewe to
the early fetus (32 to 53 days). J Comp Pathol 1988;98:215.
Szabo KT. Hydranencephaly. Cerebellar hypoplasia. Arthrogryposis. In:
Szabo KT, editor. Congenital Malformation in Laboratory and Farm
Animals. London: Academic Press; 1989. p. 112, 124, 184.
438.e2

Further reading
Conraths FJ, et al. Schmallenberg virus, a novel orthobunyavirus infec-
tion in ruminants in Europe: potential global impact and preventive
measures. N Z Vet J 2013;61:63-67.
Garigliany MM, et al. Schmallenberg virus: a new Shamonda/Sathuperi-
like virus on the rise in Europe. Antiviral Res 2012;95:82-87.
 438.e3

Further reading
Akashi H, et al. Detection and differentiation of Aino and Akabane
Simbu serogroup bunyaviruses by nested polymerase chain reac-
tion. Arch Virol 1999;144:2101-2109.
Yanase T, et al. Genetic characterization of Aino and Peaton virus field
isolates reveals a genetic reassortment between these viruses in
nature. Virus Res 2010;153:1-7.
Pathology of the Genital System of the Nongravid Female
America. Serologic data indicate it infects pigs, horses, rac-
coons, foxes, and domesticated and wild ruminants, including
cattle, sheep, caribou, and deer, as well as humans. It is believed
to be spread by insects and has been isolated from a variety
of mosquitoes and midges, including Culiseta inornata, Pso-
rophora columbiae, Aedes sollicitans, Ae. taeniorhynchus, Anoph-
eles grabhamii, An. crucians, An. uadrimaculatus, and Culicoides
spp.
There is considerable evidence supporting CVV as the
cause of a severe epizootic in a flock of sheep in Texas, where,
of 360 lambs delivered, 92 were mummified, stillborn, or born
with congenital anomalies. Sixty-nine lambs had arthrogryposis
and hydranencephaly. All of the ewes bearing affected lambs
had neutralizing antibody to CVV, and affected lambs had
precolostral antibody to the virus. In the months before preg-
nancy, 5% of ewes had antibody to the virus and after preg-
nancy, 63.4% were positive. Following the outbreak, a sentinel
sheep was placed in the area, and CVV was eventually recov-
ered from a blood sample.
Examination of 15 lambs stillborn at term during the epi-
zootic revealed that CNS and muscle and joint lesions were
frequently present in the same animal, and lesions between
lambs mainly differed in severity. Gross lesions in limb joints
consisted of articular rigidity with articulations held in the
flexed position. The limbs appeared long for the size of the
body. In addition, kyphosis, scoliosis, and torticollis were fre-
quently observed. Muscles associated with the affected limbs
and spine were described as shrunken, pale, and firm. Lesions
in the brain consisted of hydrocephalus, porencephaly, and
hydranencephaly. The cerebrum, cerebellum, and spinal cord
were often markedly reduced in size, and the cerebellum was
occasionally mildly lissencephalic.
Microscopic lesions were observed in skeletal muscles,
brain, and 2 placentas. In affected muscle, fibers were small,
lacked striations, and nuclei were sparse. Fibers were separated
by loose connective tissue and adipocytes; rarely, a few neu-
trophils and mononuclear cells were present. Histologic exam-
ination of the brain confirmed gross findings, and cavities not
visible grossly were occasionally observed. In regions of
marked hydranencephaly, the cerebral cortex was reduced to
a few layers of neurons within the meninges. Entire lobes of
the cerebellum were often absent, but adjacent lobes were
often near normal, with only minor loss of cells in the molecu-
lar layer. The density of axons in the spinal cord was markedly
reduced, especially in dorsal tracts, and whereas ventral horn
neurons were only slightly reduced in the cranial cord, hardly
any remained in caudal portions. Inflammatory cells were
scant in lesions except in 2 of the 5 placentas examined,
wherein a mild perivascular neutrophil infiltrate was evident.
Inoculation of 36 ovine fetuses in utero with CVV has added
further credibility to the role of CVV as the cause of the
epizootic. Following in utero inoculation of the virus, several
of the fetuses developed arthrogryposis and hydranencephaly;
some were mummified, others died and were absorbed, and a
few had oligohydramnios. Lambs infected at 27-35 days of
gestation had the greatest mortality rate, whereas lambs
infected between days 36 and 45 of gestation had more
congenital anomalies. Virus was recovered from fetuses before
69 days but not after 76, regardless of when they were
infected, and this was coincident with the development of
neutralizing antibody in the fetus. The virus was recovered
from allantoic fluid in 11 of 17 fetuses euthanized at <76 days
of gestation.
Abortion and Stillbirth 439
The diagnosis of CVV infections resulting in fetal loss and
congenital anomalies in lambs is most easily accomplished by
examining precolostral serum or cavity fluids of lambs with
arthrogryposis and hydranencephaly for antibodies to CVV.
CVV antigen may be detected in aborted fetuses by immu-
nohistochemistry, in situ hybridization, or PCR. Differential
diagnoses should include infection by Akabane virus, as the
lesions are remarkably similar.
Further reading
Rodrigues Hoffmann A, et al. Identification of the target cells and
sequence of infection during experimental infection of ovine
fetuses with Cache Valley virus. J Virol 2012;86:4793-4800.
Rift Valley fever virus infection of cattle and sheep
Species Rift Valley fever virus (RVFV) is in the family Bunya-
viridae and is the type species of genus Phlebovirus (Zinga
virus is a strain of RVFV). RVFV infects many domestic, wild,
and laboratory animals and humans. It occurs in at least 18
countries over a 6,700-km north-south range in Africa, plus
Saudi Arabia. Infection by RVFV causes a disease characterized
by rapid onset and high mortality in lambs, low mortality in adult
sheep and calves, and even lower or no mortality in cattle. There
is frequently a high rate of abortion, approaching 100% in sheep
and cattle. People may also become infected, often from
contact with body fluids or organs of infected animals, and
develop influenza-like illness; mortality is generally low, but
morbidity is high and the degree of debility often extreme.
Hepatic necrosis is the prominent lesion and occurs in all affected
species and age groups, including the fetus. Host resistance to
fatal hepatic disease has been shown in laboratory animals to
be inherited as a simple Mendelian dominant gene. Suscepti-
bility is age and sex related; the young are more susceptible,
and males less resistant than castrates and females. Although
2/3 of sheep are genetically resistant to fulminant hepatic
disease, sheep are regarded as the most susceptible domestic
animal.
RVFV is transmitted primarily by mosquitoes, and Culex
pipiens is a major vector in parts of Africa. Generalized infec-
tion in the mosquito is necessary before transmission occurs
effectively, and movement of virus from the insect gut is
facilitated by the presence of microfilariae in ingested blood.
Aedes spp. are capable of transovarial transmission. Aedes
albopictus, a strain of mosquito in the United States, can trans-
mit the virus, and movement of animals either incubating
infection or in viremia raises the possibility of international
spread of the virus. Biting midges and ticks are also implicated
in transmission. The virus probably does not spread from
animal to animal in the absence of insects; however, experi-
mentally the virus can be transmitted by just about every
route, including aerosols or application into nasal passages,
to scarified skin, or on the conjunctiva. Aborted fetuses and
membranes have a very high titer of virus. Epizootics often
follow a period of heavy rain, particularly after drought,
and outbreaks may be separated by periods of 10-15 years
without a case.
In mature sheep, cattle, or camels, the disease is manifest
in peracute, acute, subacute, chronic, and convalescent forms. In
sheep, the subacute form, in which the animal is febrile for
24-96 hours, is common, and up to 100% of pregnant ewes
can abort during this phase or when convalescing. In cattle,
 439.e1

Further reading
Chung SI, et al. Congenital malformations in sheep resulting from in
utero inoculation of Cache Valley virus. Am J Vet Res 1990;51:1645.
Edwards JF. Cache Valley virus. Vet Clin North Am Food Anim Pract
1994;10:515-524.
Rodrigues Hoffmann A, et al. Ovine fetal immune response to Cache
Valley virus infection. J Virol 2013;87:5586-5592.
Wang H, et al. A duplex real-time reverse transcriptase polymerase
chain reaction assay for the detection of California serogroup and
Cache Valley viruses. Diagn Microbiol Infect Dis 2009;65:
150-157.
440 CHAPTER 4  •  Female Genital System
the peracute form is rare, and abortions occur during the acute
or convalescent period in 10-85% of pregnancies. Camels sero-
convert and may amplify the virus locally; some may die.
Deaths in cows are uncommon. Infertility occurs in both
sheep and cattle and may follow retention of fetal membranes
and endometritis. Signs are unpredictable in goats. They tend
to be less susceptible than sheep, but if infected can abort.
During viremia, the organism is carried to the placenta and
fetus, where the liver appears to be the primary site of multiplica-
tion. Hepatocyte destruction is probably related to the
repeated cycles of virus growth and release of virus from
infected cells.
Lesions are much the same in cattle or sheep fetuses and,
except for one report where experimental inoculation of preg-
nant ewes with an attenuated RVFV resulted in hydranen-
cephaly and arthrogryposis, infection by RVFV usually results
in death of the fetus in utero. This occurs at any gestational age
and, as it occurs rapidly, the fetus is aborted in an autolysed
state. On gross examination, the liver is swollen and discolored
orange to brown and occasionally to dark red. Microscopically,
the most consistent lesion seen in almost 100% of fetuses
examined is multifocal to massive hepatic necrosis. A few degen-
erating neutrophils may be present in these lesions. Acidophilic
intranuclear inclusions of various shapes (fusiform, round,
oval) are frequently present in hepatic cells of ovine fetuses
and are helpful in the diagnosis. These are seen less often in
bovine fetuses and may be difficult to find when autolysis is
advanced. Mineralization of individual or clusters of hepato-
cytes is also common. Cholestasis may be evident in canaliculi.
Other lesions reported include degeneration of lymphocytes
in spleen and lymph nodes and degenerative lesions in heart
muscle and renal tubules.
The hepatic lesion is considered diagnostic; however, in
areas where the condition is not endemic, definitive diagnosis
depends on identification of the virus. It can be detected early
in infection in blood or serum by RT-PCR. It is abundant in
fetal tissues and placenta and may be cultured or detected
using the indirect fluorescent antibody technique on frozen
sections of liver or by immunohistochemistry. Differential
diagnoses in sheep include infections by bluetongue virus and
Wesselsbron virus.
Further reading
Ikegami T, Makino S. The pathogenesis of Rift Valley fever. Viruses
2011;3:493-519.
Odendaal L, et al. Sensitivity and specificity of real-time reverse tran-
scription polymerase chain reaction, histopathology, and immuno-
histochemical labeling for the detection of Rift Valley fever virus in
naturally infected cattle and sheep. J Vet Diagn Invest 2014;
26:49-60.
Circovirus postweaning multisystemic
wasting syndrome
Species Porcine circovirus 2 (PCV-2), family Circoviridae,
genus Circovirus, is associated with the postweaning multisys-
temic wasting syndrome (PMWS), and appears to act with
other cofactors that cause stimulation of the pig’s immune
system. Porcine circovirus–associated disease (PDVAD) is
associated with wasting and mortality in young pigs and can
result in lesions of the respiratory, enteric, reproductive, and
renal systems. PMWS was first reported in western Canada in
Miscellaneous Lesions
Figure 4-96  Fetal myocarditis in an aborted piglet, caused by
porcine circovirus 2.
1991 and has since been found in the United States and in
many European and Asian countries. The disease primarily
affects pigs 5-18 weeks of age and is characterized by failure to
grow and eventual emaciation. Affected pigs may have gastric
ulcers in addition to a wide variety of lesions, including pneu-
monia and diarrhea.
A reproductive failure syndrome has been observed in several
herds and is characterized by late-term abortions of mummi-
fied, macerated, or autolysed piglets, and piglets born weak or
stillborn. Lesions in these piglets included enlargement of the
liver; congestive heart failure, with excess fluid in the thorax;
and abdominal cavities. The heart may be enlarged and irregu-
lar in shape, and on histologic examination, extensive areas of
myocardial degeneration, edema, and necrosis with mild fibro-
sis and diffuse infiltrates of lymphocytes and macrophages
may be observed (Fig. 4-96). The virus can be demonstrated
by immunohistochemistry in heart muscle cells. No other
viruses were detected in this investigation. Stress factors and
co-infections with other porcine viruses were not detected;
however, environmental, husbandry, and genetic factors may
be important in the progression of clinical PMWS.
Further reading
Cushing TL, et al. Pathology in practice: myocarditis attributable to
PCV-2 infection in a pig fetus. J Am Vet Med Assoc 2013;242:317-
319.
Hansen MS, et al. Detection of porcine circovirus type 2 and viral
replication by in situ hybridization in primary lymphoid organs from
naturally and experimentally infected pigs. Vet Pathol 2013;50:
980-988.
MISCELLANEOUS LESIONS OF
THE POSTPARTUM UTERUS
Endometrial cysts, adjacent to caruncles, develop in some cows
and ewes during the process of uterine involution. Adhesion of
the caruncular stalk to adjacent glandular tissue causes block-
age of the underlying glands. The retention cysts enlarge pro-
gressively with age, and care must be taken to differentiate
them from estrogen-linked cystic hyperplasia.
 440.e1

Further reading
Gerdes GH. Rift valley fever. Vet Clin North Am Food Anim Pract
2002;18:549-555.
Van der Lugt JJ, et al. Distribution of viral antigen in tissues of new-born
lambs infected with Rift Valley fever virus. Onderstepoort J Vet Res
1996;63:341-347.
440.e2

Further reading
Segalés J, et al. The natural history of porcine circovirus type 2: from
an inoffensive virus to a devastating swine disease? Vet Microbiol
2001;165:13-20.
Segalés J, et al. Porcine circovirus diseases. Anim Health Res Rev
2005;6:119-142.
Silva FM, et al. Porcine circovirus-2 viral load versus lesions in pigs:
perspectives for post-weaning multisystemic wasting syndrome.
J Comp Pathol 2011;144:296-302.
West KH, et al. Myocarditis and abortion associated with intrauterine
infection of sows with porcine circovirus 2. J Vet Diagn Invest
1999;11:530-532.
Pathology of the Cervix, Vagina, and Vulva
Figure 4-97  Subinvolution of placental sites (SIPS) in a bitch.
Fusiform enlargement of uterine horns at sites of failure of
involution.
Figure 4-98  Subinvolution of placental sites. Hemorrhage and
necrotic debris within the endometrium at placental attachment
sites.
Subinvolution of placental sites in the bitch is manifested
clinically by a prolonged, blood-tinged vaginal discharge. In
the normal bitch, overt uterine bleeding usually ceases within
7-10 days following whelping, but the affected bitch may
bleed for several weeks or months. In some cases, the blood
loss causes severe anemia and occasionally death. Ellipsoidal
enlargements, located in the areas of previous placental attach-
ment, are evident in the uterine cornua (Fig. 4-97). The endo-
metrium in the affected areas is hemorrhagic, irregularly
thickened, and gray to brown. The endometrium between the
enlargements is normal in appearance. The surface epithelium
is often detached, but when present, it has heavily vacuolated
cytoplasm, indicating progestational stimulation. Corpora
lutea are invariably present, but progesterone concentrations
are low in the few cases in which the determination was made.
Pathology of the Cervix 441
Figure 4-99  Decidual cells, trophoblast cell, and inflammatory
cells at a nonhealing placental attachment site in a bitch with
SIPS.
The uterine mass adjacent to the uterine lumen is composed
of an admixture of amorphous eosinophilic debris, fibrin,
degenerating placental site tissue, and regenerating endome-
trium (Fig. 4-98). The deeper tissue contains numerous
irregular-shaped cells with large nuclei and abundant vacuo-
lated cytoplasm (Fig. 4-99). They are interpreted as syncytial
trophoblasts or alternatively as decidual cells, and are far more
numerous than in the normal gravid uterus. Some degree of
invasion of the myometrium by these cells is not unusual, and
in some cases there is perforation of the serosa, allowing
uterine contents to escape into the peritoneal cavity. The
condition appears to be more prevalent in young bitches, but
the cause has not been established.
Further reading
LeBlanc SJ. Postpartum uterine disease and dairy herd reproductive
performance: a review. Vet J 2008;176:102-114.
Sontas HB, et al. Full recovery of subinvolution of placental sites in an
American Staffordshire terrier bitch. J Small Anim Pract 2011;
52:42-45.
PATHOLOGY OF THE CERVIX, VAGINA,
AND VULVA
PATHOLOGY OF THE CERVIX
Cysts of the cervix occur in cows, and probably all are reten-
tion cysts formed by fusion of the rugae. Loss of the original
epithelium of the rugae is first necessary and may be incidental
to the lacerations of parturition, artificial insemination, or
inflammation. The cysts are usually small and not significant.
Larger ones may cause partial occlusion of the cervical canal,
but this is seldom of importance.
Stenosis of the cervix is extraordinary. It is acquired rather
than congenital and consists of fusion across epithelial surfaces
and scarification. It may follow severe laceration or long-
standing inflammation.
Cervicitis is not in itself an entity but, instead, is an exten-
sion of endometritis or vaginitis. The mucus-secreting
 441.e1

Further reading
Fernández PE, et al. Characterisation of cytotrophoblastic-like cells
present in subinvolutioned placental sites of the bitch. Histol Histo-
pathol 1998;13:995-1000.
442 CHAPTER 4  •  Female Genital System Pathology of the Vagina and Vulva

epithelium provides good defense against bacterial invasion

and, if the epithelium breaks down, it exposes densely arranged
connective and muscular tissues, which are not especially sen-
sitive to the actions of bacteria. In the cow, the epithelium
lining the external os and the adjacent few rugae is of the
simple vaginal type, and this is more susceptible to irritation
than the mucus-secreting surface cranial to it. Most inflam-
mations then are superficial, but there are some exceptions,
such as necrobacillosis. The circumstances in which cervicitis
occurs have been mentioned in the section on pathology of
the uterus or will be mentioned under pathology of the vagina
and vulva, later. The usual form of bovine simple cervicitis is
seen as a swelling of the caudal annular rugae, which are
edematous and hyperemic. They soon protrude through the
external os into the vagina, and thin mucopurulent exudate
accumulates between the folds and collects in the vagina.
Histologically, there is epithelial degeneration and desquama-
tion, and inflammatory cells are predominantly mononuclear.
Neutrophils penetrate the epithelium and become mixed with
mucus, or in more acute cases, there may be frank suppura-
tion. Cervicitis is not usually more severe than this, although
in older cows the prolapse and swelling of the rings may be
grossly obvious. Although degrees of prolapse result from Figure 4-100  Cystic segment of a mesonephric duct in the
inflammation, they may also predispose to it. Slight but vagina of a cow (cystic Gartner’s duct). These cysts are common
progressive degrees of eversion of the cervical rings occur in cattle and are found in the ventrolateral area of the floor of the
with succeeding pregnancies to expose portions of the cranial vagina. They are uncommon in other species.
cervical mucosa to the contaminated environment of the
vagina. Chronic cervicitis may lead in time to enlargement
of the cervix with some stenosis, but enlargement is not a
criterion of inflammatory sclerosis. Discrete cervical abscesses follow inflammatory stricture of the short excretory ducts.
or suppurative fistulous tracts occasionally result from acci­ Abscessation may follow localization of infection in the cysts.
dental injury acquired during uterine irrigation or artificial Ruptures of the vagina and vulva are quite frequently
insemination. acquired as parturient injuries and rarely with bull:cow size
mismatch at mating. The mucosa alone may be ruptured, or
the entire thickness of the vaginal wall. Hemorrhages occur
PATHOLOGY OF THE VAGINA AND VULVA
into the vagina or the perivaginal wall from fetal pressure or
Cysts in the vagina or vulva are not important in themselves, vascular disruption. Pelvic fat may herniate into the vagina; it
but they do have some diagnostic significance. They occur as is often mistaken for a neoplasm. Defects that extend deeper
cystic dilations in Gartner’s ducts and Bartholin’s glands in than the mucosa heal with cicatrization, which may, in turn,
cattle. Gartner’s ducts are remnants of the embryonic meso- result in partial stricture. Otherwise, the outcome depends on
nephric (Wolffian) ducts, which lie, one on each side of the whether the lacerations become infected and, if so, with what.
floor of the vagina, beneath the epithelium. They are invari- Occasionally, diffuse cellulitis, abscess, gangrene, or peritonitis
ably present to some degree in cattle, although when normal, are sequelae.
they are only detectable microscopically as discontinuous
ducts lined by simple epithelium and found in the cranial Swelling of the vulva
vagina and disappearing caudally. They become cystic in cows Vulval swelling is a physiologic response to estrogens. Vulvar
poisoned with highly chlorinated naphthalenes, in cows with enlargement may be marked during the normal estrous period
ovarian follicular cysts, and occasionally following acute vagi- or may be persistent when resulting from exposure to endog-
nitis. With lesser degrees of dilation, the cysts are more readily enous or exogenous estrogens. Abnormal patterns and concen-
palpable than visible, but in well-developed instances, they are trations of endogenous estrogens may occur from cystic
clearly visible through the elevated and thinned vaginal wall follicular disease, estrogen-secreting tumors (granulosa cell
(Fig. 4-100). The cysts may be isolated or they may have a tumors), or from exogenous sources such as mycotoxins. Vulval
string-of-beads disposition, or the whole duct may be present, swelling is most common in the sow and bitch and must be
dilated to 1-2 cm and tortuous. differentiated from vulvitis (bite wounds), physical trauma, or
Cysts of Bartholin’s glands occur under the same stimuli, dystocia. Prepubertal pups exposed to creams used in human
but chiefly as a consequence of inflammation. The glands lie estrogen therapy will develop vulval development and
one on each side of the floor of the vestibule and normally swelling.
are about 3 × 1.5 cm in dimension. They become visible when Vulval swelling in swine may be due to exposure to myco-
enlarged, especially if the vestibular mucosa is slightly everted. toxins. A distinctive syndrome characterized by vulval hyper-
These glands are very sensitive to estrogens, responding with emia and edema occurs in swine fed moldy grains. The
the elaboration of thin mucus and hyperplasia of the ductal mycotoxin that causes this estrogenic effect is zearalenone, or
epithelium. Gross exaggeration of responses in hyperestrogen- F-2, which is produced by at least 4 different Fusarium spp.,
ism accounts for the cystic development. Large retention cysts F. graminearum being the most common.
Pathology of the Cervix, Vagina, and Vulva
Young gilts are chiefly affected, older animals being more
resistant. There is remarkable edematous swelling of the vulva
and vagina, which may be severe enough to lead to eversion
and prolapse of the mucosa. Prolapse of the vagina may occur
in up to 30% of cases, and secondary rectal prolapse occurs in
a lesser percentage. The uteri of affected animals may be
enlarged by endometrial gland hyperplasia and edema. The
ovaries become inactive and atrophic, or polycystic. Gilts may
also show mammary gland enlargement with squamous meta-
plasia of the ductal epithelium. Decreased libido, testicular
atrophy, and balanoposthitis have been reported in young
boars.
Strains of Fusarium vary in toxigenic potency, in regard not
only to zearalenone but also to trichothecene toxins, which,
if produced in quantity, may broaden the clinical picture to
include anorexia and vomition.
Inflammatory diseases of the vagina and vulva
The mucous membrane of the vagina and vulva shares with
mucous membranes, in general, a sensitivity to irritants.
Although the cranial vagina is of paramesonephric duct origin,
the original epithelium is replaced by stratified squamous
epithelium from the urogenital sinus. This epithelium prolifer-
ates and matures under the influence of estrogen and is then
more resistant to infection. This enhanced resistance may be
due to mechanical factors in the thickened keratinized epithe-
lium and to local production of lactic acid from the glycogen
that is deposited in the epithelium under the influence of
estrogens.
Granular vulvitis
Papular eruptions of the vulval mucosa are common in most
domestic species but are best known in the bovine species by
the previous name or as nodular venereal disease or granular
vaginitis. The term vaginitis is a misnomer, as the papules are
strictly limited to the vulval mucosa and are not found in the
vagina, although in acute cases, there may be an associated
nonspecific vaginitis. Vulval granules may be found in any
herd, affecting animals of any age, but are usually more promi-
nent in heifers bred naturally. They are much less common in
pregnancy and are almost never present about the time of
parturition. In severe cases, the papules may be found on all
aspects of the vulval mucosa, but they are usually clustered
in the ventral commissure about the clitoris as pale or pink
elevations a few millimeters in diameter and covered by a
normal intact vulval mucosa. When numerous, they are likely
also to be more active, larger, often coalescent, congested,
and red, with concurrent catarrhal vulvitis and vulval
swelling. The overlying epithelium is then easily injured, and
bleeding occurs freely from the papules. The resting papules
are composed of respectably organized lymphoid follicles
(Fig. 4-101).
When the vulval mucosa is irritated, these become red,
with small intrafollicular hemorrhages and edema, and hyper-
plastic, the mitotic frequency being quite high. The same
lesions occur on the penis and prepuce of the bull and often
persist for many months, as do those of the vulva. These
papules have been produced experimentally with Ureaplasma
diversum and occur commonly in herds with natural U. diver-
sum infection but are not specific for this organism. The devel-
opment of subepithelial lymphocytic foci is a characteristic
response of mucous membranes to mild persistent or recur-
rent irritation, and the simplest explanation of granular
Pathology of the Vagina and Vulva 443
Figure 4-101  Bovine granular vulvitis, with submucosal lym-
phoid hyperplasia.
vulvitis is that it is the result of mild inflammation of the vulval
mucosa.
Infectious bovine cervicovaginitis and
epididymitis (“epivag”)
This is a specific infectious disease that has been an important
cause of infertility in eastern and southern Africa. A slow-
growing cytomegalovirus of the bovine herpesvirus 4 group has
been recovered from infected animals. In limited studies, these
isolates have not reproduced the full spectrum of clinical signs,
so there remains some uncertainty about their role in the
disease. The slow-growing herpesviral strains are not serologi-
cally related to the bovine herpesvirus 1 of infectious bovine
rhinotracheitis.
Natural transmission is solely by coitus. Experimental trans-
mission is easy if infective discharges are placed in the vagina
or prepuce. After incubating for a few days, diffuse purple
inflammatory streaks or patches develop in the cranial vagina,
to be followed by the development of copious tenacious
creamy discharge in which there are large numbers of neutro-
phils but few or no organisms. The infection spreads readily
from the vagina to the cervix and uterus, also with the produc-
tion there of the same copious pus. About 25% of infected
females are sterile because of the development of chronic
salpingitis with hydrosalpinx and bursal adhesions. In the bull,
there is early but slight palpable enlargement of the deferent
duct and epididymis. The disease usually commences in one
epididymis but later involves both organs and spreads from
the tail of the epididymis to the head of it and ultimately to
the testis. The lesion is apparently an interstitial epididymitis
with the production of excessive peritubular fibrosis and
tubular obstruction. Testicular changes are probably secondary
to those in the epididymis and to obliterative adhesions in the
cavity of the vaginal tunics. Similar productive inflammatory
lesions occur in the ampullae and the vesicular glands.
Infectious pustular vulvovaginitis of cattle
We are assuming for this description of infectious pustular
vulvovaginitis that it is the disease that for many decades has
been variously termed vesicular venereal disease, vesicular
vaginitis, coital exanthema, coital vesicular exanthema, and
Blaschenausschlag. The assumption is probably valid, but
proof is lacking and may no longer be obtainable. Infectious
pustular vulvovaginitis is caused by the same herpesvirus
(bovine herpesvirus 1) that causes infectious bovine
444 CHAPTER 4  •  Female Genital System
Figure 4-102  Necrotizing vulvitis caused by bovine herpes­
virus 1.
rhinotracheitis (see Vol. 2, Respiratory system), or at least is
caused by a subtype of that virus that is serologically indistin-
guishable from it. As a rule, nasal and vaginal infections behave
epidemiologically as distinct diseases, although occasionally
the syndromes occur together in individual animals. The infec-
tion can be transmitted to sheep and goats, producing
vaginitis.
Infectious pustular vulvovaginitis is highly contagious. It is
frequently transmitted by coitus, but it can also be transmitted
by other mechanical means and is contagious by close contact.
It may involve individual or a few animals in a herd, but fre-
quently spreads rapidly to involve all exposed females in a few
days. The disease subsides in about 10 days, leaving immunity
that is fragile and transient. Reinfection can occur, but early
reinfection produces only mild disease.
The incubation period is 1-3 days but may be as brief as
12 hours. The lesions are restricted to the genital tract, but a
viremic phase probably occurs because there is early fever and
leukopenia. Initially, the vaginal and vulval mucosa is hyper-
emic with focal hemorrhages in the lymphocytic follicles of
the submucosa. The severity of the vulvovaginitis increases
rapidly, and edema of the vulva with hemorrhage develops (Fig.
4-102). When the damaged tissues become secondarily
infected, mucopurulent vaginal discharge develops. The focal
lesions replace the hemorrhages over the lymphoid follicles
and consist of small (2-3 mm) pock-like foci, slightly elevated,
pale, soft, and friable.
The focal lesions, being related to the lymphoid follicles,
may be in short linear arrangements. The epithelium in the
focal lesions erodes or ulcerates so that in a few days the foci
are flat, gray, semitransparent plaques the size of the original
lesions.
The virus is epitheliotropic, the initial and most severe
alterations occurring in the epithelium of the vagina and vulva.
There is ballooning degeneration of the epithelial cells, and at
about 24 hours, intranuclear inclusions can be found in the
epithelium (Fig. 4-103). The inclusions are lightly acidophilic
Pathology of the Vagina and Vulva
B
Figure 4-103  A. Intranuclear inclusion bodies in vaginal epithe-
lial cells in bovine herpesvirus 1 infection that has caused necrosis
and ulceration of the vaginal wall (B).
or amphophilic and large; they can be found for 3-4 days, by
which time the lesion has reached its zenith and is beginning
to resolve. The infected cells undergo necrosis, and epithelial
disruption and ulceration occur, accompanied by an intense
infiltration by neutrophils (see Fig. 4-103). Vesicles and true
pustules do not form. Acute inflammation occurs in the
lamina propria, with hyperemia and edema and numerous
plasma cells and lymphocytes. Many of the small vessels are
occluded by adventitial and endothelial swelling. The lympho-
cytic follicles are remarkably hyperplastic and edematous, and
their outlines are obscured by the infiltrating cells in the
lamina propria. Resolution occurs in about 8 days, with hyper-
plastic lymphoid follicles and slight epithelial thickening as
residues.
Although most cows that are served naturally by infected
bulls do not appear to experience infertility, susceptible heifers
that are inseminated with semen containing virus fail to con-
ceive. Intranuclear inclusions may be found in the epithelial
cells of the luminal endometrium within 48 hours but are
absent by 72 hours after exposure. The surface epithelium and
the underlying connective tissue become necrotic and contain
many neutrophils. There is pronounced edema of the lamina
Pathology of the Cervix, Vagina, and Vulva
Figure 4-104  Contagious equine metritis (CEM). The clitoris
and clitoral fossa of a mare infected with Taylorella equigenitalis
appear grossly normal, but these are the sites of chronic bacterial
infection in mares. Mats of bacteria can be found on the mucosal
surface of the sinuses and crypts of the clitoris in CEM.
propria and mononuclear cells; especially, lymphocytes are
present. The uterine tubes are involved, but to a less severe
degree.
The virus can produce similar lesions on the mucous mem-
brane of the penis of infected bulls. Because recrudescence
with viral shedding is a feature of this as well as other herpetic
diseases, animals with inapparent infections can also transmit
the disease.
A herpesvirus identified as equid herpesvirus 3 produces a
comparable genital disease in horses—equine coital exanthema.
It is discussed with diseases of the penis, in Vol. 3, Male genital
system. Caprine herpesvirus infection in goats causes a com-
parable disease of the vulva also.
Contagious equine metritis
Contagious equine metritis, caused by Taylorella equigenitalis,
is a sexually transmitted disease of horses. As discussed previ-
ously in the section on endometritis, acute infection of mares
causes purulent endometritis and cervicitis. In mares that have
become carriers, the Taylorella organisms reside within the
crypts and fossa of and around the clitoris. Although the
mare’s clitoral area, shown in Figure 4-104, is grossly normal,
she had large numbers of Taylorella coccobacilli within the
clitoral fossa, which was associated with only a mild lympho-
cytic reaction. An atypical Taylorella sp. also capable of causing
transient endometritis and endometritis has been isolated
from donkeys in the United States.
Necrotic vaginitis and vulvitis
Necrotic vaginitis is a deep diphtheritic inflammation of the
vaginal mucosa; it occurs in 2 fairly distinct syndromes—either
vulvovaginitis or cervicovaginitis. Necrotic vulvovaginitis is
uncommon, but may involve a number of cows in a herd. It
is primarily due to trauma with contamination, often the
result of bite wounds by pigs or dogs. Necrotic cervicovaginitis
(Fig. 4-105) is a complication of parturition and is chiefly
Pathology of the Vagina and Vulva 445
Figure 4-105  Necrotizing vaginitis in a cow, associated with dys-
tocia and associated pressure necrosis.
observed in ewes and cows as a consequence of dystocia. A
number of influences, mainly prolonged pressure necrosis, lac-
eration, and abrasion, usually acting in combination, are
responsible for the lesion. Severe necrotic cervicovaginitis is
frequently fatal, either with direct extension of the inflamma-
tion to the peritoneum or with the uterine complications of
prolonged dystocia and fetal emphysema.
Lacerations associated with dystocia commonly occur in
mares, sometimes extending to involve the rectum and
perineum. Scarring of the vulva from previous trauma from
delivery is a common finding in large domestic animals (Fig.
4-106). Disfigurement may result from neoplasms that invade
the perineal area (Fig. 4-107).
Dourine
Dourine of horses and their relatives is caused by Trypano-
soma equiperdum and is primarily a venereal disease. The
other trypanosomiases of domestic animals are discussed in
Vol. 3, Hematopoietic system, being essentially hemic infec-
tions with arthropod vectors. Dourine differs from other try-
panosomiases in that the organisms are in the blood only
intermittently or in very virulent infections, and transmission
is effected not by blood-sucking insects but by contact of
infected mucous membranes. Natural transmission is by coitus,
so the disease is almost exclusively one of stallions and breed-
ing mares. Rare cases occur in unbred animals and in young
foals. The disease prevails in the Balkans, much of Africa, Asia,
and South America. It has been eradicated from most of
Europe and North America.
Strains of T. equiperdum vary considerably in their viru-
lence, although not notably in their capacity to infect. Irre-
spective of the route of experimental infection in horses, the
trypanosomes demonstrate some predilection for genital
mucosae. Following natural infection, the organisms are fre-
quently numerous in vaginal discharges and the male urethra.
There are periods, however, sometimes of several weeks or
446 CHAPTER 4  •  Female Genital System
Figure 4-106  Disfigured vulva of a sow, resulting from trauma
during delivery.
Figure 4-107  Multinodular pigmented masses involving the
vulva and perineum of a mare. This malignant melanoma had also
metastasized to regional lymph nodes. These are common neo-
plasms that involve the vulva and perineum of the mare. Squa-
mous cell carcinomas also occur in this area.
months, in which the organisms are not present in these sites,
so infected animals are not always infective for others at
breeding. The organisms penetrate intact mucosa at the site
of implantation and proliferate in the submucosal lymph
spaces. The incubation period may be several weeks or months,
during which time trypanosomes are present in the genital
discharges, so there is a possibility that they may proliferate
in the lumen of the genital tract for long periods before
Pathology of the Vagina and Vulva
invading the tissues. From the initial lesions, the organisms are
disseminated in the blood to other parts of the body, and
edematous swellings occur where they localize. Infection of
the blood may be intermittent or continuous, and there may
be few organisms or many, depending on the virulence of the
strain and the susceptibility of the host. Strains of low viru-
lence may not be demonstrated in the blood by direct smears,
but may be demonstrated by centrifuging plasma or directly
by transfusing blood in large volumes. In these mild infections,
it may also be possible to demonstrate the organisms in genital
washes or discharges, but diagnostic problems are simplified
by an efficient complement-fixation test.
The signs and course of the infections vary considerably,
depending on the virulence of the organism and on the sus-
ceptibility of the host. The resistance of the host can be greatly
modified by climatic conditions, physical condition, intercur-
rent disease, and nutritional status, and the South African
varieties of the disease can be asymptomatic in animals that
are well husbanded. Animals affected with this insidious type
of the disease do act as carriers and reservoirs of infection.
When the infection is attended by clinical signs, the course is
variable; it may be severe and fatal in a few weeks, fatal after
a chronic or intermittent course of from several months to 2
years, or clinical recovery may occur.
The signs of dourine can be divided into genital, cutaneous,
nervous, and general manifestations, which occur separately or
concurrently. The initial signs are usually genital, but may be
nervous or cutaneous. The incubation period of the genital
signs varies from several days to several months, during which
the organisms are present in genital discharges or washings.
The external genitalia are swollen and doughy, but character-
istically the swellings are neither hot nor painful. The degree
of swelling varies considerably from case to case and periodi-
cally in an established case, with a tendency to be permanent
because of induration in chronic infections. The swelling,
when severe, extends to the perineum and ventral abdominal
wall. The lymphocytic follicles of the mucosa of the female
genitalia become hyperplastic and ulcerate, and at this stage,
there may be copious fluid discharge. In males, the swelling
involves the head of the penis as well as the prepuce, and may
cause prolapse of the urethra and penis. In virulent infections,
flat circular ulcers develop in the head of the penis. Healed
ulcers in both males and females often remain as depigmented
scars, and pigmentary atrophy of the skin and genital mucosa
may also occur in the absence of ulceration, the loss of pigment
being, when present, a very characteristic sign of this disease.
Cutaneous lesions may never occur in the mild disease. In
virulent infections, edematous urticaria-like plaques, usually
circular but sometimes linear or in rings, occur in the skin,
especially on the sides of the body and croup. The swelling
may be up to 15 cm in diameter and painless and free of itch.
They disappear in a few days and new ones form. There is
usually no residuum, but sometimes there are local distur-
bances of sweating and pigmentation.
Nervous manifestations develop late in the course and usually
lead to death. There is acute hyperesthesia initially, which may
be generalized or localized to the distribution of particular
nerves. Later there is diminished sensitivity or even anesthesia,
and this is accompanied by paresis or paralysis of individual
motor nerves. The pareses are either unilateral in distribution
or asymmetric in severity and most commonly involve the
facial nerves and the motor nerves of the hindlimbs. Decubi-
tus follows.
Pathology of the Cervix, Vagina, and Vulva Neoplastic Conditions of the Tubular Genitalia 447

The general manifestations are chiefly of continued or
remittent fever, emaciation, and severe anemia. Noninflamma-
tory synovial effusions, superficial lymphadenopathy, uveitis,
and optic atrophy are described.
Apart from changes in the peripheral nerves that are
responsible for the paralytic phenomena, pathologic changes
additional to those that are clinically observable are not
reported. Degenerative changes occur chiefly in the lumbar
and fifth and seventh cranial nerves, being most severe in
the roots and also involving the ganglia. The neuropathy is
probably preceded by edema and inflammation, and these
may still be present at death. The large nerve trunks are trans-
formed into fibrous cords that are fused with the surrounding
muscular fascia. Microscopically, there is edema, mononuclear
cells, and fibrosis of the perineurium. There is slight endoneu-
ral reactivity in fascicles, in which there is extensive fiber
degeneration. Sclerosing changes are also present in the
ganglia.
neoplasms, there is as yet no precise knowledge of the role of
estrogen.
Genital smooth muscle tumors may grow to be as large as
10-12 cm in diameter but most are not invasive. The smaller
tumors are cellular but, as they enlarge, become firm or hard
(hence the clinical term fibroid) because of the connective
tissue stroma. On cut surface, they have a watered-silk appear-
ance, and the color, whether more cellular or white, depends
on relative amounts of muscle and connective tissue. Figure
4-108 shows characteristic gross features of a smooth muscle
tumor in the uterus of a cow. These tumors are not encapsu-
lated but are well demarcated, firm, light tan to white, and
easily shelled out. In almost all cases, the tumors project as

Further reading
Bryans JT, Allen GP. In vitro and in vivo studies of equine “coital”
exanthema. Proc 3rd Int Conf Equine Infect Dis 1973;322-336.
Kirkland PD, et al. Infertility and venereal disease in cattle inseminated
with semen containing bovine herpesvirus type 5. Vet Rec
2009;165:111-113.
Nandi S, et al. Bovine herpes virus infections in cattle. Anim Health Res
Rev 2009;10:85-98.

NEOPLASTIC CONDITIONS OF
THE TUBULAR GENITALIA
Isolated reports have described both benign and malignant
tumors of all histologic components of the tubular genitalia.
Some are common in some locales and warrant brief
A
discussion.
Tumors of the vulva are similar to the tumors of the skin.
Squamous cell carcinoma is well known in the mare, cow, and
ewe, and indeed, a high incidence in cows is reported in tropi-
cal countries. These bovine cases are analogous to the orbital
tumors of cattle, thought to be initiated in a solar dermatosis,
their incidence negatively correlated with the degree of local
epithelial pigmentation.

Smooth muscle tumors (leiomyoma,

leiomyosarcoma)
Leiomyomas are the most common tumors of the tubular genitalia
of the bitch. Leiomyomas are less common in other species but,
regardless of species, leiomyomas have characteristic gross fea-
tures. Their location is the smooth muscle in the wall of the
uterus, cervix, or vagina, and although they may be solitary,
they are sometimes multiple. Most smooth muscle tumors in
the bitch are benign regardless of their histological features,
and some are hormone dependent. It rarely occurs in the bitch
earlier than middle age and is frequently associated with
ovarian follicular cysts or estrogen-secreting tumors, and often
also with endometrial hyperplasia, mammary hyperplasia, and B
mammary neoplasia. Bitches spayed early in life are usually
exempt, and established tumors may regress following neuter- Figure 4-108  A. Leiomyoma seen as a single mass in the dorsal
ing. This tumor has been provoked in guinea pigs by continu- wall of the uterus of a cow. B. The serosa and myometrium over
ous low-level doses of estrogen, but for spontaneous smooth the mass and outer half of the mass have been removed to reveal
muscle tumors as well as endometrial and mammary the typical firm white appearance of leiomyomas.
 447.e1

Further reading
Afshar A, et al. Granular vulvovaginitis (nodular venereal disease) of
cattle associated with Mycoplasma bovigenitalium. Vet Rec
1966;78:512-519.
Katz JB, et al. Clinical, bacteriologic, serologic, and pathologic features
of infections with atypical Taylorella equigenitalis in mares. J Am
Vet Med Assoc 2000;216:1945-1948.
Roth C, et al. Antigenic variation in Trypanosoma equiperdum. Res
Microbiol 1991;142:725-730.
Zablotskij VT, et al. The current challenges of dourine: difficulties in
differentiating Trypanosoma equiperdum within the subgenus Try-
panozoon. Rev Sci Tech 2003;22:1087-1096.
448 CHAPTER 4  •  Female Genital System
B This tumor differs from other infectious tumors in that the
Figure 4-109  A. Leiomyoma arising within the uterine wall of a
bitch. This leiomyoma has expanded outwardly from the serosal
surface. The tumor has been hemisectioned, and both surfaces are
shown. B. Subgross section of a uterine leiomyoma from tissues
of a different bitch. In this case the tumor has grown within the
wall circumferentially. Note the uniform dense nature of the mass.
globose or elliptical masses or as bulbous polyps into the
lumen of the vagina, uterus, or cervix. Some extend outward
from the serosal surface, and a few are found in the mesome-
trium. Figure 4-109A shows a canine uterus with 2 smooth
muscle tumors in the uterus of a bitch. One extends into the
uterine lumen, the other is a mass on the surface of the uterus
near the bifurcation. The subgross photograph in Figure
4-109B shows the dense, homogeneous features typical for
leiomyomas. Some smooth muscle tumors (called Leiomyosar-
comas) are much more irregular, invasive, and frequently
contain areas of necrosis.
Histologically, the tumor is composed of whorling bundles
of smooth muscle cells with abundant stroma but scant inter-
cellular connective tissue. The organization does not depart
much from normal, and often the presence of neoplasm is best
appreciated by the naked-eye appearance of the tissue. Cyto-
logic features, such as pleomorphism, rate of mitoses, and
invasiveness, are used to separate leiomyomas from leiomyo-
sarcomas But there is no correlation between histologic clas-
sification and clinical behavior in dogs. Leiomyosarcoma is
reported in older Saanen goats (Fig. 4-110), with occurrence
reported in siblings, suggesting that in this breed there may
be a genetic defect.
Canine transmissible venereal tumor
This tumor is a contagious neoplasm, transmitted most commonly
by coitus, and occurs on the external genitalia of either sex. It is
Neoplastic Conditions of the Tubular Genitalia
Figure 4-110  Leiomyosarcoma effacing the uterine body, cervix,
and cranial vagina in a Saanen goat, a breed that has a predilection
for this tumor.
also known as Sticker’s sarcoma. It has a histiocytic phenotype.
infecting cells are transplanted and grow like a graft, thus is a
xenograft. This was the first neoplasm in the history of pathol-
ogy to be transmitted experimentally; this was accomplished
by the Russian veterinarian Novinsky in 1863.
The tumor has been reported worldwide. There are marked
fluctuations in its prevalence in endemic areas over the course
of a few years. The tumor tends to be common where dogs
are allowed to run free and is rare where dogs are controlled.
The tumor is not confined to the genitalia, but in some few
cases, is found in cutaneous locations. Metastasis sometimes
occurs to regional lymph nodes, but spontaneous regression can
occur in <6 months.
The diploid number of chromosomes in dogs is 78, and
normally they are acrocentric except for X and Y. The chro-
mosome complement of tumor cells originating in separated
areas of Japan and North America is closely similar, most
tumor cells containing ~59 chromosomes; the minor varia-
tions in chromosome numbers in some cells and in chromo-
some morphology are within the variability accepted for stem
lines of transplantable tumors and long-term cell cultures.
Molecular techniques were used to identify that CTVT from
different continents and collected decades apart are clonal,
and, while there are 2 subtypes, they have a common origin.
The DNA of the CTVT has closely related DNA to wolves
and East Asian dog breeds.
In the vulva and vagina, the tumor arises in the epithelium
and subjacent stroma as one or more gradually enlarging
papular or papillary proliferations (Fig. 4-111). Expansive
growth also occurs mainly in the submucosa, and the overly-
ing epithelium becomes stretched and attenuated. With
rupture or penetration of the epithelium, the tumor projects
into the vagina as an irregular, ulcerated, and friable mass that
may protrude from the vulva. Histologically, the tumor varies
depending on the stage of growth or regression. During the
Pathology of the Cervix, Vagina, and Vulva
Figure 4-111  Transmissible venereal tumor in the vagina of a
bitch. These tumors are transmitted from dog to dog by trans-
plantation of neoplastic cells. (Courtesy Francesca Ivaldi, Brian
Butler, St. George’s University.)
early stage of growth, the tumor is composed of round, oval,
or polyhedral cells with indistinct boundaries and poorly
stained or clear cytoplasm. The nuclei are large in proportion
to cell size with a single, well-defined nucleolus and many
chromatin granules. Variability in the size of the cells is rather
characteristic, and mitoses are frequent. The number of intra-
tumoral lymphocytes increases as growth of the tumor slows
and the tumor begins to regress. Most of the lymphocytes are
T cells.
In the skin also, the tumor seems to arise in the subcutis,
and the epidermis is not usually penetrated. It is suggested
that natural cutaneous implantation occurs in bite or other
wounds. In any locale, the tumor shows a marked tendency to
break down after a few months of rapid progression, and on
incision, the necrotic tissue resembles pus.
The cells of a CTVT are able to avoid detection by immune
cells. They downregulate MHC-1 molecules and there is no
MHC-2 activity, because they secrete inhibitory cytokines
(TGFβ1 and IL-6). In the initial proliferative phase of CTVT,
they express little MHC-1 or -2. After about 12 weeks in an
experimental model, MHC expression increased dramatically
and was associated with the presence of lymphocytes; and at
the same time, the masses stopped growing. It appeared that
the lymphocytes stimulated MHC expression and were
responsible for regression of the tumors.
Dogs are resistant to challenge after natural regression of
the tumor. Secondary tumor challenges begin to regress on
day 9 and disappear after about 2 weeks. The secondary
tumors are rapidly infiltrated by lymphocytes, most of which
are T cells, and undergo degeneration. The tumor is transmis-
sible not only between dogs but also to the fox, coyote, and
jackal.
The life history of the tumors as outlined previously, and
especially the limited metastatic capability, are not constant,
and greater contagiousness and more virulent expressions may
be expected in immunosuppressed individuals and in a canine
population of suboptimal physiologic status. Such appears to
Neoplastic Conditions of the Tubular Genitalia 449
be the case, for example, in the promiscuous, scavenging,
malnourished, feral populations. There, metastases are
common in both sexes as sequelae to the primary lesions. In
the female, extension occurs to the uterus, cervix, and uterine
tubes. In both sexes, there is early spread to inguinal nodes,
which become large and firm. Cutaneous involvement is
also common, with few or many lesions, some up to 6 cm in
diameter, often ulcerated and hemorrhagic. Buccal lesions
and large periorbital tumors are also described. Ocular lesions
are common in this disease, but apart from the sites men-
tioned, conventional metastatic patterns in internal viscera
are rare.
Fibropapilloma of the vulva
This is probably the most common tumor of the bovine vulva
(except in tropical countries) and affects young animals primarily.
It is, briefly, a papilloma growing on a mucous membrane, the
nature of the host tissue apparently determining the reaction
to the virus of bovine verrucae (bovine papillomavirus 1). This
virus infecting the keratinized bovine skin provokes the typical
papilloma of relatively scant connective tissue core and abun-
dant epidermal overgrowth. Transplanted instead to the penile
or vulval mucosa, the contribution of the 2 moieties is reversed,
the bulk of the tumor being connective tissue with just enough
epithelium to cover it. Histologically, the bulk of the tumor
consists of interlacing bundles of fibrocytes. In the younger
tumors, there may be many mitotic figures, and such cases
have often been misdiagnosed as fibrosarcomas. Many of the
plump spindle cells have large nuclei with bizarre nucleoli and
sometimes pale, eosinophilic inclusion-like intranuclear struc-
tures. Collagen formation from the stroma is progressive with
duration. Surface ulceration is followed by superficial
inflammation.
The vulval tumors are usually sessile, rounded growths
initially, but become progressively more cauliflower-like.
Those attached to the penis are often pedunculated. The
natural history of the genital fibropapilloma is the same as that
of the common cutaneous papilloma; spontaneous regression
occurs in 1-6 months or so. Within this period, surgical excision
may be followed by recurrence.
Transmissible genital papilloma of the pig
Ordinary cutaneous warts are not described in pigs. A trans-
missible papilloma occurs in the preputial diverticulum of the
boar. It is transmissible to the lightly scarified vulval mucosa
with an experimental incubation period of ~8 weeks. The
lesions are 1-3 cm in size and papular, some of the larger
lesions being papillary. The clinical course is not many weeks,
after which the lesions begin to regress and are eventually
sloughed. Recovered animals are immune to reinfection.
The lesion, histologically, is typically papillomatous with
extensive uneven acanthosis and epithelial overgrowth, but
with none of the abundant mesodermal reaction that occurs
in the bovine disease outlined previously. The lesions have
intracytoplasmic inclusions that are large, spherical, homoge-
neous with acidophilic stains, and often surrounded by a halo.
A lymphocytic inflammatory response occurs in the underly-
ing dermis.
Carcinoma of the endometrium and cervix
These are rare neoplasms in domestic animals, and therein lies
their interest. The rarity is real and not, as has been implied,
apparent because of inadequate postmortem examination.
450 CHAPTER 4  •  Female Genital System Neoplastic Conditions of the Tubular Genitalia

Figure 4-113  Lymphosarcoma diffusely involving the bovine

uterus on the right has caused massive enlargement of the uterus.
The uterus on the left is from a normal cow.

Figure 4-112  Uterine adenocarcinoma in the wall of a bovine

uterus. These neoplasms stimulate a marked desmoplastic
response, which results in the typical firm, depressed and con-
tracted appearance.

Because cystic endometrial hyperplasia in dogs is common but

carcinoma is rare, there does not seem to be any correlation.
Carcinoma of the endometrium appears to occur more
frequently in cattle than in other domestic animals. The tumors
may be single or multiple, hard, nodules of variable size in the
uterine wall. Desmoplastic reaction is commonly a prominent
feature, which leads to umbilication of the serosal surface (Fig.
4-112). The regional lymph nodes and the lungs are the usual
sites of metastatic lesions.
As noted earlier, focal proliferative lesions of the endome-
trium and normal or prolonged endometrial repair post- Figure 4-114  Cross-section of a uterine horn from a cow with
delivery may be confused as being neoplastic changes in the lymphosarcoma. The wall is infiltrated and grossly thickened by
endometrium. This is especially true in the bitch and queen, the invading neoplasm. Lymphosarcoma has a characteristic tan,
and caution should be exercised before making a diagnosis of slightly soft appearance.
endometrial carcinoma in those species.
Primary skin tumors that occur in the perineal area and
frequently involve the vulva include squamous cell carcino- Lesions of corresponding type occur in the vagina, but do so
mas and melanomas in mares (see Fig. 4-107). less commonly.

Lymphosarcoma Metastatic tumors

Involvement of the uterus is common in the multicentric form
of bovine lymphoma but is uncommon in other species. As
elsewhere, there are 2 anatomic forms of uterine involvement:
diffuse and nodular. In either event, the initial deposition
seems to occur in the endometrium. The diffuse lesion involves
both horns, body, and occasionally the cervix in a more or less
uniform thickening, leaving a uterus that can be very large,
but retaining its typical shape (Fig. 4-113). The thickened wall
loses its elasticity and on cut surface is typically tan and
uniform (Fig. 4-114). Gentle pressure may expel small quanti-
ties of cloudy, highly cellular fluid. There is patchy ulceration
of the endometrial mucosa. There is nothing peculiar to the
nodular form of the disease. These nodules, few or many, may
attain large size and cause corresponding deformity. Central
liquefactive necrosis is common in them. Microscopically,
there is, with either form of the disease, gradual replacement
of the normal uterine structures by infiltrating tumor cells.
With the exception of lymphoma, secondary neoplastic dis-
eases of the tubular genitalia are rather rare. Serosal implanta-
tions occur in peritoneal carcinomatosis. There are a few
reports of results of immunohistochemical staining of tumors
involving either the uterus or ovary in cattle.
Further reading
Ganguly B, et al. Canine transmissible venereal tumour: a review.
Vet Comp Oncol 2013;doi:10.1111/vco.12060; [Epub ahead
of print].
Murchison EP, et al. Transmissible dog cancer genome reveals the
origin and history of an ancient cell lineage. Science 2014;343:
437-440.
Sycamore KF, Julian AF. Lipoleiomyoma of the reproductive tract in a
Huntaway bitch. N Z Vet J 2011;59:244-224.
 450.e1

Further reading
Belov K. Contagious cancer: lessons from the devil and the dog. Bioes-
says 2012;34:285-292.
Cave TA, et al. Uterine carcinoma in a 10-month-old golden retriever.
J Small Anim Pract 2002;43:133-135.
Garcia-Iglesias MJ, et al. Incidence and pathomorphology of uterine
tumours in the cow. Zentralbl Vet A 1995;42:421-429.
McEntee K. Reproductive Pathology of Domestic Mammals. San Diego:
Academic Press; 1990
Mizuno S, et al. Role of lymphocytes in dogs experimentally
re-challenged with canine transmissible sarcoma. Jpn J Vet Sci
1989;51:86-95.
Pérez-Martínez C, et al. Expression of cytokeratins and vimentin in
normal and neoplastic tissue from the bovine female reproductive
tract. J Comp Pathol 2001;124:70-78.
Tanaka H, et al. Nodal, uterine and meningeal gamma(delta) T-cell
lymphomas in cattle. J Vet Med A Physiol Pathol Clin Med
2003;50:447-451.
Whitney KM, et al. Caprine genital leiomyosarcoma. Vet Pathol
2000;37:89-94.
Yang TJ. Immunobiology of a spontaneously regressive tumor, the
canine transmissible venereal sarcoma. Anticancer Res 1988;
8:93-96.
Pathology of the Cervix, Vagina, and Vulva
PATHOLOGY OF THE MAMMAE
The mammae provide the newborn with passive immunity
and nourishment. They may also be a source of infection with
viruses, bacteria, and helminths, either as part of the patho-
genesis of the infection or accidentally from mastitis.
Disease of the mammary gland is commonly of 2 types:
mastitis of dairy animals, and neoplastic disease of dogs and
cats. Diseases of the skin of the mammae, including the papilla
(teat, nipple) of the mammary gland, are discussed in Vol. 1,
Integumentary system.
Developmental biology
The mammary gland is a secretory unit including the mammary
glandular lobules, the lactiferous ducts, lactiferous sinus (when
present), and the papillary duct. The papillary duct exits via
an ostium, around which is a sphincter. Within lobules are
acini surrounded by myoepithelial cells just as occurs in apo-
crine glands of skin.
The glands form on the mammary line or ridge in the
ventrolateral ectoderm of the embryo. This line extends from
the urogenital sinus to the mouth. The ectodermal cells of the
mammary ridge, which are destined to develop into the
mammary glands, congregate in specific areas, of number and
location appropriate to the species, to form the mammary
buds. From the buds, primary sprouts push into the mesen-
chyme, the number of sprouts from each bud determining the
number of glands that will develop. Only one primary sprout
develops from each bud in cattle, sheep, and goats. Secondary
sprouts develop from the primary sprout to form the early
lactiferous ducts.
Horses, sheep and goats develop 2 mammae, cows and
camelids have 4, pigs have 10-13, dogs have 10, and cats have
8 (Table 4-1). Each mamma has one papilla. Cattle, sheep and
goats have one mammary gland per mamma. Pigs, horses, and
camelids have 2 mammary glands in each mamma and thus
2 papillary ducts per papilla. Cats have 3-7, and dogs have
about 14 glands for each mamma. Thus in species with mul-
tiple papillary ostia, the mamma is a composite of mammary
glands, the number corresponding to the number of papillary
Table • 4-1  damage to the ends of the papilla when milking procedures
Normal mammary tissue arrangement in
domestic species
Species Mammae* Glands per mamma†
Bovine 4 1
Porcine 12 2 Innate and acquired resistance of mammae
Equine 2 2
Ovine 2 1
Caprine 2 1
Canine 10 Up to 14
Feline 8 3-7
Camelids 4 2
*Previously and commonly called mammary gland, or quarter in
cattle.
†
Functional unit is the mammary gland. Many species have more than
one gland in each mamma.
Pathology of the Mammae 451
ducts, and each is autonomous and separate from its
neighbors.
Mammary development in males is similar to females in
the embryonic and fetal stages. Male horses (and mice and
rats) do not have papillae; the primary sprouts separate from
the surface epithelium of the mammary bud under the influ-
ence of androgenic hormone and regress. The male mammary
gland is susceptible to hormonal stimulation but is not as
sensitive as the female. Alveolar structures are not present
usually, and the enlargement that occurs under the influence
of estrogen is due to ductal hyperplasia. This is seen in dogs
with hyperestrogenism syndromes, such as in Sertoli-cell
tumors.
Supernumerary papillae (teats, nipples) are common, espe-
cially in cattle. Prevalence is up to 30% and probably subject
to genetic control. They occur in males, except in male horses,
which do not develop papillae. Many supernumerary papilla
have functional mammary tissue.
Inflammatory disease of the mammary glands
Mastitis is inflammation of the mammary gland, and this is
mostly from bacterial infection. The usual route of invasion is
through the papillary ostium and duct (teat canal). Hematog-
enous spread and localization occurs in mycoplasmosis, tuber-
culosis, and brucellosis, and it is possible for direct extension
from local dermatologic conditions of the skin or papilla. The
pathogenesis is complex, with contributing interactions of
innate and adaptive immunity, physical damage to the papil-
lary sphincter, and factors associated with mechanical milking.
The pathogenesis and mechanisms are intensively studied only
in cows. A primary and critical barrier to infection is the
ostium and duct of the papilla and its sphincter. The establish-
ment of a bacterial population in the lactiferous sinus is fol-
lowed by inflammation, but the application of even large
numbers of bacteria to the papillary ostium of an otherwise
healthy papilla results in infection in only a few cases. The
length of the papillary duct seems not to be important. Suc-
cessful defense systems, both innate and acquired, control
entry, proliferation, and tissue invasion and involve a spectrum
of tissue, cellular, and cytokine responses.
Mechanical injury
Machine milking of dairy cattle is prone to induce significant
and the milking equipment are not optimal. This damage,
associated with high vacuum, poor liners, ineffective pulsa-
tions, and overmilking, leads to partial eversion of the duct,
ulceration, fibrosis, and bacterial growth. Papillary injury from
overmilking reduces the keratin plug that helps protect from
ascending infections.
The major factors in whether an animal develops mastitis are
the innate immune response, the pathogen, and the environ-
ment. The major focus is the innate immune response, reduc-
ing exposure to pathogens, and minimizing the effects of the
puerperium.
Reducing contamination of the mammary papilla is the
cornerstone of prevention of mastitis as it reduces potential
exposure to pathogens. Reducing trauma at milking and
chemical injury to the papilla is also well recognized in reduc-
ing intramammary infections through reducing “teat end
lesions,” which are circular or horseshoe-shaped rings around
452 CHAPTER 4  •  Female Genital System
the opening of the papilla. Mastitis only occurs when bacteria
enter the gland; this requires entry through the physical
barrier of the papillary duct (streak canal). This opens at par-
turition when the offspring suckle and during milking. It
remains open for 1-2 hours after milking; this is when most
mammary infections occur. When closed, the canal seals with
keratin and a waxy plug. Mastitis often occurs in the peripar-
turient period when neutrophil migration is inhibited and
fewer reactive oxygen species are produced.
Once inside the lactiferous sinus or ducts, bacteria encoun-
ter macrophages and neutrophils (called somatic cells) in milk
and the lining epithelial cells. These have specific pattern
recognition receptors (PRR), especially toll like receptors
(TLR), which recognize bacterial pathogen-associated molec-
ular patterns (PAMP) and induce the innate or nonspecific
immune response. Activation of intracellular pathways results
in release of immune modulating substances, such as TNF-α,
interleukin-8 (IL-8),and RANTES (regulated on activation,
normal T-cell expressed and secreted) that attract neutrophils
and induce inflammation.
Complement (C5a), lactoferrin, and lysozyme facilitate
this response. Complement 5 is present in mammary secretions
and is cleaved to C5a, probably by mammary macrophages,
the dominant cell in healthy mammary glands. C5a induces
the release of proinflammatory cytokines, attracts neutrophils,
and enhances phagocytosis. Lactoferrin is an iron-binding
protein present in secretions and in neutrophils that inhibits
multiplication of bacteria with high iron requirements. The
high concentration of citrate in normal milk prevents the
action of lactoferrin, but it is effective in the secretion of
the nonlactating gland. Lysozyme is locally synthesized in the
gland, and although the concentration in milk is low, there is
some correlation between milk titer and susceptibility to
infection. The titer may be increased during inflammation.
The most common pathogens in cows are E. coli and Staphy-
lococcus aureus. E. coli mediates inflammation through endo-
toxin and PRR such as TLR-4. S aureus mediates inflammation
by exotoxins and lipoproteins, peptidoglycans, and lipotei-
choic acid. TLR-2 is important. Adaptive immune mecha-
nisms occur but are not as important as the innate system.
There are differences between species in the nature of immu-
noglobulins in colostrum and milk. In the cow, the immuno-
globulins are predominantly of the IgG class and are selectively
transferred from serum to milk. The levels are low in normal
glands, but permeability changes in inflammation allow the
titer to increase. The same class of antibody is identified with
the concentration of plasma cells in the distal papillary part
of the lactiferous sinus and papillary duct, and may affect
organisms resident in the papillary duct. The major role of these
antibodies is to promote opsonization of microorganisms. IgA is
also present in milk and may have a defensive effect on bacte-
rial adherence to epithelial surfaces.
Bovine mastitis
Bovine mastitis is typically a response to ascending infection
of the gland, and bacteria are the most common pathogens.
Potential mammary pathogens are ubiquitous. Modern tech-
niques of microbial classification have identified more than
100 species, subspecies, and serovars isolated from the
mammary gland. Streptococcus agalactiae and some types of
Staphylococcus aureus are obligate parasites of the gland and
inevitable pathogens, but the great majority of infections are
opportunistic.
Pathology of the Mammae
Mastitis is an inflammatory disease rather than an infec-
tious disease; it is the host response to bacteria that determines
if there is local or systemic disease and how severe it is. The
process ranges from transient to persistent and from mild or
subclinical to severe, peracute, and fatal. Notwithstanding the
large number of microbial species that may be isolated from
the diseased mammary gland, bovine mastitis is dominated by
staphylococci and coliforms; the streptococci are now much
less common because of dry cow therapy. Some infections,
such as caused by Cryptococcus and the atypical mycobacteria,
are usually iatrogenic. Some other infections, such as caused
by Pseudomonas and Prototheca, indicate heavy environmental
contamination.
Staphylococcal mastitis
Staphylococcal mastitis is predominantly an infection of
heifers (“heifer mastitis”) at the time of parturition and their
first mechanical milking. Coagulase-negative staphylococci
are the most common cause of heifer mastitis, mastitis around
the time of the first parturition, and before the application of
mechanical milking. S. aureus, a coagulase-positive bacterium,
is a more common cause of mastitis in the older age groups.
Pathogenic strains of staphylococci are always of human or
animal origin and persist as permanent inhabitants of the skin
and mucous membranes; thus infection of the udder is conta-
gious. Little is still known of the pathogenicity of the staphy-
lococci as some strains may produce gangrenous mastitis on
some occasions and only a mild disease on others, with little
correlation of toxin production to toxigenicity.
Staphylococcal mastitis can be subclinical or clinical; mild
or severe and fulminating; and peracute, acute, or chronic. The
severe forms of the disease typically occur shortly after par-
turition, and there is necrosis (gangrene) of affected mammae
and high mortality. The affected mammae are swollen and
tense, hot and firm, and very painful. There is almost complete
stagnation of secretion, and only a few milliliters of brown,
blood-stained, or straw-colored watery fluid can be expressed
from the papilla. Uninfected mammae are also swollen and
tense, and the secretion is reduced but otherwise normal.
Gangrene (Fig. 4-115) usually first affects the papilla and
adjacent portions of or the whole mamma. The tissues become
Figure 4-115  Gangrenous mastitis in a cow.
Pathology of the Cervix, Vagina, and Vulva Pathology of the Mammae 453

Figure 4-117  Hyperemia of the papillary portion of the lactifer-

ous sinus in a cow with severe mastitis.
Figure 4-116  Fibrinosuppurative exudate within the lactiferous
ducts and sinus of a cow with severe mastitis.

blue and eventually black and are softer, insensitive, and cold.
There is pitting edema of the inguinal area, flank, and ventrum,
and the necrotic skin begins to exude serum and to slough,
and gas bubbles develop beneath it. The amount of tissue
involved in the gangrenous process is quite variable, and
groups of necrotic lobules adjoin others that are near normal.
Separation of the gangrenous areas begins a week after onset,
proceeds slowly, and the surface is suppurative and fistulae
develop.
The changes in glands shedding nonhemolytic, coagulase-
negative staphylococci of low pathogenicity without
clinical signs of infection are mild progressive fibrosis and
lobular atrophy. Hemolytic coagulase-positive staphylococci
Figure 4-118  Prominent mammary lobules in clinical mastitis in
produced lobular lesions of greater extent and rate of
a cow. It is difficult to differentiate involuting gland from inflamed
progression.
mammary tissue.
The nongangrenous and mild forms of the disease are the
same for the majority of bacterial mastitides. The gross appear-
ance varies according to severity. The lesions are mostly in the and ductal lumens of some lobules (Fig. 4-119). There is
distal portion of the gland about the lactiferous sinus and large minimal interstitial vascular change. Neutrophils migrate from
ducts. The lactiferous sinus and ducts fill with secretion in the venules through the interstitium (Fig. 4-120), and epithelium
early stage of the disease, the secretion being serous and floc- to contribute to somatic cells in milk. Epithelia of the ducts
cular or distinctly purulent (Fig. 4-116). The epithelial lining become hyperplastic and with increasing severity, develop
of the sinus and papilla may be normal, or it may be red and squamous metaplasia. Lymphocytes and plasma cells accumu-
granular (Fig. 4-117). The adjacent glandular tissue is swollen late in the interstitium, and lymphoid follicles can form, espe-
and turgid (Fig. 4-118). Surface lobulations are distinct cially around the lactiferous sinus and ducts. With increasing
because the swollen lobules protrude. There is no recognizable severity, there is death of the epithelium, sloughing of cells
interstitial edema. The affected lobular tissue is gray and often into the lumen, and erosion. Granulation tissue will form, and
cannot be differentiated from involuting glands, whereas the periductal fibrosis develops. In experimental infection, the
normal lactating tissue is milky white. With time, the lactifer- bacteria enter the tissues and induce a severe reaction with
ous sinus and larger ducts have a thickened lining and small interstitial edema and emigration of neutrophils throughout
rounded polypoid projections into the lumen. The periductal all the tissues. Stromal lymphatics are widely dilated and
tissues become white and tough with fibrosis and a lack of contain numerous neutrophils. The acinar epithelium becomes
glandular tissue. The tissues away from the ducts are not as vacuolated and dies. Granulation and fibrosis progress and
affected. Histologically, the range of changes is very wide, eventually obliterate many of the acini. The inflammation and
depending on the severity, which depends on invasiveness of retention of milk and exudate causes involution in affected
the bacteria, toxin production, and the degree of the host and unaffected acini nearby. The processes of fibrosis and
response. In subclinical mastitis, neutrophils enter the acinar involution continue until the end stages, when some lobules
454 CHAPTER 4  •  Female Genital System
Figure 4-119  Large numbers of neutrophils are within glandular
acini of a mammary lobule in subclinical and clinical suppurative
mastitis in a cow.
Figure 4-120  Early lesion in streptococcal mastitis in a cow.
Neutrophils within the interstitium of the gland migrate from
venules to the lumen of glandular acini, where the bacteria are
present.
show normally involuted tissue, some are obliterated by fibro-
sis, and others have combinations of the two. Because infection
and inflammation progress to involve adjacent tissue, many
lobules are out of phase with each other; and there is a suc-
cession of events from mild to severe as more gland is involved.
Progressive involvement of ducts results in granulation tissue
and fibrosis, and obstruction to milk flow. Upstream tissues
are dilated and contain stagnant milk, exudate, and numerous
organisms. There is concomitant proliferation of periductal
fibrous tissue spreading centrifugally to involve and obliterate
large amounts of lobular tissue. Such granulation tissue in time
cicatrizes, and the duct epithelium can be restored. Similar
changes occur in the larger lactiferous ducts and sinus, but
they are less exuberant, and the epithelium can become squa-
mous and sometimes keratinized.
Persistent foci of infection transition into a granulomatous
reaction previously known as botryomycosis. Initially, necrotic
foci form and are surrounded by an intense neutrophilic and
histiocytic response, and fibrosis develops rapidly. Each granu-
lomatous focus is up to 2 cm in diameter and may be numer-
ous and involve a large proportion of the mamma. The
Pathology of the Mammae
Figure 4-121  Distinct and well-demarcated region of glandular
necrosis, and marked subcutaneous edema, typical of bovine coli-
form mastitis.
granulomas have colonies of large cocci in the center, a
surrounding ring of neutrophils, and sometimes there is a
Splendore Hoeppli reaction. Epithelioid macrophages and
multinucleated giant cells develop and are subsequently sur-
rounded by fibrosis.
Coliform mastitis
Coliform bacteria, especially E. coli, produce mastitis that is
usually severe and in some herds are the major causative
agents. Little is known of the pathogenesis, but coliform mas-
titis is a serious problem in herds where the more common
mammary infections are suppressed or eliminated. The other
Enterobacteriaceae that cause mastitis include bacteria of the
genera Enterobacter, Klebsiella, Citrobacter, Serratia, and
Proteus. These organisms are part of the environmental flora,
and they do not have a predilection for the mammary gland;
mammary infection may be correlated with the level of envi-
ronmental exposure. Each usually produces a clinically severe
form of the disease with systemic reaction and, especially in
the case of E. coli, endotoxemia. A milder progressive type of
disease can also occur.
It is generally accepted that coliform mastitis is an ascend-
ing infection. This infection is often limited to one mamma,
and typically there is a distinct region of dead gland sharply
demarcated from surrounding normal gland (Figs. 4-121,
4-122). Extensive edema and, if very severe, hemorrhage, is
characteristic. The content of the lactiferous sinus and major
ducts is often scant and watery or cloudy and blood stained;
it contains floccules of fibrin and coagulated casein. Coagu-
lated protein forms plugs in the lactiferous ducts. There is
usually severe edema of the subcutis of the gland and ventral
abdomen (see Fig. 4-121).
Microscopically, the inflammatory reaction is centered on
the ducts. The lining of the larger ducts is missing and replaced
by fibrinosuppurative exudate. The lining of the smaller, intra-
lobular ducts is also destroyed and contain plugs of necrotic
detritus. The acini are filled with serous fluid in which there
are vacuolated desquamated epithelial cells, but leukocytes
are few or absent, either in the alveoli or in the septa (Fig.
4-123). The septal tissues, especially the interlobular septa, are
widened by edema, and the lymphatics are widely dilated
and contain fibrin. This can transition to interstitial fibrosis
Pathology of the Cervix, Vagina, and Vulva
Figure 4-122  A distinct region of mammary glandular necrosis
becomes a sequestrum over time in bovine coliform mastitis.
Figure 4-123  Marked epithelial necrosis and interstitial edema
are features of early bovine coliform mastitis.
(Fig. 4-124). In areas of hemorrhage, red blood cells are
throughout the septal connective tissue and within acini.
If the course of the severe inflammation is prolonged
beyond 1-2 days, extensive death of tissue may occur. If the
animal survives, the necrotic tissue, usually most of one
quarter, forms a sequestrum.
Streptococcal mastitis
Bacteria of the family Streptococcaceae are important potential
causes of bovine mastitis, but modern preventive techniques
largely control disease. Streptococcus agalactiae, S. dysgalac-
tiae, and S. uberis are the most frequently implicated. The
common streptococci have the mammary gland of the cow,
Pathology of the Mammae 455
Figure 4-124  Fibrinonecrotic debris within small interlobular
lactiferous ducts and surrounding fibrosis occurs with time fol-
lowing subclinical or clinical bovine mastitis. (Courtesy Murray
Hazlett, University of Guelph.)
goat, and camelid as their natural and sole habitat; environ-
mental factors are important only in the transfer of infection
from animal to animal. Less common isolates cause sporadic
disease only.
The only significant portal of entry of S. agalactiae into the
mammary gland is through the papillary ostium and duct.
Streptococcal mastitis is usually permanent. The organism main-
tains its numbers in the lactiferous sinus and ducts in balance
with inflammatory products. Following the establishment of
infection, the bacterial population may suddenly increase and
penetrate the epithelium, usually for a brief period. The det-
rimental effects of improper machine milking, including
changes in vacuum, rate of pulsation, and period of applica-
tion, plus individual alternations in susceptibility result in
flare-ups of established quiescent infections. Repeated inva-
sion of the epithelium causes inflammatory and reparative
reactions, which, if unchecked, culminate in fibrosis and invo-
lution of the affected quarter.
As with most bacterial mammary pathogens, the severity
of the clinical signs and lesions of streptococcal mastitis vary.
The severe cases have systemic disturbances and the milder
ones not. With streptococci, which do not penetrate the epi-
thelium readily, toxic products of the organisms or of the
inflammation are responsible for necrosis and systemic illness.
The period of epithelial penetration is brief, being of only a
few hours’ duration as the streptococci are rapidly destroyed,
and no bacteria may be cultured.
Summer mastitis
“Summer mastitis” or “Holstein udder plague” is mastitis of
dairy cows that occurs during the summer months, tradition-
ally the dry cow period. This is usually a mixed bacterial
infection affecting immature and nonlactating glands of
animals at pasture. Trueperella (Arcanobacterium) pyogenes is a
common isolate along with S. dysgalactiae, Peptostreptococcus
indolicus, Bacteroides melaninogenicus, Fusobacterium necropho-
rum, and microaerophilic and unidentified obligate anaerobes.
Infection is acquired via the papillary ostium and duct and
contamination by flies attracted to pre-existing lesions of the
mammary papilla.
The lesion is suppurative, necrotic, and centered on the
lactiferous sinus and ducts, thus it is a necrosuppurative
456 CHAPTER 4  •  Female Genital System Pathology of the Mammae

galactophoritis. There is minimal involvement of the acinar

tissue. Grossly visible abscesses form where the exudate
remains stagnant in the ducts. Smaller abscesses occur in the
intralobular ducts. Local death of epithelium and neutrophilic
inflammation are followed by periductal fibrosis, and there are
many lymphocytes and plasma cells within fibrous septa. The
smaller intralobular abscesses may heal with obstruction of
the ducts and lobular scarring. The large abscesses are centered
on the larger ducts, the walls of which are remodeled by
exuberant granulation tissue. The ducts are lined in part by
hyperplastic and squamous epithelium. Bacteria are numerous
in the abscesses and in the lumen of affected ducts. The walls
of the lactiferous sinus and papillary duct are thickened by
granulation tissue and are narrowed or stenotic.

Mycoplasma mastitis
Mycoplasmas are prominent causes of bovine mastitis in some Figure 4-125  Mycoplasma bovis mastitis in cattle differs from
herds. There is rapid spread from an infected mamma to other causes of mastitis in having prominent lymphocytes and
adjoining mammae and to others in the herd. Response to plasma cells within the glandular interstitium. Neutrophils are
therapy is poor. Shedding of the organisms from infected within glandular acini.
quarters is inconsistent, adding to the challenge of clinical
diagnosis and control.
The diseases produced by Mycoplasma spp. and Achole-
plasma spp. are similar. Mycoplasma bovis is the most fre-
quent of these infections, although infections by M. canadense,
M. bovigenitalium, and M. californicum are also common.
The disease begins with a sudden onset of agalactia. The
mamma is initially swollen, firm, and painless. Ordinarily there
are no systemic signs, but other manifestations of systemic
Mycoplasma infection, such as arthritis, may occur. Coexisting
mammary infection with bacteria occur, and the clinical signs
are worse than with a sole infection. The disease spreads
rapidly in a herd; animals in full lactation tend to be affected
simultaneously in all glands. The milk from an infected
mamma appears as normal, but separates into floccular and
clear components. The presence of pus or blood probably
indicates coexistent bacterial infection.
Affected mammae are, in the active stages, swollen and
firm but later become flaccid as rapid involution occurs.
Altered secretion and mammary enlargement may persist for
Figure 4-126  Marked dilation of lactiferous ducts with necrotic
several weeks. Clinical recovery may occur without return to
debris in Mycoplasma mastitis. The gross appearance is caseous
full normal function, and such animals may continue to
exudate.
excrete the organism intermittently for more than a year. It is
not clear whether clinical relapses occur or whether over this
long period there is cumulative mammary injury.
The route of infection of the mammary gland is not clear. septa and subsequent alveolar atrophy. The ductal epithelium
The experimental disease is induced by intramammary or becomes hyperplastic too, and squamous metaplasia develops.
intravenous inoculation and is severe. The usual clinical disease There is also surrounding progressive fibroplasia. The numbers
suggests spread from mamma to mamma, but the occurrence of interstitial lymphocytes continue to increase. Concurrent
of arthritis indicates systemic dissemination. epithelial erosion occurs, and exuberant granulation tissue
The histologic lesions in the gland are different from other forms. When severe, there are polypoid protrusions into the
types of mastitis. Neutrophil migration begins within a few lactiferous ducts and sinuses. Retention of exudate occurs in
hours of experimental infection as perivascular accumulations small ducts, with subsequent mineralization and granuloma
in walls of the lactiferous sinus and lobular interstitium, which formation (Fig. 4-126).
is edematous. The reaction is patchy at first but quickly
involves most of the parenchyma. After several days, lympho- Miscellaneous infections
cytes, plasma cells, and macrophages appear and become There are hundreds of potential mammary pathogens. From a
dense focal lymphocytic aggregates in the intralobular and historical perspective, tuberculous mastitis is an important
periductal connective tissue (Fig. 4-125). These persist for classic disease. It is rare in a majority of countries, but is still
many months. The epithelial cells of alveoli and ducts develop important in those without a modern dairy industry. Its impor-
large lipid vacuoles that are discharged into the lumen. The tance is in its zoonotic potential. Mammary tuberculosis
alveolar epithelium becomes hyperplastic and multilayered. usually develops insidiously without clinical signs of inflam-
This transitions over several weeks to fibrosis of intralobular mation. The gland progressively increases in size and firmness,
Pathology of the Cervix, Vagina, and Vulva
Figure 4-127  Multiple variably sized abscesses and pyogranulo-
mas in Nocardia mastitis in a cow.
and the majority do not have the classic miliary lesions seen
in other organs. The caseous inflammation of the lactiferous
sinus and ducts (galactophoritis) form also occurs. Lactiferous
ducts are especially involved, and bacilli are in the milk before
gross lesions of tuberculosis are evident. The milk may be
physically normal for a long period after infection, even
though it contains the bacilli. In the later stages, there is
reduced watery secretion with floccules of caseous exudate
and large numbers of bacilli. Mycobacterium bovis is the main
pathogen. The inflammatory reaction is similar to other loca-
tions with granulomatous caseous inflammation, pyogranulo-
matous inflammation with distinct granulomas, and/or a
diffuse histiocytic reaction.
Nocardia spp., other Mycobacterium spp., fungi and yeasts
(Cryptococcus neoformans, Candida spp.), and algae (Proto-
theca zopfii) produce granulomatous mastitis. These usually
develop from environmental contamination or after infusion
of contaminated intramammary preparations. Herd outbreaks
or sporadic individual cases occur.
These agents may be present in mammary secretions for
months without causing clinical signs of mastitis. In other
cases, the response to infection is a mild chronic involvement
of the mammary gland, whereas in yet other cases, the reac-
tion is of sudden onset and severe clinical course. Severe
reactions occur near the time of parturition especially. There
may be spread of infection to mammary lymph nodes and
lungs in some cases. Affected quarters enlarge rapidly and
become firm from fibrosis. In some cases, there is a palpable
nodularity, the nodules being 2-5 cm in diameter. These may
be sinus tracts discharging on to the skin. In nocardial mastitis,
some infections are purulent in small foci (Fig. 4-127), but
larger abscesses occur when there is a mixed infection with
Pseudomonas aeruginosa, T. pyogenes, or other organisms. The
lesion in the majority of infections is galactophoritis, similar
to summer mastitis (Fig. 4-128). The range of inflammatory
reactions is identical to infections elsewhere.
Mastitis in swine
E. coli, S. aureus, and, to a lesser extent, Streptococcus spp. are
important mammary pathogens of sows. Little is known of the
pathogenesis, but the range of lesions is identical to bovine mas-
titis. In particular, clinical mastitis caused by coliform bacteria
occurs as a severe infection shortly after parturition. It affects
Pathology of the Mammae 457
Figure 4-128  Chronic galactophoritis results in nodules of lym-
phoid hyperplasia and epithelial hyperplasia of the lactiferous
ducts in bovine mastitis.
more than one mamma and is recognized when there is an
accompanying severe systemic reaction.
An important syndrome in sows is known as the mastitis-
metritis-agalactia syndrome or postpartum dysgalactia syn-
drome. Sows become lethargic; anorexic; and develop fever, a
vulvovaginal discharge and mammary redness, edema, swell-
ing, firmness, and agalactia. Failure of lactation and systemic
signs dominate the syndrome. The syndrome involves a
complex interaction between environment, host, and
pathogens.
Chronic granulomatous mastitis (previously known as bot-
ryomycosis) affecting one or more glands is occasionally
observed in old sows, and most cases are caused by S. aureus.
Mastitis in horses
Mastitis in mares is rare. They are seldom used as dairy
animals and therefore do not have the usual environmental
exposure and mechanical injury that accompanies milk har-
vesting. Bacteria cultured from lactating mares are similar in
spectrum to other species and include streptococci and staph-
ylococci. Mastitis is recognized as excessive swelling of a
mamma in a lactating mare. Lesions are similar to those in
other species.
Mastitis in sheep and goats
Mastitis in the ewe and goat is usually caused by S. aureus or
Mannheimia haemolytica. Corynebacterium pseudotuberculosis
and T. pyogenes also occur. Mastitis in the ewe and doe is
especially important in dairy animals and because the case
fatality rate can be as high as 50%. Except for infection by M.
agalactiae, clinical mastitis usually affects only one mamma.
The range of organisms causing bacterial disease includes the
species pathogenic in the cow.
S. aureus mastitis has a similar course and consequences to
the disease in the cow. The morbidity, however, is higher and
may approach 25% of a flock. M. haemolytica causes mastitis
in sheep on summer range at or near the end of lactation and
affects ~5% of a flock. This is a severe disease with systemic
reaction; if the ewe survives, the systemic reaction subsides
within 48 hours. The affected gland, usually one side, is greatly
enlarged, tense, blue-black, and the secretion becomes watery
and contains flakes. Widespread necrosis of tissue occurs.
Animals that do not die develop abscesses in the course of a
458 CHAPTER 4  •  Female Genital System
week or so; these rupture, fistulate, and eventually most of the
affected gland sloughs. Pneumonia in lambs may accompany
this form of mastitis.
Contagious agalactia caused by M. agalactiae is primarily
a disease of goats, and sheep are less susceptible. The disease
is endemic in countries bordering the Mediterranean Sea. The
organisms are eliminated in the milk and in other discharges
for many months in animals that survive the initial stages of
the disease. This disease begins with septicemia, during which
the organism can be cultured from all tissues and from blood.
It is often fatal. If the infected animal survives, there are signs
of localization in the eyes, periarticular tissues and the lactat-
ing mammary gland. Lactating females and kids are particu-
larly susceptible. Pregnant females may abort or deliver live
but infected fetuses. Lameness, keratoconjunctivitis, and
changes in the milk occur. Mastitis primarily affects the inter-
stitial tissue with secondary changes in the acini. Mild inflam-
mation causes cessation of lactation, but the more severe
reactions may lead to progressive fibrosis with parenchymal
atrophy. Lameness is from arthritis and periarthritis, particu-
larly of the carpal and tarsal joints. The synovial membranes
may be normal, or they may be red or ulcerated with an
increased volume of turbid fluid that may be blood stained.
The ocular lesions, which are present in ~50% of cases, consist
of mucopurulent conjunctivitis and keratitis that may be com-
plicated by ulceration and staphyloma.
Mastitis affecting both mammae of ewes is a common
manifestation of infection by the lentivirus of maedi-visna
(ovine progressive pneumonia; see Vol. 2, Respiratory system).
The mammary disease has an earlier onset and higher preva-
lence than neurologic or pulmonary disease, although the
expression of the various syndromes may be strongly influ-
enced by breed and genotype of the hosts. The presenting
signs are reduced milk yield, poor preweaning growth of
lambs, and progressive atrophy of both mammae. The virus is
present in mammae shortly after exposure. The severity of the
lesions increases with the duration of infection. The virus
replicates in circulating monocytes and more freely in tissue
macrophages. The presence of macrophages in the mammary
interstitium encourages a local inflammatory response consist-
ing largely of lymphocytes and plasma cells. These are promi-
nent in the interstitial and periductal connective tissue, and
lymphoid nodules form. Fibrosis is not a feature. Degeneration
and loss of acinar and ductular epithelium that is present in
advanced lesions may be a consequence of inflammation and
not a direct virus effect.
The lentivirus of caprine arthritis-encephalitis is closely
related to maedi-visna virus (MVV), and the pathogenesis is
similar. Mastitis, although similar to the ovine disease, is not
a prominent feature.
Mammary injury is reported in lactating goats that ingest
persin, the toxic principle of the avocado, Persea americana.
The gland becomes swollen, firm, and red, especially in dorsal
parts, and there may be subcutaneous edema affecting the
gland and adjacent body wall. Histologically, there is wide-
spread degeneration and necrosis of secretory epithelium,
especially at the centers of the lobules. Ductal epithelium is
similarly affected. Cellular inflammatory response is minimal.
Mastitis in dogs and cats
Mastitis is uncommon in dogs and cats. It occurs in lactating
or pseudopregnant animals and occasionally in those
with mammary neoplasia. Staphylococci, streptococci, and
Pathology of the Mammae
Figure 4-129  Severe mastitis in a cat with a distinct region of
mammary necrosis.
coliforms are usually responsible. Staphylococcal mastitis is
more common. Necrosis can occur (Fig. 4-129), and affected
animals are systemically ill; abscesses form. The severely
affected glands are large, firm, and edematous, and the overly-
ing skin becomes taut and shiny. Only a small amount of gray
secretion can be expressed; it may be blood tinged or contain
pus. Mastitis is often superimposed on cystic dilation of
mammary ducts, with or without mammary neoplasia.
Mastitis in camelids
Surveys of the milk from camels, llamas, and alpacas suggest
that infection of the mammary gland is very common; most
cases are subclinical. Clinical disease appears to be very
uncommon. Based on culture, Staphylococcus spp. and Strepto-
coccus spp. represent the vast majority of bacteria isolated.
There is the same range of clinical disease as in other species,
and the pathophysiology is assumed to be the same. Severe
mastitis with sepsis, suppurative mastitis, and chronic fibrosing
mastitis all occur. Poor cria growth rate is often an indication
of mastitis.
Further reading
Ballou MA. Growth and development symposium: inflammation: role
in the etiology and pathophysiology of clinical mastitis in dairy
cows. J Anim Sci 2012;0:1466-1478.
Bergonier D, et al. Mastitis of dairy small ruminants. Vet Res 2003;
34:689-716.
Biddle MK, et al. Patterns of mycoplasma shedding in the milk of dairy
cows with intramammary mycoplasma infection. J Am Vet Med
Assoc 2003;223:1163-1166.
Corbellini LG, et al. Bovine mastitis due to Prototheca zopfii: clinical,
epidemiological and pathological aspects in a Brazilian dairy herd.
Trop Anim Health Prod 2001;33:463-470.
De Vliegher S, et al. Invited review: mastitis in dairy heifers: nature of
the disease, potential impact, prevention, and control. J Dairy Sci
2012;95:1025-1040.
Gómez-Martín A, et al. Contagious agalactia due to Mycoplasma spp.
in small dairy ruminants: epidemiology and prospects for diagnosis
and control. Vet J 2013;198:48-56.
Nicholas RA, Ayling RD. Mycoplasma bovis: disease, diagnosis, and
control. Res Vet Sci 2003;74:105-112.
 458.e1

Further reading
Aalbaek B, et al. Mycoticc and algal bovine mastitis in Denmark. APMIS
1994;102:451-456.
Baer C, Bilkei G. Ultrasonographic and gross pathological findings in
the mammary glands of weaned sows having suffered recidiving
mastitis metritis agalactia. Reprod Domest Anim 2005;40:544-547.
Benites NR, et al. Aetiology and histopathology of bovine mastitis of
spontaneous occurrence. J Vet Med 2002;49:336-370.
Bhutto AL, et al. Udder shape and teat-end lesions as potential risk
factors for high somatic cell counts and intra-mammary infections
in dairy cows. Vet J 2010;183:63-67.
Bradley A. Bovine mastitis: an evolving disease. Vet J 2002;164:116-
128.
Burton JL, Erskine RJ. Immunity and mastitis: some new ideas for an
old disease. Vet Clin North Am Food Anim Pract 2003;19:1-45.
LeMaréchal C, et al. Molecular basis of virulence in Staphylococcus
aureus mastitis. PLoS ONE 2012;6:e27354.
Oelrichs PB, et al. Isolation and identification of a compound from
avocado (Persea americana) leaves which causes necrosis of the
acinar epithelium of the lactating mammary gland and the myocar-
dium. Nat Toxins 1995;3:344-349.
Pedersen LH, et al. Early pathogenesis and inflammatory response in
experimental bovine mastitis due to Streptococcus uberis. J Comp
Pathol 2003;128:156-164.
Regassa A, et al. Prevalence, risk factors, and major bacterial causes of
camel mastitis in Borana Zone, Oromia Regional State, Ethiopia.
Trop Anim Health Prod 2013;45:1589-1595.
Sanchis R, et al. Inoculation of lactating ewes by the intramammary
route with Mycoplasma agalactiae: comparative pathogenicity of
six field strains. Vet Res 2000;31:329-337.
Stevens MG, et al. Compromised neutrophil function and bovine E. coli
mastitis: is C5a the missing link? Vet Immunol Immunopathol
2012;149:151-156.
Tibary A, et al. Infectious causes of reproductive loss in camelids.
Theriogenol 2006;66:633-647.
Whelehan CJ, et al. Experimental Staphylococcus aureus infection of
the mammary gland induces region-specific changes in innate
immune gene expression. Vet Immunol Immunopathol 2011;140:
181-189.
Pathology of the Cervix, Vagina, and Vulva Mammary Masses Including Neoplasia 459

Preziuso S, et al. Experimental maedi visna virus infection in sheep: a Mammary hypertrophy is when a whole mamma or
morphological, immunohistochemical and PCR study after three mammae become larger than normal for the physiologic state.
years of infection. Eur J Histochem 2003;47:373-378. It is common in dogs because of their propensity to lactate
Wellnitz O, Bruckmaier RM. The innate immune response of the bovine during pseudopregnancy, as an adaptation to enhance survival
mammary gland to bacterial infection. Vet J 2012;192:148-152. of pups in a pack situation. Precocious mammary develop-
ment and lactation occurs with exposure to exogenous hor-
mones, such as transcutaneous human hormonal replacement
MAMMARY MASSES INCLUDING therapy. Some high-producing lines of dairy cattle and goats
NEOPLASIA have mammary hypertrophy and lactation, including males.
Some dogs spayed while in diestrus will develop hypertrophy
Neoplasia of mammae is extremely important from an indi- and lactation because of a prolactin surge in response to a
vidual or comparative perspective. Not every mass in a sudden reduction in progesterone concentration. The histo-
mamma is neoplastic, but neoplasia is usually the top of the logic change is generalized hyperplasia of all mammary tissue.
list of diagnostic hypotheses. Neoplasia is very common in the Localized mammary hyperplasia is recognized when the
dog, less so in the cat, and rare in other species. The prognosis gland should be involuted (Fig. 4-131). Hyperplasia within a
for neoplasia in the mammary glands is most important. It is gland is either of the epithelium of a duct or of the lobule of
usually poor for all species except the dog. Diagnosis of a gland. Papillary hyperplasia within a duct is often an inci-
mammary neoplasia is best achieved by excisional biopsy; dental finding or causes cystic ductal dilation. Lobular hyper-
cytology can be of use in identifying inflammation and malig- plasia (Fig. 4-132) or subsequent dysplasia occurs at any stage
nant stromal neoplasms in dogs, and is very accurate in all of mammary physiologic events and results in enlargement of
other species, especially in cats. one or more lobules, a whole mammary gland, and or mamma
This section will cover non-neoplastic diseases first; neo- and mammae. Lobular hyperplasia has 3 main manifestations.
plastic disease will follow. The first is hyperplasia of the epithelium of the glandular
acini, often with luminal dilation from secretion. Second is
Non-neoplastic mammary enlargement
and masses
Mammary tissue undergoes physiologic change at the time of
puberty when ducts proliferate under hormonal influences of
estrogen, progesterone, growth hormone, and prolactin, to
name a few. With pregnancy, the gland undergoes further
development and enlargement, especially with lactation. Invo-
lution of the gland follows, and acinar tissue disappears in
most species. The common non-neoplastic lesions of the
mammary gland are cystic dilation of mammary ducts and
mammary hypertrophy and hyperplasia.
Cystic dilation of mammary ducts (Fig. 4-130) is very
common, especially in dogs and cats. It is usually secondary
to obstruction of a duct or the papillary canal by periductal
fibrosis, localized hyperplasia, or neoplasia. Continued secre-
tion and buildup of content dilates the duct, and the epithe-
lium accommodates the larger diameter by a lining that is
attenuated or normal in appearance.
Figure 4-131  Focal hyperplasia of the mammary gland in a cow.

Figure 4-130  Cystic dilation of mammary ducts secondary to Figure 4-132  Mammary lobular hyperplasia with lactation in
obstruction of secretion outflow in a cat. a dog.
460 CHAPTER 4  •  Female Genital System
Figure 4-133  Proliferation of lactiferous ducts and surrounding
stroma in fibroepithelial mammary hyperplasia in a young cat.
adenosis (also called epitheliosis), when the epithelium under-
goes hyperplasia and the lumen is filled with basiloid epithe-
lial cells. The third is fibroadenomatous hyperplasia.
Fibroadenomatous hyperplasia is common in cats, espe-
cially intact female cats <2 years of age. This spontaneous
condition occurs in the luteal phase of estrus, early in preg-
nancy or after progestin therapy, and accompanies a high
serum concentration of progesterone.
Progesterone mediates hyperplasia through growth
hormone and insulin-like growth factor 1 in the ductal buds.
In young queens, there may be an exaggerated tissue response
to prolactin. Resolution is spontaneous; antiprogestin therapy
or ovariohysterectomy are effective. Megestrol acetate or
other progestins will induce this in old neutered males and
females, and drug withdrawal and mastectomy is curative.
Whole lobules, glands, or mammae are affected. Clinical
enlargement is dramatic, and the affected mamma or mammae
are hot and painful, mimicking mastitis. The histologic change
is dramatic proliferation of lactiferous ducts that are widely
separated by loosely arranged and often concentrically arranged
fibrous stroma (Fig. 4-133). Hemorrhage and/or coagulative
necrosis of affected glands may occur.
Galactostasis is when a lactating mammary gland is filled
with milk, but there is no let-down of milk because of inhibi-
tion of release of oxytocin, often from stress. It also occurs
after weaning or in pseudopregnancy. It is common in dairy
animals of all species. The mammae become engorged, hot,
and painful from milk retention; there is no systemic illness
or other indicators of mastitis. Agalactia is the other extreme,
where no mammary enlargement or lactation occurs after
parturition. This is rare and the cause is unknown. The udders
are hard (hence the colloquial name of “hard udder”), but no
milk is produced. In caprine arthritis encephalitis virus
(CAEV) in goats and maedi-visna virus (MVV) infection in
sheep, there is usually microscopic lymphocytic interstitial
inflammation.
Mammary neoplasia in dogs
There is much research in canine mammary neoplasia because
it is common and may be a model for breast cancer in women.
Little is known of its cause or pathogenesis. Risk factors are
well known, and age at neutering has a major effect on its
development. Overall prevalence of mammary neoplasia is
Mammary Masses Including Neoplasia
2-4%. Study populations vary considerably as spaying bitches
at a young age is very common in some regions and not in
others. The window of susceptibility of developing mammary
neoplasia is up to 2 years of age. Ovariectomy before the first
estrus reduces the prevalence to about 0.05%, after the first
estrus and before the second about 0.8%, and after the second
estrus increases it to about 26%. Late ovariectomy has some
protective effect. A high-protein diet decreases susceptibility;
medroxyprogesterone acetate treatment and being a purebred
increases it. Although the initiating event is unknown, most
accept progression from mammary hyperplasia to dysplasia to
benign neoplasia and to malignant neoplasia. The majority of
publications examine aspects of pathogenesis, particularly
molecules, receptors, and genes that are then related to one
or more of the classified phenotypes.
Prognosis and grading of mammary neoplasia
The basis of prognosis of neoplasia is determining phenotype
and relating this to patient outcome, often with determining
a grade. More than 35 phenotypes are described for mammary
neoplasia; 7 are benign and the rest are considered histologi-
cally malignant (Table 4-2). The large number of types and
subtypes is because of wide heterogeneity of mammary
tumors in dogs. Surprisingly, studies of prognosis based on
patient outcome are few and often have considerable meth-
odologic bias. Results vary greatly, so it is difficult to provide
accurate survival data.
The majority of publications concern canine mammary
carcinoma. Little is written about mammary sarcomas or
those with malignant epithelial and stromal elements (carci-
nosarcomas) (see later). Some specific types of mammary
neoplasia have a poor prognosis. Mammary osteosarcoma, ana-
plastic carcinoma, lipid-rich carcinoma, micropapillary inva-
sive carcinoma, inflammatory carcinoma, comedocarcinoma,
and squamous cell carcinoma are aggressive and usually have
short survival times after diagnosis. These are the minority of
cases.
Benign mammary neoplasms
Mammary neoplasms with an epithelial and mixed epithelial
and myoepithelial component are the most common type in
dogs. Benign neoplasms represent more than half of mammary
masses. Affected dogs may have one clinically detectable
tumor, but they usually have multiple microscopic neoplasms.
It is common to see different types within the same mamma.
The masses are usually well circumscribed and solid (Fig.
4-134). They have a histologically benign appearance, includ-
ing lack of invasion, minimal anisokaryosis/pleomorphism,
and a low mitotic index (usually <10 per 10 high-power
fields). These are divided into adenomas (simple, complex,
and basaloid) (Fig. 4-135), fibroadenomas (low and high cel-
lularity), benign mixed tumors (those complex tumors con-
taining bone), and ductal papillomas (Fig. 4-136).
Mammary carcinomas
Although less common than their benign counterparts,
mammary carcinomas are usually the main focus of studies of
pathogenesis and prognosis. They are very heterogeneous, and
classification schemes are becoming increasingly complex.
There are special types of carcinoma with a poor prognosis
and short survival times; for the others there are prognostic
factors. Few studies have an end point of death from neoplas-
tic disease. Many studies use the end point of carcinoma
Pathology of the Cervix, Vagina, and Vulva Mammary Masses Including Neoplasia 461

Table • 4-2 
Histologic classification of canine
mammary tumors
Benign mammary Adenoma, simple
tumor Intraductal papillary adenoma
Ductal adenoma (subtypes include
basaloid adenoma and adenoma with
squamous differentiation)
Fibroadenoma
Myoepithelioma
Complex adenoma
Benign mixed tumor
Mammary Carcinoma, in situ
carcinomas Carcinoma, simple (subtypes are tubular,
tubulopapillary, cystic-papillary,
cribriform) Figure 4-134  Multiple mammary adenomas in a dog.
Carcinoma, solid
Carcinoma, anaplastic
Carcinoma, micropapillary invasive
Comedocarcinoma
Carcinoma arising in a complex adenoma/
mixed tumor
Carcinoma, complex type
Carcinoma and malignant myoepithelioma
Carcinoma, mixed type
Ductal carcinoma
Intraductal papillary carcinoma
Mammary Squamous cell carcinoma
carcinomas, Adenosquamous carcinoma
special types Mucinous carcinoma
Lipid-rich (secretory) carcinoma
Spindle cell carcinomas
Malignant myoepithelioma
Squamous cell carcinoma, spindle cell
variant
Carcinoma, spindle cell variant Figure 4-135  Complex mammary adenoma with epithelial and
Inflammatory carcinoma myoepithelial components. Myoepithelial proliferation predomi-
Mammary Osteosarcoma nates in this example in this dog.
sarcomas Chondrosarcoma
Fibrosarcoma
Hemangiosarcoma
Other sarcomas
Malignant mixed Carcinosarcoma, malignant mixed
mammary tumor mammary tumor

classification, lymphatic invasion, or regional lymph node

metastasis as a proxy instead. Publications that use death from
neoplasia as an end point report that 20-50% of those diag-
nosed as carcinoma on histologic criteria result in death from
neoplasia. The metastatic rate is variable in reports and is as
low as 10%. Most types of mammary carcinoma do not have
a sufficient number of cases with 2-year follow-up to have
meaningful results. Mammary carcinomas are more prevalent
in the older age groups that have a shorter life expectancy
anyway. This adds to the complexity and difficulty in provid-
ing a valid and accurate prognosis.
Simple carcinomas, solid carcinomas, and complex carcino- Figure 4-136  Intraductal papilloma in a dog that resulted in
mas are the more common types. There is considerable cystic ductular dilation.
462 CHAPTER 4  •  Female Genital System
Figure 4-137  A well-circumscribed mammary carcinoma in a dog
showing compressed fibrous tissue at the periphery. The prognosis
is much better than a similar carcinoma that has peripheral
invasion.
Figure 4-138  A poorly circumscribed canine mammary carci-
noma with peripheral invasion has a poor prognosis.
variation in the survival times reported, but only low numbers
of these metastasize. Cytology and metastatic potential do not
correlate well. In general, the prognosis of mammary carcino-
mas is based on:
• Age of dog at diagnosis
• Size of neoplasm
• Peripheral infiltrative growth pattern (poorly circum-
scribed tumors)
• Lymphatic invasion
• Lymph node metastasis
• Poor differentiation and special types
• Grade
A mammary carcinoma >3 cm in diameter has a poorer
prognosis, with a significantly shorter disease-free interval and
time until death.
Infiltration of a carcinoma into surrounding tissue, vari-
ously called peripheral invasion, poorly circumscribed, or infil-
trative pattern (Figs. 4-137, 4-138), indicates a poor prognosis,
with markedly reduced survival after diagnosis. Despite this,
not all carcinomas with this behavior metastasize. Poorly
circumscribed or invasive types have a much shorter survival
time; for example, 26% of invasive solid carcinomas have
Mammary Masses Including Neoplasia
Figure 4-139  Lymphatic invasion of a canine mammary carci-
noma indicates a very poor prognosis.
Figure 4-140  Anaplastic canine mammary carcinoma has poor
differentiation and invasion; both are poor prognostic indicators.
a 12-month survival versus 73% for well-circumscribed
examples.
Lymphatic invasion (Fig. 4-139) or lymph node metastasis
(clinical stage) in mammary neoplasms carries a poor progno-
sis with short survival intervals after diagnosis. This is particu-
larly the case in the subtype of mammary carcinoma known
as inflammatory carcinoma. Inflammatory carcinoma is named
for its clinical signs of swelling and heat. Histologically, there
are neoplastic emboli in dermal lymphatics and no histologic
inflammatory reaction.
Carcinomas with decreasing degrees of differentiation are
more likely to metastasize; thus simple, solid, and anaplastic
carcinomas have, in turn, a greater chance of metastasis and a
shorter survival time. Thus classification of the tumor is prog-
nostic (Fig. 4-140). Anaplastic carcinoma, lipid-rich carci-
noma, micropapillary invasive carcinoma, comedocarcinoma,
and squamous cell carcinoma are aggressive and usually have
short survival times after diagnosis.
Grading schemes for carcinomas, using modification of the
Elston and Ellis/Nottingham method for human breast carci-
noma, are available. There is variability in how the criteria are
applied, and the number of cases with good follow-up is
Pathology of the Cervix, Vagina, and Vulva Mammary Masses Including Neoplasia 463

Table • 4-3 
Grading scheme for mammary carcinomas
Characteristic Feature Points

Tubule formation Formation of tubules in >75% 1

Formation of tubules in 10-75% (moderate formation of 2
tubular arrangements admixed with areas of solid growth)
Formation of tubules in (<10%) (minimal or no tubule 3
formation)
Nuclear pleomorphism Uniform or regular small nucleus and occasional nucleoli 1
Moderate degree of variation in nuclear size and shape, 2
hyperchromatic nucleus, presence of nucleoli (some of
which can be prominent)
Marked variation in nuclear size, hyperchromatic nucleus, 3
often with >1 prominent nucleoli
Mitoses per 10 HPF 0-9 mitoses/10 HPF 1
10-19 mitoses/10 HPF 2
≥20 mitoses/10 HPF 3
Grade 3-5 total points I (low, well differentiated)
6-7 total points II (intermediate, moderately differentiated)
8-9 total points III (high, poorly differentiated)
HPF, High-power fields.

relatively low. The schemes are based on degree of tubule

formation (in mixed tumors, this is best done in the epithelial-
predominant part), nuclear pleomorphism, and particularly,
mitotic index (in the region with the highest number of
mitoses) (Table 4-3). Those with a grade of III have a worse
prognosis.

Mammary sarcomas
Mammary sarcomas represent about 5% of mammary tumors.
These are located within mammary tissue and are separate
from those that arise in the skin and subcutis. They are identi-
cal to their soft tissue counterparts in their appearance and
histologic criteria (see Neoplasms of skin and soft tissue). The
most well-known is the mammary osteosarcoma (Fig. 4-141),
a unique type of soft tissue osteosarcoma that has an especially
poor prognosis and a very short survival time. The overall
prognosis for mammary sarcoma is very poor, and the 6-, 12-, Figure 4-141  Mammary osteosarcomas in dogs are highly meta-
and 24-month survival is 50, 30 and 10%, respectively. static and have a very short survival time after diagnosis.

Mammary neoplasia in cats

Mammary neoplasms are much less common in cats than in
dogs, at 20-31 per 100,000 females. Neoplasia in males also
occurs. About 75-90% are carcinomas, and most of these are
eventually metastatic. The primary tumor is usually adjacent
to the nipple. It metastasizes to lymph nodes, lungs, and other
mammae. The Siamese and other short-haired pure breeds are
particularly affected. There is a 7-9 year-old risk plateau.
Intact animals are at a slightly greater risk. Cats spayed before
1 year of age have much less risk of developing mammary
carcinoma.
Mammary carcinomas in cats are much less heterogeneous
than in dogs, and a myoepithelial component is rare, as are
unique or special types such as inflammatory carcinoma. Most
are tubulopapillary, solid, or cribriform carcinomas (Figs.
4-142, 4-143). There is no convincing difference in outcome,
so most pathologists do not subclassify feline mammary
carcinomas. The majority are estrogen receptor, progesterone
receptor, and human epidermal growth factor receptor-2 neg-
ative on immunohistochemistry too.
The prognosis of feline mammary carcinomas is based on
• Age at diagnosis
• Volume or diameter of the tumor
• Aggressiveness of surgery
• Presence of lymph node involvement (clinical stage)
• Grade
There is a general lack of good long-term follow-up of
mammary neoplasia; most studies have only low numbers
and are not based on thorough postmortem and histologic
evaluation. It does appear that older cats diagnosed with
mammary carcinoma have a shorter survival time, but why is
not known. Carcinomas usually occur in older cats, however.
Mammary carcinomas >3-cm diameter have the worst
464 CHAPTER 4  •  Female Genital System
Figure 4-142  Feline mammary carcinoma that is well circum-
scribed with a necrotic center. Most are metastatic.
Figure 4-143  Photomicrograph of tubule formation in a feline
mammary carcinoma.
prognosis, and a survival time of 6 months is anticipated.
Those with a tumor diameter of <2 cm have a median survival
of >3 years, and those between 2 and 3 cm, 2 years. Mammary
carcinomas treated with complete mastectomy appear to have
a longer survival compared to lumpectomy. Clinical stage as
Mammary Masses Including Neoplasia
determined by lymphatic invasion and metastasis to the super-
ficial inguinal or axillary lymph nodes is a poor prognostic
indicator.
Grade is an independent prognostic factor. The human
mammary carcinoma grading scheme of Elston and Ellis/
Nottingham scheme (see Table 4-2) is applied to feline
mammary carcinomas, and there is a significant difference in
survival time between grades. Those with grade II and III
tumors seldom survive beyond 48 and 12 months, respec-
tively. Most mammary carcinomas are grade II or III. Mitotic
index is especially important in this scheme.
Mammary neoplasia in other species
Mammary neoplasia is reported in every domestic species, but
apart from the dog and cat, is very rare. Mammary adenomas
are especially rare and would be undetected unless they cause
enlargement of the whole mamma. Reported neoplasms are
carcinomas, and most have metastases. Nothing is known of
risk factors or of pathogenesis.
Further reading
Dalton LW, et al. Histologic grading of breast cancer: linkage of patient
outcome with level of pathologist agreement. Mod Pathol
2000;13:730-735.
Goldschmidt M, et al. Classification and grading of canine mammary
tumors. Vet Pathol 2011;48:117-131.
Hughes K, Dobson JM. Prognostic histopathological and molecular
markers in feline mammary neoplasia. Vet J 2012;194:19-26.
Im KS, et al. Analysis of a new histological and molecular-based clas-
sification of canine mammary neoplasia. Vet Pathol 2013;51:549-
559.
Morris J. Mammary tumours in the cat: size matters, so early interven-
tion saves lives. J Feline Med Surg 2013;15:391-400.
Peña L, et al. Prognostic value of histological grading in noninflamma-
tory canine mammary carcinomas in a prospective study with two-
year follow-up; relationship with clinical and histological
characteristics. Vet Pathol 2013;50:94-105.
Rasotto R, et al. A retrospective study of those histopathologic param-
eters predictive of invasion of the lymphatic system by canine
mammary carcinomas. Vet Pathol 2012;49:330-340.
For more information, please visit the companion site:
PathologyofDomesticAnimals.com
 464.e1

Further reading
Bostock DE. The prognosis following the surgical excision of canine
mammary neoplasms. Eur J Cancer 1975;11:389-396.
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. The
value of histologic grade in breast cancer: experience from a large
study with long term follow-up. Histopathology 1991;19:403-410.
Giménez F, et al. Early detection, aggressive therapy: optimizing the
management of feline mammary masses. J Feline Med Surg
2010;12:214-224.
Hellmén E, et al. Prognostic factors in canine mammary tumors: a
multivariate study of 202 consecutive cases. Vet Pathol 1993;30:
20-27.
Kristiansen VM, et al. Effect of ovariohysterectomy at the time of tumor
removal in dogs with benign mammary tumors and hyperplastic
lesions: a randomized controlled clinical trial. J Vet Intern Med
2013;27:935-942.
Loretti AP, et al. Clinical, pathological and immunohistochemical study
of feline mammary fibroepithelial hyperplasia following a single
injection of depot medroxyprogesterone acetate. J Feline Med Surg
2005;7:43-52.
Matos AJ, et al. Prognostic studies of canine and feline mammary
tumours: the need for standardized procedures. Vet J 2012;193:
24-31.
Ordás J, et al. Immunohistochemical expression of progesterone recep-
tors, growth hormone and insulin growth factor-I in feline fibroad-
enomatous change. Res Vet Sci 2004;76:227-233.
Overley B, et al. Association between ovarihysterectomy and feline
mammary carcinoma. J Vet Intern Med 2005;19:560-563.
Sleeckx N, et al. Canine mammary tumours, an overview. Reprod
Domest Anim 2011;46:1112-1131.
Valarmathi MT, Biechler SV. Feline mammary neoplasms: the cancer
stem cell hypothesis. Vet J 2013;196:277-278.
CHAP TER 5 
Male Genital System
Robert A. Foster
GENERAL CONSIDERATIONS 465
Sampling of the male genital tract 465
Spermatogenesis 466
Oxidative stress and testicular function 467
Testicular immune function 467
Immunity in the reproductive tract 468
DISORDERS OF SEXUAL DEVELOPMENT 468
SCROTUM 471
VAGINAL TUNICS 473
TESTIS AND EPIDIDYMIS 474
Disorders of sexual development 476
Cryptorchidism 476
Testicular hypoplasia 478
Other testicular disorders of development 479
Disorders of mesonephric and paramesonephric structures 480
Variation in testicular and epididymal size 481
Testicular atrophy and degeneration 481
Testicular hypertrophy 485
Inflammation of the testis and epididymis 485
Orchitis 485
Epididymitis 487
Circulatory disturbances 491
Neoplasms of the testis and epididymis 492
Sex cord−gonadal stromal tumors 492
Germ cell tumors 495
ACKNOWLEDGMENT
We gratefully acknowledge the contributions of all previous
authors to this chapter, including Drs. Ken Jubb, Peter Kennedy,
Nigel Palmer, and Phil Ladds.
GENERAL CONSIDERATIONS
The pathology of the male reproductive system is closely
linked to theriogenology, so the clinical significance and patho-
genesis of lesions and diseases are very important. For each
species, there is a short list of common diseases. We highlight
these for each anatomic location.
Information on basic mechanisms of reproductive disease
in companion animals is gleaned and extrapolated from a
variety of human, laboratory animal, and/or toxicologic
studies. There are physiologic differences between species that
can impact outcome, however. Diseases of production animals
are frequently handled pragmatically by culling and replace-
ment, so in-depth studies are not always available.
The bridge between theriogenology and pathology is hin-
dered by differing meanings of diseases. Orchitis is a common
clinical diagnosis to denote any swelling of the scrotum, rather
than its literal “inflammation of the testis.” Similarly, the ability
of spermatozoa to stimulate a florid inflammatory reaction is
overlooked, and epididymal “abscess” is used even though
there may be no or few neutrophils. We highlight those terms
where the clinical meaning differs from the usage in pathology.
Mixed germ cell−sex cord stromal tumor 496
Other primary tumors 496
Miscellaneous diseases of the testis and epididymis 497
SPERMATIC CORD 497
Varicocele 497
Other vascular lesions 498
Scrotal hernia 498
Miscellaneous diseases of the spermatic cord 498
ACCESSORY GENITAL GLANDS 499
Vesicular glands and ampullae 499
Disorders of sexual development 499
Inflammation of the vesicular glands 499
Prostate and bulbourethral glands 500
Disorders of sexual development 500
Inflammation of the prostate and bulbourethral gland 501
Hyperplasia and metaplasia of the prostate and
bulbourethral gland 502
Neoplasms of the prostate and bulbourethral gland 503
Miscellaneous conditions of accessory genital glands 504
PENIS AND PREPUCE 505
Inflammation of the penis and prepuce
(phaloposthitis) 506
Neoplasms of the penis and prepuce 508
From a functional and pathogenetic point of view, the male
reproductive system is designed to deliver viable spermatozoa
to the female. It is composed of a production unit (the testis),
a maturation and maintenance unit (epididymis), and a trans-
portation unit (various parts of the ducts and accessory genital
glands). Each will be dealt with in turn. The male still com-
prises 50% of the reproductive unit.
Sampling of the male genital tract
The foundation of macroscopic and histologic evaluation of
any system is the problem-based approach. The standard diag-
nostic protocol is to interpret clinical information, develop
diagnostic hypotheses or differential diagnoses, and perform
suitable tests to confirm or exclude the possible causes. Each
test, such as macroscopic evaluation, will exclude some pos-
sibilities and perhaps add others. Eventually a final diagnosis
can be reached. Evaluation of each component of the male
genital tract requires knowledge of normal anatomy. For a
thorough examination, all components should be examined
carefully. Examination of the accessory genital glands usually
requires their removal from the pelvis.
For histologic evaluation of the majority of components of
the male tract, standard collection procedures apply and for-
malin fixation and paraffin embedding is adequate and cost
effective. The testis, however, requires a separate approach.
Although the function of the testis is the same for each
species, this organ varies greatly both in its anatomy, histology,
and response to injury. It is important to know the resistance
465
466 CHAPTER 5  •  Male Genital System
of the testis of each species to autolysis and handling pressure.
It is also important to know the orientation of the testicular
mediastinum, efferent ductules, and the seminiferous tubules.
The type and number of samples collected will also depend
on the suspected diseases.
One of the simplest evaluations is for testicular neo­
plasia. Standard formalin-fixed paraffin-embedded samples
of testicular tumors are sufficient for diagnosis. Evaluation
of the stages of spermatogenesis requires much more
sophistication.
The first step in evaluating spermatogenesis is to determine
how sensitive the testis is to handling pressure and autolysis.
It is best to fix testicular tissues within minutes of anesthesia
or euthanasia and removal. The testes of rams, for example,
require immediate fixation, whereas bovine testes can remain
refrigerated for several hours. The testes of some species are
susceptible to the effects of handling and the pressure applied
while tissue slices are made. It is best to always use sharp
instruments and to minimize pressure on the testicular paren-
chyma during sampling.
Fixation of the testis will depend on the end use. Formalin
fixation is adequate for cursory evaluation of spermatogenesis
for all species. Detailed evaluation requires the tissue to be
fixed more rapidly and or rendered harder to withstand
histologic section production. Bouin’s solution is a mainstay
for many laboratories. It is readily available. Davidson’s
fluid is now being used by many laboratories. Embedding
in plastics or acrylics is superior to paraffin but is much
more expensive and requires specialized equipment and
training.
Testicular diseases affect different parts of the testis and
different parts of each seminiferous tubule. The number and
location of sections depends on the unique characteristics of
the species at hand and the types of suspected diseases. Mac-
roscopic evaluation of the testis usually directs location and
size of appropriate histologic samples. For example, rams often
develop degeneration dorsally and bulls ventrally. Small rumi-
nants often develop initial degenerative lesions of the seminif-
erous tubules near the testicular mediastinum.
The evaluation of testicular histology will also vary with
the orientation of the seminiferous tubules. In general, the
seminiferous tubules are oriented perpendicular to the tes-
ticular mediastinum. A sample taken from the mediastinum
to the testicular capsule will provide multiple cross sections
of a small number of seminiferous tubules. A sample taken
parallel to the mediastinum will sample a limited portion of
many more seminiferous tubules. Routine sampling requires
sagittal sectioning of the testis, multiple transverse sections
(bread-loafing), and fixation of testicular tissue so that histol-
ogy can be examined from an appropriate region of normal
and abnormal testis both along and across the path of the
seminiferous tubules.
Spermatogenesis
Spermatogenesis is a complex process involving stem cells,
gene expression, cellular interactions, apoptosis, and cytokine
and other hormonal interactions. It is clear that testicular
function in general, and spermatogenesis in particular,
requires a complex interaction of all cells within the testis and
not just germ cells, Sertoli cells, and interstitial endocrine
(Leydig) cells.
The testis is divided into the tubular and extratubular com-
partments. The cells within the tubules are the Sertoli cells
General Considerations
and the germinal cells—spermatogonia, spermatocytes, sper-
matids, and spermatozoa.
Sertoli cells are very complex in their structure and func-
tion. The majority of Sertoli cells are present at birth or soon
after. They extend from the basement membrane to the
lumen, and have a large surface area. Attachment between
adjacent Sertoli cells and to germinal cells is by a variety of
junctional complexes, and this forms a major part of the
blood-testis barrier. Sertoli cells function to maintain the
integrity of the germinal cells, compartmentalize the germinal
cells into basal and luminal compartments, secrete fluid,
form the tubular lumen, phagocytose degenerating and dead
cells, deliver nutrients to germinal cells, metabolize steroids,
translocate germinal cells, secrete proteins, regulate the sper-
matogenic cycle, and mediate hormonal effects on the germi-
nal cells. These many functions are potential targets for
abnormalities.
Spermatogenesis begins with stem cells that proliferate by
mitosis, undergo a meiotic phase, and finally differentiate.
These stages correspond to spermatogonia, spermatocytes, and
spermatids, respectively. The spermatogonia are divided into
proliferative and differentiating types of stem cells. They
divide by mitosis to produce the cells that go on to form
spermatozoa. Meiotic division has a prolonged prophase, but
subsequent phases proceed rapidly. The spermatids are formed
as a final, differentiating step. Spermiation is the active release
of spermatozoa by Sertoli cells to the lumen, for subsequent
transport through the duct system.
Spermatogonia are exposed to testicular interstitial tissue
fluids. Occluding junctions of Sertoli cells mostly form the
blood-testis barrier. Spermatocytes and spermatids within the
tubule are “external” to the blood-testis barrier. Apoptosis of
germ cells at each stage of development occurs as a natural
phenomenon (see later), and Sertoli cells take up degenerative
and dead cells.
Control of spermatogenesis involves a complex interaction
of central endocrine and local paracrine-autocrine factors.
Central factors involve the hypothalamic-pituitary-gonadal
axis. Gonadotropin-releasing hormone (GnRH) from the
hypothalamus stimulates release of luteinizing hormone (LH)
and follicle-stimulating hormone (FSH) from the pituitary.
Interstitial endocrine cells have LH receptors that, when
coupled with LH, produce testosterone. Testosterone is essen-
tial for spermatogenesis and several other testicular functions;
Sertoli cells, germinal cells, and myoid cells have androgen
receptors, but the contribution of testosterone for the function
of germinal cells and myoid cells is not known. Testosterone
is known to inhibit apoptosis of germ cells. FSH directly
stimulates the Sertoli cells and perhaps the germinal cells. FSH
and testosterone probably act synergistically. FSH action on
Sertoli cells results in release of the hormones estrogen,
inhibin, and activin. Estrogen is important in the function of
other cells and spermatogenesis. Inhibin and activin are
members of the transforming growth factor (TGF) superfam-
ily. Inhibin enters the blood stream and inhibits FSH produc-
tion, whereas activin stimulates FSH production. Both also
have local effects and are part of the paracrine-autocrine
system. Sertoli cells also produce anti-Müllerian hormone
(AMH, previously known as Müllerian inhibitory substance
[MIS]) during development but usually not in adults.
Local control of spermatogenesis is also highly dependent on
local paracrine and autocrine factors; the number of factors
recognized is increasing exponentially. The extensive crosstalk
 General Considerations
between all cell types is essential for spermatogenesis and for
controlling inflammation and the altered immunocompetent
state of the testis. Germinal cells, Sertoli cells, peritubular
myoid cells, and interstitial endocrine cells secrete many cyto-
kines and growth factors. These cells are influenced, in turn,
by a large number of similar signaling molecules. Also impor-
tant in spermatogenesis is the presence of death receptors on
germ cells, in particular, Fas (APO-1, CD95), a transmem-
brane receptor molecule that transmits an apoptotic signal in
the cell when it is bound by a Fas ligand. Sertoli cells express
Fas ligand, and regulators of apoptosis are found in the testis,
including the Bcl-2 family of proteins and the p53 protein.
Apoptosis is a normal phenomenon regulating cell popula-
tions, but induction of apoptosis or increased apoptosis also
occurs with exposure to toxic compounds, depletion of growth
factors, alteration of hormonal support, exposure to heat
or radiation, transient ischemia, free radical status, or treat-
ment with drugs. Testes with impaired spermatogenesis, such
as hypospermatogenesis or maturation arrest, may have
increased apoptosis. There are also antiapoptotic proteins and
substances produced in the testis that counterbalance apop-
totic pathways.
There are well-recognized changes in spermatogenesis
with age. There is a dramatic increase in testicular size at
the time of puberty. The seminiferous tubules increase in
length and diameter, and the testicular volume increases. The
size of the testis then decreases progressively from puberty
into adult life. From early adulthood onward, there is a gradual
reduction in tubular diameter. The absolute number of Sertoli
cells probably declines from puberty on. A decline in the
number of spermatocytes and an increase in apoptosis both
contribute to reduced testicular mass to various degrees in
different species. A concurrent increase in the mass of the
testicular interstitial tissue typically occurs with age, and
the basal lamina of the seminiferous tubule increases in
thickness.
Domestic mammals usually have continuous spermatogen-
esis from puberty until death; however, there is species varia-
tion in the percentage of seminiferous tubules with active
spermatogenesis. Spermatogenesis is normally divided into
stages, and a single cross-section of a seminiferous tubule
has a single stage. An adjoining length of the same seminifer-
ous tubule will have a different stage, but not necessarily the
next stage. A complete series of stages over time becomes
the cycle of the seminiferous epithelium. Not all seminiferous
tubules have complete stages of spermatogenesis at any
one time, and every species has what is termed normal back-
ground change that mimics changes seen at puberty or result-
ing from a degenerative event. This is particularly the case
in boars.
Further reading
Alves MG, et al. Hormonal control of Sertoli cell metabolism regulates
spermatogenesis. Cell Mol Life Sci 2013;70:777-793.
Elcock LH, Schoning P. Age-related changes in the cat testis and epi-
didymis. Amer J Vet Res 1984;45:2380-2384.
Fukuda T, et al. Age related changes in the testes of horses. Equine
Vet J 2011;33:20-25.
Giampietri C, et al. Germ cell apoptosis control during spermatogen-
esis. Contraception 2013;72:298-302.
Guazzone VA, et al. Cytokines and chemokines in testicular inflamma-
tion: a brief review. Microscopy Res Techn 2009;72:620-628.
467
Hochereau-de Reiers MT, et al. Spermatogenesis and Sertoli cell
numbers and function in rams and bulls. J Reprod Fertil Suppl
1987;34:101-114.
Jan SZ, et al. Molecular control of rodent spermatogenesis. Biochim
Biophys Acta 2012;1822:1838-1850.
Lowseth LA, et al. Age-related changes in the prostate and testes of
the beagle dog. Vet Pathol 1990;27:347-353.
Mayerhofer A. Human testicular peritubular cells: more than meets the
eye. Reproduction 2013;145:R107-R116.
Roser JF. Regulation of testicular function in the stallion: an intricate
network of endocrine, paracrine and autocrine systems. Anim
Reprod Sci 2008;107:179-196.
Russell LD, et al. In: Histological and Histopathological Evaluation of
the Testis. Clearwater FL: Cache River Press; 1990. p. 286.
Turner RM, et al. The emerging pathophysiology of age-related testicu-
lar degeneration with a focus on the stallion and an update on
potential therapies. Reprod Dom Anim 2012;47:178-186.
Oxidative stress and testicular function
Antioxidative systems are important factors in normal testicu-
lar and epididymal function and, by extension, diseases of the
testis. The high rates of cell division cause high rates of oxygen
consumption in a low oxygen tension environment. This is
combined with large amounts of unsaturated fatty acids and
the presence of systems to generate reactive oxygen species
such as xanthine and NADPH-oxidases and cytochrome
P450. The intratubular compartment is particularly vulnera-
ble to oxidative stress and free radical damage.
The protective systems include antioxidant enzymes and
free radical scavengers, such as intracellular superoxide dis-
mutase, glutathione peroxidase, and glutathione-S-transferase.
The balance between production and removal is of major
importance in spermatogenesis.
Further reading
Aitken RJ, Roman SD. Antioxidant systems and oxidative stress in the
testes. Adv Exp Med Biol 2008;636:154-171.
Koziorowska-Gilun M, et al. Antioxidant enzyme activity and mRNA
expression in reproductive tract of adult male European bison (Bison
bonasus, Linnaeus 1758). Reprod Dom Anim 2013;48:7-18.
Testicular immune function
Testicular parenchyma is a unique immunologic environment.
Both innate and acquired immune function is actively sup-
pressed. This environment is maintained by testosterone and
its influence on peritubular myoid cells, endothelial cells of
capillaries, veins and lymphatic vessels, and testicular macro-
phages. This environment is maintained partially because sper-
matocytes, spermatids, and spermatozoa are antigenic, and
outside the blood-testis barrier. Any condition that causes
leakage of spermatozoa or spermatozoal antigens into the extra-
tubular compartment is potentially complicated by inflammatory
and immunologic responses. The response to spermatozoa is
variable, but innate or nonspecific immunity and acquired
mechanisms including humoral and cellular defences are
involved. This also occurs in the tubules and ducts of the
reproductive tract, including the epididymis.
Spermatozoa incite a foreign body/granulomatous response,
and degradation is slow because of their number and composi-
tion of fatty acids, lipids, phospholipids, and keratin molecules.
 467.e1

Further reading
Carreau R, et al. Oestrogens and spermatogenesis. Phil Trans R Soc
2010;365:1517-1535.
Erkkila K, et al. Testosterone regulates apoptosis in adult human
seminiferous tubules in vitro. J Clin Endocrinol Metab 1997;82:
2314-2321.
Head JR, Billingham RE. Immune privilege in the testis: evaluation of
local factors. Transplantation 1985;40:269-275.
Heindel JJ, Treinen KA. Physiology of the male reproductive system:
endocrine, paracrine and autocrine regulation. Toxicol Pathol
1989;17:441-445.
Hermann M, et al. Aging of the male reproductive system. Exp Geron-
tol 2000;35:1267-1279.
Holdcraft RW, Braun RE. Hormonal regulation of spermatogenesis. Int
J Androl 2004;27:335-342.
Lee J, et al. The Fas system is a key regulator of germ cell apoptosis in
the testis. Endocrinol 1997;138:2081-2088.
Lin WW, et al. In situ end-labeling of human testicular tissue demon-
strates increased apoptosis in conditions of abnormal spermatogen-
esis. Fertil Steril 1997;68:1065-1069.
Moura AA, Erickson BH. Age-related changes in peripheral hormone
concentrations and their relationships with testis size and number
of Sertoli and germ cells in yearling beef bulls. J Reprod Fertil
1997;110:183-190.
Nipken C, Wrobel KH. A quantitative morphological study of age
related changes in the donkey testis in the period between puberty
and senium. Andrologia 1997;29:149-161.
Richburg RH. The relevance of spontaneous- and chemically-induced
alterations in testicular germ cell apoptosis to toxicology. Toxicol
Lett 2000;112-113:79-86.
467.e2

Further reading
Koziorowska-Gilun M, et al. Antioxidant defence system of boar cauda
epididymidal spermatozoa and reproductive tract fluids. Reprod
Dom Anim 2011;46:37-47.
Turner TT, et al. Oxidative stress: a common factor in testicular dysfunc-
tion. J Androl 2008;29:488-494.
468 CHAPTER 5  •  Male Genital System
In addition, immune responses are florid and many plasma
cells and CD4 and CD8 lymphocytes are present. Up-regulation
of major histocompatibility complex (MHC) II in epithelial
cells also occurs. The reaction leads to chronic inflammation
and fibrosis, and continued obstruction and disruption of
tubules. Spermiostasis, spermatocele, and/or further sperm
granulomas are the consequence.
Antispermatozoal antibodies are found in serum, genital
secretions, or both. They occur in infertile individuals in
several species, including humans. There is a lack of informa-
tion on their presence in genital fluids, where they have the
greatest impact. Spermatozoal antigens gain entry to the inter-
stitium as a result of trauma, rupture of a duct or tubule, or
leakage from either failure of the barrier between tissue and
spermatozoa following inflammation or obstruction. Specific
conditions include blind-ended efferent ductules (spermatic
granuloma of the epididymal head or efferent ductules), seg-
mental aplasia of the mesonephric ducts, adenomyosis, and
epididymitis. Infection of dogs with Brucella canis can cause
the formation of antispermatozoal antibody, and it occurs in
vasectomy and other causes of obstruction of ducts.
Serum immunoglobulin may gain access to the spermato-
zoa through any part of the reproductive tract, but the effer-
ent ductules and epididymis are probably the most accessible
sites, because the barrier between the internal and external
compartments is less tight. Local immunoglobulin production
can occur at any location in the tract, but the accessory genital
glands are the most common site (see later).
Further reading
Chiu WW, Chamley LW. Clinical associations and mechanisms of action
of antisperm antibodies. Fertil Steril 2004;82:529-535.
Hedger MP. Immunophysiology and pathology of inflammation in the
testis and epididymis. J Androl 2013;23:625-640.
Jessop TS, Ladds PW. The immunopathology of unilateral vasectomy in
the ram. Vet Immunol Immunopathol 1995;47:123-133.
Immunity in the reproductive tract
Innate and acquired immunity occur in the male genital tract.
Both male and female reproductive tracts have a unique
ability to co-opt immune cells for normal physiologic func-
tions. There are different populations of cells of a similar
type—some that are involved in regulation of spermatogenesis
and others that are proinflammatory. Testicular macrophages/
antigen-presenting cells are present in the normal interstitial
tissues of all species and their importance is increasingly rec-
ognized. They are involved in the regulation of spermatogen-
esis, steroidogenesis, and immune regulation. Those that reside
in the testis contribute to reduced immune function to form
a tolerant environment maintained by natural killer (NK) and
regulatory T (Treg) cells. Lymphocytes entering the testis are
proinflammatory but must overcome the local environment.
Systemic inflammatory disease affects testicular function by
the stimulation of immune and inflammatory pathways.
Pattern recognition receptors such as toll-like receptors are
important in this.
The male genital tract has little ability to compensate for
direct injury. The testes are bound by the tough and relatively
inelastic capsule, and any sudden increase in internal pressure
or swelling, be it caused by hemorrhage or edema, results in
testicular necrosis. Injury to the seminiferous tubules can
Disorders of Sexual Development
result in a breakdown of the blood-testis barrier and subse-
quent immune reactions. The epididymis and deferent duct
form a single small-diameter tube that is easily obstructed and
damaged, and it is free from the usual systemic immune sur-
veillance. There is always the specter of inflammation and
acquired immunity to spermatozoal or secretory products.
Normally, little immunoglobulin enters the seminal fluids,
and with a few exceptions, lymphocytes are rare in the inter-
stitium of reproductive structures in normal male animals.
Those entering the testis are actively destroyed.
Epithelium throughout the reproductive ducts and duct-
ules can express MHC II molecules if inflammation is present.
The various ducts of the male reproductive tract contain
intraepithelial leukocytes, especially CD8 lymphocytes. The
accessory genital glands are believed to be the main location
for plasma cells, which presumably add immunoglobulins to
the seminal fluid to help prevent access of ascending agents
to the deferent duct and epididymis. Local humoral immunity
develops in the accessory genital glands, and is predominantly
IgA-based in several species.
One of the unfortunate side effects of having spermatozoa
not recognized as “self” is the necessity of maintaining these
cells completely separate from immune surveillance. This pro-
vides microbial organisms a location within the lumen of
ducts and tubules where they can grow and cause damage.
Once the body recognizes the injury and recruits inflamma-
tory cells, there often is too much damage to permit repair or
regeneration. In addition, the very processes of inflammation,
including the release of free radicals by leukocytes, damage
the tract further. As in many other sensitive tissues, the damage
done by inflammation may be a major cause of dysfunction.
Further reading
Filippini A, et al. Control and impairment of immune privilege in the
testis and in semen. Hum Reprod Update 2001;7:444-449.
Foster RA, et al. Immunoglobulins and immunoglobulin containing
cells in the reproductive tract of normal rams. Aust Vet J
1988;65:16-20.
Hedger MP. Toll like receptors and signalling in spermatogenesis and
testicular responses to inflammation—a perspective. J Reprod
Immunol 2011;88:130-141.
Saramanavuthu V, et al. T and B lymphocyte subsets in spermatic
granulomas in five rams. Vet Pathol 1991;28:482-491.
Winnall WR, et al. Phenotypic and functional heterogeneity of the
testicular macrophage population: a new regulatory model.
J Reprod Immunol 2013;97:147-158.
DISORDERS OF SEXUAL DEVELOPMENT
Disorders of sexual development (DSD) include all congenital
anomalies of the reproductive tract including those of a major
or minor nature.
Production of a normal ejaculate depends on the normal
development of the reproductive tract, including normal sper-
matogenesis, spermatozoa maturation and transport, normal
accessory genital gland function, and nervous, musculoskele-
tal, and psychological factors.
Sexual differentiation requires appropriate sequential gene
expression; production of proteins and other hormones; recep-
tor expression; and the complex development and regression
of the paramesonephric (Müllerian) ducts, mesonephric
 468.e1

Further reading
George L, Carmichael L. Antisperm responses in male dogs with
chronic Brucella canis infections. Am J Vet Res 1984;45:274-281.
Zhang J, et al. Antisperm antibodies in the semen of a stallion follow-
ing testicular trauma. Equine Vet J 1990;22:138-141.
468.e2

Further reading
Bedford JM. Adaptations of the male reproductive tract and the fate
of spermatozoa following vasectomy in the rabbit, rhesus monkey,
hamster and rat. Biol Reprod 1976;14:118-142.
Foster RA, et al. Pathology of reproductive tracts of merino rams in
north western Queensland. Aust Vet J 1989;66:262-264.
Pollanen P, Maddocks S. Macrophages, lymphocytes and MHC II
antigen in the ram and rat testis. J Reprod Fertil 1988;82:
437-445.
 Disorders of Sexual Development
(Wolffian) tubules and ducts, and the tissues of the gonadal
ridge/primitive bipotent gonads. When all steps occur nor-
mally, sex chromosome genotypic, gonadal, and phenotypic
sex is matched. Male domesticated mammals normally have
an XY genotype, although XX males can occur if a sex-
determining factor is present.
SF1 is a gene activated at the beginning of the sex deter-
mination period in both males and females, but it reduces in
amount dramatically at the end of the sex determination
period in males. It is also involved in the development of
adrenal and hypothalamic-pituitary axis. In normal XY males,
SRY, the gene that is the sex-determining region of the Y
chromosome, encodes a transcription factor that contains a
high mobility group (HMG)-box DNA binding domain. This
binds to specific DNA sequences, causes bending of the DNA
and results in Sertoli cell differentiation. WT1+KTS, GATA4
and FOG2 are part of the transcriptional or post-transcriptional
regulation of SRY. SRY, the product of SRY, regulates tran-
scription by binding to promoter sites of SRY-like HMG-box
protein 9 (SOX9). SOX9 also has 2 transcriptional activation
domains that act on the testis determining pathway. M33
(Cbx2) and ATRX are involved in gonadal development. SRY,
M33, and ATRX either activate testis-determining genes or
inhibit pro-ovarian genes.
SRY is very important in Sertoli cell development, and
testes do not develop unless there are sufficient Sertoli cells.
Formation of Sertoli cells is influenced by many genes and
products, including SF1 and AMH, the gene that produces
anti-Müllerian hormone (AMH). Activation of AMH, which
causes regression of the paramesonephric ducts, marks the end
of the sex determination period in males. DAX1 is a gene that
appears to act downstream of SRY and is important in early
Sertoli cell differentiation. DAX1 inhibits the male sex deter-
mining pathway, and if DAX1 is activated in males, a female
develops.
As part of testicular development, endothelial cells migrate
from the mesonephros to the testis. The formation of this
extra vasculature is important in testis development, espe-
cially sex cord formation. At this time, the formation and
function of the interstitial endocrine (Leydig) cells is acquired.
Thus the formation of the Sertoli cells, interstitial endocrine
cells and vasculature combined is necessary for testis develop-
ment. Interstitial endocrine cells develop from the same cell
population as the adrenal cortex, that is, from vascular smooth
muscle cells and pericytes of testicular capillaries—vascular
cell types that act as stem cells. SF1, desert hedgehog gene
(DHH), and PDGFA are involved with this. Also ARX (the
homeobox gene aristaless-related) has a function.
During early embryonic development, primordial germ
cells (PGC) migrate to the gonads and there are many
genes and gene products that can be detected. They are not
necessary for testicular development. Testicular cord develop-
ment results in the blocking of PGC proliferation in the
G0/G1 phase of mitosis and they differentiate into
prospermatogonia.
The constituents of the primitive gonad are the germ cells,
mesenchymal cells, coelomic epithelial cells, and mesonephric
epithelial cells. These form the 4 major cell types in the
gonad—the germ cells, supporting cells, steroid-producing
cells, and unspecialized mesenchyme. SRY causes the germ
cells to go into mitotic arrest, the supporting cells become the
Sertoli cells, the steroid-producing cells become the interstitial
endocrine cells (of Leydig), and the mesenchyme develops the
469
testicular pattern. The mesonephric tubules form the rete
testis and the efferent ductules. The epididymis, deferent
ducts, and vesicular glands are derived from the mesonephric
ducts. The prostate and bulbourethral glands form from the
urogenital sinus, and the penis, prepuce, and scrotal sac
develop from the urogenital sinus and tubercle when testos-
terone is present.
The male phenotype depends on the production by the
Sertoli cells of AMH, which causes the paramesonephric
(Müllerian) duct to regress. Interstitial endocrine cells produce
testosterone and INSL3 that inhibits further female differen-
tiation, prevents the mesonephric ducts from regressing, and
induces development of the prostate, bulbourethral glands,
penis, and scrotum.
The testis, epididymis, and associated structures descend
from the urogenital ridge into the scrotum. Testicular and
epididymal descent occurs in 3 main stages: the relative trans-
abdominal migration phase, the intra-inguinal phase, and extra-
inguinal migration. Testosterone is not necessary for testicular
descent but it does assist in the growth of the vaginal process
and gubernaculum. The first phase may be partially controlled
by AMH, the second phase requires increased intra-abdominal
pressure, and the third involves interaction of androgen, cal-
citonin gene-related protein, the genitofemoral nerve, and
perhaps other factors. In early fetal life, a cranial gonadal
suspensory ligament supports the testis. It may be retained
when there is a lack of androgens, in which case subsequent
development of the testicular gubernaculum also is impaired.
The testicular gubernaculum is a gelatinous cord of tissue that
extends from the caudal pole of the testis to the inguinal area
and it exerts traction on the testis. A mutation in the GREAT
gene, which is highly expressed in the gubernaculum and may
mediate response to hormones, has been associated with intra-
abdominal cryptorchidism in humans and, experimentally, in
mice. The exact mechanisms are yet to be elucidated in
domestic mammals, but they no doubt are complex and
involve an interrelationship of systemic and local factors.
The effects of endocrine disruptors on male development
are increasingly important, because multiple disorders of
sexual development, such as reduced anal-genital distance,
delayed preputial separation, hypospadias, and ectopic and
maldescended testes, can all be induced by antiandrogenic and
estrogenic chemicals (the endocrine disruptors).
Disorders of sexual development (DSD) are now divided
into 3 general categories: sex chromosome DSD, disorders
with an XX genotype (XX DSD), and XY DSD. XX and XY
DSDs are divided into groups based on whether the gonads
are normal or not. Many DSD result in a female or feminine
phenotype and are considered in more detail in Vol. 3, Female
genital system. Those mentioned here are mostly DSD with
a male genotype, gonads, or genitalia.
• Sex chromosome DSD are those with an altered sex chromo-
some complement such as the classic XXY (Klinefelter
syndrome). These are manifested clinically as ambiguity in
phenotype and/or infertility. Animals with XXY chromo-
somes or a mosaicism with XXY chromosomes may have
hypoplastic internal genitalia. Well known of these are
male tortoiseshell or calico cats. They are almost always
infertile, and have testicular hypoplasia. Hybrids of the
horse and donkey (with 64 and 62 chromosomes, respec-
tively), the mule and hinny, have 63 chromosomes and are
sterile. The classic sex chromosome DSD in animals is the
freemartin (Fig. 5-1).
470 CHAPTER 5  •  Male Genital System Disorders of Sexual Development

Figure 5-1  A bovid with a sex chromosome disorder of sexual

differentiation (freemartinism). There is gonadal dysgenesis, the
tubular genitalia are predominantly mesonephric (male) includ-
ing vesicular glands, and there are female external genitalia with
a prominent clitoris.

Figure 5-3  Unilateral abdominally retained testis (right) from

a ram. The contralateral testis (left) was within the scrotum
and is more bulbous than normal because of compensatory
hypertrophy.

Figure 5-2  A ram lamb with complete hypospadias, including

bifurcation of the scrotum.

• XX DSD with abnormal gonads have a female genotype

but have either testes or ovotestes. They have varying
development of male and female internal genitalia. They
are usually masculinized and some may be indistinguish- Figure 5-4  Testes and epididymides of 4 rams of the same age.
able from normal males. Such cases, commonly called XX There is a gradation of testicular hypoplasia from severe (upper
sex reversal, are reported in most species. In goats this is left) to normal (lower right).
called the polled/intersex syndrome (PIS) because it is
common in polled animals, in which polled XX homozy-
gotes have both male and female gonads (true hermaphro-
dites); loss of the FOXL2 gene product is responsible. They
range from sterile males to females with testes. Dogs of the
American Cocker Spaniel breed are commonly affected. In
pigs, it is a common DSD confused with freemartinism.
• XY DSD form the largest group because any disorder of
development of the male genital tract in genotypic males
is included. Common DSD such as hypospadias (Fig. 5-2),
cryptorchidism (Fig. 5-3), testicular hypoplasia (Fig. 5.4), and
cystic remnants of embryonic ducts (Fig. 5-5) are all now
categorized in this group.
• The most extreme type of XY DSD are those animals with
a normal female phenotype but with an XY genotype and Figure 5-5  Bilateral congenital retention cysts at the junction of
gonads that are testes (their full category name is XY, SRY+, the head of the epididymis and testis of a ram.
 Scrotum
Figure 5-6  Miniature Schnauzer dog with an XY disorder of
sexual development commonly called persistent Müllerian duct
syndrome. This dog was phenotypically male with retained testes
(sectioned) and well-developed uterine horns and body.
testicular DSD, with female phenotype). These usually
lack androgen receptors—they have testes, no tubular geni-
talia, but are phenotypically female. All species develop
this type of DSD.
• A well-recognized but less extreme form is found in Min-
iature Schnauzer dogs that are XY, SRY +, testicular DSD
with male phenotype and retention of paramesonephric
ducts (Fig. 5-6). They lack functional anti-Müllerian
hormone (AMH) receptors and have a syndrome called
persistent Müllerian duct syndrome (PMDS). Affected Min-
iature Schnauzer dogs may develop hydrometra and pyo-
metra. Many are also cryptorchids.
Gynecomastia is occasionally seen as a solitary lesion in
males. There are reports of bucks from high milk production
lines that develop mammary glands. It also occurs in hyperes-
trogenism syndromes.
Further reading
Amann RP, Veeramachaneni DN. Cryptorchidism in common eutherian
mammals. Reproduction 2007;133:541-561.
Breshears MA, et al. Ambiguous genitalia in a fertile, unilaterally
cryptorchid male miniature schnauzer dog. Vet Pathol 2011;48:
1038-1040.
Buijtels JJCWM, et al. Disorders of sexual development and associated
changes in the pituitary-gonadal axis in dogs. Theriogenol
2012;78:1618-1626.
Hughes IA. Disorders of sex development: a new definition and
classification. Best Pract Res Clin Endocrinol Metab 2008;22:
119-134.
Hughes IA, et al. Factors controlling testis descent. Eur J Endocrinol
2008;159:S75-S82.
Meyers-Wallen VN. Gonadal and sex differentiation abnormalities of
dogs and cats. Sex Dev 2012;6:46-60.
471
Poth T, et al. Disorders of sex development in the dog—adoption of a
new nomenclature and reclassification of reported cases. Anim
Reprod Sci 2010;121:197-207
Villagomez DAF, et al. Equine disorders of sexual development in 17
mares including XX, SRY-negative, XY, SRY-negative and XY, SRY-
positive genotypes. Sex Dev 2011;5:16-25.
SCROTUM
The scrotum is an outpouching of perineal skin with an inner
lining of peritoneum and direct communication with the peri-
toneal cavity. Many terrestrial mammals have their testes
within a scrotum, but the reason is the subject of theories. In
these species the intrascrotal temperature is less than core
temperature. Most assume the testis must be lower in tem-
perature but the epididymis also may operate better when
cooler. The maturation of spermatozoa is a slow process and
the epididymis is one long and coiled tube. The testicular
artery is long and coiled, and changes the blood flow from
pulsatile and high pressure to a constant low-pressure system.
This makes the oxygen tension in the testis lower than
expected, and the oxidant-antioxidant balance is less robust.
The blood supply to the epididymis is separate and shorter.
The scrotum maintains the testis and epididymis at a tem-
perature less than core. The scrotal skin is thinner than skin
elsewhere and has little or no subcutaneous fat or connective
tissue. It is lightly haired, except in the cat, and has prominent
apocrine sweat glands. The contractility of the scrotum is a
property of the dartos tunic that consists of fibroelastic tissue
and smooth muscle. Thermoregulatory function is shared with
the cremaster muscle, which regulates the proximity of the
testis to the abdominal wall, and the pampiniform plexus of
testicular artery and veins, which ensures maximum contact
of cooled venous blood with the warmer arterial blood. If the
testes of the common domestic animals are at or above normal
body temperature, degeneration of the seminiferous epithe-
lium occurs. Retained testes do not develop normal spermato-
genesis or testicular and epididymal size.
The formation of the scrotum from the paired genital
swellings of the embryo, and its full development at puberty,
requires testosterone and is dependent on the development of
normal testes. Disorders of scrotal development include absence
of the scrotum in cryptorchidism. A bifurcated scrotum and
scrotal clefts or notches represent failures of fusion of the
paired primordia. These may be isolated defects, accompanied
by hypospadias (see Fig. 5-2) and other defects such as atresia
ani, or occur in a variety of disorders of sexual development.
Enlargement of the scrotum can be the result of lesions of
the scrotal skin, vaginal tunics and cavity, testis, epididymis,
pampiniform plexus, inguinal canal, and superficial inguinal
lymph node. Disease of each of these anatomic regions is
covered later in this chapter.
Thickening of the scrotal skin and dartos tunic is mostly
due to edema of local or systemic origin, or because of inflam-
mation or neoplasia. The skin of the scrotum can be part of
disease of the skin elsewhere. We will concentrate here on
diseases that primarily affect the scrotum.
In bulls, scrotal dermatitis is caused by contact with irritant
substances from the environment, ectoparasites such as biting
insects (Simuliidae and Culicoides), lice (Haematopinus eurys-
ternus), and mites (Chorioptes bovis); fungi; protozoa (Besnoi-
tia besnoiti, Trypanosoma spp); bacteria (Dermatophilus
 471.e1

Further reading
Benirschke K, et al. Somatic chromosomes of the horse, the donkey
and their hybrids, the mule and the hinny. J Reprod Fertil
1962;4:319-326.
Boulanger L, et al. FOXL2 is a female sex-determining gene in the goat.
Curr Biol 2014;24:404-408.
Centerwall WR, Benirschke K. An animal model for the XXY Klinefel-
ter’s syndrome in man: tortoiseshell and calico male cats. Am J Vet
Res 1975;36:1275-1280.
Quilter CR, et al. X/XY/XYY mosaicism as a cause of subfertility in
boars: a single case study. Anim Genet 2003;34:51-54.
Soller M, et al. Cytogenetics of Saanen goats showing abnormal devel-
opment of the reproductive tract associated with the dominant
gene for polledness. Cytogenetics 1969;8:51-67.
472 CHAPTER 5  •  Male Genital System
Figure 5-7  Scrotal frostbite in a ram.
congolensis); and viruses (poxviruses) to name a few. These
may occur as diffuse or focal lesions.
Range bulls and occasionally rams exposed to extreme cold
may develop scrotal frostbite (Fig. 5-7). A higher incidence of
lesions in old bulls is attributed to their more pendulous
scrotums. Lesions are well demarcated regions of necrosis of
skin on the ventral aspect of the scrotum and can involve up
to 75% of the scrotum. Scrotal swelling, tunic adhesions, and
decreased semen quality accompany the more severe lesions.
The scrotal skin of bulls is especially susceptible to infection
by Dermatophilus congolensis. Severe, prolonged infection may
result in thickening of the skin to 1 cm, with advanced tes-
ticular degeneration and infertility. Infection of scrotal skin by
Besnoitia besnoiti also may lead to severe testicular degenera-
tion. This infection is not limited to skin, and the small nodules
containing white gritty material are seen grossly in the subcu-
tis of the scrotum as well as in the tunics, the parenchyma of
the testis, and in the epididymis. Vascular damage is important
in the development of lesions, and large numbers of Besnoitia
cysts may be present in the intima of vessels in the pampini-
form plexus. Neoplasia is rare in bulls, but papilloma, mela-
noma, and hemangioma occur. Varicose dilations of scrotal veins
occur in older bulls. They appear as flattened and irregular
thickenings of the scrotal skin. The overlying epithelium
usually is normal unless it ulcerates and bleeds. The affected
venous channels are irregular in shape, widely dilated, and
have thickened walls; thrombosis occurs in many.
In boars, hemangiomas are common. They are multiple
exophytic and variegated or papillary lesions that may bleed.
They do not appear to affect fertility. Such lesions are benign
and may not be true neoplasms. Age, altered hemodynamic
forces in the capillary bed of the scrotal dermis, and genetic
predisposition are factors that might be involved in their
development. Any cutaneous disease of the pig could poten-
tially affect the scrotum.
In the stallion, trauma from the kick of a mare occurs and
the local effects include swelling and edema plus ulceration
and hemorrhage. Abscessation can occur. The scrotum is often
affected in dependent edema from systemic and or intestinal
diseases as an extension from preputial edema. Peritonitis,
equine viral arteritis, and other vasculitides including purpura
hemorrhagica, and surra, caused by Trypanosoma evansi infec-
tion, are potential causes. Dourine (Trypanosoma equiperdum)
Scrotum
Figure 5-8  Fistulous tract through the scrotum of a ram with
severe epididymitis and periorchitis.
affects the prepuce and can secondarily affect the scrotum.
Parasitic dermatitis occurs in horses—mostly from the second-
ary effects of self-trauma from rubbing. Biting flies, including
Culicoides, and Onchocerca microfilariae in the scrotal skin can
lead to dermatitis. Eosinophilic superficial perivascular or
nodular dermatitis will occur; microfilariae will be found in
onchocerciasis. Habronema larvae infect wounds of the
scrotum and cause large granulomatous nodules. The most
common neoplasm of the skin of the horse is the equine
sarcoid, and scrotal masses may occur. Melanoma of the
perineum involves the scrotum rarely.
In rams, parasitic dermatitis from Chorioptes bovis is
common and the scrotum appears to be a preferred site for
the mite. The lesions can be mild but are frequently suffi-
ciently severe to cause testicular atrophy and infertility. In
such cases there is marked thickening of skin and matting of
overlying hair and wool by secretions and exudate. Linogna-
thus pedalis, the foot louse of sheep, can also affect the scrotal
skin. Cutaneous myiasis and dermatophilosis rarely affects the
scrotum. Draining tracts through the scrotal skin from perior-
chitis and epididymitis may occasionally occur (Fig. 5-8).
In bucks, sarcoptic mange, with typical crusted lesions and
thickening of the skin, can involve the scrotum.
In dogs, disease of the scrotum is uncommon. Pyoderma,
both superficial and deep, and folliculitis and furunculosis can
affect the scrotum. Brucella canis is reported to cause scrotal
dermatitis and ulcers, but many cases are the result of licking
and self-trauma from the pain and discomfort of epididymitis
and periorchitis. Ehrlichia spp and Rickettsia rickettsii may
cause scrotal edema, infarction, and ulceration from vasculitis.
Fungal infections of the scrotum occur in dermatophytosis
and infection with Microsporum and Trichophyton spp. Mallas-
sezia and other yeasts such as Candida species can affect the
scrotum too, and they produce a superficial intraepidermal
pustular and hyperplastic disease. Blastomycosis (Blastomyces
dermatitidis), sporothricosis (Sporothrix schenckii), and proto-
thecosis (Prototheca wickerhamii) cause nodular pyogranulo-
matous dermatitis. Protozoal infections of the scrotum include
leishmaniasis (Leishmania spp) and have the typical lesions of
 Vaginal Tunics
a plasma cell–rich or pyogranulomatous nodular-to-diffuse
dermatitis. Parasitic diseases of the scrotum of dogs include
infection with Cuterebra emasculator, which results in a drain-
ing tract from an abscess and local necrosis of the tissue.
Sarcoptes scabiei, Demodex species, and Pelodera strongyloides
affect the scrotum, as they do in other locations. Migration of
hookworm larvae can also occur through scrotal skin. Of the
many other cutaneous diseases seen in dogs, contact irritant
and hypersensitivity reactions occur, as does atopy, food
hypersensitivity, fixed drug eruptions, and a plethora of
immune-mediated diseases. The scrotum can be affected by
physicochemical injury including burns, sunburn, abrasions
and lacerations from fighting and motor vehicle accidents, and
frostbite. Neoplasms of the scrotum include any neoplasm of
skin, and if they are common elsewhere in skin, they are likely
to occur on the scrotum. Examples include mast cell tumors
and vascular tumors such as hemangiomas and hemangiosar-
coma. There does not appear to be any increased susceptibility
to a particular neoplasm in this area.
In both cats and camelids, bite wounds from other males
occur in the scrotum. Other primary spontaneous scrotal
disease is rare.
Further reading
Cerundolo R, et al. Review of cutaneous lesions of the canine scrotum.
Vet Dermatol 2002;13:63-76.
Foster RA. Common lesions in the male reproductive tract of cats and
dogs. Vet Clin North Am Small Anim Pract 2012;42;527-545.
Nikolopoulos W, et al. Scrotal cooling and its benefits to male fertility:
a systematic review. J Obstet Gynaecol 2013;33:338-342.
Raj K, et al. Congenital hypospadia associated with atresia ani et recti
and rectovesical fistula in a kid. J Vet Sci Anim Sci 1994;25:172.
Smith KC, et al. A survey of congenital reproductive abnormalities
in rams in abattoirs in south west England. Reprod Dom Anim
2012;47:740-745.
Teankum K, et al. Capillary haemangiomas of the scrotum and testicle
in boars. J Comp Pathol 2008;139;177-186.
VAGINAL TUNICS
The vaginal tunic is a membrane of dense fibrous tissue over-
laid with a single mesothelial layer continuous with and struc-
turally similar to the peritoneum. The scrotum and intrascrotal
contents are covered by the parietal and visceral layers, which
form the boundaries of the cavity of the vaginal tunic.
The cavity of the vaginal tunics communicates with the
peritoneal cavity and is susceptible to the accumulation of
ascitic fluid. Fluid within the cavity around the scrotal con-
tents is called hydrocele. It forms for exactly the same reasons
as ascites. Hydrocele may lead to severe testicular degenera-
tion on the involved side and to a lesser extent on the opposite
side. Scrotal hydrocele, with diminished sperm quality, is a
herd problem in bulls in some regions. Clinically, the fluctuant
nature of the enlarged scrotum, with a scrotal circumference
up to 60 cm, is indicative of edema, and if affected bulls are
examined at autopsy, there is obvious ascites. If hydrocele
persists, the tunics become increasingly fibrotic. Ostertagiasis
and hemotropic mycoplasma (Mycoplasma wenyonii) infec-
tion are incriminated as causes of this syndrome. Hydrocele
in other species occurs with ascites of heart failure or any
other cause of fluid buildup in the peritoneal cavity. It can
473
also occur in conditions that cause edema of the scrotum (as
listed previously).
Hematocele is the accumulation of blood in the vaginal
cavity. It is the result of trauma and is seen in stallions with
mating injury and in boars housed together.
The visceral tunic is an integral part of the testicular
capsule. It is composed of inelastic collagen and fibrous tissue,
and smooth muscle through which the vascular tunic is nor-
mally visible. In spite of the presence of smooth muscle, the
capsule is not significantly contractile; it probably contributes
to the flow of semen by maintaining intratesticular pressure.
The tunic is thickened and opaque in testicular hypoplasia and
atrophy.
Inflammatory changes in the vaginal tunic may be part of
disseminated infection, with typical lesions of feline infectious
peritonitis, tuberculosis, caseous lymphadenitis, and diseases
causing polyserositis in all species. Suppurative and fibrinous
inflammation also occurs as an extension of scrotal injury or
from epididymitis. Inflammation of the tunics is often called
periorchitis.
Severe periorchitis is a complication of epididymitis irrespec-
tive of cause, but is particularly found in bulls with Trypano-
soma brucei infection, in rams infected with Brucella ovis or
Actinobacillus seminis (Fig. 5-9), and dogs with Escherichia coli
epididymitis (Fig. 5-10). Setaria labiatopapillosa causes granu-
lomatous periorchitis in bulls, and lesions occur particularly
after adults are killed by anthelmintic treatment. A high prev-
alence of eosinophilic, then granulomatous, periorchitis in
water buffaloes is attributed to Setaria sp. Ectopic parasites,
such as migrating equine strongyle larvae (Strongylus edenta-
tus), can be found on the tunics. Periorchitis in rams is very
common in infectious epididymitis. Pyocele or hemipyocele is
reported rarely as a spontaneous condition and is reported in
the ram with Staphylococcus capitis infection. Cysts of taenid
larvae, mostly Cysticercus tenuicollis, may be found in the
scrotal cavity of rams, without inflammation. In dogs, rare
Figure 5-9  Periorchitis secondary to epididymitis in a ram. Fibrin
and edema fluid are present within the cavity of the vaginal tunics.
 473.e1

Further reading
Althouse GC, et al. Episodic scrotal mutilation with concurrent bilateral
sperm granuloma in a dog. J Am Vet Med Assoc 1993;202:
776-777.
Blanchard TL, et al. Identifying, treating, and preventing scrotal skin
disorders of large animals. Vet Med 1990;290-294.
Kambarge DM. Sarcoptic mange infestation in goats. Bull Anim Hlth
Prod Africa 1992;40:239-244.
Rhodes AP. The effect of extensive chorioptic mange of the scrotum
on reproductive function of the ram. Aust Vet J 1976;52:
250-257.
Schoeb TR, et al. Scrotal and testicular changes in canine brucellosis:
a case report. J Am Vet Med Assoc 1978;172:598-599.
474 CHAPTER 5  •  Male Genital System
Figure 5-10  Severe epididymitis and periorchitis in a dog. The
tail of the epididymis is large and edematous, and there is fibrin
and exudate in the cavity of the vaginal tunic. The testis is necrotic.
The ventral scrotum was ulcerated from self-trauma.
peritoneal cestodiasis caused by larvae of Mesocestoides spp.
may involve the vaginal tunics, with saccular dilations within
the tunics, thickening of the spermatic cord, and pyogranulo-
matous inflammation involving the testicular capsule and
extending into the testes. There is also a report of pentastome
larvae of Porocephalus crotali within the testicular capsule of
a dog.
Adhesions between the visceral and parietal layers of the
vaginal tunic are common, especially in older animals. Adhe-
sions are at first fibrinous, reflecting acute periorchitis (see Fig.
5-9), but later become fibrous. Fine, thread-like, fibrous adhe-
sions located at the epididymal tail in bulls are normal. Exten-
sive adhesions result from infectious periorchitis secondary to
epididymitis. Most adhesions are focal and solitary, and do not
have lesions in the testis or epididymis; they probably are of
little consequence.
Cystic lesions of the vaginal tunic may be loculations
within adhesions. Very small cysts, probably of paramesoneph-
ric duct origin, are common adjacent to the head of the epi-
didymis in the horse, and are referred to as appendix testis
or Morgagni’s hydatid. In rams they are called inclusion cysts
(see Fig 5-5).
Neoplastic disease involving the vaginal tunic is rare, even
as secondary extension from the testis or scrotum. Mesothelio-
mas with primary involvement of the vaginal tunic occur in
the dog and bull (Fig. 5-11). Extension of the tumor into the
peritoneal cavity has been observed in the dog. Ultrastructural
study or immunohistochemistry is necessary to differentiate
mesotheliomas from metastatic adenocarcinoma. The origin
of intrascrotal mesothelioma from the paramesonephric duct
remnant is suggested. There is a report of a lipoma occupying
the right scrotal cavity in a ram, causing compression of, but
apparently not directly involving, the testis.
Testis and Epididymis
Figure 5-11  Papillary mesothelioma of the vaginal tunic that
completely covers the scrotal contents of a dog.
Further reading
Abbitt B, et al. Scrotal hydrocele secondary to ascites in 28 bulls. J Am
Vet Med Assoc 1995;207:753-756.
Brookins MD, et al. Massive visceral pentastomiasis caused by
Porocephalus crotali in a dog. Vet Pathol 2009;46:460-463.
Hagos A, et al. Serological and parasitological survey of dourine in
the arsi-bale highlands of Ethiopia. Trop Anim Health Prod
2010;42:769-776.
Lacasta D, et al. Unilateral scrotal pyocele in ram caused by Staphylo-
coccus capitis. Aust Vet J 2009;87:484-486.
Vascellari M, et al. Malignant mesothelioma of the vaginal tunic testis
in a dog: histological and immunohistochemical characterization. J
Vet Diagn Invest 2011;23:135-139
Welles EG, et al. Eperythrozoon infection in young bulls with
scrotal and hindlimb edema, a herd outbreak. Theriogenol
1995;43:557-567.
TESTIS AND EPIDIDYMIS
Spermatozoa develop in the seminiferous tubules and pass
through the straight tubules into the intratesticular rete within
the mediastinum testis. They leave the testis via the rete testis
and enter the efferent ductules. The efferent ductules number
between 13 and 20, depending on the species. Most join the
single duct of the epididymis, but it is common in most species
for one or more to end blindly. The epididymis is long and
tortuous, and divided into many distinct areas. For this discus-
sion, 3 main areas will be referred to: the head, body, and tail.
The tail terminates in the deferent duct. Disease of one area
has effects on other regions.
Pathologists often examine the testes or biopsies of indi-
vidual animals rather than whole groups of animals. Gross and
histologic assessment of reproductive tissues is a valuable tool
if used appropriately. Complete definition of a clinical problem
often requires collaboration of the cytogeneticist, endocri-
nologist, theriogenologist, and pathologist, who alone may not
be able to determine the complete pathogenesis. For the
pathologist to function optimally, appropriate samples must
be collected and processed. For many of the diseases and the
tissues, routine fixation with 10% formalin is adequate, but for
 474.e1

Further reading
Cihak RW, et al. Malignant mesothelioma of the vaginal tunic in a dog.
Vet Pathol 1986;96:460-461.
Holyoak GR, et al. Pathological changes associated with equine arteritis
virus infection of the reproductive tract in prepubertal and peripu-
bertal colts. J Comp Pathol 1993;109:281-293.
Ladds PW, Crane CK. Scrotal mesothelioma in a bull. Aust Vet J
1976;52:534-535.
Shore MD, et al. Outcome of scrotal hydrocele in 26 bulls. J Am Vet
Med Assoc 1995;207:757-760.
Zeman DH, et al. Scrotal cestodiasis in a dog. Cornell Vet
1988;78:273-279.
 Testis and Epididymis 475

a detailed assessment of spermatogenesis, or the histologic loop that begins and ends at the mediastinum, and turns
appearance of seminiferous tubules, rapid fixation after death completely at the testicular capsule. In ruminants, the testes
or collection (within minutes in many species) in Bouin’s, are oriented in a dorsoventral plane, the stallion has a more
Zenker’s, or Davidson’s fluid, with paraffin embedding, is nec- craniocaudal orientation, the dog is oblique, and the boar and
essary. Plastic embedding is the method of choice for a detailed cat are inverted oblique. The basic microscopic appearance is
assessment of the spermatogenic cycle. Inadequate fixation or similar—the testis is divided into the interstitial (extratubular)
suboptimal processing of testicular tissues will cause artifacts or intertubular compartment and the seminiferous tubular com-
that cannot be distinguished from degeneration. partment. The interstitial endocrine cells are the major resi-
The normal testis is pale pink or even almost white. This dent of the intertubular compartment; macrophages are
is presumably because of the large quantity of chromatin another important cell type. In the boar, the interstitial endo-
material. Abnormalities that result in a lowering of spermato- crine cells are particularly prominent and numerous (Fig.
genesis result in the dominance of other pigments—especially 5-13). In young horses, there are lipofuscin-containing mac-
lipochrome pigment. The testes of boars become progressively rophages in the interstitium, remnants of gonadal atrophy of
brown with age, and are brown if degenerate. A frequent mis- the fetal gonad (Fig. 5-14). The normal tubular diameter is
diagnosis is made in equine fetal and neonatal gonads. Fetal 270 µm in the bull, 146 µm in the stallion, 180 µm in the
testes undergo hypertrophy because of hyperplasia of the dog, and 236 µm in the boar. It is normal to see spermatogenic
interstitial endocrine cells as they produce precursors for pla- arrest in some seminiferous tubules in some species.
cental hormones. These cells and testicular macrophages
contain lipochrome pigments that are especially noticeable
during the atrophic stage that occurs prior to birth. Many a
practitioner and pathologist are fooled by the apparent brown
discoloration of the testicular parenchyma of the neonatal
equine testis (Fig. 5-12). The testis varies in gross and micro-
scopic appearance among the species. The stallion has promi-
nent fibrous tissue septa; it is less prominent in the dog and
boar, and absent in ruminants.
Sampling of the testis should be planned. Taking a random
sample of any part of the testis is adequate for generalized
disease; however, such a sample may not be representative of
the entire testicular parenchyma. There is species and indi-
vidual variability in the part of the testis initially affected
by degenerative processes, including variations between the
dorsal and ventral parts of the ruminant testis, variations
between seminiferous tubules, and along the length of indi-
vidual seminiferous tubules. Sampling of the testis to maximize
the number of seminiferous tubules examined should be at right Figure 5-13  Normal spermatogenesis within a normal seminifer-
angles to the direction of the tubules. In general, the seminiferous ous tubule of an adult boar. Note the prominent interstitial endo-
tubules run at right angles to the mediastinum. Each forms a crine cells.

Figure 5-12  Equine fetal testis and epididymis (upper) with Figure 5-14  Testis of a neonatal foal with prominent interstitial
physiologic gonadal hypertrophy; testis is dark brown. Testes cells, macrophages containing lipochrome pigment, and immature
undergo atrophy to become the size of the normal neonatal testis seminiferous tubules that have prominent and centrally located
(lower) before passing through the inguinal ring. germ cells.
476 CHAPTER 5  •  Male Genital System Testis and Epididymis

Further reading
McEntee K. Reproductive Pathology of Domestic Mammals. London:
Academic Press; 1990. p. 224-251.
Russell LD, et al. In: Histological and Histopathological Evaluation of
the Testis. Clearwater FL: Cache River Press; 1990. p. 162-193,
195-295.
Setchell BP. Male reproductive organs and semen. In: Cupps PT, editor.
Reproduction in Domestic Animals. 4th ed. New York: Academic
Press; 1991. p. 221-250.

Disorders of sexual development

Nomenclature and classification of anomalies of the reproduc-
tive tract has changed and all are now called disorders of
sexual development (DSD, see previous section). Also listed
earlier are the normal processes involved in development of
each component of the reproductive tract. Factors that apply Figure 5-15  End-stage retained testicular tissue with marked
to individual species are listed later. interstitial fibrosis, mineralized remnants of seminiferous tubules,
and lipofuscin-containing macrophages.
Cryptorchidism
Incomplete descent of the testes and associated structures
(cryptorchidism) is one of the most common DSD of the male
reproductive system. Its classification is XY, SRY+, testicular
DSD with failure of testicular descent. It is the most common
genital abnormality of the stallion and tomcat. Descent of the
testes, epididymides, and spermatic cord (including the tes-
ticular artery and vein and the deferent duct) is a complex
series of events. Individual cases may be due to chromosomal,
hormonal, structural, or environmental causes. Complete tes-
ticular descent usually occurs before birth in most species,
with the exception of the dog.
Maldescent creates several problems. Most cases are pre-
sumed to be inherited, and breeding from affected individuals
is not recommended. Retained testes lack spermatogenesis, and
fertility is compromised. Increased rates of testicular neoplasia
occur with cryptorchidism in several species, most notably the
dog. Finally, testicular torsion is found almost exclusively in
maldescended testes, although the stallion is an exception. Figure 5-16  Testicular hypoplasia in a boar, with arrested sper-
Diagnostic pathologists receive tissue removed during matogenesis. Appearance is identical to immature testis.
cryptorchidectomy to confirm it is testis. The retained testis
fails to develop after puberty and resembles an immature
testis. Over time, it degenerates or undergoes torsion and only normal location. In postpubertal animals, the testes are smaller
a small remnant remains (Fig. 5-15). The most difficult cases than their normal scrotal counterparts (see Fig 5-3) and often
are those in which all that remains is dense fibrous tissue and have a “Sertoli cell only” pattern (Figs. 5-16, 5-17). This is
lipofuscin-containing macrophages. Anorchia is very rare and, because of the deleterious effect of normal body temperature
where possible, differentiated from degeneration or death of on spermatogenesis. In older animals, degenerative changes
a retained testis. such as interstitial fibrosis and thickening of basement mem-
A hereditary basis for cryptorchidism is established or sug- branes are superimposed on the immature appearance. In
gested in all species. In addition, chromosomal abnormalities extreme forms, the outlines of distorted basement membranes
are present in some rams, bulls, and stallions. Multiple studies are in fibrous tissue (see Fig. 5-15). Hyperplastic foci of Sertoli
of human males with cryptorchidism show that 2-4% have cells occur in some retained testes, and these may be sites of
sex chromosome disorders of the sex chromosomes; thus this development of Sertoli cell tumors (see Fig. 5-17). In unilat-
is a manifestation of a chromosomal DSD. When there are eral testicular maldescent, which is typical, the contralateral
outbreaks of cryptorchidism, hormonal and environmental testis is hypertrophied (see Fig. 5-3).
factors are more likely. Failure of descent sometimes occurs Cryptorchidism is infrequently reported in bulls, but the
because structural disorders anchor the testis so it cannot prevalence is much higher. Retention of the testis and epididy-
migrate to the scrotum. Splenogonadal fusion, retention of the mis is mostly in the subcutaneous/inguinal region, and occurs
cranial gonadal suspensory ligament, and abnormalities of the about twice as often on the left as compared to the right side.
gubernaculum and vaginal process are all reported. Polled Hereford and Shorthorn cattle are more at risk than
Retained testes in prepubescent animals are identical to other breeds. Little is known of the pathogenesis of cryptor-
descended testes prior to puberty. Germ cells are in the lumen chidism in bulls, although it is believed to be hereditary. The
of the tubules or close to the basement membrane in their histologic appearance of the cryptorchid testis is similar to
 476.e1

Further reading
Hemeida NA, et al. Ductuli efferentes in the epididymis of the boar,
goat, ram, bull and stallion. Am J Vet Res 1987;39:1892-1900.
 Testis and Epididymis
Figure 5-17  Focal Sertoli cell hyperplasia in the cryptorchid
testis of a ram.
Figure 5-18  Torsion of the retained testis of a boar.
that of hypoplastic testes and epididymides. Neoplasia in
cryptorchid testes is very rare in bulls, with an interstitial cell
tumor and a fibrolipoma reported.
Cryptorchidism is common in boars. There is a hereditary
basis, with the trait being recessive, and there may be recessive
genes at more than one locus in the Duroc breed. Abnormal
development of the gubernaculum, including underdevelop-
ment, excessive growth, and an abnormal location, is the main
underlying structural change in cryptorchidism in pigs. The
usual location for the retained testes in pigs is intra-abdominal,
and torsion is seen in slaughtered pigs (Fig. 5-18).
There are many reports of cryptorchidism in stallions. Tes-
ticular retention is usually unilateral, with about equal fre-
quency as to side affected. Abdominal retention of left testes
is more common than inguinal; the reverse is the case on the
right side. Neoplasia of the retained testis is occasional, with
teratomas, seminomas, and Sertoli cell tumors reported.
In rams, cryptorchidism often has an autosomal recessive
mode of inheritance, but may also be due to a dominant gene
with incomplete penetrance. Unilateral maldescent is more
common (see Fig. 5-3) than bilateral involvement, and the
right testis is most often retained. Hemicastration is likely in
unilateral cryptorchid animals. Some ram lambs, inadvertently,
have only their scrotum removed during attempted castra­
tion, leaving the testes in an “induced cryptorchid” state.
477
Figure 5-19  Intra-abdominal testis of a dog that developed a
Sertoli cell tumor. The testis subsequently underwent torsion and
venous infarction.
Cryptorchidism in sheep has an increased prevalence in polled
animals.
Cryptorchidism occurs sporadically in goats, mainly
involving the right testis. It is a regular feature of the goat
disorder of sexual development known as the polled/intersex
syndrome (PIS).
In dogs, cryptorchidism may be an autosomal recessive
inherited disease in some breeds, although there is some doubt
that this is the main cause. Although it is a frequent clinical
finding, little is known of the mechanism and features of the
condition. The association between testicular neoplasia and
testicular maldescent is well recognized. Sertoli cell tumors
are the most common, especially in abdominally retained
testes. Seminomas are the second most common neoplasm,
and they occur mostly in inguinally retained testes. Miniature
Schnauzers with persistent Müllerian duct syndrome (PMDS)
often have unilateral or bilateral testicular maldescent. Tes-
ticular torsion usually involves cryptorchid testes—especially
if there is a concomitant testicular neoplasm (Fig. 5-19).
Other diseases linked to retained testes are patellar sublux-
ation, hip dysplasia, penile and preputial defects, and umbili-
cal and inguinal hernias. Dogs are more likely to have retention
of the right testis—perhaps because of a longer pathway for
descent of that testis, or a less well-defined gubernaculum on
the right. Inguinal testes predominate over intra-abdominal.
Testicular neoplasms—Sertoli cell tumor and seminoma—
are more prevalent in the right side also. Descent is usually
complete by 3 months of age in the dog. Hormonal studies
suggest that LH is lower in cryptorchid dogs, and the crypt-
orchid testis mediates the inhibition of LH secretion. As with
other species, cryptorchidism could indicate a sex chromo-
some DSD (see previous section, Disorders of sexual
development).
Cryptorchidism is the most common disease of the repro-
ductive tract in male cats, and Persians are over-represented.
The failure of testicular descent in cats tends to be unilateral
without a bias to one side or the other. The testis can be
anywhere along the migration path, although inguinal crypt-
orchidism predominated in one study.
478 CHAPTER 5  •  Male Genital System
Camelids can have retained testes, with a prevalence
of about 3% in alpacas. The testes are often inguinally
retained.
Further reading
Amann RP, Veeramachaneni DN.. Cryptorchidism in common eutherian
mammals. Reproduction 2007;133:541-561.
Bernal-Mansas CM, et al. Proliferation and apoptosis of spermatogonia
in postpuberal boar testes with spontaneous unilateral and bilateral
abdominal cryptorchidism. Acta Histochem 2005;107:365-372.
Gorlov IP, et al. Mutations of the GREAT gene cause cryptorchidism.
Hum Mol Genet 2002;11:2309-2318.
Hayes HM. Epidemiological features of 5009 cases of equine cryptor-
chidism. Equine Vet J 1986;18:467-471.
Kersten W, et al. Bilateral cryptorchidism in a dog with persistent
cranial testis suspensory ligaments and inverted gubernacula:
report of a case with implications for understanding normal and
aberrant testis descent. J Anat 1996;189:171-176.
Ladds PW. Congenital abnormalities of the genitalia of cattle, sheep,
goats and pigs. Vet Clin North Am Food Anim Pract 1993;9:
127-144.
Osawa T, et al. Fibrolipoma of a cryptorchid testis in a young bull. J Vet
Med Sci 2011;73:1253-1255.
Searle D, et al. Equine castration: review of anatomy, approaches,
techniques and complications in normal, cryptorchid and monor-
chid horses. Aust Vet J 1999;77:428-434.
Yates D. Incidence of cryptorchidism in dogs and cats. Vet Rec
2003;152:502-504.
Testicular hypoplasia
Hypoplastic testes fail to grow to a normal size. Testicular
hypoplasia occurs in sex chromosome DSD, cryptorchidism, and
as an “uncomplicated” disease. This latter situation is catego-
rized as an XY SRY+ testicular DSD. It can be unilateral or
bilateral, and is confirmed after puberty when an immature
testis does not develop to its expected normal size. The small
size is because of a reduction in the amount of seminiferous
epithelium, thus there are fewer Sertoli cells, spermatogonia,
spermatocytes, elongated spermatids, and spermatozoa. An
affected testis is grossly similar to a normal prepubertal testis
in almost every way (see Fig. 5-4).
Studies of hypoplasia are mostly observational at the clini-
cal, gross, or microscopic level. Evaluation of mutant mice has
aided the study of pathogenesis, mostly by identifying the
effects of lack of cytokines and growth factors. Research indi-
cates there is an alteration of control of spermatogenesis, so
there are many similarities with testicular degeneration (see
later). From a pathogenetic point of view, hypoplasia occurs
when spermatogenesis is affected prior to or at the time of
puberty, and degeneration occurs from a similar cause after
puberty.
Hypoplasia is known or suspected to be hereditary in the
bull, ram, and buck. The exact genetic abnormality is often
not established. There are few studies of hypoplasia in domes-
ticated animals, but there are some special features of the
disease in selected species discussed later.
Hypoplasia is the potential outcome of a large number of
different abnormalities that may operate at a systemic or local
level. The small size of the testis is theoretically because of an
abnormally small number, length, or diameter of tubules, or
Testis and Epididymis
Figure 5-20  Testicular hypoplasia in a cat. Seminiferous tubules
contain only Sertoli cells and a few germ cells. There is some
degeneration of Sertoli cells with vacuolation. The interstitial
endocrine cells are very prominent.
one or more combinations of these (see Figs. 5-14, 5-16, 5-17).
Germ cells may be absent, or be present but fail to produce
enough spermatozoa. Thus germ cells may fail to migrate to
the genital ridge in utero, fail to migrate in sufficient numbers,
fail to survive, have arrested development, undergo excessive
apoptosis, or undergo degeneration (Fig. 5-20). The underlying
cause can be abnormal sex chromosomes (thus a sex chromo-
some DSD), a deficiency of gonadotropins, or other altered
environment of the testis during development.
At the sex chromosome level, testicular hypoplasia is rec-
ognized in animals with a condition resembling Klinefelter
syndrome. Affected, bulls, pigs, horses, sheep, dogs, and cats
have an XXY genotype or a mosaicism with XXY chromo-
somes. The best known of these is the male tortoiseshell or
calico cat. In Saanen goats with the gene for polledness (PIS),
testicular hypoplasia is seen in individuals that have XX sex
chromosomes but have testes and a male phenotype. A variety
of other sex chromosome abnormalities are identified with
hypoplasia.
A deficiency of gonadotrophins occurs with hypoplasia
(hypogonadotrophic hypogonadism) in men and mice, but
studies in domesticated mammals indicate a normal or raised
serum concentration of FSH and LH. Testosterone concentra-
tion was lower than normal in some bulls with hypoplasia;
in sheep, testosterone and inhibin concentration may be
normal.
Microscopic abnormalities include a total lack of germ
cells, arrested spermatogenesis in all tubules, or arrested sper-
matogenesis that varies from tubule to tubule (see Fig. 5-20).
Hypoplastic testes with a total lack of germ cells are very small
and fail to enlarge from their size at birth (see Fig. 5-4). Those
testes with arrested development of all tubules fail to progress
beyond a certain stage of spermatogenesis. It is common to
see some hypoplastic tubules in a normal testis.
Further reading
Borel N, et al. Testicular hypoplasia in a bull persistently infested with
bovine diarrhoea virus. J Comp Pathol 2007;137:169-173.
 478.e1

Further reading
Claxton JH, Yeates NTM. The inheritance of cryptorchidism in a small
crossbred flock of sheep. J Hered 1972;63:141-144.
Dolling CHS, Brooker MG. Cryptorchidism in Australian Merino sheep.
Nature 1964;203:49-50.
Hayes HM, et al. Canine cryptorchidism and subsequent testicular neo-
plasia: case control study with epidemiological update. Teratol
1985;32:51-56.
Humphrey JD, Ladds PW. Pathology of the bovine testis and epididymis.
Vet Bull 1975;45:787-797.
Kawakami E, et al. Peripheral plasma levels of LH, testosterone, and
estradiol-17 β before and after orchiopexy in unilaterally cryptorchid
dogs. Nippon Juigaku Asshi 1990;52:179-181.
Marshall LS, et al. Persistent Müllerian duct syndrome in miniature
Schnauzers. J Am Vet Med Assoc 1982;181:798-801.
Millis DL, et al. Cryptorchidism and monorchidism in cats: 25 cases
(1980-1989). J Am Vet Med Assoc 1992;200:1128-1130.
Romagnoli SE. Canine cryptorchidism. Vet Clin North Am Small Anim
Pract 1991;21:533-544.
Rothschild MF, et al. Evidence for multigene control of cryptorchidism
in swine. J Hered 1988;79:313-314.
Soller M, et al. Cytogenetics of Saanen goats showing abnormal devel-
opment of the reproductive tract associated with the dominant
gene for polledness. Cytogenetics 1969;8:51-67.
St. Jean G, et al. Cryptorchidism in North American cattle: breed pre-
disposition and clinical findings. Theriogenol 1992;38:951-958.
Tarigan S, et al. Genital pathology of feral male goats. Aust Vet J
1990;67:286-290.
Watt DA. Testicular pathology of Merino rams. Aust Vet J 1978;54:
473-478.
478.e2

Further reading
Centerwall WR, Benirschke K. An animal model for the XXY Klinefel-
ter’s syndrome in man: tortoiseshell and calico male cats. Am J Vet
Res 1975;36:1275-1280.
Galloway DB, et al. An outbreak of gonadal hypoplasia in a sheep
flock: clinical, pathological and endocrinological features, and aeti-
ological studies. Vet Rec 1992;131:506-512.
Gimbo A, et al. Ram testicular hypoplasia: anatomical and histopatho-
logical observations. Schweiz Arch Tierheilk 1987;129:481-491.
Olson PN. Clinical approach for evaluation dogs with azoospermia or
aspermia. Vet Clin North Am Small Anim Pract 1991;21:591-607.
Sponenberg DP, et al. Unilateral testicular hypoplasia in a goat. Vet
Pathol 1983;20:503-506.
Veeramachaneni D, et al. Pathophysiology of small testes in beef bulls:
relationship between scrotal circumference, histopathologic fea-
tures of testes and epididymides, seminal characteristics, and endo-
crine profiles. Am J Vet Res 1986;47:1988-1999.
 Testis and Epididymis
Han K, et al. Pathogenesis of type 1 (European genotype) porcine
reproductive and respiratory syndrome virus in male gonads of
infected boar. Vet Res Commun 2013;37:155-162.
Kay GW, et al. Heritable testicular hypoplasia in Nguni (Bos indicus)
bulls: vascular characteristics and testosterone production. J Reprod
Fertil 1992;96:537-547.
Olson PN, et al. Clinical and laboratory findings associated with actual
or suspected azoospermia in dogs: 18 cases (1979-1990). J Am Vet
Med Assoc 1992;201:478-482.
Settergren I, McEntee K. Germ cell weakness as a cause of testicular
hypoplasia in bulls. Acta Vet Scand 1992;33:273-282.
Smith KC, et al. A survey of congenital reproductive abnormalities in
rams in abattoirs in south west England. Reprod Dom Anim
2012;47:740-745.
Hypoplasia in bulls.  Testicular hypoplasia in bulls, and
especially in some breeds such as the Belgian blue, is very
common. Breeding soundness examination and the culling of
bulls with a scrotal circumference below the normal range is
common and in some breeds exceeds 90% of tested individu-
als. The causes are probably multifactorial. Studies suggest it
is hereditary in the Swedish Highland breed, in which it has
a recessive inheritance with incomplete penetrance. Animals
with white body and ears are particularly likely to have hypo-
plasia. The majority of unilateral hypoplastic testes are on the
left side. In one Bos indicus breed, heritable hypoplasia is
linked to branching of the testicular artery near the aorta of
the same side, suggesting that reduced blood flow may
be responsible. Testosterone secretion was reduced in the
affected testis.
Microscopic changes of hypoplasia include cessation of
spermatogenesis at some stage, with either degeneration or
excessive apoptosis of the germinal epithelium. The most
severe cases of hypoplasia have a Sertoli cell-only pattern or
they have some normal and abnormal tubules intermixed,
often with affected tubules being in the more dorsal part of
the testis.
Persistent infection of bulls with bovine viral diarrhea virus
(BVDV) may affect testicular development.
Hypoplasia in boars.  Most research on boar fertility and
altered spermatogenesis has focused on chromosomal abnor-
malities, including abnormal complement of sex chromo-
somes, translocations of parts of the X chromosome, and other
disorders. These result in abnormal spermatogenesis or inabil-
ity to produce an appropriate litter size in the face of normal
semen parameters. Porcine reproductive and respiratory syn-
drome virus (PRRSV) infection of the testis and increased
apoptosis of germ cells is reported and may contribute to
infertility of infected boars.
Hypoplasia in stallions.  Testicular hypoplasia of horses is
not well studied and prevalence is not available, partly because
most male horses are gelded. It occurs with sex chromosome
DSD and as a sporadic condition. Many cases are mild and
unilateral—one testis is smaller than the other.
Hypoplasia in rams.  Testicular hypoplasia of rams is con-
sistently the most commonly reported DSD of the male
reproductive tract. It is usually a sporadic disease that is either
bilateral or unilateral. The disease is not well studied. A condi-
tion resembling Klinefelter syndrome, with an XXY genotype,
is reported. Zinc deficiency is implicated in some cases.
479
Various degrees of hypoplasia are recognized, and affected
testes may have tubules that, at the extreme are ∼90 µm in
diameter (normal 160 µm) and lined by mostly fetal Sertoli
cells. There is a report of an outbreak of gonadal hypoplasia
of multiple rams born within a short time frame. The affected
testes were uniformly small and had a “Sertoli cell-only”
pattern histologically. An environmental cause was
suspected.
Hypoplasia in bucks.  There are several types of hypoplasia
recorded in bucks. It is a common abnormality in the polled/
intersex (PIS) syndrome of polled Saanen goats, in which the
animals have XX sex chromosomes but have testes and are
phenotypically male. The testes of affected animals have rudi-
mentary seminiferous tubules. Other sporadic forms of hypo-
plasia occur, and the cause is not known.
Hypoplasia in cats.  Testicular hypoplasia is a sporadic
disease of cats. In male cats with a tricolor or calico coloration
and therefore a XXY sex chromosome complement, there are
no germ cells and the testes are markedly hypoplastic with
small diameter tubules. Chimeric animals may be fertile.
Hypoplasia in dogs.  About 6% of dogs may have testicular
hypoplasia. A diagnosis is usually made after azoospermia is
found during an investigation of infertility. Congenital azo-
ospermia occurs in some lines of dogs. This suggests a familial
or hereditary basis, implicating inbreeding. Confirmation of
congenital azoospermia because of testicular hypoplasia
requires historical information or testicular biopsy after the
expected date of puberty.
Hypoplasia occurs in animals with failure of testicular
descent and in sex chromosome abnormalities such as those
with XX or XXY sex chromosome DSD. Offspring of bitches
treated with diethylstilbestrol may have hypoplastic testes.
Other testicular disorders of development
Monorchia is the presence of only one testis. As a general
term, monorchism is the result of cryptorchidism, severe uni-
lateral testicular degeneration, or agenesis. True agenesis occurs
when there is a failure of one testis to develop. The differentia-
tion between true agenesis and a cryptorchid with total tes-
ticular degeneration is impossible, but true agenesis is
considered to be very rare. Likewise, supernumerary testes
(polyorchidism) or fusion of abdominal testes is very rare.
The presence of testicular tissue outside the testis is
reported in pigs, in which nodules of tissue were found
throughout the peritoneal cavity. In the dog and cat, Sertoli
cell tumors and interstitial cell tumors can arise from ectopic
testicular tissue in the scrotal skin or spermatic cord. Previous
surgical implantation of normal cells is suspected. In the cat,
heterotopic interstitial endocrine cells occur in the epididy-
mis, and neoplasia of this tissue is reported.
Fusion of the testes to abdominal organs such as the spleen
and variations in the shape of testes are described. “Hour-glass”
shaped, round, and horizontally placed testes of ruminants are
all reported.
Accessory or ectopic adrenal tissue is reported in horses
and rams, and rarely in other species. Most are located in the
region of the head of the epididymis and distal spermatic cord
(Fig. 5-21).
A variety of cystic structures have been described in and
around the testis and epididymis. Some arise from the rete
testis and others are remnants of mesonephric ducts or duct-
ules, or paramesonephric ducts.
480 CHAPTER 5  •  Male Genital System Testis and Epididymis

Figure 5-21  Ectopic adrenal nodule (cut) on the deferent ductule

region of a ram.
Figure 5-22  Segmental aplasia of the mesonephric duct in a cat.
The entire epididymis is missing. The deferent duct remains on
Further reading
the bulbous testis
Doxsee AL, et al. Extratesticular interstitial and Sertoli cell tumors in
previously neutered dogs and cats: a report of 17 cases. Can Vet J
2006;47: 763-766.
Tamminen TM, et al. A polyorchid dog. Reprod Dom Anim
2012;47:26-28.
Wakui S, et al. Testicular efferent ductule cyst of a dog. Vet Pathol
1997;34:230-232.

Disorders of mesonephric and

paramesonephric structures
The rete testis and efferent ductules are derived from the
mesonephric tubules. The epididymis, deferent duct, and
ampullae (and vesicular glands) form from the mesonephric
duct. These transport spermatozoa and fluid from the testis
to the pelvic urethra. Maturation and storage of spermatozoa
also occurs in this conduction system. There is a single duct
from the efferent ductules to the urethra, and any interruption
has catastrophic effects to the fertility of that side. The even-
tual effect of continuous spermatozoal production and disrup-
tion of one of the efferent ductules has a similar outcome.
Segmental aplasia of the mesonephric duct (SAMD) is an
important condition because it prevents fertility of the affected
side. Segmental aplasia is rare, but found in all species. Uni-
lateral aplasia may be an inherited condition. Absence of the Figure 5-23  Spermatic granuloma of the epididymal head in a
tail of the epididymis is the most frequently recognized DSD bull. The efferent ductular region and the head of the epididymis
(Fig. 5-22). Without a part of the epididymis, continuous are large and contain spermatic granulomas. The body and tail of
production of spermatozoa results in spermiostasis, tubular the epididymis is very small.
dilation, formation of spermatic granulomas, dilation of the
mediastinum testis, and testicular atrophy from increased
pressure. A smaller vesicular gland on the affected side— granuloma. The induced inflammation and fibrosis will even-
presumably because of a lack of trophic stimuli—is usually tually cause obstruction of other efferent ductules and the
also present. Hypertrophy of the contralateral testis is likely. epididymal duct. The result will be complete obstruction to
Spermatic granuloma of the epididymal head (Figs. flow of spermatozoal-rich fluid and progressive formation of
5-23, 5-24) results from failure of one or more of the 12-25 more spermatic granulomas. The distal epididymal tissues do
efferent ductules to join with the epididymal duct. After not reach adult size, the mediastinum testis dilates, and the
puberty, the blind-ended ductule(s) fill with spermatozoa and, testis undergoes pressure atrophy. This condition is misdiag-
with spermiostasis, may rupture and/or form a spermatic nosed as infectious epididymitis and the potential congenital
 480.e1

Further reading
McEntee K. Reproductive Pathology of Domestic Mammals. London:
Academic Press; 1990. p. 230-231.
Parks AH, et al. Monorchidism in the horse. Equine Vet J
1989;21:215-217.
 Testis and Epididymis
Figure 5-24  Spermatic granuloma of the epididymal head in
a dog.
or hereditary basis for the problem is missed. Spermatic gran-
uloma of the epididymal head is a more commonly found in
polled Saanen goats, where they may be bilateral, and in
Boston terrier dogs (see Fig. 5-24).
Many cystic lesions are reported in the testicular capsule,
epididymis, spermatic cord, and adjacent to the accessory
genital glands. These are dilated remnants or duplications of
the mesonephric tubules or paramesonephric and mesoneph-
ric ducts. Their location in the reproductive tract is the best
indicator of their origin. Remnants of the mesonephric duct
include the paradidymis (internal and external), epididymal
cysts, and appendix epididymis. So-called retention cysts are
very common in the region of the head of the epididymis,
especially in rams (see Fig. 5-5). They are usually up to 3 mm
in diameter, contain clear fluid, and lined by epithelium similar
to that of the epididymis. The paradidymis occurs proximal
to the epididymis in the spermatic cord as one or several small
cysts, particularly in neonates. Other cysts, seen particularly
in the epididymis, can be microscopic or up to 4 cm in
diameter.
Remnants of the paramesonephric ducts include the appen-
dix testis, the uterus masculinus near the accessory genital
glands, and in some cases a completely retained duct that runs
beside the testis. Histologically these may have the appearance
of a juvenile uterus with prominent musculature and uterine
glands.
Many other disorders of development of the epididymis
have minor significance. Melanosis of the epididymis occurs
in rams and bulls. Adrenal ectopia is seen occasionally. Ectopic
interstitial endocrine cells and ectopic interstitial cell tumors
are reported in the testicular capsule, mediastinum testis, or
spermatic cord of cats.
Further reading
Estrada A, et al. Azoospermia associated with bilateral segmental
aplasia of the ductus deferens in a stallion. J Am Vet Med Assoc
2003;222:1740-1742.
Foster RA, et al. Pathology of reproductive tracts of merino rams in
northwestern Queensland. Aust Vet J 1989;66:263-264.
Ortega-Pacheco A, et al. Pathological conditions of the reproductive
organs of male stray dogs in the tropics: prevalence, risk factors,
morphological findings and testosterone. Reprod Dom Anim
2006;41:429-237.
481
Williams HJ, et al. Clinical, ultrasonic and pathologic findings in a bull
with segmental aplasia of the mesonephric duct. Reprod Dom Anim
2010;42:212-216.
Variation in testicular and epididymal size
The daily testicular output of spermatozoa is highly correlated
with testicular volume. This is estimated by measuring scrotal
circumference, for which reference ranges have been estab-
lished by species or breed. Testes above this range are hyper-
trophied; those below the range are too small because of
atrophy or hypoplasia. Even experienced pathologists have dif-
ficulty in differentiating hypoplastic from atrophic testes in adults.
This is because there are variations in the degree of hypoplasia
and, over time, hypoplastic testes may undergo degeneration.
The best method to separate atrophy from hypoplasia is to
document a decrease from normal testicular weight or size
over time. In contrast, hypoplastic testes are smaller than
normal and remain so.
In hypoplastic testes, the testis and epididymis fail to
increase in size to the normal reference range at puberty (see
Fig. 5-4). As such, the ratio of the weight of the testis to epi-
didymis is similar to that of normal testes. The size of both is
smaller than normal and there are histologic features of sper-
matogenic arrest in tubules that are smaller than age- and
breed-matched controls. Testicular hypoplasia is discussed in
a previous section covering testicular disorders of sexual
development.
The general terminology used for a reduction in the size
of the testis is to use atrophy for the macroscopic reduction
in size and degeneration to refer to the histologic observations.
Atrophic testes should have a ratio of testicular to epididymal
weight that is reduced as the reduction in size of the testis is
greater than the reduction in size of the epididymis. The base-
ment membrane of appropriately fixed atrophic testes is
thicker than normal and often has a buckled or “wavy” outline.
Pathologists are usually required to make the distinction on a
single observation, a diagnosis of “suspect atrophy” or “suspect
hypoplasia” is not necessarily an indication of ignorance;
rather, it is an indication of appropriate caution.
When one testis is larger than the other, a common assump-
tion is that the larger testis is enlarged from neoplasia. It may
be normal or hypertrophied and the contralateral testis is
hypoplastic or atrophic.
Testicular atrophy and degeneration
Testicular degeneration is manifested clinically and grossly as
atrophy, mineralization, and fibrosis. Microscopically, it begins
as a reduction in spermatogenesis, shrinking of tubular diam-
eter, reduction in the number of Sertoli cells, reduction in
interstitial endocrine cell size, and a wavy and thickened
hyaline basement membrane.
The pathophysiology is extremely complex and involves
influences external to or internal within the testis. There is a
seemingly endless list of potential causes from aging to toxi-
cosis, as outlined in Box 5-1. The close interrelationship of all
testicular components and especially the Sertoli cells, intersti-
tial endocrine cells, and germ cells means that insults to any
one or several of them eventually affects them all. Regulation
of testicular function involves systemic and local testicular
components, so the manifestation in the testis is not always
bilateral or uniform within a testis. Eventually there is reduced
testosterone production by interstitial endocrine cells and
 481.e1

Further reading
Campero CM, et al. Lesions of presumed congenital origin in the acces-
sory sex glands of bulls. Aust Vet J 1989;66:80-85.
Humphrey JD, Ladds PW. Pathology of the bovine testis and epididymis.
Vet Bull 1975;45:787-797.
Ladds PW, et al. Epididymal aplasia in two rams. Aust Vet J
1990;67:457-458.
Wrobel KH, Hees H. Heterotopic Leydig cells in the cat. Anat Histol
Embryol 1987;16:289-292.
482 CHAPTER 5  •  Male Genital System Testis and Epididymis

BOX • 5-1 
Causes of testicular degeneration

• Advancing age
• Chemicals
1. Chemotherapy
2. Chlorinated naphthalenes
3. Halogenated compounds, including hexachlorophene
4. Nitrogen-containing compounds, including
benzimidazoles, nitrofurans
5. Metal compound toxicosis
• Epididymitis
• Heat
• Hormones
1. Dexamethasone
2. Estrogen
3. Testosterone
4. Zearalenone
• Neoplasia
1. Pituitary tumors
• Nutritional disorders
1. Negative energy balance Figure 5-25  Unilateral testicular atrophy in a ram. The epididy-
2. Fatty acid deficiency mis of the atrophic testis appears disproportionately large.
3. Hypovitaminosis A
4. Hypervitaminosis A
5. Hypovitaminosis B
6. Hypovitaminosis C
7. Hypovitaminosis E
8. Protein and amino acid deficiency
9. Zinc deficiency
• Plants
1. Locoweed (Astragalus)
2. Lysine seeds (gossypol)
• Radiation
• Stress/corticosteroid therapy
• Trauma
• Ultrasound
• Viral infection
1. Porcine reproductive and respiratory syndrome virus
2. Canine distemper virus
3. Bovine viral diarrhea virus

Figure 5-26  Unilateral testicular atrophy in a stallion secondary

reduced inhibin release from Sertoli cells. It is a perplexing
phenomenon that a cause acting locally in one testis can affect
the opposite testis. To some extent, alteration in oxidant-
antioxidant balance can explain this.
Testes undergoing atrophy are reduced in size (Fig. 5-25).
In early or rapidly progressing degeneration, the testis is
soft and flabby, lacks turgor, and the cut surface does not
bulge. Wrinkling of the testicular capsule may be apparent.
With ongoing loss of fluid and reduction in the germinal epi-
thelium relative to the stroma, the result is a smaller testis of
firm consistency. The substance of the testis is a darker color
that is often brown (Figs. 5-26, 5-27). The epididymis is
usually less affected than the testis and will appear dispropor-
tionately large. With continued degeneration and fibrosis, the
testis becomes increasingly hard and tough (see Fig. 5-25).
Spermiostasis in parts of individual seminiferous tubules is
identified as white linear regions, especially at the mediasti-
num, and these may mineralize (see Fig. 5-27). Continued
to unilateral scrotal hernia.
mineralization can result in petrification of a part of or the
whole testis.
Testicular degeneration may be uni- or bilateral, and it is
assumed that unilateral degeneration is the result of a local event,
whereas bilateral degeneration is the result of a systemic problem.
The testes of aged bulls frequently degenerate from the
ventrum, and those from rams degenerate from the dorsum.
This variable pattern of change means biopsies of testes should
be interpreted with caution and respect for whether the
sample is representative of the whole.
Histologic changes in degeneration (Figs. 5-28, 5-29) vary
in degree, but are relatively stereotypic. In the early stages,
Sertoli cells develop either fine basal vacuolation or more
dramatic vacuolation of the apical cytoplasm. There also is
disorganization and exfoliation of germ cells, or spermatogenic
arrest at one of the many stages of the spermatogenic cycle.
 Testis and Epididymis
Figure 5-27  Testicular atrophy and resultant darker testicular
color, and multifocal mineralization of seminiferous tubules in
a buck.
Figure 5-28  Testicular degeneration in a dog. Tubules are at
various stages of degeneration including a Sertoli cell only pattern,
reduced spermatogenesis, and buckling of basement membranes,
hyalinized tubules, and depletion of both germinal and Sertoli
cells. Prominent and hyalinized blood vessels are in the
interstitium.
In some cases there may be failure of release of germ cells
from Sertoli cells (spermiation) and spermatozoa are phago-
cytized by Sertoli cells.
Early changes in the germ cells include failure of matura-
tion of spermatozoa and degeneration of spermatids; many
spermatids are apoptotic and or necrotic and others produce
characteristic spermatid multinuclear giant cells (Fig. 5-30).
When the degeneration is more advanced, the affected areas
are more extensive and degenerative changes appear in the
precursors of spermatids. Depending on the insult, there may
be cytoplasmic vacuolation and nuclear pyknosis, or apoptotic
bodies are seen. Progression of changes results in loss of
483
Figure 5-29  Advanced testicular degeneration with spermato-
genic arrest in the seminiferous tubule of a dog.
Figure 5-30  Early stages of testicular degeneration in a dog.
Multinucleated spermatids are within the lumen.
germinal cells, and eventually, loss of even the resistant Sertoli
cells (see Fig. 5-28). Basement membrane thickening is a fre-
quent finding, and as a result, there is shrinkage and collapse
of tubules. The basement membrane becomes wavy, buckled,
and thickened. The periodic acid–Schiff (PAS) stain clearly
accentuates the changes to the basement membrane. In ultra-
structural studies of the testes of normal bulls and bulls with
atrophy or hypoplasia, mean thicknesses of the basal lamina
was ∼0.7, 1.5, and 1.0 µm, respectively.
Once-only scrotal heating can cause the appearance of
spermatid giant cells in degenerate testes and perhaps in the
semen. Two types of giant cells, mononuclear giant cells prob-
ably derived from pachytene spermatocytes that fail to dif-
ferentiate further, and multinucleated cells, considered to be
derived from coalescence of identical spermatids, are observed
histologically. Even extremely brief heating, of several minutes
only, induces giant cell formation. Such giant cells are seen as
early as 6 hours and as late as 7 weeks post-heating, but they
seem to be most prevalent at about 1 week. The fate of these
cells is unclear. They may disintegrate or pass out of the testis.
In addition to giant cell formation, minor increases in testicu-
lar temperature in sheep produce a marked accumulation of
spermatogonia; histologically there are many cells in which
mitosis is incomplete.
484 CHAPTER 5  •  Male Genital System
Figure 5-31  Spermiostasis and mineralization in a seminiferous
tubule with multinucleated giant cell response and interstitial
lymphocytic orchitis.
Granulomas can form in degenerate testes, especially
where there is spermiostasis (Fig. 5-31). This, and the presence
of lymphocytes and plasma cells, indicates an immune response
to spermatozoa but complicates the differentiation of simple
degeneration from interstitial orchitis. Alteration of interstitial
endocrine cell function reduces testosterone production and
a change from an anti-inflammatory to a proinflammatory
cytokine profile. Mineralization and eventually osseous metapla-
sia sometimes occurs in tubules affected by spermiostasis for
a long time.
Mineralization is a common sign of degeneration, and it
may involve all or part of one seminiferous tubule, or whole
regions (see Fig. 5-31). The basic mechanism of degeneration
of the cells that make up the germinal epithelium is presumed
to be via increased apoptosis.
The testis is very susceptible to changes in its local environ-
ment, such as free radical–oxidant and antioxidant balance,
and cytokine signaling within the testis. A slight shift in the
balance to free radical production results in degeneration and
altered spermatogenesis. The intratubular compartment is
particularly vulnerable to oxidative stress and free radical
damage, so a change in testicular temperature, blood flow,
oxygen tension, and systemic inflammation will cause degen-
eration. This shift in balance is believed to be responsible for
testicular degeneration in the contralateral testis of a testis
with degeneration from another cause, such as varicocele,
stress, or systemic disease.
The testis is very susceptible to increased scrotal temperature.
Both testicular and epididymal function are altered when
intrascrotal temperatures increase. In the epididymis, an
increase in temperature reduces mRNA expression of a sper-
matozoal membrane glycoprotein (CD52) in a testosterone-
independent manner. An inability to maintain the testes at a
temperature lower than normal body temperatures can occur
with pyrexia, increased environmental temperatures, scrotal
thickening and hair and wool cover, and by the presence of
intrascrotal inflammation or scrotal dermatitis. Varicocele is
also implicated in the failure to maintain testicular thermo-
regulation. The progressive degeneration of maldescended
testes is believed to be the result of abnormally high testicular
temperature.
Degeneration of the testes with advancing age is a recognized
phenomenon. The cause is not known, and there is no clear
definition of what actually constitutes age-associated
Testis and Epididymis
degeneration. It may be secondary to degenerative vascular
lesions within the testis or pampiniform plexus. A progressive
alteration of the function of interstitial endocrine cells and
reduced testosterone production occurs, and Sertoli cells alter
their production of inhibin. It is not clear which changes are
cause and which are effect. Old bulls and rams have a diffuse
increase in intertubular stroma and a decreased proportion of
tubular mass. Other changes include increased thickness of
tunics and tubular basement membrane, increased proportion
of degenerate tubules, and an apparent increased number of
interstitial endocrine cells, which contain increasing amounts
of lipofuscin. Older stallions have more degenerate tubules,
basement membranes are thicker, and there is more collagen
IV and elastin in the interstitial compartment. Myoid cells are
swollen, interstitial endocrine cells appear to be increased in
number, and there are lipofuscin-containing macrophages in
the intertubular space. Arterioles may have a hyaline wall.
Dogs have a reduced area of their seminiferous tubules that
continues to decline with age. Degenerate testes usually have
arterioles with a thickened wall.
Gonadotrophins are essential for the normal development
and function of the reproductive tract. The pathology of endo-
crine disrupting chemicals (EDCs) is a major focus because of
the potential effects of antiandrogenic and estrogenic sub-
stances on male development and reproduction. Many differ-
ent EDCs are known, including those that bind to the estrogen
receptor, increase aromatase expression, inhibit aromatase, are
antiandrogenic, or are estrogenic. Substances in this group
include lead, ethanol, diethyl stilbestrol, various insecticides
including DDT, and bisphenol A. Each could adversely affect
spermatogenesis and cause degeneration, although in most
cases it is only mild.
There are directly acting reproductive toxicants in domesti-
cated mammals. Biotransformation of such compounds can
occur in the testis; those formed elsewhere may not attain
significant intratesticular concentrations. The toxicant may
affect any one or several of the cell types, including the inter-
stitial endocrine cells, Sertoli cells, spermatogonia, spermato-
cytes, spermatids, spermatozoa, or the epididymal tissues.
Interstitial endocrine cell toxicants, as expected, affect testos-
terone production. Ketoconazole, ethanol, acetaldehyde, and
cannabinoids are examples. Their effects include alteration of
Sertoli cell function and maturation of germ cells, especially
pachytene spermatocytes and spermatids.
Direct Sertoli cell toxicants will have detrimental effects on
the blood-testis barrier, orientation and translocation of germ
cells, hormonal and nutritional support of germ cells, and
phagocytosis of residual bodies. The targets for toxicants
include the actin filaments, intermediate filaments, and micro-
tubules. Cytochalasin disrupts actin filaments, acrylamide dis-
rupts intermediate filaments, and colchicine, vinblastine, and
vincristine affect microtubules. Fortunately, many of these
drugs, when used at therapeutic doses, have a temporary effect
that reverses when therapy ceases. Effects seen microscopi-
cally include vacuolation or swelling of Sertoli cells and germ
cell changes including increased apoptosis. Failure of spermia-
tion can occur.
Toxicants that affect the germ cells prevent rapid mitotic
division, and the spermatogonia are the major targets. Adria-
mycin and cyclophosphamide are examples. Damage by these
compounds to the genetic composition of stem cells will also
have effects on the later stages of development. Toxicants of
the other germ cells are little recognized in domestic species,
 Testis and Epididymis
although in rodents, ethyl glycol alkyl ethers affect spermato-
cytes, nitroimidazoles affect spermatids, and compounds that
impinge on energy metabolism affect spermatozoa. Damage
to various stages causes apoptosis, with a rapid uptake of the
detritus by Sertoli cells. Within 48 hours, there may no longer
be evidence of apoptosis—just the appearance of “maturation
arrest.”
Toxicants can also affect the efferent ductules and epididy-
mis and/or the spermatozoa in transit. The difficulty with
investigating efferent ductular toxicosis is separating the effect
caused by alteration in testosterone concentration, and direct
toxic effects. Substances that affect the efferent ductules
include cyclophosphamide, methyl chloride, and reserpine.
Such toxicants decrease spermatozoal concentration and
cause spermiostasis, spermatic granuloma formation, and
necrotic and degenerative changes to the epithelium. Several
have direct effects on spermatozoa in the ducts.
There are few reports of direct viral infection and their
effects on spermatogenesis. However, porcine reproductive
and respiratory syndrome virus replicates in germ cells, alters
spermatogenesis, and induces apoptosis. Bovine viral diarrhea
virus is implicated in infertility. Canine distemper virus infec-
tion of dogs can cause testicular degeneration.
Further reading
Creasy DM. Pathogenesis of male reproductive toxicology. Toxicol
Pathol 2001;29:64-76.
Creasy DM, et al. Proliferate and nonproliferate lesions of the rat and
mouse male reproductive system. Toxicol Pathol 2012;40:40-121.
De Coster S, van Larebeke N. Endocrine-disrupting chemicals: associ-
ated disorders and mechanisms of action. J Environ Public Health
2012;2012:713696.
Fukuda T, et al. Age related changes in the testes of horses. Equine
Vet J 2011;33:20-25.
Sur JH, et al. Evidence for the localization of porcine reproductive and
respiratory syndrome virus (PRRSV) antigen and RNA in ovarian
follicles in gilts. Vet Pathol 2001;38:58-66.
Turner RM, et al. The emerging pathophysiology of age-related testicu-
lar degeneration with a focus on the stallion and an update on
potential therapies. Reprod Dom Anim 2012;47:178-186.
Vandenberg LN, et al. Hormones and endocrine-disrupting chemicals:
low dose effects and nonmonotonic dose responses. Endocr Rev
2012;33:378-455.
Testicular hypertrophy
Enlargement of an otherwise normal testis is rarely a primary
disorder. Secondary or compensatory hypertrophy is a unilateral
condition that indicates an underlying disease in the contra-
lateral testis. It is a well-recognized phenomenon in hemicas-
trates, and in hypoplasia, cryptorchidism (see Fig. 5-3), or
atrophy of the contralateral testis (see Fig. 5-25). In rams and
bulls, hypertrophy occurs when the unilateral condition is
present during the peripubertal period, and with increased
FSH production. The increase in size can be double and is due
to an increase in the diameter and length of the seminiferous
tubules with more numerous and larger Sertoli cells and more
germinal cells per Sertoli cell. Hemicastration of prepubertal
boars, especially in those younger than 3-4 months, results in
dramatic hypertrophy of the contralateral testis.
The presence of dilated cystic remnants and pseudocysts
can also cause, or be confused with, enlargement of a testis.
485
Occlusion of the efferent ductules can lead to dilation of the
rete and mediastinum testis and appear as testicular enlarge-
ment, although the thickness and fibrous nature of the testicu-
lar capsule makes sudden enlargement of the testis less likely.
Adhesions and thickenings of the vaginal tunic can also appear
clinically as testicular enlargement. To the unsuspecting,
lesions of the scrotum or its contents are mistaken as testicular
enlargement; hydrocele, epididymitis, or the presence of sper-
matic granulomas are examples.
Further reading
Lunstra DD, et al. Sertoli cells in the boar testis: changes during devel-
opment and compensatory hypertrophy after hemicastration at
different ages. Biol Reprod 2003;68:140-150.
Putra DKH, Blackshaw AW. Quantitative studies of compensatory tes-
ticular hypertrophy following unilateral castration in the boar. Aust
J Biol Sci 1985;38:429-434.
Inflammation of the testis and epididymis
Orchitis
Apart from bulls in areas endemic for Brucella abortus or
tuberculosis, and in some cases of canine epididymitis, orchitis
is a rare and sporadic disease in domesticated animals. The vast
majority of cases diagnosed clinically as orchitis are actually
epididymitis (see later). Focal accumulations of lymphocytes
are occasionally seen in the testes of most species as incidental
findings. Lymphocytic (or nonsuppurative) inflammation is
seen in some infertile animals; an immunologic pathogenesis
is invoked as immunization of guinea pigs and bulls with
spermatozoa induced inflammation of the rete testes espe-
cially. Efferent ductules are also involved experimentally.
Orchitis as the primary and severe disease has historically
been attributed to brucellosis or tuberculosis. Tuberculous
orchitis is a multifocal granulomatous disease that is much less
common now because of eradication in many countries. Bru-
cellosis is similarly reduced in prevalence. Brucella abortus
(bulls), Brucella suis (pigs), Brucella canis (dogs), and Brucella
melitensis (goats) can cause orchitis as a dominant change.
However, epididymitis is often the main manifestation.
Orchitis is traditionally divided into 3 major categories:
interstitial orchitis, intratubular or granulomatous orchitis, and
necrotizing orchitis.
Further reading
Ali Al Ahmed MZ, et al. Detection of viral genomes of caprine arthritis-
encephalitis virus (CAEV) in semen and in genital tract tissues of
male goat. Theriogenol 2008;69:473-480.
Foster RA, et al. Chronic fibrinous and necrotic orchitis in a cat. Can
Vet J 1997;37:681-682.
Manna L, et al. Detection of Leishmania parasites in the testis of a dog
affected by orchitis: case report. Parasit Vectors 2012;5:216-220.
Noguchi J, et al. Early regression of spermatogenesis in boars of an
inbred Duroc strain caused by incident orchitis/epididymo-orchitis.
J Reprod Dev 2013;59:273-281.
Ramirez-Mendoza H, et al. Lesions in the reproductive tract of boars
experimentally infected with porcine rubulavirus. J Comp Pathol
1997;117:237-252.
Sigurdardottir OG, et al. Orchitis in a cat associated with coronavirus
infection. J Comp Pathol 2001;124:219-222.
 485.e1

Further reading
Boekelheide K, et al. The Sertoli cell cytoskeleton: a target for toxicant-
induced germ cell loss. Toxicol Appl Pharmacol 1989;101:
373-389.
Chapin RE, Williams J. Mechanistic approaches in the study of testicular
toxicity: toxicants that affect the endocrine regulation of the testis.
Toxicol Pathol 1989;17:446-451.
Creasy DM, Foster PMD. The male reproductive system. In: Haschek
WM, Rousseaux CG, editors. Handbook of Toxicologic Pathology.
San Diego, CA: Academic Press; 1991. p. 860-874.
Hess RA. Effects of environmental toxicants on the efferent ducts,
epididymis and fertility. J Reprod Fertil Suppl 1998;53:247-259.
Lowseth LA, et al. Age-related changes in the prostate and testes of
the beagle dog. Vet Pathol 1990;27:347-353.
Pera I, et al. Body temperature (37 C) specifically down-regulates the
messenger ribonucleic acid for the major sperm surface antigen
CD52 in epididymal cell culture. Endocrinol 1996;137:4451-4459.
485.e2

Further reading
Boockfor FR, et al. Effects of unilateral castration and unilateral crypt-
orchidism of the Holstein bull on plasma gonadotropins, testoster-
one and testis anatomy. J Anim Sci 1983;56:1376-1385.
Cox JE. Factors affecting testis weight in normal and cryptorchid
horses. J Reprod Fertil Suppl 1982;32:129-134.
Schanbacher BD, et al. Testicular compensatory hypertrophy in the
hemicastrated calf: effects of exogenous estradiol. Biol Reprod
1987;36:1142-1148.
 485.e3

Further reading
Aubry P, et al. Septic orchitis in an alpaca. Can Vet J 2000;41:
704-706.
Fritz TE, et al. Pathology and familial incidence of orchitis and its rela-
tion to thyroiditis in a closed beagle colony. Exp Mol Pathol
1976;24:142-158.
Holyoak GR, et al. Pathological changes associated with equine arteritis
virus infection of the reproductive tract in prepubertal and peripu-
bertal colts. J Comp Pathol 1993;109:281-293.
Lewis KM, et al. Abdominal ultrasonographic findings associated with
feline infectious peritonitis: A retrospective review of 16 cases.
J Am Anim Hosp Assoc 2010;46:152-160.
McEntee K. Reproductive Pathology of Domestic Mammals. London:
Academic Press; 1990. p. 224-358.
Njenga MJ, et al. Semen characteristics of goats with subacute, acute
and chronic besnoitiosis. J S Afr Vet Assoc 1999;70:18-20.
Van Camp SD. Common causes of infertility in the bull. Vet Clin North
Am Food Anim Pract 1997;13:203-231.
486 CHAPTER 5  •  Male Genital System
Interstitial orchitis.  Interstitial orchitis may not be recog-
nized macroscopically, but histologically there are lympho-
cytes in the interstitial stroma, with concurrent or subsequent
fibrosis. In bulls, small clusters of lymphocytes are frequently
observed adjacent to seminiferous or rete tubules or efferent
ductules of otherwise normal testes. In stallions, interstitial
perivascular lymphocytic foci are particularly common and
occur in areas of degeneration. Lymphoid aggregates are fre-
quently seen in Beagle dogs used as laboratory animals. Foci
of lymphocytes in cats are considered an age-associated
change.
Intratubular orchitis.  Intratubular orchitis is inflammation
focused on the seminiferous tubules. Some cases result from
ascending infection but in others there is no epididymitis to
confirm this. Alternative explanations include a breakdown of
the blood-testis barrier allowing agents into the tubules, or
spermatozoal antigens leaking into the interstitium. Macro-
scopically, there are solitary or multiple white-yellow foci of
up to 1 cm diameter. Histologically, the tubule outline is
retained in the affected area, but the seminiferous epithelium
is either degenerate or obliterated and replaced by macro-
phages and multinucleated giant cells that surround neutro-
phils and debris (Fig. 5-32). In some cases, the reaction is
predominantly lymphocytic, suggesting an autoimmune
pathogenesis. The pathogenesis of the granulomatous orchitis
is comparable to spermatic granuloma formation in the epi-
didymis. Sertoli cell hyperplasia and mineralization may
accompany these changes.
Necrotic orchitis.  Necrotizing orchitis is characteristic of
brucellosis but may result from other infections, or conditions
causing severe trauma or ischemia of the testis. Severe perior-
chitis may reduce blood supply to the testis so that it becomes
a necrotic mass encased within the markedly thickened tunics.
Necrotic areas are dry, yellow, often laminated, and slightly
mineralized. The histologic picture is coagulative necrosis bor-
dered by fibrosis and inflammatory cells. Abscessation and
fistulation through the scrotum may accompany necrotizing
or other forms of orchitis.
Orchitis in bulls.  In bulls, many viruses have been isolated
from testes or semen. Histologic changes are seldom found.
Persistent infection with bovine viral diarrhea virus results in
spermatozoal defects but no distinct histologic lesions in the
testis. Severe interstitial orchitis and testicular degeneration
Figure 5-32  Severe intra-tubular neutrophilic necrotizing orchi-
tis in a dog.
Testis and Epididymis
and inflammation of spermatic arteries occur in bovine malig-
nant catarrhal fever (alcelaphine herpesvirus 1 and ovine her-
pesvirus 2). In experimental bluetongue virus infection in
bulls, interstitial orchitis accompanies arteritis. Clinical orchi-
tis and aspermatogenesis were listed as findings in bovine
enterovirus 1 infection, but lesions are not described. A focal
nodular orchitis is reported in lumpy skin disease (lumpy skin
disease virus) of bulls.
Orchitis in bulls is similar grossly and histologically, regard-
less of the causative bacterium. The best descriptions are of
Brucella abortus infection in endemic regions. In most instances
the orchitis is acute and severe. It may be unilateral but
affected animals are sterile. The scrotum swells and is hot and
doughy as a result of inflammatory changes in the tunics and
to a lesser extent in the epididymis. Swelling of the testis is
limited by the inability of the testicular capsule to stretch, and
any swelling constricts venous and then arterial flow causing
infarction. The cavity of the vaginal tunics distends with fibri-
nopurulent exudate. Scattered yellow foci of necrosis coalesce
to produce total testicular necrosis. Sequestration by inflam-
mation and thickening of the tunics follows. Sometimes the
necrotic parenchyma liquefies and the organ then is a pus-
filled cavity surrounded by a thick connective-tissue capsule.
Rupture may occur but is unusual.
Microscopically, the inflammation of the tunics results in
extremely dense adhesions between the parietal and visceral
layers. Within the testes, the infection appears to progress
along the lumen of the seminiferous tubules. The seminal
epithelium becomes necrotic and desquamates. Large numbers
of the organisms are visible in the lumen. At the early stage,
neutrophils, macrophages, and lymphoid cells are in the inter-
stitial tissues and form cuffs about the tubules. The tubules
and the interstitial tissues then become necrotic. There is often
focal necrotizing epididymitis complicated by the develop-
ment of spermatic granulomas.
Tuberculous orchitis in bulls is an uncommon lesion,
even in areas of endemic infection. The granulomatous
response to the tubercle bacilli is similar to the granulomas
that occur to spermatozoa. Involvement of the testis may be
either miliary or regional. In the miliary form, small or large
caseous and mineralized foci are irregularly scattered through-
out the testes but may spare the epididymis entirely. The
path of infection is probably intratubular from a primary
epididymal lesion.
Other bacteria causing orchitis in bulls, sometimes with
overt abscessation, include streptococci, staphylococci, True-
perella pyogenes, Escherichia coli, Histophilus spp., Salmonella
spp., Actinomyces bovis, Actinobacillus spp., and Nocardia spp.
In nocardiosis especially, the lesions are at first nodular but
ultimately transform the whole testis into an abscess, the
capsule of which is the vaginal tunic.
Infection of bulls with Chlamydophila spp. causes orchitis,
and in field cases, focal granulomatous lesions are observed.
The spontaneous occurrence of orchitis and epididymitis
caused by Mycoplasma spp. infection is reported.
Orchitis in boars.  Viral infection of the testis and shedding
in the semen of boars is identified in many, but inflammation
in natural disease is not well documented, or is not reported.
Intratesticular inoculation is used in an experimental setting,
and this overwhelms natural defences and adds local trauma
as a complication. Experimental orchitis and epididymitis is
reported in porcine rubulavirus (a paramyxovirus responsible
for the disease “blue eye”) infection. The virus targets the head
 Testis and Epididymis
of the epididymis, where it causes interstitial inflammation
and spermatic granulomas. Interstitial fibrosis is seen in animals
that recover. Suid herpesvirus 1 infection (pseudorabies,
Aujeszky’s disease) may cause edema of the scrotal region;
intratesticular inoculation results in exudative periorchitis.
Porcine parvovirus 1, porcine reproductive and respiratory
syndrome virus, and porcine circovirus 2 replicate in the
reproductive tract and may cause testicular degeneration.
Orchitis caused by Brucella suis results in multiple abscesses
rather than confluent necrosis. Some cases have fibrinopuru-
lent and hemorrhagic periorchitis. Abscessation develops in
the epididymis as well as in the testis; there is central caseation
surrounded by a zone of epithelioid macrophages, and these
in turn by a broad connective-tissue capsule and lymphocytes
and plasma cells.
In some tropical countries, orchitis caused by infection
with Burkholderia pseudomallei occurs in boars and other
domestic mammals. Lesions can occur in the vesicular glands,
prostate, and other organs. Extreme enlargement of the testis
caused by purulent inflammation may occur. The main histo-
logic lesion is multifocal necrosis with marked lymphocytic
inflammation and encapsulation by much fibrous connective
tissue. Severe testicular degeneration accompanies orchitis.
Other organisms isolated from boars with orchitis include
Trueperella pyogenes, Streptococcus zooepidemicus, Streptococcus
equisimilis, and Salmonella spp.
An inbred strain of Duroc boars developed a high preva-
lence of lymphocytic interstitial orchitis suggesting a genetic
predisposition. The orchitis caused degeneration of the semi-
niferous tubules and predominantly unilateral testicular
atrophy.
Orchitis in stallions.  In stallions, mild interstitial orchitis
is common and incidental. Similar lesions may be part of
generalized vascular involvement in equine viral arteritis.
Infarcts may also occur in equine infectious anemia. Orchitis
can occur as part of systemic disease, and is reported in glan-
ders (Burkholderia mallei), and as an acute suppurative, some-
times abscess-forming orchitis in infection with Salmonella
abortus-equi, Streptococcus equi, and Streptococcus zooepi-
demicus. Focal lesions attributed to the migrating larvae of
Strongylus edentatus are reported in the testis, tunics, and
epididymis, especially of young horses. Cryptorchid testes are
more commonly affected. Hemorrhagic 2-mm wide tracts
containing the migrating larvae are seen. The histologic lesions
are initially hemorrhagic and then become eosinophilic. Hali-
cephalobus gingivalis can cause granulomatous orchitis as a
consequence of systemic spread. A pseudocyst is reported in
a horse as a sequel to fibrinonecrotic orchitis. The lesion was
associated with trauma, and secondary infection with Strepto-
coccus zooepidemicus occurred.
Testicular rupture, hemorrhage, and orchitis can occur with
trauma to the testis, such as when a stallion is kicked while
mating a mare. Spermatic granulomas in the testis occur
secondarily.
Periorchitis in horses occurs as part of generalized septic
disease, peritonitis, and as a complication of trauma, penetrat-
ing injury, or surgery.
Orchitis in small ruminants.  In rams, nodular orchitis
occurs in sheep pox in a similar fashion to lumpy skin disease
in bulls. Chronic interstitial orchitis is reported in rams
infected with the ovine lentivirus maedi-visna virus. The most
common causes of orchitis are bacteria that also cause epi-
didymitis. It is unusual to find orchitis in the absence
487
of epididymitis. Sporadic testicular abscesses result from
infection with Trueperella pyogenes and Corynebacterium
pseudotuberculosis.
In bucks, caprine arthritis-encephalitis virus is found in
semen and in the testis and epididymis but without lesions.
Orchitis may result from infection with Brucella melitensis. It
can be severe enough to induce a fibrinonecrotic disease.
Orchitis also occurs in breeding goats as a component of
besnoitiosis.
Orchitis in dogs and cats.  Dogs with canine distemper
virus infection develop intranuclear and cytoplasmic inclu-
sions in Sertoli cells. The majority of seminiferous tubules
degenerate, and inflammation occurs in some tubules.
Orchitis is seen with bacterial epididymitis, where there is
retrograde spread from the epididymis. Escherichia coli, Proteus
vulgaris, and other coliforms are usually responsible. An acute
inflammatory response in either the epididymis or testis is
usually necrosuppurative, with the formation of one or more
abscesses (see Fig. 5-32). The vaginal tunic is involved by
extension, and fistulation through the scrotal skin to the exte-
rior may occur. Dogs will traumatize their scrotum and
produce a fistula. Acute inflammation usually is centered on
the ducts, with degeneration and desquamation of the epithe-
lium, and edema and neutrophils in the surrounding stroma.
Healing occurs by scarring. With time, the affected testis
becomes firm, small, and irregular. Lymphocytes and plasma
cells predominate and fibrosis is well developed.
Other bacterial causes of orchitis in dogs include Brucella
canis and Burkholderia pseudomallei, both of which cause epi-
didymitis (see later). A familial occurrence of interstitial, lym-
phocytic orchitis, associated with testicular atrophy and
reduced fertility, was observed in inbred Beagle dogs with
lymphocytic thyroiditis; immune factors were implicated.
Fungi such as Blastomyces dermatitidis can cause orchitis as
part of systemic disease. Protozoal orchitis caused by Leishma-
nia spp. is reported in dogs. Penetrating wounds of the scrotum
affect the scrotal contents including the testis.
Orchitis in cats is very rare. Feline infectious peritonitis
virus can induce a primary orchitis (Fig. 5-33); however, peri-
orchitis is the usual manifestation. Orchitis can be a sequel to
traumatic injury to the scrotum.
Orchitis in camelids.  Orchitis is uncommon in camelids.
Septic orchitis from Streptococcus equi subsp. zooepidemicus is
reported in an alpaca. Camels are susceptible to Brucella
abortus and Brucella melitensis, and some develop orchitis.
Epididymitis
Inflammation of the epididymis is very common. Regardless of
cause, damage to the epididymal duct results in a response to
spermatozoa and other luminal contents, spermatic granulo-
mas, and subsequent development of chronic epididymitis.
The exception is in prepubertal animals in which there are no
spermatozoa; in these cases, true abscesses occur. Epididymitis
in the absence of sperm granulomas is possible in adults, but
it usually is a subclinical or early event.
Epididymitis is usually infectious, and infectious disease
frequently causes a spectrum of lesions, including inflamma-
tion of the accessory genital glands. The effects of epididymitis
are usually more dramatic than prostatitis, vesicular adenitis,
or ampullitis, and these are often overlooked. Sterile epididy-
mitis with spermatic granulomas does occur in congenital
ductal disorders of sexual development, adenomyosis, trauma,
and reflux of urine.
488 CHAPTER 5  •  Male Genital System
Figure 5-33  Pyogranulomatous orchitis from feline infectious
peritonitis virus infection in a cat.
Figure 5-34  Unilateral epididymitis of the tail of the epididymis
in a ram. Spermatic granuloma is visible. Brucella ovis.
Bacteria cause most infections of the epididymis. Many
viruses replicate in the epididymis but seldom induce epididy-
mitis. Any agent causing orchitis is capable of inducing
epididymitis.
Primary infection with Brucella spp. in each species results
in epididymitis. B. suis, Brucella ovis (Figs. 5-34, 5-35), B. meli-
tensis and B. canis are especially virulent for the epididymis.
Infection is systemic, beginning with contact of mucous mem-
branes, spread throughout the body, and localization in the
epididymis and accessory genital glands. Retrograde infection
from the prepuce and via the ducts is theoretically possible.
Testis and Epididymis
Figure 5-35  Chronic epididymitis in a ram, with marked epi-
didymal enlargement, fibrosis of the tunics, and testicular atrophy.
Brucella ovis.
Almost all species develop infection of the epididymis by the
ascending route (with the exception of brucellosis). This was
studied in the ram, where Actinobacillus seminis and Histophi-
lus somni are classic isolates. Preputial organisms migrate to
the accessory genital glands and infect the epididymis by
retrograde movement. The privileged environment of the
lumen of the epididymal duct allows the organisms to infect
the organ and incite damage. The subsequent formation of
spermatic granulomas means that the reproductive potential
of the affected side is lost. Complete return to normal is rare.
Dogs with epididymitis will self-traumatize the scrotum (see
Fig. 5-10). Endotoxin-producing bacteria such as Escherichia
coli further complicate epididymitis by causing systemic
illness.
Prevention of infection of the epididymis is reliant on
innate mechanisms, particularly isolation from exposure to
infectious organisms, and constant flushing with antimicrobial
substances in fluid. Microbial pattern recognition molecules,
such as toll-like receptors, are present on the epithelial cells
of the epididymis and other parts of the tract. Stimulation of
local immunity to prevent epididymitis is unlikely. The epi-
didymis has no natural local immune system of antigen recep-
tors, nor known recirculation of immunocytes, and no local
plasma cell population. Aggregates of lymphocytes occasion-
ally occur in otherwise normal animals. After infection, the
epididymis must develop a local immune system, but unfor-
tunately the damage is usually so extensive, and the sequel so
severe, that the response is too late. Even so, the epithelial
cells do have the ability to express MHC I and II, and lym-
phocytes and plasma cells can be recruited after challenge.
Direct infection of the epididymis by penetrating injury is
a rare event. Secondary infection from periorchitis or perito-
nitis is a possibility.
Once initiated, the course of epididymitis is variable. The
acute stage, with edematous enlargement, precedes abscess
and spermatic granuloma formation, sometimes with
 Testis and Epididymis
Figure 5-36  Microscopic changes in necrosuppurative epididy-
mitis in a dog.
Figure 5-37  Chronic epididymitis in a ram, with interstitial fibro-
sis, epididymal epithelial hyperplasia, and intraepithelial lumina
formation.
perforation, periorchitis and peritonitis, and increasing fibrosis
(see Figs. 5-10, 5-35).
Macroscopically, increased epididymal size and dissymme-
try in shape are apparent, especially in unilateral cases in
comparison with the contralateral side. Fibrinous and then
fibrous adhesions may be present between affected epididymis
and adjacent tunics. Consistency will depend on duration of
inflammation and the development of spermatic granulomas.
With time, the amount of fibrous tissue produced is dramatic
(see Fig. 5-35), both within the epididymis and between the
tunics. The epididymal duct may not be recognizable or visible
as dilated spaces with inspissated spermatozoa in the lumen.
With mineralization of the spermatozoa, hard “sperm stones,”
the end products of spermiostasis, may be present within such
ducts. Concurrent testicular atrophy will result in the epididy-
mis appearing disproportionately large in relation to the testis
(see Fig. 5-35).
Intraluminal fibrin, neutrophils, and spermatozoa dominate
the microscopic changes in the initial phase of bacterial infec-
tion. The epithelium disintegrates and interstitial lakes of
neutrophils with fibrin form (Fig. 5-36). Macrophages, and
multinucleated giant cells, many of which contain spermato-
zoa, are found later in the course of disease. Other features of
spermatic granuloma, including a prominence of interstitial
lymphocytes and plasma cells, become apparent (Figs. 5-37,
489
Figure 5-38  Microscopic appearance of chronic epididymitis in
a ram showing intraluminal neutrophils, interstitial fibrosis, and
many lymphocytes and plasma cells, especially around vessels.
5-38). Epithelial hyperplasia, with the development of intra-
epithelial lumina (see Fig 5-37), occurs in most domestic
species with epididymitis. Such lumina also occur in nonin-
flammatory lesions. In chronic epididymitis, there may be
squamous metaplasia of epithelium. Progressive fibrosis is
usual.
Further reading
Cerri D, et al. Epididymitis by Brucella ovis: experimental infection in
virgin ram lambs. New Microbiol 1999;22:227-231.
Collin M, et al. Constitutive expression of the antibacterial CXC che-
mokine GCP-2/CXCL6 by epithelial cells of the male reproductive
tract. J Reprod Immunol 2008;79:37-43.
Foster RA, et al. Identification of Brucella ovis in formalin fixed paraffin
embedded genital tissues of naturally infected rams by the indirect
peroxidase antiperoxidase technique. Aust Vet J 1988;65:
324-326.
L’Abee-Lund TM, et al. Mycoplasma canis and urogenital disease in
dogs in Norway. Vet Rec 2003;153:231-235.
Palladino MA, et al. Localization of toll-like receptors on epididymal
epithelial cells and spermatozoa. Am J Reprod Immunol 2008;
60:541-555.
Wanke MM. Canine brucellosis. Anim Reprod Sci 2004;82-83:
195-207.
Epididymitis in bulls.  Viral causes of epididymitis are rare.
Bulls in Kenya and South Africa developed a specific infec-
tious epididymitis, called epididymitis-vaginitis (“epivag”).
Lesions consist initially of soft swelling of the epididymis with
subsequent enlargement and fibrosis. Other lesions include
“abscess” formation, tunic adhesions, ampullitis, vesicular ade-
nitis, and testicular degeneration. Sometimes, however, the
vesicular glands only are affected. The possible role of bovine
herpesvirus 4 in the pathogenesis of “epivag” is discussed in
Vol. 3, Female genital system.
 489.e1

Further reading
Blue MG, McEntee K. Epididymal spermatic granuloma in a stallion.
Equine Vet J 1985;17:246-251.
Constable PD, Webber JJ. Escherichia coli epididymitis in rams. Aust
Vet J 1987;64:123.
Held JP, et al. Bacterial epididymitis in two stallions. J Am Vet Med
Assoc 1990;197:602-604.
Holzmann A, et al. Orchiepididymitis in a bull with Mycoplasma in its
ejaculate. Zbl Vet Med A 1983;30:760-766.
Kadota K, et al. Granulomatous epididymitis related to Rhodotorula
glutinis infection in a dog. Vet Pathol 1995;32:716-718.
Saravanamuthu V, et al. T and B lymphocyte subsets in spermatic
granuloma in the ram. Vet Pathol 1991;28:482-491.
Vermeulen SO, et al. Brucella ovis as a possible cause of epididymitis
in an Angora goat. J S Afr Vet Assoc 1988;54:177-179.
490 CHAPTER 5  •  Male Genital System
Brucella abortus rarely causes epididymitis in the absence
of orchitis. Actinobacillus seminis, a frequent cause of epididy-
mitis in rams, has been isolated from the semen of a bull with
bilateral epididymitis. Epididymitis is observed in bulls with
vesicular adenitis induced by inoculation of Mycoplasma bovi-
genitalium, but the role of mycoplasmas and chlamydias in
causing epididymitis awaits clarification. Epididymitis may
accompany orchitis, periorchitis, and testicular degeneration
in cattle, horses, sheep, goats, and dogs infected with Trypano-
soma brucei.
Epididymitis in boars.  Brucella suis infection is a classical
cause of epididymitis, and the lesions are variable. Single or
multiple “abscesses” are frequent in the epididymis, but less
so in the testes, which may be enlarged or atrophic. Enlarge-
ment of the vesicular glands caused by localization of B. suis
may also occur, and abscessation, perhaps seen only micro-
scopically, occurs in the vesicular glands and prostate and
bulbourethral glands.
Epididymitis in stallions.  In the stallion, migrating stron-
gyle larvae are implicated as a cause of epididymitis and
spermatic granuloma of the epididymis; adenomyosis is a
further cause. Rare sporadic cases of bacterial epididymitis are
reported with Streptococcus zooepidemicus isolated from such
cases.
Epididymitis in small ruminants.  Epididymitis is of par-
ticular importance in rams, in which it is a frequent and
serious cause of reduced fertility. Although either Brucella ovis
or Actinobacillus seminis are usually responsible, many other
bacteria, such as Histophilus somni, Mannheimia haemolytica,
Escherichia coli, and Trueperella pyogenes, are isolated from
sporadic cases of epididymitis. Whereas Brucella ovis is a cause
of epididymitis in mature rams, other gram-negative pleomor-
phic organisms are commonly cultured from epididymitis in
virgin rams, suggesting the existence of two separate disease
entities.
Ovine epididymitis caused by Brucella ovis is an important
cause of reduced fertility in many countries and is studied
extensively. Progression of the infection is very slow, from a
local infection persisting in the exposed mucus surface for 1
month, to a regional one involving adjacent lymph nodes,
leading to bacteremia. The bacteremic stage subsides after
about 2 months, but organisms localize in the genital tract,
spleen, kidney, and liver, where they persist for an indefinite
period. Following experimental infection, neither gross nor
microscopic lesions are seen in organs other than genitalia.
In the vast majority of epididymides with lesions caused
by Brucella ovis, the epididymal tail is involved, and lesions in
this location probably occur in all epididymides infected with
this organism. Initial localization of the bacteria produces
edema, and lymphocytes and macrophages appear. Later, neu-
trophils appear. Early epithelial changes include degeneration
and then hyperplasia, with the formation of intraepithelial
lumina (see Fig. 5-37). At the same time there is increasing
fibrosis in interstitial areas (see Figs. 5-37, 5-38). The combina-
tion of inflammation, fibrosis, and epithelial hyperplasia
obstructs the lumen and causes spermiostasis. These changes
can develop over many months, and large numbers of organ-
isms are in the ejaculate. Subsequent events depend on the
extravasation of spermatozoa and formation of spermatic
granulomas. The tail of the epididymis in these cases may be
enlarged 4-5 times (see Fig. 5-35), and the lesion is often
bilateral. If the inflammatory reaction and extravasated sper-
matozoa enter the cavity of the vaginal tunic, adhesions will
Testis and Epididymis
result and testicular degeneration increases. Unlike brucellosis
in the bull, there is seldom a primary orchitis. Lesions in the
deferent duct similar to those in the epididymis may occur,
but there is no sperm stasis or leakage. There is pronounced
epithelial hyperplasia, with thickening and folding of the wall,
and the lamina propria contains many lymphocytes, plasma
cells, and histiocytes. Many rams do not develop detectable
gross lesions or they develop them only late in the course of
the disease. Identification of B. ovis in histologic sections is
difficult, but is aided by immunohistochemistry.
Actinobacillus seminis and related strains of the so-called
gram-negative pleomorphic organisms also induce epididymi-
tis. Both H. somni and A. seminis are temporarily resident in
the prepuce and become opportunistic pathogens by ascend-
ing infection. This usually occurs at puberty, when there are
elevated levels of gonadotrophin releasing hormones. The
pathogenesis of E. coli epididymitis in rams probably is similar.
Typically, these are severe infections in young rams, and there
may be severe and diffuse periorchitis. In epididymitis caused
by Actinobacillus seminis, there is fibrinosuppurative and
necrotic inflammation of one or both epididymides, and these
may fistulate through the scrotal wall. Histologically, the
initial epididymal lesion is similar to that of Brucella ovis. In
the chronic form of the disease seen in older rams, the epi-
didymides are large and fibrotic, and the testes are atrophic
(see Fig. 5-35). The vesicular glands also may be affected.
Experimental inoculation of rams by various routes with Acti-
nobacillus seminis has shown that part of or the entire genital
tract may become infected, but that the epididymis is most
constantly involved.
Epididymitis is less studied in bucks than in rams. Brucella
melitensis, Actinobacillus seminis, Staphylococcus aureus, Esche-
richia coli, or Pseudomonas spp. may be isolated from lesions,
and there is a report of possible Brucella ovis epididymitis in
an Angora goat.
Epididymitis in dogs and cats.  Viral epididymitis is rare
but it reported in canine distemper virus infection. Cytoplas-
mic and intranuclear inclusions are present in the epithelial
cells and there is a lymphocytic interstitial epididymitis. Eosin-
ophilic cytoplasmic bodies are normally present in the head
of the epididymis and should not be confused with viral inclu-
sion bodies; immunohistochemistry will differentiate these
inclusions.
In male dogs infected with Brucella canis, there is epididy-
mitis, prostatitis, scrotal dermatitis, and testicular atrophy.
These changes can be unilateral. Infected animals are bacte-
remic and the organism can persist in tissues (e.g., the pros-
tate) for many months. Recovery can eventually occur and
recovered dogs are immune to reinfection. Venereal transmis-
sion to females by infected males can occur, although the
organism is not consistently isolated from semen. Scrotal
swelling is apparent 1-2 weeks after experimental intravenous
inoculation, or 3-5 weeks after oral infection. Such swelling is
from fibrinopurulent exudate in the cavity of the vaginal
tunics. Scrotal ulceration is the result of persistent licking of
the scrotum caused by the pain of epididymitis. Testicular
lesions are seldom if ever observed but testicular necrosis (as
observed in the bull) may occur rarely, and there is concurrent
marked fibrous thickening of tunics.
Microscopically there is coagulative necrosis from necrotiz-
ing vasculitis and associated thrombosis, and a predominantly
lymphoid response peripherally. More frequently, however,
there is interstitial epididymitis and prostatitis, and testicular
 Testis and Epididymis
atrophy. Lymphocytic inflammation of epididymal stroma is
variable. Fibrosis may be extensive but, in contrast to brucel-
losis in other species, obliteration or stricture of ducts is
unusual. Neutrophils and macrophages are present in the
epididymal duct. In chronic cases, there is marked enlarge-
ment of the epididymis, especially the tail, with involvement
of the deferent duct. The ejaculate of male dogs with chronic
brucellosis contains inflammatory cells, abnormal spermato-
zoa, and spermatozoa agglutinins. The resulting infertility may
be mediated by isoimmune reactions resulting from the
heightened nonspecific phagocytic activity of cells attracted
to the sites of bacterial growth in the epididymis. Brucella suis
also may cause spontaneous granulomatous epididymitis and
prostatitis in the dog.
Escherichia coli or other gram-negative bacteria cause most
sporadic cases of canine epididymitis (see Fig. 5-36). The
epididymitis often has concurrent severe systemic disease
from endotoxemia. Scrotal swelling and mutilation are
common. The range of lesions is similar to those of canine
brucellosis, although the lesions are usually more severe.
Following infection with Burkholderia pseudomallei, dogs
develop pyrexia, lethargy, scrotal swelling, edema of one or
more limbs, and lameness. Macroscopically, the epididymides
are enlarged 3-4 times normal, are firm and hemorrhagic, and
may contain small necrotic foci. The testis and deferent duct
may also be involved.
Mycoplasma canis can cause urinary tract infection in dogs,
with subsequent purulent epididymitis and prostatitis.
Mycotic epididymitis caused by Rhodotorula glutinis or Blas-
tomyces dermatitidis produces granulomatous epididymitis
with a reaction pattern similar to disease in other tissues. The
complication of spermatic granulomas adds to the granuloma-
tous nature of the disease.
Ascending epididymitis is exceedingly rare in cats. Epididy-
mitis can occur in feline infectious peritonitis.
Camelids develop epididymitis rarely. Camels are suscep-
tible to Brucella abortus and Brucella melitensis, and develop
orchitis and epididymitis.
Circulatory disturbances
The spermatic artery is long because of the coiled portions of
the pampiniform plexus proximal to the testis. The degree of
coiling is marked in ungulates and the spermatic artery is
several meters long. Testicular blood flow is low in relation to
metabolic needs, and hypoxia and oxidative stress develops
quickly if increasing testicular temperature increases meta-
bolic demand or if blood flow is impaired. By the time the
artery penetrates the testicular capsule, pulsatile flow is almost
eliminated and the structure of the vessel changes. The diam-
eter enlarges, the wall becomes thinner, and the elastic fibers
are reduced. Increased intratesticular pressure will reduce
blood flow dramatically.
The interstitial tissue of the testis has abundant lymphatics.
In addition to the usual role in fluid exchange, they probably
assist in transportation of hormones between interstitial endo-
crine cells and the tubules. Edema of the testis occurs after
trauma and is a frequent early change in orchitis. Although
the testicular capsule is relatively indistensible, some enlarge-
ment can occur. With edema, there is separation and dilation
of tubules, diffuse vacuolation of germinal epithelium, and
dilation of lymphatics.
The walls of arterioles become thicker and hyaline in
wedge-shaped areas of fibrosis in the testes of old bulls, but
491
the precise cause of this lesion is not clear. In old dogs, arteries
and arterioles in regions of testicular degeneration have thick-
ened hyaline walls. Initial lesions occur in the testicular capsule
and parenchyma, but the artery in the spermatic cord is
affected too. Focal areas of ischemia and infarction may occur
with severe vascular lesions. Atheromatous change is rare; in
dogs this change may indicate hypothyroidism or diabetes
mellitus.
Thrombosis of testicular arteries, usually of unknown cause,
is seen occasionally in bulls. Such thrombi are present in both
the parenchyma and tunics and may be partially mineralized
and sometimes occluding. The degenerative changes in semi-
niferous tubules are usually mild, however. In experimental
Trypanosoma vivax infection in sheep, thrombosis of testicular
vessels probably contributes to testicular degeneration. Sub-
sequent infarction and necrosis may sometimes occur. Venous
thrombosis was observed in the testes of rams in isolated
accounts. The thrombi were solitary and laminated. Some
affected rams had a concurrent varicocele; testicular degenera-
tion was mild.
Inflammation of the testicular artery occurs in the horse.
The known causes are migrating strongyle larvae and equine
arteritis virus infection, but a cause was not found in many
cases. The usual lesions in testicular tissue include focal
aggregates of lymphocytes and degeneration of seminiferous
tubules adjacent to the inflamed arteries and arterioles. The
inflammatory reaction is rarely severe enough to cause throm-
bosis and infarction. Horses infected with equine arteritis
virus may have acute necrotic vasculitis, edema, and hemor-
rhage. Chronic cases will have lymphocytic vasculitis and
perivasculitis.
A striking vasculitis with marked interstitial epididymitis,
orchitis, and testicular degeneration occurs in malignant
catarrhal fever in buffaloes and bulls. Dogs may develop vas-
culitis as part of a localized or generalized polyarteritis, and it
may occur in juvenile systemic necrotizing polyarteritis/
vasculitis (“Beagle pain syndrome”).
Occlusion of the testicular artery with resulting ischemia of
the testis may result from torsion (see Figs. 5-18, 5-19), contu-
sion of the spermatic cord, inappropriate placement and/or
hypotension during surgery, or the use of an emasculatome
for castrating young lambs and calves. Experimentally, destruc-
tion of germinal epithelium can be demonstrated after isch-
emia of more than 1 hour. Necrosis of testicular parenchyma
follows after 4-6 hours, although spermatozoa are relatively
resistant to lysis and may retain their staining characteristics
for weeks or months. The outermost part of the testis may
survive with diffusion of oxygen and nutrients from the
vaginal tunics. Islets of seminiferous tubules at the capsule
(Moskoff’s islets) may survive, and regeneration occurs during
the ensuing months. As the regenerated tubules lack a normal
drainage system, there is spermiostasis and ultimately degen-
eration. In addition and following ligation of the spermatic
artery in prepubertal rams, revascularization of the testicular
capsule occurred by penetration of capillaries from the epi-
didymal arteries.
Torsion of the testis is rare unless there is incomplete descent.
The stallion appears to be the exception, as spontaneous
torsion of an intrascrotal testis is a recognized cause of “colic.”
In other species, such as cats, there are individual reports. In
dogs especially, testicular neoplasia is often also present, to
provide sufficient weight to maintain the torsion. The usual
clinical presentation is acute abdominal pain, and the testis is
492 CHAPTER 5  •  Male Genital System
Figure 5-39  Massive testicular hemorrhage from trauma in a
ram.
dark red to black as a result of venous infarction, and is some-
times unidentifiable as testis. Spontaneous torsion of the
cryptorchid testis of boars is seen commonly at slaughter (see
Fig. 5-18). Torsion with complete ischemia and infarction will
cause complete loss of spermatogenesis of the affected testis.
Correction of torsion in laboratory animals and humans can
save the testis, but some continue to be aspermatogenic even
if infarction does not occur. Interstitial endocrine cells and
Sertoli cells retain their ability to function, but reactive oxygen
species and proinflammatory cytokines such as TNFα and
IL-1α may induce germ cell apoptosis and loss, and chemo-
taxis of neutrophils. Experimental unilateral torsion in pigs
leads to degeneration in the contralateral testis, suspected to
be from lower blood flow and then reperfusion and oxidative
injury.
Testicular hemorrhage occurs with trauma or with some
forms of necrosis of the testis. Trauma from fighting (Fig. 5-39)
or motor vehicle accidents is the usual cause.
Further reading
Foster RA, et al. Pathology of reproductive tracts of merino rams in
north western Queensland. Aust Vet J 1989;66:263-264.
Giuliano A. Testicular torsion in a normally descended testicle in a cat.
J Small Anim Pract 2013;54:164.
Lysiak JJ. The role of tumor necrosis factor-alpha and interleukin-I in
the mammalian testis and their involvement in testicular torsion and
autoimmune orchitis. Reprod Biol Endocrinol 2004;2:9.
Smith K, et al. Bilateral testicular haemorrhage in a Bleu du Maine ram:
clinical, ultrasonographic and histologic features. Reprod Dom
Anim 2009;44:350-352.
Neoplasms of the testis and epididymis
Testicular neoplasms are most commonly found in the dog. There
is no satisfactory explanation for this, but intact pet dogs live
a long time and are watched closely. Male cats tend to be
castrated early and fewer intact males live to old age. Neo-
plasms arise in all species sporadically, and with the exception
of the dog, it is possible to predict the histologic type of
Testis and Epididymis
neoplasm based on species and age. Seminoma is the common
tumor of the aged horse, and teratoma is more common in
the young. Boars, rams, bucks, and cats rarely get testicular
neoplasms, and both seminoma and Sertoli cell tumor are
reported. Bulls are more likely to have interstitial cell tumors,
but Sertoli cell tumors are reported.
The 3 main testicular neoplasms of dogs are the sex cord-
stromal tumors (the Sertoli cell tumor and interstitial [endocrine]
cell tumor) and the germ cell tumor (the seminoma). The fourth
most common, but rare, is a mixed germ cell-gonadal stromal
neoplasm. Multiple types of neoplasia may be found in one
testis. Most primary testicular neoplasms in dogs are benign.
Exceptions are rare, but malignant Sertoli cell tumors and
seminomas are reported. Identification of metastasis in lym-
phatics, spermatic cord, lymph node, or distant sites is the only
way to determine that the neoplasm is malignant; there are
no good cytologic or histologic markers of malignancy.
Most neoplasms cause enlargement of the testis. In general,
seminomas are white, soft, and bulge on cut section. Sertoli
cell tumors induce fibrous tissue so they are white and tough.
The interstitial cell tumor is yellow, soft, and often contains
areas of hemorrhage. Sertoli cell tumors, and rarely interstitial
cell tumors, may produce a hyperestrogenism syndrome and femi-
nization. In dogs, this causes attractiveness to other male dogs,
gynecomastia, and alopecia. Prostatomegaly and squamous
metaplasia of the prostate also occur. Some animals will
develop bone marrow suppression and poorly responsive pan-
cytopenia. Preputial epithelial cytology changes so that more
superficial epithelial cells are seen. Affected animals return to
normal after removal of the neoplasm. Not all dogs will have
a raised serum estrogen concentration. Inhibin secretion by
the neoplastic Sertoli cells inhibits the secretion of FSH and
LH by the pituitary, which in turn inhibits testosterone pro-
duction and presumably alters the ratio of estrogen to testos-
terone. Feminization is much more common when the
neoplasm is larger, and therefore is more common in cryptor-
chid dogs. It is also in these dogs that the unfortunate sequel
of testicular torsion can occur.
Testicular tumors arise mostly in mature and old animals;
the occurrence of interstitial cell tumors in dogs increases with
increasing age. Canine testicular tumors are found more fre-
quently in the right than in the left testis, and this is also true
for cryptorchid testes.
Other neoplasms of the testis include the mixed germ cell–
sex cord–stromal neoplasms, rete adenoma and adenocarci-
noma, embryonal carcinoma, histiocytic sarcoma, leiomyoma,
peripheral nerve sheath tumor, osteosarcoma, hemangioma,
hemangiosarcoma, lymphangiosarcoma, and mast cell tumor.
Metastasis of neoplasms to the testis is rare. Lymphoma in
the horse, dog, and bull, and hemangiosarcoma in the boar
and dog are reported. The list will no doubt increase in length
if pathologists routinely examine the testes at all autopsies.
Ectopic interstitial cell tumors are described in cats, and
extratesticular Sertoli cell tumors occur in dogs. Epididymal
neoplasms are exceedingly rare.
Sex cord−gonadal stromal tumors
Interstitial (Leydig) cell tumor.  Interstitial cell tumors have
the phenotype of the interstitial endocrine cells. They are grouped
with Sertoli cell tumors in resembling tissue of the sex cords
or stroma. Interstitial cell hyperplasia occurs periodically and
there are varying opinions for when hyperplastic nodules
become truly neoplastic, if they do. Some categorize these by
 492.e1

Further reading
Holyoak GR, et al. Pathological changes associated with equine arteritis
virus infection of the reproductive tract in prepubertal and peripu-
bertal colts. J Comp Pathol 1993;109:281-293.
Nguyen L, et al. Effect of unilateral testicular torsion on blood flow and
histology of contralateral testes. J Pediatr Surg 1999;34:680-683.
Parker JE, Rakestraw PC. Intra-abdominal testicular torsion in a horse
without signs of colic. J Am Vet Med Assoc 1997;210:375-357.
Turner TT, et al. Acute testicular ischemia results in germ cell specific
apoptosis in the rat. Biol Reprod 1997;57:1267-1274.
 Testis and Epididymis
size—either related to the size of the diameter of seminiferous
tubules or in centimeters. Such a separation is artificial.
In the dog, interstitial cell tumors occur in older animals.
They also occur in the bovine testis, in the older age groups,
and mainly in Guernseys. There are very few reports of tes-
ticular neoplasia in boars, but interstitial endocrine cell hyper-
plasia and tumor are more common than others. In horses, the
tumor develops almost exclusively in a cryptorchid testis. Cats
develop interstitial cell tumors rarely; ectopic tumors are
reported, especially in previously castrated animals.
Some interstitial cell tumors of dogs produce excess andro-
gen, but most tumors do not cause signs of hyperandrogenism.
Signs of hyperestrogenism were observed in a few dogs with
interstitial cell tumors and estradiol concentration in testicular
venous blood of affected dogs may be elevated. The condition
is corrected by removal of the neoplasm. Multiple perianal
hepatoid adenomas, tail gland hyperplasia, and prostatic
enlargement may also be found.
Nodular hyperplasia may be a preneoplastic change in the
dog. Hyperplastic nodules occur especially in testes that have
undergone senile atrophy and, although they may be macro-
scopically visible, the nodules are small, nonencapsulated, and
consist of an increased number of interstitial endocrine cells
in the intertubular stroma. Hyperplastic cells are regular in
form and size with increased acidophilia of the cytoplasm;
mitoses are not seen.
Interstitial cell tumors in the dog are often multiple, but
may be solitary and unilateral or bilateral (Fig. 5-40). Most are
from 1 mm to 2 cm diameter; only exceptionally are they
large enough to increase the size of the organ. They may make
the organ irregular in contour with the rounded bulge of the
tumor being visible in an otherwise small, soft, atrophic testis.
On cut surface, the tumors are well demarcated, spheroidal,
and yellow. They are prone to hemorrhage, which causes dark
discoloration and cyst formation. Large tumors are often
Figure 5-40  Intratesticular interstitial cell tumor in a dog. These
are soft and tan, with regions of hemorrhage. The adjacent testis
is atrophic.
493
multinodular. The consistency is soft, there being little stroma,
and the cut surface is slightly greasy.
Interstitial cell tumors grow slowly and expansively with
surrounding compression atrophy. They are not notably inva-
sive. In bulls with interstitial cell tumors, semen production
and fertility may be reduced.
The cells in the dog are well differentiated interstitial endo-
crine cells, being round or polyhedral, with abundant cyto-
plasm that may be granular or vacuolar and that often contains
yellow or brown lipochrome pigment (Fig. 5-41). The neo-
plastic cells in the bull are not vacuolated and contain very
little lipid. Sometimes and in some tumors the cells have a
more mesenchymal appearance, being spindle-shaped with an
indistinct cytoplasmic outline and a streaming arrangement. It
is in such tumors especially that necrosis and cyst formation
occur. The nuclei are regular in size and stain affinity, and
mitoses are rare. The stroma is scant, and vessels may resemble
sinusoids, as occurs in endocrine organs.
Intranuclear cytoplasmic invaginations or inclusions occur in
up to 15% of neoplastic cells in canine interstitial cell tumors.
The inclusions, which are strongly PAS-positive and composed
of smooth and rough endoplasmic reticulum, vesicles and lipid
vacuoles, myelin figures, and disrupted membranous profiles,
were not found in other testicular tumors. Nuclei containing
these invaginations are larger. Except where invaginations are
present, the ultrastructural appearances of neoplastic and
normal interstitial endocrine cells in the dog are similar.
Immunohistochemistry of canine interstitial cell tumors is
usually not required because the histologic findings are char-
acteristic. A variety of antibodies were used on interstitial cell
tumors and GATA4 appears to be consistently positive.
A high incidence of telangiectasis of the liver, thyroid C
(parafollicular) cell tumors, and infertility was observed in
Guernsey bulls with interstitial cell tumors, but a cause and
effect was not proven.
Interstitial cell tumors in stallions occur most often in
undescended testes. They contain 2 cell types; the first is
essentially a hypertrophic interstitial endocrine cell but the
other is a pleomorphic fusiform cell with fibrillar, vacuolated
cytoplasm and indistinct borders. Increased hormone
Figure 5-41  Microscopic appearance of an interstitial cell tumor
in a dog. Neoplastic cells are in an endocrine pattern, with large
polygonal cells packeted into groups by a vascular fine fibrous
stroma.
494 CHAPTER 5  •  Male Genital System Testis and Epididymis

concentration is reported in horses with these tumors, and

viciousness corrected by castration was observed.
Extratesticular interstitial cell tumors are reported in cats
and rarely in dogs. In cats, they are found in the scrotal skin
and spermatic cord of previously neutered males, some of
which develop male behaviors of spraying and male odors.
Deposition of interstitial endocrine cells in the peritesticular
tissues at the time of castration is believed to be the initiating
event—continuous stimulation of the cells by LH results in
hyperplasia and subsequently neoplasia. Epididymal intersti-
tial cell tumors in tomcats arising from ectopic tissue are
reported.
Interstitial cell tumors in other species, including camelids,
are very rare.
Sertoli cell tumor.  The Sertoli cell tumor is common in dogs
but rare in other domestic species. It is reported in the bull,
stallion, ram, and tomcat. They cause enlargement of the
affected testis, some animals develop a hyperestrogenism syn-
drome, and metastasis is rare.
Feminization is part of a hyperestrogenism syndrome that
includes squamous metaplasia of prostate and suppression of
bone marrow. Not all dogs with feminization or other com-
ponents of that syndrome have a higher concentration of Figure 5-42  Sertoli cell tumor in a dog. These are white, tough
serum estrogen. When present, the syndrome is from excess and often have fine septa of fibrous tissue visible.
estrogen or excess inhibin secretion reducing testosterone con-
centration. Larger tumors are responsible for the hyperestro-
genism syndrome, so the mass of the tumor is correlated with
the quantity of hormone elaborated. Poorly differentiated
tumors may not produce hormones, regardless of size.
In the hyperestrogenism syndrome, attractiveness to other
male dogs is well known. Other changes include reduction of
libido, female distribution of body fat, cutaneous and pilose-
baceous atrophy leading to symmetrical alopecia and hyper-
pigmentation, atrophy of testes and penis, an estrogenic form
of mammary development, swelling of the prepuce, and
hyperplasia or squamous metaplasia of the prostate. Enlarge-
ment of the seminal colliculus with partial obstruction of the
urethral lumen may also accompany prostatic changes in these
dogs.
Some dogs develop depression of myelopoiesis with resultant
thrombocytopenia and hemorrhage, anemia caused by blood
loss and/or reduced erythropoiesis, and infection and fever A
with neutropenia. Recovery may follow castration and sup-
portive therapy.
Metastasis of Sertoli cell tumor, although rare, is often into
the spermatic cord. Obstruction of the testicular vein and
lymphatics may result in hydrocele with massive swelling of
the scrotum. Metastasis to the regional lymph node and
beyond is unusual.
The macroscopic appearance of a Sertoli cell tumor is
distinctive. They are usually either solid or cystic, and the
larger tumors are multinodular, lobulated and enclosed in a
tense testicular capsule (Fig. 5-42; see also Fig. 5-19). The cut
surface usually is white and tough. The firmness of the tumor
is due to the abundance of its fibrous stroma, something the
other two common testicular tumors have in small amounts
only.
Histologically, Sertoli cell tumors begin within seminifer- B
ous tubules and progress with penetration of the basement
membrane and finally to the formation of a macroscopically Figure 5-43  A. Histologic appearance of Sertoli cell tumor in a
visible mass. It is unusual to see hyperplastic or preneoplastic dog showing tubular structures separated by abundant fibrous
microscopic foci in normal testes. Stroma is always plentiful, tissue. B. On higher magnification, the cells tend to bridge from
and it may be dense collagen (Fig. 5-43A). The stromal tissues one side of the tubular structure to the other.
 Testis and Epididymis
contribute to a tubular pattern, and the neoplastic cells tend
to palisade. In smaller tubules they stretch from one side of
the tubule to the other (Fig. 5-43B). Some form cystic struc-
tures that may be confused with carcinoma. In the well-
differentiated tumors, the cells resemble normal Sertoli cells,
being elongate with foamy acidophilic cytoplasm and small,
basally located, nuclei. In less differentiated varieties, the cells
are still elongate, have eosinophilic cytoplasm, but the nuclei
are oval and pleomorphic, and are no longer basally located
against the trabecular pole. In the less common form of the
tumor, the cells show little or no tendency to palisade but are
discrete and spherical with well-defined eosinophilic cyto-
plasm and anisokaryosis. Mitoses are sparse in most. Lipids are
demonstrable in the neoplastic cells as large droplets and
globules in more differentiated tumors, and as fine droplets in
the least differentiated tumors. There is little correlation
between histologic type and metastasis.
It is not possible to generalize about the detailed immuno-
histochemical staining characteristics of Sertoli cell tumors
because of variable results. Neoplastic cells should be positive
for vimentin (as are interstitial endocrine cells) and negative
for cytokeratin stains (but not always). There are varied
reports of staining for many different antigens including S100,
melan A, GATA4, inhibin, and anti-Müllerian hormone
(AMH) to name a few. If inhibin and AMH staining are
present, a diagnosis is made with greater confidence.
Canine Sertoli cell tumors have characteristic electron
microscopic structures including intercellular junctions and
crystals of Charcot-Bottcher. If these are not visible, Sertoli
cell tumors have abundant organelles that allow differentia-
tion from interstitial cell tumors and seminomas.
Extratesticular Sertoli cell tumors occur in dogs. They are
located in the prescrotal and scrotal region or spermatic cord
of neutered dogs. They presumably develop from remnants
implanted at castration. Prolonged stimulation of testicular
remnants eventually allows transition from hyperplasia to
neoplasia. The tumors are identical to Sertoli cell tumors
within the testis, and some produce a hyperestrogenism syn-
drome. No metastases are documented.
In general, the gross and microscopic appearance of Sertoli
cell tumors in the bull resembles those in the dog. Early age
of slaughter of most food animals precludes studies on true
tumor occurrence with increasing age. In one study in which
bulls and buffaloes were kept until 9-14 years for draft pur-
poses, 20 of 161 testes examined contained neoplasms; all but
one were Sertoli cell tumors. Seven tumors were in unde-
scended testes. In contrast to dogs, bovine Sertoli cell tumors
are often in newborn or young calves, suggesting altered
embryogenesis. They sometimes have laminated intratubular
concretions resembling those seen in bovine testicular hypo-
plasia and cryptorchidism. A simultaneous occurrence of
Sertoli cell tumor and epididymal aplasia was observed. One
bovine Sertoli cell tumor was in a testis of an animal in which
castration by the burdizzo method was attempted 5 years
previously. Metastasis of Sertoli cell tumor to the pampini-
form plexus is reported in a bull; there is no clear evidence of
a hyperestrogenism syndrome.
One case of Sertoli cell tumor in a stallion involved the
single descended testis; a ductal pattern of neoplastic Sertoli
cells, which contained clusters of distinct hyaline bodies, was
evident.
Sertoli cell tumors in the ram are comparable to those in
the bull. Hyperplastic Sertoli cells occur in cryptorchid rams
495
(see Fig. 5-17), but their potential to develop into neoplasms
seems unlikely, given the rarity of the tumors.
Sertoli cell tumors in other species, including camelids, are
very rare.
Germ cell tumors
Seminomas.  Seminomas are common in canine testes and
are reported in the bull, boar, stallion and mule, ram, buck,
tomcat, and bull camelids. They occur in older animals and are
disproportionately common in cryptorchid testes. Their phe-
notype is usually spermatocytic, and there is subclassification
into classical and spermatocytic types based on periodic acid
Schiff (PAS) and placental alkaline phosphatase (PLAP) stain-
ing. Classical seminoma is positive for both. Although a soli-
tary tumor is observed macroscopically, they are histologically
multifocal in the affected testes. These tumors typically do not
produce hormones; if there is evidence of a hyperestrogenism
syndrome, other possibilities must be completely excluded.
They are usually benign, but metastatic examples are reported.
There are no known factors to predict the metastatic potential
of seminomas.
The main presenting sign is testicular enlargement. Sudden
enlargement of the testis and pain caused by hemorrhage and
necrosis in the tumor, can occur. In all species, the cut surface
is coarsely lobulated by a few fine trabeculae. The color is
usually white or gray-white, except in stallions in which they
are often tan (Fig. 5-44), and the texture is soft; they usually
bulge from the cut testicular surface (see Fig. 5-44). If lightly
squeezed, a milky fluid may exude from them. The texture
and color closely resemble that of neoplastic lymphoid tissue.
Microscopically, intratubular and diffuse types are recognized.
The earliest development of the tumor is intratubular and
even in some large examples, intratubular growth is still
evident elsewhere (Fig. 5-45A). Rupture of the tubules soon
occurs and the growth becomes confluent, forming broad
sheets of closely packed cells with scant supporting stroma.
The cells are large and round or polyhedral, with a rim of
visible cytoplasm that may be basophilic or eosinophilic (Fig.
5-45B). The nuclei are large, round, and hyperchromatic, with
one or more large acidophilic nucleoli. In some tumors, the
nuclei are larger and vesicular but still regular in shape. In
many seminomas, it is possible to find scattered mono- or
multinucleated giant cells with abundant granular acidophilic
cytoplasm. A useful distinguishing feature is the presence of
focal nodules of, or diffuse, CD8+ lymphocytes. Whereas
degeneration of tubules at the edge of the tumor is normally
Figure 5-44  Multinodular and yellow tan appearance of a semi-
noma in a horse. In other species, the neoplastic tissue varies from
white to tan and is friable.
496 CHAPTER 5  •  Male Genital System
A white solid masses with fibrous, adipose, cartilaginous, and
B in the epithelial cells supports the diagnosis.
Figure 5-45  Seminomas usually have a combination of intratu-
bular (A) and diffuse growth. The adjacent testis may be degener-
ate, as was the case in this dog. B. Histologically, the cells are large
round cells with scant cytoplasm and large nuclei with prominent
nucleoli. Mitoses are frequent.
evident, occasional foci of intratubular germ cells and intratu-
bular seminoma is seen.
Ultrastructurally, neoplastic cells resemble normal germi-
nal epithelium and have oval nuclei, straight cell borders, a
distinct Golgi complex, and a scarcity of cytoplasmic organ-
elles. Intercellular bridges, as seen in normal germinal cells, are
present in seminomas. In all cases the cells are distinct from
cells of interstitial or Sertoli cell tumors.
Germ cells stain by immunohistochemistry using antibod-
ies including calretinin, KIT, PGP 9.5, E cadherin, GATA4,
inhibin alpha, and NSE, but no staining pattern differentiates
them from other testicular tumors except GATA4 staining
because germ cells are negative but the majority of Sertoli cell
and interstitial cell tumors are positive.
In the stallion, seminomas occur in older animals and often
in cryptorchid testes. They can weigh up to 9 kg, and some
are metastatic with spread to most parts of the abdominal
cavity and occasionally to the thoracic cavity.
Intratubular seminomas are reported in mature and aged
rams that have concurrent testicular degeneration. The prolif-
erating cells are multifocal within seminiferous tubules and
do not attain sufficient size to be recognized grossly. Rarely a
Testis and Epididymis
malignant form of seminoma occurs in the ram, producing
overall enlargement of the testis, hemorrhage, necrosis, and
obliteration of the entire testis.
Seminomas are exceedingly rare in other species.
Teratoma.  Teratoma of the testis is found periodically in foals,
but is rare in other domesticated mammals. It occurs in crypt-
orchid equine testes, but whether it forms preferentially in
retained testes or it prevents normal descent is not known.
There is a report of testicular teratoma that caused partial
obstruction of the colon in a neonatal foal.
Macroscopically, teratomas are single or multiple and vary
in color and texture. They are usually <10 cm in diameter but
may be >25 cm. A cystic and/or multilocular structure is
common and hair and mucoid or sebaceous secretions are
seen, hence frequent use of the term dermoid cyst. Yellow-
bony tissue are also frequent.
Histologically, structures from all embryonic germ layers
may be present, including ectodermal (dermoid cysts, hair,
teeth), neuroectodermal (nervous tissue, melanoblasts),
endodermal (salivary gland, respiratory), or mesodermal
(fibrous or adipose tissue, bone, muscle). Nervous tissue is
almost always present, and adipose tissue is also very common.
Testicular tissue adjacent to a teratoma may have reduced
spermatogenesis, with various degrees of tubular degeneration.
Gonadal teratoma is further discussed in Vol. 3, Female
genital system.
Embryonal carcinoma.  Embryonal carcinoma is exceedingly
rare in animals but it is a well-known malignant testicular
neoplasm of humans. The cells are of indifferent embryonic
types, thus it is similar to teratoma but much more primitive.
Trophoblastic differentiation and demonstrable α-fetoprotein
Teratocarcinoma, a neoplasm with features of teratoma and
embryonal carcinoma, is reported in the horse.
Mixed germ cell−sex cord stromal tumor
These neoplasms, the fourth most common primary testicular
tumor in the dog, are a combination of germ cells (seminoma)
and sex cord stromal cells (interstitial endocrine cells and
Sertoli cells). Cell types are found together and are different
to when a Sertoli cell tumor collides with a seminoma. Gonad-
oblastoma is a synonym. These are likely underreported. The
lesions grossly resemble Sertoli cell tumors because they are
firm, white to tan, and expansile. Larger neoplasms may be
hemorrhagic. Histologically, they are a combination of seminoma
and Sertoli cell tumor, with the tubular structures of Sertoli cell
tumors containing germ cells. Immunohistochemical staining
helps confirm the dual nature of this neoplasm.
Mixed germ cell−sex cord stromal tumors are also reported
in stallions.
Other primary tumors
Adenomas and adenocarcinomas presumably originating from
the rete testis are described in horses and dogs. These have
tubulopapillary structures with scant supporting stroma. The
papillae and anastomosing tubules are lined by small closely
packed cells with scant cytoplasm either in single or multiple
layers. Evidence of transformation from normal to neoplastic
rete epithelium is a useful criterion for diagnosis. Exclusion of
teratoma by taking multiple sections, or of it being a distant
metastasis, is also required. Immunohistochemically, they will
stain with antibody to cytokeratin.
 Spermatic Cord
Reports of mesenchymal tumors of the testis are mostly
individual cases. They include leiomyoma and leiomyosar-
coma, hemangioma, hemangiosarcoma, lymphangioma, and
peripheral nerve sheath tumor. Mast cell tumor and histiocytic
sarcoma are also reported.
Neoplasia of the epididymis is a very rare event. Any tissue
may transform, and carcinoma is reported. Metastases from
elsewhere occur too, and lymphoma may occur. Interstitial cell
tumor of the epididymis of the cat is a recognized disease and
arises from ectopic interstitial endocrine cells.
Further reading
Ali A, et al. Unilateral seminoma in a dromedary camel. Reprod Dom
Anim 2013;48:17-19.
Banco B, et al. Immunohistochemical evaluation of the expression of
anti-mullerian hormone in mature, immature and neoplastic canine
Sertoli cells. J Comp Pathol 2012;146:18-23.
Dreimanis U, et al. Evaluation of preputial cytology in diagnosing oes-
trogen producing testicular tumours in dogs. J Sm Anim Pract
2012;53:536-541.
Grieco V, et al. Canine testicular tumours: a study on 232 dogs. J Comp
Pathol 2008;138:86-89.
Jensen KL, et al. Malignant Sertoli cell tumour in a young Simmenthal
bull—clinical and pathological observations. Reprod Dom Anim
2008;43:760-763.
Kennedy PC, et al. Histological classification of tumors of the genital
system of domestic animals. WHO International Histological Clas-
sification of Tumors of Domestic Animals, Series 2, vol III. Washing-
ton, DC: AFIP, ARP; 1998.
Marino G, et al. Activins and inhibins: expression and role in normal
and pathological canine reproductive organs: a review. J Vet Med
2013;42:1-8.
McEntee MC. Reproductive oncology. Clin Tech Small Anim Pract
2002;17:133-149.
Mischke R, et al. Blood plasma concentrations of oestradiol-17β,
testosterone and testosterone/oestradiol ratio in dogs with
neoplastic and degenerative testicular diseases. Res Vet Sci
2002;73:267-272.
Nodtvedt A, et al. Breed differences in the proportional morbidity of
testicular tumours and distribution of histopathologic types in a
population-based canine cancer registry. Vet Comp Oncol
2011;9:45-54.
Peters MA, et al. Use of antibodies against LH receptor, 3β-hydroxysteroid
dehydrogenase and vimentin to characterize different types of tes-
ticular tumour in dogs. Reproduction 2001;121:287-296.
Quartuccio M, et al. Sertoli cell tumors associated with feminizing
syndrome and spermatic cord torsion in two cryptorchid dogs. J Vet
Sci 2012;13:207-209.
Ramos-Vara JA, Miller MA. Immunohistochemical evaluation of GATA-4
in canine testicular tumors. Vet Pathol 2009;46:893-896.
Reis-Filho JS, et al. Bilateral gonadoblastomas in a dog with mixed
gonadal dysgenesis. J Comp Pathol 2004;130:229-233.
Yu C-H, et al. Comparative immunohistochemical characterization
of canine seminomas and Sertoli cell tumours. J Vet Sci
2009;10:1-7.
Miscellaneous diseases of the testis
and epididymis
Spermatic granulomas occur at any location. The most recog-
nized syndrome is spermatic granuloma of the epididymal head,
a condition resulting from blind-ending efferent ductules. It
497
occurs in virtually every species; it is not reported yet in
the cat.
Adenomyosis of the mesonephric ducts is a histologic
finding in which diverticula of the epithelium of the epididymis
or deferent duct protrude through the muscular wall. Spermato-
zoa may become entrapped and incite an inflammatory reac-
tion. Hyperestrogenism may be an inciting cause. Adenomyosis
is the suspected underlying defect when a sperm granuloma
is found in a location apart from where blind-ending efferent
ductules would be expected. Virtually every species develops
adenomyosis of the mesonephric duct.
The rete testis is a series of interconnected channels that
join the seminiferous tubules to the efferent ductules. It has
intratesticular and extratesticular segments. Spermatophagia
occurs in this area, and immune reactions to spermatozoa may
be manifested by inflammation. There are 2 main primary
diseases of the rete: neoplasia and cyst formation. The epithelial
cells are the origin of adenomas and adenocarcinomas in
horses, dogs, and other species. Cysts of this region occur in
the stallion, dogs, and cats. Secondary dilation of the rete testis
occurs with obstruction of the efferent ductules or
epididymis.
SPERMATIC CORD
The spermatic cord is composed of the 3 arteries, veins, lymphatics,
3 nerves, and deferent duct. It is covered by 3 layers, including
the cremaster muscle and fascias. These are critical structures
for the function of the testis and epididymis. Scrotal hernia
and varices of the pampiniform plexus are the most com-
monly recognized diseases of the spermatic cord. Most of the
other diseases become differential diagnoses for these.
Varicocele
A varicocele is a dilation and tortuosity of the veins of the pampi-
niform plexus. Varices of the spermatic veins are most common
in old rams (Fig. 5-46). They occur sporadically in others,
such as the bull, stallion, and dog, as an incidental finding or
secondarily to conditions in which there is constriction of
the veins of the spermatic cord. Experimental induction
is achieved by generating partial obstruction of the left
renal vein.
Varices are seldom recognized unless they are thrombosed.
There is no concrete evidence that small varicoceles are det-
rimental. Large ones are, because of their size and the reduced
ability of the animal to raise the testis to maintain thermo-
regulation, or because of alteration of blood flow and changed
testicular oxidant/antioxidant balance. The pathogenesis of
varicocele is poorly understood. In humans, the left unilateral
location is the result of altered hemodynamics from insertion
of the testicular vein to the renal vein rather than directly to
the vena cava. Evidence in humans with varicose veins of the
legs suggests that the elastic properties of the walls of the
veins, arterial flow, and valves in veins are major factors. It is
difficult to implicate intimal sclerosis of the spermatic vessels
as older animals of all species develop this, but so few develop
varicocele.
Varicoceles appear as dark red, up to 3-cm diameter,
nodules enclosed in fascia of the spermatic cord proximal to
the testis. Varicoceles may have large organizing laminated
thrombi, typical of venous thrombi. Differential diagnoses of
varicocele include neoplasia (mesothelioma), scrotal hernia,
scrotal lymphadenitis, spermatic granuloma of the epididymal
 497.e1

Further reading
Banco B, et al. An immunohistochemical study of normal and neoplas-
tic canine Sertoli cells. J Comp Pathol 2010;143:239-247.
Bazzo R, et al. Sertoli cell tumour with Call-Exner-like bodies in a dog.
J Vet Med A Physiol Pathol Clin Med 2002;49:535-537.
Brinsko SP. Neoplasia of the male reproductive tract. Vet Clin North Am
Equine Pract 1998;14:517-533.
Doxsee AL, et al. Extratesticular interstitial and Sertoli cell tumors in
previously neutered dogs and cats: a report of 17 cases. Can Vet J
2006;47:763-766.
Grieco V, et al. Classical and spermatocytic seminoma in the dog:
histochemical and immunohistochemical findings. J Comp Pathol
2007;137:41-46.
Grieco V, et al. Inhibin-alpha immunohistochemical expression in
mature and immature canine Sertoli and Leydig cells. Reprod Dom
Anim 2011;46:920-923.
Luby CD, et al. Theriogenology question of the month. J Am Vet Med
Assoc 2007;231:10.
McEntee K. Reproductive Pathology of Domestic Mammals. London:
Academic Press; 1990. p. 230-231.
Murakami Y, et al. Immunohistochemical analysis of cyclins in canine
normal testes and testicular tumors. J Vet Med Sci 2001;63:
909-912.
Owsten MA, et al. Histologic and immunohistochemical characteriza-
tion of a testicular mixed germ cell sex cord-stromal tumor and a
Leydig cell tumor in a dog. Vet Pathol 2007;44:936-943.
Patnaik AK, Mostofi FK. A clinicopathologic, histologic and immuno-
histochemical study of mixed germ cell-stromal tumors of the testis
in 16 dogs. Vet Pathol 1993;30:287-295.
Peters MA, et al. Ageing, testicular tumours and the pituitary-testis axis
in dogs. J Endocrinol 2000;166:153-161.
Radi ZA, et al. Rete testis mucinous adenocarcinoma in a dog. Vet
Pathol 2004;41:75-78.
Taniyama H, et al. Immunohistochemical detection of inhibin-α, -βB,
and -βA chains and 3β-hydroxysteroid dehydrogenase in canine
testicular tumors and normal testes. Vet Pathol 2001;38:661-666.
Weaver DM, et al. Bilateral testicular interstitial cell tumour in an aged
boar. Vet Rec 2000;146:224.
498 CHAPTER 5  •  Male Genital System
Figure 5-46  Varicocele with thrombosis in a ram. The grossly
dilated and thrombosed pampiniform plexus causes a large mul-
tilobular mass above the testis in the spermatic cord.
head or deferent duct, and cystic retained mesonephric or
paramesonephric ducts.
Varicocele is most common in the ram, where it is bilateral,
or unilateral with no apparent predisposition as to side. Large
varicoceles are always thrombosed and there is overt testicular
degeneration, occasional thrombosis of testicular vessels, and
reduced testis:body weight ratios.
Other vascular lesions
Intimal sclerosis of testicular veins is common in older males,
and described in rams and bucks. The arterial changes, which
tend to be bilateral, consist of fibroplasia of the intima. Intimal
and/or medial mineralization also occurs in branches of the
testicular artery.
Vasculitis of testicular, deferential, and cremaster arteries
may be found in malignant catarrhal fever and bovine viral
diarrhea virus infection of bulls. Dogs, particularly Beagles
with canine juvenile systemic vasculitis, and occasionally in
other vasculitides, have involvement of these vessels. Apparent
hypoplasia of veins of the spermatic cord is reported in bulls
with thickening and degeneration of the testicular artery.
Although studies in the bull have not demonstrated a
direct connection between venous and arterial blood vessels
of the pampiniform plexus, functional arteriovenous anastomo-
ses through small vessels do occur in normal bulls, boars, and
rams, and may represent a further means of thermoregulation
of the testis. A large anastomosis of the spermatic artery and
vein is reported in a stallion with an abdominal testis.
Scrotal hernia
Inguinal hernia occurs when abdominal contents bulge into
the inguinal canal. Scrotal hernia occurs when abdominal con-
tents are within the space between the vaginal tunics (the
vaginal sac). It occurs in all species as either congenital or
acquired disease. A genetic cause is either proven or suspected.
Spermatic Cord
Scrotal hernias develop if there is failure of closure of the
internal inguinal ring, incomplete obliteration of the vaginal
process, weakness of the triangle of the inguinal region, an
abnormality in smooth muscle in the wall of the hernia, or
increased intra-abdominal pressure.
In boars, 3 or 4 candidate genes are linked to scrotal hernia.
There is a possible link with genes involved with cryptorchi-
dism. In stallions, the disorder is either congenital and often
resolves by 3-6 months of age, or it is acquired and is poten-
tially life threatening because of intestinal strangulation. In the
congenital form, a portion of the jejunum enters the vaginal
sac; rupture of the vaginal tunics at birth may result in the
loop of intestine lying in a subcutaneous location. In the
acquired form in entire animals, exercise or some activity such
as serving a mare may precede development. Left- and right-
sided hernias occur with equal frequency. Herniation of the
intestine usually obstructs vascular supply to the testis, neces-
sitating castration at the time of surgical repair. The acquired
form is very rare in geldings.
Miscellaneous diseases of the spermatic cord
Other lesions of the spermatic cord may involve the deferent
duct, blood vessels, nerves, lymphatics, cremaster muscle, or
tunics. Some of these diseases, particularly disorders of sexual
development, are described elsewhere in more detail.
Inflammation of the spermatic cord is funiculitis; it follows
open castration. Pigs and other species where environmental
bacterial contamination is high develop necrotic funiculitis.
Ascending infection with subsequent diffuse peritonitis, and
tetanus, are common complications. “Scirrhous cord” is the
condition when there is an open draining scrotal wound,
abscessation, and granulation of the cord. The prevalent form
occurs in steers and geldings. The classical scirrhous cord of
geldings is a pyogenic infection, usually by staphylococci,
which produces the pyogranulomatous inflammation com-
monly called botryomycosis. Brucella canis can cause funiculitis
in infected dogs. Funiculitis occurs in cats that have hair
trapped at the site of severance of the cord at castration. It
accompanies reactions to, or infection of, suture material at
castration.
Neoplasms arise in these structures, or are metastases from
other locations. The range of neoplasms is similar to those of
the scrotum and testis (listed earlier). Primary neoplasms of
any of the structures can occur, including fibrous tissue, skel-
etal and smooth muscle, endothelium, or mesothelium. Neu-
tered dogs and cats can develop extratesticular Sertoli and
interstitial cell tumors of the spermatic cord.
Verminous granulomas caused by migrating larvae of
Strongylus spp. occur in the spermatic cord and testes of
horses.
Spermatic granuloma of the deferent duct is a sequel to vasec-
tomy, and is occasionally seen as spontaneous disease.
Ectopic adrenal tissue is occasionally found in the spermatic
cord, often near the efferent ductules or head of the epididy-
mis. Ectopic splenic tissue can also be found here.
Disease of the scrotal lymph node can be confused with
disease of the spermatic cord. Caseous lymphadenitis in sheep
and lymphoma in dogs are 2 common diseases that may cause
enlargement of the node and be mistaken for varicocele,
hernia, or other abnormality. Lymph and therefore inflamma-
tory infiltrates, spermatozoa, and metastases from intrascrotal
neoplasia can drain to the superficial inguinal, or lateral and
medial iliac nodes.
 Accessory Genital Glands 499

Further reading
McEntee K. Reproductive Pathology of Domestic Mammals. Academic
Press.1990, p281.
Smith KC, et al. A survey of congenital reproductive abnormalities in
rams in abattoirs in south west England. Reprod Dom Anim
2012;47:740-745.
Turner TT. The study of varicocele through the use of animal models.
Hum Reprod Update 2001;7:78-84.
van der Velden MA, van der Harst MR. Inguinal herniation in foals.
Literature review and a case report. Tijdschr Diergeneeskd
2004;129:286-292.
Zhao X, et al. Association of HOXA10, ZFPM2 and MMP2 genes with
scrotal hernias evaluated via biological candidate gene analysis in
pigs. Am J Vet Res 2009;70:1006-1011.

ACCESSORY GENITAL GLANDS

Vesicular glands and ampullae
Disorders of sexual development
An important disorder of sexual development affecting the Figure 5-47  Chronic vesicular adenitis in this bull caused fibro-
vesicular glands (seminal vesicles) and ampullae of the defer- sis, loss of lobulation, and shrinkage of the glands.
ent ducts is segmental aplasia of the mesonephric duct. This
has been studied in the bull, in which it appears to be heri-
table. Aplasia or hypoplasia of this duct can be complete and
thus the deferent duct and epididymis may also be affected,
but usually only a segment is missing and it is usually the
epididymal tail that is missing. Aplasia is mostly unilateral and
the ampulla on the affected side is completely absent or rudi-
mentary and the vesicular gland is markedly hypoplastic and
sometimes cystic. Vesicular gland hypoplasia of variable sever-
ity may occur independently of aplasia of the ampullae or
deferent duct. The vesicular glands on the side of hypoplastic
testes are usually smaller than normal.
Other disorders of development of the vesicular glands and
ampullae of the bull include fusion of the vesicular glands and
appendages of the ampullae. There is variation in the anatomic
relationship of ampullae to the vesicular glands in normal bulls;
the ampullae are entirely dorsal to the vesicular glands in 40% Figure 5-48  Microscopically visible vesicular adenitis in a ram
of bulls, are entirely ventral in 40% of bulls, and in the remain- with Brucella ovis infection. Large numbers of lymphocytes and
ing 20% of animals are intermediate. These disorders of devel- plasma cells are in the interstitium. The glands contain debris.
opment and anatomic variations are identified at rectal
examination. Anomalous glands are predisposed to inflamma- (see Fig. 5-47) where the glands are increased in size and are
tion, may affect the freezability of semen, but are unrelated firm and lack lobulation from fibrosis. In the degenerative
to fertility in natural breeding systems. form, neutrophils, sloughed epithelium and cellular debris,
Cystic dilation of the lumina of occasional lobules, or a and intensely basophilic material fill acini. The chronic inter-
general dilation of ducts in one, and sometimes both, vesicular stitial form is dominated by fibrosis and many lymphocytes,
glands, occurs in bulls, horses, and swine. plasma cells, histiocytes, neutrophils, and occasional eosino-
phils within the stroma. The epithelium usually is normal but
Inflammation of the vesicular glands may be metaplastic in some areas. Acini contain a small
Vesicular adenitis, often with inflammation in ampullae, is a amount of finely granular eosinophilic material, occasional
common lesion in the bull (Fig. 5-47), and is rare in the stal- neutrophils, and desquamated epithelium.
lion and boar. Macroscopically apparent vesicular adenitis and Numerous infectious agents are isolated from bovine vesicu-
or ampullitis is rare in the ram, but histologic lesions are fre- lar adenitis, but the precise roles of most have yet to be
quent in animals infected with Brucella ovis, Actinobacillus determined. In chronic vesicular adenitis, bacteriologic inves-
seminis, and Histophilus somni (Fig. 5-48), particularly if they tigations are often negative. Trueperella pyogenes is the most
have epididymitis caused by these organisms. Vesicular adeni- common isolate. Large abscesses may be present also and these
tis in bulls is detected on rectal palpation, and by the presence may involve adjacent tissue, and adhesions and fistulas form
of neutrophils or pus in semen. Young bulls, less than 2 years with the rectum or bladder. Staphylococci and streptococci
of age, are frequently affected. generally do not form large abscesses, but more often small
Two general forms of vesicular adenitis occur in the bull. focal or diffuse suppurative inflammation. Vesicular adenitis
There is a degenerative or necrotic form in which there is a slight caused by Brucella abortus is fibrinopurulent, progressing
increase in size and consistency, and a chronic interstitial form to necrosis, suppuration, and dystrophic mineralization;
 499.e1

Further reading
Ezzi A, et al. Pathology of varicocele in the ram. Aust Vet J
1988;65:11-15.
Nistal M, Paniagia R. Testicular and Epididymal Pathology. New York:
Thieme and Stratton; 1984.
Perkins NR, Frazer GS. Reproductive emergencies in the stallion. Vet
Clin North Am Equine Pract 1994;10:671-683.
Roberts SJ. Scrotal hernia in rams: a case report. Cornell Vet
1988;78:351-352.
500 CHAPTER 5  •  Male Genital System Accessory Genital Glands

granuloma formation is rarely observed. Tuberculous vesicular including cryptorchidism. A prostatic appendage is reported
adenitis causes an increased size of vesicular glands with char- in the bull where a polyp-like protrusion of prostatic tissue
acteristic caseation and granulomas. bulged into the urethral lumen. Congenital retention cysts
Several viruses, including the virus of infectious bovine occur in the bull and a cryptorchid boar. In some dogs, the
rhinotracheitis-infectious pustular vulvovaginitis (bovine her- dorsal median groove of the prostate may be indistinct so the
pesvirus 1), may infect the accessory genital glands of the bull. bilobed structure is not evident.
Clinical signs of vesicular adenitis in such cases are reported Prostatic cysts and pseudocysts in the dog may be congeni-
to be mild and transitory. The vesicular glands and prostate tal or secondary to hyperplasia, neoplasia, or inflammation
are the most productive sites for viral replication in bovine (see later). Cysts within the prostate may be multiple cysts in
viral diarrhea virus infection in bulls, but neither gross nor prostatic hyperplasia, retention cysts, and cysts with squamous
microscopic lesions are observed. Mycoplasma bovis, Myco- metaplasia. Those outside the prostate are called paraprostatic
plasma bovigenitalium, and ureaplasmas were isolated from cysts or pseudocysts (Fig. 5-49). Those lined by epithelium are
bulls with vesicular adenitis, and unequivocal lesions have true cysts (Fig. 5-50) and those without epithelium are pseu-
resulted from experimental infection. Apart from variable docysts. The precise origin of paraprostatic cysts is not clear.
numbers of eosinophils in these lesions, they are nonspecific. Most cysts attach to the prostate at a small localized area. The
Mycoplasma bovigenitalium, however, was isolated from vesic- cysts are up to 30 cm long and 14 cm in diameter, and have
ular gland secretions from a large proportion of normal pubes- a wall of compressed collagen and even bone (see Fig. 5-50).
cent bulls. As with the mycoplasmas, Chlamydophila spp. are Fibrin may be present on the inner aspect of the larger cysts,
isolated from the semen and epididymides of bulls, and their as well as polypoid bony extensions into the lumen. Cysts
possible role in vesicular adenitis is unknown. The vesicular become infected to form a prostatic abscess, although most
glands may also be an important site for localization of Lep-
tospira spp. Leptospira interrogans serovar hardjo was isolated
with equal frequency from vesicular glands and kidneys of
naturally infected bulls, thereby suggesting the possibility of
venereal transmission.
The pathogenesis of bovine vesicular adenitis is unresolved.
Hematogenous infection of the glands seems probable in some
cases, but ascending infection from the urethra is probable.
Stress, reflux of urine or semen into the vesicular glands, and
congenital defects in the mesonephric duct system predispose
to infection.
In pigs, sheep, and goats, vesicular adenitis is of less impor-
tance than in the bull. It occurs in brucellosis caused by
Brucella suis, Brucella ovis, and Brucella melitensis, respectively.
The characteristic lesion is chronic, and resembles the chronic
interstitial form seen in the bull (see Fig. 5-48). In boars,
abscessation of the vesicular glands and prostate may accom-
pany orchitis caused by Burkholderia pseudomallei. Abscesses
in the vesicular glands of barrows may be the result of infec-
tion at the time of castration.
In the stallion, purulent, abscessating vesicular adenitis is Figure 5-49  Paraprostatic cyst (upper) distorting the contour of
described, but appears to be uncommon. Virus is shed for the prostate (lower) in a dog. The bladder is to the right.
months in the semen of stallions infected experimentally with
equine arteritis virus. The ampullae and bulbourethral glands
are predilection sites. It is unclear whether there are lesions
in infected tissues, or associated spermatozoal abnormalities.
Bacterial vesicular adenitis and ampullitis occur sporadically
and may be a cause of “colic.”

Prostate and bulbourethral glands

The prostate and bulbourethral glands arise from endodermal
epithelial buds from the middle or pelvic part of the urogeni-
tal sinus. Their responses to injury are similar. In bulls and
rams, a local secretory IgA-based immune system develops
here.

Disorders of sexual development

Disorders of development of the bulbourethral gland include
congenital retention cysts in bulls, rams, and cats, and aplasia,
hypoplasia, and fusion in bulls. Melanosis of the bulbourethral
glands has been observed in the bull and boar. Figure 5-50  Microscopic appearance of paraprostatic cyst with
Malformations of the prostate are infrequent and occur epithelial lining, underlying fibrous tissue, and osseous metaplasia
with disorders of development of the remaining genitalia (right).
 Accessory Genital Glands
Figure 5-51  Cystic uterus masculinus (center) overlies the
ampullae of this ram.
have a sterile content and are devoid of pus, urine, and sper-
matozoa. Hyperplastic prostatic and paraprostatic cysts are par-
tially lined by prostatic epithelium, and probably arise as
outpouching of prostatic glandular epithelium through the
discontinuous muscle coat of the gland. Cysts that are cen-
trally located on the dorsal surface of the prostate may have
arisen from vestiges of the paramesonephric duct, and form a
uterus masculinus. Uterus masculinus occurs in males of most
species, and they are in the connective tissue between the
ampullae or deferent ducts (Fig. 5-51).
A true cystic uterus masculinus is lined by stroma and
simple columnar epithelium that resembles endometrium. A
cystic uterus masculinus occurs in old dogs and appears to be
stimulated by estrogen, as occurs in Sertoli cell tumor. These
may cause constipation, dysuria, or anuria. Paraprostatic lym-
phatic cysts are reported. They have no epithelial lining, are
multilobular, and may have an endothelial lining. About 18%
of paraprostatic cysts have a fluid content that is high in cre-
atinine indicating it is urine. They are called paraprostatic
urinary retention cysts. These may begin as hyperplastic pros-
tatic cysts and thus communicate readily with the urethra.
Serosal inclusion cysts and hematomas are other possibilities.
For most, the lack of any characteristic feature makes deter-
mining their origin impossible.
Inflammation of the prostate and
bulbourethral gland
Inflammation of the bulbourethral gland in the bull often
accompanies vesicular adenitis. The cause and tissue response
are identical. Concretions may result from chronic inflamma-
tion. Inflammation of this gland in other species is very rare.
Prostatitis is a common and classic disease in the dog. It is
often a disease of older dogs in which hyperplastic prostatic
changes are present. The inflammatory changes contribute to
the enlargement in a significant proportion of the cases,
but the disease may occur in younger dogs with normal pros-
tates. The infecting agents are usually urinary pathogens, Esch-
erichia coli, Proteus vulgaris, streptococci, and staphylococci,
which invade via the urethra and prostatic duct. Prostatitis
occurs in brucellosis of dogs.
Prostatitis is usually recognized when there are systemic
signs of illness from endotoxemia, and about two-thirds of
501
Figure 5-52  Transverse section of a canine prostate with acute
prostatitis. Hemorrhage and edema involve the prostate and the
periprostatic tissues.
affected dogs have a history of urinary tract signs that include
blood and or pus in the urine, urethral discharge, incontinence,
or dysuria. Except for dramatic elevations in the numbers of
neutrophils in the blood in dogs with prostatic abscesses,
hematologic data are mostly equivocal, so that cytologic eval-
uation and culture of prostatic fluid collected by prostatic
massage or ejaculation is necessary to differentiate prostatic
diseases in the dog.
Diffuse necrotic and hemorrhagic prostatitis is the most severe
form. The whole gland is affected by the necrosuppurative
process. Septicemia, endotoxemia, peritonitis, severe pelvic
edema and cellulitis, and death can ensue. The gland is often
asymmetrically enlarged, hemorrhagic and edematous (Fig.
5-52). It pits on digital pressure and the fluid that drains
from the cut surface is either blood and edema fluid, or pus.
Prostatitis may become emphysematous in the presence of
gas-forming organisms. Less severe lesions are multifocal or
regional in extent. Some are more suppurative and centered
on the acini or hyperplastic cysts, whereas others have variable
interstitial involvement; neutrophils dominate in all lesions
(Fig. 5-53A). Localization in and destruction of acini proceeds
to abscess formation and these may become confluent, con-
verting the whole gland into a multiloculate abscess cavity,
but this is unusual. Severe acute inflammation may resolve
and leave only extensive scarring, or it may become chronic,
with small walled-off foci.
Chronic prostatitis in the dog is a common lesion (Fig. 5-53B).
Because affected dogs are often older, there is variable glan-
dular hyperplasia and cystic hyperplasia. The inflammation is
segmental and may spare large portions, or is multifocal and
coalescing. The prostatic epithelium varies from hyperplastic
columnar cells with prominent eosinophilic globules in the
apical cytoplasm of individual acinar cells to atrophic where
they are cuboidal or squamous in type, and the apical cyto-
plasm loses eosinophilic staining. Focal squamous metaplasia
occurs, and may be mistaken for prostatic intraepithelial neo-
plasia. The lumina of the glands contain a variable number of
neutrophils and macrophages, and debris. The interstitium has
lymphocytes and plasma cells and aggregates of lymphocytes;
true lymphoid follicles are common. Fibrosis is variable; often
some regions have extensive fibrosis such that the interstitium
has a larger area than acini. Dogs with clinical prostatitis are
often treated with antibiotics and neutering—the latter results
in superimposition of physiologic prostatic atrophy on the
effects of fibrosis and chronic cellular reaction.
502 CHAPTER 5  •  Male Genital System
A marbled cut surface. They may also contain cysts that are large
B entire prostate is larger; nodular hyperplasia is very rare. The
Figure 5-53  A. Histologic appearance of suppurative prostatitis
with destruction of glandular lumina with predominantly neutro-
phils, lesser numbers of macrophages, and interstitial edema.
B. Lymphocytic prostatitis with lymphocytes, plasma cells, and
abundant fibrous tissue in the interstitium of the prostate of
a dog.
Prostatitis is a constant feature of Brucella canis infection.
Typically, involvement is extensive but lobular in distribution,
and consists of many lymphocytes in the interstitium. There
is often fibrosis and atrophy or loss of adjacent epithelium.
Apart from bacterial prostatitis, systemic fungal infections
caused by Blastomyces dermatitidis, Cryptococcus neoformans,
and Coccidioides immitis may involve the prostate. There are
reports of prostatitis with Mycoplasma canis and Leishmania
spp. recovered from the lesion or seminal fluid.
Prostatitis in bulls, boars, stallions, rams, bucks, and tomcats
is very rare, but when present, has a similar range of changes
as occurs in the dog.
Hyperplasia and metaplasia of the prostate and
bulbourethral gland
Hyperplasia or metaplasia of the bulbourethral glands is rare.
Reversible enlargement of the bulbourethral glands with squa-
mous metaplasia, hyperplasia, and cystic dilation occurs in
wethers ingesting strains of clover with high estrogenic potency,
such as Trifolium pratense, T. repens, T. subterraneum. In wethers,
but not in rams, grazing potent green clover pastures induces
the bulbourethral glands to become large and firm with a
Accessory Genital Glands
Figure 5-54  Prostatic hyperplasia in a dog with almost symmetri-
cal enlargement of the prostate gland.
enough to cause fluctuant swelling of the perineal region.
These are filled with urine and cellular detritus because they
communicate with the urethra via the ducts of the gland. The
epithelial hyperplasia may obstruct the urethra. Cystic uterus
masculinus develops too, and there may be mammary devel-
opment (for effect on females, see Vol. 3, Female genital
system). Prolapse of the rectum also occurs. The prostatic
changes are visible as chalky or yellow streaks and flecks on
the dorsal surface of the urethra. Microscopically, there is
squamous metaplasia with central keratinization.
Marked squamous metaplasia, especially of the vesicular
glands, of bulls follows ingestion of chlorinated naphthalenes.
Nodular hyperplasia of the bulbourethral glands of rams
occurs occasionally as an incidental finding.
Prostatic hyperplasia is very common in dogs, and is tes-
tosterone dependent (Fig. 5-54). It also occurs in the bull. The
prevalence and degree of hyperplasia increases with advancing
years, such that 80% or more of mature or old dogs have an
enlarged prostate.
Enlargement of the prostate frequently causes obstipation.
The colon is obstructed when the prostate is forced into the
pelvic inlet as the dog assumes the position for defecation and
increases abdominal pressure. Less common is interference with
urination. Urinary retention occurs. It is impossible to demon-
strate compression of the urethra, the urethra is not sur-
rounded by the prostate gland, and in the living animal,
incontinence is common and urine can be expressed easily.
Pressure of the enlarged gland on the sacral parasympathetic
nerves may be responsible, as is attenuation of the urethral
lumen by longitudinal stretching when the prostatic enlarge-
ment is sufficient to cause displacement forward into the
abdomen. Acute infections of the urinary tract and hydrone-
phrosis often complicate urinary retention.
A higher estrogen:testosterone ratio underlies prostatic hyper-
plasia in dogs. Prolactin may also be involved. Hyperplasia
does not occur in castrated dogs, and castration causes a reduc-
tion in size. The exception is extremely rare, that is, when a
castrated dog has an estrogen-secreting tumor. At puberty,
epithelial hyperplasia is coincidental with normal testicular
development and hormone production. Throughout life, the
testosterone and dihydrotestosterone concentration in serum
is unchanged, but it increases in prostatic secretion with age.
Testosterone receptor content in each cell is not changed. The
17β estradiol:testosterone ratio is increased in those dogs with
prostatic hyperplasia. Estrogens act synergistically with andro-
gens to potentiate hyperplasia of the epithelium. It is unclear
 Accessory Genital Glands
in spontaneous prostatic hyperplasia, however, whether and
to what extent estrogen induces accompanying stromal
changes.
The hyperplastic gland is large and the surface is either
smooth and regular or irregularly nodular (see Fig. 5-54).
Larger prostates have a less obvious bilobed appearance. Fluc-
tuating cysts and venous and lymphatic ectasias may be
present beneath the capsule. The appearance of the cut surface
depends on the degree of acinar and stromal hyperplasia and
on the presence and size of cysts. The lobules vary in size and
may be poorly defined, or well defined if there is a prominent
increase in amount of the interlobular stroma.
The glandular elements are often sponge-like in appear-
ance because there are numerous small cysts containing milky
fluid. The cysts are irregularly distributed, but the largest ones
tend to be located beneath the capsule. The prostatic urethra
may have small yellow elevations of the mucosa correspond-
ing to the papillae of the excretory ducts. Microscopically
there is lobular hyperplasia, stromal hyperplasia and conden-
sation, and cyst formation variously interspersed. The acinar
hyperplasia consists of hyperplasia and hypertrophy of the
epithelial cells often with papillae, but there is always a single
layer of epithelial cells on an intact basement membrane.
Within the same lobule, some acini may be cystic, and these
are of irregular size, round, and lined by epithelium that is
attenuated (Fig. 5-55). There may be secretion in the lumen.
The interlobular connective tissue is increased in amount to
various degrees and density, and may exist as broad sheets with
some extension into the intralobular stroma. In most instances,
this interstitial tissue contains some lymphocytes and plasma
cells but the epithelium or acinar lumen is not affected.
There is no clear distinction between a normal prostate and
one that is in the early stages of hyperplasia, although arbitrary
decisions are based on the weight or size of the gland relative
to body weight and for a specific age. The relative weight cor-
rected for age is fairly consistent, except in Scottish Terriers
in which the relative weight of the prostate is about 4 times
that of any other breed. Although estrogen is therapeutically
effective in causing temporary regression of an enlarged pros-
tate, rapid enlargement of the gland follows.
Squamous metaplasia of the epithelium may occur in dogs
with Sertoli cell tumors, or following the administration of
Figure 5-55  Microscopic appearance of prostatic hyperplasia.
The acinar epithelial cells are tall columnar with prominent eosin-
ophilic granules in their apical cytoplasm, and the acini are cystic.
503
estrogens. The metaplastic change may involve acini in all parts
of the gland as well as the prostatic urethra, uterus masculinus,
and ducts. Affected epithelium becomes stratified squamous
in type, with keratin squames in the lumen. Neutrophils and
macrophages are often in the lumina too. There is no evidence
that squamous metaplasia of the canine prostate is a preneo-
plastic change.
Squamous metaplasia occurs in swine exposed to estro-
genic mycotoxins such as zearalenone. In cats, prostatic
enlargement with epithelial hyperplasia and cystic dilation of
glands follows estrogen administration. Metaplastic cornifica-
tion is restricted to urethral epithelium.
Neoplasms of the prostate and bulbourethral gland
Neoplasia of the accessory genital glands is rare in all domestic
mammals, although carcinoma of the prostate in dogs is a
well-known and intensely studied disease used in comparison
with human prostatic carcinoma. The original site of develop-
ment and the classification of carcinomas is debated and opin-
ions vary. Neoplasms may arise from the pelvic urethra,
prostatic ducts, or glandular acini, and the phenotypes vary
from adenocarcinoma to transitional cell carcinoma to squa-
mous cell carcinoma and mixtures of several types. The major-
ity are poorly differentiated and a mixture of types. Because
dogs castrated prior to puberty develop carcinoma with equal
frequency to nonneutered males, a urothelial phenotype is
often suggested, given that about half of cases will express
urothelial phenotypic markers (such as uroplakin). Immuno-
histochemical and proteomic studies have failed to adequately
classify these tumors accurately or to show a prognostic
difference.
The prostate and urethra arises embryologically from endo-
dermal epithelium, so separation of the different types is
fundamentally difficult. Studies so far have failed to conclu-
sively indicate a prognostic difference between the types. It is
better to group the neoplasms as carcinoma of the prostate,
and to avoid classification without ironclad outcome-based
data.
The cause of prostatic carcinoma is unknown. The prevalence
of hyperplasia of the prostate and the rarity of neoplasia
suggest they are not linked. Low-grade prostatic intraepithelial
neoplasia (PIN), as occurs in human males, does not occur as
a solitary lesion in dogs except in very rare situations. Even
then, separation of PIN from squamous metaplasia or other
change in prostatitis is difficult. High-grade PIN does occur in
prostates with carcinoma.
The high relative prevalence in previously neutered dogs
suggests that hormonal influences are not involved, at least
not in those animals. Prostatic neoplasia is not causally related
to testicular neoplasia.
Prostatic carcinoma occurs mostly in old dogs, especially
those older than 10 years. Clinical signs mimic those of
prostatic disease generally, and fall into 2 main categories.
Many dogs develop dysuria, stranguria, and obstruction. Some
have fecal obstipation, whereas others have emaciation and
hindlimb locomotory disturbances, apparently a result of
metastasis to the lower lumbar vertebrae, bones of the pelvis,
and long bones of the rear limbs. Spread of neoplastic cells to
bone is via the vertebral venous plexus, systemic circulation,
or direct extension.
Enlargement of the prostate with carcinoma is more likely
to be asymmetric and irregular than in hyperplasia (Figs. 5-56,
5-57). A severe fibrosing reaction with neoplastic cells may
504 CHAPTER 5  •  Male Genital System
Figure 5-56  Carcinoma of the prostate in an older dog castrated
before puberty. The phenotype is transitional cell carcinoma that
had a small primary with a central cavity of necrosis. This neo-
plasm was widely metastatic.
Figure 5-57  Carcinoma of the prostate in a dog. Extensive inva-
sion of the neoplasm into the surrounding tissues with filling of
the pelvis is evident. No distant metastases were found.
occur, and such neoplasms are hard and tough and sometimes
contain foci of bone. The capsule of the prostate and adjacent
organs often is invaded and becomes adherent to the pelvis
(see Fig. 5-57). Cyst formation is common. Neoplastic tissue
may extend into the sublumbar area. Metastasis is to iliac and
pelvic lymph nodes, bone, kidneys, bladder, lungs, liver, heart,
mesentery, and omentum. Neoplastic cells may also be
observed in the urine and occasionally in blood smears. Hyper-
trophic osteopathy can result.
Microscopically, heterogeneity and poor differentiation is
a feature of carcinoma of the prostate. Pleomorphism, aniso-
karyosis, and a high mitotic index are usual. A high proportion
of carcinomas have a mixed phenotype with glandular and
ductular components, and transitional cell morphology (Fig.
5-58). Attempts to subdivide carcinomas into different types
is subjective, and there is a lack of consistency and rigor.
Spindle cell carcinoma is very rare.
Other, rare, neoplasms of the canine prostate include
adenoma, soft tissue sarcoma, hemangiosarcoma, leiomyosar-
coma, and osteosarcoma.
Accessory Genital Glands
Figure 5-58  Carcinoma of the prostate in a dog. The carcinoma
has variable phenotypes with both transitional cell and glandular
differentiation.
Carcinoma of the prostate occurs in the cat. The prostate
is separate from and at a distance caudal to the bladder and
it covers the urethra dorsally and laterally. As in the dog there
is usually a history of dysuria and hematuria. Affected pros-
tates measure up to 2 cm or greater, are white to cream, and
microscopically have acinar or ribbon arrangement of pleo-
morphic epithelial cells. Mitoses are frequent. Pulmonary
metastases may occur.
Secondary tumors, especially lymphoma, are found with
disseminated disease, although the prostate is not routinely
examined by many. Transitional cell carcinomas of the neck of
the bladder may invade the prostate.
Neoplasia of the bulbourethral gland is exceptionally rare.
Hemangiosarcoma was found in the bulbourethral gland of
the goat.
Miscellaneous conditions of accessory
genital glands
Atrophy of the accessory genital glands occurs following cas-
tration, in advanced age, and sometimes with chronic inflam-
mation. The glands become small, dense, and of tough
consistency. Atrophy of the vesicular glands and ampullae
accompany epididymal or deferent duct obstruction of the
ipsilateral side.
In the dog, rapid atrophy occurs after adult castration.
The degree of atrophy is dependent on its size at castration—
many become one-fourth the normal size. Microscopically,
acinar and ductal epithelial cells decrease in size, become
less differentiated and more basophilic until epithelium is
flat, and after 3 months the acinar lumina are small or
nonexistent. The stroma becomes more conspicuous, and
smooth muscle of the capsule and trabeculae disappears and
is replaced by dense fibrous tissue. Ultrastructurally, within
3 days the epithelial cells were small and contained large
lipid droplets.
Corpora amylacea occur in the accessory genital glands of
domestic animals. Concretions in the vesicular glands, bulbo-
urethral glands, or prostate develop from retained secretions
or in cases of chronic inflammation. In bulls, vesicular gland
concretions are up to 1.5 cm or more in diameter, irregular,
friable, rough externally, and distinctly laminated on section.
They are usually found in inflamed vesicular glands and the
 Penis and Prepuce
lining of the concretion cavity varies from normal to pseu-
dostratified. Their structure is amorphous eosinophilic debris
with occasional clumps of enmeshed nuclear material. Con-
cretions are composed of organic components, phosphates,
carbonates, and spermatozoa—so-called “semen stones.” Micro-
concretions are common in the vesicular glands of rams, unas-
sociated with inflammation.
In dogs, the occurrence of prostatic concretions or calculi
is extremely rare and such calculi may be confused with
urinary calculi. One report of a 30 × 20 × 10 mm laminated
prostatic calculus composed of calcium carbonate and struvite
suggested that it resulted from reflux of urine. Calculi are
normally 1-5 mm in diameter, hard, white, and spherical, and
consist of phosphates and carbonates of calcium as well as
urates and oxalates. These form around a crystallization point
of organic material—mostly desquamated gland epithelium.
Calculi seldom elicit clinical signs. Prostatic calculi are reported
in sheep.
Metaplastic ossification of prostatic stroma occurs in the
dog, usually with neoplasia. Foci of mineralized bone could
be mistaken for calculi on radiographic examination.
Intraductal foreign (plant) material and chronic adenitis
affected the bulbourethral gland of a bull.
Further reading
Caney SMA, et al. Prostatic carcinoma in two cats. J Small Anim Pract
1998;39:140-143.
Cornell KK, et al. Clinical and pathologic aspects of spontaneous
canine prostate carcinoma: a retrospective analysis of 76 cases.
Prostate 2000;45:173-183.
Grieco V, et al. Cytokeratin and vimentin expression in normal and
neoplastic canine prostate. J Comp Pathol 2003;129:78-84.
Kirchof N, et al. Prostatic calculus in a dog. Praktische Tiearzt
1996;77:113-116.
Lai C-L, et al. Histopathological and immunohistochemical character-
ization of canine prostate cancer. Prostate 2008;68:477-488.
LeRoy BE, Northrup N. Prostate cancer in dogs: comparative and clinical
aspects. Vet J 2009;180:149-162.
Teske E, et al. Canine prostate carcinoma: epidemiological evidence of
an increased risk in castrated dogs. Mol Cell Endocrinol
2002;197:251-255.
PENIS AND PREPUCE
The penis and prepuce develop from the urogenital tubercle.
The preputial cavity only forms when the epithelial recess
separates just before puberty. The penis attaches to the
ischium and ends with the head of the penis. In all species
except the dog, the intrapreputial component of the penis
includes the head and a short part of the body of the penis.
The head of the penis is longest in the dog, where it includes
the erectile bulbs of the penis and is the only intrapreputial
part. The penile urethra forms ventrally. Small ruminants have
a urethral process, and in the cat, the penile spines or barbs are
testosterone dependent. The stallion has a sebaceous secretion
in its prepuce that is smegma. In the other species, the internal
prepuce is a mucous membrane.
Disorders of development of the penis are many, and are
part of the myriad disorders of sexual development (DSD).
Some are surgically correctable, others are functional abnor-
malities, and others prevent intromission and or do not allow
505
fertilization. The number and complexity of the disorders of
development is great, so only the more common and or impor-
tant are listed here.
Penile and preputial hypoplasia results from a lack of testos-
terone at critical time periods—from development of the
penis to puberty. This occurs in early castration and in many
DSD. Bulls have a form of hypoplasia described as congenital
short penis, possibly associated with shortening of the retractor
penis muscle. Penile protrusion (penile tip to preputial orifice)
is 10-22 cm as opposed to 25-42 cm in normal matched con-
trols. Partial or complete lack of the sigmoid flexure of the penis
occurs in bulls and rams. Hypoplasia of the head of the penis
only is reported. Other rare disorders of sexual development
in the bull include abnormal insertion of the retractor penis
muscle, with stretching of the skin cranial to the testis during
erection, partial or complete duplication of the penis, super-
numerary ectopic penis, and detached urethral process in
which the free end of the penis has a bifid appearance resem-
bling diphallia. Diphallia is reported in several species, includ-
ing the bull, ram, and tomcat.
Defects of the urogenital system may have a penile urethral
component. Congenital dilation of the penile urethra is
described in the goat.
Directional deviations of the erect penis occur with persis-
tence of balanopreputial folds—regions in which the prepuce
failed to separate from the penile epithelium. A well-known
fold is the persistent penile frenulum, which occurs when the
penile frenulum fails to separate from the prepuce. Persistent
penile frenulum is reported in the bull, boar, buck, dog, and
tomcat. Although studies in the boar have indicated some
breed susceptibility for persistent frenulum, there is no defi-
nite evidence for inheritance of this trait in any domestic
species. Deviation of the penis occurs with asymmetrical devel-
opment of the cavernosum of the penis in the horse and
donkey, malfunction of the apical ligament in the bull and
ram, and congenital curvature of the os penis in the dog.
Erectile dysfunction, failure of erection of the penis, is rare.
Erection requires central nervous system control, local nervous
control with contraction of the ischiocavernosus muscles, and
vasoconstriction of veins. This allows arterial input to the
erectile tissue of the cavernosum and spongiosum but occludes
venous drainage. Vascular defects of the penis that cause
failure of erection are studied in the bull and boar, but their
precise diagnosis antemortem or postmortem requires injec-
tion of contrast material and radiography, or injection of
plastic into vessels to form casts. Vascular shunts from the
cavernosum to the spongiosum of the penis or to peripenile
vasculature prevent effective erection. Congenital shunts from
the cavernosum to neighboring veins in boars can be inherited.
Immunohistochemical studies of impotence in the boar pro-
vided evidence that defective innervation contributes, with
depletion of vasointestinal polypeptide (VIP) reactivity in
penile nerves.
Penetrating injuries and traumatic fistulas of the erectile
tissue and the urethra or external tissues leads to hemorrhage
that can be life threatening. This, in the bull, includes forced
deviation and rupture of the penis with subsequent hematoma
formation. Penile hematoma resulting from forced deviation
of the penis occurs in bulls and rams at the distal bend of the
sigmoid flexure, but sometimes proximal to it (Fig. 5-59). In
stallions, rupture of the cavernosum outside an intact tunic
(tunica albuginea) of the penis is more frequent; trauma is the
likely cause. Other vascular lesions include varicosities of
 505.e1

Further reading
Ahmad N, et al. Seminal vesiculitis and epididymitis in an Anglo-Nubian
buck. Vet Rec 1993;133:322-323.
Girard C, Despots J. Mineralised paraprostatic cyst in a dog. Can Vet J
1995;36:573-574.
Hayden DW, et al. Prostatic leiomyosarcoma in a dog. J Vet Diagn
Invest 1999;11:283-286.
Kirkland PD, et al. Replication of bovine viral diarrhoea virus in the
bovine reproductive tract and excretion of virus in semen during
acute and chronic infections. Vet Rec 1991;128:587-590.
LeRoy BE, et al. Canine prostate carcinomas express markers of uro-
thelial and prostatic differentiation. Vet Pathol 2004;41:131-140.
Randles JL. Clinical, pathological and histopathological findings in
lambs implanted with a growth promoting product containing pro-
gesterone and oestradiol. J S Afr Vet Assoc 1990;61:126-127.
Rohleder JJ, Jones JC. Emphysematous prostatitis and carcinoma in a
dog. J Am Anim Hosp Assoc 2002;38:478-481.
Schoofs S, et al. Streptococcus pneumoniae in a prostatic abscess in a
dog. Vlaams Diergeneeskundig Tijdschrift 1997;66:229-230.
506 CHAPTER 5  •  Male Genital System
Figure 5-59  Forced deviation of the penis resulted in rupture of
penile tunic and hematoma proximal to the sigmoid flexure in
a bull.
Figure 5-60  Preputial eversion and prolapse in a bull. The
prepuce cannot be retracted and is ulcerated and hemorrhagic.
preputial veins in stallions that may lead to thrombosis, edema,
and inflammation. In dogs, trauma to the cavernosum or root
of the penis may occur during attempted copulation and
results in hindquarter pain and/or lameness, dysuria, and peri-
neal edema but no obvious hematomas. Extensive thrombosis
of the corpus cavernosum penis occurs in stallions, dogs, and
cats with priapism, and it was unclear whether the thrombi
were the cause or result of pain and persistent erection. In
separate stallions, concurrent nematodiasis and metastatic
melanoma were considered the primary cause.
Eversion of the preputial mucosa as a temporary event is
common in bulls. Bos indicus bulls develop prolonged eversion
because many have inadequate muscles in the prepuce.
Trauma to the everted epithelium and desiccation lead to
edema and inflammation (Fig. 5-60).
A preputial diverticulum is anatomically normal in the boar
but abnormal in other species, such as the bull and water
buffalo. Deflection of the penis into the diverticulum by boars
results in accumulation of debris, urine, and semen that pre-
dispose to local infection and inflammation.
Tearing of preputial mucosa, typically at the ventral prepu-
tial fornix, is a common injury that occurs in bulls used for
artificial insemination. The precise cause is unknown.
Priapism is prolonged or persistent erection of the penis.
More specific definitions include an erection lasting longer
Penis and Prepuce
than 4 hours without sexual stimulation, or continuous,
usually nonsexual erection of the penis, especially caused by
disease. Prolonged erect penises become traumatized, dry, or
undergo necrosis. Little is reported about the pathogenesis in
dogs. In humans, there is a nonischemic form caused by
increased arterial flow, and an ischemic form with reduced
venous outflow. Dilation and thrombosis of the cavernous
sinuses of the penis are found histologically, but it is unknown
whether this is a cause or result of priapism. Thrombi are
often laminated, suggesting progressive enlargement. A sec-
ondary paraphimosis occurs and there will be necrosis of the
mucosa, bacterial infection of the eroded surface, and even
total penile necrosis.
Paraphimosis, or inability to retract the penis, is a particular
problem in the stallion. Trauma is the most common cause,
but inflammation from other causes, neoplasia, or primary
penile paralysis may be involved. Penile paralysis occurs in
severely debilitated stallions, after administration of phenothi-
azine tranquilizers, or from local neurologic disorders.
In the dog, fracture of the os penis leads to obstruction of
the urethra. Mineralization and ossification of the penis caudal
to the os penis is a frequent (usually radiographic) finding and
its prevalence increases with age. Urethral obstruction with
hydronephrosis and bladder rupture resulting from aberrant
localization of Ancylostoma caninum in the caudal os penis is
described.
Inflammation of the penis and prepuce
(phaloposthitis)
Inflammation of the head of the penis (balanitis) is frequently
accompanied by inflammation of the prepuce (posthitis).
Many organisms reside in the preputial cavity, and there is
innate and acquired local immunity. Viruses such as bovine
parainfluenza virus 3 in bulls and herpesviruses in many
species, nonpathogenic and potentially pathogenic bacteria
such as Corynebacterium renale and Histophilus somni, fungi,
mycoplasmas and ureaplasmas, chlamydias, and protozoa are
isolated from preputial cavities that are normal or have lesions.
Ascribing pathogenicity to organisms is therefore difficult, and
reports on whether these organisms cause lesions in the
prepuce are conflicting and often do not withstand scientific
scrutiny.
Lymphocytes, plasma cells, and even lymphoid follicles are
commonly found in normal preputial mucosa. They indicate
an acquired immune response but the initiating antigens are
unknown. Immunoglobulins are present in preputial washings.
They are derived from plasma cells of the prepuce or the
accessory genital glands. In the bull, the number of plasma
cells tends to increase with age. Small (T) lymphocytes, fre-
quently seen in preputial and penile epithelium, participate
in cell-mediated immune reactions. The epithelium of the
penis and prepuce is of the squamous or transitional type, thus
active transport of secretory IgA is unlikely. Innate immunity,
with a limited exposure to the external environment, epithe-
lial barrier, and antimicrobial molecules, is very important.
Bovine herpesvirus 1 causes phaloposthitis (commonly
called balanoposthitis) in the bull. This virus causes both respi-
ratory disease (infectious bovine rhinotracheitis, IBR) and
genital disease (infectious pustular vulvovaginitis, IPV). The
clinical disease in the bull results in a thin purulent preputial
discharge. Simultaneous occurrence of the respiratory and
genital forms of the disease is rare. Within 2-3 days of expo-
sure, there are numerous up to 3-mm gray-white opaque foci
 Penis and Prepuce
of necrosis on the penis. These may form confluent and flat
efflorescences. In severe cases, edema of the penis and prepuce
may occur. The foci of necrotic mucosa exist for 1-2 days only,
then the surface sloughs and sharp erosions remain, especially
in the area of the head of the penis. Many erosions are sur-
rounded by a red zone of hyperemia. In uncomplicated cases,
healing is complete in 2 weeks. As with any infection of the
prepuce, lymphoid follicles develop and are pale to dark red
1-2 mm nodules that raise the mucosal surface.
The microscopic lesions are foci of dead cells within the
epithelium and spongiosis. Intranuclear inclusion bodies may
appear in epithelial cells. Dead cells slough and shallow ulcers
form. Neutrophils migrate into the affected epithelium and
lymphocytes appear in the submucosa. As with other herpes-
viral infections, latency occurs and viral production is reacti-
vated naturally or following treatment with corticosteroids.
Although orchitis is reported in bulls, it is exceptional.
The pathogenesis of equine coital exanthema, caused by
equid herpesvirus 3, are comparable to BoHV-1 in cattle,
although the penile and preputial lesions and subsequent ero-
sions are larger, being up to 15 mm in diameter. Lesions in the
stallion tend to involve the body of the penis more frequently
than the head. They first appear 2-5 days post exposure as
vesicles, but rapidly progress to circumscribed yellow pustules
with raised borders and depressed centers. Resolution usually
occurs within a few weeks, leaving depigmented spots.
Herpesviral infection of male goats (CapHV-1) causes similar
lesions that can progress to extensive suppurative and necro-
tizing phaloposthitis involving the head of the penis, fornix,
and entire urethral process.
In dogs, the genital lesions of canid herpesvirus 1 infection
consist of hyperemia, petechial hemorrhages, and the develop-
ment of lymphoid nodules, especially over the base of the
penis and the preputial reflection. There is a serous discharge
from the preputial orifice. Lesions appear about 3 days after
experimental infection, but are self-limiting, and regress 4-5
days subsequently, with no apparent sequelae. Simultaneous
conjunctivitis may occur. Recurrence of lesions, an important
feature of the disease in bitches, seems to be less common in
the male. Pustule formation and ulceration do not appear to
be a feature of genital herpesvirus infection in the male dog
even though virus can be isolated from the penis of infected
dogs following immunosuppression with prednisolone.
A mild balanoposthitis, not associated with herpesvirus
infection and presumed to be bacterial in origin, is common
in dogs. Depending on duration, there is intense hyperemia of
the epithelium, erosion, and mucopurulent exudate. Lym-
phoid follicles become enlarged and prominent. Hemolytic
strains of Escherichia coli are most frequently isolated from
such cases, other common isolates being Proteus vulgaris and
hemolytic streptococci.
Multiple pale dome-shaped papules up to ∼3 mm in diam-
eter on hairless parts of the equine prepuce, and on the
muzzle, may result from infection with the molluscum con-
tagiosum virus (Molluscipoxvirus) (for details see Vol. 1,
Integumentary system). Histologically, discrete epithelial
hypertrophy and hyperplasia with characteristic “molluscum
bodies” are present.
Outbreaks of ulcerative posthitis in bulls occur occasion-
ally, but these are less severe than in sheep (see later). The
cause and pathogenesis of this condition is unknown. Coryne-
bacterium renale, an inhabitant of the prepuce of apparently
healthy bulls, is frequently isolated from bulls with ulcerative
507
posthitis, and as animals on a high plane of nutrition are pre-
disposed, a parallel of this condition with ovine posthitis is
suggested. However, it is not clear why steers are infrequently
affected. Mild to severe erosions and ulceration with edema
are confined to the preputial orifice and cranioventral area of
the prepuce. Lesions begin as small raised areas of necrosis
that leave shallow erosions. The ulcers are irregular in shape,
may be several centimeters in diameter, are sharply defined
and frequently bleed. The histologic appearance of lesions is
nonspecific, with superficial necrosis, reactive epithelial hyper-
plasia, and underlying granulation tissue. Causal organisms
cannot be demonstrated histologically in the lesions that
precede ulceration. In more severe forms there is increasing
edema, abscessation, and even myiasis. Deformity of the pre-
putial orifice and phimosis may occur following healing of
ulcers.
Traumatic injury with subsequent infection by such organ-
isms as Trueperella pyogenes, Escherichia coli, streptococci, and
staphylococci is common in bulls. Less common lesions
include balanoposthitis from infection with the larvae of
Strongyloides papillosus. Tuberculous balanoposthitis, with
characteristic granulomas involving the penis or prepuce, is
seen occasionally in bulls from infected herds, sometimes as
the only lesion. Genital transmission is possible. The presence
of Campylobacter fetus subsp. venerealis in the preputial sac
does not produce gross or histologic changes. Likewise, specific
lesions do not accompany preputial infection in bulls by Tri­
trichomonas foetus. Microscopic examination of infected penile
and preputial epithelium may reveal cells and debris in crypts,
and a typical lymphocytic submucosal reaction. Rarely can
trichomonads be demonstrated in histologic sections. Recogni-
tion of the carrier state in bulls in the absence of lesions in
both campylobacteriosis and trichomoniasis emphasizes the
need for diagnosis by culture or molecular techniques.
Preputial diverticulitis occurs in swine, and the character-
istic plaques and ulcers occur in the preputial diverticula of
25-40% or more of castrated and entire male pigs. The lesions
begin as foci of hyperkeratosis and progress to distinct white-
gray plaques 2-4 mm in diameter with obvious para- and
dyskeratosis. Yellow-brown ulcers up to ~10 mm in diameter
with raised borders form (Fig. 5-61) following central necrosis,
sloughing of epithelium, and infiltrating neutrophils. Such
lesions may become confluent, and hemorrhage from them is
common. Calculi may be present in the diverticulum. The
precise cause of preputial diverticulitis in pigs is unclear, but
Figure 5-61  Ulcers of the preputial diverticulum of a boar.
508 CHAPTER 5  •  Male Genital System
accumulation and decomposition of urine is important. Acti-
nobaculum suis, a cause of pyelonephritis and cystitis in sows,
may be isolated from the prepuce of boars with diverticulitis
and healthy boars alike; the likelihood of venereal transfer
exists. Other bacteria frequently present in the diverticulum
include Proteus spp. and staphylococci. There is no correlation
between types of bacteria present and boar performance.
Older pigs are more likely to develop ulcers. An age-related
change in the bacterial flora of the diverticulum occurs, Acti-
nobaculum suis being generally more common in pigs >4
months of age and in adult boars than in younger animals.
Spirochetes also colonize the preputial diverticulum and may
contribute to inflammation.
Marked and apparently selective infestation of muscles of
the penile urethra in pigs may occur several months after
infection with Sarcocystis miescheriana from dogs. Microscopi-
cally, there is degeneration of muscle fibers; eosinophils with
fewer lymphocytes and macrophages are present.
Balanoposthitis is an uncommon lesion in the stallion but
occurs in dourine, caused by Trypanosoma equiperdum (see
also Vol. 3, Female genital system). Primary infection in
dourine occurs in the genitalia, following transmission by
coitus. There is marked edema of the prepuce and adjacent
areas, and phimosis may result. In many cases, yellow-red
nodules up to ∼8 mm in diameter may subsequently appear
on the penis especially near the urethral orifice. These later
transform to shallow ulcers, which after healing may leave
distinct nonpigmented foci on the skin of the penis, prepuce,
scrotum, and perineum. In cutaneous habronemiasis (for
detailed discussion, see Vol. 1, Integumentary system) the
lesions may affect the penis, especially around the urethral
meatus, and or the preputial mucosa at about the point of its
contact with the end of the retracted penis. The lesions are
elevated, ulcerated, and bleed; they consist of exuberant
fibrous tissue enclosing few or many larvae of Habronema spp.
and may be sufficiently large to cause paraphimosis. There are
large numbers of eosinophils that form small eosinophilic
“abscesses” around immobilized and dead larvae; they corre-
late to small yellow foci on the cut surface. The lesion devel-
ops during the summer months. These larvae often infect
squamous cell carcinomas, so lesions should be examined for
neoplasia. Nodules in the prepuce of the stallion are also
caused by adults, larvae, and ova of Halicephalobus spp., or by
mycotic infection, particularly pythiosis. Geldings develop a
nonspecific posthitis with accumulation of smegma and detri-
tus, presumably because of reduced penile extrusion.
In sheep, ulcerative posthitis of wethers, and occasionally
of rams, is common and important. Vulvitis may occur in ewes
in affected flocks. Wethers are particularly susceptible, sug-
gesting incomplete development of the prepuce and penis,
and/or the tendency of wethers to urinate within their sheath.
Development of the primary lesion depends on the occur-
rence of a transmissible, urea-hydrolyzing bacterium such as
Corynebacterium renale, and on the excretion of urine rich in
urea. In one outbreak, Rhodococcus equi and Corynebacterium
hofmanni, both of which produce urease, were isolated from
lesions. Other factors in urine, possibly hormonal in origin,
may also be involved. High protein and especially leguminous
diets predispose to the disease and the incidence is lowest
during the summer. It is presumed that wethers are infected
by the transmission of material on contaminated bedding,
herbage, or by flies. Venereal transmission from rams to ewes
also occurs.
Penis and Prepuce
The lesion in wethers begins as a small yellow area of
epithelial necrosis at the orifice of the prepuce, often dorsally.
This ulcerates and there is slow expansion of the lesion and
granulation that results in stenosis and occlusion of the pre-
putial orifice. Secondary lesions occur when the prepuce
becomes swollen from the accumulation of urine or pus.
Extensive internal ulceration of the prepuce develops, the
urethral process is destroyed, and the head of the penis ulcer-
ates. The common name applied is pizzle rot.
A severe ulcerative balanitis, distinct from the aforemen-
tioned condition, occurs in border Leicester rams and in
Dorper sheep. Ewes mated to them develop vulvovaginitis.
Outbreaks occur in a flock. Deep ulcers up to several centi-
meters in diameter occur on the ventral surface of the penis.
Excessive granulation tissue and variable hemorrhage follows.
Necrotic and purulent material covers the head of the penis
and urethral process. Adhesions of the penis and prepuce
result. Ewes in contact with affected rams have shallow ulcers
on the ventral commissure of the labia and posterior vagina.
The causative agent(s) is not known, and it is not clear why
these rams are predisposed.
Traumatic injury by the cocklebur (Xanthium strumarium)
may cause outbreaks of severe “acroposthitis” in rams with
subsequent suppurative vaginitis in ewes mated to them.
Proliferative lesions of the penis and prepuce occur in dogs
with leishmaniasis, and misdiagnosed as transmissible vene-
real tumor. The lesions, which develop over a period of several
months, are multiple ulcerated nodules up to ∼1 cm in diam-
eter located on the penile tip and preputial mucosa, as well
as other organs. Histologically, macrophages containing amas-
tigotes of Leishmania infantum dominate the lesions.
Miscellaneous conditions causing variable inflammation of
the penis and prepuce include intrapreputial foreign bodies
such as sand, and “hair ring” in the bull, ram, buck, and cat, in
which hairs encircle and may constrict the penis.
Neoplasms of the penis and prepuce
The important primary tumors are fibropapilloma in the bull,
squamous papilloma and squamous cell carcinoma in the
horse, and papillomas and transmissible venereal tumor of
dogs. Additional details on bovine fibropapillomas and canine
transmissible venereal tumor are in Vol. 3, Female genital
system.
Fibropapillomas in bulls caused by bovine papillomavirus
1 occur on the head of the penis. They are most common in
young bulls, 1-2 years of age, and are noticed after mating,
when hemorrhage occurs. They are usually multiple and up
to several centimeters in diameter (Fig. 5-62). Tumors are pink
or gray-white on section and are composed mainly of fibrous
tissue with an epithelial covering (Fig. 5-63). Histologically,
there are differences between tumors in young and old bulls,
those in young bulls being more cellular with frequent mitoses.
Although benign, large fibropapillomas in bulls interfere
with free movement of the penis through the preputial orifice
and prevent retraction of the head of the penis. In such cases,
preputial hairs may surround the prolapsed penis and cause
strangulation. Alternatively, continued growth of the mass
within the preputial cavity may prevent penile protrusion.
The urethra can become obstructed and rupture, causing
extensive cellulitis.
A transmissible genital papilloma occurs in swine and the
virus is likely a Sus scrofa papillomavirus. Both the natural and
experimental papillomas regress with time. The tumors are
 Penis and Prepuce
Figure 5-62  Transmissible fibropapilloma in a bull. The exo-
phytic growth may be mistaken for squamous cell carcinoma.
Figure 5-63  Histologic details of transmissible fibropapilloma in
a bull. The stroma is fibrous tissue and the epithelium has long
projections that extend into the stroma.
small, round, and project 3 mm from the mucosal surface of
the penis or within the preputial diverticulum. Histologically,
they have marked thickening of the epithelium. There is little
proliferation of the underlying connective tissue. A thin layer
of keratinizing cells covers the hyperplastic epithelium.
Squamous papilloma in all species is a benign, keratinizing
epithelial papilliform tumor with little fibrous stroma; it is
usually small. Squamous papilloma is most common in the
horse and dog. They can progress to squamous cell carcinoma.
Although not all have identifiable virus, many probably are
the result of papillomavirus infection.
Squamous cell carcinoma (SCC) of the penis and prepuce
is described in the horse most commonly, and also in the dog
and bull. It is possible the bovine cases were misdiagnosed
fibropapillomas. In the horse, SCCs occur with about equal
frequency in stallions and geldings and the average age is >12
years. Because SCC in the equine penis and prepuce occur at
sites of prior removal of squamous papilloma, any papilloma
in these locations should be considered as premalignant. Equus
caballus papillomavirus 2 is implicated in the formation of
SCC. Over-expression of p53 is also involved. Tumors arise
mostly from the head of the penis, and the desmoplastic
509
Figure 5-64  Squamous cell carcinoma of the penis of a horse.
Squamous cell carcinomas cause enlargement of the penis; some
form an exophytic mass (seen here), others form a large tough
penis from the desmoplastic response to the neoplastic cells.
reaction is such that many cause the head of the penis to be
larger, and firm and tough. Superficial ulceration and necrosis
of large tumors are common (Fig. 5-64). Histologically, the
penile tumor is well differentiated and keratinization is usually
present. Eosinophils are common around the tumor, and foci
of necrosis and mineralization are frequent. The tumor invades
the corpus cavernosum and metastasizes, especially to the
inguinal lymph nodes and less frequently to other organs such
as lung or liver.
In the dog, SCC of the penis and prepuce is thought to be
papillomavirus related. Its appearance is similar to equine
SCC but may be nonkeratinizing. Approximately 25% of
reported cases had metastasized, chiefly to the inguinal lymph
nodes.
Canine transmissible venereal tumour (CTVT) in the
male dog arises on the penis or within the prepuce. They may
be single or multiple, sessile or pedunculated, nodular or pap-
illary, soft to firm consistency, and up to ∼15 cm in diameter
(Fig. 5-65). Histologically, they are solid sheets of uniform
round, ovoid, or polyhedral cells with large round vesicular
nuclei. The vacuolation of the cytoplasm at the cell mem-
brane, a characteristic finding cytologically, is sometimes seen
histologically. The mitotic index is high. Metastasis occurs in
up to 5% of cases and may involve the superficial inguinal
lymph nodes, skin, and multiple other organs. Most cutaneous
metastases are probably from trauma and mechanical implan-
tation. Spontaneous regression of some tumors occurs, and
most are sensitive to chemotherapy with vincristine.
CTVT is the first naturally occurring neoplasm that is
spread by the transferring of cells from an affected dog to
another, thus is an allograft. It is venereally transmitted. The
cells of CTVT have a chromosomal number of 57, 58, or 59.
The dog has 78. Chromosomal and molecular techniques
show that neoplasms from different continents and collected
decades apart are clonal, and, although there are 2 subtypes,
510 CHAPTER 5  •  Male Genital System
Figure 5-65  Canine transmissible venereal tumor on the penis of
a dog.
they have a common origin. The DNA of the CTVT has
closely related DNA of wolves and East Asian dog breeds.
The cells of a CTVT avoid detection by immune cells. They
downregulate MHC I molecules and there is no MHC II activ-
ity, because they secrete inhibitory cytokines (TGFβ1 and IL
6). In the initial proliferative phase of CTVT, they express
little MHC class 1 or 2. After about 12 weeks in an experi-
mental model, MHC expression increased dramatically and
lymphocytes appear; at the same time, the masses stopped
growing. It appeared that the lymphocytes stimulated MHC
expression and are responsible for regression of the tumors.
The phenotype of the cells was the subject of considerable
debate. Immunohistochemical staining characteristics suggest
they are of histiocytic origin, as they are positive when stained
with vimentin, often positive with α1-antitrypsin and lyso-
zyme, and negative for CD3, immunoglobulins, and cytokera-
tin (for more detail, see Vol. 3, Female genital system).
Less common tumors of the penis or prepuce in dogs include
the epithelial, mesenchymal, round cell and other tumors
(such as melanoma) found in other parts of the body. Of the
epithelial tumors, apocrine sweat gland adenocarcinoma is
reported. Mesenchymal tumors include lipoma, hemangioma,
hemangiosarcoma, soft tissue sarcoma, mesenchymoma, and
osteosarcoma, chondrosarcoma, and ossifying fibroma of the
os penis of the dog. Sarcoids are found in the penis and
prepuce of the horse. Round cell tumors include lymphoma,
Penis and Prepuce
mast cell tumor, and plasmacytoma. Malignant melanoma is
reported in several species.
Further reading
Axner E, et al. Reproductive disorders in 10 domestic male cats. J Small
Anim Pract 1996;37:394-401.
Bleier T, et al. Canine osteosarcoma of the penile bone. J Vet Med A
Physiol Pathol Clin Med 2003;50:397-398.
Johnston SD, et al. Ovarian and testicular function in the domestic cat:
clinical management of spontaneous reproductive disease. Anim
Reprod Sci 1996;42:261-274.
Kidanemariam A, et al. Ulcerative balanitis and vulvitis of Dorper sheep
in South Africa: a study on its aetiology and clinical features. J S
Afr Vet Assoc 2005;76:197-203.
Knight CG, et al. Equine penile squamous cell carcinomas are associ-
ated with the presence of equinepapillomavirus type 2 DNA
sequences. Vet Pathol 2011;48:1190-1194.
Mukaratirwa S, Gruys E. Canine transmissible venereal tumour: cyto-
genetic origin, immunophenotype, and immunobiology. A review.
Vet Q 2003;25:101-111.
Murgia C, et al. Clonal origin and evolution of a transmissible cancer.
Cell 2006;126:477-487.
Musser JM, et al. Penile hematoma in bulls: 60 cases (1979-1990). J
Am Vet Med Assoc 1992;201:1416-1418.
Newkirk KM, et al. Detection of papillomavirus in equine periocular
and penile squamous cell carcinoma. J Vet Diagn Invest
2014;26:131-135.
Trichard CJ, et al. The identification of Mycoplasma mycoides mycoides
LC as the aetiological agent of balanoposthitis and vulvovaginitis
in sheep in South Africa. Onderstepoort J Vet Res 1993;60:29-37.
van der Harst MR, et al. Priapism in the stallion. Tijdschr Diergeneeskd
2002;127:746-751.
Vogel FS, et al. Intrapreputial infection of young bulls with bovine
herpesvirus type 1.2 (BHV-1.2): acute balanoposthitis, latent infec-
tion and detection of viral DNA in regional neural and non-neural
tissues 50 days after experimental reactivation. Vet Microbiol
2004;98:185-196.
For more information, please visit the companion site:
PathologyofDomesticAnimals.com
 510.e1

Further reading
Bolton LA, et al. Aberrant migration of Ancylostoma caninum to the
os penis of a dog. J S Afr Vet Assoc 1996;67:161-162.
Chafin MK, et al. Multicentric cutaneous pythiosis in a foal. J Am Vet
Med Assoc 1992;201:310-312.
Dalin AM, Rodriguez-Martinez H. Vasointestinal polypeptide (VIP)—
immunoreactive nerves in the boar penis. J Vet Med 1992;39:
792-797.
Dunn DG, et al. Nodular granulomatous posthitis caused by Halicepha-
lobus (syn. Micronema) sp. in a horse. Vet Pathol 1993;30:
207-208.
Felleisen RSJ, et al. Detection of Tritrichomonas foetus by PCR and DNA
enzyme immunoassay based on rRNA gene unit sequences. J Clin
Microbiol 1998;36:513-519.
Font A, et al. Canine mucosal leishmaniasis. J Am Anim Hosp Assoc
1996;32:131-137.
Ghanem M, et al. Atresia ani with diphallus and separate scrota in a
calf: a case report. Theriogenol 2004;61:1205-1213.
Gilbert RO, et al. Communication between the corpus cavernosum
penis and the corpus spongiosum penis in a bull diagnosed by
modified contrast cavernosography: a case report. Theriogenol
1990;33:577-581.
Lobetti RG, et al. Suspected corpus cavernosum trauma in three dogs.
Vet Rec 1995;137:492.
MacDonald RK. Urethral prolapse in a Yorkshire terrier. Compend
Contin Educ Pract Vet 1989;11:682-683.
Mair TS, et al. Surgical treatment of 45 horses affected by squamous
cell carcinoma of the penis and prepuce. Equine Vet J 2000;32:
406-410.
Mirkovic TK, et al. Urinary obstruction secondary to an ossifying
fibroma of the os penis in a dog. J Am Anim Hosp Assoc
2004;40:152-156.
Nasir L, Saveria Campo M. Bovine papillomaviruses: their role in the
aetiology of cutaneous tumours of bovids and equids. Vet Dermatol
2008;16:243-254.
Payan-Carreira R et al. Priapism associated with lumbar stenosis in a
dog. Reprod Dom Anim 2013;48:e58-e64.
Pritchard G, et al. Infectious pustular vulvovaginitis/infectious pustular
balanoposthitis in cattle. Vet Rec 1997;140:587.
I NDEX
Entries followed by “f,” “b,” and “t” refer to figures and tables, respectively. The volume number of the entry is indicated in italics at the beginning
of the page number.
A Accessory cortical nodules, 3:343
Abdominal distention, 2:44
Abdominal fat necrosis, 2:76-77, 2:249,
2:249f
Abdominal trauma, 2:246-247, 2:246f
Abdominal wall, ventral hernia, 2:80
Abdominally retained testis, 3:470f
Aberdeen Angus cattle
bovine familial convulsions and ataxia,
1:319
brachygnathia inferior, 2:3
hip dysplasia, 1:135-136
Abiotrophy, 1:265
cerebellar, 1:276, 1:276f, 1:318-326
Abomasal fistulae, 2:49
Abomasal helminthosis, 2:205-211, 2:205f
Abomasitis, 2:52
associated with viral infection, 2:54
chemical, 2:52
mycotic, 2:54, 2:54f
Abomasum. See Stomach and abomasum
Abortion, 3:395, 3:398-440. See also Female
genital system; Gestation
bacterial causes of, 3:402-417
diagnosing infectious causes of,
3:399-402
epizootic bovine, 3:419-420
infectious causes of, 3:399b
in mares, 3:417-418
mycotic, 3:418-419, 3:418f-419f
protozoal causes of, 3:420-424
Abscess(es), 1:636-637
Brodie’s, 1:98, 1:98f
cerebral, 1:358-362, 1:358f, 1:360f
epidural/subdural, 1:353-354, 1:354f
jowl, 3:208-209, 3:208f-209f
liver, 2:315-316, 2:315f
lung, 2:520
lymph node, 3:203f, 3:203.e1f
meningitis, 1:359f
ovarian, 3:371
pancreatic, 2:361
pulmonary hemorrhage and, 2:490
splenic, 3:183-184, 3:184f
subdural/intradural, 1:354f
uterine, 3:390
Abyssinian cats
atopic dermatitis, 1:593
feline ceruminous cystomatosis, 1:507
retinal degeneration, 1:469-470
Acacia cambadgei, 3:34
Acacia georginae, 3:34
Acanthamoeba, 2:574
Acanthocephalan infections, 2:227
Acantholysis, 1:518, 1:518f
Acantholytic cells, 1:518
Acantholytic dermatoses
cattle, 1:537-538
dogs, 1:537-538, 1:537.e1f
Acanthomatous ameloblastomas, 2:22-23,
2:23f-24f
Acanthosis, 1:518
Accessory adrenal cortical tissue, 3:338,
3:338f
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Accessory lung, 2:484-485
Accessory pancreatic tissue, 2:356
Accessory spleens, 3:162-163, 3:163f
Accessory thyroid tissue, 3:310
Accreditation, laboratory, 1:14
Acetaminophen, 2:327
Acetylcholine, 2:45
Acetylcholinesterase, 1:170
Achalasia, esophageal, 2:33
Achlorhydria, 2:47
Achondroplasia, 1:37t
Acid-base imbalance, 2:384
Acidophil adenomas, 3:286, 3:286f
Acidosis, carbohydrate overload, 2:40-43
Acid treatment, of hemoglobin, 2:55-56
Acid urine, antibacterial effect of, 2:459
Acinar cells, 2:355
necrosis, 2:356
Acinic cell carcinomas, 2:30
nasal, 2:478-479
Acne, 1:549
Acorn poisoning, acute, 2:85
Acoustic trauma, 1:493
Acquired cysts, 2:396
Acquired deafness, 1:493
Acquired diaphragmatic hernia, 2:246-247,
2:246f
Acquired Fanconi syndrome, 2:428
Acquired hyperpigmentation, 1:554
Acquired hypopigmentation, 1:557,
1:557f
Acquired melanosis, 2:270
Acquired platelet disorders, 3:260
Acquired porphyria, 1:59-60
Acquired portosystemic shunts
liver, 2:290, 2:298-299, 2:299f
vascular, 2:266f
Acquired thrombocytopenia, 3:258
Acral lick dermatitis, 1:561-562, 1:561f-562f
Acrocyanosis, 3:65
Acrodermatitis, lethal, 1:533, 1:533.e1f
Acromegaly, 3:286, 3:286f
Acromelanism, 1:555
Actinic diseases of skin, 1:575-580
Actinobacillosis, 2:18-19, 2:18f
Actinobacillus equuli, 2:113-114, 2:433,
2:433f, 2:452, 2:543, 3:417-418,
2:433.e1f
endocarditis and, 3:30-31
liver and, 2:314-315
myocarditis and, 3:42
Actinobacillus pleuropneumoniae (APP),
2:531-532, 2:531f, 2:543, 3:69
Actinobacillus seminis, 3:490
Actinobacillus suis, 2:543
Actinobaculum, 2:459
Actinobaculum suis, 2:459
Actinomyces spp.
cutaneous, 1:637-639, 1:638f
inflammation in buccal cavity due to,
2:13-14
tonsillitis, 2:20
tooth decay and, 2:9
Actinomyces weissii, 2:19
Activated clotting time (ACT), 3:263
Activated partial thromboplastin time
(APTT)
prolonged, 3:263
Active hyperemia, 3:169
Acute arthritis in cats, 1:154
Acute bacterial endocarditis, 3:32
Acute bovine liver disease, 2:343-344,
2:343.e1f
Acute eosinophilic (or acidophilic)
degeneration, 1:253-254, 1:253f
Acute hepatitis, 2:301
Acute intermittent porphyria, 1:59
Acute interstitial lung disease in feedlot
cattle, 2:513f, 2:513.e1
Acute kidney injury (AKI), 2:398
Acute local peritonitis, 2:39
Acute lymphadenitis, 3:202-203
Acute lymphocytic-plasmacytic
chorioretinitis, 1:474
Acute lymphoid leukemia (ALL), 3:132-133,
3:133f
Acute myeloid leukemia (AML), 3:129-134,
3:130f-132f
Acute osteomyelitis, 1:95, 1:95f
Acute pancreatic necrosis, 2:357-360,
2:359f-360f
Acute pancreatitis, 2:360
Acute polyradiculoneuritis, 1:394
Acute renal failure (ARF), 2:383-384, 2:398,
2:418
Acute rupture of chordae tendineae,
3:27
Acute selenium toxicosis, 3:36
Acute serous uveitis, 1:448-449
Acute toxic hepatic injury, 2:327, 2:328f
Acute tubular injury (ATI), 2:383, 2:386,
2:398, 2:421-422
epithelial injury, 2:422f
Acute tubular necrosis (ATN), 2:382, 2:398,
2:422
Addison’s disease, 1:225
Adenocarcinomas. See Carcinomas/
adenocarcinomas
Adenohypophysis, 3:276
bacterial septicemia, 3:289
functional cytology, 3:276-277
hypothalamic control of, 3:277,
3:278f
inflammation, 3:289-290
Adenoid cystic carcinomas, 2:478-479
Adenomas, 2:462. See also Carcinomas/
adenocarcinomas
acidophil, 3:286, 3:286f
adrenal cortex, 3:344-345, 3:345f
aortic body, 3:354-355, 3:354f
carotid body, 3:355-356
corticotroph (ACTH-secreting), 3:281-282,
3:281f, 3:283f-284f
endocrine gland, 3:271
exocrine pancreatic, 2:366
hepatocellular, 2:346, 2:346f
lactotroph, 3:286-287
511
512 Index

Adenomas (Continued) Afibrinogenemia, 3:265 Alimentary system (Continued)

mammary, 3:460, 3:461f Aflatoxins, 2:333-334, 2:334f, 2:333.e1f diagnosis of gastrointestinal disease,
papillary African horse sickness (AHS), 3:72-74, 3:74f, 2:111-117
ears, 1:500 3:72.e2f diarrhea
pulmonary, 2:495 African swine fever (ASF), 3:74-76, bovine coronavirus, 2:112
thyroid, 3:327 3:75f-76f, 3:181-182, 3:181f-182f, bovine herpesvirus 1, 2:112
parathyroid glands, 3:302 3:75.e1f, 3:181.e1f bovine torovirus, 2:112
pars distalis, 3:287-288 Afrikander cattle, hypothyroidism in, 1:588 in calves, 2:112-113
pars intermedia, 3:282-285, 3:283f-284f Agammaglobulinemia, 3:139 Chlamydophila infection, 2:113
somatotroph, 3:285-286, 3:285f-286f Agenesis, 2:392 Cryptosporidium parvum, 2:112
testicular, 3:496 adrenal gland, 3:338 enterotoxigenic E. coli, 2:112
thyroid, 3:322, 3:323f, 3:326-327, cerebellar, 1:275-276, 1:275f rotavirus, 2:112
3:327f-328f corpus callosum, 1:269, 1:269f salmonellosis, 2:112
C-cell, 3:333, 3:334f ovary, 3:366 enteritis
thyrotroph, 3:286 pancreas, 2:355 cats, 2:117
Adenomatous hyperplasia Aggrecan (ACAN) gene, 1:38 dogs, 2:116-117
focal papillary/papillotubular proliferation, Aggregation, platelet, 3:257-258 horses, 2:116
2:104 Aging changes esophagus, 2:30-35
Lawsonia intracellularis, 2:105 canine nasodigital hyperkeratosis, forestomachs, 2:35-44
rectal papillary adenoma, 2:104 1:549-550 gastroenteritis
Adenomatous polyposis coli (APC), choroid plexus, 1:304, 1:304f cattle, 2:114-115
2:102-103 gross examination of, 1:7 sheep, 2:115
Adenomyosis, 3:385, 3:385f, 3:497 hearing, 1:493 swine, 2:115-116
Adenosine triphosphate (ATP) in rigor meninges, 1:304 infectious/parasitic diseases, 2:117-244
mortis, 1:186 “old dog” encephalitis and, 1:384-385 bovine viral diarrhea virus (BVDV),
Adenosquamous (mucoepidermoid) ovaries, 3:371, 3:371f 2:122-128, 2:125f
carcinomas, 2:478-479 pancreas, 2:358 fetal infections, 2:122
pulmonary, 2:497, 2:498f spermatogenesis, 3:467 mucosal disease, 2:123
Adenovirus, 2:116, 2:432 tendon, 1:247 PI calves, 2:122
cattle, 2:143, 2:143f-144f, 2:542 vascular system, 3:56 vesicular stomatitis (VS), 2:119-120
deer, 2:145, 2:145f Agnathia, 2:4 viral diseases, foot-and-mouth disease
dogs, 2:577 Aino virus (AINOV), 1:280, 1:381, 3:438 (FMD), 2:117-119
horses, 2:145, 2:569 Airedale Terrier dogs mycotic diseases, 2:201-203
pigs, 2:144-145, 2:144f dilated cardiomyopathy, 3:48 neonatal animals, undifferentiated diarrhea
sheep and goats, 2:557 recurrent flank alopecia, 1:590 of, 2:111
Adhesion(s) Airway, upper, 2:466-467, 2:466f oral cavity, 2:2-28
peritoneal, 2:76-77 disease, 2:500-504, 2:500.e1f protistant infections, 2:227-244
platelet, 3:256 Akabane virus (AKAV), 1:280, 1:381, salivary glands, 2:28-30
Adiaspiromycosis, 2:584-585, 2:585f 3:437-438 stomach and abomasum, 2:44-60
Adipocytes, 1:187, 1:188f Akita dogs Alkali disease, 1:571
Adrenal glands, 3:336-348, 3:336f canine uveodermatologic syndrome, 1:557 Alkaline phosphatase, 1:27
biosynthesis and hormone action, peripheral vestibular disease, 1:494 Alkaline urine pH, 2:456
3:337-338 polyarthritis, 1:158 Alkaloids, pyrrolizidine, 2:336-338, 2:337f,
development, structure, and function, sebaceous adenitis, 1:551 2:337.e1f
3:336-338 Alaria spp., 2:225-227 Allantoic sac, 3:397
diseases, 3:338-343, 3:338f Alaskan Husky dogs Allergic reactions, 1:590-600
neoplasms, 3:343-348 gangliosidosis, 1:58-59 contact dermatitis, 1:596-597
pituitary adenomas and, 3:288, 3:288f spongy encephalomyelopathies, to food, 1:594-596, 1:595f
Adrenal medulla, 3:348-354 1:346-347 inhalant dermatitis, 1:592
development, structure, and function, Alaskan Malamute dogs rhinitis, 2:476, 2:476.e1f
3:348-354 alopecia X, 1:589-590 All-trans-retinoic acid (ATRA), 1:82
neoplasms, 3:349-352 canine uveodermatologic syndrome, 1:557 Alopecia
Adrenal sex hormones, 3:337 chondrodysplasia, 1:43f areata, 1:614-615, 1:615f
Adrenal tissue, accessory or ectopic, 3:479, cone dysplasia, 1:469 canine recurrent flank, 1:590, 1:590f,
3:480f Factor VII deficiency, 3:264 1:590.e1f
Adrenocorticotropic hormone (ACTH), hypothyroidism, 1:587 cicatricial, 1:698
3:270-272 motor neuropathy, 1:335 color-dilution, 1:557
biosynthesis, 3:337-338 vitiligo, 1:555-556 congenital hypotrichosis, 1:538-539
corticotroph (ACTH-secreting) adenoma, zinc-responsive dermatoses, 1:585-586 associated with pigmentary alteration,
3:281-282, 3:281f, 3:283f-284f Alaskan sled dogs, 3:51 1:539-541
functional cytology of adenohypophysis Albumin, 2:401 cats, 1:539
and, 3:276-277 Alcelaphine herpesvirus 1 (AlHV-1), 2:132 cattle, 1:538-539
Adult polycystic disease, liver 2:265 Alcelaphine herpesvirus 2 (AlHV-2), 2:132 dogs, 1:539, 1:539.e1f
Adventitia, vascular system, 3:54 Aleutian mink cattle, Chediak-Higashi equine linear, 1:550, 1:550f
Adventitial placentation, 3:396-397 syndrome in, 3:259 feline paraneoplastic, 1:691, 1:692f
Adventitious bursae, 1:155 Alexander disease, 1:262, 1:341 mucinosa, 1:697
Adynamic ileus, 2:74-75, 2:77 Algal diseases of skin, 1:665 psychogenic, 1:561
Aelurostongylus abstrusus, 2:590-591, Alimentary system, 1:250-406. See also rabies vaccine-induced vasculitis and,
2:590.e5f Entries beginning gastrointestinal; 1:612-613
Afghan dogs specific components; specific infections/ traction, 1:560
hypothyroidism, 1:587 organisms X, 1:589-590, 1:590f
myelopathy, 1:340f bacterial diseases, 2:158-201 A1-Antitrypsin deficiency, 2:304-305
necrotizing myelopathy, 1:340, 1:340f buccal cavity and mucosa, 2:12-19 α-cells, endocrine pancreas, 2:368

α-dystroglycan deficiency, 1:196
α-1,4-glucosidase deficiency, 1:290
α-granules, 3:257
α-L-fucosidosis, 1:289
α-L-iduronidase, 1:289
α-Mannosidosis, 1:288, 1:288f
α-naphthylthiourea (ANTU), 2:519-520
Alphaherpesviruses
cattle, 2:537
horses, 2:568, 2:568.e2f
Alphaviruses, 1:376-377, 1:377f
Alport syndrome, 2:415-416, 2:417f,
2:415.e3f. See also Hereditary nephritis
Alsike clover, 1:579, 2:341-342, 2:341f
Altered gut flora, 2:71-72
Aluminum, 3:298
phthalocyanine tetrasulfonate, 2:329
Alveld, 2:340
Alveolar atrophy, 2:7-8
Alveolar ducts, 2:467
Alveolar emphysema, 2:486
Alveolar filling disorders, 2:516-518
Alveolar histiocytosis, 2:517
Alveolar macrophages, 2:470-472
Alveolar microlithiasis, 2:517, 2:517f
Alveolar overinflation, 2:486, 2:487.e1f
Alveolar parenchyma, 2:469
Alveolar phospholipidosis, 2:517, 2:517.e1f
Alveolar proteinosis, 2:517
Alveolar rhabdomyosarcoma, 1:241-243
Alveolar stage of lung growth, 2:484,
2:484.e1f
Alzheimer type II cells, 1:262, 1:262f,
2:88
Amanitins, 2:330-331
Amaranthus retroflexus, 2:386, 2:427
toxicity, 2:427f
Amblyomma maculatum, 1:506
Amebiasis, 2:242
Amebic encephalitis, 1:386, 1:386f
Amelanotic malignant melanoma, glomerular
micrometastasis of, 2:444.e1f
Ameloblastic fibroma, 2:24
Ameloblastic fibro-odontomas, 2:24
Ameloblastomas, 2:22-23, 2:23f
Ameloblasts, 2:5
Amelogenesis imperfecta, 2:7
American Brown Swiss cattle, bovine
hypomyelinogenesis in, 1:338-339
American Bulldogs, ichthyosis in, 1:531,
1:531.e1f
American Cocker Spaniel dogs
chronic hepatitis, 2:304, 2:305f
phosphofructokinase (PFK) deficiency,
1:204-205
American Eskimo dogs, alopecia X in,
1:589-590
American Hairless Terrier dogs, congenital
hypotrichosis in, 1:538
American Staffordshire Terrier dogs,
demodectic mange in, 1:679
Amikacin, 1:494, 2:424
Amine precursor uptake decarboxylation
(APUD), 2:105-106
Aminoglycosides
nephrotoxicity, 2:424
tubulotoxic effects of, 2:424
Amiodarone, 2:329
Ammonia toxicity, 2:291
Amniotic plaques, 3:397
Amniotic sac, 3:397
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Amphotericin B, 1:562
Amycolatopsis, 3:417
Amylo-1,6-glucosidase deficiency, 1:290
Amyloid
definitive characterization, 2:415
degeneration, 1:297-298
deposition in adrenal glands, 3:339
eosinophilic in H&E sections, 2:415
fibrils, 2:413-414
histologically, 2:414-415
localization of, 2:414
medullary interstitial amyloidosis, 2:415f
pale amorphous, 2:91f
-producing odontogenic tumors, 2:23
Amyloidosis, 2:91, 3:298f
cutaneous, 1:614
liver, 2:278-279, 2:279f, 2:278.e1f
nasal, 2:473, 2:474f
parathyroid gland, 3:297-298
spleen, 3:163-164, 3:165f, 3:164.e1f
thyroid, 3:315, 3:315f
Amylopectinosis, 1:290
Anaerobiospirillum sp., 2:99, 2:199
Anagen phase, hair, 1:516
Angioleiomyomas, 3:52
Anagyrine, 1:90
Anal glands, 1:517
Anal sac, aprocrine adenocarcinoma of,
3:307f-308f, 3:308
Anaphylaxis, 2:512-513
Anaplasma centrale, 3:117
Anaplasma marginale, 3:116, 3:116f
Anaplasma phagocytophilum, 3:111, 3:178
Anaplasma platys, 3:128-129
Anaplasmosis, 3:116-117
Anaplastic diffuse large B-cell lymphomas
(DLBCLs), 3:221
Anaplastic large T-cell lymphoma (ALTCL),
3:230
Anatrichosoma spp., 1:690
Anchoring filaments, 1:513-514
Ancylostoma spp., 2:214
Andersen disease, 1:290
Andersonstrongylus milksi, 2:587
Androgen in bone, 1:25t
Anemia, 1:539, 2:73, 3:112
aplastic, 3:127-128, 3:128f
blood loss, 3:112-114
classification by mechanism, 3:113t
of decreased production, 3:126-128
hemolytic, 3:114-126
immunohemolytic, 3:114, 3:115f
of inflammatory disease (AID), 3:127
iron deficiency, 3:112-114, 3:114f
in uremic animals, 2:385
Anencephaly, cerebral, 1:266-267, 1:266f
Anesthesia
deaths, 1:2-3
postanesthethic myopathy in horses,
1:213
Aneurysmal bone cysts, 1:126
cats, 1:126f
Aneurysms, 3:62-63, 3:62f
congenital, 3:23
portal vein, 2:266
Angiocentric lymphoma, 1:734
Angioedema, 1:594
Angiofibroma, nasopharyngeal, 2:480
Angioimmunoblastic T-cell lymphoma, 3:230
Angioinvasive lymphoma, 2:499, 2:499f
Angiokeratoma, 1:727, 3:99
Index 513
Angioma, 3:99
Angiopathy, cerebrospinal, 1:298, 1:298f
Angiosarcomas, 3:99-101
Angiostrongylus vasorum, 1:390-391,
1:451-452, 2:586-587
Angiotensin converting enzyme (ACE), into
angiotensin II, 2:379
Angora goats
aural melanoma, 1:504-505
spongy encephalomyelopathies, 1:347
Angular limb deformities, 1:31-33, 1:32f
horses, 1:31-32
sheep, 1:32, 1:33f
Angus cattle
bovine hypomyelinogenesis, 1:338-339
brachygnathia superior, 2:3
genetic acantholytic dermatoses, 1:537-538
hip dysplasia, 1:135-136
osteopetrosis, 1:51
Anichkov cells, 3:37, 3:38f
Aniline derivatives, 3:325
Ankyloglossia, 2:4
Ankylosing spondylosis
dogs, 1:145-146, 1:145f
pigs, 1:146
Annual ryegrass toxicosis, 1:298, 1:298f
Annular pancreas, 2:355
Annulus fibrosus, 1:128-129
Anodontia, 2:6
cattle, 1:538
Anoikis, 2:280
Anomalous pulmonary venous drainage,
2:485
Anophthalmos, 1:410, 1:410f
Anorexia, 2:69, 2:72
Anovulatory cystic ovarian disease, 3:372
Anovulatory luteinized cysts, 3:373, 3:373f
Anoxia, 1:305-307
Anterior segment dysgenesis, 1:416, 1:416f
Anterior staphyloma, 1:437
Anterior synechiae, 1:432, 1:432f
Anterior uveitis, 1:446
Anterograde degeneration, 1:256
Anthracosis, 2:518, 3:200, 3:200.e1f
Anthrax, 3:171-174, 3:172.e1f
cattle, 3:172, 3:173f
dogs, 3:174
horses, 3:173
pigs, 3:173-174
sheep, 3:173
Anthropophilic dermatophytes, 1:649
Antibiotic-responsive diarrhea (ARD),
2:86
Antibody defense proteins, lung, 2:471
Antibody-dependent cytotoxicity (ADCC),
3:143-144
Antibody-mediated rejection, acute, 2:387
Anticoagulants, endogenous, 3:265-266
Anticonvulsant drugs and osteoporosis, 1:67
Antidiuretic hormone (ADH), 2:377, 2:401,
2:430, 3:10, 3:290
Anti-GBM glomerulonephritis, 2:408
Antimicrobial factors in lungs, 2:472
Antithrombin (AT), 3:265
Antithrombosis, 3:55
balance between thrombosis and, 3:53.e1f
Aorta
coarctation, 3:23, 3:23f
complete transposition of pulmonary
artery and, 3:22.e1f
double arch, 3:23
514 Index
Aorta (Continued)
rupture, 3:62-63, 3:62f
vascular anomalies, 3:23-24, 3:23f
Aortic-iliac thrombosis, 3:64, 3:64.e1f
Aorticopulmonary septal defect, 3:23
Aortic valve
aortic and subaortic stenosis, 3:20-21,
3:21f
semilunar, 3:2-3
subendocardial fibrosis, 3:30
Aphakia, 1:422
Aplasia
cerebral, 1:266-267, 1:266f
enamel, 2:5
pancreas, 2:355
paramesonephric duct, 3:368, 3:369f
pure red cell, 3:127-128, 3:128f
segmental, 1:277-279
Aplastic anemia, 3:127-128, 3:128f
Apocrine glands, 1:517
carcinoma, 1:720, 1:720f
Aponeuroses, 1:247-249
Apophyses, 1:30
Apoptosis, 1:186, 1:518
liver, 2:279-280, 2:279f
Appaloosa horses, osteopetrosis in, 1:52
Aprocrine adenocarcinoma of anal sac,
3:307f-308f, 3:308
Aptyalism, 2:28
Aqueous flare, 1:448-449
Arabian horses
atlantoaxial subluxations, 1:137
cerebellar abiotrophy, 1:319
equine adenovirus, 2:569
severe combined immunodeficiency
(SCID), 3:139-141
Arachnoid cysts, 1:279, 1:280f
Arachnomelia, 1:48-49
Argasidae, 1:684
“Armadillo Westie syndrome”, 1:553
Arnold-Chiari malformation, 1:276-277,
1:277f
Arrector pili muscles, 1:515
Arrhythmogenic right ventricular
cardiomyopathy (ARVC)
dogs, 3:49, 3:49f
-like syndrome in cats, 3:47
Arsenic poisoning, 1:327-328, 1:570
Arterial embolism, 3:63-66, 3:63f-64f
Arterial hypertrophy, 3:66-67
Arterial thrombosis, 3:63-66, 3:63f, 3:63.e1f
Arteries, 3:54, 3:56-88
bronchial, 2:467-468, 2:468f
congenital anomalies, 3:56
degeneration, 3:56-61
hepatic, 2:260
mineralization, 3:60-61, 3:61f
obstructions, 1:299-300, 1:299f
pulmonary, 2:467-468, 2:468f
rupture, 3:62-63, 3:62f
transposition, 3:22.e1f
Arteriopathy, plexiform, 2:492, 2:492f
Arteriosclerosis, 3:36, 3:56-57, 3:59-60
Arteriovenous fistula, 3:56
Arteritis
MCF microscopic, 2:135
severe, 2:398.e1f
Arthritis
coliform, 1:151
erysipelas, 1:149-150
fibrinous, 1:146-147, 1:147f
fungal, 1:154-155
infectious, 1:148-155
Arthritis (Continued)
myocplasmal, 1:153-154
protozoal, 1:155
purulent (suppurative), 1:147-148, 1:148f
rheumatoid, 1:157, 1:157f
staphylococcal, 1:151
streptococcal, 1:150-151
viral, 1:154
Arthrogryposis, 1:137, 1:187-189, 1:188f,
1:281f
Arthropod ectoparasites, 1:666-684
Arthropod infections and central nervous
system, 1:389-391
Articular capsule, 1:130
fibrinous arthritis, 1:147
Articular cartilage, 1:129
response to injury, 1:131-132
Articular disks, 1:130
Artiodactyla. See Malignant catarrhal fever
(MCF)
Arylsulfatase-B deficiency, 1:290
Asbestosis, 2:518
Ascarid nematodes, 2:76, 2:255
Ascaris suum, 2:116, 2:218, 2:218f, 2:319,
2:319f, 2:536-537
respiratory system and, 2:536-537,
2:556-557, 2:557f, 2:537.e1f
Ascarops spp., 2:54
Ascending pyelonephritis, acute,
2:441.e1f
Ascites, 2:248-249, 2:294-295
Asian cat breeds, peripheral vestibular disease
in, 1:494
Aspartate aminotransferase (AST)
canine dermatomyositis, 1:198
canine X-linked muscular dystrophy,
1:192-193
centronuclear myopathy of Labrador
Retrievers, 1:197
congenital myotonia in cats, 1:201
diaphragmatic dystrophy in cattle,
1:199
masticatory myositis, 1:226
polymyositis, 1:227
purpura hemorrhagica, 1:229
Aspergillus clavatus, 1:327
Aspergillus flavus, 2:426
Aspergillus fumigatus, 3:417-418
bronchitis and, 2:502, 2:502.e1f
mycotic rhinitis, 2:579, 2:580f
Aspergillus niger, 2:426
Aspergillus spp., 1:156, 1:156f, 1:660, 2:201
abortion and, 3:399-400
liver toxicity, 2:333
pulmonary, 2:573, 2:573f
pulmonary vasculitis and, 2:494
Aspergillus terreus, 3:183, 3:184f, 3:183.e1f
Aspiration pneumonia, 2:508-509, 2:508f-
509f, 2:508.e1f
meconium, 2:516, 2:516.e1f
Assimilation, epithelial phase of, 2:69-70
Asthma, feline, 2:502-503, 2:503.e1f
Astrocytes, 1:260-262, 1:261f
Astrocytoma, 1:398-399, 1:399f
Astrovirus, 2:117
Asynchrony, esophageal, 2:33
Atadenovirus, 2:145
Ataxia, 2:425
bovine familial convulsions and, 1:319
enzootic, 1:328-329, 1:328f
progressive, 1:341f
Atelectasis, 2:486, 2:486.e2f
fetal, 2:486.e2f
Atherosclerosis, 3:57-59, 3:58f-59f,
3:57.e2f
with hypothyroidism, 3:318-319, 3:319f
Atlantoaxial subluxations, 1:137
horses, 1:137
Atopic dermatitis, 1:591-593, 1:591f,
1:592.e1f
Atresia ani, 2:74
Atresia coli, 2:74
Atresia ilei, 2:74
Atresia intestinalis, 2:74
Atria, heart, 3:2
restricted filling, 3:6
Atrial natriuretic factor (ANF), 3:3, 3:10
Atrial septal defect (ASD), 3:16, 3:16f
Atrichial sweat glands, 1:518
tumors, 1:719
Atrioventricular (AV) valves, 3:3
dysplasia of right, 3:21-22
malformation of, 3:19-22, 3:19f
septal defect, 3:17, 3:17f
Atrioventricular (AV) waves, 3:2
Atrophic dermatosis, 1:529-530, 1:529f
Atrophic rhinitis, 2:533
nonprogressive (NPAR), 2:533
pigs, 1:102
progressive (PAR), 2:533
Atrophy, 1:174f
alveolar, 2:7-8
brain and spinal cord, 1:304-305
cerebellar, 1:276, 1:276f, 1:318-326
cerebrocortical, 1:7f
denervation, 1:173-178, 1:175f-177f
disuse, 1:175-177, 1:177f
dog, 1:176f
endocrine disease, 1:178, 1:178f
endometrium, 3:382
epidermis, 1:518-519
exocrine pancreas, 2:362-363, 2:362f
follicular, 1:520, 3:316f
heart, 3:34
hepatocellular, 2:269, 2:269f, 2:269.e1f
horse, 1:176f
hypertrophy, 1:178-180, 1:178f-179f
hypothyroidism and, 1:224
idiopathic follicular, 3:315-316, 3:315f,
3:317f
lymphoid, 3:198, 3:199f
male genital glands, 3:504
myopathic, 1:178, 1:178f
neuronal, 1:253
parathyroid gland, 3:308, 3:309f
pericardial fat, 3:25, 3:25f
resulting from malnutrition or cachexia,
1:177, 1:177f
testicular, 3:481-485, 3:482f-483f
thymic, 1:6f, 3:123, 3:144-147, 3:145f
Attaching-effacing E. coli (AEEC), 2:161-
163, 2:162f
Atypical adenomatous hyperplasia,
2:495
Atypical mycobacteriosis, 1:640, 1:640f
Atypical pneumonia, 2:509
Auditory tube, 1:495-496
Aujeszky’s disease, 2:20
Aural hematoma, 1:504
Aural melanoma, 1:504-505
Aural plaques, 1:504
Auricular chondritis, 1:504, 1:697
Australian Cattle dogs
cochleosaccular degeneration, 1:492
spongy encephalomyelopathies, 1:346
spongy myelinopathy, 1:343

Australian Kelpie dogs, globoid cell
leukodystrophy in, 1:339
Australian Shepherd dogs
choroidal hypoplasia, 1:413
cobalamin deficiency, 3:127
cochleosaccular degeneration, 1:492
spindle cell tumor, 1:486
Autoimmune dermatoses, 1:600-607
pemphigus complex, 1:518, 1:600-603
Autolytic changes in retina after death,
1:467
Autopsy. See Gross and histologic
examinations
Autopsy-in-a-jar pathology, 1:2
Autosomal recessive congenital ichthyoses
(ARCI), 1:530, 1:531f
Autosomal recessive PKD (ARPKD),
2:396
Autosomal recessive severe combined
immunodeficiency, 3:140-141
Avascular chorion, 3:397
Avipoxvirus, 1:616
AV node, 3:2
heart examination and, 3:13-14
impulse formation disturbances, 3:5
Avocado poisoning, 3:38
Axillary nodular necrosis, 1:695
Axonal dystrophy, 1:257-258, 1:258f,
1:324-325
Axonopathy, 1:256, 1:318-334
distal, 1:257
peripheral, 1:334-336
proximal, 1:257, 1:257f
Axons, 1:255-258, 1:256f
growth disorders, 1:268-269
Ayrshire cattle, cropped and notched pinnae
in, 1:502
B Barbados Blackbelly sheep, osteogenesis
Babesia bigemina, 3:119
Babesia bovis, 3:118
Babesia caballi, 3:119-120
Babesia canis, 1:665, 3:119, 3:119.e1f
Babesia divergens, 3:119
Babesia felis, 3:120
Babesia gibsoni, 1:665, 2:412
Babesia major, 3:119
Babesia rossi, 3:119
Babesia spp., 1:611, 3:117-120, 3:117f
differential diagnosis, 3:119
splenic babesiosis, 3:161, 3:161f
Baccharis cordifolia, 2:89
Baccharis megapotamica, 2:89
Baccharis pteronioides, 2:89
Bacillary angiomatosis, 1:646
Bacillary hemoglobinuria, 2:317, 2:317f
Bacillus anthracis, 3:171-174
Bacillus fragilis, 2:113
Bacillus piliformis, 3:42
Bacterial arthritis, 1:148-154
Bacterial diseases, tooth surface, 2:9
Bacterial endophthalmitis, 1:449
Bacterial enterotoxin, 2:71
Bacterial granulomas, 1:637-642
Bacterial hemolysins, 3:126
Bacterial infections
abortion and stillbirth due to, 3:398,
3:399b, 3:402-417
alimentary tract, 2:158-201
central nervous system, 1:353-365
endocarditis, 3:30-33, 3:31f
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Bacterial infections (Continued)
liver, 2:314-318
lungs and, 2:472-473
myocarditis, 3:42
pneumonia, 2:562-563, 2:562f
respiratory system, 2:531-532, 2:531f
cats, 2:589
cattle, 2:542-551
dogs, 2:577-579
horses, 2:569-573
pigs, 2:531-533
sheep and goats, 2:562-563
skin, 1:629-646
lesions in, 1:645-646
teeth, 2:9
Bacterial osteomyelitis, 1:98-103, 1:98f-99f
cats, 1:99-100
cattle, 1:99
dogs, 1:99-100
horses, 1:99, 1:99f, 1:101f
Bacterial overgrowth, small intestine, 2:364
Bacterial pododermatitis of horses and
ruminants, 1:642-645
Bacterial pseudomycetoma, 1:642, 1:642f
Bacterial septicemia, 3:289, 3:290f
Bacteriology, 1:10-11
Bacteroides fragilis, 2:113, 2:199
Bacteroides spp., 2:9
Balanoposthitis, 3:507
Balantidium, 2:243-244, 2:244f
Baldy calf syndrome, 1:538
Bali cattle, Jembrana disease in, 3:195-196,
3:195f
Balloon cell malignant melanomas, 1:722
Ballooning degeneration of epidermis, 1:519,
1:519f
Bandera’s neonatal ataxia, 1:318-319
Banzi virus, 1:281
imperfecta in, 1:50
Bartholin’s glands, 3:442
Bartonella, 1:646
endocarditits and, 3:30-31
liver and, 2:318
Bartonella berkhoffi, 1:646
Bartonella henselae, 3:42
Bartonella vinsonii, 1:99-100, 1:646
Basal cell carcinomas, 1:714
Basement membrane zone (BMZ), 1:513-514
Basic multicellular unit (BMU), 1:26
Basidiobolomycosis, 1:660
granulomatous rhinitis and, 2:476
Basilar membrane, 1:489-490
Basophilia, 3:111
Basophilic intranuclear viral inclusions, 2:22
Basosquamous carcinomas, 1:714
Basset Hound dogs
canine atopic dermatitis, 1:591
degenerative diseases of cartilaginous
joints, 1:143-144
globoid cell leukodystrophy, 1:339
granulomatous hepatitis, 2:318
platelet dysfunction, 3:259
seborrhea, 1:548
severe combined immunodeficiency
(SCID), 3:139
Baylisascaris procyonis, 1:390-391
B-cells
chronic lymphocytic leukemia/small
lymphocytic lymphoma (B-CLL/SLL),
3:219-220
Index 515
B-cells (Continued)
diffuse large B-cell lymphomas, 3:220-222,
3:221f
follicular-derived B-cell lymphomas,
3:222-226, 3:223f
lymphoid hyperplasia, 3:201
in masticatory myositis, 1:226-227
Reed-Sternberg cell, 3:219
T-cell-rich B-cell lymphoma, 3:221-222,
3:222f
Beagle dogs
chondrodysplasia, 1:44, 1:45f
cobalamin deficiency, 3:127
Factor VII deficiency, 3:264
globoid cell leukodystrophy, 1:339
hypertrophy type 1 and 2, 1:225
iatrogenic acromegaly, 3:286f
lymphomas, 3:238
osteogenesis imperfecta, 1:50
osteoporosis, 1:67
pain syndrome, 1:158, 3:70
peripheral vestibular disease, 1:494
selective deficiencies of immunoglobulins,
3:139
Beagle pain syndrome. See Steroid-responsive
meningitis-arteritis
Beauceron dogs, canine atopic dermatitis in,
1:591
Bedlington Terriers, 2:303, 2:303.e1f
Belgian Blue cattle
dermatosparaxis, 1:48
osteopetrosis, 1:51-52
Belgian Gorenendael Shepherd dogs, canine
X-linked muscular dystrophy in, 1:192
Belgian Malinois dogs, vitiligo in, 1:556.e1f
Belgian Tervuren dogs
canine atopic dermatitis, 1:591
vitiligo, 1:555-556
Benign bone cysts, 1:126
Benign cortical fibromas, 2:447
Benign epithelial neoplasms, 2:478-479,
2:479f
Benign mammary neoplasms, 3:460
Benign melanocytic tumors, 1:721
Benign spindle cell tumors, 1:722-723
Benign tumors of joints, 1:160-162
Bergmann’s glia, 1:261
Bergmeister’s papilla, 1:417-419, 1:418f
Bernese Mountain dogs
afibrinogenemia, 3:265
Alexander disease, 1:341
canine hypomyelinogenesis, 1:338
degenerative radiculomyelopathy,
1:330
vasculitis, 3:70
Besnoitiosis, 1:661-663, 1:662f
granulomatous rhinitis and, 2:476
Besnoitia spp., 2:239
B-cells, endocrine pancreas, 2:368
β-glucuronidase-deficient MPS, 1:290
β-Mannosidosis, 1:289, 1:492
B2-microglobulin, 2:385
Betaherpesviruses, 2:537
Bibersteinia trehalosi, 2:543, 2:562-563
Bichon Frise dogs, canine atopic dermatitis,
1:591
Bilateral extraocular muscle myositis of dogs,
1:228
Bilateral hypoplasia, 2:392
Bile cast nephropathy, 2:430
Bile peritonitis, 2:250
516 Index

Bilharziasis, 3:91-94 Blood supply Border Collie dogs

Biliary tract bone, 1:27-28, 1:28f cobalamin deficiency, 3:127
ducts, 2:261 brain, 1:296-301, 1:296f cochleosaccular degeneration, 1:492
hyperplasia, 2:287-288, 2:289f heart, 3:2, 3:5 myopathy, 1:198
necrosis, 2:285, 2:286f abnormal pattern of flow, 3:6 sensory and autonomic neuropathy, 1:334
hyperplastic and neoplastic lesions, regurgitant flow, 3:5 Border disease virus (BDV), 1:104, 1:282-
2:344-352 hepatic, 2:260, 2:288 283, 2:128
infarcts, 2:292-293 pituitary gland, 3:278 goats, 3:426-427
inflammatory diseases, 2:300-309 spleen, 3:158-162, 3:160f pigs, 1:104
obstruction, 2:308-309 “Blue-eye disease”, 2:530 sheep, 1:104, 3:426-427
pigmentation, 2:270-271 Blue-green algae, 2:330 Border Leicester sheep, congenital myopathy
plugs, 2:271f Bluetick Hound dogs, globoid cell in, 1:200
Biomarkers of glomerular disease, leukodystrophy in, 1:339 Border-Leicester-Southdown sheep, collagen
2:401 Bluetongue virus (BTV), 1:281, 2:136-139, dysplasia in, 1:544
Biopsy 2:137f, 3:430-431 Bordetella bronchiseptica
bone marrow, 3:105f cattle, 2:138 cats, 2:589
endometrial, 3:393 sheep, 2:138-139 dogs, 2:578, 2:578f
formats, 1:2 B-lymphocytic acute myeloid leukeumia, Borna disease virus (BDV), 1:377-378, 1:378f
interpretation, 2:62 3:132-133, 3:133f Borrelia burgdorferi, 1:147, 1:152
specimen trimming, 1:8-9 Body mange, 1:676 Borreliosis, 1:152, 1:646
techniques, 2:383 Bone-forming tumors, 1:109-116, 1:109f dogs, 1:152
Biosafety/biocontainment, 1:14 Bone-lining cells, 1:18 Borzoi dogs, gastric volvulus in, 2:49
Biotin deficiency, 1:582 Bone marrow, 3:103-138, 3:103f Boston Terrier dogs
Birbeck granules, 1:513 in anemia, 3:116 canine atopic dermatitis, 1:591
Bird tongue, 2:4 biopsy, 3:105f color dilution alopecia, 1:539-540
Birman cats chronic inflammation and leukocytosis, corneal edema, 1:429
congenital hypotrichosis, 1:539 3:104-106, 3:106f corneal endothelial dystrophy, 1:433
peripheral and central distal axonopathy, erythroid hyperplasia, 3:106f hyperadrenocorticism, 1:588
1:333 histologic examination, 3:107, 3:107t malignant melanoma, 2:26
Birnavirus, 2:113 sample procurement and processing, myxomatous valvular degeneration, 3:27
Biventricular failure, 3:6 3:107-109, 3:108f vascular ring anomalies, 2:33
Black disease, 2:316 Bone(s). See also Joint(s) Botryoid rhabdomyosarcoma, 1:244f, 2:463f,
Black hair follicular dysplasia, 1:540, 1:540f, ash, 1:30 2:464
1:557 blood supply, 1:27-28, 1:28f Botryomycosis, 1:233-234
Black Labrador dogs, diffuse uveal cellular elements, 1:17-19, 1:17f Botulism, 1:317
melanocytosis in, 1:484-485 development and anatomy, 1:21-24, Bouvier des Flandres dogs
Blackleg, 1:230-233, 1:231f, 3:34 1:22f motor neuropathy, 1:335
Bladder diseases, 1:17-127 myopathy, 1:198
cells, 1:442 general considerations, 1:17 Bovine adenovirus (BAdV), 2:143, 2:143f-
neoplasia, 2:462 genetic and congenital, 1:36-60, 144f, 2:542
wall 1:37t Bovine alimentary papillomatosis, 2:43-44
hypertrophy, 2:452 hyperostotic, 1:91-94 Bovine anthrax, 3:172, 3:173f, 3:172.e1f
rupture, 2:452 inflammatory and infectious, 1:97-107 Bovine besnoitiosis, 1:661-662
Blastomas nutritional and hormonal, 1:60-84 Bovine cardiomyopathies, 3:50-51, 3:50f
hepato-, 2:347-348, 2:348f osteonecrosis, 1:94-97 Bovine chondrodysplasia, 1:38, 1:38f
pulmonary, 2:498 toxic, 1:84-91 Bovine congenital hematopoietic porphyria,
Blastomyces dermatitidis, 1:104, 1:449, 2:580, tumors and tumor-like lesions, 1:579
3:491 1:107-127 Bovine coronavirus (BCoV), 2:112, 2:148-
lymph nodes and, 3:206f viral infections, 1:104-105 150, 2:149f, 2:541-542, 2:542.e1f
Blastomycosis, 1:449-450, 1:450f, 2:580-582, fracture repair, 1:33-36, 1:34f-35f Bovine cutaneous angiomatosis, 3:99
2:582f, 2:580.e1f growth plate damage, 1:30-31 Bovine cutaneous onchocerciasis, 1:688
Blebs, 2:487, 2:487f, 2:487.e1f hypercalcemia with tumors metastatic to, Bovine ephermeral fever virus (BEFV), 3:79
Blepharitis, 1:423 3:309 Bovine erythropoietic protoporphyria, 1:579
Blind staggers, 1:571 matrix, 1:19-20 Bovine familial convulsions and ataxia,
Blister beetle, 2:52 mineralization, 1:20 1:319
myocardial necrosis and, 3:36 modeling, 1:24-25 Bovine farcy, 3:96
Bloat line in esophagus, 2:37f periosteal damage, 1:33 Bovine generalized glycogenesis type II, 3:46,
Block vertebrae, 1:57 postmortem examination of, 1:28-30 3:50
Blood-brain barrier (BBB), 1:263, 1:350 remodeling, 1:26-27 Bovine herpesviral encephalitis, 1:381-382,
Blood cells response to mechanical forces and injury, 1:381f
erythrocyte disorders, 3:112 1:30-36 Bovine herpesvirus 1, 1:625-627
hemostasis disorders, 3:255-268 sialoprotein, 1:19 Bovine herpesvirus 2, 1:625-627
leukocyte disorders, 3:109-112 skull, 1:21 Bovine herpesvirus 4, 1:626, 3:435
platelet disorders, 3:128-129 congenital abnormalities, 1:56, Bovine herpesvirus in pregnant uterus,
Blood-cerebrospinal fluid barrier (BCSFB), 1:56f 3:433-435
1:350 craniomandibular osteopathy, 1:91-92, Bovine hypomyelinogenesis, 1:338-339
Blood clots, 2:37 1:92f Bovine kidney, 2:395
Bloodhound dogs, gastric volvulus in, fractures, 1:302-303 Bovine leukemia virus (BLV), 3:235
2:49 sutures, 1:128 Bovine lymphoma, 3:235-237
Blood left shift, 3:109 stress-related lesions in horse, 1:36 Bovine malignant catarrhal fever-associated
Blood loss. See also Hemorrhage structure and function, 1:17-28 uveitis, 1:453
anemia, 3:112-114 tissue, 1:20-21 Bovine mastitis, 3:452-457, 3:452f
chronic, 2:73 Bony labyrinth of ear, 1:488, 1:489f Bovine metabolic myopathy, 1:208

Bovine necrotizing meningoencephalitis,
1:381-382, 1:381f-382f
Bovine ovarian lymphosarcoma, 3:378,
3:379f
Bovine papillomaviruses, 1:706-707, 1:707f,
2:22
Bovine papular stomatitis virus (BPSV),
1:616, 1:618-619, 2:39-40, 2:139-140,
2:140f
Bovine parainfluenza virus 3 (BPIV-3),
2:541
Bovine paramyxoviral
meningoencephalomyelitis, 1:382
Bovine parvovirus (BPV), 2:157-158,
3:429-430
–induced papilloma, 2:44
Bovine respiratory syncytial virus (BRSV),
2:539-541, 2:540f, 2:540.e2f, 2:540.e1f
Bovine rhinitis virus (BRAV), 2:542
Bovine rotaviral infection, 2:151-152, 2:152f
Bovine spongiform encephalopathy (BSE),
1:349
Bovine torovirus, 2:112
Bovine trypanosomiasis, 3:122-124
Bovine tuberculosis, 2:547-551, 2:549f
Bovine viral diarrhea virus (BVDV), 1:104,
1:105f, 1:281-283, 2:112, 2:114,
2:122-128, 2:123f-125f, 2:542, 2:542.e3f
esophageal lesions, 2:124, 2:124f
fetal infections, 2:122
mucosal disease, 2:123
-negative cattle, 2:413
noncytopathic (NCP), 2:122-128
PI calves, 2:122
pregnant uterus, 3:425-426
secondary infections, 2:127
severe acute, 2:122-123
thymic atrophy and, 3:145
Bowie, 1:90-91
Bowman’s capsules, 2:406-407, 2:437-438,
2:407.e1f
thickening and lamination, 2:407.e1f
Bowman’s space, 2:406-407
Boxer dogs
acne, 1:549
canine atopic dermatitis, 1:591
canine leproid granuloma, 1:503, 1:641
canine persistent (recurrent) ulcer
syndrome, 1:434, 1:435f
chondrosarcoma, 1:118
congenital myotonia, 1:201
degenerative radiculomyelopathy, 1:330
diffuse fibrous hyperplasia, 2:21-22
dilated cardiomyopathy, 3:48
factor VII deficiency, 3:264
hyperadrenocorticism, 1:588
hyperestrogenism, 1:589
hypothyroidism, 1:587, 3:315
immune-mediated myositis, 1:228
intestinal lymphomas, 3:239
lymphomas, 3:238
malignant lymphoma, 1:123-124
malignant oral tumors, 2:21
myotonic dystrophy-like disorder,
1:202-203
progressive axonopathy, 1:329-330
recurrent flank alopecia, 1:590
spongy encephalomyelopathies, 1:346
typhlocolitis, 2:97-98, 2:98f
Brachycephalic airway syndrome, 2:482,
2:482f
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Brachycephalic type dwarfism, 1:39, 1:39f
Brachydont teeth, 2:5
Brachygnathia inferior, 1:56, 1:56f, 2:3
Brachygnathia superior, 1:56, 2:3
Brachyspina, 1:57
Brachyspira pilosicoli, 2:182
Brachyspira hyodysenteriae, 2:182
Brachyspira spp., 2:98
Bracken fern, 1:471, 2:461
Brain. See also Spinal cord
age changes in, 1:304
atrophy, 1:304-305
cerebellar hypoplasia, 1:275f
cerebellum
agenesis, hypoplasia, and dysplasia,
1:275-276, 1:275f
Arnold-Chiari malformation, 1:276-277,
1:277f
atrophy, 1:276, 1:276f
Dandy-Walker syndrome, 1:277
development, 1:274-277
hypoplasia, 1:275f
intracranial arachnoid cyst, 1:280f
vascular leakage, 1:298f
cerebrum, 1:266-274
cerebral aplasia, anencephaly, 1:266-267,
1:266f
defects in cerebral corticogenesis,
1:268
disorders of axonal growth, 1:268-269
encephalocele, meningocele, 1:267,
1:267f
holoprosencephaly, 1:269-270, 1:269f
hydranencephaly, porencephaly,
1:272-274, 1:272f
hydrocephalus, 1:270-272, 1:271f
periventricular leukomalacia of neonates,
1:274
edema, 1:293-295, 1:295f
embolism, 2:490
increased intracranial pressure, 1:293-295
lesions of blood vessels and circulatory
disturbances, 1:296-301, 1:296f
hemorrhagic, 1:300-301
ischemic, 1:297-300, 1:297f
microcirculation of, 1:263-264, 1:264f,
1:263.e1f
traumatic injuries, 1:301-303
tumors, 1:296f
Branched-chain α-ketoacid decarboxylase
deficiency, 1:344, 1:345f
Brangus cattle, Chediak-Higashi syndrome in,
3:259
Brassica rapa, 2:342
Braunvieh x Brown Swiss cattle, congenital
myopathy in, 1:199-200
Braxy, 2:53, 2:53f
Braxy-like clostridial abomasitis, 2:53f
Brazilian Terrier dogs, Sly syndrome in, 1:58
Breda virus, 2:112
Breed-related nephropathies, 2:388t-390t
in domestic species, 2:388t-390t
Brick inclusions, 2:430
Brittany Spaniel dogs
canine X-linked muscular dystrophy,
1:192
hypothyroidism, 1:587
late-onset progressive spinocerebellar
degeneration, 1:319
Brodie’s abscess, 1:98, 1:98f
Bronchi, 2:468-469
Index 517
Bronchial arteries, 2:467-468, 2:468f
Bronchial atresia, 2:485
Bronchial gland carcinoma, 2:497
Bronchiectasis, 2:503-504, 2:503f, 2:503.e3f,
2:501.e1f
Bronchiolar necrosis and inflammation,
2:504-506, 2:504f
Bronchioles, 2:469
Bronchiolitis obliterans, 2:504, 2:504f,
2:504.e2f
Bronchioloalveolar hyperplasia, 2:505,
2:504.e2f
Bronchitis, 2:500-504
cats, 2:502-503
chronic, 2:501-503, 2:502.e1f
Bronchogenic cysts, 2:484-485
Bronchointerstitial pneumonia, 2:511-512,
2:514.e2f
foals, 2:514
Bronchopneumonia, 2:506-509, 2:506f,
2:507t
bacterial, in cattle, 2:542-546, 2:545f
caseonecrotic, 2:553f
chronic suppurative, 2:508, 2:508.e1f
death from, 2:507-508
morphology, 2:507
opportunistic bacterial pathogens and,
2:532-533
reduced lung function, 2:508
resolution and sequelae, 2:507-508
sequestrum, 2:508
Bronchopneumopathy, eosinophilic,
2:501-502, 2:502f, 2:501.e1f
Bronchopulmonary dysplasia, 2:516
Bronchopulmonary segment, 2:467
Bronchus-associated lymphoid tissue (BALT),
2:472
Brown recluse spider, 1:568
Brown Swiss cattle, progressive
myeloencephalopathy of, 1:325
Brucella abortus, 3:402-406, 3:485-487,
3:490
Brucella canis, 1:449, 3:490
abortion and, 3:403-404, 3:404f,
3:406
Brucella melitensis, 3:406
Brucella ovis, 3:405-406, 3:405f
abortion and, 3:473-474, 3:490
Brucella suis, 3:490
abortion and, 3:404-405
Bruch’s membrane, 1:445
Brugia, 3:98
Brunn nests, 2:449
Brush cells, 2:469
Bubalus arnee, 2:117-118
Buccal cavity, 2:12-19
circulatory disturbances, 2:12-13
foreign bodies in, 2:13
inflammation of, 2:13-19
parasitic diseases, 2:19
pigmentation, 2:12
salivary glands, 2:28-30
tonsil diseases, 2:19-20
Buccal mucosal bleeding time (BMBT),
3:257
Bucked shins, 1:36
Budd-Chiari syndrome, 2:298
Budgerigars, 3:286
Bufadienolide cardiac glycoside-containing
plants, 3:35
Buffalopox virus, 1:620-621
518 Index
Bulbourethral gland, 3:500-504, 3:500f
disorders of sexual development, 3:500-
501, 3:500f
hyperplasia and metaplasia, 3:502-503,
3:502f
inflammation, 3:501-502, 3:501f
neoplasms, 3:503-504, 3:504f
Bullae, 1:524
pneumothorax and, 2:487, 2:487f
Bullmastiff dogs
acne, 1:549
calvarial hyperostosis of, 1:92
canine leproid granuloma, 1:503, 1:641
spongy encephalomyelopathies, 1:346-347
Bullous immune skin diseases, 2:14
Bullous pemphigoid (BP), 1:603-604, 2:15
Bull Terrier dogs, 2:416-417
autosomal recessive acrodermatitis, 3:141
canine atopic dermatitis, 1:591
cochleosaccular degeneration, 1:492
lethal acrodermatitis, 1:533, 1:533.e1f
melanocytopenic hypomelanosis, 1:555
subvalvular aortic stenosis, 3:20
Bully Whippets, 1:191, 1:191f
Büngner’s bands, 1:256
Bunina bodies, 1:255
Burkholderia mallei, 2:573
Burkholderia pseudomallei, 1:637, 3:491
respiratory system and, 2:563
splenic abscesses, 3:183-184
splenic lesions, 3:188-189, 3:188f
Burkitt-like lymphoma (BKL), 3:226
Burmese cats, primary endocardial
fibroelastosis in, 3:22
Burns, 1:564-566, 1:565f
Bursitis, 1:155-156
sheep, 1:155f
Butterfly vertebrae, 1:57
C Campylobacter spp., 2:98, 2:117
Cabugi breed sheep, 1:42
Cachectic atrophy, lymph node,
3:198-199
Cache valley virus (CVV), 1:280,
3:438-439
Cachexia, atrophy resulting from, 1:177,
1:177f
Cadmium, 1:67
Caffey’s disease, 1:53
Cairn Terrier dogs
canine atopic dermatitis, 1:591
diabetes mellitus, 2:373
globoid cell leukodystrophy, 1:339
hyperestrogenism, 1:589
polycystic kidney and liver disease,
2:265
primary portal vein hypoplasia,
2:267-268
progressive neuronopathy, 1:332-333
Calcinosis circumscripta, 1:563, 1:563f
Calcinosis cutis, 1:562, 1:588, 1:589f
Calcinosis universalis, 1:562-563
Calcitonin, 1:62, 3:296-297
biological actions, 3:297
biosynthessis and secretion, 3:297
in physis, 1:25t
Calcitriol
biological action, 3:295-296
biosynthesis, 3:295
Calcium
carbonate, 1:562, 2:458
chelation, 2:426
chloride, 1:562
Calcium (Continued)
crystal-associated arthropathy
(pseudogout), 1:156-157
dogs, 1:156-157
deficiency, 2:8. See also Hypocalcemia
odontodystrophy, 2:8
osteoporosis, 1:61, 1:65-66
rickets, 1:61, 1:66, 1:69
vitamin D, 1:61
functions, 3:291-292
hypercalcemia, 3:305-310, 3:305f
hypocalcemia, 3:299
malabsorption, 2:70
muscle necrosis and, 1:181-182, 1:181f
oxalate, 2:457
phosphate, 2:458
phosphorus homeostasis and, 1:61-63
-regulating hormones, 3:291-310, 3:291f
salts, deposition of, 1:443, 1:519
Calculi, 2:452
salivary, 2:29
urinary, 2:453t
Calf diphtheria, 2:17
Calicium pyrophosphate dihydrate,
1:156-157
Calicivirus, 1:154, 1:628, 2:117
California encephalitis virus
meningoencephalomyelitis, 1:383
Call-Exner body, 3:376
Calliphorine myiasis, 1:669
Callipyge phenotype in sheep, 1:191
Calluses, 1:524, 1:559-560
Calodium hepaticum, 2:320
Calvarial hyperostosis of Bullmastiffs, 1:92
Camelostrongylus, 2:54-55
Camelpox virus, 1:616, 1:621
Campylobacter fetus, 3:406-408, 3:408f,
3:424, 3:507
liver and, 2:314-315
enteritis associated with, 2:180-181
Canalicular domain, liver, 2:262
Canalicular stage of lung growth, 2:484
Canal of Hering, 2:262
Cancrum oris, 2:18
Candida albicans, 1:647, 2:32, 2:202,
2:459
Candida parapsilosis, 3:30-31
granulomatous rhinitis and, 2:476
Candida tropicalis, 2:202
Candidiasis, 2:202
Canid herpesvirus 1, 3:507
Canine acanthosis nigricans, 1:555
Canine adenovirus 1 (CAV-1), 1:105,
1:452-453, 2:410
hepatitis, 2:310-312, 2:311.e1f
Canine adenovirus 2 (CAV-2), 2:577
Canine atopic dermatitis, 1:591-593
Canine blastomycosis, 2:459
Canine bocavirus, 2:577
Canine cardiomyopathies, 3:48-49, 3:48f
Canine colitis, 2:94
Canine congenital myasthenia, 1:209
Canine coronavirus (CCoV), 2:116, 2:150
Canine cutaneous histiocytoma (CCH),
1:728-729, 3:243-245, 3:244f-245f,
3:244.e1f, 3:243.e1f
Canine cutaneous Langerhans cell
histiocytosis, 1:729, 3:245-246, 3:246f
Canine cyclic hematopoiesis, 3:110
Canine demodicosis, 1:679-682, 1:679f
Canine dermatomyositis, 1:198, 1:541-542,
1:542f-543f
Canine dietary factors, 2:457
Canine distemper virus (CDV), 1:104-105,
1:384-385, 1:474, 2:116-117, 2:574-576,
2:575.e1f
acquired deafness and, 1:493
lymph nodes and, 3:207f
thymic atrophy and, 3:145
Canine dynamin 1 (DNM1) gene, 1:198
Canine ehrlichiosis, 1:474-475
Canine eosinophilic granuloma, 1:694
Canine epitrichical ductular adenomas,
1:718-719
Canine exertional rhabdomyolysis, 1:223
Canine familial glomerulonephritides, 2:412
Canine familial nephropathies, 2:391
Canine hepacivirus, 2:577
Canine hepatozoonosis, 1:94, 1:94f
Canine herpesvirus-1 (CaHV-1), 2:577,
3:431-432, 3:432f, 3:434f
encephalitis, 1:383
Canine hypomeylinogenesis, 1:337-338
Canine immune-mediated hemolytic anemia,
3:265
Canine infectious respiratory disease (CIRD)
complex, 2:574
Canine influenza, 2:577
Canine juvenile cellulitis, 1:690-691, 1:691f
Canine juvenile pancreatic atrophy, 2:363,
2:363f
Canine kidneys, 2:378
Canine leproid granuloma, 1:503, 1:641,
1:641f
Canine lymphomas, 3:238-239, 3:239f,
3:239.e1f, 3:239.e2f, 3:238.e2f
Canine minute virus (CnMV), 2:157, 3:430
Canine monocytotropic ehrlichiosis, 3:111
Canine multifocal retinopathy, 1:469
Canine nasodigital hyperkeratosis, 1:549-550
Canine necrotizing meningoencephalitis
(NME), 1:392-393, 1:392f
Canine panosteitis, 1:106-107, 1:107f
Canine papillomavirus 1 (CPV1), 2:22, 2:22f
Canine parainfluenza (CPIV), 2:576
Canine parvovirus, 2:116-117
thymic atrophy, 3:145
Canine parvovirus 2 infection (CPV-2),
2:156-157, 2:156f-157f
Canine perivascular wall tumors (PWTs),
1:723, 1:724f
Canine persistent (recurrent) ulcer syndrome,
1:434, 1:435f
Canine pigmented plaques, 1:710-711,
1:711f
Canine pneumovirus, 2:577
Canine pseudoplacentational endometrial
hyperplasia, 3:383, 3:384f
Canine pulmonary veno-occlusive disease
(PVOD), 2:493, 2:493f, 2:493.e1f
Canine reactive histiocytosis, 3:247-250,
3:248f, 3:247.e1f
cutaneous, 3:247-249, 3:248f, 3:249.e1f,
3:247.e1f
systemic, 1:729, 3:249-250, 3:249f
Canine recurrent flank alopecia, 1:590,
1:590f, 1:590.e1f
Canine respiratory coronavirus (CRCoV),
2:576
Canine transmissible veneral tumor (CTVT),
3:448-449, 3:449f, 3:509, 3:510f
Canine tubulointerstitium, 2:382f
Canine urothelial cell carcinomas, 2:462-463
Canine uveodermatologic syndrome, 1:557,
1:557f-558f, 1:613

Canine X-linked muscular dystrophy,
1:192-194, 1:193f-195f, 3:49
Capillaries, 3:54
Capillarization, liver, 2:288
Capped elbow, 1:155
Capped hocks, 1:155
pigs, 1:156
Capillarization of sinusoids, 2:260
Caprine arthritis-encephalitis virus (CAEV),
1:154, 1:154f, 1:378-380, 1:379f,
2:558-560, 2:559.e1f
mastitis with, 3:458
Caprine besnoitiosis, 1:662
Caprine herpesvirus 2, 1:625-627
Caprine herpesvirus 3, 2:132
Caprine lymphomas, 3:237
Capripoxvirus, 1:616, 1:622-624
Capsular pseudocysts, 2:396f
Capsular sclerosis, 3:339
Capture myopathy, 1:223
Cara inchada, 2:12
Carbadox, 3:343
Carbohydrate overload, 2:40-43
Carbolic dips, 2:519
Carbon dioxide excretion, 2:381
Carbon monoxide poisoning, 1:306
Carboxyterminal telopeptide of type I
collagen (ICTP), 1:27
Carcinoids, 2:497-498
hepatic, 2:349, 2:350f
Carcinomas/adenocarcinomas, 2:30, 2:463.
See also Neoplasia; Tumors
adrenal gland, 3:345-346, 3:346f
aortic body, 3:354-355, 3:354f
carotid body, 3:355-356
derived from apocrine glands of the anal
sac, 3:307f-308f, 3:308
endometrium and cervix, 3:449-450,
3:450f
exocrine pancreatic, 2:366-367,
2:367f
feline pulmonary, 2:497.e1f
gastrointestinal, 2:101-104
of gland of the third eyelid, 1:482
hepatocellular, 2:346, 2:346.e1f
lower urinary tract, 2:462
mammary, 3:460-463, 3:462f, 3:463t
nasal, 2:478, 2:478f-479f
ovine pulmonary, 2:560-562, 2:561f,
2:561.e1f
pulmonary, 1:736, 2:495-500, 2:496t,
2:497f-498f, 2:495.e2f
rectal, 2:103f
splenic, 3:194, 3:194f
testicular, 3:496
thymic, 3:156-157, 3:157f
thyroid, 3:329-332, 3:330f
tracheal, 2:483
Carcinosarcoma, 2:497
Cardenolide cardiac glycoside, 3:35
Cardiac dilation, 3:7-9, 3:7f
Cardiac fibrosis, 2:298
Cardiac gland mucosa, 2:44, 2:46
Cardiac hypertrophy, 3:7-9
Cardiac myocytes, 3:3
Cardiac output no-reflow phenomenon,
2:398
Cardiac rhabdomyomas, 1:241
Cardiac rhabdomyosarcomas, 1:243
Cardiac skeleton, 3:2
Cardiac syncope, 3:10
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Cardigan Welsh Corgi dogs, severe combined
immunodeficiency (SCID) in, 3:139
Cardiomyopathies, 3:44-51, 3:45.e1f
cats, 3:46-48, 3:46.e2f
cattle, 3:50-51, 3:50f
dogs, 3:48-49, 3:48f, 3:48.e2f
Cardiovascular system, 3:1-101. See also
Circulatory disturbances
conduction system diseases, 3:51
endocardial disease, 3:27-33
heart
congenital abnormalities, 3:14-24
diseases, 3:2-54
examination, 3:12-14
failure, 3:6-12
neoplasms, 3:52-54, 3:52f
lymphatics, 3:94-98
myocardial disease, 3:33-51
pericardial disease, 3:24-27
vascular system diseases, 3:54-101
veins, 3:88-94
Cardiovirus, 3:43
Caries, dental, 2:9-11, 2:10f
Caroli disease, 2:265
Carotid body adenoma and carcinoma,
3:355-356
Carpal hygromas, 1:154
Carprofen, 2:329
Cartilage, articular, 1:129
response to injury, 1:131-132
Cartilage-forming tumors, 1:116-121
Cartilaginous emboli, 1:299f
Cartilaginous end plates, 1:128-129
Cartilaginous joints, 1:128-129
degenerative diseases of, 1:143-145
dogs, 1:143-144
Caruncles, 3:400
Caryospora spp., 1:664
Case coordination, 1:12
Case interpretation and client service in
postmortem examinations, 1:12-14,
1:13f
Casein clot formation, 2:38
Caseonecrotic bronchopneumonia, 2:553f
Caseous lymphadenitis (CLA), 2:562,
3:204-208, 3:207f-208f, 2:562.e1f,
3:205.e1f
Caseous tuberculosis, 3:389
Cassia occidentalis, 1:220, 1:220f
myocardial necrosis and, 3:36
Castor beans, 2:117
Catagen phase, hair, 1:516
Cataract, 1:442-444, 1:442f
congenital, 1:422
deposition of calcium salts in, 1:443
diabetic, 1:443
galactose-induced, 1:443
megavoltage X-radiation, 1:444
Soemmering ring, 1:444, 1:444f
sunlight-induced, 1:443-444
uveitis and, 1:447-448
Catarrhal bronchitis, 2:501
Catarrhal stomatitis, 2:14
Catecholamine, 3:271
hormone biosynthesis, 3:348-349,
3:350f
Caterpillar cells, 3:37
Cat fur mite, 1:683
Cattle, epidermolysis bullosa in, 1:534-535
Cauda equina, neuritis of, 1:394-395
Caudal fossa, 1:274-277
Index 519
Caudal regression syndrome, 1:56-57
Cauliflower-like growths, 2:103-104
Cavalier King Charles Spaniel dogs, 2:457
caudal fossa, 1:277
ichthyosis, 1:531-532
inherited thrombocytopenia, 3:258
muscle hypertonicity, 1:203
myxomatous valvular degeneration, 3:27
oral eosinophilic granuloma, 2:16
otitis media with effusion, 1:498
Cavitating leukodystrophy, 1:339-340
CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-
nitrosourea), 2:329
CD8+ T-cells
in masticatory myositis, 1:226-227
in polymyositis, 1:228-229
CD4+ T-cells in masticatory myositis,
1:226-227
Cebocephaly, 1:270
Cecal dilation, 2:78
Cecocolic intussusception, 2:84f
in horse, 2:84
Cell-mediated immunity, 2:548-549
Cellular crescent, 2:406.e1f
Cellular elements of bone, 1:17-19, 1:17f
Cellularity, of glomerular tuft, 2:405
Cellular swelling, acute, 2:421-422
Cellulitis, 1:636-637
canine juvenile, 1:690-691, 1:691f
Celomic epithelium tumors, 3:377, 3:377f
Cementing lines, 1:27, 1:27f
Cementum, 2:5-6
hyperplasia, 2:6
hypertrophy, 2:6-8
Central and peripheral neuronopathies,
1:326-334
Central chromatolysis, 1:252f-253f, 1:314,
1:333f
Central nervous system (CNS). See also
Nervous system
anoxia and, 1:305-307
degeneration, 1:303-350
fixed macrophage system, 1:262
inflammation, 1:350-396, 1:351t-352t
bacterial and pyogenic infections,
1:353-365
chlamydia disease, 1:391-392
helminth and arthropod infections,
1:389-391
idiopathic inflammatory diseases,
1:392-396, 1:392f
microsporidian infections, 1:385-386
parasitic infections, 1:386-391
viral infections, 1:365-385
injury and myocardial necrosis, 3:39
malformations, 1:264-284
with BVDV, 3:426-427
viral causes, 1:280-284
microcirculation, 1:263-264, 1:264f,
1:263.e1f
muscular defects, 1:187-189
neoplastic diseases, 1:396-406
oligodendrocytes in, 1:258
spinal cord, 1:277-279
arachnoid cysts, 1:279
diplomyelia, 1:278f
dysraphism, 1:278f
embolism, 2:490
lymphoma, 3:240f
myelodysplasia, 1:277-279, 1:278f
segmental hypoplasia of, 1:277f
520 Index
Central nervous system (CNS) (Continued)
spina bifida, 1:57, 1:279
subdural hemorrhage of, 1:303f
subdural/intradural abscess, 1:354f
syringomyelia, 1:278f
storage diseases, 1:284-293
traumatic injuries, 1:301-303
Wallerian-like degeneration, 1:256-257
Central osteosarcomas, 1:110
Centrilobular liver
fibrosis, 2:289, 2:289f
necrosis, 2:282
Centronuclear myopathy of Labrador
Retrievers, 1:197, 1:197f
Cercopithifilaria spp., 1:690
Cerebellar atrophy, 1:276, 1:276f
Cerebellar cortical degeneration, 1:318-320
Cerebellum
agenesis, hypoplasia, and dysplasia,
1:275-276, 1:275f
Arnold-Chiari malformation, 1:276-277,
1:277f
atrophy, 1:276, 1:276f
Dandy-Walker syndrome, 1:277
development, 1:274-277
hypoplasia, 1:275f
intracranial arachnoid cyst, 1:280f
vascular leakage, 1:298f
Cerebral abscess, 1:360f
Cerebral aplasia, 1:266-267, 1:266f
Cerebral corticogenesis defects, 1:268
Cerebral edema, 1:295f
Cerebral swelling, 1:293-295
Cerebrocortical necrosis, 1:5f
Cerebrocortical atrophy, 1:7f
Cerebrospinal angiopathy, 1:298, 1:298f, 3:60
Cerebrospinal fluid (CSF), 1:270-272
Cerebrospinal vasculitis, 1:298-299, 1:298f
Cerebrum, 1:266-274
cerebral aplasia, anencephaly, 1:266-267,
1:266f
defects in cerebral corticogenesis, 1:268
disorders of axonal growth, 1:268-269
encephalocele, meningocele, 1:267,
1:267f
holoprosencephaly, 1:269-270, 1:269f
hydranencephaly, porencephaly, 1:272-274,
1:272f
hydrocephalus, 1:270-272, 1:271f
periventricular leukomalacia of neonates,
1:274
Ceroid/lipofuscin, 1:254
Ceroid-lipofuscinoses, 1:290-292, 1:291f
Ceroid lipofuscinosis, 1:291f
Certification of pathologists, 1:14
Ceruminous glands
cysts and tumors, 1:719
neoplasms, 1:507-508
Cervical vertebral malformation-
malarticulation, 1:136, 1:136f
dogs, 1:136, 1:136f
horses, 1:136, 1:136f
Cervicitis, 3:441-442
Cervicovaginitis, bovine, 3:443
Cervix
carcinoma, 3:449-450, 3:450f
dilations and diverticula, 3:369
hypoplasia, 3:368-369
pathology, 3:441-442
Cestodes, 2:221-223, 2:319-320
central nervous system and, 1:389
Cestrum spp., 2:331
Chabertia ovina, 2:215-216
Chabertia spp., 2:215-216
Chagas disease, 3:44, 3:44f
Chain-of-custody, 1:2
Chalazion, 1:423, 1:423f
Channel Island cattle, spontaneous rupture of
gastrocnemius muscle, 1:211
Channelopathies, 1:200
Characteristic granular pattern, 2:407-408
Charolais cattle
hip dysplasia in, 1:135-136
progressive ataxia, 1:341, 1:341f
Chediak-Higashi syndrome (CHS), 1:556,
3:110, 3:259
Chemical abomasitis, 2:52
Chemical gastritis, 2:52
Chemical injury
lungs, 2:518-520
parathyroid glands, 3:298
rodenticide intoxication, 3:264
to skin, 1:566-575
Chemical peritonitis, 2:250
Chemodectomas, 3:354-356
aortic body adenoma and carcinoma,
3:354-355, 3:354f
carotid body adenoma and carcinoma,
3:355-356
development, structure, and function,
3:354
extra-adrenal paragangliomas, 3:356
heart-base tumors derived from ectopic
thyroid, 3:356
Chemokines, 2:408
Chemosensory cells, 2:469
Chemotactic cytokines, 2:408
Chesapeake Bay Retriever dogs
degenerative radiculomyelopathy, 1:330
follicular dysplasia, 1:540-541, 1:540.e1f
Cheyletiellosis, 1:678
Chief cell adenoma, 3:302, 3:303f
Chief cells, 2:45
Chihuahua dogs
axonal dystrophy, 1:325
color dilution alopecia, 1:539-540
corneal edema in, 1:429
corneal endothelial dystrophy, 1:433
myxomatous valvular degeneration,
3:27
Chimerism, 3:363
Chinaberry tree, 2:89
Chinese Crested dogs
congenital hypotrichosis, 1:538-539
hereditary striatonigral and cerebello-
olivary degeneration, 1:319
Chinese Shar Pei dogs
canine atopic dermatitis, 1:591
cobalamin deficiency, 3:127
cutaneous mucinosis, 1:546
demodectic mange, 1:679
familial AA amyloidosis, 2:278-279
familial Chinese Shar Pei fever, 1:158
intestinal lymphomas, 3:239
seborrhea, 1:548
selective deficiencies of immunoglobulins,
3:139
vasculitis, 3:70
Chlamydia, 2:53
abortion and, 3:414, 3:415f
arthritis, 1:152-153
central nervous system and, 1:391-392
respiratory system and, 2:551, 2:563,
2:590
Chlamydia abortus, 3:414, 3:415f
Chlamydophila felis, 1:425, 2:590
Chlamydophila psittaci, 2:551, 2:590
Chlamydophila spp., 2:53, 2:113
Chlorella algae, 1:665
Choanal atresia, 2:473
Cholangiocarcinomas, 2:348, 2:349f
Cholangiocellular tumors, 2:348-349, 2:348f
mixed hepatocellular and, 2:349, 2:349.e1f
Cholangiocytes, 2:262
Cholangiohepatitis, 2:301, 2:307-308,
2:307.e1f
Cholangitis, 2:301, 2:307-308, 2:308f
Cholecalciferol, 3:295-296
-25-hydroxylase, 3:295
Cholestasis, 3:265
Cholecystitis, 2:301, 2:306-307
Choledochal cysts, 2:265-266
Choledochitis, 2:301
Cholelithiasis, 2:308-309, 2:309f
Cholestasis, 2:292-294, 2:292f
Cholestatis injury, 2:327
Cholesteatoma, 1:499, 1:499f
Cholesteatosis of choroid plexus, 1:304,
1:304f
Cholesterol granuloma, 1:304f
middle ear and, 1:497
Chondritis, laryngeal, 2:481-482, 2:481.e2f
Chondroblastic osteosarcomas, 1:113-114,
1:113f
Chondrocytes, 1:22-24
Chondrodysplasias, 1:37-46, 1:37t
cats, 1:45-46, 1:46f
cattle, 1:38-39, 1:38f
dogs, 1:37-46, 1:43f-44f
horses, 1:42, 1:43f
pigs, 1:42
sheep, 1:40-42, 1:40f-42f
Chondrodystrophy, 1:37
dogs, 1:143-144
manganese deficiency in, 1:80
Chondroid bone, 1:21
Chondromas, 1:116
laryngeal, 2:482, 2:482.e1f
Chondromatosis, synovial, 1:162, 1:162f
Chondrosarcomas, 1:118-121, 3:52
dogs, 1:118, 1:119f
nasal, 2:480, 2:480.e1f
Chordoma, 1:404, 1:404f
Chorioallantoic membranes, 3:400
Chorioptic mange, 1:676-677, 1:677f
Chorioretinitis, 1:446
Choristoma, 1:520
Choroidal hypoplasia, 1:413, 1:414f
Choroidal melanocytomas, 1:483
Choroiditis, 1:357f
Choroid of uvea, 1:445
Choroid plexus, 1:262
age changes, 1:304, 1:304f
carcinoma, 1:401f
papilloma, 1:401, 1:401f
Chow Chow dogs
alopecia X, 1:589-590
canine hypomyelinogenesis, 1:337
color dilution alopecia, 1:539-540
congenital myotonia, 1:200f, 1:201
early onset diabetes mellitus, 2:373
hypothyroidism, 1:587
malignant melanoma, 2:26
Chromatolysis, 1:252f, 1:314
central, 1:252f-253f, 1:314, 1:333-334,
1:333f
peripheral, 1:253
Chromoblastomycosis, 1:654-655
Chromogranin A, 3:294
 Index 521

Chromomycosis, 1:654-655, 1:655f
Chromosomes
disorders of sexual development and,
3:469
sex
disorders, 3:363-365, 3:363f-365f, 3:469
genotype, 3:360
Chronic bronchitis, 2:501-502, 2:502.e1f
cats, 2:503
Chronic cardiac glycoside poisoning, 3:35
Chronic degenerative joint disease, 1:138-
140, 1:140f
Chronic endometritis, 3:389-390
Chronic eosinophilic enteritis in horses, 2:96
Chronic erosive colitis, 2:93f
Chronic erysipelas, 1:149-150
Chronic gingivostomatitis, 2:15-16
Chronic hepatitis, 2:301-306
cats, 2:305
dogs, 2:302-305, 2:305f
horses, 2:305, 2:305.e1f
Chronic hepatotoxic injury, 2:328
Chronic hypertrophic pyloric gastropathy,
2:48
Chronic inflammatory bowel disease, 2:2,
2:92
Chronic interstitial pancreatitis, 2:360,
2:361f
Chronic lymphadenitis, 3:203-204, 3:203f,
3:204.e1f
Chronic lymphocytic leukemia (CLL), 3:136
Chronic lymphocytic leukemia/small
lymphocytic lymphoma (B-CLL/SLL),
3:219-220
Chronic metabolic acidosis, 1:67
Chronic polypoid cystitis, 2:460-461
Chronic pressure overload, 3:7
Chronic renal disease, 2:16-17
anemia and, 3:127
hyperparathyroidism secondary to,
3:300-301, 3:300f
hypertension and, 3:59
Chronic renal failure (CRF), 2:377-378,
2:384, 2:413-414
Chronic rhinitis, 2:475
Chronic suppurative bronchopneumonia,
2:508, 2:508.e1f
Chronic suppurative sinusitis, 2:477-478,
2:477.e1f
Chronic ulcerative paradental syndrome, 2:16
Chronic ulcerative stomatitis, 2:16
Chronic volume overload, 3:7
Chronic wasting disease (CWD), 1:349
Chrysomyia bezziana, 1:669-670
Chuzan virus (CHUV), 1:281, 3:431
Chylothorax, 2:521, 3:95-96, 2:521.e3f
Chylous ascites, 3:96
Cicatricial alopecia, 1:698
Cicuta douglasii, 3:36
Cilia-associated respiratory bacillus (CAR),
2:547, 2:547f
Ciliary body of uvea, 1:445
Ciliary dyskinesis, 1:496
Ciliated cells, 2:469
Circoviruses, 2:116
circoviral antigen stains, 2:116
Circovirus postweaning multisystemic
wasting syndrome (PMWS), 2:527-529,
3:210-212, 3:210f-212f, 3:440, 3:440f
Circulating nonhematopoietic neoplastic
cells, 3:137-138
Circulation, micro-, 1:263-264
Circulatory disturbances, 2:51-52
brain, 1:296-301, 1:296f
buccal cavity and mucosa, 2:12-13
circulatory failure, 3:6, 3:10-12
edema, 2:51
gastric venous infarction, 2:51
hyperemia, 2:51
lung, 2:487-494
muscle, 1:210-213, 1:211f
compartment syndrome, 1:211
downer syndrome, 1:212
muscle crush syndrome, 1:212
postanesthethic myopathy in horses,
1:213
vascular occlusive syndrome, 1:212,
1:212f
nasal cavity, 2:473-474
ovary, 3:381-382
spleen, 3:169-171
stomach, 2:51-52
testes, 3:491-492
uremic gastritis, 2:51
Circumventricular organs (CVOs), 1:263,
1:263.e1f
Cirrhosis, 2:289-290
hepatic fatty, 2:276, 2:276.e1f
hypertrophic hepatic, 2:306
Cisplatin, 1:494
Citrobacter koseri, 3:42
Classical swine fever virus (CSFV), 1:283,
3:77-79, 3:78f, 3:178-181, 3:179f-180f,
3:77.e1f, 3:78.e1f, 3:79.e1f
pigs, 1:104
pregnant uterus, 3:79, 3:424-425
sheep, 1:104
thymic atrophy and, 3:145
Classic equine viral papillomatosis, 1:707-
710, 1:708f, 1:708t
Classic hepatic lobule, 2:261
Classification of lymphomas, 3:215-243,
3:217t
Clear cell basal cell carcinomas, 1:714
Clear cell epitrichial carcinomas, 1:719
Cleft palates, 2:3, 2:3f
primary, 2:3
secondary, 2:3f
Clefts, epidermal, 1:519, 1:519f
Clonality, 3:215
Clonorchis sinensis, 2:323-324
Clostridial myositis, 1:230-233, 1:231f
Clostridium botulinum, 2:77, 2:183-194
Clostridium chauvoei, 2:183-194, 3:42
Clostridium difficile, 2:100, 2:183-194,
2:192f-194f
acute necro-hemorrhagic colitis, 2:99f
Clostridium haemolyticum, 3:126
liver and, 2:317
Clostridium novyi, 3:126
liver and, 2:316
Clostridium perfringens, 2:53-54, 2:183-194,
2:187f, 2:452, 3:126
gastritis, 2:57
type A, 2:113
type C, 2:84, 2:100, 2:113, 2:187,
2:187f-188f
type D enterotoxemia, 2:115, 2:188-191,
2:189f-190f
Clostridium piliforme, 2:98-99, 2:113-114,
2:183-194, 3:42
liver and, 2:314-315, 2:317, 2:317f-318f
Clostridium septicum, 2:53, 2:183-194
Clotting times, 3:263
Club cells, 2:469, 2:469.e1f
Coagulase-positive staphylococci, 2:456
Coagulation
liver disease and, 3:264-265
regulation of, 3:265-266
Coagulative myocytolysis, 3:37
Coagulative necrosis, 3:37
gastric wall, 2:56
liver, 2:281
Coarctation of the aorta, 3:23, 3:23f
Coat color
dilution and black hair follicular dysplasia,
1:557
-linked hair follicle dysplasia, 1:540
Cobalamin
deficiency, 3:127
malabsorption, 2:69-70
Coccidioides immitis, 1:449-450, 2:583-584,
2:584f
adrenal cortex and, 3:340
Coccidioides posadasii, 2:583-584
Coccidioides spp., 1:103-104, 1:104f,
2:115-116
respiratory system and, 2:583-584
Coccidiosis, 2:227-235
cattle, 2:229-231, 2:230f
dogs and cats, 2:235-239
horses, 2:233-234
pigs, 2:234-235, 2:234f
sheep and goats, 2:231-233, 2:232f
Cochlear duct, 1:489, 1:489f
Cochleosaccular degeneration, 1:492
Cochliomyia hominivorax, 1:669-670, 2:43
Cochliomyia macellaria, 1:669-670
Cocker Spaniel dogs
axonal dystrophy, 1:325
dilated cardiomyopathy, 3:48
lymphomas, 3:238
malignant melanoma, 2:26
malignant oral tumors, 2:21
multisystem neuronal degeneration,
1:320
myxomatous valvular degeneration, 3:27
peripheral vestibular disease, 1:494
seborrhea, 1:548
Codman’s triangle, 1:33
Coenurus cerebralis, 1:389
Coffee senna plant, 1:219-220
COL4A3 gene, 2:416
COL4A4 gene, 2:416
COL4A5 gene, 2:415-416
Cold agglutinin disease, 1:608
Cold injury, 1:564
Coliform arthritis, 1:151
Coliform mastitis, 3:454-455, 3:454f-455f
Colitis. See also Clostridium difficile
cats, 2:98-99
cystica profunda, 2:97
idiopathic mucosal, 2:92-93
canine, 2:94
necrotic, 2:99, 2:99f
spirochetal, in pigs, 2:181-183
weaner colitis of sheep, 2:180-181
Collagen dysplasia, 1:543-544
cats, 1:545, 1:545f
cattle, 1:544
dogs, 1:544-545, 1:545f
horses, 1:544, 1:544.e1f
sheep, 1:544

Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510

522 Index
Collagen fibers, 1:129
degeneration, 1:519
dermal, 1:514
Collagenofibrotic glomerulonephropathy,
2:419f, 2:418.e1f
Collagenous hamartomas, 1:723
Collagenous metaplasia, 1:304
Collapse, tracheal, 2:483f, 1:192.e1
Collie dogs
afibrinogenemia, 3:265
axonal dystrophy, 1:324
canine dermatomyositis, 1:198
choroidal hypoplasia, 1:413
Collie eye anomaly, 1:413-414, 1:414f
hereditary deafness, 1:492
hyperestrogenism, 1:589
melanocytopenic hypomelanosis, 1:555
motor neuron disease, 1:331
retinal folding, 1:419
Collie eye anomaly (CEA), 1:413-414,
1:414f
Colliquative myocytolysis, 3:37
Colloid goiter, 3:322, 3:322f
Colloid mineralization, 3:314, 3:315f
Coloboma, 1:412, 1:412f
Colon
adenocarcinoma
cats, 2:103f
metastasis, 2:102-103
bacteria, 2:65
colonic glands, 2:61-62
epithelial cell proliferation, 2:68
impaction, 2:76
invasive carcinoma, 2:105f
lamina propria, 2:62
left dorsal displacement, 2:78-79, 2:79f
mesenteric attachments anomaly, 2:74
neoplasms, 2:117
osmotic overload, 2:71-72
right dorsal displacement, 2:78
tympany, 2:78
volvulus, 2:79
Color dilution alopecia, 1:539-540, 1:540f,
1:557
Combined ocular and skeletal dysplasia, 1:45
Comedo, 1:524
Committed myoblasts, 1:167
Compact cell carcinoma of thyroid, 3:330,
3:331f
Compartment syndrome, 1:211
Complement-leukocyte-dependent
mechanism, 2:408
Complete blood count (CBC), 3:257
Complex partial cluster seizures with
orofacial involvement, 1:307-308
Complex secretory epitrichial adenomas,
1:718-719
Complex vertebral malformation (CVM),
1:57
Compositae/asteracae, 2:331
Compound granular corpuscles, 1:263
Compressive atelectasis, 2:486
Compressive optic neuropathy, 1:320
Computed tomography (CT), 1:30
Concentric cardiac hypertrophy, 3:8, 3:8f
Concussion, 1:302
Conduction, heart impulse, 3:5
Conduction hearing loss, 1:496
Condylar fractures, 1:36
Cone dysplasia, 1:469
Congenital absence of the pericardium,
3:22
Congenital aneurysm, 3:23
Congenital atelectasis, 2:486
Congenital chondrodystrophy of unknown
origin (CCUO), 1:80
Congenital colonic aganglionosis, 2:74
Congenital corneal opacities, 1:421-422
Congenital cystic adenomatoid malformation,
2:485, 2:485.e1f
Congenital diaphragmatic clefts, 1:191-192
Congenital dilation of large and segmental
bile ducts, 2:265
Congenital duplication cysts, 2:31
Congenital enzyme defects of adrenal cortex,
3:339
Congenital erythropoietic porphyria, 1:59-60,
1:59f
cats, 1:59
cattle, 1:59-60
pigmentation of teeth in, 2:7
Congenital flexures, 1:189
Congenital follicular parakeratosis, 1:532
Congenital hearing impairment, 1:491-492
Congenital heart abnormalities, 3:14-24,
3:15t, 3:66-67
Congenital hematomas, 3:22-23
endocardium, 3:30
Congenital hepatic fibrocystic diseases,
2:265
Congenital hepatic fibrosis, 2:265,
2:265f-266f
Congenital histiocytosis, 1:730
Congenital hyperostosis (diaphyseal
dysplasia), 1:53, 1:53f
Congenital hypothyroidism with
dyshormonogenic goiter, 3:314, 3:323f
Congenital hypotrichosis, 1:538-539
associated with pigmentary alteration,
1:539-541
cats, 1:539
cattle, 1:538-539
dogs, 1:539, 1:539.e1f
Congenital idiopathic megaesophagus (CIM),
2:33-34
Congenital inguinal hernia, 2:80
Congenital intrahepatic arterioportal fistulae,
2:266f
Congenital melanosis, 2:270
Congenital myasthenia gravis, 1:209
Congenital spinal stenosis, 1:81
Congenital status spongiosus of Gelbvieh-
cross calves, 1:347
Congenital stenosis of pancreatic duct,
2:355-356
Congenital tremor (CT), 1:338
Congenital trigeminal nerve hypoplasia,
1:187, 1:188f
Congenitally ectopic lenses, 1:422
Congestion, pulmonary, 2:487
Congestive brain swelling, 1:294
Congestive heart failure, 2:115, 3:6, 3:10-12,
3:11f, 3:9.e1f
Congo red (CR) stain, 2:415
Conidiobolomycosis, 1:659-660
granulomatous rhinitis and, 2:476
Conium maculatum, 1:90, 2:3
Conjunctiva, 1:424-427
neoplasms, 1:479-480, 1:479f-480f
tumors, 1:481-482
Conjunctivitis, 1:424-427
eosinophilic, 1:426
feline lipogranulomatous, 1:427, 1:427f
immune-mediated, 1:426-427
ligneous, 1:426-427
Connective tissue disorders, 1:542-546
Constrictive pericarditis, 3:26, 3:27f
Contact activation pathway, 3:261
Contact dermatitis
allergic, 1:596-597
irritant, 1:566-568, 1:567f
phytophoto, 1:578-579
Contagious agalactia, 3:458
Contagious bovine pleuropneumonia
(CBPP), 2:551-552
Contagious caprine pleuropneumonia
(CCPP), 2:563-564
Contagious equine metritis (CEM), 3:445,
3:445f
Contagious footrot, 1:643-644
Contagious ovine digital dermatitis (CODD),
1:644
Contagious pustular dermatitis, 1:617-618,
1:617f
Continuing education for pathologists,
1:14-15
Contractility disturbances, 3:4-5
Contractures, muscle, 1:213-214
Contusions, head, 1:302
Convulsions, bovine familial, 1:319
Coonhound paralysis, 1:394
Cooperia spp., 2:213
Coopworth sheep, 1:324
Copper
deficiency, 1:559f, 2:115
myocardial necrosis and, 3:34
neonatal, 1:328-329, 1:328f
osteochondrosis and, 1:81
osteoporosis and, 1:66
pigmentation and, 1:558, 1:558f
liver toxicity, 2:342-343
staining in liver, 2:303, 2:303f
Corgi dogs
canine dermatomyositis, 1:198
degenerative diseases of cartilaginous joints
in, 1:143-144
degenerative radiculomyelopathy,
1:330
severe combined immunodeficiency
(SCID), 3:139
tongue atrophy, 1:228
Cornea, 1:427-441
anomalies, 1:421-422
cutaneous metaplasia, 1:429, 1:429f
degeneration, 1:434-436
dermoid, 1:421, 1:422f
dystrophies and deposits, 1:433-434
endothelial dystrophy, 1:433
keratitis, 1:436-441
lipid and crystalline, 1:433
normal, 1:428f
secondary to injury, 1:434, 1:434f
secondary to metabolic disease,
1:433-434, 1:433f
wound healing, 1:429-432, 1:430f,
1:431t, 1:432f
edema, 1:428-429, 1:428f, 2:136f
perforation, 1:437, 1:437f
sequestrum in horses, 1:435
Corneodesmosomes, 1:513
Cornified envelope (CE), 1:513
Coronary embolism, 3:36
Coronavirus, 2:146-151
cats, 2:117, 2:150-151, 2:587-588
cattle, 2:112, 2:148-150, 2:149f, 2:541-
542, 2:542.e1f
dogs, 2:150, 2:576
horses, 2:150
pigs, 2:113, 2:115, 2:147-148, 2:529

Corpora amylacea, 3:504-505
-like bodies, 3:314
Cor pulmonale, 3:6
Corpus callosum, agenesis of, 1:269, 1:269f
Cortical adenomas, 3:344-345, 3:345f
Cortical dysplasia, 1:268
Cortical granuloma, 2:442.e3f
Cortical nephrons, 2:377
Corticogenesis, cerebral, 1:268
Corticosteroid-induced osteoporosis, 1:67
Corticosteroids, hypokalemia, 2:394
Corticotroph (ACTH-secreting) adenoma,
3:281-282, 3:281f, 3:283f-284f
Corticotropin-releasing hormone (CRH),
3:338
Cortisol levels and hyperadrenocorticism,
1:224-225, 3:346-347, 3:347f
Cor triatriatum, 3:22
dexter, 3:22
Corynebacterium pseudotuberculosis, 1:230,
2:433, 3:69, 3:97
caseous lymphadenitis and, 3:204-208,
3:207f-208f, 3:205.e1f
splenic abscesses, 3:183-184
Corynebacterium renale, 2:459
Corynetoxin poisoning, 1:309
Coughing, 2:471-472
Countercurrent exchange system, 2:379,
2:381
Cowdriosis, 3:80-82
Cowpox virus, 1:616, 1:619-620, 1:619f
cats, 2:587-588
Coxiella burnetti, 3:416-417, 3:416f
Coyotillo, 1:219-220
poisoning, 1:326
Cranial bones, 1:21
Cranial nerves
internal ear neoplasia and, 1:494
nuclei, 2:77
peripheral vestibular disease and,
1:494
Craniomandibular osteopathy, 1:91-92
dogs, 1:91, 1:92f
Craniopharyngioma, 1:404, 3:287, 3:287f
Creatine kinase (CK)
canine dermatomyositis, 1:198
canine X-linked muscular dystrophy,
1:192-193
centronuclear myopathy of Labrador
Retrievers, 1:197
congenital myotonia in cats, 1:201
diaphragmatic dystrophy in cattle, 1:199
glycogenosis type II, 1:208
ischemic damage, 1:211
masticatory myositis, 1:226
nemaline myopathy of cats, 1:198
polymyositis, 1:227-229
purpura hemorrhagica, 1:229
Crenosoma vulpis, 2:586
Crescentic proliferative glomerulonephritis,
2:412f
Cretan Hounds, canine hypomyelinogenesis
in, 1:338
Cricopharyngeal dysphagia, 2:33
Crofton weed, 2:519
Cropped pinnae, 1:502
Crossiella equi, 3:417
Crossed renal ectopia, 2:392
Crotalaria retusa, 2:3
Crooked-calf disease, 1:90
Crusts, 1:519, 2:123-124
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Cryopathies, 1:608
Cryptococcus gatti, 2:582
Cryptococcus neoformans, 1:449
adrenal cortex and, 3:340
granulomatous rhinitis and, 2:476
lymph nodes and, 3:207f
respiratory system and, 2:582, 2:583f
Cryptococcus osteomyelitis, 1:104, 1:104f
Cryptococcus spp., 1:104, 1:104f, 1:450,
1:450f, 2:582-583
Cryptocotyle, 2:225-227
Cryptorchidism, 3:476-478, 3:476f-477f
Cryptosporidiosis, 2:239-241, 2:240f-241f
Cryptosporidium andersoni, 2:54-55, 2:241
Cryptosporidium parvum, 2:111, 2:241,
3:140
Crystal-associated cholangiohepatopathy,
2:340, 2:340f
Crystalline dystrophies, corneal, 1:433
Cytauxzoon felis, 3:120-121
Culicoides hypersensitivity, 1:598-599, 1:599f
Culicoides oxystoma, 3:431
Cushing’s disease, 1:224-225, 3:346-347,
3:347f
Cutaneous adverse food reaction, 1:594-596,
1:595f
Cutaneous amyloidosis, 1:614
Cutaneous anaplastic large T-cell lymphoma,
3:234-235, 3:234f
Cutaneous and systemic reactive histiocytosis
(CRH), 1:729, 1:729.e1f
Cutaneous angiomatosis, 1:727
Cutaneous asthenia, 1:545, 1:545f
Cutaneous bacterial granulomas, 1:637-642
Cutaneous epitheliotropic T-cell lymphoma
(CTCL), 1:733-734
Cutaneous habronemiasis, 1:685-686,
1:685f
Cutaneous histiocytoma, canine, 3:243-245,
3:244f-245f, 3:244.e1f, 3:243.e1f
Cutaneous horns, 1:551, 1:705
Cutaneous iodism, 1:570
Cutaneous Langerhans cell histiocytosis,
1:729, 3:245-246, 3:246f
Cutaneous leishmaniasis, 3:174-175
Cutaneous lupus erythematosus, 1:605-607
Cutaneous lymphomas, 1:733-735, 1:733f,
3:237.e1f
Cutaneous mucinosis, 1:546
Cutaneous oomycosis, 1:657-659
Cutaneous paraneoplastic syndromes,
1:691-693
Cutaneous plasmacytoma, 1:735, 1:735f,
3:228f, 3:226.e1f
Cutaneous pseudolymphomas, 1:734-735
Cutaneous reactive histiocytosis, 3:247-249,
3:248f-249f, 3:249.e1f
Cutaneous T-cell lymphoma (CTCL),
3:232-235
Cutaneous tumors of neural origin, 1:724
Cutaneous xanthoma, 1:700
Cuterebra spp., 1:391, 1:426, 1:668, 1:668f
Cutting cones, 1:64
Cyanide poisoning, 1:305-306
Cyanobacteria, 2:330
Cycadales, 2:331
Cycad poisoning, 1:322, 1:323f
Cyclic adenosine monophosphate (cAMP),
2:71
toxin-stimulated, 2:71
Cyclic hematopoiesis, 1:556-557
Index 523
Cyclitic membrane, 1:447
Cyclooxygenase-2 expression, neoplastic
urinary bladder epithelium, 2:462-463
Cyclopamine, 1:90
Cyclophosphamide-induced lesions, 2:460
Cyclopia, 1:269, 1:269f, 1:410-411, 1:411f
Cyclosporin and osteoporosis, 1:67
Cylicospirura felineus, 2:211
CYP isozymes, 2:519
Cystadenomas
epitrichial, 1:718
thyroid, 3:326
Cystic adenomas, 3:326-327
Cystic dental inclusions, 2:7
Cystic dilation of pancreatic duct, 2:355-356
Cystic diseases, of kidney, 2:394
Cystic endometrial hyperplasia, 3:382-385,
3:382f-383f, 3:391, 3:391f-392f
Cystic epoophoron, 3:371
Cysticerci, 2:255
Cysticercosis, 1:239-240, 1:239f
Cysticercus bovis, 1:239, 1:389
Cysticercus cellulosae, 1:239, 1:239f, 1:389
Cysticercus ovis, 1:239-240, 1:239f
Cysticercus tarandi, 1:240
Cysticercus tenuicollis, 3:473-474
liver and, 2:318-319, 2:319f
Cystic eye, 1:411-412, 1:411f
Cystic follicular disease, 3:372
Cystic mucinous hyperplasia, 2:345
Cystic nasal conchae, 2:478
Cystic ovarian disease in cows, 3:372-374,
3:373f
Cystic paroophoron, 3:371
Cystic placental mole, 3:396
Cystic rete, 3:371, 3:372f
Cystic septum pellucidum, 1:269
Cystic subsurface epithelial structures of the
bitch, 3:371-372
Cystic uterus masculinus, 3:501, 3:501f
Cystine stones, 2:458
Cystitis, 2:439, 2:459-461
chronic, 2:460-462
emphysematous, 2:459, 2:460f
eosinophilic, 2:460
feline interstitial, 2:460
follicular, 2:460-461, 2:460f
sterile hemorrhagic, 2:460
Cystocaulus ocreatus, 2:565, 2:565t, 2:567
Cystoisospora spp., 2:235-239
Cystoisospora suis, 2:113, 2:234-235, 2:234f
Cysts, 1:703-705
adrenal cortex, 3:339, 3:339f
arachnoid, 1:279, 1:280f
bone
benign, 1:126
subchondral (juxtacortical), 1:126,
1:134, 1:134f
bronchogenic, 2:484-485
cerebral cortex, 1:299f
cervical, 3:441
congenital duplication, of esophagus,
2:31
dentigerous, 2:6-7, 2:7f
epidermal inclusion, 2:478
epidermoid, 1:404
epithrichial, 1:705
hepatic, 2:264
liver fatty, 2:274-275, 2:274f
Neospora caninum, 1:388f
odontogenic, 2:6-7
524 Index

Cysts (Continued) Dalmatian dogs Degenerative joint diseases, 1:137-146

orbital, 1:478 canine atopic dermatitis, 1:591 cats, 1:143
ovarian, 3:371-372, 3:372f canine hypomyelinogenesis, 1:337 cattle, 1:143, 1:143f
germinal inclusion, 3:372, 3:372f canine X-linked muscular dystrophy in, chronic, 1:138-140, 1:140f
and uterine remnants, 3:366-367, 1:192 dogs, 1:138, 1:138f-139f, 1:142-145,
3:367f-368f cavitating leukodystrophy, 1:339-340 1:143f-144f
paranasal sinus, 2:478 chronic hepatitis, 2:304 gross lesions, 1:138, 1:138f
parathyroid, 3:297-302 deafness, 3:51 horses, 1:141-142, 1:141f-142f
peritoneum, 2:256 hereditary deafness, 1:492 synovial joints, 1:137-143
pharyngeal, 2:29 interstitial lung disease, 2:515 Degenerative mucinotic mural folliculitis,
pituitary, 3:279-281, 3:280f melanocytopenic hypomelanosis, 1:555 1:697
prostatic, 3:500-501 motor neuropathy, 1:335 Degenerative myopathies, 1:221-224
retrobulbar, 1:412, 1:412f nephritis, 2:416-417 Degenerative radiculomyelopathy of adult
Sarcocystis, 1:234-236 solar radiation and, 1:566 dogs, 1:330
serosal inclusion, 3:386-387, 3:387f Dandy-Walker syndrome, 1:277 Degenerative suspensory desmitits,
skin Darier disease (DD), 1:537 1:247
dermoid, 1:547, 1:704-705 Deafness Degradation of hormone, 3:275
epithelial, 1:500 acquired, 1:493 Dehydration, 2:384, 2:399
epitrichial, 1:705 hereditary, 1:492-493, 1:492f Dells, 1:524
ganglion, 1:162-163 traumatic causes of, 1:493-494 β-cells, endocrine pancreas, 2:368
hybrid, 1:704 Death Demodecosis, 1:681, 1:681f
infundibular, 1:704 adenosine triphosphate (ATP) in rigor Demodectic mange, 1:678-682, 1:680f
isthmus, 1:704 mortis, 1:186 Demodex cati, 1:681
lacrimal duct, 1:424 bronchopneumonia, 2:507-508 Demodex gatoi, 1:681
matrical, 1:704 causes of unexpected, 1:4t Demodex injai, 1:679-680, 1:680f
sebaceous duct, 1:705 diapedesis of red cells, 1:301 Demodex phylloides, 1:682
splenic, 3:189 embryonic, 3:395-396 Demodex spp., 1:506, 1:678-682
subepiglottic, 2:481 fetal, 3:395 Demyelinating diseases, 1:259
synovial, 1:162-163 gastric rupture and, 2:48 Demyelinating neuropathy, 1:341-342
thymic, 3:151, 3:152f, 3:151.e1f liver, 2:295-296 Dendritic cells
thyroglossal duct, 2:29, 3:310, 3:314 cell, 2:279-285 lung, 2:470
uveal, 1:446, 1:446f muscle changes after, 1:186 trafficking, 2:64
vaginal, 3:442 Phalaris poisoning and sudden, 1:293 Dendritic reticular cells, lymph node,
valvular, 3:30 retina after, 1:467 3:197-198
Cytauxzoonosis, 3:120-121, 3:120f ruminal mucosa after, 2:36 Denervation atrophy, 1:173-175, 1:174f-177f
splenic histiocytosis, 3:184f Decision analysis, 1:12, 1:13f Dental attrition, 2:7-8
Cytoarchitectural changes in muscle fibers, Decreased protein intake, 2:72 Dental calculus, 2:9
1:185, 1:185f Decubitus ulcers, 1:559 Dental caries, 2:9-11, 2:10f
Cytochrome P450 (CYP) isozymes, 2:519 Deep bacterial pyoderma, 1:634-637, Dental follicle, 2:4
Cytokeratin-7 expression, 2:462.e1 1:635f Dental lamina, 2:4
Cytokines in degenerative joint diseases, Deep plexus, dermal, 1:514 Dental lesions with canine distemper virus,
1:140-141 Deep stomatitides, 2:17-19 2:576
Cytopathic (CP) biotype, 2:122 Deer fly fever, 3:184-186, 3:185f Dentigerous cysts, 2:6-7, 2:7f
Cytoplasmic basophilia, 2:67 Defective mineralization, 1:68 Dentin, 2:5
Cytoplasmic plaque, 1:513-514 Deforming cervical spondylosis, 1:88 pigmentation of, 2:7
Cytotoxic edema, 1:294 Degeneration Deoxypyrolidine (DPD), 1:27
Cytotoxic hepatocellular injury, 2:327 adrenal cortex, 3:339-340, 3:339f Deoxyribonucleic acid (DNA) extraction,
amyloid, 1:297-298 1:30
D arteries, 3:56-61 Deposits
Dachshund dogs arteriosclerosis, 3:59-60 calcium salts, on lens, 1:443
canine acanthosis nigricans, 1:555 atherosclerosis, 3:57-59, 3:57.e2f corneal, 1:433-434
canine congenital myasthenia, 1:209 central nervous system, 1:317-336 cutaneous tissue, 1:562-564
cochleosaccular degeneration, 1:492 cerebellar cortical, 1:276, 1:276f Depression, 2:425
color dilution alopecia, 1:539-540 corneal, 1:434-436 Dermal edema, 1:519
corneal edema, 1:429 endocardium, 3:27-30 Dermal fibers, 1:514
degenerative diseases of cartilaginous exocrine pancreas, 2:356-364 Dermal perivascular unit, 1:515
joints, 1:143-144 fibrinoid, 1:520 Dermanyssus gallinae, 1:683
familial myoclonic epilepsy, 1:205 hydropic, 1:522, 1:522f Dermatitis
hyperadrenocorticism, 1:588 myocardial, 3:34, 3:34f acral lick, 1:561-562, 1:561f
hypothyroidism, 1:587, 3:315 nervous system, 1:303-350 atopic, 1:591-593, 1:591f, 1:592.e1f
malignant melanoma, 2:26 optic nerve, 1:476 contact
motor neuron disease, 1:331 ovarian, 3:371, 3:371f allergic, 1:596-597
myxomatous valvular degeneration, 3:27 parathyroid gland, 3:297-298 phytophoto-, 1:578-579
osteogenesis imperfecta, 1:50 pleura, 2:520 primary irritant, 1:566-568, 1:567f
osteopetrosis, 1:52 reticular, 1:523 with edema, eosinophilic, 1:696
seborrhea, 1:548 retinal, 1:468-469 eosinophilic, 1:693-696
sensory and autonomic neuropathy, spleen, 3:163-165 fibrosing, 1:528
1:334 teeth and dental tissue, 2:7-9 fly-bite, 1:552, 1:666-671
sick sinus syndrome, 3:51 testicular, 3:481-485, 3:482b, 3:483f hookworm, 1:685
vitiligo, 1:555-556 thyroid gland, 3:314-315 horn fly, 1:670
Dacryoadenitis, 1:423-424 uvea, 1:445-446 interface, 1:525, 1:526f
Dactylomegaly, 1:54-55 vacuolar, 1:185, 1:185f, 1:254, 1:254f, intraepidermal vesicular and pustular,
Daft lambs, 1:319 1:522 1:527, 1:528f

Dermatitis (Continued)
Malassezia, 1:548-549, 1:553, 1:593,
1:647-649, 1:648f
nodular and diffuse, 1:526-527
papillomatous digital, 1:644-645,
1:644f
Pelodera, 1:689, 1:689f
perforating, 1:699, 1:699f
perivascular, 1:525, 1:525f
photosensitization, 1:577-580, 1:578f
porcine juvenile pustular psoriasiform,
1:698, 1:698f
psoriasiform, 1:698
pyotraumatic, 1:560
pyrexia with, 1:574
radiant heat, 1:566
solar, 1:576, 1:576f
subepidermal vesicular and pustular,
1:527-528, 1:528f
superficial necrolytic, 1:586-587,
1:587f
thymoma and exfoliative, 1:691-692
Dermatobia hominis, 1:668
Dermatohistopathology, 1:518-530
gross terminology, 1:524
histologic terms, 1:518-524
pattern analysis, 1:524-530
Dermatologic diseases of external ear,
1:503-504
Dermatomyositis, canine, 1:198, 1:541-542,
1:542f-543f
Dermatophagoides farinae, 1:683
Dermatophagoides pteronyssinus, 1:683
Dermatophilosis, 1:503, 1:632-634,
1:633f
Dermatophilus congolensis, 2:19
Dermatophytosis, 1:649-653, 1:650f-651f
cats, 1:652-653
cattle, 1:650-651, 1:651f
dogs, 1:652, 1:652f
horses, 1:651-652
pigs, 1:651
sheep and goats, 1:651
Dermatoses
acantholytic, 1:537-538
atrophic, 1:529-530, 1:529f
autoimmune, 1:600-607
hypersensitivity, 1:590-600, 1:670-671
immune-mediated, 1:590-615
mineral-responsive, 1:583-586, 1:584f
photoaggravated, 1:580
porcine, 1:698-699
vitamin-responsive, 1:581-583, 1:582f
Dermatosis vegetans, 1:546-547, 1:546f
Dermatosparaxis, 1:544
Dermis, 1:514-515
muscles, 1:515
Dermoid cysts, 1:547, 1:704-705
Dermoid sinus, 1:279
Descemet’s membrane, 1:427, 1:432,
1:439-440
Desmoglein, 2:14
Desmoplasia, 1:519
Destructive cholangitis, 2:308
Developmental anomalies/diseases
central nervous system, 1:264-284,
3:426-427
viral causes, 1:280-284
ear
external, 1:501-502
middle, 1:496
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Developmental anomalies/diseases
(Continued)
eye, 1:409-427
joints, 1:132-137
cervical vertebral malformation-
malarticulation, 1:136
hip dysplasia, 1:135-136
luxations and subluxations, 1:137
osteochondrosis, 1:132-135
liver, 2:264-268
lungs, 2:484-485, 2:485.e1f
muscle, 1:186-210
malignant hyperthermia, 1:209-210
metabolic myopathies, 1:204-209
muscular defects, 1:189-192
muscular dystrophy, 1:192-197
myasthenia gravis, 1:209
myopathies, 1:197-200
myotonic and spastic syndromes,
1:200-204
primary central nervous system
conditions, 1:187-189
pancreas, exocrine, 2:355-356
peritoneum, 2:245
pleura, 2:520
ureters, 2:449-450
Devon Rex cats
atopic dermatitis, 1:593
α-dystroglycan deficiency, 1:196
vitamin-K-dependent γ-glutamyl
carboxylase deficiency, 3:264
Dexter chondrodysplasia, 1:38
Dextrocardia, 3:23
Diabetes, fatty liver of, 2:275
Diabetes insipidus, 3:290
Diabetes mellitus, 2:370-373, 2:371f
cats, 2:372, 2:373f
cattle, 2:372
diabetic cataract, 1:443
dogs, 2:373
horses, 2:372
metabolic neuropathies, 1:335
retinopathies, 1:472
Diagnosis. See also Gross and histologic
examinations
defined, 1:1
genetics, 1:12
imaging, 1:11-12
introduction to, 1:1
purpose of gross and histologic
examinations in, 1:2-15
Diapedesis of red cells, 1:301
Diaphragm
congenital clefts of, 1:191-192
diaphragmatic hernias, 2:80
myopathy in cattle, 1:199
Diaphyseal dysplasia, 1:53, 1:53f
Diaphysis, 1:22
Diaporthe toxica, 2:334
Diarrhea, 2:111-112, 2:542, 2:542.e3f. See
also Bovine viral diarrhea virus
(BVDV)
Bacteroides fragilis-associated,
2:199
bovine coronavirus, 2:112
bovine herpesvirus 1, 2:112
bovine torovirus, 2:112
calves, 2:112-113
in calves, 2:112-113
Chlamydophila infection, 2:113
chronic erosive colitis in cat, 2:93f
Index 525
Diarrhea (Continued)
Cryptosporidium parvum, 2:112
enterotoxigenic E. coli, 2:112
foals, 2:113-115
neonatal ruminants, 2:113
neonatal swine, 2:113
rotavirus, 2:112, 2:151-153
salmonellosis, 2:112, 2:169
Diarthrodial joints, 1:129-131
Diazepam, 2:329
Dichelobacter nodosus, 1:643-644
Dicrocoelid flukes, 2:322, 2:322f
Dicrocoelium dendriticum, 2:323, 2:323f,
2:323.e1f
Dicrocoelium hospes, 2:322-323
Dictyocaulus filaria, 2:565-567, 2:565t, 2:574,
2:566.e2f
Dictyocaulus viviparus, 2:554-556, 2:556f,
2:555.e1f
Dieffenbachia, 2:13-14
Diffuse alveolar damage (DAD), 2:509-511,
2:510f, 2:514.e2f
Diffuse cortical hyperplasia, 3:343
Diffuse fibrinous pleuritis, 2:522, 2:521.e1f
Diffuse fibrous hyperplasia, 2:21-22
Diffuse gastric mucosal hypertrophy,
2:53
Diffuse hyperplasia, 3:300, 3:300f
Diffuse idiopathic skeletal hyperostosis
(DISH), 1:146
Diffuse large B-cell lymphomas (DLBCLs),
3:220-222, 3:221f
anaplastic, 3:221
Diffuse sclerosing actinobacillosis,
2:18-19
Diffuse tissue mineralization, pathogenesis of,
2:387
Diffuse transmural inflammation, 2:38
Diffuse uveal melanocytosis, 1:484-485
DiGeorge syndrome, 3:144
Digits, defects of, 1:37t
Diiodotyrosine (DIT), 3:311
Dilated cardiomyopathy (DCM), 3:45,
3:47f
cats, 3:46-47
cows, 3:50, 3:50f
dogs, 3:48, 3:48f
Dilated lymphatics, 2:87
Dilated pore of Winer, 1:704, 1:704f
Dilation
abomasal, 2:51
bladder, 2:451
gastric, 2:48-50, 2:49f
of rumen, forestomach, 2:36, 2:37f
salivary ducts, 2:29
Dimethylnitrosamine, 2:340
Dioctophyma renale, 2:255, 2:443f,
2:443.e1f
Dipetalonema reconditum, 3:83-84
Diphtheria, 2:17
Diphyllobothrium spp., 2:223
Diplodiosis, 1:345-346
Diplomyelia, 1:278f
Diplostomum spathaceum, 1:451-452
Direct inguinal hernia, 2:80
Direct salt poisoning, 1:314
Dirofilaria immitis, 1:451-452, 1:690, 2:418,
3:83-85, 3:84f, 3:85.e1f
microfilaria, 2:411f
pulmonary vasculitis and, 2:494
Dirofilariasis, chronic, 2:410-411
526 Index
Diskospondylitis, 1:156, 1:156f
dogs, 1:156, 1:156f
horses, 1:156
pigs, 1:156
sheep, 1:156f
Dislocation of the lens, 1:441-442
Disproportionate dwarfism, 1:41
dogs, 1:45
sheep, 1:41-42
Disseminated cavernous hemangiomas,
3:99
Disseminated discoid lupus erythematosus,
1:606, 3:65b
Disseminated histiocytic sarcoma, 1:729
Disseminated intravascular coagulation
(DIC), 2:84, 2:398-399, 3:64-66,
3:266-268, 3:68.e1f
Distal axonopathy, 1:257
Distichiasis, 1:421
Distribution of edema, 3:11
Disturbance of retrograde axonal transport,
1:257-258
Disuse atrophy, 1:175-177, 1:177f
Disuse osteoporosis, 1:67
Diverticula, 2:450
bladder, 2:450
esophageal, 2:31
DNA damage, 3:341
Doberman Pinscher dogs
acne, 1:549
canine leproid granuloma, 1:641
cervical vertebral malformation-
malarticulation, 1:136
chronic hepatitis, 2:303
color dilution alopecia, 1:539-540
dilated cardiomyopathy, 3:48
follicular dysplasia, 1:540-541
hepatitis, 2:318
hypothyroidism, 1:587, 3:315
maxillary or mandibular fibrosarcoma,
1:121
motor neuron disease, 1:331
myxomatous valvular degeneration,
3:27
nephritis, 2:417
neuroepithelial degeneration, 1:492
peripheral vestibular disease, 1:494
seborrhea, 1:548
spastic syndromes, 1:203
sudden unexpected death, 3:51
vitiligo, 1:555-556
Dogues de Bordeaux
dysplasia of right atrioventricular valve,
3:21-22
ichthyosis, 1:532
subvalvular aortic stenosis, 3:20
Dolichocephalic dwarfs, 1:39
Donkey pulmonary fibrosis (DPF), 2:514,
2:514.e2f
Dorsal and ventral longitudinal ligaments,
1:129
Dorsal displacement of soft palate,
2:481
Dorset Down sheep, wattles in, 1:532
Double aortic arch, 3:23
Double-chambered right ventricle, 3:22
Double muscling, 1:190-191
Dourine, 3:445-447
Downer syndrome, 1:212
Doxorubicin cardiotoxicosis, 3:39
Doxycycline, 2:424
Dracunulus medinensis, 1:689
Draschia megastoma, 2:54, 2:210f
Drug
eruptions, 1:607-615
-induced disorders
liver injury, 2:326, 2:329
platelet dysfunction, 3:260
polyarthritis, 1:158
thrombocytopenia, 3:258
reactions and lung injury, 2:520
Dryland distemper, 1:230
Dual energy X-ray absorptiometry (DEXA),
1:30
Ductal cells, pancreas, 2:355
Ductal epitrichial carcinomas, 1:719
Ductal plate malformations, 2:265, 2:265f
Ductular reaction, 2:262
Duodenal lesions, 2:116
Duodenal sigmoid flexure volvulus, 2:83
Duodenal stenosis, 2:59
Duodenitis-proximal jejunitis, 2:116
Duodenum, 2:354
Duplication
of ovaries, 3:366, 3:366f
of spleen, 3:163
Dwarfism
dogs, 1:45
horses, 1:42
pigs, 1:42
sheep, 1:41-42
Dynamin 1 gene, 1:198
Dysautonomia, 1:333-334, 2:77
distinctive ultrastructural appearance,
2:77
Dysentery
swine, 2:100, 2:181-182, 2:182f
winter, 2:149, 2:150f
Dysgerminoma, 3:377
Dyshormonogenesis, 1:587
Dyskeratosis, 1:518-519
cattle, 1:539
Dysmyelinating diseases, 1:260
Dysontogenic (cartilaginous or osseous)
metaplasia, 2:393
Dysphagia, 2:33-34, 2:34f
Dysplasia
adrenal gland, 3:338, 3:338f
black hair follicular, 1:540, 1:540f
cerebellar, 1:275-276, 1:275f
coat-color-linked hair follicle, 1:540
collagen, 1:543-544
cats, 1:545, 1:545f
cattle, 1:544
dogs, 1:544-545, 1:545f
horses, 1:544, 1:544.e1f
sheep, 1:544
cortical, 1:268
epidermal, 1:519
inherited epidermal, 1:538
pectinate ligament, 1:462-463
right atrioventricular valve, 3:21-22
sebaceous gland, 1:699, 1:699.e2f
Dysraphism, 1:278f
Dysrhythmias, 3:4-5
Dystrophic epidermolysis bullosa, 1:534
dogs, 1:536
goats, 1:535
Dystrophic mineralization, 1:519
Dystrophies
axonal, 1:257-258, 1:258f, 1:324-325
corneal, 1:433-434
equine coronary band, 1:553-554
follicular, 1:520
Dystrophin in muscular dystrophy, 1:194,
1:195f
E
Ear(s), 1:488-508. See also Hearing
external, 1:500-508
dermatologic diseases of, 1:503-505
developmental disease, 1:501-502
hearing and, 1:501
histologic preparation and examination,
1:508
otitis externa, 1:497, 1:502-503, 1:502f,
1:497.e2f
parasitism, 1:505-507
pinnal tumor-like growths and neoplasia,
1:504-505
general considerations, 1:488
internal, 1:488-495
hearing and, 1:491
impairment, 1:491-494
Horner and Pourfour du Petit
syndromes, 1:494-495
neoplasia, 1:494
peripheral vestibular disease, 1:494
margin dermatosis, 1:553
middle, 1:495-500
developmental disease, 1:496
epithelial neoplasia, 1:500
hearing and, 1:496
jugulotympanic paragangliomas, 1:500
non-neoplastic and neoplastic disease,
1:498-499
otitis media, 1:496-498, 1:497.e1f
parasites, 1:498
temporohyoid osteoarthropathy, 1:500
porcine ear necrosis syndrome (PENS),
1:503, 1:645, 1:503.e1f
East Coast fever, 3:176-178, 3:177f, 3:177.e1f
Ebstein’s anomaly, 3:21-22
Eccentric cardiac hypertrophy, 3:8, 3:8f-9f
Ecchondromas, 1:116
Echinochasmus, 2:225-227
Echinococcus equinus, 2:574, 2:574.e2f
Echinococcus granulosus, 2:319, 2:320f,
2:556-557, 2:567
Echinococcus multilocularis, 2:319-320,
2:320f
Economic considerations in postmortem
examinations, 1:13
Ectopia cordis, 3:22, 3:23f
Ectopic adrenal tissue, 3:498
ovaries, 3:366, 3:367f
Ectopia lentis, 1:441-442
Ectopic ossification, 1:127
Ectopic pancreatic tissue, 2:356
Ectopic ureter, 2:449-450, 2:449f
Ectromelia virus, 1:616
Edema, 2:401
ascites and, 2:294-295
cerebral, 1:293-295, 1:295f
cytotoxic, 1:294
vasogenic, 1:294, 1:295f
corneal, 1:428-429, 1:428f, 2:136f
dermal, 1:519
disease, 1:298, 1:298f, 2:163-166, 2:164f
distribution of, 3:11
eosinophilic dermatitis with, 1:696
fluid, 3:6
of gastric rugae, 2:51
intracellular, 1:522
laryngeal, 2:481
pulmonary, 2:487-489, 2:488b, 2:489.e1f
serosal, 2:195-196, 2:196f
tracheal, 1:192, 2:483f
Egyptian Mau cats, spongy myelinopathy in,
1:343-344

Ehlers-Danlos syndrome (EDS), 1:543-544
Ehrlichia canis, 2:414, 2:418, 3:111
platelet dysfunction, 3:260
Ehrlichia platys, 3:260
Ehrlichia ruminantium, 3:80-82
Ehrlichiosis, 1:449
Eimeria alabamensis, 2:230-231
Eimeria apsheronica, 2:233
Eimeria arloingi, 2:232, 2:232f
Eimeria auburnensis, 2:230
Eimeria bareillyi, 2:231
Eimeria bovis, 2:229
Eimeria bukidnonensis, 2:230-231
Eimeria caprina, 2:231
Eimeria christenseni, 2:231-232
Eimeria crandallis, 2:233
Eimeria gilruthi, 2:54-55
Eimeria leuckarti, 2:233-234, 2:233f
Eimeria ninakohlyakimovae, 2:231
Eimeria ovinoidalis, 2:231
Eimeria zuernii, 2:229
Elaeophora bohmi, 3:88
Elaeophora poeli, 3:88, 3:88.e1f
Elaeophora schneideri, 1:390, 1:451-452,
3:88
Elaeophoriasis, 3:88
Elaphostrongylus cervi, 1:390
Elaphostrongylus panticola, 1:390
Elaphostrongylus rangifera, 1:390
Elastic fibers, dermal, 1:514
abnormalities of, 1:545
Elbow hygroma, 1:155, 1:155f
Electrical burns, 2:13
Electrolytes
abnormalities and myopathies, 1:225
balance, 2:384
Ellipsoids, 1:256
Ellis van Creveld syndrome 2, 1:39,
1:39f
Elokomin fluke fever, 3:149
Embolic pneumonia, 2:520, 2:520.e2f
Embolic suppurative myocarditis,
3:42.e1f
Embolism
arterial, 3:63-66, 3:63f-64f
coronary, 3:36
pulmonary, 2:489, 2:490f
fat, 2:490
septic, 2:490
septic, 1:358-362, 1:358f
Embryonal carcinoma, 3:496
Embryonal rhabdomyosarcoma, 1:241-243,
1:243f
Embryonal tumors, 1:401-403
Embryonic death, 3:395
with persistence of membranes, 3:396
Embryonic stage of lung growth, 2:484
Emmonsia crescens, 2:584
Emmonsia parva, 2:584
Emphysema
fetal, 3:396
lymph node, 3:199
pulmonary, 2:486-487, 2:487f
Emphysematous cystitis, 2:459, 2:460f
Emphysematous pyelonephritis, 2:440
Empyema, 1:353-354
of sinus, 2:477, 2:477f
Enamel, 2:5
hypoplasia, 2:7f
loss, 2:10
Encephalitozoon, 1:451
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Encephalitozoon cuniculi, 1:385-386, 2:431,
3:418
Encephalocele, 1:267, 1:267f
Encephalomalacia, 1:307
focal symmetrical, 1:300-301, 1:301f
pigs, 1:308-309
nigropallidal, 1:314, 1:314f
Encephalomyelopathies, spongy, 1:342f,
1:345f, 1:346-347
Encephalomyocarditis virus (EMCV), 3:43
Enchondromatosis, 1:116
Endoarteritis, 2:84
Endocardiosis, 3:27, 3:28f-29f
Endocarditis, 3:30-33, 3:31f, 3:31.e1f
Endocardium, 3:3
disease, 3:27-33
degenerative lesions, 3:27-30
mural and valvular, 3:4
Endochondral ossification, 1:22, 1:22f
rickets and, 1:71-72
Endocrine cells, 2:45
Endocrine pancreas, 2:368-375
diabetes mellitus, 2:370-373, 2:371f
cats, 2:372, 2:373f
cattle, 2:372
diabetic cataract, 1:443
dogs, 2:373
horses, 2:372
retinopathies, 1:472
hyperplastic and neoplastic diseases,
2:373-375, 2:374f
Endocrine system, 3:269-357
adrenal cortex, 3:336-348
adrenal medulla, 3:348-354
diseases/disorders, 2:384-385
atrophy of, 1:178, 1:178f
mechanisms, 3:272-276
myopathies associated with, 1:224-225
of skin, 1:587-590
general considerations, 3:270-276
hormones
calcium-regulating, 3:291-310, 3:291f
catecholamine and iodothyronine, 3:271
steroid, 3:271
thyroid, 3:311-312
types, 3:270-271
multiple endocrine neoplasia (MEN),
3:356-357
paragangliomas, 3:354-356
parathyroid gland, 3:292-295, 3:292f
pituitary gland, 3:276-291
proliferative lesions, 3:271-272
thyroid gland, 3:310-336
tumors, 3:272
Endogenous anticoagulants, 3:265-266
Endogenous lipid pneumonia, 2:517
Endogenous protein, 2:72-73
Endometritis, 3:388-389, 3:388f
Endolymph, 1:489
Endometrial biopsy, 3:393
Endometrial cups, 3:394, 3:394f
Endometrial polyps, 3:385, 3:386f
Endometritis, 3:388-389, 3:388f
chronic, 3:389-390
Endometrium, 3:382-387, 3:382f
carcinoma, 3:449-450
cysts, postpartum, 3:440
endometritis, 3:388-389, 3:388f
Endophthalmitis, 1:446
bacterial, 1:449
mycotic, 1:449-451
Index 527
Endophthalmitis (Continued)
parasitic, 1:451-452
protozoal, 1:451
viral, 1:452
Endothelial cells
hepatic, 2:262-263
sinusoidal, 2:260
vascular, 3:55
disorders, 3:255-268
Endothelial protein C receptor (EPCR),
3:265-266
Endothelium-mediated fibrinolysis, 3:266
End-stage kidneys, 2:377-378
English Bulldogs
acne, 1:549
brachycephalic airway syndrome, 2:482,
2:482f
demodectic mange, 1:679
factor VII deficiency, 3:264
hypothyroidism, 1:587, 3:315
keratoconjunctivitis sicca, 1:436
recurrent flank alopecia, 1:590
English Cocker Spaniel hereditary nephritis,
2:416
English Pointer dogs
chondrodysplasia, 1:44
motor neuron disease, 1:331
sensory and autonomic neuropathies,
1:334
English Setter dogs, atopic dermatitis in,
1:591
English Springer Spaniel dogs
canine congenital myasthenia, 1:209
canine hypomyelinogenesis, 1:337
chronic hepatitis, 2:304
gangliosidosis, 1:58-59
lichenoid-psoriasiform dermatosis,
1:552-553
malignant hyperthermia, 1:210
persistent atrial standstill, 3:51
phosphofructokinase (PFK) deficiency,
1:204-205
polymyopathy, 1:198
prolonged APTT, 3:263
retinal folding, 1:419
seborrhea, 1:548
sensory and autonomic neuropathy,
1:334
Enrofloxacin, 1:472
Entamoeba histolytica, 2:98-99, 2:242
Enteric clostridial infections, 2:183-194
Enteric coronaviral infections,
2:146-151
Enteric disease, pathophysiology of, 2:69-73,
2:107
anemia, 2:73
diarrhea, 2:70-72
increased intestinal motility, 2:72
increased permeability, 2:71
large-bowel, 2:71
malabsorptive, 2:71
secretory, 2:71
small-bowel, 2:71
inappetence/anorexia, 2:69
malassimilation, 2:69-70
assimilation of fat, 2:70
lipids, malabsorption of, 2:70
polysaccharides, maldigestion of,
2:70
protein maldigestion, 2:70
protein-energy malnutrition, 2:69
528 Index
Enteric disease, pathophysiology of
(Continued)
protein metabolism, 2:72-73
albumin, elevated hepatic synthesis of,
2:73
anorexia, 2:72
decreased protein intake, 2:72
peptides/amino acids, malabsorption of,
2:72
protein-losing gastroenteropathy,
2:72
Enteric nervous system, 2:62
Enteritis
adenoviral, 2:143, 2:143f-144f, 2:542,
2:568
Campylobacter spp., 2:180-181
Enterococcus spp., 2:198-199
eosinophilic, 2:96
granulomatous, 2:97
necrotizing, 2:187, 2:187f-188f
parvoviral, 2:153-158
Enteroaggregative E. coli heat stabile toxin
(EAST1), 2:160, 2:160f-161f
Enterococcus durans, 2:113-114
Enterococcus spp. enteritis, 2:198-199
Enterocolitis, protothecal, 2:203-204
Enterocytes, 2:60-61
invasion and salmonellosis, 2:168
Enteroendocrine cells, 2:60
Enterohemorrhagic colibacillosis, 2:112,
2:162f
Enterohemorrhagic E. coli (EHEC),
2:162
Enteroinvasive E. coli, 2:166
Enteroliths, 2:75
Enteropathogenic colibacillosis, 2:161-163
Enteropathy-associated T-cell lymphoma
(EATL), 3:230-232, 3:231f, 3:232.e1f
Enterotoxemia, 2:115, 2:188-191,
2:189f-190f
Enteroviral encephalomyelitis, 1:373f
Enterovirus/teschovirus
polioencephalomyelitis of pigs, 1:372-
373, 1:373f
Entheses, 1:130
Entomophthoromycosis, 1:659-660, 2:201,
2:573-574
Envenomation, 1:568
Environmental contaminants
liver and, 2:330-333
thymic atrophy and, 3:144
Enzootic ataxia, 1:328-329, 1:328f
Enzootic bovine leukosis, 3:235-236, 3:236f,
3:236.e1f, 3:236.e2f
Enzootic hematuria, 2:461-462
hemorrhagic urinary bladder mucosa,
2:461f
Enzootic nasal tumor, 2:560, 2:560f
Enzootic pneumonia, 2:539
Enzyme(s)
defects of adrenal cortex, 3:339
lysosomal, 1:284
Eosinophilia, 3:111
Eosinophilic bronchopneumopathy, 2:501-
502, 2:502f, 2:501.e1f
Eosinophilic conjunctivitis, 1:426
Eosinophilic cystitis, 2:460
Eosinophilic dermatitis, 1:693-696
with edema, 1:696
Eosinophilic enteritis
cats, 2:96, 2:96f
dogs, 2:92f
horses, 2:96
Eosinophilic epitheliotropic disease, 2:16
Eosinophilic folliculitis and furunculosis,
1:696
Eosinophilic gastroenteritis, 2:96
Eosinophilic granuloma
complex (EGC), feline, 1:693-694,
1:693f-694f
dogs, 1:694
horses, 1:694-695, 1:695f
Eosinophilic interstitial pneumonia, 2:513.e1
Eosinophilic meningoencephalitis, 1:396
Eosinophilic myocarditis, 3:43
Eosinophilic myositis, 1:236-237, 1:236f-
237f, 2:34
Eosinophilic pulmonary granulomatosis,
2:513.e1
Eosinophilic pustulosis, 1:696
Eosinophilic rhinitis, 2:476, 2:476.e1f
Eosinophilic sialoadenitis, 2:29-30
Eosinophilic ulcers, 2:16
Eosinophilic vascular infiltrates, 1:611
Eosinophilic vasculitis, 1:526
Eosinophils, 1:527
Ependymal cells, 1:262
Ependymoma, 1:400-401, 1:401f
Epicardium, 3:3
Epicauta spp., 2:52
Epidermal collarette, 1:524
Epidermal growth factor (EGF), 2:46, 3:257,
3:257f
Epidermal hamartomas, 1:705
Epidermal inclusion cysts, 2:478
Epidermal mast cells, 1:519
Epidermal vesicles, 2:118
Epidermis, 1:512-513, 1:520
basement membrane zone, 1:513-514
dermatohistopathology, 1:518-530
disorders of differentiation, 1:547-554
acne, 1:549
canine nasodigital hyperkeratosis,
1:549-550
ear margin dermatosis, 1:553
equine coronary band dystrophy,
1:553-554
exfoliative dermatoses, 1:553
hyperplastic dermatosis of West
Highland White Terriers, 1:553
ichthyosis, 1:554
keratoses, 1:550-551
Labrador Retriever nasal parakeratosis,
1:550
lichenoid-psoriasiform dermatosis,
1:552-553
Schnauzer comedo syndrome, 1:549
sebaceous adenitis, 1:551-552, 1:552f
seborrhea, 1:548-549, 1:549f
tail gland hyperplasia, 1:549
vitamin A-responsive dermatosis, 1:552
tumors, 1:706-714, 1:706f
Epidermoid cysts, 1:404
Epidermolysis bullosa, 1:533-537, 1:534f,
2:15
cats, 1:536-537
cattle, 1:534-535
dogs, 1:536, 1:536f
dystrophic, 1:534
goats, 1:535
horses, 1:535-536
junctional, 1:534
sheep, 1:535
simplex, 1:534-535
Epidermolysis bullosa acquisita (EBA), 1:604
Epidermolytic ichthyosis, 1:531,
1:531.e1f
Epididymis. See Testes and epididymis
Epididymitis, 3:473-474, 3:474f, 3:487-491,
3:488f-489f
boars, 3:490
bulls, 3:489-490
dogs and cats, 3:490-491
infectious bovine, 3:443
small ruminants, 3:490
stallions, 3:490
Epidural/subdural abscess, 1:353-354, 1:354f
Epilepsy, familial myoclonic, 1:205
Epinephrine, 3:348, 3:350f
Epiphyseal arteries, 1:27
Epiphysiolysis, 1:31
Epiphysis, slipped, 1:31
Epiploic foramen, herniation through,
2:79
Episclerokeratitis, 1:476
Epistaxis, 2:473-474
Epithelial cells, 2:61-62
of neonate, 2:63
Epithelial cysts, 1:500
Epithelial hyperplasia, 1:442-443, 3:151,
3:151f
Epithelial inclusions, 3:22
Epithelial integrity, restoration of, 2:67
Epithelial neoplasia, middle ear, 1:500
Epithelial regeneration, 2:422-423
Epithelial renewal
large intestine, 2:68-69
small intestine, 2:66-67
villus atrophy, 2:67-68
Epithelial rests of Malassez, 2:6
Epithelial tumors
pulmonary, 2:495
skin, 1:703
thymic, 3:152-153
Epitheliogenesis imperfecta, 2:4, 2:4f
Epithelioid macrophages, 1:527
Epitheliomas, sebaceous, 1:717
Epitheliomatous sebaceous carcinomas,
1:717-718
Epitheliotropic T-cell tumors, 2:107-108
Epitheliotropism, 3:232
Epithelium
exfoliation in coronavirus, 2:146
nasal, 2:466, 2:466f
Epithrichial cysts, 1:705
Epitrichial sweat glands, 1:517-518
carcinomas, 1:719
tumors, 1:718
Epizootic bovine abortion (EBA), 3:148,
3:149f, 3:419-420
Epizootic catarrhal enteritis of ferrets (ECE),
2:150-151
Epizootic hemorrhagic disease virus (EHDV),
2:39-40, 2:137, 2:137f, 3:431
Epizootic lymphangitis, 3:97-98
ε-cells, endocrine pancreas, 2:368
Epulis, 2:20, 2:24, 2:24f
Equid alphaherpesviruses (EHV), 2:568
Equid besnoitiosis, 1:662
Equid gammaherpesviruses, 2:568-569
Equid herpesvirus 1, 3:435-437, 3:436f,
2:568.e2f
spleen and, 3:183f
thymic atrophy and, 3:145-146
Equid herpesvirus 2, 1:626-627, 2:514
Equid herpesvirus 3, 1:625-627
Equid herpesvirus 5, 1:626-627
Equine anterior uveal melanocytomas, 1:483

Equine arteritis virus (EVA), 3:71-72, 3:72f,
3:427-428
Equine aural plaques, 1:504
Equine bacterial pneumonia, 2:571-572
Equine bone fragility syndrome, 1:91, 1:91f
Equine canker, 1:642-643
Equine cannon keratosis, 1:550
Equine coital exanthema, 3:507
Equine coronary band dystrophy, 1:553-554
Equine coronavirus (EqCoV), 2:150
Equine cutaneous onchocerciasis, 1:687-688
Equine degenerative myeloencephalopathy
(EDM), 1:322-324
Equine ear papillomas, 1:707-708
Equine encephalitides, 1:376-377, 1:377f
Equine encephalitis, 1:377f
Equine eosinophilic nodular diseases,
1:694-695, 1:695f
Equine exercise-induced fatal pulmonary
hemorrhage (EAFPH), 2:491-492,
2:491.e1f
Equine exercise-induced pulmonary
hemorrhage (EIPH), 2:490-491, 2:491f,
2:490.e1f
Equine genital papillomas, 1:707-708
Equine grass sickness, 3:51
Equine herpesviral myeloencephalopathy,
1:383-384, 1:384f
Equine hyperlipemia, 2:276-277
Equine infectious anemia virus (EIAV),
3:114-116
Equine influenza, 2:567-568, 2:567.e3f
Equine intestinal clostridial diseases, 2:99
Equine laryngeal hemiplegia, 1:334-335
Equine linear alopecia, 1:550, 1:550f
Equine lymphomas, 3:237-238, 3:238f,
3:238.e1f
Equine multinodular pulmonary fibrosis
(EMPF), 2:568, 2:569f
Equine onchocerciasis, 1:452
Equine polysaccharide storage myopathy,
1:205-207, 1:206f-207f
Equine postanesthetic degenerative
myopathy, 1:224
Equine protozoal myeloencephalitis,
1:386-387, 1:387f
Equine purpura hemorrhagica, 1:612
Equine recurrent ophthalmitis, 1:455-456
Equine sarcoidosis, 1:700-701
Equine self-mutilation syndrome, 1:562
Equine serum hepatitis, 2:313-314, 2:314f
Equine stringhalt, 1:335
Equine strongylosis, 2:216
Equine suprascapular neuropathy, 1:335
Equine systemic calcinosis, 1:223-224,
1:224f
Equine thrush, 1:643
Equine viral arteritis, 3:71.e2f
Ergotism, 1:572-573, 1:573f
Erosions
BVDV, 2:123-124, 2:124f
erosive and ulcerative stomatitides, 2:15-17
erosive esophagitis, 2:31-32
erosive polyarthritis, 1:157-158
laryngeal, 2:481, 2:481.e2f
teeth, 2:9-11
Eructation, 2:36-37, 2:40
Eryptosis, 3:114
Erysipelas
pigs, 1:149-150, 1:150f
sheep, 1:150
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Erysipelothrix rhusiopathiae, 1:150, 2:20,
2:433, 3:30-31
Erysipelothrix tonsillarum, 3:30-31
Erythema multiforme (EM), 1:607, 1:609-
610, 1:610f
Erythrocyte disorders, 3:112, 3:255-268. See
also Anemia
hereditary, 3:126
Erythrocytosis, 3:128
Erythroid hyperplasia, 2:73, 3:106f
Erythrosine, 3:325
Eschar, 1:524
Escherichia coli, 2:51, 2:111, 2:115, 2:158-
167, 2:159f, 2:452, 2:589
abortion and, 3:417
bovine, 2:112
in Boxer dogs, 2:95
coliform arthritis due to, 1:151
edema disease and, 2:163-166, 2:164f
endocarditits and, 3:30-31
enteroinvasive, 2:166
enterotoxigenic, 2:112
epididymitis due to, 3:491
gastric venous infarction due to, 2:51
mastitis, 3:454-455, 3:454f
penis and prepuce injury, 3:507
E-selectin, 1:515
Eskimo Spitz dogs, platelet dysfunction in,
3:259
Esophageal diverticula, 2:31
Esophageal sarcocysts, 2:34
Esophagitis, 2:31-32, 2:32f
Esophagorespiratory fistulae, 2:31
Esophagus, 2:30-35
anomalies, epithelial metaplasia, and
similar lesions, 2:31
anomalies/epithelial metaplasia/similar
lesions, 2:31
congenital duplication cysts, 2:31
dysphagia, 2:33-34, 2:34f
congenital idiopathic megaesophagus
(CIM), 2:33-34
cricopharyngeal dysphagia, 2:33
megaesophagus, 2:33
pharyngeal dysphagia, 2:33
esophageal diverticula, 2:31
esophageal obstruction/stenosis/
perforation, 2:32-33
esophagitis, 2:31-32
erosive/ulcerative esophagitis, 2:30
hiatus hernia, 2:32
reflux esophagitis, 2:32
thrush, 2:32
esophagorespiratory fistulae, 2:31
lesions, 2:124, 2:124f
neoplasia, 2:43-44
obstruction, stenosis, and perforation,
2:32-33, 2:33f
papillomas, 2:43-44
parasitic diseases, 2:34-35, 2:35f
Spirocerca lupi, 2:34-35
Estrela Mountain dogs, dilated
cardiomyopathy in, 3:48
Estrogen in physis, 1:25t
Ethylene glycol, 2:425
intoxication, 2:425f
Eucoleus aerophilus, 2:585, 2:591
Eucoleus boehmi, 2:585
Eumycotic mycetoma, 1:653-654,
1:654f
Eupatorium rugosum, 3:36
Index 529
Eurytrema, 2:365
Eventration, 2:78
Eversion, of the bladder, 2:451
Excess free cytosolic calcium, 2:399
Excessive moderator bands, 3:47
Excess renal tissue, 2:392
Excitotoxicity, 1:254
Excrete metabolic wastes, 2:384
Exertional myopathies, 1:221-223
dogs, 1:223
horses, 1:221-223, 1:222f
other species, 1:223
Exfoliative cutaneous lupus erythematosus
(ECLE), 1:606, 1:606f
Exfoliative dermatitis, 1:691-692
Exfoliative dermatoses, 1:553
Exocrine pancreas, 2:353-368
atrophy, 2:362-363, 2:362f
developmental anomalies, 2:355-356
hyperplastic and neoplastic lesions,
2:365-368, 2:365f-366f
insufficiency, 2:69, 2:363-364
necrosis, 2:357-360, 2:359f-360f
pancreatitis, 2:360-362
parasitic diseases, 2:365
regressive changes, 2:356-364
Exocytosis, 1:519-520
Exogenous porcine growth hormone, 1:225
Exogenous steroids, 3:341
Exostoses, 1:33
osteitis and, 1:97-98
vitamin A toxicity and, 1:87
Expansile nodules, symptomatic tumors of,
2:110
ExPEC, 2:578
Experimental disease, 1:3
External acoustic meatal stenosis, 1:502
External ear, 1:500-508
dermatologic diseases of, 1:503-505
developmental disease, 1:501-502
hearing and, 1:501
histologic preparation and examination,
1:508
otitis externa, 1:497, 1:502-503, 1:502f,
1:497.e2f
parasitism, 1:505-507
pinnal tumor-like growths and neoplasia,
1:504-505
External hernias, 2:79-81, 2:245
External hordeolum, 1:423
Extra-adrenal paragangliomas, 3:356
Extrahepatic biliary anomalies, 2:265-266,
2:266.e1f
Extramedullary hematopoiesis (EMH),
2:300-301, 2:441, 3:191
Extramedullary plasmacytomas (EMP),
2:27-28, 2:109, 3:226-228, 3:226.e1f
Extranodal T-cell lymphoma, 3:232
Extraskeletal osteosarcomas, 1:115
Extrathyroidal lesions in hypothyroidism,
3:318-319
Extrinsic compression, 2:74
Exuberant fracture callus, 1:127
Exuberant granulomas, 2:13
Exudative epidermitis, 2:17
of pigs, 1:630-632, 1:631f
Eyelid(s)
abortion and, 3:401
canine cutaneous histiocytoma, 3:244f
developmental anomalies and acquired
diseases, 1:423
530 Index
Eyelid(s) (Continued)
neoplasms
Meibomian adenoma, 1:480-481, 1:481f
squamous cell, 1:479-480, 1:479f-480f
Eye(s), 1:408-488
developmental anomalies, 1:409-427
anomalies of mesenchyme, 1:413-414
anomalies of neuroectoderm, 1:419-421
anomalies of surface ectoderm,
1:421-423
defective differentiation, 1:413-423
defective organogenesis and, 1:410-412,
1:410f
defects primarily in anterior chamber
mesenchyme, 1:415-417
early ocular organogenesis and,
1:409-410
incomplete atrophy of posterior segment
mesenchyme, 1:417-419
general considerations, 1:408-409
histologic section, 1:408-409, 1:409f
lesions with canine distemper virus, 2:576
lymphomas, 3:239f, 3:239.e1f
neoplasia, 1:478-488
melanocytic tumors, 1:482-485
ocular neuroectoderm, 1:485-486,
1:485f
ocular adnexa, 1:423-427
ocular fixation, 1:408-409
F Feline infectious peritonitis virus (FIPV),
Facial clefts, 2:2-3, 2:3f
Facial eczema, 2:335
Factor IX deficiency, 3:263
Factor VII deficiency, 3:264
Factor VIII deficiency, 3:263-264
Factor XII deficiency, 3:263-264
Fading follicular hyperplasia (FFH),
3:222-223
Failure of omasal transport, 2:39
Falciform ligament, 2:245
Fallopian tubes pathology, 3:379-380
False tendons, 3:22
Familial AA amyloidosis, 2:278-279
Familial Chinese Shar Pei fever, 1:158
Familial hyperlipoproteinemia, 2:277-278
Familial myoclonic epilepsy, 1:205
Fanconi anemia, 1:57
Fanconi syndrome, 2:428, 2:428f
Farcy, 1:641-642, 3:96
Fasciola gigantica, 2:322, 2:556-557
Fasciola hepatica, 2:255, 2:320, 2:321f,
2:556-557, 2:322.e1f, 2:321.e1f
Fascioloides magna, 2:322, 2:322.e1f
Fat, muscle steatosis and, 1:191, 1:191f
Fatal gastric hemorrhage, 2:58
Fat embolism, 2:490
Fat-granule cells, 1:263
Fatty acid deficiency, 1:581
Fatty cysts, liver, 2:274-275, 2:274f
Fatty liver, 2:275-276
Feeding rations deficient, 2:40
Feedlot cattle
acute interstitial lung disease, 2:513f,
2:513.e1
bloat, 2:37
peracute fibrinous bronchopneumonia,
2:545f
pleuritis, 2:522f
Felid herpesvirus 1, 1:425, 1:625-627, 1:627f,
2:588-589, 2:588.e2f
Feline buccal bone expansion, 1:99-100
Feline calicivirus (FCV), 2:15, 2:589
Feline cardiomyopathies, 3:46-48, 3:46.e2f Feline viral rhinotracheitis, 2:16, 2:588-589
Feline ceruminous cystomatosis, 1:507 Feline X-linked muscular dystrophy,
Feline chronic gingivostomatitis, 2:16 1:194-195, 1:195f
Feline chronic progressive polyarthritis, 1:158 Felty’s syndrome, 1:157
Feline congenital myasthenia, 1:209 Female genital system, 3:358-464. See also
Feline corneal sequestrum, 1:434, 1:434f Abortion; Gestation
Feline coronavirus (FCoV) , 2:117, 2:150-151, endometrium, 3:382-387, 3:382f
2:587-588 mammae, 3:451-459
Feline enteric coronavirus (FECV), 2:117, neoplastic conditions of tubular genitalia,
2:150-151, 2:587-588 3:447-450
Feline demodecosis, 1:680-681 normal sexual differentiation, 3:360-361
Feline diffuse iris melanomas, 1:483-484, ovaries, 3:366, 3:366f
1:484f pathology, 3:370-375
Feline eosinophilic granuloma complex pathology
(EGC), 1:693-694, 1:693f-694f of cervix, vagina, and vulva, 3:441-442
Feline eosinophilic keratitis, 1:438-439, of gravid, 3:393-398
1:439f of nongravid, 3:359-441
Feline epitrichial ductular adenomas, sexual development disorders, 3:360-370,
1:718-719, 1:719f 3:361f-362f
Feline hepatic steatosis, 2:277, 2:277f uterine (fallopian) tube pathology,
Feline hereditary cerebellar cortical atrophy, 3:379-380
1:319 uterus
Feline herpesvirus, 1:105 cysts arising from, 3:366-367
Feline hippocampal necrosis, 1:307-308 mucometra, 3:374, 3:374f
Feline hyperesthesia, 1:199 pathology, 3:380-382, 3:380f
Feline idiopathic pulmonary fibrosis (IPF), vaginal anomalies, 3:369-370
2:497 Femoral hernias, 2:80
Feline immunodeficiency virus (FIV), Ferrets, 2:52
1:627-628, 3:240 adrenal tumors in, 3:347-348, 3:349f
Feline inductive odontogenic tumor, 2:24 epizootic catarrhal enteritis of, 2:150-151
fibrous osteodystrophy in, 1:78f
2:253-255, 2:254f, 3:90, 3:90f gastritis, 2:52
-associated uveitis, 1:453, 1:453f Fescue toxicosis, 1:573
lymph nodes and, 3:206f Festoons, 1:520
spleen and, 3:184f Fetlock joint, synovial pad proliferation of,
Feline interstitial cystitis, 2:460 1:163
Feline ischemic encephalopathy, 1:297, Fetus
1:297f atelectasis, 2:486.e2f
Feline leishmaniasis, 1:663-664, 1:664f bovine viral diarrhea and, 2:122
Feline leprosy, 1:640-641 death, 3:395
Feline leukemia virus (FeLV), 1:105, endocrine function, 3:274-275, 3:275f
1:627-628 infections, 2:122
anemia and, 3:127, 3:127f lobulations, kidney, 2:392-393
lymphomas, 3:235, 3:239-240 lung development, 2:484
thymic atrophy and, 3:145 maceration and emphysema, 3:396,
Feline lipogranulomatous conjunctivitis, 3:396f
1:427, 1:427f mummification of, 3:395-396, 3:395f
Feline lower urinary tract disease (FLUTD), pneumonia, 3:404, 3:404f
2:456, 2:460 Fiber balls, 2:75-76
Feline lymphomas, 3:239-241 Fibrin exudation, in urinary space, 2:405-406
Feline mannosidosis, 1:288f Fibrin formation, 3:262-263
Feline multifocal uveal melanocytoma, 1:483 disorders, 3:265
Feline Niemann-Pick disease type C, 1:325 laboratory evaluation, 3:262-263
Feline panleukopenia virus (FPLV), 1:283-284, Fibrinocellular crescent, 2:406f, 2:405.e1f
2:98-99, 2:153-156, 2:155f Fibrinogen, 3:256
Feline paraneoplastic alopecia, 1:691, 1:692f concentration, 3:262-263
Feline parvoviral infection, 3:145 Fibrinoid
Feline plasma cell gingivitis-pharyngitis, 2:16 degeneration, 1:520
Feline post-traumatic sarcoma, 1:486, 1:487f necrosis, 1:520, 2:492.e1f
Feline progressive histiocytosis (FPH), 1:730, Fibrinoid leukodystrophy, 1:341
3:252f-253f, 3:253-254, 3:253.e1f Fibrinolysis, 3:266-267
Feline proliferative necrotizing otitis externa, endothelium-mediated, 3:266
1:503-504 plasma-mediated, 3:266-267
Feline pulmonary adenocarcinoma, 2:497.e1f Fibrinonecrotic bronchitis, 2:501
Feline pulmonary Langerhans cell Fibrinonecrotic (diphtheritic) membranes,
histiocytosis, 2:499, 3:246-247, 3:246.e1f 2:474-475
Feline scleromyxedema, 1:697 Fibrinopurulent arthritis, 1:147-148
Feline spinal myelinopathy, 1:341 Fibrinopurulent exudate, 1:356f
Feline spongiform encephalopathy (FSE), Fibrinosuppurative exudate with mastitis,
1:349 3:453-454, 3:453f
Feline ulcerative stomatitis, 2:16 Fibrinous arthritis, 1:146-147
Feline ventral abdominal cattle, 1:147f
lymphangiosarcomas, 1:728 Fibrinous exudate, 1:6f
 Index 531

Fibrinous inflammation, 1:353 Fibrous osteodystrophy (Continued) Follicular atrophy, 1:520

Fibrinous pericarditis, 3:25-26, 3:26f goats, 1:76, 1:77f Follicular cell adenomas, 3:326-327,
Fibroadenomatous hyperplasia, 3:460, gross lesions, 1:75 3:327f-328f
3:460f horse, 1:75, 1:76f Follicular cell carcinomas, 3:329-332,
Fibroadnexal hamartomas, 1:705 horses, 1:76, 1:76f 3:330f
Fibroblast growth factor 23 (FGF23), 1:18, pigs, 1:76, 1:76f Follicular cystitis, 2:460-461, 2:460f
3:296 premature osteoclastic resorption of Follicular-derived B-cell lymphomas,
Fibroblastic metaplasia, 1:442-443 trabeculae in, 1:79-80, 1:80f 3:222-226, 3:223f
Fibroblastic osteosarcomas, 1:114, 1:114f Fibrous tumors of bone, 1:121-122, Follicular dystrophy, 1:520
Fibroblastic sarcoids, 1:708 1:121f-122f Follicular hamartomas, 1:705
Fibroblasts Filaggrin, 1:513 Follicular hyperplasia, 3:222-223, 3:223f
alveolar wall, 2:470 Filaroides hirthi, 2:587 thymus, 3:150-151, 3:150f
dermal, 1:514 Filtration secretion, 2:71-72 Follicular keratosis, 1:520
Fibrodysplasia ossificans progressiva (FOP), Fimbriae, 2:168 Follicular lipidosis, 1:697
1:127, 1:128f, 1:248-249, 1:249f Final reports in postmortem examinations, Follicular lymphoma (FL), 3:223-224,
Fibrohistiocytic nodules of spleen, 3:190-191, 1:14 3:224f
3:190f-191f, 3:191.e1f Fire ants, 1:671 Follicular mucinosis, 1:697
Fibromas, 1:723, 2:463-464 First-degree burns, 1:564-566 Folliculitis, 1:520, 1:521f
ear, 1:505 Fissures Staphylococcal, 1:634-636, 1:635f
ossifying, 1:109, 1:109f caries, 2:10 sterile eosinophilic, 1:696
Fibromatous disorders of tendons and splenic, 3:163, 3:163f Food reaction, cutaneous, 1:594-596,
aponeuroses, 1:248-249 Fistulae, esophagorespiratory, 2:31 1:595f
fibrodysplasia ossificans progressiva, 1:127, Fistulous tract, 3:472, 3:472f Foot-and-mouth disease (FMD), 1:233,
1:128f, 1:248-249, 1:249f Fistulous withers, 1:155-156 1:233f, 2:117, 2:118f-119f
musculoaponeurotic fibromatosis, 1:248, 5´-deiodinase, 3:325 Foothills abortion, 3:419
1:248f Fixed macrophage system of CNS, 1:262 Footrot, 1:643-644
Fibromatous epulis, 2:25f Flagellates, 2:242-243 virulent, 1:644
of periodontal ligament origin, 2:24, Flame figure, 1:519 Foreign bodies, 2:75
2:24f-25f Flame follicles, 1:520, 1:520f forestomachs, 2:38
Fibronectins, 1:514 Flaviviral encephalitides, 1:373-376 oral cavity, 2:13, 2:13f
Fibropapillomas, 2:44 Flea, 1:672-673 in peritoneal cavity, 2:247-249
epidermis, 1:706 -bite hypersensitivity, 1:597-598 salivary glands, 2:29
esophagus, 2:44 collar dermatitis, 1:566-567 stomach and abdomen, 2:50-51
penis and prepuce, 3:508 Fleece rot, 1:634 Foreign-body glossitis, 2:13f
vulva, 3:449 Flexispira rappini, 3:408 Foreign-body stomatitis, 2:13
Fibroplasia, 1:520 Flies, 1:552, 1:666-671 Forelimb-girdle muscular anomaly, 1:189
Fibrosarcomas, 1:121, 1:121f, 1:725, myiasis, 1:668-670 Forensic autopsy, 1:2
2:27 warbles, 1:668-669 Forestomachs, 2:35-44
dogs, 2:21 Fluid accumulation in heart failure, 3:9 dilation of rumen, 2:36-38
ear, 1:505 Fluid volume regulation, 2:384 dystrophic and hyperplastic changes in
liver, 2:350 Fluorescent markers, 1:29-30 ruminal mucosa of, 2:36, 2:36f
nasal, 2:480 Fluorine poisoning, 2:8 foreign bodies in, 2:38
solitary, 1:725 Fluoroacetate poisoning, 1:306, 3:37-38 inflammatory lesions, 2:39-40
Spirocerca granuloma and, 2:35f Fluorosis, 1:84-86 mild inflammation of, 2:40
vaccinal, 1:725 cattle, 1:85f-86f neoplasia, 2:43-44
virus-induced, 1:725 dogs, 1:86 neoplasia of esophagus, 2:43-44
Fibrosis, 1:528 pigs, 1:86 fibropapillomas, 2:44
donkey pulmonary (DPF), 2:514, Foam cells, 1:527, 2:418 mesenchymal tumors, 2:44
2:514.e2f Foamy (synctium-forming) virus, 1:154 parasitic diseases, 2:43, 2:43f
equine multinodular pulmonary fibrosis Focal atrophy of brain and spinal cord, postmortem change, 2:36
(EMPF), 2:568, 2:569f 1:305 rumen dilation, 2:36-38
idiopathic pulmonary fibrosis in cats, Focal contused injuries, 1:302 primary tympany, 2:36
2:515, 2:515f, 2:515.e2f Focal hepatitis, 2:282, 2:282f secondary tympany, 2:37-38
interstitial, 2:510 Focal hyperplasia rumenitis, 2:39-40
cats, 2:515, 2:515f C cells, 3:332-333, 3:333f and acidosis caused by carbohydrate
dogs, 2:514-515, 2:515f thymus, 3:151 overload, 2:40-43
liver, 2:288-289, 2:289f Focal macular melanosis, 1:554 rumenitis/acidosis caused by carbohydrate
muscle, 1:184-185 Focal myocardial necrosis, 3:36, 3:38f overload, 2:40-43
subendocardial, 3:30 Focal necrosis, 2:281-282, 2:282f Fusobacterium necrophorum,
thymic, 3:147f Focal scarring/fibrosis of ventricular wall, 2:41
Fibrotic myopathies, 1:213-214 3:5 mycotic rumenitis, 2:42
Fibrous astrocytes, 1:260-261 Focal segmental glomerulosclerosis (FSGS), ruminal mucosa, dystrophic/hyperplastic
Fibrous capsule, 1:130 2:405f, 2:417, 2:401.e5f changes, 2:36
Fibrous dysplasia, 1:109-110 Focal symmetrical encephalomalacia, traumatic reticuloperitonitis, 2:38-39
Fibrous epulis (fibrous hyperplasia), 2:21, 1:300-301, 1:301f pericarditis, 2:39
2:21f pigs, 1:308-309 tympanitic distention of, 2:36
Fibrous hyperplasia, 2:21, 2:21f Focal symmetrical poliomyelomalacia, 1:308, Formalin, 1:8, 1:408
Fibrous joints, 1:128 1:308f 4-Ipomeanol, 2:519
Fibrous osteodystrophy, 1:61, 1:74-80 Foci of hematopoietic cells, 3:339 Fourth-degree burns, 1:565
cats, 1:77, 1:77f-78f, 1:80f Follicle-stimulating hormone (FSH), Foveolar mucous cells, 2:45
dogs, 1:77, 1:78f-79f 3:276-277 Fowlpox virus, 1:616

Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510

532 Index
Fox Terrier dogs
motor neuron disease, 1:331
myxomatous valvular degeneration,
3:27
Fractional catabolic rate, 2:72
Fractures, 1:33-36
micro-, 1:34, 1:34f
repair
complications of, 1:35-36
process, 1:34-35, 1:35f
skull, 1:302-303
stress-related, in horses, 1:36
types of, 1:34
Fragile histidine triad (Fhit) protein,
2:462.e1
Francisella tularensis, 3:184-186
Frank-Starling relationship, 3:7
Freemartinism, 3:470f
Free-radical–mediated damage, 2:81
Free radicals, 1:215
Freeze branding, 1:564
French Bulldogs
canine atopic dermatitis, 1:591
typhlocolitis, 2:97-98
Friesian cattle, 2:38
bovine hypomyelinogenesis, 1:338-339
congenital axonopathy, 1:325
congenital myopathy, 1:200
hypertrichosis, 1:541
lethal trait A46, 3:141
spastic syndromes, 1:203
vitiligo, 1:555-556
Frostbite, 1:564
scrotal, 3:472, 3:472f
Froth, tracheal, 2:483, 2:483f, 2:483.e1f
Frothy bloat, 2:36, 2:37f
Frozen tail, 1:214
Full-thickness intestinal biopsy, 2:89
Fumonisin, 2:334, 2:519-520
Functional obstruction, 2:74-75
Fundic/oxyntic gland acid-secretory mucosa,
2:44
Fungal arthritis, 1:154-155
Fungal infections
fungal osteomyelitis, 1:103-104
dogs, 1:104f
gastrointestinal tract, 2:201
liver and, 2:324-325, 2:324f, 2:330-331
lymph nodes and, 3:206f
respiratory system, 2:535-536, 2:554,
2:573-574, 2:579-585
skin
cutaneous, 1:646-661
subcutaneous, 1:653-661
Furocoumarins, 1:578-579
Furunculosis, 1:520, 1:521f, 1:528
staphylococcal, 1:634-636, 1:635f
sterile eosinophilic, 1:696
Fusarium spp., 3:442-443
Fusobacterium equinum, 2:18
Fusobacterium necrophorum, 2:17, 2:39, 2:41,
2:41f-42f
laryngitis and, 2:481
liver and, 2:316, 2:316.e1f
rhinitis and, 2:474-475
splenic abscesses, 3:183-184, 3:183.e1f
Fusobacterium spp., 2:13-14
G Gastric ulcers, 2:59
Galactocerebrosidosis, 1:288
Galactose-induced cataract, 1:443
Galactosialidosis, 1:288
Galenia africana, 3:35
Gallbladder
agenesis, 2:266.e1f
anomalies, 2:265-266
duplication of, 2:355-356
infarction, 2:307, 2:307f
mucocele, 2:307, 2:345, 2:345f
Gallotannins, 2:427-428
Galloway cattle, hip dysplasia in,
1:135-136
Gallstones, 2:308-309, 2:309f
Gammaherpesviruses, equid, 2:568
Gammel Dansk Høneshund, canine
congenital myasthenia in, 1:209
Gangioneuroma, 3:353
Gangliocytomas, 1:401
Ganglion cysts, 1:162-163
Ganglioneuritis, 1:373f
Gangliosidoses, 1:286f-287f, 1:287-288
cats, 1:58-59
cattle, 1:58-59
dogs, 1:58-59
sheep, 1:58-59
Gangrene, 3:65
Gangrenous ergotism, 1:572-573,
1:573f
Gangrenous stomatitis, 2:18
Gartner’s ducts, 3:442, 3:442f
Gas gangrene, 1:232
Gasterophilus spp., 2:19, 2:34
esophagus and, 2:34
Gastric adenocarcinoma, 2:102f
Gastric biopsies, 2:47
Gastric carcinomas, 2:102
Gastric changes, 2:94
Gastric dilation
abomasal volvulus, 2:49-50
displacement, 2:48-50, 2:49f
gastric rupture, 2:48
gastroduodenal intussusception, 2:50
gastroesophageal intussusception,
2:50
pylorogastric intussusception, 2:50
volvulus, 2:49
Gastric distention, 2:31
Gastric foreign bodies
impaction, 2:50-51
by inspissated content in horses,
2:50
primary abomasal impaction in cattle,
2:50
Gastric lymphomas, 2:107-109, 3:241f,
3:241.e1f
Gastric motility, 2:45-46
Gastric mucosa, 2:46
atrophy, 2:94
barrier, 2:46
hypertrophy, 2:53
mineralization, 2:386f
mucous metaplasia and hyperplasia,
2:47
parietal cell mass, atrophy of, 2:47
response, 2:46-48
restitution, 2:46
Gastric parasitism, 2:209-210, 2:209f
Gastric rupture, 2:48
Gastric secretion, 2:44
Gastric squamous cell carcinomas, 2:106-
107, 2:106f
Gastric venous infarction, 2:51
Gastric volvulus, 2:49, 2:49f
dogs, 2:49f
Gastrin, 2:45
Gastrinomas, 2:375
Gastritis, 2:52-55
abomasitis associated with viral infection,
2:54
braxy, 2:53f
chemical, 2:52
chemical gastritis/abomasitis, 2:52
Chlamydophila, 2:53
diffuse gastric mucosal hypertrophy,
2:53
due to hypertrophic antritis, 2:53
due to infection, 2:52, 2:55
Gasterophilus, 2:54
gastric mucosal hypertrophy, 2:53
Helicobacter pylori, 2:52
hypertrophic antritis, 2:53
infectious agents, in small animals, 2:52
mechanical, 2:52
mycotic, 2:54
mycotic gastritis/abomasitis, 2:54
parasitic, 2:54
parasitic gastritis, 2:54
Gastroduodenal intussusception, 2:50
Gastroduodenal ulceration, 2:55-60
abomasal ulcers in cattle, 2:57
acid hypersecretion, factors implicated,
2:55
duodenal ulcers, 2:56
gastric ulcers in swine, 2:57
horses, ulcers, 2:59
mucosal protective mechanisms, 2:55
peptic ulcers in dogs, 2:56
Zollinger-Ellison syndrome, 2:56
Gastroesophageal intussusception, 2:32,
2:50
Gastrointestinal adenocarcinomas,
2:101-104
adenocarcinoma of stomach, 2:102
intestinal adenocarcinomas, 2:102-103
intestinal carcinomas, 2:104
Gastrointestinal carcinomas, histologic lesion
of, 2:101
Gastrointestinal disease, diagnosis of,
2:111-117
diarrhea
in calves, 2:112-113
in foals, 2:113-115
in neonatal ruminants, 2:113
in neonatal ruminants, swine, and horses,
2:111-112
in neonatal swine, 2:113
diarrhea, in calves
bovine coronavirus, 2:112
bovine herpesvirus 1, 2:112
bovine torovirus, 2:112
Chlamydophila infection, 2:113
Cryptosporidium parvum, 2:112
enterotoxigenic E. coli, 2:112
rotavirus, 2:112
salmonellosis, 2:112
enteritis
cats, 2:117
dogs, 2:116-117
ascarid infection, 2:117
canine parvovirus 2, 2:116-117
Salmonella infection, 2:117
horses, 2:116
horses, duodenitis-proximal jejunitis,
2:116
gastroenteritis
cattle, 2:114-115
sheep, 2:115
swine, 2:115-116

Gastrointestinal disease, diagnosis of
(Continued)
gastroenteritis, cattle, gastrointestinal
parasitism, 2:114
neonatal animals, undifferentiated diarrhea
of, 2:111
Gastrointestinal helminthosis, 2:204-227
Gastrointestinal malabsorption in humans,
1:69
Gastrointestinal mast cell tumors, 2:109
Gastrointestinal microbiota, 2:65
Gastrointestinal mucosal defense, 2:63
Gastrointestinal mucosal mast cell tumors,
2:109
Gastrointestinal neuroendocrine carcinomas,
2:105-106
goblet-cell carcinoids, 2:106
Gastrointestinal parasitism, 2:114
Gastrointestinal tract, 2:62-63
bacterial diseases, 2:158-201
carcinoid tumors, 2:106
mycotic diseases, 2:201-203
neoplasms metastatic, 2:101
Gastrointestinal ulceration, 2:109
Gedoelstia spp., 1:426
Geeldikkop, 2:338-339
Gelbvieh cattle
congenital status spongiosus, 1:347
motor neuron disease, 1:332
necrotizing vasculopathy, 1:200, 1:200f
Geminous teeth, 2:6
Gemistocytes, 1:261-262, 1:261f
Generalized cerebral edema, 1:294
Generalized Shwartzman-like reaction
(GSR), 3:65
Generalized skeletal dysplasias, 1:37
Genetic disease/disorders
of bone, 1:36-60, 1:37t
connective tissue, 1:542-546
indirectly affecting the skeleton,
1:57-60
of muscles, 1:186-210
osteochondrosis, 1:132
rickets, 1:69-70
vasculitis, 3:70
Genetics, diagnostic, 1:12
Genital tritrichomoniasis, 3:423-424
Gentamicin, 1:494, 2:424
Geophilic dermatophytes, 1:649
German Boxer dogs, cleft palate in, 2:3
German Pinscher dogs, vascular ring
anomalies in, 2:33
German Shepherd dogs
acquired protoporphyria, 2:271
bronchitis, 2:502
canine panosteitis, 1:107f
chondrosarcoma, 1:118
congenital idiopathic megaesophagus,
2:33-34
corneal edema, 1:429
corneal endothelial dystrophy, 1:433
degenerative radiculomyelopathy, 1:330
diskospondylitis, 1:156, 1:156f
fibrotic myopathy, 1:213-214
giant axonal neuropathy, 1:330
hyposomatotropism, 1:589
malignant lymphoma, 1:123-124
masticatory myositis, 1:226
maxillary or mandibular fibrosarcoma,
1:121
motor neuron disease, 1:331
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
German Shepherd dogs (Continued)
motor neuropathy, 1:335
mucous membrane pemphigoid, 2:15
myxomatous valvular degeneration, 3:27
panhypopituitarism, 3:280, 3:280f
pannus keratitis, 1:438
peripheral vestibular disease, 1:494
platelet dysfunction, 3:259-260
primary parathyroid hyperplasia, 3:301
pyoderma, 1:635
pyotraumatic dermatitis, 1:560
seborrhea, 1:548
selective deficiencies of immunoglobulins,
3:139
Sly syndrome, 1:58
subvalvular aortic stenosis, 3:20
sudden unexpected death, 3:51
vascular ring anomalies, 2:33
vasculitis, 1:612, 3:70
vitiligo, 1:555-556
German Shorthaired Pointer dogs
acne, 1:549
canine X-linked muscular dystrophy, 1:192
epidermolysis bullosa, 1:536
malignant oral tumors, 2:21
sensory and autonomic neuropathy, 1:334
subvalvular aortic stenosis, 3:20
vitiligo, 1:555-556
Germ cell tumors
ovary, 3:377-378
suprasellar, 1:403-404, 3:287, 3:287f
testes, 3:495-496, 3:495f
thymic, 3:158
Gestation, 3:393-398. See also Female genital
system
abortion and stillbirth, 3:395, 3:398-440
diagnosing infectious causes of,
3:399-402
in mares, 3:417-418
protozoan infections causing, 3:420-424
adventitial placentation, 3:396-397
amniotic plaques, placental mineralization,
and avascular chorion, 3:397
embryonic death, 3:395
with persistence of membranes, 3:396
fatty liver in, 2:275
fetal death, 3:395
fetal maceration and emphysema, 3:396
general considerations, 3:393-394
hydramnios and hydrallantois, 3:397
mummification of fetus, 3:395-396,
3:395f
mycotic abortion in cattle, 3:418-419
postpartum uterus, 3:440-441
prolonged, 3:397-398
toxemia, 2:275
viral infections during, 3:424-440
Ghrelin, 2:368
Giant axonal neuropathy of German
Shepherds, 1:330
Giant cell
granuloma, peripheral, 2:21
hepatitis, 2:306, 2:306f, 2:438
multinucleated syncytial, 3:297-298,
3:298f
-rich osteosarcomas, 1:114
sarcomas, 1:244
thyroid carcinoma, 3:331, 3:331f
tumor
of bone, 1:122
of tendon sheath, 1:161-162
Index 533
Giant Schnauzer dogs, cobalamin deficiency
in, 3:127
Giardia, 2:113, 2:242-243
Gingivitis, 2:11-12
foreign-body stomatitis and, 2:13,
2:13f
Gitter cells, 1:263, 1:263f
Gla-containing proteins, 1:19
Gland acid–secretory mucosa, 2:44
Glanders, 2:573
Glandular structures, 2:452
Glanzmann thrombasthenia, 3:259
Glasser’s disease, 1:151-152
Glaucoma, 1:459-465
histologic lesions of, 1:460-462, 1:460f
lesions causing, 1:462-465
retinal changes in, 1:460, 1:461f
Glial fibrillary acidic protein (GFAP), 1:10f,
1:261-262
Glia limitans, 1:261
Glial reactions, 1:366
Gliomatosis cerebri, 1:400f
Gliosis, focal and diffuse, 1:262-263,
1:263f
Glipizide, 2:329
Glisson’s capsule, 2:260
Global assays of hemostasis, 3:263
Global glomerulosclerosis, 2:401.e6f
Globe and orbit tumors, 1:488
Globoid cell leukodystrophy, 1:339-342,
1:339f
Glomangiomas, 3:99
Glomerular amyloidosis, 2:414, 2:416f,
2:415.e2f
Glomerular basement membrane (GBM),
2:377, 2:380f
anti-GBM glomerulonephritis, 2:408
familial abnormalities of, 2:415-417
size-dependent barrier, 2:380
thickening/remodeling, 2:406
type IV collagen, 2:415-416
Glomerular capillary walls, 2:406
Glomerular cellular crescent, 2:406f
Glomerular cystic atrophy, 2:407
Glomerular damage, monocytes, 2:409
Glomerular disease, 2:377-378,
2:401-421
amyloidosis, 2:413-414
in dog, 2:416f, 2:415.e2f
eosinophilic in H&E sections,
2:415
histologically, 2:414-415
familial glomerulopathies, in dog breeds,
2:416f
immune-complex, 2:413-415
renal amyloidosis, in cat, 2:414f
global glomerulosclerosis, 2:401.e6f
glomerular blood flow, 2:401
glomerulonephritis (GN), 2:401
classification, 2:401
glomerulosclerosis, focal segmental,
2:401.e5f
membranoproliferative glomerulonephritis
(MPGN), 2:404f, 2:401.e4f
membranous glomerulonephropathy
(MGN), 2:402f, 2:401.e2f
mesangioproliferative
glomerulonephropathy, 2:403f,
2:401.e3f
proliferative glomerulonephropathy, 2:403f,
2:401.e3f
534 Index
Glomerular filtration, 2:400
membrane, 2:379-380
Glomerular filtration rate (GFR), 2:377, 3:10
intrarenal blood flow, 2:379
Glomerular hyperperfusion, 2:387
Glomerular injury
mechanisms of, 2:408-409
nonimmunologic causes of, 2:409
Glomerular lipid emboli, 2:420f, 2:418.e4f
Glomerular lipidosis, 2:418-421, 2:420f,
3:319, 3:319f, 2:418.e3f
Glomerular sites immune complexes
localization of, 2:408
modification of, 2:408
Glomerular tuft, cellularity of, 2:405
Glomeruli, 2:401
in neonatal kidneys, 2:382
reactions, 2:383
Glomerulitis, 2:401
Glomerulocystic atrophy, 2:407f,
2:407.e2f
Glomerulocystic disease, 2:396, 2:396f
Glomerulonephritis (GN), 2:381-382,
2:401
acute fatal, 2:412-413
acute phase of proliferative, 2:409
anti-GBM, 2:408
capillary walls, hyalinosis of, 2:407f,
2:406.e2f
cellular crescent, 2:406.e1f
cellularity, 2:405
chronic, 2:409f
classification of, 2:401
factor H deficiency, 2:412-413
glomerulocystic atrophy, 2:407f,
2:407.e2f
histologic changes, 2:405-407
immunologic evidence, 2:413
membranoproliferative, 3:123-124
morphology of, 2:409-410
acute glomerulonephritis, 2:409
chronic glomerulonephritis, 2:409f
intratubular red blood cell cast,
2:409.e1f
nonglomerular histologic changes, 2:407
pathogenesis of, 2:407-408
prevalence of, 2:410-413
cat glomerulonephritides, 2:412
crescentic proliferative, 2:412f
dogs, 2:410-412
horses, 2:412
ruminants, 2:413
swine, 2:412-413
subacute, 2:409
swelling of foot processes, 2:406
thickening
and lamination, 2:407.e1f
remodeling, 2:406
tubulointerstitium, 2:407f
Glomerulopathy, 2:401
Glomerulosclerosis, 2:417-418
global, 2:405f
segmental, 2:418
Glomerulus, 2:377
Glomus jugulare tumors, 3:99
Glomus pulmonale tumors, 3:99
Glossitis, 2:16-17
necrotic, 2:17f
stomatitis and, 2:17f
Glucagon and hypoglycemic effects of
insulin, 2:368
Glucagonomas, 2:374-375
Glucocerebrosidosis, 1:287
Glucocorticoids, 2:55
biosynthesis, 3:337
in physis, 1:25t
Glucose-6-phosphatase deficiency, 1:290
Gluten-sensitive enteropathy, 2:69-70, 2:95
Glycogen brancher enzyme deficiency, 1:207,
1:208f
Glycogenoses, 1:290
Glycogenosis type II (Pompe’s disease),
1:208
Glycogen storage disease type Ia, 2:273
Glycogen storage disease type II, 1:204
Glycogen storage disease type III, 2:273
Glycogen storage disease type IV, 1:205,
1:205f, 2:273
Glycoproteinoses, 1:288-289, 1:492
Glycoproteins, 1:514
Gnathostoma, 2:54
Gnathostoma spinigerum, 2:210-211
Goatpox virus, 1:616, 1:622-624, 2:557
Goblet-cells, 2:60
carcinoids, 2:106
hyperplasia, 2:60
Goiter, 1:6f, 3:273
colloid, 3:322, 3:322f
congenital, 3:321, 3:321f
congenital hypothyroidism with
dyshormonogenic, 3:314, 3:323f
goitrogenesis, 3:320-323, 3:320f, 3:324f
inherited dyshormonogenic, 3:322-323
nodular, 3:322, 3:322f
Golden Retriever dogs
bilateral extraocular muscle myositis,
1:228
canine atopic dermatitis, 1:591
canine X-linked muscular dystrophy,
1:192, 3:49
chondrosarcoma, 1:118
cobalamin deficiency, 3:127
demyelinating neuropathy, 1:341-342
epidermolysis bullosa, 1:536
hypothyroidism, 1:587, 3:315
ichthyosis, 1:531, 1:531.e1f
iris cysts, 1:446
lymphomas, 3:238
malignant oral tumors, 2:21
maxillary or mandibular fibrosarcoma,
1:121
motor neuron disease, 1:331
osteogenesis imperfecta, 1:50
peliosis hepatis, 2:318
peripheral hypomyelination, 1:338
pyotraumatic dermatitis, 1:560
subvalvular aortic stenosis, 3:20
vitiligo, 1:555-556
Gomen disease, 1:319-320
Gomphoses, 1:128
Gonad phenotype, 3:360
Gongylonema pulchrum, 2:34, 2:35f, 2:43
Gongylonema spp., 2:19, 2:35f
esophagus and, 2:34
Goniodysgenesis, 1:417, 1:417f
Gordon Setter dogs, canine
hypomyelinogenesis in, 1:338
Gossypol, 1:220
“Gotch ear”, 1:506, 1:506f
Gousiekte, 3:38
Graft-versus-host disease (GVHD),
1:608-609
Granular cell tumors, 1:245, 2:27
heart, 3:52-53
laryngeal, 2:482, 2:482.e1f
pulmonary, 2:498
Granular trichoblastomas, 1:716
Granular vulvitis, 3:443, 3:443f
Granulation tissue, 1:520
Granulomas, 1:527
exuberant, 2:13
nasal, 2:476
oral eosinophilic, 2:16
pigment, 2:274-275, 2:275f
spermatic, 3:480-481, 3:480f-481f, 3:497
sterile, 1:699-702
testicular degeneration, 3:484
Granulomatous and pyogranulomatous
meningoencephalomyelitis, 1:362, 1:362f
Granulomatous encephalitis, 1:393f-394f
Granulomatous enteritis, 2:97
Granulomatous infections, pancreatic, 2:361
Granulomatous inflammation, 1:353, 2:38
Granulomatous interstitial pneumonia, 2:513
Granulomatous lesions, 1:233-234
Granulomatous lympadenitis, 3:203-204,
3:203f
Granulomatous lymphangitis, 2:196, 2:196f
Granulomatous meningoencephalomyelitis
(GME), 1:362f, 1:393-394, 1:393f-394f
Granulomatous pneumonia, 1:6f
Granulomatous radiculitis, 1:396
Granulomatous typhlocolitis, 2:100
Granulomatous uveitis, 1:449
Granulosa-theca cell tumors, 3:375,
3:376f-377f
Grass sickness, in horses, 2:77
Greasy-pig disease, 1:630-632, 1:631f
Great Dane dogs
acne, 1:549
calcium crystal-associated arthropathy
(pseudogout), 1:157
cervical vertebral malformation-
malarticulation, 1:136
cochleosaccular degeneration, 1:492
congenital idiopathic megaesophagus,
2:33-34
gastric volvulus, 2:49
hypothyroidism, 1:587, 3:315
inherited myopathy, 1:197-198
melanocytopenic hypomelanosis, 1:555
motor neuropathy, 1:335
Greater Swiss Mountain dogs, Chediak-
Higashi syndrome in, 3:259
Great Pyrenees dogs
canine multifocal retinopathy, 1:469
chondrodysplasia, 1:44
cochleosaccular degeneration, 1:492
prolonged APTT, 3:263
Grenz zone, 1:520
Greyhound dogs
canine exertional rhabdomyolysis, 1:223
erosive polyarthritis, 1:157-158
hip dysplasia, 1:135
malignant hyperthermia, 1:210
periodontal osteomyelitis, 1:101f
vasculitis, 3:70
Griffon Briquet Vendéen dogs, motor neuron
disease in, 1:331
Griffon Korthal dogs, recurrent flank alopecia
in, 1:590
Griseofulvin, 2:329
Gross and histologic examinations, 1:2-15
acute pancreatic necrosis, 2:359
aging changes and other incidental lesions,
1:7
bone marrow, 3:107-109, 3:108f
case interpretations and client service,
1:12-14, 1:13f

Gross and histologic examinations
(Continued)
classification of tumors, 1:107, 1:108b
diagnostic imaging, 1:11-12
external ear, 1:508
eye, 1:408-409, 1:409f
feline panleukopenia, 2:155
genetics, 1:12
heart, 3:6, 3:12-14, 3:12f, 3:13t
hematoxylin and eosin (H&E) stains, 1:9,
1:29
immunohistochemistry, 1:9, 1:10f
immunology, 1:11
initial and ongoing competence of
pathologists in, 1:14-15
liver, 2:277
lungs, 2:489
male genital tract, 3:465-466
methodologies, 1:2
microbiology, 1:10-11
molecular biology, 1:11
morphologic diagnosis in, 1:5
osteosarcoma, 1:112-114, 1:113f
parasitology, 1:11
photography, 1:12
problem-oriented, 1:7
quality assurance of pathology services
and, 1:14
sample selection and preservation, records,
1:8
of severely osteoporotic bones, 1:64
skeleton, 1:28
special stains, 1:9
systematic, 1:4-6
techniques and stains in postmortem
examination of skeleton, 1:28-29,
1:29f
preparation artifacts in, 1:29, 1:29f
toxicology, 1:11
trimming of fixed autopsy and biopsy
specimens, 1:8-9
types of investigations, 1:2-3, 1:3f
Ground substance, congenital abnormalities
of, 1:545-546
Ground (interstitial) substance, dermis, 1:514
Growing axonal sprouts, 1:256
Growth arrest line, 1:60, 1:60f, 1:64
Growth factors in bone matrix, 1:20
Growth hormone (GH), 1:25t, 3:276-277
adenomas, 3:285-286, 3:285f-286f
castration-responsive dermatosis, 1:589
Growth plate, 1:22, 1:22f, 1:24
bulldog type chondrodysplasia, 1:38, 1:38f
copper deficiency and, 1:81
damage, 1:30-31
fibrous osteodystrophy and, 1:79-80
hormonal regulation of, 1:24, 1:25t
mucopolysaccharidoses, 1:58
thickness, 1:23-24
Growth rate
growth retardation lattices, 1:104, 1:105f
osteochondrosis, 1:132
Guernsey cattle, cyclopia in, 1:269-270
Guinea pigs
ptyalism, 2:29
scurvy, 1:83, 1:83f-84f
Gurltia paralysans, 1:390-391
Gut
external muscle, 2:62
flora, 2:65
immune reactions, 2:67-68
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Guttural pouch, 1:495-496, 2:480-481
disease, 1:498
myocosis, 2:480-481, 2:480f
squamous cell carcinoma of, 1:500
Gynecomastia, 3:471
Gyr cattle, Rhabditis bovis in, 1:507
H congestive, 3:6, 3:10-12, 3:11f, 3:9.e1f
Habronema spp., 2:567, 3:508
splenic abscesses, 3:183-184
Haematobia irritans, 1:670
Haemonchus, 2:54-55
Haemonchus contortus, 3:112-114
Haemophilus, 1:151-152
Haemophilus parasuis, 2:543
Haflinger horses, axonal dystrophy in, 1:324
Hailey-Hailey disease (HHD), 1:537
Hair
congenital and hereditary diseases of
congenital hypotrichosis, 1:538-541
hypertrichosis, 1:539-541
follicles, 1:515-517
tumors arising from, 1:714-717
Hairy vetch, 1:574, 2:306, 3:43
Halicephalobus gingivalis, 1:98, 1:390, 1:390f,
2:19, 2:444f
Halogenated hydrocarbons, 2:332
Halogenated salicylanilide toxicosis, 1:345
Halogeton glomeratus, 2:425-426
Halothane, 2:329
Hamartomas, 1:404, 1:520, 1:705, 3:98
collagenous, 1:723
liver, 2:264, 2:264f
ovarian, 3:366, 3:378-379
pulmonary, 2:485
Hammondia, 2:239
Hampshire sheep, abomasal dilation and
emptying defect in, 2:51
Hansen type II intervertebral disk
herniations, 1:144f, 1:145
Hansen type I intervertebral disk herniations,
1:144, 1:144f
Hard callus, 1:35
Harlequin ichthyosis, 1:530, 1:531f
Hassall’s corpuscles, 3:142
Havanese dogs, sebaceous adenitis in, 1:551
Haversian systems, 1:20, 1:21f
Head. See also Brain
defects, 1:37t
traumatic injuries, 1:301-303
Hearing. See also Ear(s)
external ear and, 1:501
impairment, 1:491-494
acquired deafness, 1:493
congenital, 1:491-493
traumatic causes of deafness and,
1:493-494
internal ear and, 1:491
middle ear and, 1:496
Heart
-base tumors dervied from ectopic thyroid,
3:356
blood supply, 3:2
cardiac rhabdomyomas of, 1:241
cholesterol granuloma, 1:304f
congenital abnormalities, 3:14-24, 3:15t,
3:66-67
diseases, 3:2-54
cardiomyopathies, 3:44-51, 3:48.e2f,
3:45.e1f, 3:46.e2f
conduction system, 3:51
Index 535
Heart (Continued)
endocardial, 3:27-33
heart failure and, 3:2.e1f
morphologic patterns, 3:4-5
pathophysiologic patterns, 3:5-6
examination, 3:12-14, 3:12f, 3:13t
failure, 2:493, 2:493f, 3:6-12, 2:493.e1f
heart disease and, 3:2.e1f
systemic responses in, 3:9-10
hemorrhages, 3:33
neoplasms, 3:52-54, 3:52f
valves, 3:4
weight, 3:2
Heartwater, 3:80-82, 3:81f-82f
Heartworm disease, 3:83-85, 3:84f, 3:85.e1f
Heat-stable toxin, 2:160
Heinz bodies, 3:126f, 3:238.e1f
Helcococcus ovis, 2:562
Helianthrones, 1:578
Helichrysum blandowskianum, 2:331
Helicobacter acinonychis, 2:52
Helicobacter heilmannii, 2:58
Helicobacter pylori, 2:52
gastritis and, 2:52, 2:55
liver and, 2:318
Helicobacter spp., 2:55
chronic, 2:52
colonization, 2:52
Helminthic infections
central nervous system and,
1:389-391
gastrointestinal, 2:204-227
liver, 2:318-324
skin, 1:685-690
Hemal nodes, 3:162, 3:162f, 3:162.e1f
Hemangioendothelioma (HE), 3:98
Hemangiomas, 1:122, 1:726-727, 1:727f,
2:28, 2:447, 3:98-99
conjunctival, 1:481-482, 1:482f
liver, 2:349-350
ovarian, 3:378
scrotal, 3:472
Hemangiosarcomas, 1:122, 1:244-245,
1:245f, 1:727, 3:99-101, 3:100f-101f
ear, 1:505
metastasis, 1:736
splenic, 3:192-194, 3:193f, 3:192.e1f
Hematin, 2:271
Hematocele, 3:473
Hematogenous osteomyelitis, 1:98
Hematomas
aural, 1:504
congenital, 3:22-23
endocardium, 3:30
progressive ethmoid, 2:477
splenic, 3:166f
thymic, 3:147-148, 3:147f-148f,
3:146.e2f
Hematopoiesis, 2:264, 2:264f
Hematopoietic neoplasia, 3:129-136,
3:129t
Hematopoietic stem cells (HSC), 3:103
Hematopoietic system, 3:102-268. See also
Lymphomas
bone marrow, 3:103-138, 3:103f
histiocytic proliferative diseases,
3:243-255
leukocyte disorders, 3:109-112
lymph nodes, 3:196-243
lymphoid organs, 3:139-141
536 Index
Hematopoietic system (Continued)
sample procurement and processing,
3:107-109, 3:108f
spleen and hemolymph nodes, 3:158-196
thymus, 3:141-158
Hematopoietic tumors, 1:403
Hematoxylin and eosin (H&E) stains, 1:9,
1:29
Hemerocallin, 1:345
Hemidesmosomes, 1:513-514
Hemimelia, 1:55-56
Hemivertebrae, 1:57
Hemochromatosis, 2:272
Hemoconcentration, 3:343
Hemocysts, 3:30
Hemodynamic effects of valvular
abnormalities, 3:4.e1f
Hemoglobinuria, 2:436
-associated ATI, 2:422-423
Hemolysis, intravascular, 3:114, 3:115f
Hemolytic anemia, 3:114-126
Hemolytic-uremic syndrome (HUS),
3:65
Hemomelasma ilei, 2:216-217, 2:217f
Hemonchosis, 2:207-208, 2:207f-208f
Hemopericardium, 3:25, 3:25f
Hemoperitoneum, 2:247
Hemophagocytic histiocytic sarcoma,
3:254-255, 3:254f-255f, 3:254.e1f
Hemophilia A, 3:263-264
Hemophilia B, 3:263
Hemorrhage, 2:57
adrenal gland, 3:339-340, 3:340f
central nervous system, 1:300-301
heart, 3:33, 3:78.e1f
intrafollicular (ovary), 3:370
liver, 2:294
lymph node, 3:200f
pulmonary, 2:490-492, 2:490.e1f
retinal, 1:473
septicemia of cattle, 2:546-547
subendocardial, 3:4
testicular, 3:492, 3:492f
thymic, 3:147-148, 3:146.e2f
tracheal, 1:192, 2:483f
Hemorrhagic adrenal necrosis, 3:65
Hemorrhagic bowel syndrome, 2:114. See
also Jejunal hematoma
Hemorrhagic glomeruli turkey egg pattern,
2:399
Hemorrhagic infarcts, 1:299f-300f
Hemorrhagic inflammation, 1:353
Hemorrhagic shock, 2:84
Hemosiderin, 1:434, 2:271, 3:165, 3:165f
Hemosiderosis, chronic hemolytic anemia,
2:429
Hemostasis disorders, 3:255-268
dysregulation of hemostasis, 3:267-268
fibrin formation, 3:265
fibrinolysis, 3:266-267
platelet plug formation, 3:255-257
regulation of coagulation, 3:265-266
thrombin formation, 3:260-261, 3:263-265
Hemothorax, 2:521, 2:521.e3f
Hemotropic mycoplasmas, 3:124-125
Hendra virus, 2:569
Henle loop, 2:377
Hepatic acinus of Rappaport, 2:261
Hepatic arterial buffer effect, 2:260
Hepatic arteriovenous malformations, 2:266,
2:266f
Hepatic artery, 2:260
injury, 2:296-300
Hepatic carcinoids, 2:349, 2:350f
Hepatic coccidiosis, 2:324, 2:324f
Hepatic cysts, 2:264
Hepatic dendritic cells, 2:263
Hepatic dysfunction, 2:290-295
Hepatic encephalopathy (HE), 1:262, 1:262f,
1:344, 1:344f, 2:291-292
Hepatic endothelial cells, 2:262-263
Hepatic fatty cirrhosis, 2:276, 2:276.e1f
Hepatic iron overload, 2:272
Hepatic lipodystrophy, 2:278
Hepatic progenitor cells (HPCs), 2:262
Hepatic regeneration, 2:286-287
Hepatic sinusoids, 2:260
Hepatic stellate cells (HSC), 2:263
Hepatic susceptibility, 2:325-326, 2:260
Hepatic veins, 2:260
injury, 2:296-297
thrombosis, 2:298
Hepatitis
acute, 2:301
B antigen, 3:71
chronic, 2:301-306, 2:305.e1f
cats, 2:305
dogs, 2:302-305, 2:305f
horses, 2:305
lobular dissecting, 2:305, 2:305f,
2:305.e1f
equine serum, 2:313-314, 2:314f
focal, 2:282, 2:282f
giant cell, 2:306, 2:306f
infectious canine, 2:310-312, 2:310f-311f,
2:311.e1f
necrotic, 2:316, 2:316.e1f
nonspecific reactive, 2:306
periportal interface, 2:301-302, 2:302f,
2:304f
Hepatoblastomas, 2:347-348, 2:348f
Hepatocellular atrophy, 2:269, 2:269f,
2:269.e1f
Hepatocellular carcinoma, 2:346, 2:346.e1f
mixed cholangiocellular and, 2:349,
2:349.e1f
Hepatocellular cholestasis, 2:293
Hepatocellular hypertrophy, 2:269-270,
2:269f
Hepatocellular steatosis, 2:273-278,
2:274f-276f, 2:274.e1f, 2:276.e1f
Hepatocutaneous syndrome, 1:586-587,
2:295, 2:329, 2:295.e1f
Hepatocytes, 2:261-264
Hepatocytotropic T-cell lymphoma (HC-
TCL), 3:232
Hepatogenous photosensitization, 1:579-580,
2:294, 2:294f
Hepatoid glands, 1:517
Hepatopancreatic ampullary carcinoma
(HC-TCL), 2:367
Hepatorenal syndrome, 2:294, 2:430
Hepatosis dietetica, 2:284, 2:285f
Hepatosplenic T-cell lymphoma (HS-TCL),
3:232
Hepatozoon americanum, 1:98, 1:240, 2:414,
3:110-111
Hepatozoon canis, 3:110
Hepatozoonosis, 1:240
Hereditary deafness, 1:492-493, 1:492f
cryptorchidism, 3:476-478, 3:476f
Hereditary equine regional dermal asthenia
(HERDA), 1:544
Hereditary footpad hyperkeratosis,
1:532
Hereditary hypopigmentation, 1:555-557
Hereditary nephritis, 2:417f, 2:415.e3f
Hereditary nephropathy, 2:388-391
Hereditary renal diseases, 2:391
Hereditary striatonigral and cerebello-olivary
degeneration, 1:319
Hereditary zinc deficiency, 1:532-533
Heredity. See Genetic disease/disorders
Hereford cattle
bovine familial convulsions and ataxia,
1:319
bovine hypomyelinogenesis, 1:338-339
Chediak-Higashi syndrome, 3:259
congenital hypotrichosis, 1:538-539
hip dysplasia, 1:135-136
idiopathic spongy myelinopathies,
1:342-343
motor neuron disease, 1:332, 1:332f
osteopetrosis, 1:51
Hernias
acquired diaphragmatic, 2:246-247,
2:246f
diaphragmatic, 2:80
direct inguinal, 2:80
external, 2:79-81, 2:245
femoral, 2:80
hernial contents, 2:79-80
hiatal, 2:32
indirect inguinal, 2:80
inguinal, 2:80, 3:498
internal, 2:79
mesenteric, 2:79
omental, 2:79
pelvic, 2:79
perineal, 2:80
prepubic, 2:80
scrotal, 3:498
sequelae of, 2:80
through natural foramen, 2:79
umbilical, 2:80
ventral hernia of abdominal wall, 2:80
Herniation, natural foramen, 2:79
Herpesviral infections, 1:625-627
adrenal cortex and, 3:340
alphaherpesviruses
cattle, 2:537
horses, 2:568, 2:568.e2f
Canid herpesvirus-1 (CaHV-1), 2:577,
3:431-432, 3:432f, 3:434f
cats, 1:425, 1:625-627, 1:627f, 2:588-589,
2:588.e2f
general features, 2:537
male goats, 3:507
myocardial necrosis and, 3:34
pigs
causing abortion in, 3:432-433
pregnant uterus, 3:433
pups and pregnant bitches, 3:431-432,
3:432f
Herpetic keratitis of cats, 1:438
Hertwig’s epithelial root sheath (HERS),
2:4-5
Heterobilharzia americana, 2:323, 3:93-94,
3:94f
Heterophilic otitis media, 1:493, 1:493.e2f
Heterotopic polyodontia, 2:6
Hexachlorophene poisoning, 1:344-345,
1:345f
Hiatal hernia, 2:32
Hidradenitis, 1:520
“High-altitude disease” of cattle, 3:66
High-endothelial venules (HEV), 3:196
Highland cattle, cropped or notched pinnae
in, 1:502

Highly chlorinated naphthalene toxicosis,
1:571
Himalayan cats, feline corneal sequestrum in,
1:434, 1:434f
Hip dysplasia
cats, 1:135
cattle, 1:135-136
dogs, 1:135-136, 1:135f
Hirano-like bodies, 1:255
Histamine, 2:45
Histiocytes in nodular and diffuse dermatitis,
1:526
Histiocytic proliferative disorders, 1:728-730,
3:243-255
canine cutaneous histiocytoma, 3:243-245,
3:244f-245f, 3:244.e1f, 3:243.e1f
canine cutaneous Langerhans cell
histiocytosis, 1:729, 3:245-246,
3:246f
canine reactive histiocytosis, 3:247-250,
3:248f-249f, 3:247.e1f, 3:249.e1f
feline progressive histiocytosis (FPH),
1:730, 3:252f-253f, 3:253-254,
3:253.e1f
feline pulmonary Langerhans cell
histiocytosis, 2:499, 3:246-247, 3:247f,
3:246.e1f
hemophagocytic histiocytic sarcoma,
3:254-255, 3:254f-255f, 3:254.e1f
histiocytic sarcoma (HS), 1:159-160,
1:160f, 1:729-730, 3:250-253,
3:250f-252f, 3:250.e2f, 3:250.e1f
Histiocytic sarcoma (HS), 1:159-160, 1:160f,
1:403, 1:729-730, 3:250-253, 3:250f-
252f, 3:250.e2f, 3:250.e1f
multifocal, 2:448f
pulmonary, 2:498-499, 2:499f
Histiocytic ulcerative colitis, 2:97-98, 2:98f
Histochemical fiber types, 1:169-170,
1:169f-170f
Histologic examinations. See Gross and
histologic examinations
Histophilus somni, 1:151-152, 1:364f-365f
abortion and, 3:414
cattle, 2:543-544, 2:546, 2:546.e1f
central nervous system and, 1:364-365,
1:364f-365f
liver and, 2:314-315
pleuritis, 2:522f
pulmonary vasculitis and, 2:494
sheep, 2:562
Histoplasma capsulatum, 1:104, 1:449-450,
1:450f, 2:98, 2:202, 2:203f, 3:97, 3:340,
2:324.e1f
spleen and, 3:186-187, 3:186f-187f,
3:186.e2f
Histoplasmosis, 1:450, 1:450f
intestinal, 2:202-203, 2:203f
H3N8 influenza A virus, 2:577
HoBi-like BVDV, 2:122
Hodgkin-like lymphomas (HLL), 3:219
Holoprosencephaly, 1:269-270, 1:269f
Holstein cattle, 2:38
bovine hypomyelinogenesis, 1:338-339
cardiomyopathies, 3:50
congenital axonopathy, 1:325
congenital hypotrichosis, 1:538-539
degenerative joint disease, 1:143
diaphragmatic dystrophy, 1:199
prolonged APTT, 3:263
vitiligo, 1:556
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Hookworms
dermatitis, 1:685
of ruminants, 2:214-215
Hormonal hypersensitivity, 1:599
Hormones
abnormal degradation of, 3:275
adrenal, 3:337-338
calcium-regulating, 3:291-310,
3:291f
catecholamine and iodothyronine, 3:271,
3:348-349, 3:350f
excess, syndromes of iatrogenic,
3:275-276
hypersecretion by non-endocrine tumors,
3:274
pancreatic, 2:368, 2:369f
polypeptide, 3:270-271, 3:270f
steroid, 3:271
thyroid, 3:311-312
types, 3:270-271
Horn cysts, 1:520
Horner syndrome, 1:494-495
Horn fly dermatitis, 1:670
“Horsepox”, 1:621
Horsepox virus, 1:616, 1:621
Horseshoe kidney, 2:392, 2:393f
“Hot spots”, 1:560, 1:598
House-dust mites, 1:683
Howship’s lacunae, 1:18, 1:19f, 1:78-79
Humans
arrhythmogenic right ventricular
cardiomyopathy, 3:49
atherosclerosis, 3:57
benign bone cysts, 1:126
carcinoids, 2:497-498
Fanconi anemia, 1:57
Hashimoto’s disease, 3:316
ichthyosis, 1:530
infantile cortical hyperostosis, 1:53
inflammatory bowel disease, 1:66-67
light-induced retinal degeneration,
1:470
metabolic myopathies, 1:204
muscular dystrophy, 1:192
necrotizing sialometaplasia, 2:30
ocular onchocerciasis, 1:452
osteochondromatosis, 1:54
osteoporosis, 1:63-64, 1:67
renal failure, 1:80
rickets and osteomalacia, 1:69
steroid-induced bone necrosis, 1:95
tuberculosis in, 2:548
Werdnig-Hoffman disease, 1:331
Humoral hypercalcemia of malignancy
(HHM), 3:274, 3:305-310, 3:306f
Hunter syndrome, 1:58
Hurler’s syndrome, 1:58
Hyaline arteriosclerosis, 3:60
Hyaline droplets, 2:421-422
Hyaline necrosis, 1:297-298
Hyaline scars, 2:504, 2:504.e2f
Hyalinization of dural collagen, 1:304
Hyalinosis, 2:406, 3:60, 3:60f
of capillary walls, 2:407f, 2:406.e2f
pulmonary, 2:517
Hyalohyphomycosis, 1:653, 1:655
Hyaluronan, 1:131
Hybrid cysts, 1:704
Hybrid sorghum, 1:91
Hydatid disease, 2:537
Hydrallantois, 3:397
Index 537
Hydramnios, 3:397
Hydranencephaly, 1:272-274, 1:272f
orbiviruses and, 1:281
Hydrocarbons, halogenated, 2:332
Hydrocele, 3:473
Hydrocephalus, 1:270-272, 1:271f
Hydrogen ion excretion, 2:381
Hydrometra, 3:386, 3:386f
Hydromyelia, 1:278
Hydronephrosis, 2:400-401
development of, 2:400
glomerular filtration, 2:400
gross changes, 2:400-401
microscopically, 2:401
in sheep, 2:400f
Hydropericardium, 3:24-25, 3:24f
Hydropic degeneration, 1:522, 1:522f
Hydrosalpinx, 3:379-380, 3:379f
Hydrothorax, 2:521.e3f
Hydroureter, 2:451
in goat, 2:451.e1f
Hydroxyapatite, 1:20
Hydroxyl radical, 2:81
Hyena disease, 1:88
Hygroma, 1:155, 1:155f, 1:559
Hygromycin B, 1:444
Hymen, 3:368-369, 3:370f
Hymenopteran insects, 1:568
Hymenoxon odorata, 2:52
Hyostrongylus rubidus, 2:210
Hyostrongylus spp., 2:47
Hyperacute infection, 2:437
Hyperadrenocorticism, 1:224-225,
1:588-589, 1:588f, 3:346-347,
3:347f
muscle myopathies and, 1:224-225
spontaneous and iatrogenic, 1:67
Hypercalcemia, 2:441, 3:305-310, 3:305f,
3:343
with tumors metastatic to bone,
3:309
Hypercalcemic nephropathy, 2:383, 2:441,
2:441f, 2:456
cause, 2:441
mineralization, 2:441
renal failure, 2:441
Hypercellularity, 2:405
Hypercementosis, 2:6
Hypercholesterolemia, 3:318-319
Hyperemia, 2:51
lungs and, 2:487
mastitis, 3:453-454, 3:453f
Hyperestrogenism, 1:589
Hyperfibrinogenemia, 3:265
Hypergammaglobulinemia, 2:95
Hyperglobulinemia, 2:72-73
Hypergranulosis, 1:520
Hyperimmune states, 3:163
Hyperkalemic periodic paralysis (HYPP),
1:186-187, 1:202
Hyperkeratosis
canine nasodigital, 1:549-550
esophageal epithelium, 2:31
hereditary footpad, 1:532
hypothyroidism with, 3:318
perivascular dermatitis with, 1:525
stratum corneum, 1:520, 1:522f
Hyperkinetic equilibrium, 2:72-73
Hyperlipemia, equine, 2:276-277
Hypermotility, 2:72
Hypernatremia, 1:225
538 Index

Hyperostotic diseases, 1:91-94 Hypersensitivity pneumonitis, 2:512-513 Hypoplasia (Continued)

calvarial hyperostosis of Bullmastiffs, 1:92
canine hepatozoonosis, 1:94, 1:94f
craniomandibular osteopathy, 1:91-92,
1:92f
hypertrophic osteopathy, 1:92-94, 1:93f
Hyperoxaluria, primary, 2:426
Hyperparathyroidism, 3:273-274
nutritional, 3:274
secondary, 1:75
primary, 1:74, 3:304-305
renal secondary, 1:74-75, 1:77-78
secondary, 1:74
to renal disease, 3:300-301, 3:300f
secondary to nutritional imbalances,
3:301
Hyperpigmentation, 1:520-521, 1:554-555
acquired, 1:554
focal macular melanosis, 1:554
hypothyroidism with, 3:318
Hyperplasia, 2:387. See also Neoplasia
adrenal cortex, 3:343, 3:344f
adrenal medullary, 3:352
atypical adenomatous, 2:495
bile duct, 2:287-288, 2:289f
bronchiolar epithelial, 2:505, 2:504.e2f
cementum, 2:6
dermatosis of West Highland White
Terriers, 1:553
diffuse, 3:300, 3:300f
ductular epithelium, 2:365-366
endocrine gland nodular, 3:271
endometrial, 3:382-385, 3:382f-384f,
3:391, 3:391f-392f
epidermal, 1:521, 1:522f
perivascular dermatitis with, 1:525
epithelial, 1:442-443, 3:151, 3:151f
erythroid, 3:106f
esophageal epithelium, 2:31
fibroadenomatous, 3:460, 3:460f
follicular, 3:222-223, 3:223f
liver, 2:344-352
lymph node, 3:200-202
male genital system
prostate and bulbourethral gland,
3:502-503, 3:503f
testicular, 3:470f, 3:493
mucous, 2:47
muscular, 1:190-191
nodular
adrenal cortex, 3:343
liver, 2:344, 2:344f
spleen, 3:189-190, 3:190f, 3:189.e2f
thyroid, 3:322, 3:322f
pancreas
endocrine, 2:373-375
exocrine, 2:365, 2:365f-366f
parathyroid, 3:299-300, 3:299f-300f
primary, 3:301
pharyngeal lymphoid, 2:480.e3f
plasma cell, 3:201
pseudoepitheliomatous, 3:151
sebaceous gland, 1:523
Sertoli cell, 3:477f
splenic, 3:169f, 3:189-191, 3:189f
tail gland, 1:549
thymic, 3:150-151, 3:150f
thyroid, 1:6f, 3:320-323, 3:320f
Hyperplastic dermatosis of West Highland
White Terriers, 1:553
Hypersensitivity dermatoses, 1:590-600
hormonal, 1:599
insect, 1:597-599, 1:670-671
Hypersensitivity-related idiosyncrasies, 2:327
Hypersomatotropism, 1:589
Hypertension, 2:398, 3:59-60
portal, 2:297
pulmonary, 2:492-494, 3:60
canine pulmonary veno-occlusive disease
(PVOD), 2:493, 2:493f, 2:493.e1f
causes, 2:492b
pulmonary arterial hypertension (PAH),
2:492-494, 2:492f, 3:66-67
Hypertensive retinopathy, 1:472, 1:473f
Hyperthyroidism
associated with thyroid tumors, 3:327-329,
3:328f
concentric cardiac hypertrophy and, 3:9
muscle myopathies and, 1:224
osteoporosis and, 1:67
Hypertrichosis, 1:541, 3:284, 3:284f
Hypertrophic antritis, 2:53
Hypertrophic cardiomyopathy (HCM), 3:45
cats, 3:46, 3:47f
cattle, 3:50
dogs, 3:49
Hypertrophic osteodystrophy (HOD),
1:105-106, 1:105f
Hypertrophic osteopathy, 2:444
dogs, 1:92-94, 1:93f
horses, 1:93f
Hypertrophic pulmonary osteopathy, 2:35
Hypertrophic reaction, 1:262-263
Hypertrophic zone, 1:23
Hypertrophy, 1:178-180, 1:178f-179f, 3:2
arterial, 3:66-67
cardiac, 3:7-9
cementum, 2:6-8
gastric mucosal, 2:53
hepatocellular, 2:269-270, 2:269f
of pulmonary arteries of cats, 3:67, 3:67f
smooth muscle of esophagus, 2:31
testicular, 3:485
of the tongue, 2:4
Hypoadrenocorticism, 1:225
lesions, 3:341-343, 3:342f
Hypoalbuminemia, syndromes of, 2:95
Hypoalbuminemic animal, 2:73
Hypocalcemia, 3:299
Hypoderma bovis, 1:668-669
Hypoderma lineatum, 1:668-669, 2:34
Hypoderma spp., 1:668-669
Hypoglycemia, 3:343
nervous system and, 1:306-307
Hypoglycin A., 1:220
Hypokalemia, 2:430
cats, 1:225
cattle, 1:225
Hypomyelinating diseases, 1:259-260, 1:260f
Hypomyelination, 1:336-337
Hypoparathyroidism, 3:298-299
Hypophosphatemia, 1:225
Hypophosphatemic rickets, 1:70, 1:70f
Hypophyseal form of diabetes insipidus,
3:290
Hypopigmentation
disorders, 1:555-558
acquired, 1:557, 1:557f
hereditary, 1:555-557
leukoderma and leukotrichia, 1:555
epidermis, 1:521-522
iris, 1:415
Hypoplasia
adrenal cortex, 3:338-339
cerebellar, 1:275-276, 1:275f
cervical, 3:368-369
corpus callosum, 1:269, 1:269f
enamel, 2:5
iris, 1:415
optic nerve, 1:420-421, 1:421f
ovaries, 3:366
pancreas, 2:355
penile and preputial, 3:505
pulmonary, 2:484, 2:484.e3f
renal, 2:392
segmental, 1:277-279, 1:277f
splenic, 3:163
testicular, 3:478-479, 3:478f
thymic, 3:144
thyroid, 3:314, 3:314f
tracheal, 2:482, 2:482f
Hypoproteinemia, 2:73, 2:248
Hypopyon, 1:356f, 1:449
Hyposomatotropism, 1:589
Hypospadias, 3:470, 3:470f
Hypotension, 2:398
Hypothalamic neurons, 3:277
Hypothalamus, 2:377
control of adenohypophysis, 3:277, 3:278f
Hypothyroidism, 1:31-32, 1:224, 1:587-588,
3:273, 3:315-319, 3:315f, 3:318f,
1:587.e2f
acquired myasthenia gravis and, 1:229
Hypotrichosis, congenital, 1:538-539
associated with pigmentary alterations,
1:539-541
cats, 1:539
cattle, 1:538-539
dogs, 1:539, 1:539.e1f
Hypotrophy, muscle, 1:187, 1:188f
Hypovitaminosis A, 1:470-471, 1:581-583
Hypoxia, 2:37, 2:275
Hypsodont teeth, 2:5
I
Iatrogenic acromegaly, 3:286f
Ibaraki disease, 2:138-139
Ibex MCF virus, 2:132
Ibizan hounds, multisystem axonal
degeneration in, 1:325
I-cell disease, 1:58
Ichthyosis, 1:530-532, 1:530f, 1:554,
1:531.e1f
harlequin, 1:530, 1:531f
nonepidermolytic, 1:531-532
vulgaris, 1:530
IC-mediated glomerulonephritis (ICGN),
2:401-404
Idiopathic follicular atrophy, 3:315-316,
3:315f-317f
Idiopathic generalized or systemic
granulomatous disease, 1:700-701
Idiopathic granulomatous marginal
blepharitis, 1:423
Idiopathic immune-mediated uveitis,
1:453-455, 1:454f
Idiopathic inflammatory bowel disease,
2:91-96
Idiopathic lymphocytic uveitis in dogs, 1:456
Idiopathic lymphonodular uveitis in cats,
1:456
Idiopathic lymphoplasmacytic rhinitis, 2:476
Idiopathic mucosal colitis, 2:92-93
cats, 2:98-99
Idiopathic multifocal osteopathy
cattle, 1:54
dogs, 1:54

Idiopathic polyarthritis, 1:158
Idiopathic pulmonary fibrosis in cats, 2:515,
2:515f, 2:515.e2f
Idiopathic spongy myelinopathies, 1:342-344
Idiopathic squamous papillomas, 1:705
Idiopathic thyroid atrophy, 1:587
Idiosyncratic hepatotoxins, 2:327
IgA-producing lymphocytes, 2:64
IgE autoantibodies, 2:15
IGF-1, 1:25t
IgG autoantibodies, 2:15
IgG-producing plasma cells, 2:64
Iliac thromboembolism, 3:46
Imaging, diagnostic, 1:11-12
Immune-mediated disorders, 1:225-230,
1:226f
acquired myasthenia gravis, 1:229-230
conjunctivitis, 1:426-427
dermatoses, 1:590-615
glomerulonephritis, 2:410b
horses, 1:229
immune-mediated thrombocytopenia
(IMT), 3:129
masticatory myositis of dogs, 1:226-227,
1:226f
other myositides of dogs, 1:228
polyarthritis, 1:157-159
polymyositis
cats, 1:228-229
dogs, 1:227-228, 1:228f
pulmonary immune responses and, 2:472
rabies vaccine-induced vasculitis and
alopecia, 1:612-613
thrombocytopenia (ITP), 3:258
Immune privilege, 1:454
Immune system
male genital system, 3:468
testes and, 3:467-468
skin and, 1:515
upper respiratory tract, 2:474
Immunocompromise, 2:44
Immunodeficiency syndromes, lymphoid
systems, 3:139-141
Immunofluorescence (IF), 2:384
evaluation, 2:383
Immunoglobulin A (IgA), 2:13-14
Immunoglobulin deficiencies, 3:139
Immunoglobulin-derived amyloidosis,
2:414
Immunoglobulin G (IgG), 2:401
Immunohemolytic anemia, 3:114, 3:115f
Immunohistochemical reactivity, 2:110
Immunohistochemistry, 1:9, 1:10f, 2:445
Immunoinflammatory, 2:65
Immunologically mediated tubulointerstitial
disease, 2:431
Immunology, 1:11
Immunoperoxidase techniques, 2:384
Immunophenotyping, 3:214-215
Immunoreactive peptides, 3:285, 3:285f
Immunosuppressive therapy, complications
of, 2:387
Immunosuppressive agents and osteoporosis,
1:67
Impaction, gastric, 2:50-51
Impairment of steroidogenesis, 3:340
Imperforate hymen, 3:368-369, 3:370f
Imperforate pectinate ligament, 1:462-463
Impetigo, 1:630, 1:630f
Imported fire ants, 1:568
Impulse formation disturbances, 3:5
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Inappetence, 2:69
Incidental lesions, gross examination of, 1:7
Incisor anodontia, 1:538
Inclusion bodies
neuronal diseases, 1:320
in neurons, neuroglia, and microglia, 1:367
rhinitis, 2:529-530, 2:530f
Inclusion cysts
ovarian, 3:372, 3:372f
serosal, 3:386-387, 3:387f
Incomplete atrophy of anterior chamber
mesenchyme, 1:415, 1:415f
Incomplete atrophy of posterior segment
mesenchyme, 1:417-419, 1:418f
Incomplete cortical fractures, 1:36
Increased intestinal motility, 2:72
Indirect inguinal hernia, 2:80
Indirect salt poisoning, 1:315
Indolent cutaneous T-cell lymphoma,
1:734
Indolent ulcer, 1:694, 1:694f
Indospicine, 2:340-341, 2:341.e1f
Indubrasil cattle, Rhabditis bovis in, 1:507
Induced storage diseases, 1:292-293
Infantile cortical hyperostosis, 1:53
Infarction
adrenal cortex, 3:340, 3:340f
cerebral, 1:299-300, 1:299f-300f
gallbladder, 2:307, 2:307f
laryngeal, 2:481
lymph node, 3:199
pulmonary, 2:490.e1f
retinal, 1:473
splenic, 3:170f-171f, 3:170.e1f
Infection(s)
abortion due to, 3:399-402, 3:399b
acquired platelet disorders and, 3:260
arthritis, 1:148-155
fibrinous, 1:147
bacterial. See Bacterial infections
BVDV secondary, 2:127
canine hepatitis, 2:310-312, 2:310f
fungal. See Fungal infections
gastritis due to, 2:52, 2:55
granulomatous rhinitis and, 2:476
liver
bacterial, 2:314-318
helminthic, 2:318-324
viral, 2:309-325, 2:309f-310f
lymphoid tissues, 3:171-182
microsporidian, 1:385-386
mycoplasmal. See Mycoplasmal infections
myositis due to, 1:230-234
clostridial, 1:230-233, 1:231f
granulomatous lesions, 1:233-234
malignant edema and gas gangrene,
1:232
muscle changes secondary to systemic
infections, 1:234, 1:234f
specific diseases with muscle alterations,
1:233
suppurative, 1:230, 1:230f
Toxoplasma and Neospora myositis,
1:237
nervous system changes with, 1:351t-352t
parasitic. See Parasitic infections
parvoviral, 1:628
respiratory tract, 2:149
retroviral, 1:627-628
small intestinal bacterial overgrowth, 2:364
viral. See Viral infections
Index 539
Infectious bovine cervicovaginitis and
epididymitis, 3:443
Infectious bovine keratoconjunctivitis, 1:440
Infectious bovine rhinotracheitis (IBR),
1:425, 2:140-142, 2:525f, 2:537-539,
2:538f
Infectious canine hepatitis, 2:310-312,
2:310f-311f, 2:311.e1f
Infectious keratoconjunctivitis of sheep and
goats, 1:440-441
Infectious pustular vulvovaginitis of cattle,
3:443-445, 3:444f
Infertility, 2:438
Infiltrative variant of lipoma, 1:245, 1:246f,
1:726
Inflamed nonepitheliotropic T-cell
lymphoma, 1:734
Inflammation/inflammatory response
adenohypophysis, 3:289-290
adrenal cortex, 3:340, 3:340f
anemia of inflammatory disease, 3:127
bronchiolar, 2:504-506, 2:504f
central nervous system, 1:350-396,
1:351t-352t
bacterial and pyogenic infections,
1:353-365
helminth and arthropod infections,
1:389-391
idiopathic inflammatory diseases,
1:392-396, 1:392f
viral infections, 1:365-385
corneal, 1:436-441
diseases of bone, 1:97-107
bacterial osteomyelitis, 1:98-103,
1:98f-99f
canine panosteitis, 1:106-107
fungal osteomyelitis, 1:103-104
metaphyseal osteopathy, 1:105-106,
1:105f
viral infections of bones, 1:104-105
dysregulation of hemostasis and,
3:267-268
endothelial cells and, 3:55
epidermal
fibrosis, 1:528
interface dermatitis, 1:525
intraepidermal vesicular and pustular
dermatitis, 1:527, 1:528f
nodular and diffuse dermatitis, 1:526-
527, 1:527f
panniculitis, 1:528-529, 1:529f
perifolliculitis, folliculitis, and
furunculosis, 1:528
perivascular dermatitis, 1:525, 2:363f
subepidermal vesicular and pustular
dermatitis, 1:527-528, 1:528f
vasculitis, 1:525-526, 1:526f
epididymitis, 3:473-474, 3:474f, 3:487-
491, 3:489f
exocytosis, 1:519-520
forestomachs, 2:42
gross diagnosis, 1:5
joints
degenerative joint diseases, 1:141
diseases, 1:146-159
large intestine, 2:97-100
colitis cystica profunda, 2:97
colitis in cats, 2:98-99
feline panleukopenia virus (FPLV),
2:98-99
necrotic colitis, 2:99
540 Index
Inflammation/inflammatory response
(Continued)
typhlocolitis in dogs, 2:97-98
typhlocolitis in horses, 2:99-100
ciliate protozoa, 2:99
equine intestinal clostridial diseases,
2:99
Potomac horse fever, 2:99
subacute/chronic diarrhea in horses,
2:99
typhlocolitis in ruminants, 2:100
typhlocolitis in swine, 2:100
dysentery, 2:100
postweaning colibacillosis, 2:100
lesions of joint structures, 1:155-159
liver and biliary tract, 2:300-309,
2:326
lupus erythematosus (LE), 1:604-607
lymph nodes, 3:202-212
male genital system
penis and prepuce, 3:506-508
prostate and bulbourethral gland,
3:501-502, 3:502f
spermatic cord, 3:498-499
testis and epididymis, 3:485-491
vesicular glands, 3:499-500, 3:499f
mammae, 3:451-452
mucosa, 2:47
muscle necrosis and, 1:182, 1:182f
myocarditis, 3:41-44, 3:42f, 3:42t
nervous system and, 1:351t-352t
oral cavity, 2:13-19
salivary glands, 2:29
spleen, 3:182-189, 3:182.e1f
teeth, 2:9-12
thymus, 3:148-150
uterine (fallopian) tubes, 3:380
uterus, 3:387-393
vaginal and vulval, 3:443
vasculitis, 3:67-88, 3:68b
Inflammatory airway diseases, 2:506
Inflammatory aural polyps, 1:498-499,
1:498.e2f
Inflammatory bowel disease (IBD), 1:66-67,
2:91, 2:93f
idiopathic, 2:91-96
Inflammatory ceruminous otitis externa,
1:548
Influenza
cats, 2:587-588
dogs, 2:577
horses, 2:567-568, 2:567.e3f
pigs, 2:526-527, 2:526f, 2:526.e1f,
2:527.e1f
Infractions, 1:34, 1:34f
Infundibular cysts, 1:704
Infundibular keratinizing acanthoma, 1:714,
1:715f
Infundibular necrosis, 2:10, 2:10f
horses, 2:10, 2:10f
Infundibular stalk, 3:277
Infundibulum, 1:516
Ingesta, 2:247
Inguinal hernias, 2:80, 3:498
Inhalation
oxygen, 2:518
smoke
lung injury, 2:518
trachea and, 2:483, 2:483f
toxic gases, 2:518
Inherited dyshormonogenic goiter, 3:322-323
Inherited erythrocyte enzyme deficiencies,
3:126
Inherited myopathy of Great Dane dogs,
1:197-198
Inherited photoreceptor dysplasias, 1:469
Inherited storage diseases, 1:286-292, 1:287f
Inherited thrombocytopenia, 3:258
Injections
interstitial lung disease reactions to,
2:512
site reactions, 1:560
Injury. See Trauma; specific injuries
Inorganic (mineral) component of bone
matrix, 1:20
Insects
caterpillar larvae, 1:671
fire ants, 1:671
fleas, 1:672-673
flies, 1:666-671
horn fly, 1:670
hypersensitivity, 1:597-599, 1:670-671
lice, 1:671-672
mites, 1:673-684
mosquito, 1:599, 1:670-671, 1:671f
Insulin, 2:368
Insulinomas, 2:374
Intact nephron hypothesis, 2:377-378
Integumentary system. See Skin
Intercellular adhesion molecules (ICAMs),
3:198
Interface dermatitis, 1:525, 1:526f
Interferons, 2:548-549
Interfollicular smooth muscles, 1:515
Interglobular dentin, 2:5
Interleukins, 2:263, 2:548-549
Internal ear, 1:488-495
hearing, 1:491
impairment, 1:491-494
Horner and Pourfour du Petit syndromes,
1:494-495
neoplasia, 1:494
peripheral vestibular disease, 1:494
Internal hernias, 2:79
Internal hordeolum, 1:423
Interphalangeal joints, 1:142
Interstitial cells
of Cajal, 2:62
tumors of testes, 3:493, 3:493f
Interstitial edema, 1:294
Interstitial emphysema, 2:486
Interstitial fibrosis, 2:510
cats, 2:515, 2:515f
dogs, 2:514-515, 2:515f
Interstitial lesions, miscellaneous, 2:441-442
acute ascending pyelonephritis, 2:441.e1f
bone, 2:442
extramedullary hematopoiesis, 2:441
renal telangiectasia, 2:442
Interstitial lung disease, 2:509, 2:510f,
2:511b
dogs, 2:514-515, 2:515f
eosinophilic, 2:513
feedlot cattle, 2:513f, 2:513.e1
foals, 2:514
granulomatous, 2:513
noninfectious, 2:512-520
Interstitial macrophages, 2:471
Interstitial myocarditis, 3:42
Interstitial nephritis, 2:431-432
acute, 2:431
chronic, 2:431
Interstitial orchitis, 3:486
Interstitial pneumonia, 2:509
Interstitium, 3:3
Intertrigo, 1:559
Intervertebral disk diseases, 1:128-129
degenerative, 1:143, 1:144f
Hansen type I intervertebral disk
herniations, 1:144, 1:144f
Hansen type II intervertebral disk
herniations, 1:144f, 1:145
Intestinal adenocarcinomas, 2:102
Intestinal carcinomas, 2:104, 2:104f
microscopic appearance, 2:103
Intestinal/colonic biopsies, interpretation of,
2:62
Intestinal diverticula, 2:74
Intestinal emphysema, 2:87f
Intestinal encephalopathy, 2:88
Intestinal eosinophils, 2:64
Intestinal fluke infection, 2:225-227
Intestinal histoplasmosis, 2:202-203,
2:203f
Intestinal ischemia
arterial thromboembolism, 2:84
colon, 2:81
infarction, 2:81-86
reduced perfusion, 2:84-86
acute acorn poisoning in horse, 2:85
nonsteroidal anti-inflammatory drugs
(NSAIDs), 2:85
shock gut, 2:85
transient/noninfarctive slow flow, 2:85
reperfusion injury, 2:81
sequelae of, 2:81-82
small intestine, 2:81
venous infarction, 2:82-84
cecal inversion, 2:84
cecocolic intussusception in horse, 2:84
displacements of, 2:83
duodenal sigmoid flexure volvulus, 2:83
intussusception, 2:83
mesenteric volvulus, 2:83
segmental ischemic necrosis of small
colon, 2:84
volvulus, large colon, 2:83
Intestinal lipofuscinosis, 2:86-87, 2:86f
Intestinal lymphangiectasis, 3:95
Intestinal lymphomas, 3:239-241, 3:240f,
3:240.e1f
Intestinal mucosa
mast cells, 2:64
microscopic lesion, 2:125-126
Intestinal mucus, 2:60
Intestinal obstruction, 2:74-78
extrinsic obstruction, 2:76-77
neoplasms, 2:76-77
functional obstruction, 2:77-78
adynamic (paralytic) ileus, 2:77
feline dysautonomia, 2:77
grass sickness in horses, 2:77
intestinal smooth muscle, intrinsic
disease of, 2:77-78
megacolon in Clydesdale foals, 2:77
pseudo-obstruction, 2:77
proximal to obstruction, 2:75
stenosis/obturation, 2:75-76
cecal rupture, 2:76
cecum/colon in horses, 2:76
enteroliths, 2:75
fiber balls, 2:75-76
foreign bodies, 2:75
impaction of colon, 2:76
small intestinal obstruction, 2:76
Intestinal parasite hypersensitivity,
1:599-600
Intestinal phycomycosis, 2:201
Intestinal sclerosis, 2:77-78

Intestinal smooth muscle, intrinsic disease of,
2:77-78
Intestinal spirochetosis, 2:100
Intestinal stromal tumors, 2:110-111
gastrointestinal, 2:110
leiomyoma, 2:110
leiomyosarcoma, 2:110
Intestinal T-cell lymphomas, 2:107-108
Intestinal tract, miscellaneous conditions,
2:86-89
chinaberry tree, 2:89
idiopathic muscular hypertrophy, 2:87
intestinal emphysema, 2:87
intestinal encephalopathy, 2:88
intestinal lipofuscinosis, 2:86-87
jejunal hematoma, 2:88
muscular hypertrophy of, 2:87
oleander toxicosis, 2:89
rectal prolapse, 2:88
small intestinal bacterial overgrowth
(SIBO), 2:86
small intestine, pseudodiverticulosis of,
2:87
Intestinal trichostrongylosis, 2:212-213
Intestine
large, 2:97-100
colitis cystica profunda, 2:97
colitis in cats, 2:98-99
feline panleukopenia virus (FPLV),
2:98-99
necrotic colitis, 2:99
typhlocolitis in dogs, 2:97-98
typhlocolitis in horses, 2:99-100
ciliate protozoa, 2:99
equine intestinal clostridial diseases,
2:99
Potomac horse fever, 2:99
subacute/chronic diarrhea in horses,
2:99
typhlocolitis in ruminants, 2:100
typhlocolitis in swine, 2:100
dysentery, 2:100
postweaning colibacillosis, 2:100
small, 2:81, 2:82f, 2:92
amyloid deposition, 2:91
cardinal finding, 2:92
eosinophilic enteritis, 2:96
chronic, 2:96
gastric changes, 2:94
granulomatous enteritis, 2:97
transmural granulomatous enteritis,
2:97
idiopathic inflammatory bowel disease,
2:91-96
idiopathic mucosal colitis, 2:92-93
lymphangiectasia, 2:90-91, 2:90f
lymphocytic-plasmacytic, 2:94
mucosa, 2:124
hypoplasia, 2:74
vascular supply, 2:61
obstruction, 2:76
dogs, 2:75f
pseudodiverticulosis of, 2:87
small intestinal bacterial overgrowth
(SIBO), 2:86, 2:364
Intestines
B/T lymphoblasts, 2:64
cecum and colon, 2:61
congenital anomalies of, 2:73-74
atresia ani, 2:74
atresia coli, 2:74
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Intestines (Continued)
congenital colonic aganglionosis, 2:74
intestinal diverticula, 2:74
persistent Meckel’s diverticulum, 2:74
segmental anomalies, 2:73
short colon, 2:74
small intestinal mucosa, hypoplasia of,
2:74
displacements, 2:78-81, 2:83
cecal/colonic dilation, 2:78
colonic volvulus, 2:79
eventration, 2:78
external hernia, 2:79-81
abdominal wall, ventral hernia of,
2:80
diaphragmatic hernias, 2:80
direct inguinal hernia, 2:80
femoral hernias, 2:80
indirect inguinal hernias, 2:80
inguinal hernia, 2:80
perineal hernias, 2:80
prepubic hernias, 2:80
sequelae of hernias, 2:80
umbilical hernia, 2:80
internal hernia, 2:79
torsion, 2:78
tympany, 2:78
electrolyte and water transport, 2:65-66
enteroendocrine cells, 2:60
gastrointestinal mucosal barrier, 2:62-65
gastrointestinal mucosal defense, elements
of, 2:63
globule leukocytes, 2:63
IgA-producing lymphocytes, 2:64
IgG-producing plasma cells, 2:64
immune elements, 2:62-65
immunoinflammatory events, 2:66
interpretation and colonic biopsies, 2:62
intestinal intraepithelial T lymphocytes,
2:63
intestinal mucosal mast cells, 2:64
intussusception, 2:83f
lamina propria, 2:61-62
muscular hypertrophy, 2:87
normal form/function, 2:60-62
oligomucous cells, 2:60
Paneth cells, 2:60
segmental anomalies of, 2:73
stem cells, 2:60
submucosa, 2:62
Intima, vascular system, 3:54
Intimal bodies, 3:61, 3:61f
Intimal sclerosis of testicular veins, 3:498
Intoxication
hepatic steatosis by, 2:276
steroidal sapogenins, 2:338-340
vitamin D, 3:301-302, 3:301f
Intracelluar edema, 1:522
Intracranial pressure, 1:293-295
Intracranial thrombophlebitis, 1:300
Intracytoplasmic inclusion bodies, 2:448f
Intradural abscess, 1:354f
Intraepidermal vesicular and pustular
dermatitis, 1:527, 1:528f
Intrafollicular hemorrhage of ovaries, 3:370
Intranuclear inclusions, 2:270
Intraosseous epidermoid cysts, 1:126-127
Intrapancreatic hepatocytes, 2:356
Intratubular orchitis, 3:486, 3:486f
Intratubular red blood cell cast, 2:409.e1f
Intravascular hemolysis, 3:114, 3:115f
Index 541
Intravascular lymphoma, 1:734, 3:99
Intrinsic cardiac responses, 3:6-9, 3:7f
Intrinsic disorders of platelet function,
3:259-260
Intrinsic hepatotoxins, 2:327
Intrinsic lesion, 2:74
Intrinsic obstruction, 2:32
Intrinsic pathway, 3:261
Intussusception, 2:82-83
Invasive tumors of bones, 1:125
Involucrum, 1:96, 1:96f, 1:98
Involution
B-dependent tonsillar lymphoid follicles,
2:20
thymic, 3:144-147, 3:146f
Iodine, 1:570
deficiency and goiter, 3:320-322, 3:320f
excess, 3:325
ion and thyroid function, 3:273, 3:311
uptake blockage, 3:325
Iodism, 1:570
Iodothyronine, 3:271
Ionophore toxicosis, 1:219
Iridociliary epithelial tumor, 1:485, 1:485f
Iridovirus, 2:430
Iriki virus, 1:280
Iris
atrophy of, 1:447
hypopigmentation, 1:415
hypoplasia, 1:413-415, 1:415f
melanomas, feline diffuse, 1:483-484,
1:484f
normal, 1:445, 1:445f
Irish Dexter cattle, cropped or notched
pinnae in, 1:502
Irish Setter dogs
canine atopic dermatitis, 1:591
color dilution alopecia, 1:539-540
congenital idiopathic megaesophagus,
2:33-34
gastric volvulus, 2:49
globoid cell leukodystrophy, 1:339
hypothyroidism, 1:587
seborrhea, 1:548
selective deficiencies of immunoglobulins,
3:139
vascular ring anomalies, 2:33
Irish Terrier dogs
canine X-linked muscular dystrophy,
1:192
ichthyosis, 1:532
Irish Wolfhound dogs
dilated cardiomyopathy, 3:48
hypothyroidism, 1:587
iris cysts, 1:446
Iron
deficiency anemia, 3:112-114, 3:114f,
3:127
in hemoglobin synthesis, 3:107
hepatotoxicity, 2:272, 2:333
Irradiation, cataract due to, 1:443-444
Ischemic damage, 1:211, 1:211f
brain, 1:297-300, 1:297f
heart failure and, 3:9
Ischemic tubular necrosis, 2:423f
Ischemic ulcers, 2:82
Islands of Calleja, 1:262
Islet amyloid polypeptide (IAPP)-derived
amyloidosis, 2:414
Islet cells, 2:355, 2:370f
hyperplasia and nesidioblastosis, 2:373
542 Index
Isthmus, hair follicle, 1:516
Isthmus cysts, 1:704
Italian Greyhound dogs, color dilution
alopecia in, 1:539-540
Italian Spinones dogs, motor neuropathy in,
1:335
Ixodidae, 1:506, 1:684
J Keratinizing basal cell carcinomas,
Jaagsiekte, 2:560-562
Jack Russell Terrier dogs
canine congenital myasthenia in, 1:209
ichthyosis, 1:531
multisystem axonal degeneration, 1:325
sensory and autonomic neuropathy,
1:334
severe combined immunodeficiency
(SCID), 3:139-141
severe factor X deficiency, 3:264
Japanese cattle
Chediak-Higashi syndrome, 3:259
congenital hypotrichosis, 1:538-539
forelimb-girdle muscular anomaly, 1:189
neuronal inclusion-body diseases, 1:320
prolonged APTT, 3:263
vitiligo, 1:556
Japanese encephalitis virus (JEV), 1:376
Japanese quail, metabolic myopathy in,
1:208-209
Jaundice, 2:292-294, 2:292f
Jejunal hematoma, 2:88, 2:88f
Jembrana disease virus (JDV), 2:136,
3:195-196, 3:195f-196f, 3:195.e1f
Jersey cattle
bovine hypomyelinogenesis, 1:338-339
brachygnathia superior, 2:3
cyclopia, 1:269-270
degenerative joint disease, 1:143
Jimsonweed, 1:90
Johne’s disease, 2:100, 2:115, 2:194-197,
2:195f-197f, 3:205f, 3:204.e1f
Joint(s). See also Bone(s)
cartilaginous, 1:128-129, 1:143-145
degenerative diseases of, 1:137-146
developmental diseases of, 1:132-137
diseases, 1:128-163
fibrous, 1:128
inflammatory diseases of, 1:146-159
synovial, 1:129-131, 1:137-143
fibrinous arthritis, 1:146-147
tumors and tumor-like lesions of,
1:159-163
benign, 1:160-162
malignant, 1:159-160
Jones’ methenamine silver (JMS) stain, 2:383
Jowl abscess, 3:208-209, 3:208f-209f
Jugulotympanic paragangliomas, 1:500
Junctional epidermolysis bullosa, 1:534
Juvenile nephropathy, 2:388-391
Juvenile-onset distal myopathy, 1:198
Juvenile-onset polyarthritis, 1:158
Juvenile panhypopituitarism, 3:280, 3:280f
Juvenile polycystic disease, 2:265
Juxtaglomerular apparatus (JGA), 2:379
Juxtamedullary nephrons, 2:377, 2:378f,
2:381
K heart failure and, 3:10
Kallikrein, 3:261
Kanamycin, 2:424
“Kangaroo gait” of lactating ewes, 1:336
K antigen, 2:459
Karakul sheep, wattles in, 1:532
Karelian Bear dogs
chondrodysplasia, 1:43-44
hyposomatotropism, 1:589
Karwinskia humboldtiana, 3:36
Keeshond dogs
alopecia X, 1:589-590
early onset diabetes mellitus, 2:373
Keratic precipitates, 1:449
1:714
Keratinocytes, 1:515
Keratin pearls, 1:520
Keratitis, 1:436-441
feline eosinophilic, 1:438-439, 1:439f
herpetic, of cats, 1:438
infectious bovine keratoconjunctivitis,
1:440
infectious keratoconjunctivitis of sheep
and goats, 1:440-441
mycotic, 1:439-440, 1:439f
pannus, 1:438
Keratoconjunctivitis sicca, 1:436
Keratomalacia, 1:436-437, 1:437f
Keratomas, 1:704
Keratoses, 1:550-551
cutaneous horns, 1:551
equine cannon, 1:550
equine linear alopecia, 1:550, 1:550f
follicular, 1:520
lichenoid, 1:551
lichenoid reaction patterns, 1:551
linear epidermal nevi, 1:551
seborrheic, 1:550-551, 1:551.e1f
solar, 1:577
Kerry Blue Terrier dogs
diffuse uveal melanocytosis, 1:484-485
hereditary striatonigral and cerebello-
olivary degeneration, 1:319
prolonged APTT, 3:263
spiculosis, 1:699
Ketoconazole, 2:329
Ketosis, acute, 2:275
Kidney(s)
Actinobacillus equuli embolic nephritis,
2:433f, 2:433.e1f
acute tubular injury, 2:433f
anatomy of, 2:378-381
anomalies of development, 2:391-397
β-mannosidosis in a newborn term Salers
calf, 2:429.e1f
Cloisonné kidney, 2:429
cortex. See Renal cortex
cortical and juxtamedullary nephrons,
diagram, 2:378f
defined, 2:377
diffuse diseases, 2:382
Dioctophyma renale, 2:443.e1f
disease. See Renal disease
duplication of, 2:392
embolic nephritis, 2:432-433
endogenous factors, 2:387
endogenous oxalates, 2:426
failure. See Renal failure
giant kidney worm, 2:442
glomerulus, 2:379-381
gross appearance, 2:399
gross examination, 2:381-382
hematoxylin and eosin (H&E),
2:383-384
histologic appearance, 2:399
histologic examination, 2:382-383
horses, 2:433
Kidney(s) (Continued)
horseshoe, 2:393f
hypoplastic, 2:392
IgA deposition, 2:412
interstitium, 2:381
leptospiral serovars, 2:434t
maintenance and incidental, 2:435t
leptospirosis, 2:433-439
lipofuscinosis, 2:429
lymphoma, 3:240f-241f
malformation, 2:391
malposition, 2:392
miscellaneous tubular conditions,
2:430-431
glycogen accumulation, 2:430
hepatorenal syndrome, 2:430
hypokalemic nephropathy, 2:430
miscellaneous histologic changes,
2:430-431
nephrogenic diabetes insipidus, 2:430
multifocal renal cortical hemorrhages,
2:432f
parasitic lesions, 2:442-443
Dioctophyma renale, 2:442-443
Halicephalobus gingivalis, 2:443
Klossiella equi, 2:443
Pearsonema plica, 2:443
Stephanurus dentatus, 2:442
Toxocara canis, 2:442
perivascular pyogranulomatous nephritis,
2:432f
pigmentary changes, 2:429-430
brown pigmentation, 2:429
cloisonné kidney, 2:429
dark brown to black, 2:429f
green-yellow discoloration, 2:429-430
primary mesenchymal tumors, 2:447
pulpy, 2:381-382
renal biopsy, 2:383-384
renal blood flow, 2:377
sagittal section, 2:437.e1f
suppurative interstitial nephritis, 2:432
swelling of, 2:409
toxic and hypoxic insults, 2:399
tubules, 2:381
tubulointerstitial nephritis, chronic,
2:433.e1f
urate calculi in renal medulla, 2:385f
vascular supply, 2:379
vitamin D, metabolism of, 2:377
white-spotted kidney, 2:431f, 2:431.e1f
Kiel classification, 3:215, 3:217
Kinesin, 1:251-252
KIRREL2 gene, 2:418
Klebsiella pneumoniae, 2:113-114, 3:388,
3:417
Klossiella equi, 2:443f
Kupffer cells, 2:260, 2:263, 2:263f, 2:271
in acute hepatitis, 2:301
Kürsteiner’s cysts, 3:297, 3:297f
Kuvasz dogs, spongy encephalomyelopathies
in, 1:346-347
Kwashiorkor, 2:362
Kyphosis, 1:37t
L
Laboratory accreditation, 1:14
Labrador Retriever dogs
Alexander disease, 1:341
axonopathy, 1:325
canine atopic dermatitis, 1:591
canine X-linked muscular dystrophy, 1:192
cavitating leukodystrophy, 1:339-340

Labrador Retriever dogs (Continued)
centronuclear myopathy, 1:197, 1:197f
chondrodysplasia, 1:45
chronic hepatitis, 2:304
dysplasia of right atrioventricular valve,
3:21-22
exercise-induced collapse, 1:198
hip dysplasia, 1:135
Hunter syndrome, 1:58
hypothyroidism, 3:315
ichthyosis, 1:532
laryngeal paralysis, 2:481
lymphomas, 3:238
malignant hyperthermia, 1:210
myxomatous valvular degeneration, 3:27
nasal parakeratosis, 1:550
pyotraumatic dermatitis, 1:560
seborrhea, 1:548
spongy myelinopathy, 1:343
true retinal dysplasia, 1:420
vitiligo, 1:555-556
X-linked myotubular myopathy, 1:197
Labyrinthitis, 1:493, 1:493.e2f
Laceration, 1:302
Lacrimal system, 1:423-424
La Crosse virus, 1:280, 1:383
Lactate dehydrogenase (LDH)
diaphragmatic dystrophy in cattle,
1:199
nemaline myopathy of cats, 1:198
Lactation, “kangaroo gait” and, 1:336
Lactational osteoporosis, 1:65-66
cattle, 1:66, 1:66f
Lactotroph adenomas, 3:286-287
Lafora bodies, 1:255, 1:255f
Lafora disease (LD), 1:292
Lagenidiosis, 1:657-659
Lamellar bodies, 1:512-513
Lamellar bone, 1:20-21
Lamina cribosa, 1:476
Lamina densa, 1:513-514
Lamina fibrous zone, 1:513-514
Lamina lucida, 1:513-514
Lamina propria, 2:51, 2:61
Laminitis, 1:702-703
Landrace pigs, 1:42
Landseer-European Continental Type (ECT)
dogs, platelet dysfunction in, 3:259
Langerhans cells
canine cutaneous histiocytosis, 1:729,
3:245-246, 3:246f
feline pulmonary Langerhans cell
histiocytosis, 3:246-247, 3:247f,
3:246.e1f
histiocytosis, 3:243
immune function, 1:515
skin, 1:513
Lantana camara, 3:36
toxicity, 2:293, 2:338
Lapland dogs, glycogen storage disease type
II in, 1:204
Large-bowel diarrhea, 2:70-71
Large cell carcinoma, 2:497
Large-cell/lymphoblastic lymphoma, 2:108
Large dark fibers in muscular dystrophy,
1:193
Large granular lymphocytic leukemia,
3:235
Large granular lymphocytic lymphoma
(LGL), 3:231, 3:231f
Large granular lymphoma, 2:108
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Large intestine, inflammation of, 2:97-100
colitis cystica profunda, 2:97
colitis in cats, 2:98-99
feline panleukopenia virus (FPLV),
2:98-99
necrotic colitis, 2:99
typhlocolitis in dogs, 2:97-98
typhlocolitis in horses, 2:99-100
ciliate protozoa, 2:99
equine intestinal clostridial diseases,
2:99
Potomac horse fever, 2:99
subacute/chronic diarrhea in horses, 2:99
typhlocolitis in ruminants, 2:100
typhlocolitis in swine, 2:100
dysentery, 2:100
postweaning colibacillosis, 2:100
Large White X Essex pigs, 1:545
Larval paramphistomes, 2:43
Larval strongyles, 2:319, 2:319f
Larynx, 2:467, 2:481-482, 2:481f
equine laryngeal hemiplegia, 1:334-335
laryngitis, 2:481
paralysis, 2:481, 2:481f
rhabdomyomas, 1:177f, 1:241, 1:242f
L-asparaginase, 3:298
Late-onset progressive spinocerebellar
degeneration, 1:319
Lateral domain, liver, 2:262
Lathyrus odoratus, 1:91
Lawsonia intracelluaris, 2:177-180, 2:178f,
3:202, 3:202f
Lead poisoning, 1:86, 1:87f, 1:316-317
Lectin staining, 2:445
Left atrioventricular valvular insufficiency or
stenosis, 3:22
Left atrium, heart, 3:2
failure, 3:6
Left-sided heart failure, 3:10-11
Left ventricle, heart, 3:2
Legg-Calvé-Perthes disease, 1:31, 1:96, 1:96f
dogs, 1:97, 1:97f
Leiomyomas, 1:726, 2:110, 2:463-464, 3:378,
3:447-448, 3:447f-448f
gastrointestinal, 2:110
liver, 2:350
Leiomyometaplasts, 2:87
Leiomyosarcomas, 1:726, 2:110, 2:110f
female genital system, 3:447-448, 3:448f
gastrointestinal, 2:110, 2:110f
liver, 2:350
urinary system, 2:463-464
Leishmania infantum, 1:240, 2:19
Leishmania spp., 1:98, 1:240, 1:503,
1:663-664, 2:412
feline, 1:663-664, 1:664f
penis and prepuce lesions, 3:508
spleen, 3:174-175, 3:175f-176f, 3:175.e1f
Lens, 1:441-444
anomalies, 1:422-423
aphakia, 1:422
cataract, 1:442-444, 1:442f
congenital cataract, 1:422
congenitally ectopic, 1:422
ectopia lentis, 1:441-442
-induced uveitis, 1:453-454, 1:457-459
lenticonus and lentiglobus, 1:422
microphakia, 1:422
Lenticonus, 1:422
Lentiglobus, 1:422
Lentigo simplex, 1:554, 1:721
Index 543
Lentiviral encephalomyelitis of sheep and
goats, 1:378-380
Lentiviruses, 2:558-560, 2:559f, 2:558.e1f
Leonberger dogs
leukoencephalomyelopathy, 1:340-341
motor neuropathy, 1:335
Leporipoxvirus, 1:616
Lepromatous leprosy, 1:641
Leprosy, feline, 1:640-641
Leptomeningitis, 1:354-358, 1:355f-357f
Leptospira borgpetersenii, 2:435-436
Leptospira fainei, 2:438
Leptospira interrogans, 2:431, 2:433-434
Leptospiral serovars, 2:434t
Leptospira spp., 2:435t
abortion and stillbirth in horses and,
3:411
abortion in cattle and, 3:409-410
abortion in sheep and, 3:411
abortion in swine and, 3:410-411
hemolytic anemia and, 3:126
liver and, 2:317-318, 2:317.e1f
Leptospires, 2:435, 2:437-438
Leptospirosis, 2:433-439
abortion, 2:435
cattle, 2:435-437
dogs, 2:437-438
in domestic animals, 2:434t
horses, 2:438-439
maintenance and incidental hosts,
2:435t
renal failure, 2:435
sheep, goats, and deer, 2:437
swine, 2:438
Lesions. See also Non-neoplastic lesions
adrenal, 3:341-343
brain
ischemic, 1:297-300, 1:297f
bronchopneumonia, 2:506f
canine distemper virus, 2:576
degenerative joint diseases, 1:138,
1:138f
dental, 2:576
diffuse alveolar damage, 2:509
endocardial, 3:27-30
endocrine gland, 3:271-272
esophageal, 2:124, 2:124f
exocrine pancreas, 2:365-368
glaucoma-causing, 1:462-465
granulomatous, 1:233-234
hypothyroidism, 3:318-319
incidental, 1:7
laryngeal, 2:481-482, 2:481.e2f
liver and bile ducts, 2:344-352
microcirculatory, 1:301
middle ear, 1:498-499
muscle, 1:171
oral cavity, 2:20-28
osteomalacia, 1:73
osteoporosis, gross, 1:63-64
ovarian, 3:370-371
pericardium, 3:24-25, 3:24f
photographs of, 1:8
photosensitization dermatitis, 1:578
postpartum uterus, 3:440-441
pulmonary idiopathic hypertension, 2:492
pyelonephritis, 2:383
retinitis, 1:474-475
rickets, microscopic, 1:72, 1:72f
rinderpest, 2:129, 2:129f
sepsis, 1:358-362, 1:358f, 2:512f
544 Index
Lesions (Continued)
skin, in systemic bacterial disease,
1:645-646
splenic, 3:188-189, 3:188f
stomach and intestine, 2:100-111, 2:101t
Lethal acrodermatitis, 1:533, 1:533.e1f
Lethal trait A46, 3:141
Leukocyte disorders, 3:109-112
Leukoderma, 1:555
Leukodystrophic and myelinolytic diseases,
1:339-342, 1:339f
Leukoencephalitis, necrotizing, 1:392-393
Leukoencephalomalacia, mycotoxic,
1:315-316, 1:315f-316f
Leukoencephalomyelopathy, 1:340-341,
1:340f
Leukomalacia, 1:307-308
periventricular, 1:274
Leukotrichia, 1:555
reticulated, 1:557-558
Lewy bodies, 1:255
L-form infections, 1:637
Lhasa Apso dogs
afibrinogenemia, 3:265
keratoconjunctivitis sicca, 1:436
sebaceous adenitis, 1:551
sebaceous epitheliomas, 1:717
Lice, 1:671-672
Lichenification, 1:524
Lichenoid keratoses, 1:551
Lichenoid-psoriasiform dermatosis,
1:552-553
Lichenoid reaction patterns, 1:551
Lichtheimia corymbifera, 3:417
Lieberkühn, epithelial lining, 2:125-126
Ligaments, 1:130
Light-induced retinal degeneration,
1:470
Lightning strikes, 1:564f
Ligneous conjunctivitis, 1:426-427
Liliaceae family, 2:428
Limbal (epibulbar) melanocytoma,
1:482-483
Limb defects, 1:37t
congenital flexures, 1:189
dysplasias, 1:54-56, 1:54f
Limb dysplasias
cats, 1:54-56
dogs, 1:54-56
Limber tail, 1:214
Limbus, 1:424
Limiting plate, liver, 2:261-262
Limnatis africana, 2:557
Limnatis nilotica, 2:19, 2:557
Linear epidermal nevi, 1:551
Linear foreign bodies, 2:75, 2:76f
Linear immunoglobulin A disease, 1:604
Linguatula serrata, 2:19, 2:585
Lining cells, bone, 1:17
Lion jaw, 1:91-92
Lipidosis, 3:319, 3:319f
Lipid(s)
dystrophies, corneal, 1:433
epidermal, 1:512-513
keratopathy, 1:433-434, 1:433f
malabsorption of, 2:90
pneumonia, 2:516-518, 2:516.e1f
storage myopathy, 1:205
vacuoles, 1:185, 1:185f
Lipofuscin, 2:262, 2:271, 3:200, 3:314
ceroid-lipofuscinoses, 1:290-292, 1:291f
Lipofuscinosis, 2:86-87
Lipolysis, 2:70
Lipomas, 1:726
infiltrative, 1:245, 1:246f, 1:726
peritoneal, 2:256, 2:257f
Lipomatosis, 2:356
Lipomeningocele, 1:279
Lipopolysaccharide (LPS) moiety of
Salmonella, 2:168-169
Lipoprotein lipase activity, 1:336
Liposarcomas, 1:123, 1:726
Liquefactive necrosis, 1:254
Lissencephaly, 1:268
Listeria monocytogenes, 1:363f, 1:449
abortion and, 3:408-409, 3:409f
central nervous system and, 1:362-364,
1:363f
liver and, 2:314-318, 2:314f
myocarditis and, 3:42
Liver, 2:258-352
abscesses, 2:315-316, 2:315f
acquired portosystemic shunting, 2:290
cell death, 2:279-285
apoptosis, 2:279-280, 2:279f
lobular necrosis, 2:282-284
necrosis, 2:280-281, 2:280f-281f, 2:283f,
2:285.e1f
tissue patterns, 2:281-285
cells, 2:261-264
cholestasis and jaundice, 2:292-294, 2:292f
cirrhosis, 2:276, 2:289-290, 2:276.e1f
developmental disorders, 2:264-268
congenital vascular anomalies, 2:266-268
cysts, 2:264
ductal plate malformations, 2:265,
2:265f
extrahepatic biliary anomalies,
2:265-266
hamartomas, 2:264, 2:264f
disease, 3:264-265
acute bovine, 2:343-344, 2:343.e1f
displacement, torsion, and rupture, 2:268
dysfunction, 2:290-295
edema and ascites, 2:294-295
enlargement and heart failure, 3:11
failure, 2:290-295
hemorrhage and, 2:294
fatty, 2:275-276
fibrosis, 2:288-289, 2:289f
general considerations, 2:259-264
cells, 2:261-264
origin, structure, and function, 2:259-
261, 2:259f
hepatic encephalopathy (HE), 1:262,
1:262f, 1:344f, 2:291-292
hepatitis, 2:301
acute, 2:301
B antigen, 3:71
cats, 2:305
chronic, 2:301-306, 2:305.e1f
dogs, 2:302-305, 2:305f, 2:310-312,
2:310f, 2:311.e1f
focal, 2:282, 2:282f
giant cell, 2:306, 2:306f
horses, 2:305
lobular dissecting, 2:305, 2:305f,
2:305.e1f
nonspecific reactive, 2:306
periportal interface, 2:301-302, 2:302f,
2:304f
hepatocellular adaptations and intracellular
accumulation, 2:269-279, 2:269f,
2:269.e1f
amyloidosis, 2:278-279, 2:279f, 2:278.e1f
atrophy, 2:269, 2:269f, 2:269.e1f
Liver (Continued)
hypertrophy, 2:269-270, 2:269f
intranuclear inclusions, 2:270
lysosomal storage diseases, 2:278, 2:278f,
2:278.e1f
pigmentation, 2:270-272, 2:271f,
2:270.e1f
polyploidy and multinucleation, 2:270
steatosis, 2:273-278, 2:274f-276f,
2:274.e1f, 2:276.e1f
vacuolation, 2:272-273, 2:272f
hepatocutaneous syndrome, 1:586-587,
2:295, 2:295.e1f
hyperplastic and neoplastic lesions,
2:344-352
infectious diseases
bacterial, 2:314-318
fungal, 2:324-325, 2:324f
helminthic, 2:318-324
protozoal, 2:324
viral, 2:309-325, 2:310f
inflammatory diseases, 2:300-309
nonspecific reactive hepatitis, 2:306
injury
mechanisms, 2:326
responses, 2:285-290, 2:287f
necrobacillosis, 2:42f
nephropathy, 2:294
photosensitization, 2:294, 2:294f
postmortem and agonal changes,
2:295-296
regeneration, 2:286-287, 2:290f
toxic hepatic disease, 2:325-344
adverse drug reactions, 2:329
agents, 2:328
tumor metastasis to, 2:351f-352f,
2:351.e1f
vascular factors in injury and circulatory
disorders of, 2:296-300
acquired portosystemic shunts, 2:298-
299, 2:299f
efferent hepatic vessels, 2:297-298
hepatic artery, 2:296
peliosis hepatis/telangiectasis, 2:299-300,
2:299f-300f, 2:299.e1f
Lobar bronchus, 2:467
Lobar pneumonia, 2:507
Lobular bronchopneumonia, 2:507
Lobular capillary hemangioma, 1:727
Lobular dissecting hepatitis, 2:305, 2:305f,
2:305.e1f
Lobulated kidney, 2:392.e3f
Localized bacterial periostitis, 1:102
Localized histiocytic sarcomas (LHS), 1:729
Localized scleroderma, 1:698
Localized skeletal dysplasias, 1:54-57, 1:54f
Locoweed, 1:91
Long-headed dwarfs, 1:39
Lordosis, 1:37t
Louisiana Catahoula Cattle dogs,
cochleosaccular degeneration in,
1:492
Louping-ill, 1:367f
Lubricin, 1:131
Lukes-Collins classification, 3:215
Luminal folliculitis, 1:528
Lumpy jaw, 1:102-103
Lumpy skin disease virus, 1:616, 1:622-624,
1:624f
Lungs, 2:484-520
abortion and, 3:401-402
abscesses, 2:520
atelectasis, 2:486, 2:486.e2f

Lungs (Continued)
cellular architecture and cell biology,
2:468-471
circulatory disturbances, 2:487-494
congenital anomalies, 2:484-485, 2:485.e1f
defenses, 2:471-473
development and growth, 2:484, 2:484.e1f
heart failure and, 3:11
hemorrhage, 2:490-492, 2:490.e1f
injury, 2:500-520, 2:500f
airway disease, 2:500-504, 2:500.e1f
interstitial lung disease, 2:509, 2:510f,
2:511b
lobes, 2:467
torsion, 2:485-486, 2:485f
mineralization, 2:494-495, 2:494f
neoplasia, 2:495-500, 2:495b
organization of, 2:467
pulmonary emphysema, 2:486-487
pulmonary hypertension, 2:492-494
thrombosis, embolism, and infarction,
2:489-490, 2:489b
toxic injury, 2:518-520
vascular supply to, 2:467-468, 2:468f
Lungworms, 2:564-567, 2:565t, 2:566f,
2:565.e2f
Lupins, 1:90
Lupinus arbustus, 2:3
Lupinus formosus, 2:3
Lupus erythematosus (LE), 1:604-607
cutaneous, 1:605-607
disseminated discoid, 1:606
exfoliative cutaneous, 1:606, 1:606f
systemic, 1:158-159, 1:605
vesicular cutaneous, 1:607
Lupus panniculitis, 1:607
Luteinized cysts, 3:373, 3:373f
Luxations and subluxations, 1:137, 1:137f
Lycoperdon spp., 2:584-585
Lyme disease. See Borreliosis
Lyme nephritis, definitive diagnosis,
2:411-412
Lymph, overproduction of, 2:248
Lymphadenitis
acute, 3:202-203
caseous, 3:204-208, 3:207f-208f,
3:205.e1f
chronic, 3:203-204, 3:203f, 3:204.e1f
suppurative, 3:203-204, 3:204f
Lymphadenopathy, 3:200-201
Lymphangiectasia, 2:89-90, 2:90f
Lymphangiomas, 1:727-728, 3:99
Lymphangiomatosis, 1:727-728
Lymphangiosarcomas, 1:727-728, 3:101
Lymphangitis, 2:195-196, 2:196f, 3:96-98,
3:96f
epizootic, 3:97-98
granulomatous, 2:196, 2:196f
parasitic, 3:98
ulcerative, 3:97
Lymphatic capillaries, 3:54-55
Lymphatics, 3:94-98. See also Lymphomas
congenital anomalies, 3:94-95
developmental diseases, 3:139-141
dilation and rupture, 3:95-96, 3:95f
liver and, 2:260-261
lung, 2:468
lymphangitis, 3:96-98, 3:96f
epizootic, 3:97-98
parasitic, 3:98
ulcerative, 3:97
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Lymphatics (Continued)
lymphoid organs, 3:138-141
spleen, 3:158-162
vessels, dermal, 1:514
Lymphatic sinus ectasia, 3:199, 3:199f
Lymphedema, 3:94, 3:95f
Lymph nodes, 3:196-243
developmental diseases, 3:198
hyperplasia, 3:200-202
inflammatory diseases, 3:202-212
neoplastic metastatic diseases, 3:212-213,
3:212f-213f
parasitic diseases, 3:212
scrotal, 3:498
structure and function of normal,
3:196-198, 3:196f
Lymphocytes
dermal, 1:514
liver, 2:263
in masticatory myositis, 1:226-227
thymic cortical, 3:143
thymic medullary, 3:143
Lymphocytic cholangitis, 2:308, 2:308f
Lymphocytic parathyroiditis, 3:298-299
Lymphocytic-plasmacytic enteritis, 2:95
in cat, 2:92f
Lymphocytic-plasmacytic stomatitis, 2:16
Lymphocytic-plasmacytic synovitis,
1:147-148
Lymphocytic-plasmacytic uveitis, 1:449
Lymphocytic thyroiditis, 3:316, 3:317f-318f
Lymphocytic vasculitis, 1:526, 1:611
Lymphocytosis, 1:147, 3:111, 3:241.e2f
Lymphoglandular complexes, 2:64
Lymphoid atrophy, 3:198, 3:199f
Lymphoid hyperplasia, 3:201
adrenal cortex, 3:343
pharyngeal, 2:480.e3f
spleen, 3:189, 3:189f
Lymphoid nodules, 1:522
Lymphoid tissue, 2:62-63
Lymphomas, 1:403, 2:107, 3:213-243, 3:309,
3:309f
angiocentric, 2:499, 2:499f
cats, 3:239-241, 3:241.e1f
cattle, 3:235-237, 3:236f-237f, 3:236.e2f,
3:236.e1f
classification, 3:215-243, 3:217t
clinical features, 3:214
cutaneous, 1:733-735, 1:733f
diagnosis, 3:214-215, 3:218f
dogs, 3:238-239, 3:239f, 3:238.e2f,
3:239.e2f, 3:239.e1f
gastric, 2:107-109, 3:241f, 3:241.e1f
heart, 3:53, 3:53f
Hodgkin-like, 3:219
horses, 3:237-238, 3:238f, 3:238.e1f
intestinal, 3:239-241, 3:240f,
3:240.e1f
intravascular, 1:734, 3:99
malignant, 1:123-124, 1:245, 1:245f,
3:241.e1f
cats, 3:241.e1f
cattle, 1:124
pigs, 3:242f, 3:241.e2f
multicentric, 3:241, 3:241f
nasal and nasopharyngeal, 2:479-480,
3:239f, 3:241, 3:241f, 3:239.e1f
ocular, 1:482
pigs, 3:241-243, 3:242f, 3:241.e2f
renal, 2:447, 3:240f-241f
Index 545
Lymphomas (Continued)
sheep and goats, 3:237, 3:237f
skin, 3:237, 3:237f, 3:239f, 3:237.e1f,
3:239.e1f
spinal cord, 3:240f
thymic, 3:157-158, 3:157f-158f, 3:237,
3:240f, 3:157.e1f
viral etiology and, 3:235
Lymphomatoid granulomatosis (LYG), 3:99,
3:222
Lymphopenia, 3:111
Lymphoplasmacytic, 2:107
Lymphoplasmacytic cystitis, chronic,
2:460.e1f
Lymphoplasmacytic myocarditis, 3:44, 3:44f
Lymphoplasmacytic stomatitis, 2:15
Lymphosarcomas, 1:403
bovine ovarian, 3:378, 3:379f
uterus, 3:450, 3:450f
Lynxacarus radovsky, 1:683
Lysosomal enzymes, 1:284
Lysosomal phospholipidosis, 2:424
Lysosomal storage diseases, 1:284-293,
1:285f-286f, 2:429
liver, 2:278, 2:278f, 2:278.e1f
skeleton, 1:57-59
spinal cord, 1:285f-286f
Lyssavirus infections, 1:367-370
M
Maceration, fetal, 3:396, 3:396f
Macracanthorhynchus hirudinaceus, 2:227
Macrocyclic trichothecene toxins, 1:573
Macrophages, 2:64
hyperplasia, 3:201-202
multinucleated, 2:540.e2f
in muscle regeneration, 1:182-183
pulmonary, 2:470
alveolar, 2:470-472
interstitial, 2:471
intravascular, 2:471, 2:471.e1f
Macroscopic hematuria, 2:461
Macroscopic lesions in horses, 2:108
Macrovesicles, 2:274
Macula densa, 2:380f
Macules, 1:524
Maduramicin, 1:219, 3:34-35
Maedi-visna, 2:413, 2:558-560, 2:559f,
2:558.e1f
Magnesium ammonium phosphate
hexahydrate, 2:455
Main Drain virus, 1:280
Malabsorptive, 2:95
Malacia, 1:299f, 1:307-317
cerebral, 1:299-300, 1:299f
Malassez, epithelial rests of, 2:4-6
Malassezia dermatitis, 1:548-549, 1:553,
1:593, 1:647-649, 1:648f
Malassimilation, 2:89-97
Maldevelopment of filtration angle, 1:417,
1:417f
Male genital system, 3:465-510
accessory genital glands, 3:499-505, 3:499f
genital considerations, 3:465-468
oxidative stress and testicular function,
3:467
penis and prepuce, 3:505-510
inflammation, 3:506-508
neoplasms, 3:508-510
prostate and bulbourethral glands,
3:500-504, 3:500f
546 Index
Male genital system (Continued)
sampling of male genital tract, 3:465-466
scrotum, 3:471-473
sexual development disorders, 3:468-471,
3:476-481, 3:476f, 3:499-501, 3:505
spermatic cord, 3:497-499
spermatogenesis, 3:466-467
testis and epididymis, 3:474-497
circulatory disturbances, 3:491-492
disorders of sexual development,
3:476-481, 3:476f
hypoplasia, 3:478-479, 3:478f
neoplasms, 3:492-497
testicular immune function, 3:467-468
vaginal tunics, 3:473-474, 3:473f-474f
Malignant angioendotheliomatosis, 3:99
Malignant catarrhal fever (MCF), 2:131-136,
2:133f-136f, 2:459-460
Malignant edema and gas gangrene, 1:232
Malignant hyperthermia, 1:209-210
dogs, 1:210
horses, 1:210
pigs, 1:209-210
Malignant lymphomas, 1:123-124, 1:245,
1:245f, 2:107-109
cats, 3:241.e1f
cattle, 1:124
large-cell/lymphoblastic lymphoma,
2:108
large granular lymphoma, 2:108
pigs, 3:242f, 3:241.e2f
small-cell lymphocytic villus lymphoma,
2:107-108
Malignant/malevolent sarcoids, 1:708
Malignant melanomas, 1:721-722, 2:26-27,
2:26f, 2:240f
cats, 2:26-27
iris, 1:483-484, 1:484f
dogs, 2:21, 2:26, 2:26f
Malignant mixed thyroid tumors, 3:331,
3:331f
Malignant neoplasms, 2:100-101
Malignant pheochromocytoma, 3:349-351
Malignant pilomatricomas, 1:717
Malignant transformation, 2:22
Malignant trichoepitheliomas, 1:715
Malignant tumors of joints, 1:159-160
histiocytic sarcoma, 1:159-160
synovial cell sarcoma, 1:159
Malleus, 1:495
Malnutrition. See Nutritional deficiency/
disease
Maltese dogs
cochleosaccular degeneration, 1:492
myelinolytic leukodystrophy, 1:341
Mammae, 3:451-459
benign neoplasms, 3:460
bovine mastitis, 3:452-457, 3:452f
carcinomas, 3:451t, 3:460-463, 3:461f-
462f, 3:463t
cats, 3:463-464, 3:464f
coliform mastitis, 3:454-455, 3:454f
developmental biology, 3:451, 3:451t
inflammatory disease, 3:451-452
innate and acquired resistance of,
3:451-452
masses including neoplasia, 3:459-464,
3:459f
mycoplasma mastitis, 3:456, 3:456f
sarcomas, 3:463, 3:463f
streptococcal mastitis, 3:455
summer mastitis, 3:455-456
Mammomonogamus auris, 1:498
Mammary gland carcinomas, 1:736
Mammomonogamus ierei, 2:557
Mammomonogamus laryngeus, 2:557
Mammomonogamus nasicola, 2:557, 2:567
Mandibular osteomyelitis, 1:103f
cattle, 1:102-103
Mandibular osteopathy, 2:9
Manganese chloride, 2:329
Manganese deficiency, 1:80
cattle, 1:80, 1:81f
Mange
chorioptic, 1:676-677, 1:677f
demodectic, 1:678-682, 1:680f
notoedric, 1:675, 1:675f
otodectic, 1:677-678
psorergatic, 1:678
psoroptic, 1:675-676
sarcoptic, 1:673-675, 1:674f
Mannheimia haemolytica, 2:557, 3:69
liver and, 2:314-315
respiratory system and, 2:543-544, 2:545f,
2:562-563, 2:540.e2f
Mantle cell lymphoma (MCL), 3:226,
3:227f
Manx cats, corneal endothelial dystrophy in,
1:433
Maple syrup urine disease, 1:344, 1:345f
Mare reproductive loss syndrome, 3:417
Marginal zone lymphoma (MZL), 3:224,
3:225f, 3:226.e1f
Marked acute tubular necrosis, 2:428.e1f
Markers of remodeling, 1:27
Maroteaux-Lamy syndrome, 1:58
Marshallagia, 2:54-55
Massive fat necrosis in cattle, 2:249
Massive liver necrosis, 2:284-285,
2:284f
Masson trichrome
method, 1:29
stain, 2:383
Mastadenovirus, 2:145
Mast cells, 1:514-515
epidermal, 1:519
liver, 2:264
tumors, 1:730-733, 1:731f, 2:27, 2:109
conjunctival, 1:482
gastrointestinal, 2:109
mastocytosis, 3:137
metastasis to lymph nodes, 3:212-213,
3:213f
metastasis to spleen, 3:194
Masticatory myositis of dogs, 1:226-227,
1:226f-227f
Mastitis
bovine, 3:452-457, 3:452f
camelids, 3:458-459
coliform, 3:454-455, 3:454f-455f
dogs and cats, 3:458, 3:458f
fibrinosuppurative exudate with, 3:453-
454, 3:453f
horses, 3:457
mycoplasma, 3:456, 3:456f
nocardia, 3:457, 3:457f
staphylococcal, 3:452-454
streptococcal, 3:453-455, 3:454f
summer, 3:455-456
swine, 3:457
tuberculosis, 3:456-457
Mastocytosis, 3:137
Materia alba, 2:9
Maternal leptospiremia, 2:435
Matrical cysts, 1:704
Matrix vesicles, 1:20
Mature (peripheral) B-cell neoplasms,
3:219-228
Mature (peripheral) T-cell neoplasms,
3:228-229
Maxillary or mandibular fibrosarcoma, 1:121,
1:121f-122f
M cells, 2:63-64
Mean platelet volume (MPV), 3:258
Mebendazole, 2:329
Mechanical forces and injury effects on
bones, 1:30-36
Mechanical gastritis, 2:52
Mecistocirrus, 2:54-55
Meconium aspiration syndrome, 2:516,
2:516.e1f
Media, vascular system, 3:54
Medial hypertrophy of pulmonary arteries,
3:67, 3:67f
Medullary necrosis, gross lesions of,
2:399-400
Medullary rays, 2:378
Medullary solute washout, 2:381
Medulloblastoma, 1:402, 1:402f
Medulloepitheliomas, 1:485-486, 1:486f
Megacolon, in Clydesdale foals, 2:77
Megaesophagus, 2:33-34, 2:34f
congenital, 2:34
Megakaryocytes, 3:106-107
hypoplasia, 3:258
pulmonary embolism and, 2:490
Megalencephaly, 1:268
Megalocornea, 1:421
Megalocytosis, 2:270, 2:337f
Megavoltage X-radiation and cataract,
1:444
Megestrol acetate, 2:329
Meibomian adenoma, 1:480-481, 1:481f
Melanin, 1:513
disorders of pigmentation, 1:554-558
lymph node, 3:200
Melanocortin receptor (MR2), 3:270-271
Melanocytes, 1:513
dermal, 1:514
tumors, 1:720-722, 1:720f-721f
Melanocyte-stimulating hormone (MSH),
3:276-277
Melanocytic tumors of eye, 1:482-485
Melanocytoma-acanthoma, 1:721
Melanocytomas, 1:481, 1:721
Melanocytopenic hypomelanosis, 1:555-556
Melanomas, 1:720-722, 1:720f-721f
malignant, 1:721-722, 2:26-27, 2:240f
cats, 2:26-27
iris, 1:483-484, 1:484f
dogs, 2:21, 2:26, 2:26f
lymph node, 3:213.e1f
Melanopenic hypomelanosis, 1:556-557
Melanosis, congenital and acquired, 2:270,
2:270.e1f
Melanotic tumors, cytologic evaluation of,
2:26
Melia azedarach, 2:89
Melioidosis, 1:637, 2:563, 3:188-189, 3:188f
Melophagus ovinus, 1:670
Membrane permeability transition (MPT)
pore, 2:281
Membrane receptor (RANK), 3:294-295
Membranoproliferative glomerulonephritis
(MPGN), 2:404f, 2:411f, 2:411.e1f,
2:401.e4f, 3:123-124
proteinuria and azotemia, 2:412
Membranous glomerulonephropathy (MGN),
2:402f, 2:401.e2f

Membranous labyrinth of ear, 1:488-489
Meningeal hemorrhages, 1:301
Meningeal sarcomatosis, 1:398
Meninges
age changes in, 1:304
tumors, 1:396-398
Meningioangiomatosis, 1:404, 3:99
Meningiomas, 1:396-398, 1:397f
intracranial, 1:494
nasal, 2:480
optic nerve, 1:487, 1:487f
Meningitis, 1:355f-357f, 1:359f
Meningocele, 1:267, 1:267f, 1:279
Meningoencephalitis, necrotizing, 1:392-393,
1:392f
Meningoencephalocele, 1:267f
Meningoencephalomyelitis, granulomatous
and pyogranulomatous, 1:362, 1:362f
Meningomyelocele, 1:279
Menisci, 1:130
Mercury toxicosis, 1:570
Merino sheep
Alexander disease, 1:341
axonal dystrophy, 1:324
brachygnathia inferior, 2:3
congenital myopathy, 1:200
focal macular melanosis, 1:554
hypothyroidism, 1:588
wattles, 1:532
Merkel cells, 1:513
tumor, 1:735
Mesangial cells, 2:409
Mesangial hyaline droplets, 2:421
Mesangial matrix, 2:380-381
Mesangioproliferative glomerulonephropathy,
2:403f, 2:401.e3f
Mesangium, 2:380-381
Mesenchymal liver hamartomas, 2:264
Mesenchymal progenitor cells, 1:21-22
Mesenchymal tumors, 2:44, 2:463-464
of ear, 1:504
lipomas, 1:245, 1:246f, 1:726
Mesenchyme, anomalies of, 1:413-414
anterior chamber, 1:415-417
Mesenteric hernia, 2:79
Mesenteric lymph nodes, 2:107-108
Mesenteric volvulus, 2:83
Mesocestoides spp., 2:223
Mesodermal somites, 1:167
Mesodermal tumor(s), 2:349-351, 2:350f
Mesodiverticular band, 2:245
Mesonephric and paramesonephric structures
disorders, 3:480-481, 3:480f
Mesonephric (Wolffian) ducts, 3:360-361
cysts, 3:368f, 3:371
Mesothelial cells, 2:81, 2:244
Mesotheliomas
peritoneal, 2:256-257, 2:256f
pleura, 2:523, 2:523.e2f
vaginal tunic, 3:474f
Mesquite toxicosis, 1:326
Metabolic acidosis, 2:75, 2:381
Metabolic alkalosis, 2:50
Metabolic bone diseases, 1:61
Metabolic disease, 2:41
corneal deposits secondary to, 1:433-434,
1:433f
Metabolic myopathies, 1:204-209
cats, 1:205
cattle and sheep, 1:207-208
dogs, 1:204-205
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Metabolic myopathies (Continued)
horses, 1:205-207, 1:206f-207f
Metanephric blastema, 2:391
Metanephros formation, 2:391
Metaphyseal arteries, 1:27
Metaphyseal osteopathy, 1:106f
dogs, 1:105-106, 1:105f-106f
Metaphysis, 1:22, 1:24, 1:26f
Metaplasia, 2:393
fibroblastic, 1:442-443
mucous, 2:47
myeloid, 3:107, 3:191
osseous, 1:304, 2:517, 2:517.e1f
osteocartilaginous, 3:34, 3:34f
peribronchiolar, 2:495, 2:495.e2f
prostate and bulbourethral gland,
3:502-503, 3:502f
Metastases, tumor, 1:245-246, 2:102-103,
2:447
to adrenal medulla, 3:353-354, 3:353f
to central nervous system, 1:404
within the globe and orbit, 1:488
hypercalcemia with, 3:309
to liver, 2:351-352, 2:351f-352f, 2:351.e1f
to lung, 2:499-500
to lymph nodes, 3:212-213, 3:212f-213f,
3:213.e1f
metastatic bone disease, 1:124, 1:124f
dogs, 1:124, 1:124f
to ovaries, 3:378
to pancreas, 2:367
to peritoneum, 2:257
to pituitary gland, 3:288-289
to pleura, 2:523
to skin, 1:736
to spleen, 3:194, 3:194f
Metastrongylus spp., 2:536, 2:536.e2f
respiratory system and, 2:536, 2:536.e2f
Metazoan parasites and pancreas, 2:365
Methimazole, 2:329
Methotrexate, 2:329
Methoxyflurane anesthesia, 2:426
Methyoxyflurane, 2:329
Metorchis conjunctus, 2:323
Metritis, 3:389-393
contagious equine, 3:445, 3:445f
Meuse-Rhine-Issel cattle, 2:38
diaphragmatic dystrophy, 1:199
Mexican Hairless dogs, congenital
hypotrichosis in, 1:538-539
Mexican Hairless pigs, congenital
hypotrichosis in, 1:538
Mibolerone, 2:329
Microabscess, 2:440.e1f
Microangiopathic hemolytic anemia (MHA),
3:65
Microbiology, diagnostic, 1:10-11
Microcirculation, 1:263-264, 1:264f, 3:54,
1:263.e1f
lesions, 1:301
Microcornea, 1:421
Microcystiis aeruginosa, 2:330
Microcystin-LR, 2:330
Microencephaly, 1:268
Microfractures, 1:34, 1:34f
Microglia, 1:262-263, 2:392.e3f
Microglial nodules, 1:262-263
Microgliomatosis, 1:403
Microhematuria, 2:461
Microlithiasis, alveolar, 2:517, 2:517f
Micronodular thymomas, 3:154, 3:155f
Index 547
Microphakia, 1:422
Microphthalmos, 1:410, 1:410f
Microradiography, 1:30
Microscopic agglutination test (MAT),
2:434-435
Microscopic lesions, 2:399-400
intestinal mucosa, 2:125-126
Microscopic polyangiitis, 3:71
Microscopic structure of muscle fibers,
1:165-167, 1:166f
Microsporidian infections, 1:385-386
Microthrombi, 2:85
Microvascular injury, 2:85-86
Microvascular maturation, 2:484
Microvescular steatosis, 2:273-274,
2:274f
Microvilli, 2:61
Microwave burns, 1:565
Middle ear, 1:495-500
developmental disease, 1:496
epithelial neoplasia, 1:500
jugulotympanic paragangliomas,
1:500
non-neoplastic and neoplastic disease,
1:498-499, 1:498.e2f
otitis media, 1:496-498, 1:497.e1f
parasites, 1:498
temporohyoid osteoarthropathy, 1:500
Middle plexus, dermal, 1:514
Midstromal corneal vascular ingrowth from
limbus, 1:437-438
Midzonal liver necrosis, 2:283, 2:283f
Mild morphologic damage, 2:81
Mimosine toxicosis, 1:572
Mineralocorticoids, 3:337
Mineral deficiency, 1:583-586
Mineral deposition
corneal, 1:434
cutaneous tissue, 1:562-564
Mineralization, 2:386f
adrenal glands, 3:339
arterial, 3:60-61, 3:61f
cartilage matrix, 1:23
colloid, 3:314, 3:315f
defective, 1:68
dystrophic, 1:519
enamel, 2:5
fibrous osteodystrophy and, 1:78-79,
1:79f
front, bone, 1:20
heart, 3:34
matrix, 1:20
parathyroid suppression associated with
vitamin D intoxication, 3:302, 3:302f
placenta, 3:397
pulmonary, 2:494-495, 2:494f
subendocardial, 3:4, 3:30, 3:30f
testicular degeneration, 3:484
Miniature Poodle dogs
Alexander disease, 1:341
chondrodysplasia, 1:44, 1:44f
diabetes mellitus, 2:373
epidermolysis bullosa, 1:536
globoid cell leukodystrophy, 1:339
malignant melanoma, 2:26
pancreatic necrosis, 2:358
Miniature Schnauzer dogs
canine atopic dermatitis, 1:591
congenital idiopathic megaesophagus,
2:33-34
congenital myotonia, 1:201
548 Index
Miniature Schnauzer dogs (Continued)
demyelinating neuropathy, 1:341-342
factor VII deficiency, 3:264
hypothyroidism, 1:587
pancreatic necrosis, 2:358
pigmented plaques, 1:710-711
Schnauzer comedo syndrome, 1:549
sick sinus syndrome, 3:51
XY disorder of sexual development, 3:471,
3:471f
Minimal change disease, 2:418, 2:420f,
2:418.e2f
Minimata disease, 1:321
Miscellaneous glomerular lesions, 2:418-421
Misshapen teeth, 2:6
Mites, 1:673-684
Demodex, 1:678-682
trombiculiasis, 1:682-683
Mitochondria, 1:251-252
Mitochondrial cytochrome P450 enzymes,
3:341
Mitochondrial myopathy
dogs, 1:205
horses, 1:207
Mitochondrial outer membrane
permeabilization (MOMP), 2:280
Mitotic index (MI), 1:721
Mittendorf’s dot, 1:417-418
Mixed-breed dogs, 2:415-416
factor VII deficiency, 3:264
severe factor X deficiency, 3:264
Mixed germ cell-sex cord stromal tumor,
3:496
Mixed liver hamartomas, 2:264
Mixed neuronal-glial tumors, 1:401
Mixed toxic insults, liver, 2:327
Modeling, 1:24-25, 1:26f
Molecular biology, 1:11
Molluscipoxvirus, 1:616, 1:621-622,
1:622f
Molybdenosis, 1:84
Molybdenum, 1:81-82
Monensin, 1:219, 3:34-35
Monkeypox virus, 1:616
Monocytes, dermal, 1:514
Monoiodotyrosine (MIT), 3:311
Monomyelocytic leukemia, 2:352f
Monorchia, 3:479
Moraxella bovis, 1:425
infectious bovine keratoconjunctivitis and,
1:440
Morgagnian globules, 1:442
Morgan horse, axonal dystrophy in, 1:324
Morphea, 1:698
Morphologic diagnosis, 1:5
Mortierella wolfii, 2:554
Mortierellosis, 2:554
Mosaicism, 3:363
Mosquito-bites
dermatitis, 1:670-671, 1:671f
flaviviruses, 1:374-376
hypersensitivity, 1:599
Motility and salmonellosis, 2:168
Motor neuron disease, 1:255, 1:255f,
1:330-332, 1:331f-332f
“shaker calf”, 1:332, 1:332f
Motor units, muscular, 1:165
Mouth. See Buccal cavity; Oral cavity
Mucinosis, 1:522-523
Mucocele
gallbladder, 2:307, 2:345, 2:345f
paranasal, 2:477, 2:477.e4f
salivary, 2:29
Mucociliary clearance, 2:471-472
Mucocutaneous leishmaniasis, 3:174
Mucocutaneous pyoderma, 1:630
Mucocyte bodies, 1:255
Mucoepidermoid carcinomas, 2:30
Mucolipidoses, 1:290
Mucometra, 3:374, 3:374f, 3:382-383,
3:383f, 3:386
Mucoperiosteal exostoses, 1:499, 1:499f
Mucopolysaccharidoses (MPS), 1:58, 1:58f,
1:289-290
hearing and, 1:491-492
Mucosa. See also Buccal cavity
-associated lymphoid tissue (MALT), 2:20
-associated lymphoid tissue (MALT)oma,
3:225f
buccal cavity and, 2:12-19
disease, 2:114, 2:123
hypertrophy, 2:48
infarction, 2:385-386
microscopic appearance, 2:67
nasal cavity, 2:466
polyps, 2:104f
ulcers, 2:82
Mucous cells, 2:469
Mucous glands, 2:378
Mucous membrane pemphigoid, 1:603,
1:603f, 2:15
Mucous metaplasia and hyperplasia, 2:47
Mucous neck cells, 2:45
Mucus, 2:471
Mucus-producing carcinomas, 2:101-102
Muellerius capillaris, 2:565, 2:565t, 2:566f,
2:565.e2f
Mulberry heart disease, 1:217, 3:39-41,
3:39f-41f, 3:39.e1f
Multicentric lymphoma, 3:241, 3:241f
Multidrug-resistance-associated protein-2
(MRP-2), 2:293
Multifocal intramural myocardial infarction,
3:36
Multifocal necrotizing panniculitis, 2:360
Multifocal osseous metaplasia, 2:517,
2:517.e1f
Multifocal polyphasic necrosis, 1:218
Multifocal renal cortical hemorrhages,
2:432f
Multifocal symmetrical myelinolytic
encephalopathy, 1:341
Multilobular tumor of bone, 1:117-118,
1:117f-118f
Multinucleated giant cells, 1:527, 2:27
Multinucleated keratinocytes, 1:523
Multinucleated macrophages, 2:540.e2f
Multinucleated syncytial giant cells,
3:297-298, 3:298f
Multinucleation, liver, 2:270
Multiple acquired cortical cysts, 2:396f
Multiple cartilaginous exostosis, 1:54
Multiple endocrine neoplasia (MEN),
3:356-357
Multiple epiphyseal dysplasia, 1:44, 1:45f
Multiple hepatic peribiliary cysts, 2:264
Multiple myeloma (MM), 3:137, 3:138f,
3:228, 3:228f
Multiple persistent vitelline duct cysts, 2:74
Multisystemic, eosinophilic, epitheliotropic
disease in the horse, 1:695-696
Multisystemic epitheliotropic syndrome, 2:96
Multisystem neuronal degeneration of
Cocker Spaniel dogs, 1:320
Mummification of fetus, 3:395-396, 3:395f
Munro’s microabscess, 1:523
Mural endocarditis, 3:32
Mural folliculitis, 1:528
Murray Grey cattle, inherited progressive
spinal myelopathy of, 1:325
Muscle crush syndrome, 1:212
Muscle(s), 1:165-246. See also Tendons
basic reactions of, 1:173-186
atrophy, 1:173-178
fibrosis, 1:184-185
hypertrophy, 1:178-180
injury and necrosis, 1:180-182
other myofiber alterations,
1:185-186
postmortem changes, 1:186
regeneration, 1:182-183
circulatory disturbances of, 1:210-213
compartment syndrome, 1:211
downer syndrome, 1:212
muscle crush syndrome, 1:212
postanesthetic myopathy in horses,
1:213
vascular occlusive syndrome, 1:212
congenital and inherited diseases,
1:186-210
malignant hyperthermia, 1:209-210
metabolic myopathies, 1:204-209
muscular defects, 1:189-192
muscular dystrophy, 1:192-197
myasthenia gravis, 1:209
myopathies, 1:197-200
myotonic and spastic syndromes,
1:200-204
primary central nervous system
conditions, 1:187-189
degenerative myopathies, 1:221-224
equine systemic calcinosis, 1:223-224
dermal, 1:515
histochemical fiber types, 1:169-170,
1:169f-170f
immune-mediated conditions, 1:225-230
masticatory myositis of dogs,
1:226-227
microscopic structure, 1:165-167,
1:166f
myogenesis, 1:167-169
myopathies
associated with endocrine disorders,
1:224-225
associated with serum electrolyte
abnormalities, 1:225
myositis resulting from infection,
1:230-234
clostridial, 1:230-233
malignant edema and gas gangrene,
1:232
suppurative myositis, 1:230
neoplastic diseases of, 1:240-246
muscle pseudotumors, 1:246,
1:246f
nonmuscle primary tumors of muscle,
1:244-245
rhabdomyoma, 1:241, 1:242f
rhabdomyosarcoma, 1:241-243,
1:243f-244f
secondary tumors of skeletal muscle,
1:244-246, 1:245f-246f
nutritional myopathy, 1:214-218
cattle, 1:215-216
etiology and pathogenesis, 1:214-215
horses, 1:218
other species, 1:218
pigs, 1:217
sheep and goats, 1:216-217
 Index 549

Muscle(s) (Continued) Mycoplasmal arthritis (Continued) parasitic, 3:43-44, 3:44.e1f

parasitic diseases and, 1:234-240
cysticercosis, 1:239-240, 1:239f
eosinophilic myositis, 1:236-237,
1:236f-237f
hepatozoonosis, 1:240
leishmaniasis, 1:240
sarcocystosis, 1:234-236, 1:235f
Toxoplasma and Neospora myositis,
1:237-238
trichinellosis, 1:237-238
physical injuries of, 1:213-214
ossifying fibrodysplasia, 1:213
strains/tears/ruptures/fibrotic
myopathies/contractures, 1:213-214
repair, 1:166-167
specialized structures, 1:170-171, 1:170f
spindles, 1:171, 1:171f
steatosis, 1:191, 1:191f
structure and development, 1:165-173
techniques for study of, 1:171-173
toxic myopathies, 1:218-220
ionophore toxicosis, 1:219
toxic plants and plant-origin toxins,
1:90-91, 1:219-220
ultrastructure, 1:167
Muscular dystrophy, 1:185, 1:185f,
1:192-197
canine X-linked, 1:192-194, 1:193f-195f
α-dystroglycan deficiency and, 1:196
feline X-linked, 1:194-195, 1:195f
ovine, 1:196-197, 1:196f
Musculoaponeurotic fibromatosis, 1:248,
1:248f
Myasthenia gravis, 1:209, 3:157
acquired, 1:229-230
cats, 1:209
dogs, 1:209
Mycetoma, 1:653
Mycobacterial infections, 1:639
canine leproid granuloma, 1:503, 1:641,
1:641f
feline leprosy, 1:640-641
liver and, 2:314-315, 2:315f
nontuberculous, 1:639-640
spleen and, 3:183f
tuberculosis, 1:639
Mycobacterium avium, 2:194, 2:548
Mycobacterium bovis, 2:547-551
Mycobacterium tuberculosis, 2:548
Mycobacterium ulcerans, 1:640
Mycology, 1:10-11
Mycoplasma agalactiae, 2:564
Mycoplasma alkalescens, 2:554
Mycoplasma arginini, 2:554
Mycoplasma bovigenitalium, 2:554
Mycoplasma bovirhinis, 2:459, 2:554
Mycoplasma bovis, 1:153-154, 1:498,
2:552-554, 2:553f, 2:552.e2f
Mycoplasma canis, 2:554, 3:491
epididymitis due to, 3:491
Mycoplasma capricolum, 2:563-564
Mycoplasma cynos, 2:579
Mycoplasma dispar, 2:554
Mycoplasma haemofelis, 3:124, 3:125f
Mycoplasma haemosuis, 3:168t, 3:170
Mycoplasma hyopneumoniae, 2:534-535,
2:535f, 3:25-26
Mycoplasma hyorhinis, 1:153
Mycoplasmal arthritis, 1:153-154
cats, 1:154
dogs, 1:154
goats, 1:153, 1:153f
pigs, 1:153
sheep, 1:153
Mycoplasmal infections, 1:646-661,
2:459
abortion and, 3:399b
guttural pouch, 2:480-481, 2:480f
respiratory system, 2:533-535, 2:551-554,
2:563-564, 2:573, 2:579, 2:590
Mycoplasma mastitis, 3:456, 3:456f
Mycoplasma mycoides, 1:153f, 1:154, 2:551,
2:564
Mycoplasma ovipneumoniae, 2:564
Mycoplasma putrifaciens, 2:564
Mycoplasmas, hemotropic, 3:124-125
Mycoplasmology, 1:10-11
Mycosis fungoides (MF), 3:232, 3:233f
Mycotic abomasitis, 2:54, 2:54f
Mycotic abortion in cattle, 3:418-419,
3:418f-419f
Mycotic diseases of gastrointestinal tract,
2:201-203
Mycotic endophthalmitis, 1:449-451
Mycotic epididymitis, 3:491
Mycotic gastritis, 2:54
Mycotic keratitis, 1:439-440, 1:439f
Mycotic omasitis, 2:42
Mycotic rhinitis, 2:579, 2:580f
Mycotic rumenitis, 2:42, 2:42f
Mycotoxic leukoencephalomalacia, 1:315-
316, 1:315f-316f
Mycotoxicosis, 1:472
ergotism, 1:572-573, 1:573f
Myelination, 1:259
Myelinic edema, 1:260
Myelin in Wallerian degeneration, 1:256-257,
1:257f
Myelinolytic leukodystrophy, 1:341
Myelinopathies, 1:336-347
spongy, 1:342-346, 1:342f-343f
Myelin sheath, 1:258-260
Myeloblasts, 3:104-106
Myelodysplasia, 1:188f, 1:277-279
Myelodysplastic syndrome (MDS), 3:129-
136, 3:135f-136f
Myelofibrosis (MF), 3:136-138, 3:137f
Myeloid metaplasia, 3:107
spleen, 3:191
Myelolipomas, 2:351f, 3:343-344
liver, 2:350-351
Myelomalacia, 1:307
Myelomas
multiple, 3:137, 3:138f, 3:228,
3:228f
plasma cell, 1:123, 1:123f, 2:27-28,
3:226-228, 3:226.e1f
Myelopathy, necrotizing, 1:340, 1:340f
Myeloproliferative neoplasm (MPN),
3:129-134, 3:134f-135f
Myiasis, 1:668-670
calliphorine, 1:669
of rumen, 2:43
screwworm, 1:669-670
Myocardial bridges, 3:22
Myocardial conduction system, 3:2,
3:3f
diseases, 3:51
Myocarditis, 3:41-44, 3:42f, 3:42t
embolic suppurative, 3:42.e1f
Myocardium, 3:3-5
contractile strength, 3:5
disease, 3:33-51
causes, 3:33t
degeneration, 1:217
myocarditis, 3:41-44, 3:42f, 3:42t
necrosis, 3:34-41, 3:36f-37f
Myofibers, 1:165, 1:166f, 1:167
congenital trigeminal nerve hypoplasia,
1:187, 1:188f
vacuolar degeneration, 1:185, 1:185f
Myofibrillar hypoplasia, 1:190, 1:190f
Myofibrils, 1:167
Myofibroblasts, 2:60-61
Myofilaments, 1:167
Myogenesis, 1:167-169
Myoglobin-induced acute tubular injury,
2:423f
Myopathic atrophy, 1:178, 1:178f
Myopathies
degenerative, 1:221-224
endocrine disorder-associated, 1:224-225
exertional, 1:221-223
inherited and congenital, 1:197-200
breed-associated, in dogs, 1:197-198,
1:197f
cats, 1:198-199
cattle, 1:199-200
horses, 1:200
sheep, 1:200
metabolic, 1:204-209
nutritional, 1:214-218
cattle, 1:215-216, 1:216f
horses, 1:218
pigs, 1:217
sheep and goats, 1:216-217
serum electrolyte abnormalities and, 1:225
toxic, 1:218-220
ionophore toxicosis, 1:219
Myophosphorylase deficiency, 1:186-187,
1:208, 1:290
Myoporaceae, 2:331-332, 2:332f
Myosin heavy chains (myHC), 1:167-168
Myositis
clostridial, 1:230-233, 1:231f
eosinophilic, 1:236-237, 1:236f-237f
granulomatous lesions, 1:233-234
infectious, 1:230-234
malignant edema and gas gangrene, 1:232
muscle changes secondary to systemic
infections, 1:234, 1:234f
specific diseases with muscle alterations,
1:233
suppurative, 1:230f
Toxoplasma and Neospora, 1:237
Myospherulosis, 1:560
Myostatin defects leading to muscular
hyperplasia, 1:190-191
Myotonia, 1:200-204
cats, 1:201
dogs, 1:200f, 1:201
goats, 1:201-202
myotonic dystrophy-like disorders in dogs
and horses, 1:202-203, 1:203f
periodic paralyses, 1:202
spastic syndromes, 1:203f
Myotonic dystrophy-like disorders in dogs
and horses, 1:202-203, 1:203f
Myotonic syndromes, 1:318
Myotubes, 1:167

Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510

550 Index
Myriad tubular functions, 2:377
Myringitis, 1:497, 1:497f, 1:497.e2f
Myxedema with hypothyroidism, 3:318,
3:318f
Myxobdella, 2:19
Myxomas, 1:723, 3:52
Myxomatous valvular degeneration, 3:27-29,
3:28f-29f
Myxoma virus, 1:616
N Necrotic stomatitis, 2:17, 2:17f
N-acetylglucosamine-6-sulfatase deficiency,
1:289-290
NADPH oxidase mechanisms, 2:81
Nanophyetus salmincola, 2:225-226,
3:148-149
Nasal-associated lymphoid tissue (NALT),
2:474
Nasal cavity, 2:466, 2:473-480
circulatory disturbances, 2:473-474
congenital anomalies, 2:473
general considerations, 2:473
nasal amyloidosis, 2:473, 2:474f
neoplasms, 2:478-480, 2:478f
non-neoplastic proliferative disorders,
2:477-478
paranasal sinus diseases, 2:477, 2:477f
polyps, 2:477-478, 2:477f, 2:579
rhinitis, 2:474-477, 2:475b
tumors, 2:560, 2:560f
Nasal chondrosarcoma, 1:119f-120f,
2:480.e1f
Nasal granulomas, 2:476
Nasal lymphomas, 3:239f, 3:241, 3:241f,
3:239.e1f
Nasal/nasopharyngeal stenosis, 2:475
Nasal papillomas, 2:479, 2:479.e1f
Nasomaxillary tumors of young horses, 2:480
Nasopharyngeal angiofibroma, 2:480
Nasopharyngeal polyps of cats, 2:477-478,
2:477f
Nasopharynx, 2:467
Natural killer (NK) cells, 2:260, 2:263,
3:219
Naturally occurring disease, 1:2
Navicular syndrome, 1:142, 1:142f
NCP biotype and BVDV, 2:122
Nebovirus, 2:113
Necrobacillary rumenitis, 2:41-42
Necrobacillosis, 2:17
cattle, 1:643
hepatic, 2:316
pigs, 1:643
rumen, 2:41f
Necrohemorrhagic vasculitis, 1:299f
Necrolytic migratory erythema, 1:692
Necrosis, 2:386f
abdominal fat, 2:76-77, 2:249, 2:249f
bronchial, 2:501, 2:504-506, 2:504f
epidermal, 1:523
fibrinoid, 1:520
hyaline, 1:297-298
infundibular, 2:10, 2:10f
liquefactive, 1:254
liver cell, 2:280-284, 2:280f-283f, 2:286f,
2:285.e1f
massive, 2:284-285, 2:284f
piecemeal, 2:285
muscle, 1:180-182, 1:180f-181f
muscular dystrophy, 1:193, 1:194f
myocardial, 3:34-41
with neuronophagia, 1:254
pancreatic, 2:356-360, 2:359f-360f
Necrosis (Continued)
retinal, 1:419
tail tip, 1:560
thymic, 3:145-146, 3:146f, 3:145.e1f
Necrosuppurative epididymitis, 3:489f
Necrotic bone. See Osteonecrosis
Necrotic colitis, 2:99, 2:99f
Necrotic hepatitis, 2:316, 2:316.e1f
Necrotic laryngitis, 2:17
Necrotic orchitis, 3:486
Necrotic vaginitis and vulvitis, 3:445,
3:445f-446f
Necrotizing enteritis, 2:187, 2:187f-188f
Necrotizing fasciitis, 1:636
Necrotizing leukoencephalitis, 1:392-393
Necrotizing meningoencephalitis, 1:392-393,
1:392f
Necrotizing myelopathy, 1:340, 1:340f
Necrotizing pododermatitis, 1:643
Necrotizing scleritis, 1:477, 1:478f
Necrotizing sialometaplasia, 2:30
Necrotizing vasculitis, 1:200, 1:200f, 3:69,
3:69f
Negative nitrogen balance, 2:73
Nemaline rods
cats, 1:198-199, 1:199f
dogs, 1:185, 1:198
Nematodes
central nervous system and, 1:389-391
external ear, 1:507
liver, 2:320
spirurid, 2:210
Nematodirus spp., 2:213
Neomycin, 2:424
Neonatal alloimmune thrombocytopenia,
3:258
Neonatal copper deficiency, 1:328-329,
1:328f
Neonatal maladjustment syndrome of foals,
1:297
Neonatal periventricular leukomalacia, 1:274
Neonatal respiratory distress syndrome,
2:515-516, 2:516.e1f
familial forms, 2:516
Neoplasia, 2:76-77, 2:89-90, 2:462. See also
Carcinomas/adenocarcinomas;
Metastasis, tumor
adrenal cortex, 3:343-348
adrenal medullary secretory cells,
3:349-352
classification of, 2:101
ear
external acoustic meatal, 1:507-508
internal, 1:494
middle, 1:498-499
endocrine system, 3:356-357
esophagus and forestomachs, 2:43-44
female genital system, 3:447-450
cervix, 3:449-450, 3:450f
ovaries, 3:375-379
uterus, 3:449-450, 3:450f
heart, 3:52-54, 3:52f
hematopoietic, 3:129-136, 3:129t
hypercalcemia associated with
nonparathyroid, 3:305-310, 3:305f
invasion of veins, 3:89, 3:89f
liver, 2:344-352
lymphoid. See Lymphomas
male genital system
penis and prepuce, 3:508-510
prostate and bulbourethral gland,
3:503-504, 3:504f
Neoplasia (Continued)
spermatic cord, 3:498-499
testis and epididymis, 3:492-497
vaginal tunic, 3:474
mammary masses including, 3:459-464,
3:459f, 3:463f
muscle, 1:240-246
muscle pseudotumors, 1:246, 1:246f
nonmuscle primary tumors of muscle,
1:244-245
rhabdomyoma, 1:241, 1:242f
rhabdomyosarcoma, 1:241-243,
1:243f-244f
secondary tumors of skeletal muscle,
1:245-246, 1:245f-246f
nasal cavity and sinuses, 2:478-480, 2:478f
nervous system, 1:396-406
ocular, 1:478-488
oral cavity, 2:20-28
ovary, 3:375-379
pancreas
endocrine, 2:373-375, 2:374f
exocrine, 2:365-368
parathyroid glands, 3:302-305
peritoneum, 2:256-257, 2:256f
pinnal tumor-like growths and, 1:504-505
pituitary gland, 3:281-289, 3:281f
pleura, 2:523
pulmonary, 2:495-500, 2:495b
salivary glands, 2:30
skin, 1:703-736
splenic, 3:169f, 3:191-196
stomach and intestine, 2:100-111, 2:101t
systemic inflammation, 3:267-268
thymic, 3:151-158, 3:152t
thyroid gland, 3:326-336
vascular, 3:98-101
Neorickettsia helminthoeca, 2:225-226,
3:148-149, 3:150f, 3:149.e1f
Neorickettsia risticii, 2:200-201
Neospora caninum, 1:387-389, 1:388f,
1:664-665
abortion and, 3:421-423, 3:422f-423f
cysts, 1:388f
myocarditis and, 3:44
Neospora myositis, 1:237
Neosporosis, 1:387-389, 1:388f, 2:238-239
Neostrongylus linearis, 2:565t, 2:567
Nephroblastomas, 2:446-447, 2:446f
grossly, 2:446
renal and perirenal lymphosarcoma,
2:447f
renal cystadenocarcinoma, 2:446.e1f
true embryonal tumors, 2:446
urothelial cell carcinoma, 2:447f
Nephrogenic form of diabetes insipidus,
3:291
Nephroliths, 2:453
Nephrons, 2:379, 2:382, 2:391
atrophy, 2:400
Nephropathy, 2:294, 2:388
familial, 2:388-391
Nephrosis, 2:422
Nephrotic syndrome, 2:401, 2:414
Nephrotoxicity, 2:426
ATI, 2:423
in domestic animals, 2:424b
nephritis, 2:408
Nerium oleander, 2:89
Nerve sheath neoplasms, 1:245
Nervous system
astrocytes, 1:260-262, 1:261f
axon, 1:255-258, 1:256f

Nervous system (Continued)
cytopathology, 1:251-264
degeneration, 1:303-350
ependymal cells, 1:262
infectious agents/diseases inducing
inflammatory changes in,
1:351t-352t
microcirculation, 1:263-264, 1:264f,
1:263.e1f
microglia, 1:262-263
neuron, 1:251-258, 1:252f
oligodendrocytes, Schwann cells, and the
myelin sheath, 1:258-260
Nesidioblastosis, 2:373
Nestin, 1:261
Nests, 1:523
of residual glia, 1:262
Netherlands cattle, diaphragmatic dystrophy
in, 1:199
Neural plate, 1:265
Neural tube, 1:265
defects, 1:265
Neuritis of cauda equina, 1:394-395
Neuroaxonal dystrophies, 1:257-258
Neuroblastomas, 1:402, 3:352-353, 3:353f
olfatory, 2:479, 2:479f
Neuroblasts, 1:252
Neurodegenerative diseases, 1:317-336
central neuronopathies and axonopathies,
1:318-326
Neuroectoderm
anomalies of, 1:419-421
tumors of ocular, 1:485-486, 1:485f
Neuroendocrine carcinomas, 2:27,
2:478-479
Neuroendocrine cells, 2:27
Neuroendocrine tumors, 2:497-498
Neuroepithelial tissue
degeneration, 1:492
tumors, 1:398-403
Neurofibromas, 1:405, 3:53, 3:53f, 3:53.e1f
Neurofibromatosis, 1:724
Neurogenic diabetes insipidus, 2:430
Neurogenic disorders of micturition, 2:451
Neurohypophysis, 3:277-278
diseases, 3:290-291
Neuromelanins, 1:254-255
Neuromuscular junction, 1:170, 1:170f
Neuromycotoxicoses, tremorgenic, 1:322
Neuronal atrophy, 1:253
Neuronal inclusion-body diseases, 1:320
Neuronal storage diseases, 1:285, 1:473
Neuronal tumors, 1:401
Neuronal vacuolar degeneration of Angora
goats, 1:347
Neuronopathies, 1:318-326
Neuronophagia, 1:263, 2:77
Neuronophagic nodules, 1:253f, 1:254
Neurons, 1:251-258
axons, 1:255-258, 1:256f
concussion and, 1:302
degenerative changes, 1:252-255, 1:252f
Neutropenia, 3:109-110
congenital, 3:110
Neutrophilic cholangitis, 2:307-308,
2:308f
Neutrophilic dermatoses, sterile, 1:696
Neutrophilic vasculitis, 1:526, 1:611
Neutrophils
in immune-mediated polyarthritis,
1:157-159
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Neutrophils (Continued)
in nodular and diffuse dermatitis, 1:526
production, 3:109
Nevi, linear epidermal, 1:551
Newfoundland dogs
dilated cardiomyopathy, 3:48
focal bone dysplasia, 1:56
hypothyroidism, 1:587
subvalvular aortic stenosis, 3:20
vitiligo, 1:555-556
New Zealand Huntaway dogs, 1:334
Niacin, 1:582
Nicotiana tabacum, 1:90
Nictitans gland, protrusion of, 1:424
Nigropallidal encephalomalacia, 1:314,
1:314f
Nipah virus, 1:380-381, 2:501, 2:501f,
2:530
Nitrate toxicity, 1:91
nervous system and, 1:306
Nitrite poisoning, 1:306
Nitrogen dioxide, 2:518
Nitrosamines, 2:340
Nocardia asteroides, 2:314-315
Nocardia mastitis, 3:457, 3:457f
Nocardioform placentitis, 3:417
Nocardiosis, 1:637-639, 1:638f
Nodal lymphomas, 3:238.e2f
Nodal T-cell lymphomas, 3:229-230
Nodular and diffuse dermatitis, 1:526-527,
1:527f
Nodular auricular chondropathy, 1:697
Nodular dermatofibrosis, 1:692, 1:723
Nodular eosinophilic vasculitis, 1:612
Nodular goiter, 3:322, 3:322f
Nodular granulomatous episcleritis (NGE),
1:476, 1:477f
Nodular hyperplasia
adrenal cortex, 3:343
liver, 2:344, 2:344f
spleen, 3:189-190, 3:190f, 3:189.e2f
Nodular pancreatic hyperplasia, 2:365,
2:365f-366f
Nodular perianal gland hyperplasia, 1:718
Nodular sarcoids, 1:708, 1:709f
Nodules
accessory cortical, 3:343
hamartoma, 1:520, 1:705
lymphoid, 1:522
neuronophagic, 1:253f, 1:254
splenic, 3:167-169, 3:167f-168f, 3:169.e1f,
3:191.e1f
Noma, 2:18
Non-angiogenic, nonhematogenic splenic
sarcomas, 3:192-194, 3:192f
Non-B, non-T leukocytic neoplasm, 1:403
Noncystic endometrial hyperplasia, 3:383
Nonepidermolytic ichthyosis, 1:531-532
Nonepithelial neoplasms, 2:367
Non-erosive polyarthritis, 1:158-159
Noninfarctive “slow flow”, 2:85
Noninflammatory thrombosis of cranial dural
sinuses, 1:300
Nonkeratinocytes, epidermal, 1:513
Nonmuscle primary tumors of muscle,
1:244-245
Non-neoplastic lesions, 1:162-163
mammary enlargement and masses,
3:459-460, 3:459f
middle ear, 1:498-499
nasal cavity and sinuses, 2:477-478
Index 551
Non-neoplastic lesions (Continued)
synovial chondromatosis, 1:162, 1:162f
synovial cysts, 1:162-163
synovial pad proliferation, 1:163
Nonparenchymal cells, 2:261-264
Nonprogressive atrophic rhinitis (NPAR),
2:533
Nonspecific reactive hepatitis, 2:306
Nonsteroidal anti-inflammatory drugs
(NSAIDs), 2:55-57, 2:85
cyclooxygenase (COX), 2:55
gastroduodenal ulceration, 2:55
toxicity, 2:399, 2:400f
Nonsuppurative meningoencephalomyelitis,
2:121
Nonsuppurative vasculitis and perivasculitis,
1:298f
Nontuberculous mycobacteria, 1:639-640
Nonviral eosinophilic cytoplasmic inclusion
bodies, 1:255
Norepinephrine, 3:348, 3:350f
Norfolk Terrier dogs, inherited
thrombocytopenia in, 3:258
Normal canine glomerular filtration barrier,
transmission electron micrograph of,
2:380f
Normal canine glomerulus, 2:380f
Northern fowl mite, 1:683
Norwegian Dala sheep, collagen dysplasia in,
1:544
Norwegian Dunker dogs, cochleosaccular
degeneration in, 1:492
Norwegian Elkhound dogs
alopecia X, 1:589-590
chondrodysplasia, 1:43-44
nephritis, 2:417
Norwegian Forest cats, glycogen storage
disease type IV in, 1:205, 1:205f
Notched pinnae, 1:502
Notoedres cati, 1:675
Notoedric mange, 1:675, 1:675f
NPHS1 gene, 2:418
Nuclear glycogenosis, 2:430
Nuclear margination, 1:252-255, 1:252f
Nucleus pulposus, 1:128-129
Nutmeg liver, 2:298
Nutrient arteries, 1:27
Nutrients, assimilation of, 2:69
Nutritional deficiency/disease, 1:60
atrophy resulting from, 1:177
of bone, 1:60-84
exocrine pancreas and, 2:355, 2:362,
2:364
fatty liver, 2:276
hyperparathyroidism secondary to,
3:301
mineral imbalances, 1:80-82
myocardial necrosis and, 3:34, 3:35f
myopathy, 1:214-218
cattle, 1:215-216, 1:216f
horses, 1:218
pigs, 1:217
sheep and goats, 1:216-217
nutritional secondary hyperparathyroidism,
1:75
odontodystrophies and, 2:9
osteochondrosis, 1:132
retinopathy, 1:470-471
of skin, 1:580-587
tooth development and, 1:65
vitamin imbalances, 1:82-84, 1:581-583
552 Index
O Onchocerca cervicalis, 1:248, 1:451-452,
Oak poisoning, acute, 2:428
Oak shrubs, 2:427-428
Obstructions
cerebrospinal artery, 1:299-300, 1:299f
cerebrospinal veins, 1:300
esophageal, 2:32-33, 2:33f
obstructive atelectasis, 2:486
obstructive cholestasis, 2:293
obstructive urolithiasis, 2:455f
obstructive uropathy, 2:461.e1
pancreatic ductal drainage, 2:362
Obturation, 2:74
Occlusion of testicular artery, 3:491
Occult dirofilariasis, 3:84
Occult sarcoids, 1:708, 1:709f
Occupational health and safety, 1:14
Ochratoxin A (OTA), 2:427
Ocular adnexa, 1:423-427
conjunctiva, 1:424-427
eyelids, 1:423
lacrimal system, 1:423-424
tumors, 1:481-482
Ocular fundus, 1:466
Ocular habronemiasis, 1:425, 1:426f
Ocular neoplasia, 1:478-488
feline post-traumatic sarcoma, 1:486,
1:487f
melanocytic tumors, 1:482-485
ocular neuroectoderm, 1:485-486,
1:485f
optic nerve tumors, 1:487, 1:487f
orbital, 1:487-488
spindle cell tumor of blue-eyed dogs,
1:486
Ocular onchocerciasis, 1:425-426, 1:452
Ocular tuberculosis, 1:449
Odocoileus adenovirus 1, 2:145, 2:145f
Odontoameloblastoma, 2:24
Odontoblasts, 2:4-5, 2:8
Odontoclastic resorptive lesions,
2:10-11
Odontodysplasia cystica congenita, 2:7
Odontodystrophies, 2:8-9
effects of, 2:9
Odontogenic cysts, 2:6-7
Odontogenic epithelium, 2:23
Odontomas, 2:24
Oesophagostomum radiatum, 2:114-115
Oesophagostomum spp., 2:116, 2:215-216
Oestrus ovis, 2:564-565, 2:564.e3f
Oil of pennyroyal, 2:329
Old dog encephalitis, 1:384-385, 2:576
Old English Sheepdogs
cochleosaccular degeneration, 1:492
mitochondrial myopathy, 1:205
vitiligo, 1:555-556
Oleander poisoning, 2:89, 3:35, 3:35f
intoxication in llama, 2:89f
Olfactory neuroblastomas, 1:401, 2:479,
2:479f
Oligoastrocytoma, 1:400
Oligodendrocytes, 1:258-260
Oligodendroglioma, 1:400, 1:400f
Oligodontia, 2:6
Oliguria, 2:423
Olivopontocerebellar atrophy, 1:319
Ollulanus tricuspis, 2:211
Omasal transport, failure of, 2:39
Omasitis, 2:42
Omental hernia, 2:79
Omphalomesenteric duct, 2:245
Onchocerca armillata, 3:87-88
Oral cavity (Continued)
1:687-688
Onchocerca gibsoni, 1:247-248, 1:688
Onchocerca gutturosa, 1:248, 1:687-688
Onchocerca lienalis, 1:248
Onchocerca reticulata, 1:248, 1:687-688
Onchocerciasis, 1:687-688, 1:688f, 3:87-88
Onchocercidae, 1:247
Oncicola canis, 2:227
Oncocytic metaplasia, 2:28
Oncocytomas, 2:478-479
1,25(OH)2D3, 1:25t
Oophoritis, 3:370-371, 3:371f
Ophthalmitis, equine recurrent, 1:455-456
Ophthalmomyiasis, 1:426
Opisthorchid flukes, 2:323
Opisthorchis felineus, 2:323-324
Opportunisitc bacterial pathogens in foals,
2:571
Optic disc cupping, 1:460, 1:462f
Optic nerve, 1:475-476
degeneration, 1:476
hypoplasia, 1:420-421, 1:421f
tumors, 1:487, 1:487f
Optic neuritis, 1:474-475
chronic, 1:476
Optic neuropathy, compressive, 1:320
Optimal cutting temperature compound
(OCT), 2:383
Oral actinobacillosis, 2:19
Oral candidiasis, 2:14
neoplastic and like lesions, 2:20-28
Oral cavity, 2:2-28. See also specific
components
buccal cavity/mucosa diseases
actinobacillosis, 2:18
bullous pemphigoid, 2:15
catarrhal stomatitis, 2:14
circulatory disturbances, 2:12-13
deep stomatitides, 2:17-19
eosinophilic ulcer, 2:16
erosive/ulcerative stomatitides, 2:15-17
feline calicivirus, 2:15
feline chronic gingivostomatitis, 2:16
feline plasma cell gingivitis-pharyngitis,
2:16
feline ulcerative stomatitis, 2:16
feline viral rhinotracheitis, 2:16
foreign bodies, 2:13
gingivostomatitis, chronic, 2:15
glossitis, 2:16
horses, with eosinophilic epitheliotropic
disease, 2:16
inflammation, 2:13-19
lymphocytic-plasmacytic stomatitis,
2:16
mucous membrane pemphigoid, 2:15
oral dermatophilosis, 2:19
oral eosinophilic granuloma, 2:16
pemphigus vulgaris, 2:14
pigmentation, 2:12
superficial stomatitis, 2:13-14
thrush/oral candidiasis, 2:14
uremia, 2:16-17
vesicular stomatitides, 2:11
buccal/mucosal disease, 2:12-19
congenital anomalies, 2:2-4
brachygnathia inferior/micrognathia,
2:3
epitheliogenesis imperfecta, 2:4
facial clefts, 2:2-3
primary cleft palate, 2:3
prognathism, 2:3
dental tissue tumors, 2:22-25
foot-and-mouth disease lesions, 1:233,
1:233f
foreign bodies, 2:13, 2:13f
inflammation, 2:13-19
neoplastic and like lesions, 2:20-28
neoplastic/lesions of, 2:20-28
dental tissues, tumors of, 2:22-25
acanthomatous ameloblastoma, 2:23
amyloid-producing odontogenic
tumors, 2:23
feline inductive odontogenic tumor,
2:24
periodontal ligament origin,
fibromatous epulis of, 2:24
epulis, 2:20
fibrosarcomas, 2:27
granular cell tumors, 2:27
mast cell tumors, 2:27
melanomas, malignant melanomas, 2:26
miscellaneous tumors, 2:28
neuroendocrine carcinomas, 2:27
oral papillomatosis, 2:22
pharynx, 2:27
plasmacytomas, 2:27-28
extramedullary plasmacytomas, 2:27
reactive/hyperplastic lesions, 2:21-22
fibrous hyperplasia, 2:21
peripheral giant cell granuloma, 2:21
pyogenic granuloma, 2:21
squamous cell carcinoma (SCC),
2:25-26
vascular tumors, 2:28
papillomatosis, 2:22
parasitic diseases, 2:19
reactive and hyperplastic lesions,
2:21-22
teeth and tooth development
fluorosis and, 1:84-86
mandibular osteomyelitis and, 1:103,
1:103f
undernutrition and, 1:65
vitamin A deficiency and, 1:82-83
teeth/dental tissue disease, 1:20-21
teeth/dental tissues diseases, 2:4-12
cementum, 2:5-6
degenerative conditions of, 2:7-9
abnormal wear, 2:8
calcium deficiency, 2:8
dental attrition, 2:7-8
odontodystrophies, 2:8-9
phosphorus deficiency, 2:8
pigmentation, 2:7
subnormal wear, 2:8
developmental anomalies of, 2:6-7
anodontia, 2:6
cystic dental inclusions, 2:7
heterotopic polyodontia, 2:6
odontogenic cysts, 2:6-7
polyodontia, 2:6
enamel, 2:5
hypercementosis, 2:6
malassez, epithelial rests of, 2:6
periodontal ligament, 2:6
teeth/periodontium, infectious/
inflammatory diseases of, 2:9-12
bacterial diseases, involving tooth
surfaces, 2:9
cara inchada, 2:12
cats, 2:10-11
cattle, 2:10
dental calculus, 2:9
 Index 553

Oral cavity (Continued) Osteocalcin, 1:19, 1:27 Osteoporosis (Continued)

dental caries, 2:9-11
pit/fissure caries, 2:10
smooth-surface caries, 2:10
gingivitis, 2:11
infundibular necrosis, 2:10
materia alba, 2:9
periodontal disease, 2:11-12
pulpitis, 2:11
sheep, 2:10
tonsils, diseases, 2:19-20
Oral dermatophilosis, 2:19
Oral dysphagia, 2:33
Oral eosinophilic granuloma, 2:16
Oral lesions, 2:121
Oral papillomatosis, 2:22, 2:22f
Orbit, 1:477-478
neoplasms, 1:487-488
Orbital celluitis, 1:478
Orbital myositis, 1:478
Orbital (extra-adrenal) paragangliomas,
3:356
Orbivirus, 1:281, 3:430-431
Orchitis, 3:485-487
boars, 3:486-487
bulls, 3:486
camelids, 3:487
dogs and cats, 3:487, 3:488f
interstitial, 3:486
intratubular, 3:486, 3:486f
necrotic, 3:486
small ruminants, 3:487
stallions, 3:487
Orf virus, 1:616-617
Organic anion-transporting polypeptide
(OATP), 2:293, 2:325
Organobromine, 1:571-572
Organochlorine, 1:571-572
Organogenesis
eye, 1:410-412, 1:410f
pancreas, 2:353-354, 2:354f
Organomercurial poisoning, 1:320-321,
1:321f
Organophosphate poisoning, 1:326
Ornithonyssus syviarum, 1:683
Orthobunyaviruses, 1:280
Orthopoxvirus, 1:616, 1:619-621
Oslerus osleri, 2:586, 2:586f
Oslerus rostratus, 2:591
Osmotic diuresis, 2:425
Osseous drift, 1:24-25
Osseous metaplasia, 1:304, 2:517,
2:517.e1f
Osseous sequestration, 1:97
Ossification, endochondral, 1:22, 1:22f
rickets and, 1:71-72
Ossification centers, 1:22
Ossification groove of Ranvier, 1:23
Ossifying fibrodysplasia, 1:213
Ossifying fibroma, 1:109, 1:109f
Ossifying pachymeningitis, 1:304
Osteitis, 1:97
Osteoarthritis, 1:137
Osteoblastic osteosarcomas, 1:113,
1:113f
Osteoblasts, 1:17-19, 1:17f
modeling, 1:24, 1:26f
necrotic bone and, 1:96
osteosarcoma, 1:111-112
remodeling, 1:26
in vitamin D toxicity, 1:89
Osteocartilaginous metaplasia, 3:34, 3:34f growth arrest lines and, 1:64
Osteochondrodysplasia, 1:44-45 histologic examination, 1:64
cats, 1:45-46 lactational, 1:65-66, 1:66f
Osteochondromas, 1:116-117, 1:117f nutritional, 1:61, 1:64-66
cats, 1:117, 1:117f parasite-induced, 1:67f
horses, 1:116 pigs, 1:64f
Osteochondromatosis, 1:54 postmenopausal, 1:64
dogs, 1:54, 1:117f senile, 1:64
horses, 1:54 starvation, 1:64-65, 1:65f
Osteochondrosis, 1:81, 1:132-135 vitamin A toxicity and, 1:67, 1:87
dissecans, 1:132-134, 1:133f-134f Osteoprotegerin (OPG), 1:26, 3:295
horses, 1:134, 1:134f Osteosarcomas, 1:95, 1:110-116, 1:110f
latens, 1:132, 1:132f cats, 1:110
manifesta, 1:132, 1:133f cytology, 1:111, 1:111f
pigs, 1:133-134 dogs, 1:95, 1:110, 1:110f
sheep, 1:135 extraskeletal, 1:115
Osteoclastic bone resorption, 1:18-19 grading systems, 1:115
Osteoclasts, 1:17-19 nasal, 2:480
remodeling, 1:26 parosteal, 1:115, 1:115f
Osteocytes, 1:17-18 radiography, 1:111
Osteofluorosis, 1:85 subtypes, 1:113-114
Osteogenesis imperfecta Ostertagia spp., 2:54-55
cats, 1:50 Ostertagiosis, 2:205-207, 2:206f
cattle, 1:37t, 1:46-50, 1:47f-49f Otitis externa, 1:497, 1:502-503, 1:502f,
dogs, 1:50 1:497.e2f
sheep, 1:49, 1:49f-50f feline proliferative, necrotizing, 1:503-504
Osteoid, 1:17-19 Otitis interna, 1:493, 1:493.e2f
seam, 1:20 Otitis media, 1:496-498, 1:497.e1f
rickets and, 1:73, 1:73f with effusion, 1:498
Osteoliposarcoma, 1:123 Otoacariasis, 1:505-506
Osteolysis, 1:109 Otobius megnini, 1:507
Osteoma, 1:109 Otodectes cynotis mite, 1:505, 1:506f
Osteomalacia, 1:61, 1:66, 1:68-74 Otodectic mange, 1:677-678
calcium deficiency in, 1:69 Otognathia, 1:496
lesions of, 1:73 Otosclerosis, 1:493, 1:496
phosphorus deficiency in, 1:68-69 Ototoxicity, 1:494, 1:494.e1f
vitamin D deficiency, 1:68 Outer hair cells of ear, 1:491
Osteomyelitis, 1:97, 2:12 Ovarian hemangiomas, 3:378
acute, 1:95, 1:95f Ovarian remnants, 3:366
bacterial, 1:98-103, 1:98f-99f cysts arising from, 3:366-367, 3:367f-368f
cats, 1:99-100 Ovarian suspensory ligaments, 2:76-77
cattle, 1:99 Ovaries, 3:366, 3:366f-367f
dogs, 1:99-100 age-related degenerative changes, 3:371,
fungal, 1:103-104, 1:104f 3:371f
horses, 1:99, 1:99f, 1:101f circulatory disturbances, 3:381-382
mandibular, 1:102-103, 1:103f, 2:11 cysts, 3:371-372, 3:372f
periodontal, 1:101f neoplastic conditions, 3:375-379
suppurative, 1:100-101, 1:102f pathology, 3:370-375
vertebral, 1:101-102, 1:102f Overinflation of alveoli, 2:486, 2:487.e1f
Osteonecrosis, 1:94-97 Ovine fleece rot, 1:634
morphology and fate of necrotic bone in, Ovine herpesvirus 2, 1:625-627, 2:132
1:95-97 Ovine lymphomas, 3:237, 3:237f
Osteonectin, 1:19 Ovine muscular dystrophy, 1:196-197,
Osteons, 1:20, 1:21f 1:196f
Osteopathy, metaphyseal, 1:105-106, Ovine parainfluenza virus, 2:557
1:105f-106f Ovine progressive pneumonia, 2:558-560,
Osteopenia, 1:61 2:559f, 2:558.e1f
Osteopetrosis, 1:37t, 1:50-53 Ovine pulmonary adenocarcinoma (OPA),
cattle, 1:51-52, 1:51f 2:560-562, 2:561f, 2:561.e1f
deer, 1:52 Ovine respiratory syncytial virus, 2:557
dogs, 1:52 Ovine white-liver disease, 2:276
horses, 1:52, 1:52f Ovotestes, 3:361-362, 3:362f, 3:365f
sheep, 1:52, 1:52f Oxalate calculi, 2:456-457
Osteopontin, 1:19 Oxalate uroliths, 2:457
Osteoporosis, 1:61, 1:63-68 prevalence of, 2:457
copper deficiency in, 1:81 Oxalic acid, 2:456
corticosteroid-induced, 1:67 Oxibendazole-diethylcarbamazine, 2:329
definition, 1:63 Oxidative stress and testicular function,
disuse, 1:67 3:467
gross lesions of, 1:63-64 Oxygen exposure and lung injury, 2:518

Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510

554 Index
Oxyphilic adenomas, 3:327
Oxyuris equi, 1:688
Ozone, 3:298
P nasal, 2:479, 2:479.e1f
Pachygyria, 1:268
Pagetoid reticulosis (PR), 3:232-234,
3:233f
Paint horses
deafness in, 1:493
equine systemic calcinosis in, 1:223-224
melanocytopenic hypomelanosis, 1:555
Palyam virus, 3:431
Panarteritis, 3:71
Pancreas, 2:353-375
abscesses, 2:361
diabetes mellitus and, 2:370-373, 2:371f
endocrine, 2:368-375
diabetes mellitus, 2:370-373, 2:371f
cats, 2:372, 2:373f
cattle, 2:372
diabetic cataract, 1:443
dogs, 2:373
horses, 2:372
retinopathies, 1:472
hyperplastic and neoplastic diseases,
2:373-375, 2:374f
exocrine, 2:353-368
atrophy, 2:362-363, 2:362f
hyperplastic and neoplastic lesions,
2:365-368
insufficiency, 2:363-364
necrosis, 2:357-360, 2:359f-360f
organogenesis, 2:353-354, 2:354f
pancreatitis, 2:360-362
parasitic diseases, 2:365
general considerations, 2:353
necrosis, 2:249
Pancreatic bladder, 2:355-356
Pancreatic endocrine neoplasia, 2:373-375
Pancreatic hypoplasia, 2:355
Pancreatic lipofuscinosis, 2:356
Pancreatic phlegmon, 2:361
Pancreatic polypeptide, 2:368
Pancreatic polypeptide-secreting islet
neoplasia (PPoma), 2:375
Pancreatitis, 2:360-362, 2:361f
Pancreatolithiasis, 2:361-362
Paneth cells, 2:61-63
Panhypopituitarism, 3:280, 3:280f
Panicum spp., 2:339, 2:339f
Panniculitis, 1:523, 1:528-529, 1:529f
sterile nodular, 1:701-702, 1:701f
Pannus keratitis, 1:438
Panophthalmitis, 1:446
Panthothenic acid, 1:582
Pantropic canine coronavirus, 2:577
Pan-vasculitis, 3:72
Papillary adenomas
ears, 1:500
pulmonary, 2:495
thyroid, 3:327
Papillary carcinomas of thyroid, 3:330
Papillary hyperplasia, 2:462
Papilledema, 1:475
Papillomas, 2:462
cats, 1:711-712, 1:712f
cattle, 1:706-707
choroid plexus, 1:401, 1:401f
conjunctival, 1:481
cutaneous, 1:706-712, 1:706f
dogs, 1:710-711, 1:710t, 1:711f
epidermal, 1:706-712
Papillomas (Continued)
horses, 1:707-710
idiopathic squamous, 1:705
laryngeal, 2:482
pigs, 3:449
sheep and goats, 1:710
Papillomatosis, 1:523
Papillomatous digital dermatitis (PDD),
1:644-645, 1:644f
Papillomaviruses, 1:628
aural plaques and, 1:504
camelids, 1:712
cats, 1:711-712, 1:712f
cattle, 1:530, 1:706-707, 1:707f
dogs, 1:710-711, 1:710f, 1:710t
horses, 1:707-710, 1:708f, 1:708t
lesions of epidermis, 1:706-712,
1:706f
rabbits, 1:712
sheep and goats, 1:710
Papillon dogs, axonal dystrophy in, 1:325
Papules, 1:524
Paracentral liver necrosis, 2:283-284,
2:284f
Paracortical tissue, lymph node, 3:197
Parafilaria multipapillosa, 1:688-689
Parafilariasis, 1:688-689
Paragangliomas, 1:406, 3:354-356
aortic body adenoma and carcinoma,
3:354-355, 3:354f
carotid body adenoma and carcinoma,
3:355-356
development, structure, and function,
3:354
extra-adrenal, 3:356
heart-base tumors derived from ectopic
thyroid, 3:356
Paragonimus spp., 2:537, 2:591, 2:591f,
2:591.e2f
Parahyperthyroidism, 1:75
Parainfluenza virus, 2:557
canine, 2:576
Parakeratosis
Labrador Retriever nasal, 1:550
swine, 1:584
Paralysis, laryngeal, 2:481, 2:481f
Paramesonephric (Müllerian) ducts,
3:360-361, 3:361f
arrested development of, 3:367-369, 3:368f
cysts, 3:371
Parametritis, 3:390, 3:390f
Paramphistomatidae, 2:43, 2:43f
Paramphistome, 2:226
Paramphistomum spp., 2:43, 2:43f
Paramyxoviral encephalomyelitis of pigs,
1:380-381
Paramyxovirus, 2:116
Paranasal meningioma, 1:396, 1:397f
Paranasal sinus diseases, 2:477, 2:477f,
2:477.e4f
cysts, 2:478
paranasal meningioma, 1:397f
Paraneoplastic hypoglycemia, 2:111
Paraneoplastic necrotizing myopathy,
1:224
Paraneoplastic syndromes, cutaneous,
1:691-693
Paranesoplastic pemphigus, 1:603
Parapoxviral infections, 2:139-142
bovine papular stomatitis virus (BPSV),
1:616, 1:618-619, 2:39-40, 2:139-140,
2:140f
Parapoxviral infections (Continued)
infectious bovine rhinotracheitis (IBR),
1:425, 2:140-142, 2:525f, 2:537-539,
2:538f
parapox virus of red deer, 1:616, 1:619
Paraquat, 2:519
Parasagittal fractures, 1:36
Parascaris equorum, 2:219, 2:574
Parasite hypersensitivity, 1:599-600
Parasite-induced osteoporosis, 1:67f
Parasitic arthropods, 1:666-684
Parasitic endocarditis, 3:32
Parasitic gastritis, 2:54
Parasitic infections, 1:234-240
abortion and, 3:421-423
central nervous system and, 1:386-391
conjunctivitis, 1:425-426
cysticercosis, 1:239-240, 1:239f
ear
external, 1:505-507
middle, 1:498
endophthalmitis, 1:451-452
eosinophilic myositis, 1:236-237,
1:236f-237f
erythrocyte, 3:114
esophagus, 2:34-35, 2:35f
forestomachs, 2:43, 2:43f
gastric, 2:209-210, 2:209f
gastritis, 2:54
hepatozoonosis, 1:240
leishmaniasis, 1:240
liver pigments and, 2:272
lymphangitis, 3:98
lymph nodes, 3:212
myocarditis and, 3:43-44, 3:44.e1f
oral cavity, 2:19
pancreas, 2:365
peritoneum, 2:255
respiratory system and, 2:536-537,
2:554-557, 2:564-567, 2:574,
2:585-587, 2:590, 2:590f, 2:536.e2f
sarcocystosis, 1:234-236, 1:235f
tendons, 1:247-248
thrombophlebitis, 3:91-94
Toxoplasma and Neospora myositis, 1:237
trachea, 2:483
trichinellosis, 1:237-238
Parasitic lymphangitis, 3:98
Parasitic thrombophlebitis, 3:91-94
Parasitology, 1:11
Parastrongylus cantonensis, 1:389, 1:390f
Parathyroid glands, 3:292-295, 3:292f
carcinomas, 3:304, 3:304f
diseases, 3:297-302
Parathyroid hormone (PTH), 1:18, 1:25t,
1:61-62, 2:385, 3:272, 3:292-295,
3:292f
biological action, 3:294-295
biosynthesis and secretion, 3:292-294
-related protein, 3:274, 3:305-306
Paratuberculosis. See Johne’s disease
Parbendazole, 1:91
Parelaphostrongylus tenuis, 1:390, 1:689-690
Parenchymal cells, 2:261-262
Parietal cells, 2:45, 2:51
atrophy, 2:47
atrophy of parietal cell mass, 2:47
mass, atrophy of, 2:47
presumably loss of, 2:47
Parietal pericardium, 3:3
Parosteal osteosarcoma
cats, 1:115, 1:115f
dogs, 1:115

Pars distalis, 3:276, 3:277f
adenoma, 3:287-288, 3:288f
Pars intermedia, 3:276
adenomas, 3:282-285, 3:283f-284f
Pars nervosa, 3:277
Parson Russell Terrier dogs, 1:325
Pars tuberalis, 3:276
Particle deposition in lungs, 2:471
Parturient paresis, 3:299
Parvoviral enteritis, 2:153-158
cats, 2:153, 2:155f
cattle, 2:44, 2:157-158, 3:429-430
dogs, 2:156-157, 2:156f-157f
Parvoviral infections, 1:628
myocardial necrosis and, 3:34
myocarditis and, 3:42, 3:43f
in pregnant uterus, 3:429-430
thymic atrophy and, 3:145
Passive congestion
of liver, 2:297-298, 2:298f, 2:298.e1f
of spleen, 3:169
Pastern leukocytoclastic vasculitis, 1:612
Pasteurellacae, 2:543, 2:562
Pasteurella multocida, 1:230, 2:543-544,
2:562
Patellar luxations, 1:137, 1:137f
dogs, 1:137, 1:137f
horses, 1:137
Patent ductus arteriosus (PDA), 3:17-18,
3:18f-19f
Pathologic fracture, 1:33-36
Pathologists, competence of, 1:14-15
Patnaik system, 1:731
Pattern recognition, 1:3-4, 1:3f
molecules, 2:63
Pautrier’s microabscess, 1:523, 1:523f
Pax genes, 1:21-22
PCR-based diagnosis, 2:435
PCR for antigen receptor rearrangements
(PARR) assay, 3:215, 3:216f
Pearsonema mucronata, 2:443
Pediculosis, 1:671
Peer review, 1:14
Pekingese dogs
degenerative diseases of cartilaginous
joints, 1:143-144
hyperestrogenism, 1:589
Pelger-Huët anomaly (PHA), 3:110
Peliosis hepatis/telangiectasis, 2:299-300,
2:299f-300f, 2:299.e1f
Pelodera dermatitis, 1:689, 1:689f
Pelvic flexure, infarction of, 2:85f
Pelvic hernia, 2:79
Pelvis deformities, 1:56-57
Pembroke Welsh Corgi dogs. See Corgi dogs
Pemphigus complex, 1:518, 1:600-603
Pemphigus erythematosus (PE), 1:602
Pemphigus foliaceus, 1:601, 1:601f
Pemphigus vegetans, 1:602
Pemphigus vulgaris (PV), 1:602, 1:602f,
2:14
Pendrin, 3:311-312
Penis and prepuce, 3:505-510, 3:506f
inflammation, 3:506-508
neoplasms, 3:508-510
Pentachlorophenol (PCP), 1:572
Pentastomiasis, 2:585
Pepsin, 2:45
Peptic ulcers, 2:55
chronic, 2:56
Peptides, immunoreactive, 3:285, 3:285f
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Perendale sheep, 1:324
Perforating dermatitis, 1:699, 1:699f
Perforation, 2:48
corneal, 1:437, 1:437f
esophageal, 2:32-33
rectal, 2:247
Perianal glands, 1:517
adenomas, 1:718, 1:718f
carcinomas, 1:718
epitheliomas, 1:718
Periapical abscess, 2:11
Periarteriolar lymphoid sheaths (PALS),
3:159-160
Periarteriolar macrophage sheath (PAMS),
3:160-161
Periarteritis nodosa, 3:71
Periarticular fibroma, 1:161
Periarticular histiocytic sarcoma, 3:252f,
3:250.e1f
Peribronchiolar metaplasia, 2:495,
2:495.e2f
Pericardial sac, 3:2-3
Pericarditis, 3:25-27
constrictive, 3:26, 3:27f
fibrinous, 3:25-26, 3:26f
purulent, 3:26
traumatic, 2:39
Pericardium, 3:5
congenital absence of, 3:22
disease, 3:24-27
noninflammatory lesions, 3:24-25,
3:24f
hemo-, 3:25, 3:25f
hydro-, 3:24-25, 3:24f
serous atrophy of fat of, 3:25, 3:25f
Perichondrial ring of LaCroix, 1:23
Periciliary liquid layer, 2:471-472
Perifolliculitis, 1:528
demodectic mange and, 1:680
Perilla ketone, 2:519
Perimetritis, 3:390
Perineal hernias, 2:80
Perinephric abscess, 2:439
Perinephric pseudocyst, 2:396.e2f
Perineurioma, 1:405
Periodic acid-Schiff (PAS) positive, amylase-
resistant inclusions, 1:204
Periodic acid-Schiff stain, 2:383
Periodic paralyses, 1:202
Periodontal bone expansion, 1:101f
Periodontal disease, 2:11-12, 2:12f
Periodontal ligament, 2:5-6
Periodontal ligament origin
fibromatous epulides of, 2:24-25
fibromatous epulis of, 2:24
Periodontal osteomyelitis, 1:101f
Periodontium, 2:6
infectious and inflammatory diseases of,
2:9-12
Perioophoritis, 3:371
Periorchitis, 3:473-474, 3:474f
Periosteal damage, 1:33
Periosteal fibrosarcomas, 1:121
Periosteum, 1:24, 1:24f
Periostitis, 1:97
Peripheral axonopathies, 1:334-336
Peripheral chromatolysis, 1:253
Peripheral circulatory failure, 3:10
Peripheral giant cell granuloma, 2:21
Peripheral nerve sheath tumors, 1:404-405,
1:406f
Index 555
Peripheral nervous system tumors, 1:404-406
Peripheral neuroblastic tumors, 1:405-406
Peripheral T-cell lymphomas, 3:229, 3:229f
Peripheral vestibular disease, 1:494
Peripheral vestibular function, 1:490
Periportal interface hepatitis, 2:301-302,
2:302f, 2:304f
Periportal liver necrosis, 2:283
Perirenal edema, 2:427f
Peritoneal milky spots, 2:244
Peritoneopericardial diaphragmatic hernia,
2:245, 3:22
Peritoneum and retroperitoneum, 2:244-257
abnormal contents in, 2:247-249
anomalies, 2:245
ascites, 2:248-249
cysts, 2:256
general considerations, 2:244-245
neoplasia, 2:256-257, 2:256f
parasitic diseases, 2:255
peritonitis, 2:249-255
reactions to injury, 2:245-246
Peritonitis, 2:249-255
cats, 2:253-255, 2:254f, 3:90, 3:90f
-associated uveitis, 1:453, 1:453f
lymph nodes and, 3:206f
spleen and, 3:184f
cattle, 2:251-252, 2:251f
consequences of, 2:250-251
dogs, 2:252-253
horses, 2:251
pigs, 2:252, 2:252f
sheep and goats, 2:252
Peritubular capillaries, 2:398
Perivascular cuffing, 1:263, 1:264f, 1:366
Perivascular dermatitis, 1:525, 1:525f
Perivascular pyogranulomatous nephritis,
2:432f
Perivascular Virchow-Robin space, 1:263
Perivascular wall tumor (PWTs), 1:723,
1:724f
Perivasculitis, cerebrospinal, 1:298-299,
1:298f
Periventricular leukomalacia of neonates,
1:274
Peromelia, 1:56
Perosomus elumbus, 1:57, 1:277-278
Persian cats
Chediak-Higashi syndrome, 3:259
epidermolysis bullosa, 1:536
feline ceruminous cystomatosis, 1:507
feline corneal sequestrum, 1:434, 1:434f
Persistence of the right aortic arch, 3:23-24,
3:23f
Persistent atrial standstill, 3:51
Persistent hyaloid artery, 1:417
Persistent hyperplastic primary vitreous,
1:417-418, 1:418f
Persistently infected (PI) calf, 2:122
Persistent Meckel’s diverticulum, 2:74
Persistent posterior perilenticular vascular
tunic, 1:417
Persistent pupillary membrane, 1:415,
1:416f
Persistent vitelline artery, 2:245
Persistent vitelline duct, 2:245
Peruvian Paso horses, osteopetrosis in, 1:52
Peste des petits ruminants virus (PPRV),
2:115, 2:130-131, 2:131f, 2:557
Pestiviruses, 1:281-283, 2:122-128
Petechiae, 2:397
556 Index

Peundculated lipoma, 2:256, 2:257f Pick bodies, 1:255 Plant toxicities (Continued)
Peyer’s patches, 2:63, 2:124-126 Picornaviridae, 2:117, 3:43 myocardial necrosis and, 3:34-41, 3:35f
PFK. See Phosphofructokinase (PFK) Piebaldism, 1:555 parathyroid suppression associated with,
deficiency Piecemeal liver necrosis, 2:285 3:301-302, 3:301f
Phacoclastic uveitis, 1:457-459, 1:458f-459f Piedra, 1:660-661 Romulea, 1:322
Phacolytic uveitis, 1:457 Pigeon fever, 1:230 sheep, 1:90-91
Phaeohyphomycosis, 1:654-655, 1:655f Pigeonpox virus, 1:616 Plaque, 2:9
Phalaris poisoning, 1:292-293, 1:293f Pigmentary incontinence, 1:523 Plaques, 1:524
myocardial necrosis and, 3:36 Pigmentation amniotic, 3:397
Pharyngeal (branchial) cysts, 2:29 buccal cavity, 2:12 canine pigmented, 1:710-711, 1:711f
Pharyngeal dysphagia, 2:33 disorders, 1:554-558 Plasma cells
Pharynx, 2:480-481 acquired hyperpigmentation, gingivitis-pharyngitis, 2:16
cysts, 2:29 1:554 hemostasis disorders, 3:255-268
dysphagia, 2:33 acquired hypopigmentation, 1:557 hyperplasia, 3:201
lymphoid hyperplasia, 2:480.e3f acromelanism, 1:555 myeloma
neuroendocrine carcinoma of, 2:27 canine acanthosis nigricans, 1:555 cats, 1:123
Phenobarbital, 2:329 copper deficiency, 1:558, 1:558f-559f dogs, 1:123, 1:123f
Phenothiazine photosensitization, 1:579 focal macular melanosis, 1:554 horses, 1:123
Phenotype, gonad, 3:360 hyper-, 1:554-555 in nodular and diffuse dermatitis, 1:527
Phenotypic sexual development, 3:360 hypo-, 1:555-558 pododermatitis, 1:613-614
Phenytoin, 2:329 leukotrichia, 1:557-558 tumor, 1:403
Pheochromocytoma, 3:89, 3:89f, 3:349-351, drug-induced thyroid, 3:325 Plasmacytic/lymphocytic synovitis, 1:159
3:350f-352f liver, 2:270-272, 2:271f Plasmacytomas, 2:27-28, 3:226-228, 3:228f,
Phlebectasia, 3:89 tooth, 2:7 3:226.e1f
Phlebitis, 3:90, 3:90f Pigment granuloma, 2:274-275, 2:275f laryngeal, 2:482
Phlebothrombosis, 3:89-91 Pigments storage, 1:254 Plasma-mediated fibrinolysis, 3:266-267
Phomopsin, 2:334-335, 2:335f Pilar cysts, 1:704 Plasma membrane, BMZ, 1:513-514
Phosphate-buffered 10% formalin, 1:8 Pilomatricomas, 1:716-717, 1:716f Plasmacytomas, 1:735, 1:735f
Phosphatonins, 1:63 Pilus adhesins, 2:168 Platelet-activating factor (PAF), 3:256
Phosphofructokinase (PFK) deficiency, Pimelea spp., 2:519-520 Platelet-derived growth factor (PDGF),
1:186-187, 1:290, 3:126 Pineal tumors, 1:403 3:257, 3:257f
English Springer Spaniels and American Pinnae, 1:501 Platelet Function Analyzer (PFA), 3:257-258
Cocker Spaniels, 1:204-205 cropped or notched, 1:502 Platelet integrin, αIIbβIII (or GPIIb/IIIa),
Phospholipidosis, 2:278 dermatologic diseases, 1:503-504 3:256
alveolar, 2:517, 2:517.e1f tumor-like growths and neoplasia, Platelets
Phosphorus 1:504-505 adhesion, 3:256
calcium homeostasis and, 1:61-63 Pinnal necrosis in pigs, 1:503, 1:503.e1f aggregation, 3:256-257
deficiency, 1:61, 2:8 Pinworms, 1:688 test, 3:257-258
odontodystrophy and, 2:8 Pit caries, 2:10 disorders, 3:257-260
osteoporosis and, 1:66 Pithomyces chartarum, 2:335 acquired, 3:260
rickets and osteomalacia and, Pituicytoma, 3:291, 3:291f intrinsic, 3:259-260
1:68-69 Pituitary gland, 3:276-291 thrombocytopenia, 3:258
liver toxicity, 2:332-333 blood supply to, 3:278 von Willebrand disease, 3:258-259
Phosphotungstic acid hematoxylin (PTAH), chromophobe carcinoma, 3:288 function evaluation, 3:257-258
1:241 cysts, 3:279-281, 3:280f hyperreactivity, 3:260
Photoaggravated dermatoses, 1:580 development, structure, and function, plug formation, 3:255-257
Photoallergy, 1:575 3:276-278, 3:276f Platynosomum fastosum, 2:322
Photography, 1:12 diseases, 3:278-281, 3:279f Pleomorphic adenomas, 2:30
Photomicroscopy, 1:12 neoplasia, 3:281-289, 3:281f Pleomorphic rhabdomyosarcoma, 1:241-243,
Photosensitization, 1:575, 2:294, 2:294f tumors 1:244f
dermatitis, 1:577-580, 1:578f granular cell, 3:289 Pleura, 2:520-523
hepatogenous, 1:579-580 metastatic to, 3:288-289, 3:289f neoplasms, 2:523
phenothiazine, 1:579 PKD1 gene defect, 2:395-396 mesothelioma, 2:523, 2:523.e2f
primary, 1:578-579 Placenta noninflammatory pleural effusions, 2:521
resulting from defective pigment synthesis, adventitial, 3:396-397 pleural effusions, 2:520
1:579 mineralization, 3:397 noninflammatory, 2:521
Phthisis bulbi, 1:448 subinvolution of placental sites, 3:441, pleuritis, 2:521-523, 2:522f, 2:521.e3f,
Phycomycosis, intestinal, 2:201 3:441f 2:521.e1f
Phylloerythrin, 1:579-580 Placentitis, 3:415, 3:415f, 3:418f pneumothorax, 2:487, 2:487f, 2:521,
Physaloptera spp., 2:54, 2:211 mycotic, 3:419, 3:419f 2:521.e3f
Physeal dysplasia in cats, 1:46, 1:46f nocardioform, 3:417 Pleuritis, 2:521-523, 2:522f, 2:521.e3f
Physicochemical diseases of skin, 1:558-575 Plant toxicities, 1:90-91, 1:219-220 suppurative, 2:522, 2:521.e1f
chemical injury, 1:566-575 avocado, 3:38 Pleuropneumonia, 2:571-572
physical injury, 1:559-566 coyotillo, 1:326 Plexiform arteriopathy, 2:492, 2:492f
Physiologic steatosis, 2:275 cyanide poisoning, 1:305-306 Pneumatosis cystoides intestinalis, 2:87
Physis, 1:22, 1:22f cycad, 1:322, 1:323f Pneumoconiosis, 2:518
bacterial osteomyelitis, 1:98-99, 1:99f fluoracetate, 3:38 Pneumocystis carinii, 2:536f, 3:140
hormonal regulation of, 1:24, 1:25t gousiekte, 3:38 respiratory system and, 2:535-536,
osteoporosis, 1:64, 1:65f hepatogenous photosensitization and, 2:536f
rickets, 1:70-71, 1:71f 1:580 Pneumonia
Physocephalus spp., 2:54 horses, 1:91 aspiration, 2:508-509, 2:508f-509f,
Phytobezoars, 2:38, 2:50, 2:75-76 liver and, 2:329-344 2:508.e1f
Phytophoto-contact dermatitis, 1:578-579 mesquite, 1:326 meconium, 2:516, 2:516.e1f
 Index 557

Pneumonia (Continued) Polycystic kidney disease (PKD), 2:395-396, Porcine reproductive and respiratory
atypical, 2:509 2:395f syndrome (PRRS), 2:523-526, 2:525f,
bacterial, 2:542-546, 2:545f, 2:562-563, congenital, 2:396 3:424
2:562f mutation of, 2:394 Porcine reproductive and respiratory syndrome
equine, 2:571-572 Polycystic liver disease, 2:265 virus (PRRSV), 1:383
bronchointerstitial, 2:511-512, Polycystic ovarian disease, 3:374-375, Porcine respiratory coronavirus (PRCoV),
2:514.e2f 3:375f 2:147, 2:529
caseonecrotic broncho-, 2:553f Polydactyly, 1:55, 1:55f Porcine salmonellosis, 2:170-172, 2:170f-172f
dogs, 2:577 Polymelia, 1:55, 1:55f Porcine stress syndrome (PSS), 1:209-210,
embolic, 2:520, 2:520.e2f Polymerase chain reaction (PCR), 1:11 3:39
eosinophilic interstitial, 2:513.e1 Polymicrogyria, 1:268 Porcine ulcerative dermatitis syndrome,
granulomatous interstitial, 2:513 Polymyositis 1:698
hypersensitivity, 2:512-513 cats, 1:228-229 Porencephaly, 1:272-274, 1:272f, 1:285f
interstitial, 2:509 dogs, 1:227-228, 1:228f orbiviruses and, 1:281
lipid, 2:516-518, 2:516.e1f Polyodontia, 2:6 Porphyromonas gingivalis, 2:11
ovine progressive, 2:558-560, 2:559f, Polypeptide hormones, 3:270-271, 3:270f Porphyromonas spp., 2:9, 2:11
2:558.e1f Polyploidy, liver, 2:270 Portal hypertension, 2:297
proliferative and necrotizing, 2:529, Polypoid intestinal adenocarcinomas, 2:102 Portal tract, liver, 2:261, 2:261f
2:529.e1f Polyps Portal veins
Pneumonyssoides caninum, 2:585 endometrial, 3:385, 3:386f aneurysms, 2:266
Pneumoperitoneum, 2:247 inflammatory aural, 1:498-499 hypoplasia, 2:267-268
Pneumothorax, 2:487, 2:487f, 2:521, nasal, 2:477-478, 2:477f, 2:579 injury, 2:296-297
2:521.e3f Pomeranian dogs thrombosis, 2:297f
Poisoning alopecia X, 1:589-590 Portosystemic shunting, 2:298-299, 3:127
arsenic, 1:327-328, 1:570 myxomatous valvular degeneration, Portosystemic vascular anomalies, 2:267,
carbon monoxide, 1:306 3:27 2:267f
copper, 2:343 Pompe’s disease, 1:208, 3:50 Portuguese Water dogs
corynetoxin, 1:309 Poodle dogs dilated cardiomyopathy, 3:48
coyotillo, 1:326 amelogenesis imperfecta, 2:7 follicular dysplasia, 1:540-541
cyanide, 1:305-306 color dilution alopecia, 1:539-540 Portulacca oleracea, 2:425-426
cycad, 1:322, 1:323f dilated cardiomyopathy, 3:48 Postanesthetic myopathy in horses, 1:213
fluoracetate, 1:306 hyperadrenocorticism, 1:588 Posterior staphyloma, 1:413
gangrenous ergotism and fescue toxicosis, hypothyroidism, 1:587 Posterior tunica vasculosa lentis, 1:418
1:572-573, 1:573f myxomatous valvular degeneration, Posterior uveitis, 1:446
hexachlorophene, 1:344-345, 1:345f 3:27 Postinfectious encephalomyelitis, 1:395-396
lead, 1:86, 1:87f, 1:316-317 osteogenesis imperfecta in, 1:50 Postmortem examination. See Gross and
mercury, 1:570 rabies vaccine-induced vasculitis and histologic examinations
mimosine, 1:572 alopecia, 1:612 Postmortem rupture of viscus, 2:247
myocardial necrosis and, 3:35, 3:37-38 sebaceous adenitis, 1:551 Postnecrotic scarring, 2:284, 2:289,
nitrate/nitrite, 1:306 Poorly differentiated chondrosarcoma, 2:289f
organochlorine/organobromine, 1:119-120, 1:120f Postoperative conjunctival inclusion cysts,
1:571-572 Poorly differentiated osteosarcoma, 1:113, 1:478
organomercurial, 1:320-321, 1:321f 1:113f Postpartum uterus, lesions of, 3:440-441
organophosphate, 1:326 Poorly differentiated sarcomas, 1:244 Postparturient vascular lesions, 3:370
Phalaris, 1:292-293, 1:293f Porcine adenovirus, 2:144-145, 2:144f Postrenal azotemia, 2:384-385
quassinoid, 1:574-575 Porcine circovirus 2 (PCV-2), 2:116, 2:412- Postvaccinal canine distemper encephalitis,
salt, 1:314-315 413, 2:527-529, 3:210-212, 3:210f-211f, 1:384
selenium, 1:570-571, 1:571f 3:440, 3:440f Postweaning colibacillosis, 2:100, 2:165,
solanum, 1:321-322 encephalopathies, 1:382-383 2:165f
thallium, 1:568-569, 1:569f Porcine deltacoronavirus (PDCoV), 2:147-148 Postweaning diarrhea, 2:115
trachyandra, 1:292 Porcine dermatitis and nephropathy Postweaning multisystemic wasting syndrome
trichothecene toxicoses, 1:573-574 syndrome (PDNS), 2:412f, 3:210-212, (PMWS), 2:527-529, 2:528f, 3:210-212,
vetch, 1:574 3:210f 3:210f-212f, 3:440, 3:440f
vitamin D, 3:61 Porcine dermatoses, 1:698-699 Potassium depletion, chronic, 2:430
yellow-wood tree, 2:428 Porcine ear necrosis syndrome (PENS), Potomac horse fever, 2:99, 2:200-201
Polioencephalomalacia, 1:297, 1:297f, 1:503, 1:645, 1:503.e1f Poultry mite, 1:683
1:310f-311f, 2:43 Porcine encephalitis associated with PRRSV Pourfour du Petit syndrome, 1:494-495
ruminants, 1:309-312, 1:310f-311f infection, 1:383 Poxviral infections, 1:616-625
Poliomalacia, 1:307-308 Porcine epidemic diarrhea virus (PEDV), sheep and goats, 2:557
Poll evil, 1:155-156 2:113, 2:147 trachea and, 2:483
Polypay sheep, osteopetrosis in, 1:52, Porcine erysipelas, 1:149 PP cells, endocrine pancreas, 2:368
1:52f Porcine hemagglutinating encephalomyelitis Precipitation of pentobarbital salts, 1:8f
Polyalveolar lobe, 2:485 virus (HEV), 1:372 Precursor lymphoblastic leukemia/
Polyarteritis nodosa, 3:71 Porcine hypomyelinogenesis, 1:338 lymphoma, 3:219, 3:220f
Polyarthritis, 1:148 Porcine intestinal spirochetosis, 2:182 Pregnancy. See Abortion; Gestation
erosive, 1:157-158 Porcine juvenile pustular psoriasiform Pregnancy toxemia in sheep, 2:419-421
feline chronic progressive, 1:158 dermatitis, 1:698, 1:698f Pre-iridal fibrovascular membrane, 1:447,
idiopathic, 1:158 Porcine lymphomas, 3:241-243 1:448f
immune-mediated, 1:157-159 Porcine parvovirus (PPV), 3:429 Prekallikrein deficiency, 3:263
non-erosive, 1:158-159 Porcine proliferative enteropathy, 2:179, Preparation artifacts in histologic sections,
-polymyositis syndrome, 1:158 2:179f 1:29, 1:29f

Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510

558 Index
Prepubic hernias, 2:80
Preputial diverticulitis, 3:507-508, 3:507f
Prerenal azotemia, 2:384
Presa Canario dogs, dilated cardiomyopathy
in, 3:48
Presbycusis, 1:493
Preservation, sample, 1:8
Primary abomasal impaction in cattle, 2:50
Primary ciliary dyskinesia, 2:504
Primary cleft palate, 2:3
Primary endocardial fibroelastosis, 3:22
Primary epithelial neoplasms of liver,
2:345-346
Primary gastric dilation, 2:48
Primary glaucoma, 1:462-463, 1:463f
Primary hairs, 1:515-516
Primary hyperaldosteronism, 1:225
Primary hyperfunction of endocrine gland,
3:272
Primary hyperparathyroidism, 1:74,
3:304-305
Primary hypofunction of endocrine gland,
3:272-273
Primary idiopathic hyperlipidemia,
2:277-278
Primary irritant contact dermatitis, 1:566-
568, 1:567f
Primary ossification center, 1:22
Primary parathyroid hyperplasia, 3:301
Primary photosensitization, 1:578-579
Primary portal vein hypoplasia (PVH),
2:267-268
Primary spongiosa, 1:23, 1:23f
Primary synovial chondromatosis, 1:162,
1:162f
Primary thyroid hypoplasia, 3:314
Primary tympany of forestomachs, 2:36,
2:37f
Primary vascular disease, 2:398
Primidone, 2:329
Primordial germ cells (PGC), 3:469
Principal bronchus, 2:467
Prion diseases, 1:347-350
Prion proteins, 2:20
Probiotics, 2:65
Procoagulant activities, 3:55
Proficiency testing of pathologists, 1:14
Profilaggrin, 1:513
Progesterone, 3:383
Prognathism, 2:3
Progressive ataxia, 1:341f
of Charolais cattle, 1:341, 1:341f
Progressive atrophic rhinitis (PAR),
2:533
Progressive axonopathy of Boxer dogs,
1:329-330
Progressive ethmoid hematomas (PEH),
2:477
Progressive motor neuron disease, 1:255,
1:255f, 1:330-332, 1:331f-332f
Progressive neuronopathy of Cairn Terrier,
1:332-333
Progressive renal mineralization, 2:441
Proinflammatory cytokines, 2:72
Prolactin, 3:276-277
Prolapse, female genital organ, 3:381
Proliferative and necrotizing pneumonia,
2:529, 2:529.e1f
Proliferative arthritis, 1:147-148
Proliferative glomerulonephropathy, 2:403f,
2:401.e3f
Proliferative hemorrhagic enteropathy,
2:179-180, 2:180f
Proliferative optic neuropathy, 1:476
Proliferative pododermatitis, 1:642-643
Proliferative zone, growth plate, 1:22-23
Prolonged gestation, 3:397-398
Prolonged renal ischemia, 2:422-423
Pro-opiomelanocortin (POMC), 3:285,
3:285f
Prosencephalic hypoplasia, 1:266-267,
1:266f
Prostaglandins, 2:46
Prostate gland, 3:500-504, 3:500f
disorders of sexual development, 3:500-
501, 3:500f
hyperplasia and metaplasia, 3:502-503,
3:503f
inflammation, 3:501-502, 3:501f
neoplasms, 3:503-504, 3:504f
Prostatitis, 3:501, 3:502f
Protein-calorie deficiency, 1:581
Protein core, epidermal, 1:513
Protein C pathway, 3:265-266
Protein-energy malnutrition, 2:69
Protein hydrolysis, 2:45
Protein-losing gastroenteropathy, 2:72
Protein-losing nephropathy (PLN), 2:418
Protein-losing syndromes, 2:89-97
Protein maldigestion, 2:70
Proteinuria, 2:401
Proteoglycans, 1:19-20, 1:514
deficiency, 1:545-546
Protistant infections, 2:227-244
Protoplasmic astrocytes, 1:260-261
Protostrongylus rufescens, 2:565-566, 2:565t
Prototheca, 1:451, 1:665, 1:666f
enterocolitis, 2:203-204
Prototheca wickerhamii, 2:476
Prototheca zopfii, 2:433, 2:476
Protozoal infections
abortion and, 3:399b, 3:420-424, 3:420f
arthritis, 1:155
diseases of skin, 1:661-665
endophthalmitis, 1:451
liver and, 2:324
Protrusion of nictitans gland, 1:424
Proud flesh, 1:560-561
Proximal axonopathy, 1:257, 1:257f
Proximal esophagus, segmental aplasia of,
2:31
Psammoma bodies, 1:304
Psammomatous meningioma, 1:397, 1:397f
Pseudallescheria boydii, 2:476
Pseudamphistomum truncatum, 2:324
Pseudoachondroplastic dysplasia, 1:44
Pseudoaneurysms, 2:398
Pseudoanodontia, 2:6
Pseudoarthrosis, 1:36
Pseudo-blackleg, 1:233
Pseudocowpox virus, 1:616, 1:618
Pseudocysts, pancreatic, 2:361
Pseudoepitheliomatous hyperplasia, 3:151
Pseudoglandular stage of lung growth, 2:484
Pseudohepatorenal syndromes, 2:430
Pseudomembranous stomatitis, 2:18
Pseudomembranous rhinitis, 2:474-475
Pseudomonas aeruginosa, 3:30-31
Pseudomonas spp., 2:459
Pseudomycetoma, 1:653
Pseudo-obstruction, 2:77
Pseudo-oligodontia, 2:6
Pseudoplacentational endometrial
hyperplasia, 3:383, 3:384f
Pseudopolyodontia, 2:6
Pseudorabies, 1:370-372, 1:371f, 2:530
Pseudotuberculosis, 3:209-210, 3:209f
Pseudotumors, muscle, 1:246, 1:246f
Psorergatic mange, 1:678
Psoriasiform dermatitis of goats, 1:698
Psoroptes spp., 1:505-506
Psoroptic mange, 1:675-676
Psychogenic alopecia, 1:561
Psychogenic injury, 1:561-562, 1:561f
Pteridium spp., 2:173-180
Ptyalism, 2:28-29
Puerperal tetany, 3:299
Pug dogs
canine atopic dermatitis, 1:591
canine necrotizing meningoencephalitis,
1:392-393
hereditary stenosis of common bundle,
3:51
motor neuron disease, 1:331
pigmented plaques, 1:710-711, 1:711f
Pulmonary adenocarcinoma, 2:447
Pulmonary arterial hypertension (PAH),
2:492-494, 2:492f, 3:66-67, 2:492.e1f
Pulmonary artery, 2:467-468, 2:468f
transposition with aorta, 3:22.e1f
Pulmonary aspergillosis, 2:573, 2:573f
Pulmonary blastomas, 2:498
Pulmonary carcinomas/adenocarcinomas,
1:736, 2:495-500, 2:497f, 2:495.e2f,
2:497.e1f
classification, 2:496t
Pulmonary edema, 2:487-489, 2:488b,
2:489.e1f
Pulmonary emphysema, 2:486-487, 2:487f
Pulmonary hamartoma, 2:485
Pulmonary hemorrhage, 2:490-492, 2:490.e1f
Pulmonary hyalinosis, 2:517
Pulmonary hypertension, 2:492-494, 3:60
canine pulmonary veno-occlusive disease
(PVOD), 2:493, 2:493f, 2:493.e1f
causes, 2:492b
pulmonary arterial hypertension (PAH),
2:492-494, 2:492f, 3:66-67
Pulmonary hypoplasia, 2:484, 2:484.e3f
Pulmonary immune responses, 2:472
Pulmonary infarcts, 2:490.e1f
Pulmonary intravascular macrophages
(PIMs), 2:471, 2:471.e1f
Pulmonary Langerhans cell histiocytosis,
2:499, 3:246-247, 3:247f, 3:246.e1f
Pulmonary macrophages, 2:470
Pulmonary mineralization, 2:494-495,
2:494f
Pulmonary neoplasia, 2:495-500, 2:495b
Pulmonary surfactant, 2:470
Pulmonary thromboembolism, 2:489, 2:489b,
2:489.e1f
Pulmonary vasculitis, 2:494, 2:494.e2f
Pulmonary veins, 2:467-468, 2:468f
Pulmonary venous hypertension, 2:492-493
Pulmonic stenosis, 3:19, 3:19f
Pulmonic valves, 3:2-3
Pulpitis, 2:11
Pure red cell aplasia, 3:127-128, 3:128f
Pure silica stones, 2:455
Purified protein derivatives (PPD), 2:548
Purkinje fibers, 3:2
Purpura hemorrhagica, 1:229, 1:229f
Purulent (suppurative) arthritis, 1:147-148,
1:148f
Purulent bronchitis, 2:501
Purulent pericarditis, 3:26
Purulent splenitis, 3:183-184
Purulent streptococcal meningitis, 1:357f
 Index 559

Pustules, 1:524 Quarter Horses (Continued) Regeneration

infectious pustular vulvovaginitis of cattle, myotonic dystrophy-like disease, liver, 2:286-287, 2:290f
3:443-445 1:202-203 muscle, 1:182-183, 1:183f-184f
sterile eosinophilic pustulosis, 1:696 Quassinoid toxicosis, 1:574-575 pancreatic cells, 2:355
Pyelonephritis, 2:382, 2:431, 2:439-441 Quercus spp., 2:427-428 Reinfection syndrome, Dictyocaulus viviparus,
acute, 2:440-441, 2:440f 2:554-556
cattle, 2:441 R Remodeling, 1:26-27
chronic, 2:439, 2:440f Rabbit fibroma virus, 1:616 markers of, 1:27
dogs and cats, 2:440 Rabbit oral papillomavirus, 1:712 Renal adenoma, 2:444f
microabscess, 2:440.e1f Rabies, 1:367-370, 1:369f Renal agenesis, 2:392
swine, 2:440-441 vaccine, 1:560 Renal amyloidosis, 2:414f
thyroidization, 2:440f -induced vasculitis and alopecia, Renal and perirenal lymphosarcoma, 2:447f
urinary tract defenses, 2:439 1:612-613, 1:613f Renal arterioles, lipid embolization of,
vesicoureteral reflux, 2:439 Racing sled dogs, exertional myopathies in, 2:418
virulence of bacteria, 2:439 1:223 Renal biopsies, 2:383, 2:412
Pyemotes tritici, 1:683 Radiant heat dermatitis, 1:566 Renal blood flow, 2:377
Pyencephaly, 1:361, 1:361f Radiation Renal cell carcinomas (RCC), 2:444-446,
Pyloric mucosa, 2:45 deafness and, 1:493 2:444f-445f, 2:445.e1f
Pyloric smooth muscle, hypertrophy of, injury, 1:566 oncocytic form, 2:445-446
2:48 thyroid carcinogenesis and, 3:332 Renal collecting system, 2:378
Pyloric stenosis, 2:48 Radiculomyelopathy, degenerative, 1:330 Renal cortex
chronic hypertrophic pyloric gastropathy, Radiography hemorrhages, 2:397
2:48 aneurysmal bone cysts, 1:126 olive-green coloration, 2:429
Pylorogastric intussusception, 2:50 bone tumors, 1:108 Renal cortical necrosis, 2:398-399
Pyodermas, 1:629 osteosarcoma, 1:111 Renal cortical petechiae, 2:397f
deep bacterial, 1:634-637, 1:635f Ragged fibers, 1:185 Renal crest, 2:378
mucocutaneous, 1:630 Raillietia spp., 1:505-506 necrosis, 2:400f, 2:399.e2f
superficial bacterial, 1:629-634, 1:630f Rangelia vitalii, 3:125, 3:125f Renal cystadenocarcinomas, 2:446, 2:446f
Pyogenic granuloma, 2:21 RANKL, 1:18, 1:26 histopathology of, 2:446.e1f
Pyogenic infections and central nervous Ranula, 2:29 Renal cysts, 2:394-397
system, 1:353-365 Rapeseed oil, 3:36 acquired cysts, 2:396
Pyogranulomas, 2:18 Rapidly growing mycobacteria (RGM), autosomal dominant, 2:395-396
sterile, 1:699-702 1:640, 1:640f autosomal recessive PKD (ARPKD),
Pyogranulomatous meningoencephalomyelitis, Rappaport classification, 3:215 2:396
1:362, 1:362f Rathke’s pouch, 3:280-281 glomerulocystic disease, 2:396
Pyometra, 3:390-393, 3:390f-391f Rats, plant toxicitiies in, 1:91 mechanisms, 2:394
cows, 3:392-393 “Rat-tail syndrome”, 1:539 simple renal cysts, 2:394-395
mare, 3:393 Rat Terrier dogs Renal disease, 2:384-388. See also Renal
Pyonephrosis, 2:439 canine hypomyelinogenesis, 1:338 failure; specific conditions
Pyosalpinx, 3:380 canine X-linked muscular dystrophy, anemia, 2:385
Pyothorax, 2:521.e1f 1:192 chronic, 2:16-17
Pyotraumatic dermatitis, 1:560 Reactive astrocytes, 1:261-262, 1:261f anemia and, 3:127
Pyrenean Mountain dogs, motor neuropathy Reactive astrogliosis, 1:262 hyperparathyroidism secondary to,
in, 1:335 Reactive histiocytosis, 3:247-250, 3:248f, 3:300-301, 3:300f
Pyrexia with dermatitis, 1:574 3:247.e1f hypertension and, 3:59
Pyridoxine, 1:582 cutaneous, 3:247-249, 3:248f-249f, CRF tends to be progressive, 2:387
Pyridoxine (vitamin B6) deficiency, 2:426 3:247.e1f, 3:249.e1f electrolyte balance, 2:384
Pyrrolizidine alkaloids, 2:336-338, 2:337f, systemic, 1:729, 3:249-250, 3:249f endocrine function, disturbances,
2:519-520, 2:337.e1f Reactive systemic amyloidosis, 2:414 2:384-385
Pyruvate kinase (PK) deficiency, 3:126 Receptor ligand (receptor activator of end-stage, 2:384
Pythiosis, 1:657-659, 1:658f, 2:203 nuclear factor κB [NFκB] ligand fluid volume regulation, 2:384
Pythium insidiosum, 2:476, 2:573f [RANKL], 3:294 nonrenal lesions of uremia, 2:385
Rectal papillary adenoma, 2:104, 2:105f systemic arterial lesions, 2:386
Q Rectal perforation, 2:247 transplantation, 2:387
Quality assurance of pathology services, Rectal prolapse, in sheep, 2:88 uremia, renal lesions of, 2:387
1:14 Rectal stricture, 2:100 uremic encephalopathy, 2:387
Quarter Horses Rectovaginal fistula, 2:450 uremic toxins, 2:385
agammaglobulinemia, 3:139 Recurrent airway obstruction in horses Renal dysplasia, 2:388-391, 2:393, 2:394f,
degenerative myopathy and rapid muscle (RAO), 2:505-506, 2:505f 2:449.e2f
atrophy, 1:229 Recurrent dermatosis of sows, 1:698-699 microscopic criteria, 2:393
equine polysaccharide storage myopathy, Recurrent uveitis, 2:438-439 Renal ectopia, 2:392
1:205-207 Recurrent vomiting, 2:48 Renal encephalopathy, 1:344
equine systemic calcinosis, 1:223-224 Red and wapiti-red crossbred (elk) deer, Renal enlargement, 2:381-382
fiber hypertrophy, 1:179 1:32-33, 1:33f acute inflammation, 2:381-382
glycogen branching enzyme deficiency, Red blood cells (RBC), 3:112 Renal failure, 2:384-388, 2:435. See also
1:208f diapedesis of, 1:301 Kidney(s); Renal disease
hereditary equine regional dermal asthenia, Red pulp, spleen, 3:161 hypercalcemic nephropathy, 2:441
1:544 Reduced enamel epithelium, 2:5 volume of urine of low specific gravity,
hyperkalemic periodic paralysis, 1:202 Reduced water intake, 2:452-453 2:410
lymphomas, 3:238 Reed-Sternberg cell, 3:219 Renal glomerular vasculopathy, 2:418-419
malignant hyperthermia, 1:210 Reflux esophagitis, 2:32, 2:32f, 2:56 Renal glucosuria, primary, 2:429

Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510

560 Index
Renal hemorrhages, 2:397
Renal hyperemia, 2:397
Renal hypoplasia, 2:392
Renal infarcts, 2:397-398, 2:397f
Renal insufficiency, 2:384
Renal interstitial cell tumors, 2:447
Renal lesions, 2:393
Renal lobule, 2:378
Renal lymphomas, 3:240f-241f
Renal lymphosarcoma, 2:447.e1f
Renal medulla, 2:383
Renal medullary necrosis, 2:399-400
amyloidosis, 2:399
analgesic nephropathy, 2:399
dehydration, 2:399
gross lesions, 2:399-400
pyelonephritis, 2:399
urinary obstruction, 2:399
Renal neoplasia, 2:444-448
adenoma, 2:444
nephroblastoma, 2:446f
renal carcinoma, 2:444-446
renal cell carcinoma, 2:445f, 2:445.e1f
renal cystadenocarcinoma, 2:446f
Renal oncocytomas, 2:447
Renal pelvis
urothelium of, 2:449
worms, 2:443
Renal position anomalies, 2:392-393
Renal secondary hyperparathyroidism,
1:74-75, 1:77-78
Renal telangiectasia, 2:398, 2:442,
2:442.e1f
Renal tissue
abnormalities, 2:392
agenesis, 2:392
hypoplasia, 2:392
Renal transplantation, 2:387
Renal tubular acidosis, 2:384, 2:428-429
Renal tubules degeneration, 1:5f
Renal vasoconstriction, 2:424-425
Ren arcuatus, 2:392
Renin-angiotensin-aldosterone system
(RAAS), 2:377, 2:401, 3:10, 3:337
Reoviridae, 3:430-431
Reparative dentin, 2:5
Repeat breeder, 2:438
Reperfusion injury, 2:81
Reports, final, 1:14
Reproductive system
abnormalities with hypothyroidism,
3:318
female, 3:358-464
male, 3:465-510
Respiratory bronchioles, 2:467
Respiratory distress syndrome, 2:515-516,
2:516.e1f
familial, 2:516
Respiratory system, 2:465-591
general considerations, 2:465-473
organization of lung, 2:467
upper airway, 2:466-467, 2:466f
infectious diseases, 2:523-591
bacterial, 2:531-533, 2:542-551,
2:562-563, 2:569-573, 2:577-579,
2:589
cats, 2:587-591
cattle, 2:537-557
dogs, 2:574-587
fungal, 2:535-536, 2:554, 2:579-585
horses, 2:567-574
mycoplasmal, 2:533-535, 2:563-564,
2:573-574, 2:579
Respiratory system (Continued)
parasitic, 2:536-537, 2:554-557,
2:564-567, 2:574, 2:585-587, 2:590,
2:590f
sheep and goats, 2:557-567
viral, 2:523-531, 2:537-542, 2:557-562,
2:567-569, 2:574-577, 2:587-589
larynx, 2:467, 2:481-482, 2:481f
laryngitis, 2:481
paralysis, 2:481, 2:481f
rhabdomyomas, 1:241, 1:242f
lungs, 2:484-520
abortion and, 3:401-402
abscesses, 2:520
atelectasis, 2:486, 2:486.e2f
cellular architecture and cell biology,
2:468-471
circulatory disturbances, 2:487-494
congenital anomalies, 2:484-485,
2:485.e1f
defenses, 2:471-473
development and growth, 2:484,
2:484.e1f
heart failure and, 3:11
hemorrhage, 2:490-492, 2:490.e1f
injury, 2:500-520, 2:500f
airway disease, 2:500-504, 2:500.e1f
interstitial lung disease, 2:509, 2:510f,
2:511b
lobes, 2:467
torsion, 2:485-486, 2:485f
mineralization, 2:494-495, 2:494f
neoplasia, 2:495-500, 2:495b
organization of, 2:467
pulmonary emphysema, 2:486-487
pulmonary hypertension, 2:492-494
thrombosis, embolism, and infarction,
2:489-490, 2:489b
toxic injury, 2:518-520
vascular supply to, 2:467-468, 2:468f
nasal cavity, 2:466, 2:473-480
circulatory distuburances, 2:473-474
congenital anomalies, 2:473
general considerations, 2:473
nasal amyloidosis, 2:473, 2:474f
neoplasms, 2:478-480, 2:478f
non-neoplastic proliferative disorders,
2:477-478
paranasal sinus diseases, 2:477, 2:477f
rhinitis, 2:474-477, 2:475b
pharynx, 2:480-481
cysts, 2:29
dysphagia, 2:33
lymphoid hyperplasia, 2:480.e3f
neuroendocrine carcinoma of, 2:27
pleura, 2:520-523
neoplasms, 2:523
noninflammatory pleural effusions,
2:521
pleural effusions, 2:520
pneumothorax, 2:487, 2:487f, 2:521,
2:521.e3f
pleuritis, 2:521-523, 2:522f, 2:521.e3f
suppurative, 2:522, 2:521.e1f
pneumonia
aspiration, 2:508-509, 2:508f-509f,
2:516, 2:516.e1f, 2:508.e1f
atypical, 2:509
bacterial, 2:562-563, 2:562f
bronchointerstitial, 2:511-512,
2:514.e2f
embolic, 2:520, 2:520.e2f
eosinophilic interstitial, 2:513.e1
Respiratory system (Continued)
granulomatous interstitial, 2:513
hypersensitivity, 2:512-513
interstitial, 2:509
lipid, 2:516-518, 2:516.e1f
proliferative and necrotizing, 2:529,
2:529.e1f
pulmonary carcinomas/adenocarcinomas,
1:736, 2:495-500, 2:497f, 2:495.e2f,
2:497.e1f
classification, 2:496t
sinuses
diseases, 2:477, 2:477f
neoplasms, 2:478-480, 2:478f
non-neoplastic proliferative disorders,
2:477-478
trachea, 1:201, 2:467-469, 2:482-483
bronchus, 2:467
collapse, 2:483f, 1:192.e1
smoke inhalation and, 2:483, 2:483f
transitional metaplasia, 2:501,
2:501.e1f
Respiratory tract infection, 2:149
Resting lines, 1:27
Resting zone, growth plate, 1:22-23
Restrictive cardiomyopathy (RCM), 3:45
cats, 3:46
Retained cartilage core, 1:32, 1:32f
Retarded endochondral ossification, 1:32
Rete testis, 3:497
Reticular degeneration, 1:523
Reticulin fibers, 2:260
Retina, 1:465-475
degeneration, 1:468-469
inherited, in cats, 1:469-470
light-induced, 1:470
miscellaneous retinopathies, 1:472-474
non-inherited, 1:470
nutritional, 1:470-471
taurine-deficiency, 1:471
toxic retinopathies, 1:471-472
dysplasia, 1:419-420, 1:420f
in cats, 1:469-470
inherited photoreceptor, 1:469
true, 1:420
folding, 1:419, 1:419f
general pathology, 1:466-467
histopathology, 1:467
necrosis, 1:419
nonattachment, 1:411-412, 1:414f
normal, 1:465-466, 1:465f
retinitis, 1:474-475, 1:474f
separation, 1:467-468, 1:467f-468f
vasculature, 1:466
Retinal pigment epithelial dystrophy,
1:469
Retinitis, 1:474-475, 1:474f
Retinoblastomas, 1:485
Retinol, 1:82
Retrobulbar cyst, 1:412, 1:412f
Retrocaval ureter, 2:449, 2:449f
Retroflexion, of the bladder, 2:451
Retroperitoneal pelvic fat bulges, 2:80
Retroperitoneum, 2:245. See also Peritoneum
and retroperitoneum
diseases, 2:257
Retroviral infections, 1:627-628
Reversal lines, 1:27
Revised European-American Classification of
Lymphoid Neoplasms (REAL), 3:217
Rhabditis bovis, 1:507
Rhabdomyolysis, 1:221-224
exertional, in horses, 1:221-223, 1:222f

Rhabdomyomas, 1:241, 1:242f, 1:726, 3:52,
3:52f
ear, 1:505
laryngeal, 2:482, 2:482f, 2:482.e1f
Rhabdomyosarcomas, 1:241-243, 1:243f-
244f, 1:726, 2:464
Rheumatoid arthritis, 1:157, 1:157f
Rheum rhaponticum, 2:425-426
Rhinitis, 2:474-477
allergic, 2:476, 2:476.e1f
atrophic, 2:533
nonprogressive (NPAR), 2:533
pigs, 1:102
progressive, 2:533
bovine rhinitis virus, 2:542
causes, 2:475b
chronic, 2:475
idiopathic lymphoplasmacytic, 2:476
inclusion body, 2:529-530, 2:530f
mycotic, 2:579, 2:580f
Rhinosporidium seeberi, 2:476, 2:579-580,
2:581f
Rhipicephalus sanguineus, 1:240, 1:506
Rhizoctonia leguminicola, 2:29
Rhodesian Ridgeback dogs
congenital myotonia in, 1:201
degenerative radiculomyelopathy, 1:330
dermoid cysts, 1:547, 1:704-705
myotonic dystrophy-like disorder,
1:202-203
Rhodococcus equi, 2:113-114, 2:197-198,
2:198f, 2:514, 3:418
lymph nodes and, 3:206f, 3:204.e1f
respiratory system and, 2:569-571,
2:571f
splenic abscesses, 3:183-184
Rhodotorula glutinis, 3:491
Rhodotorula spp., 1:661
Rib and sternum congenital abnormalities,
1:56
Ribbon trichoblastoma, 1:716, 1:716f
Riboflavin deficiency, 1:582
Ribonucleic acid (RNA) extraction,
1:30
Rickets, 1:61, 1:66, 1:68-74, 3:82-83, 3:274,
3:296
calcium deficiency in, 1:61, 1:66, 1:69
hereditary, 1:69
vitamin D-resistant, 1:70
hypophosphatemic, 1:70, 1:70f
microscopic lesions of, 1:72, 1:72f
phosphorus deficiency in, 1:68-69
rickettsial vasculitides, 3:80-83
sheep, 1:70, 1:70f
vitamin D deficiency in, 1:68
vitamin D-dependent type I, 1:69-70
Rift Valley fever virus (RVFV), 1:281,
2:312-313, 3:439-440, 2:312.e1f
Right atrioventricular valve dysplasia,
3:21-22
Right atrium, heart, 3:2
failure, 3:6
Right-sided heart failulre, 3:11
Right ventricle, heart, 3:2
double-chambered, 3:22
Rigor mortis, 1:186
Rinderpest, 2:128-130, 2:129f-130f,
3:182-183, 3:183f, 3:182.e1f
Ringbinden, 1:185, 1:185f
Ringbone, 1:142
Ringworm, 1:649-653
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Rocky Mountain spotted fever, 1:449,
1:474-475, 3:82-83
Rod cells, 1:262-263
Rodenticides, 3:301-302, 3:301f
hemothorax, 2:521.e3f
intoxication, 3:264
Roeckl’s granuloma of cattle, 1:234
Romney sheep
axonal dystrophy, 1:324
osteogenesis imperfecta, 1:49, 1:49f
Romulea poisoning, 1:322
Rosenthal fibers, 1:262
Rotavirus, 2:112, 2:115-117, 2:151-153,
2:152f
Rottweiler dogs
axonal dystrophy, 1:324
canine X-linked muscular dystrophy in,
1:192, 1:193f
diabetes mellitus, 2:373
ichthyosis, 1:532
juvenile-onset distal myopathy, 1:198
leukoencephalomyelopathy, 1:340-341,
1:340f
motor neuropathy, 1:335
nephritis, 2:417
neuroepithelial degeneration, 1:492
severe combined immunodeficiency
(SCID), 3:140-141
spongy enceophalomyelopathies, 1:346
static spinal stenosis in, 1:136, 1:136f
vitiligo, 1:555-556
Rouge-des-prés calves, central and peripheral
axonopathy of, 1:332
Roughage, 2:36
Row of tombstones, 2:14-15
Rubriblasts, 3:104
Rumen
fluid, 2:455
flukes, 2:43, 2:43f, 2:226
mycotic inflammatory lesions of, 2:39-40
papillae, adhesion of, 2:36f
Rumenitis, 2:39-40, 2:41f-42f
and acidosis caused by carbohydrate
overload, 2:40-43
mycotic, 2:42
Rumenitis-liver abscess complex,
2:41-42
Ruminal acidosis, 2:40
diagnosis of, 2:41
Ruminal carcinomas, 2:44
Ruminal drinkers, 2:38
Ruminal mucosa, 2:36, 2:36f
microscopic examination of, 2:41
Ruminal papillae, 2:36
Ruminant forestomachs, 2:44
Ruptures
abomasal, 2:50-51
arterial, 3:62-63, 3:62f
biliary tract, 2:309
gastric, 2:48
liver, 2:268
muscle, 1:213-214
spleen, 3:165-166, 3:166f, 3:166.e1f
vaginal and vulval, 3:442
vein, 3:89
S San Angelo virus, 1:280
Sabulous cystitis, in horse, 2:451f
Sabulous (matrix-crystalline) urethral plugs,
in male cats, 2:456
Saccharated iron, 3:34-35
Index 561
Saccular stage of lung growth, 2:484
Saint Bernard dogs
dilated cardiomyopathy, 3:48
gastric volvulus, 2:49
pyotraumatic dermatitis, 1:560
subvalvular aortic stenosis, 3:20
Salinomycin, 3:34-35
Salivary calculi (sialoliths), 2:29
Salivary glands, 2:28-30
acute reactions to injury, 2:28
dilations of duct, 2:29
foreign bodies, 2:29
necrotizing sialometaplasia, 2:30
neoplasms, 2:30
ptyalism, 2:29
salivary mucocele/sialocele, 2:29
sialoadenitis, 2:29
Salmonella Arizonae, 2:115
Salmonella choleraesuis, 2:170
Salmonella enterica, 2:99
Salmonella Typhimurium, 2:100, 2:171,
2:173f, 2:175f
Salmonella typhisuis, 2:172
Salmonellosis, 2:117, 2:167-176
abortion and, 3:401, 3:412-413
asymptomatic carriage of, 2:167-168
bacterial osteomyelitis and, 1:99, 1:99f,
1:101f
canivores, 2:176
cattle, 2:174-175, 2:174f
gastric venous infarction due to, 2:51
horses, 1:99f, 2:172-174, 2:173f
infectious arthritis and, 1:148
liver and, 2:314-315
pathogenesis of salmonellosis, 2:168
pigs, 2:170-172, 2:170f-172f
salmonellosis, 2:99, 2:112
sheep, 2:175-176
suppurative rhinitis and, 2:476
in tonsils of swine, 2:20
Salmon poisoning disease, 2:117, 2:226,
3:148-149, 3:150f, 3:149.e1f
Salpingitis, 3:380
Salt poisoning, 1:314-315
Saluki dogs
color dilution alopecia, 1:539-540
motor neuron disease, 1:331
Samoyed dogs
alopecia X, 1:589-590
canine hypomeylinogenesis, 1:337
canine uveodermatologic syndrome,
1:557
canine X-linked muscular dystrophy in,
1:192
chondrodysplasia in, 1:45
early onset diabetes mellitus, 2:373
sebaceous adenitis, 1:551
spongy myelinopathy, 1:343
true retinal dysplasia, 1:420
Samoyed hereditary glomerulopathy,
2:415-416
Samoyed hereditary nephropathy,
2:415-416
Sample selection and preservation, 1:8
for study of muscle, 1:171-172,
1:172f-173f
Sancassania berlesei, 1:683-684
San Miguel sea lion virus (SMSV), 2:121
Sarcina-like bacteria, 2:50
Sarcobatus vermiculatus, 2:425-426
562 Index
Sarcocystis canis, 1:389
Sarcocystis gigantea, 2:34
Sarcocystis-like protozoans, 1:665
Sarcocystis spp., 1:234-236, 1:235f, 2:239
abortion and, 3:423, 3:423f
myocarditis and, 3:43-44
Sarcoidosis, 1:700-701
Sarcoids, 1:708, 1:709f
Sarcomas, 1:245
feline post-traumatic, 1:486, 1:487f
hemophagocytic histiocytic, 3:254-255,
3:254f-255f, 3:254.e1f
histiocytic, 1:159-160, 1:160f, 1:729-730,
3:250-253, 3:250f-252f, 3:250.e2f,
3:250.e1f
pulmonary, 2:498-499, 2:499f
mammary, 3:463, 3:463f
splenic, 3:192-194, 3:192f-193f, 3:192.e1f,
3:192.e2f
undifferentiated pleomorphic, 1:725-726
vaccine-associated, 1:560
Sarcomeres, 1:167, 1:168f, 3:3
Sarcoplasm, 1:167
Sarcoptic mange, 1:673-675, 1:674f
Sarcosporidiosis, 2:34
Satellite cells, 1:166-167
Satellitosis, 1:523, 1:523f
“Sawdust”, 1:29
Sawfly larvae, 2:332
Scales, 1:524, 1:554
Scars, splenic, 3:166f
Scheibe-type deafness, 1:492
Schipperke dogs, myopathy in, 1:198
Schistosoma mattheei, 2:459-460
Schistosoma nasalis, 2:556-557, 2:567
Schistosomiasis, 2:227, 3:91-94, 3:92f,
3:93.e1f
Schmallenberg virus (SBV), 1:280, 1:281f,
3:438
Schnauzer dogs
canine X-linked muscular dystrophy,
1:192
myxomatous valvular degeneration, 3:27
recurrent flank alopecia, 1:590
Schwann cells, 1:256, 1:258-260
Schwannomas, 1:405, 1:405f, 1:494,
1:724
Sclera, 1:476-477
Scleral ectasia, 1:413
Scleroderma, 2:77-78
localized, 1:698
Scleromyxedema, feline, 1:697
Sclerosis, 1:523
Sclerotic masses, 2:104
Scoliosis, 1:37t
Scottish Blackface sheep, epidermolysis
bullosa in, 1:535
Scottish Deerhound dogs, chondrodysplasia
in, 1:44-45
Scottish Fold cats, osteochondrodysplasia in,
1:45-46
Scottish Terrier dogs
Alexander disease, 1:341
axonal dystrophy, 1:325
canine atopic dermatitis, 1:591
diffuse uveal melanocytosis, 1:484-485
idiopathic multifocal osteopathy, 1:54
malignant melanoma, 2:26
spastic syndromes, 1:203, 1:318
Scrapie-associated prion protein, 1:348,
2:20
Screwworm fly, 2:43
Screwworm myiasis, 1:669-670
Scrotum, 3:471-473
frostbite, 3:472, 3:472f
hernia, 3:498
varicose tumor of, 3:99
Scurvy, 1:83, 1:83f-84f
Sealyham Terrier dogs, melanocytopenic
hypomelanosis in, 1:555
Sebaceous adenitis, 1:551-552, 1:552f
Sebaceous carcinomas, 1:717-718
Sebaceous duct cysts, 1:705
Sebaceous epitheliomas, 1:717
Sebaceous glands, 1:517
dysplasia, 1:699, 1:699.e2f
hyperplasia, 1:523
tumors, 1:717-718, 1:717f
Sebaceous hamartomas, 1:705
Seborrhea, 1:548-549, 1:549f
Seborrheic keratoses, 1:550-551, 1:551.e1f
Secondary cleft palate, 2:3, 2:3f
Secondary demyelination, 1:257
Secondary glaucoma, 1:463-464, 1:464f
Secondary hair follicles, 1:515-516
Secondary hyperfunction of endocrine gland,
3:272
Secondary hyperparathyroidism, 1:74
nutritional, 1:75
renal, 1:74-75, 1:77-78
Secondary hypertension, 3:59-60
Secondary hypofunction of endocrine gland,
3:273
Secondary immune-mediated
thrombocytopenia, 3:258
Secondary spongiosa, 1:23
Secondary synovial chondromatosis, 1:162,
1:162f
Secondary thyroid hypoplasia, 3:314, 3:314f
Secondary tumors of skeletal muscle,
1:244-245, 1:246f
Secondary tympany of forestomachs, 2:37-38
Second-degree burns, 1:564-566
Second opinions, 1:14
Secretory granules, 3:271
Segmental aplasia, 1:277-279
of esophagus, 2:31
of the mesonephric duct (SAMD), 3:480,
3:480f, 3:499
paramesonephric duct, 3:368, 3:369f
Segmental cerebellar atrophy, 1:305
Segmental glomerulosclerosis (GS), 2:401
Segmental hypoplasia of spinal cord,
1:277-279, 1:277f
Segmental ischemic necrosis, of small colon,
2:84
Seizures, 3:51
Selenium
-accumulator plants, 2:519-520
deficiency, 1:214-215, 1:217
toxicosis, 1:570-571, 1:571f
Sellar region tumors, 1:403-404
Semicircular canals, 1:490
Semihairlessness, 1:538
Seminomas, 3:496, 3:496f
Semiplacenta diffusa, 3:396-397
Senile atrophy
of brain, 1:304-305
of lymph nodes, 3:198-199
Senile osteoporosis, 1:64
Senile retinopathy, 1:473-474
Senna plant, 1:219-220, 2:341
Sensory ganglioneuritis, 1:395
Sensory hair cells, 1:489-490, 1:490f
Sepsis, 2:511, 2:512f
Septic arthritis, 1:147-148
Septic embolism, 2:490
Septicemia
hemorrhagic, 2:546-547
salmonellosis, 2:173
Septicemic colibacillosis, 2:166-167
Septicemic pasteurellosis, 2:562-563
Septic infection, 1:31-32
Sequestrum, 1:35-36, 1:94-96, 1:96f
bronchopneumonia, 2:508
Serology, 1:11
Serosal edema, 2:195-196, 2:196f
Serosal inclusion cysts, 3:386-387, 3:387f
Serous atrophy of pericardial fat, 3:25, 3:25f
Serous retinal separation, 1:448-449
Sertoli cells, 3:466
development, 3:469
hyperplasia, 3:477f
toxicants and testicular degeneration,
3:484
tumor, 3:494-495, 3:494f
Serum albumin, 2:108
Serum calcium “set-point”, 3:294
Serum electrolyte abnormalities and
myopathies, 1:225
Serum protein levels, 2:40
Serum total and bone-specific alkaline
phosphatase (ALP), 1:115
Setaria digitata, 1:390, 2:255
Setaria labiatopapillosa, 3:473-474
Severe acute respiratory syndrome (SARS),
2:587-588
Severe combined immunodeficiency (SCID),
3:139-141, 3:141f
Severe factor X deficiency, 3:264
Severe gastrointestinal parasitism, 1:66
Sex chromosome
disorders of sexual development, 3:363-
365, 3:363f-364f
genotype, 3:360
Sex cord-gonadal stromal tumors
in females, 3:375-377
in males, 3:492-495
Sexual development disorders (DSD)
female, 3:360-370, 3:364f-365f
male, 3:468-471, 3:476-481, 3:476f,
3:499
Sézary syndrome, 3:232-234
“Shaker calf”, 1:332, 1:332f
Shaker dog disease, 1:395
Sharpey’s fibers, 1:130
Shear mouth, 2:8
Sheep-associated MCF, 2:132
Sheep grazing estrogenic pastures, 2:458
Sheep ked infestation, 1:670
Sheeppox virus, 1:616, 1:622-624, 1:623f,
2:557
Sheep scab, 1:676
Shetland Sheepdogs
canine dermatomyositis, 1:198
canine X-linked muscular dystrophy, 1:192
choroidal hypoplsia, 1:413
hyperestrogenism, 1:589
spongy myelinopathy, 1:343
Shiga toxin, 2:112
Shiga toxin-producing E. coli (STEC), 2:162
Shih Tzu dogs
keratoconjunctivitis sicca in, 1:436
lymphomas, 3:238
myelinolytic leukodystrophy, 1:341
sebaceous epitheliomas, 1:717
Shipping-fever pneumonia, 2:542-543
Shock, 3:6
Shock gut, 2:85
 Index 563

Shorter-acting sulfonamides, crystalline
nephropathy, 2:424
Shorthorn cattle
bovine hypomyelinogenesis, 1:338-339
lethal trait A46, 3:141
Shoulder joint, degenerative joint disease of,
1:143
Shunted blood flow to heart, 3:6
malformation causing, 3:16-18, 3:16f
Shunts, hepatic, 2:267, 2:267f, 2:267.e1f
acquired portosystemic, 2:290, 2:298-299,
2:299f
Shwartzman reaction, 2:398-399
Sialoadenitis, 2:29
Sialocele
nasopharyngeal, 2:477.e4f
salivary, 2:29
Siamese cats
congenital hypotrichosis, 1:539
congenital idiopathic megaesophagus, 2:34
Maroteaux-Lamy syndrome, 1:58
photosensitization, 1:579
vitiligo, 1:556
Siberian Husky dogs
alopecia X, 1:589-590
canine uveodermatologic syndrome, 1:557
degenerative radiculomyelopathy, 1:330
motor neuropathy, 1:335
oral eosinophilic granuloma, 2:16
vitiligo, 1:555-556
zinc-responsive dermatoses, 1:585-586
Sick sinus syndrome, 3:51
Siderocalcinosis, 3:61
Siderosis, 1:297, 1:298f
Siderotic pigmentation, 1:255
Siderotic plaques, splenic, 3:163, 3:164f,
3:163.e2f
Signet ring cells, 2:101-102
Signet-ring malignant melanomas, 1:722
Silica calculi, 2:455
Silicate pneumoconiosis, 2:518
Silicates, 2:518
Silky Terrier dogs
rabies vaccine-induced vasculitis and
alopecia, 1:612
spongy myelinopathy, 1:343-344
Silo gas, 2:518
Silver fox
spongiform myelinopathy, 1:343f, 1:344
status spongiosus, 1:342f
Simmental cattle
epidermolysis bullosa simplex, 1:535
inherited progressive spinal myelopathy,
1:325
osteopetrosis, 1:51
Simondsia spp., 2:54
Simple follicles, 1:515-516
Simple renal cysts, 2:394-395
Simple secretory epitrichial adenomas, 1:718
Sinus erythrocytosis, 3:199-200, 3:200f,
3:200.e1f
Sinuses
diseases, 2:477, 2:477f
neoplasms, 2:478-480, 2:478f
nonflammatory thrombosis of cranial dural,
1:300
non-neoplastic proliferative disorders,
2:477-478
Sinus hairs, 1:517
Sinusitis, chronic suppurative, 2:477-478,
2:477.e1f
Sinus node, 3:2
Sinusoidal domain, liver, 2:262
Sinusoidal endothelial cells, 2:260
Sinusoidal leukocytosis, 2:300-301
Sinusoidal lining cells necrosis, 2:285
Size-dependent barrier, 2:380
Skeletal dysplasias, 1:37t
localized, 1:54-57, 1:54f
osteochondromatosis, 1:54
Skeletal muscles, dermal, 1:515
Skeleton. See also Bone(s)
genetic and congenital diseases of, 1:36-60,
1:37t
genetic diseases indirectly affecting,
1:57-60
manganese deficiency and, 1:80
postmortem examination of, 1:28-30, 1:29f
Skin, 1:509-736
actinic diseases of, 1:575-580
algal diseases of, 1:665
bacterial diseases of, 1:629-646
basement membrane zone (BMZ),
1:513-514
canine cutaneous histiocytoma, 3:243-245,
3:244f-245f, 3:244.e1f, 3:243.e1f
canine juvenile cellutitis, 1:690-691, 1:691f
canine reactive histiocytosis, 3:247-250,
3:248f, 3:247.e1f
congenital and hereditary diseases of,
1:530-547
dermal muscles, 1:515
dermatohistopathology, 1:518-530
gross terminology, 1:524
histologic terms, 1:518-524
pattern analysis, 1:524-530
dermis, 1:514-515
endocrine diseases of, 1:587-590
epidermal differentiation disorders,
1:547-554
epidermis, 1:512-513
fungal diseases of, 1:646-661
general considerations, 1:511-518
hair follicles, 1:515-517
helminth diseases of, 1:685-690
immune-mediated dermatoses, 1:590-615
autoimmune dermatoses, 1:600-607
drug eruptions, 1:607-608
hypersensitivity, 1:590-600
immunologic function, 1:515
lesions with canine distemper virus,
2:576
lymphomas, 3:237, 3:237f, 3:239f,
3:239.e1f
neoplastic and reactive diseases, 1:703-736
nutritional diseases of, 1:580-587
paraneoplastic syndromes, 1:691-693
perianal glands, 1:517
physiochemical diseases of, 1:558-575
chemical injury, 1:566-575
physical injury, 1:559-566
pigmentation disorders, 1:554-558
protozoal diseases of, 1:661-665
sebaceous glands, 1:517
subcutis, 1:518
sweat glands, 1:517-518
tags, 1:722-723
tumor-like lesions, 1:705
viral diseases of, 1:615-628
Skin-associated lymphoid tissue (SALT),
1:515
Skin-homing memory T-cells, 1:515
Skin immune system (SIS), 1:515
Skull bones, 1:21
congenital abnormalities, 1:56, 1:56f
craniomandibular osteopathy, 1:91-92,
1:92f
fractures, 1:302-303
sutures, 1:128
Skye Terrier dogs, chronic hepatitis in, 2:304
Slaframine, 2:29
SLC2A9 gene, 2:457
SLC3A1 genes, 2:458
SLC7A9 genes, 2:458
Slipped epiphysis, 1:31
Sly syndrome, 1:58
Small-bowel diarrhea, 2:70-71
Small-cell carcinoma
neuroendocrine, 2:497-498
thyroid, 3:330-331
Small-cell lymphocytic villus lymphoma,
2:107-108
Small intestinal bacterial overgrowth (SIBO),
2:86, 2:364
Small intestine, 2:81, 2:82f
cardinal finding, 2:92
idiopathic inflammatory bowel disease,
2:92
lymphangiectasia, 2:90f
mucosa, 2:124
hypoplasia, 2:74
vascular supply, 2:61
obstruction, 2:76
dogs, 2:75f
pseudodiverticulosis of, 2:87
Small ruminant lentiviruses, 2:558-560,
2:559f, 2:558.e1f
Smoke inhalation
lung injury, 2:518
trachea and, 2:483, 2:483f
Smooth Fox Terrier dogs
canine congenital myasthenia, 1:209
multisystem axonal degeneration, 1:325
Smooth muscle cells, lungs, 2:469
Smooth-surface caries, 2:10
Snakebite envenomation, 1:568
Snowshoe hare virus, 1:383
Snorter dwarfism, 1:39, 1:39f
Sodium absorption, 2:65-66
Sodium fluoroacetate, 3:37-38
Sodium iodide symporter (NIS), 3:311
Soemmering ring cataract, 1:444, 1:444f
Soft callus, 1:34-35
Soft tissue sarcomas, 1:245
Solanaceae, 2:331
Solanum glaucophyllum, 3:301-302,
3:301f-302f
Solanum poisoning, 1:321-322
Solar dermatitis, 1:576, 1:576f
Solar elastosis, 1:577, 1:577f
Solar keratoses, 1:577
Solar radiation
burns and, 1:566
direct effect of, 1:575-577
Solid basal cell carcinoma, 1:714
Solid-cystic epitrichial adenomas, 1:718-719
Solid-cystic epitrichial carcinomas, 1:719
Solitary biliary cysts, 2:264
Solitary mucosal lymphoid nodules, 2:64
Somatostatin, 2:368
Somatostatinoma, 2:375
Somatotroph adenomas, 3:285-286,
3:285f-286f

Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510

564 Index
South Dorset Down sheep, epidermolysis
bullosa in, 1:535
Space of Disse, 2:260, 2:263
Spargana, 2:255
Spastic syndromes, 1:203-204, 1:318
Spavin, 1:142
Special stains, 1:9
Spermatic cord, 3:497-499
Spermatic granulomas, 3:497
of the epididymal head, 3:480-481,
3:480f-481f
Spermatogenesis, 3:466-467
Spherocytes, 3:114
Spheroids, 1:257
Sphincter mechanism incompetence,
2:451-452
Sphingolipidoses, 1:287-288, 1:287f
Sphynx cats
congenital hypotrichosis, 1:538
α-dystroglycan deficiency in, 1:196
Spiculosis, 1:699
Spider bites, 1:568
Spider lamb syndrome, 1:40, 1:40f-41f
sheep, 1:40, 1:40f-41f
Spina bifida, 1:57, 1:279
occulta, 1:279
Spinal cord, 1:277-279. See also Brain
arachnoid cysts, 1:279
atrophy, 1:304-305
diplomyelia, 1:278f
dysraphism, 1:278f
embolism, 2:490
lymphoma, 3:240f
myelodysplasia, 1:277-279, 1:278f
nephroblastoma, 1:402-403, 1:403f
segmental hypoplasia of, 1:277f
spina bifida, 1:57, 1:279
subdural hemorrhage of, 1:303f
subdural/intradural abscess, 1:354f
syringomyelia, 1:278f
traumatic injuries, 1:303, 1:303f
Spinal defects, 1:37t
Spinal nephroblastoma, 1:403f
Spindle cells
trichoblastomas, 1:716
tumors, 1:722-726
benign, 1:722-723
of blue-eyed dogs, 1:486
locally infiltrative and malignant,
1:723-726
Spindles, muscle, 1:171, 1:171f
Spiral colon, of ruminants, 2:66
Spiral ganglion cells, 1:490
Spiral mucosal folds, 2:60
Spiral osseous lamina, 1:489
Spirocerca-associated sarcoma, 2:35
Spirocerca lupi, 2:34-35, 2:35f
Spirochetal colitis, 2:181-183
Spirochetes, 1:645
Spirurid nematodes, 2:210
Splayleg, 1:189-190, 1:189f-190f
Spleen
abscesses, 3:183-184, 3:184f
circulatory diseases, 3:169-171
cysts, 3:189
degenerative diseases, 3:163-165
developmental diseases, 3:162-163,
3:163f
fibrohistiocytic nodules, 3:190-191,
3:190f-191f
hematopoietic alterations, 3:191
hyperplastic diseases, 3:189-191, 3:189f
infarct, 3:170f-171f, 3:170.e1f
Spleen (Continued)
inflammatory diseases, 3:182-189,
3:182.e1f
lymphomas, 3:239f
neoplastic diseases, 3:191-196
rupture, 3:165-166, 3:166f, 3:166.e1f
specific infections and, 3:171-182
splenomegaly and splenic nodules,
3:167-169, 3:167f-168f, 3:169.e1f
structure and normal function, 3:158-162,
3:160f
thrombosis, 3:171f
vascular neoplasms, 3:169f
volvulus, 3:167, 3:167f
Splenic artery, 3:159
Splenic follicles, 3:116
Splenic infarct, 3:170f
Splenomegaly, 3:167-169, 3:167f-168f
Splenosis, 3:166, 3:166f
Spondylosis
cattle, 1:145-146
dogs, 1:146
horses, 1:146
pigs, 1:146
sheep, 1:146
Spongiform myelinopathy, 1:343f
Spongiform pustule of Kogoj, 1:523
Spongiosis, 1:523, 1:524f
perivascular dermatitis with, 1:525
Spongy encephalomyopathies, 1:342f, 1:345f,
1:346-347
Spongy myelinopathies, 1:342-346,
1:342f-343f
Spontaneous and iatrogenic
hyperadrenocorticism, 1:67
Spontaneous chronic corneal epithelial
defects (SCCED), 1:434
Spontaneous hemorrhages in brain,
1:300-301
Sporadic lymphangitis, 3:96
Sporidesmin, 2:335-336, 2:336f,
2:336.e1f
Sporotrichosis, 1:655-657, 1:656f
Spotted leukotrichia, 1:557-558
Squamous cell carcinoma (SCC), 1:125,
1:125f, 2:25-26, 2:25f, 2:44, 2:106,
2:106f, 2:447, 2:463
acantholytic, 1:713-714
cats, 2:21, 2:25, 2:44
cattle, 2:26, 2:44
dogs, 2:21, 2:25, 2:25f, 2:44
esophagus and forestomachs, 2:44
eyelid and conjunctival, 1:479-480,
1:479f-480f
gastric, 2:106-107, 2:106f
guttural pouch, 1:500
horses, 2:25-26
invasive, 1:713
laryngeal, 2:482
nasal, 2:478-479
papillomaviruses and, 1:713, 1:713f
penis and prepuce, 3:509, 3:509f
pinnae, 1:504
poorly differentiated, 1:713
pulmonary, 2:497
sheep and goats, 2:44
well-differentiated, 1:713
Squamous eddies, 1:523
Squamous epithelium, 2:58
Squamous metaplasia of tracheal epithelium,
2:483
Squamous papilloma, 3:509
Srichinella spiralis, 2:19
Stachybotryotoxicosis, 1:573
Stachybotrys alternans, 2:14
Staffordshire Terrier dogs
congenital myotonia, 1:201
demodectic mange, 1:679
spongy enceophalomyelopathies, 1:346
Staghorn calculus, 2:454f
Standardbred horses, agammaglobulinemia
in, 3:139
Stanozolol, 2:329
Stapes, 1:495
Staphylococcal granuloma, 1:233-234
Staphylococcus aureus, 1:593
abortion and, 3:417
bacterial osteomyelitis and, 1:98,
1:100
mastitis, 3:452-454
polyarthritis, 1:151
Staphylococcus capitis, 3:473-474
Staphylococcus hyicus, 1:151
Staphylococcus pseudintermedius, 1:156
Staphylococcus spp., 2:455
folliculitis and furunculosis, 1:634-636,
1:635f
Starvation, 1:60, 1:581
osteoporosis and, 1:64-65, 1:65f
Status spongiosus, 1:342f, 1:345f,
1:346-347
Steatitis, 1:218, 2:249
Steatosis, hepatocellular, 2:273-278,
2:274f-276f, 2:274.e1f, 2:276.e1f
Stellate cells, 2:355
Stenosis, 2:73-74
aortic and subaortic, 3:20-21, 3:21f
cervical, 3:441
esophageal, 2:32-33
left atrioventricular valvular, 3:22
nasal/nasopharyngeal, 2:475
pulmonic, 3:19, 3:19f
vaginal, 3:369, 3:370f
Stephanofilariasis, 1:686-687, 1:687f
Stephanofilaria zaheeri, 1:507
Stephanurus dentatus, 1:391, 2:255, 2:319
encysted, 2:442f
Step mouth, 2:8
Sterile eosinophilic folliculitis and
furunculosis, 1:696
Sterile eosinophilic pustulosis, 1:696
Sterile granulomas and pyrogranulomas,
1:699-702
Sterile hemorrhagic cystitis, 2:460
Sterile neutrophilic dermatoses, 1:696
Sterile nodular panniculitis, 1:701-702,
1:701f
Sterile pyogranuloma syndrome (SPGS),
1:700, 1:700f
Sternum and rib congenital abnormalities,
1:56
Steroidal sapogenins, 2:338-340
Steroid hormones, 3:271
impairment, 3:340, 3:341f
Steroid-induced bone necrosis, 1:95
Steroid-responsive meningitis-arteritis, 1:158,
1:298-299, 1:298f, 1:395
Stevens-Johnson syndrome, 1:607, 1:609-
610, 1:610f
Stilesia hepatica, 2:319-320
Stillbirth, 3:395, 3:398-440
Stomach and abomasum, 2:44-60
adenocarcinoma of, 2:102
circulatory disturbances, 2:51-52
displacement, 2:49, 2:50f
foreign bodies and impaction, 2:50-51

Stomach and abomasum (Continued)
gastric dilation and displacement,
2:48-50
gastric mucosal barrier, 2:46
gastritis, 2:52-55
gastroduodenal ulceration, 2:55-60
heart failure and, 3:11-12
neoplastic/proliferative lesions, 2:100-111,
2:101t
tumors of lower gastrointestinal tract,
2:100-101
normal form/function, 2:44-46
mucous neck cells, 2:45
pyloric stenosis, 2:48
response of gastric mucosa to injury,
2:46-48
rupture, 2:50-51
volvulus, 2:49-50, 2:50f
Stomatitis
catarrhal, 2:14
chronic gingivostomatitis, 2:15-16
chronic ulcerative, 2:16
deep stomatitides, 2:17-19
feline ulcerative, 2:16
foreign-body, 2:13, 2:13f
lymphocytic/plasmacytic, 2:16
necrotic, 2:17, 2:17f
superficial, 2:13-14
vesicular, 2:14-15, 2:117-158, 2:120f
Storage diseases, 1:284-293
ceroid-lipofuscinoses, 1:290-292
glycogenoses, 1:290
glycoproteinosis, 1:288-289
induced, 1:292-293
inherited, 1:286-292, 1:287f
Lafora disease, 1:292
lysosomal, 1:284-293, 1:285f-286f, 2:429
liver, 2:278, 2:278f, 2:278.e1f
skeleton, 1:57-59
spinal cord, 1:285f-286f
mucolipidoses, 1:290
mucopolysaccharidoses (MPS), 1:58, 1:58f,
1:289-290
hearing and, 1:491-492
neuronal, 1:285, 1:473
Stored-product mite, 1:683-684
Strains, muscle, 1:213-214
Strangles, 2:572, 3:208-209, 3:208f, 3:208.e2f
Strangulation obstruction, 2:74-75
Stratum basale, 1:512
Stratum corneum (SC), 1:511-512
seborrhea, 1:548-549
Stratum granulosum, 1:512
Stratum spinosum, 1:512
Straw-itch mite, 1:683
Streptococcal adenitis, 3:208-209, 3:208f
dogs, 3:209
pigs, 3:208-209
Streptococcal arthritis, 1:150-151, 1:151f
Streptococcal mastitis, 3:453-455, 3:454f
Streptococcal polyarthritis, 1:148
Streptococcus canis, 1:636
Streptococcus dysgalactiae, 1:151
Streptococcus equi, 2:412
associated purpura hemorrhagica, 1:229,
1:229f
cats, 2:589
endocarditits and, 3:30-31
splenic abscesses, 3:183-184
strangles, 2:572, 3:208-209, 3:208f,
3:208.e2f
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Streptococcus equi (Continued)
suppurative myositis and, 1:230
Streptococcus equi
Streptococcus porcinus, 3:208-209, 3:208f
Streptococcus spp. in sheep, 1:151, 2:562
Streptococcus suis, 1:150-151
tonsils, 2:20
Streptococcus zooepidemicus, 2:578
Streptomyces, 3:417
Streptomycin, 2:424
Stress-related lesions, horses, 1:36
Striated myofibrils, 1:167
Stromal tumors, intestinal, 2:110-111
gastrointestinal, 2:110
leiomyoma, 2:110
leiomyosarcoma, 2:110
Strongyloides felis, 2:212
Strongyloides papillosus, 1:690, 2:212,
3:507
Strongyloides ransomi, 2:212
Strongyloides spp., 2:211-227, 2:211f
Strongyloides stercoralis, 2:212
Strongyloides tumefaciens, 2:212
Strongyloides westeri, 2:212
Strongylus edentatus, 2:216, 2:255
Strongylus equinus, 2:216, 2:255
Strongylus vulgaris, 2:84, 2:216-217, 3:85-87,
3:86f, 3:87.e1f
Struvite calculi, 2:455-456
Strychnine poisoning, 1:317
Stypandra toxicosis, 1:345
Subcapsular nephrogenic zone, 2:382.e1f
Subchondral (juxtacortical) bone, 1:129
cysts, 1:126, 1:134, 1:134f
Subcorneal pustular dermatosis, 1:696
Subcutaneous fungal infections, 1:653-661
Subcutaneous mast cell tumors, 1:245
Subcutaneous “panniculitis-like” T-cell
lymphoma, 3:234, 3:234f
Subcutis, 1:518
Subdural abscess, 1:353-354, 1:354f
Subdural hemorrhage of spinal cord, 1:303f
Subendocardial fibrosis, 3:30
Subendocardial hemorrhage, 3:4
Subendocardial mineralization, 3:4, 3:30,
3:30f
Subendothelial connective tissues, 3:55
Subepidermal vesicular and pustular
dermatitis, 1:527-528, 1:528f
Subepiglottic cysts, 2:481
Subintima, 1:130-131
Subinvolution of placental sites, 3:441,
3:441f
Subluxations, vertebral, 1:303
Submucosa, 2:62
Subnormal wear, 2:8
Substituted phenols, 3:325
Subungual squamous cell carcinomas,
1:713
Subvalvular aortic stenosis, 3:20-21
Sudan grass, 1:91
Suffolk sheep
abomasal dilation and emptying defect,
2:51
axonal dystrophies, 1:324
epidermolysis bullosa, 1:535
Suid herpesvirus 1 (SuHV-1), 2:530,
3:432-433
pseudorabies and, 1:370, 1:371f
Suid herpesvirus 2 (SuHV-2), 2:529-530,
3:433
Index 565
Suifilaria suis, 1:690
Suipoxvirus, 1:616, 1:625, 1:625f
Sulfides, absorption of, 2:40
Sulfonamides, 3:324
Sulfur compounds and PEM, 1:312
Summer mastitis, 3:455-456
Sunlight-induced cataract, 1:443-444
Superficial bacterial pyoderma, 1:629-634,
1:630f
Superficial necrolytic dermatitis, 1:586-587,
1:587f
Superficial plexus, dermal, 1:514
Superficial stomatitis, 2:13-14
Suppurative arthritis, 1:148f
Suppurative hypophysitis, 3:289, 3:290f
Suppurative lymphadenitis, 3:203-204,
3:204f
Suppurative meningitis, 1:355f
Suppurative myocarditis, 3:42
Suppurative myositis, 1:230, 1:230f
Suppurative osteomyelitis, 1:100-101
cattle, 1:102f
Suppurative pleuritis, 2:522, 2:521.e1f
Suppurative rhinitis, 2:476
Suppurative streptococcal encephalitis,
1:360f
Suppurative thymitis, 3:148, 3:149f
Suppurative uveitis, 1:449
Suprabasilar acantholysis, 2:14-15
Supragingival plaque, 2:9
Suprasellar germ cell tumor, 1:403-404,
3:287, 3:287f
Surface ectoderm, anomalies of, 1:421-423
Surgical pathology, 1:2
Surveillance, 1:1-2
Sutures, 1:21-22, 1:128
Swainsonine, 1:292, 2:29
Swayback, 1:328-329, 1:328f
Sweat glands, 1:517-518
hamartomas, 1:705
tumors, 1:718-720
Swedish Golden Retrievers, 1:334
Swedish Lapland dogs, motor neuron disease
in, 1:331
Swelled head, 1:232
Swelling
brain, 1:293-295, 1:295f
of foot processes, 2:406
vulval, 3:442-443
Swine dysentery, 2:100, 2:181-182,
2:182f
Swine influenza, 2:526-527, 2:526f,
2:526.e1f, 2:527.e1f
Swinepox virus, 1:616, 1:625, 1:625f
Swine rotaviral infection, 2:152, 2:152f
Swine vesicular disease (SVD), 2:121
Sylvatic dermatophytes, 1:649
Symmetrical lupoid onychitis (SLO),
1:702
Sympathetic nervous system neoplasms,
3:352-353
Symphyses, 1:128
Syncerus caffer, 2:117-118
Synchondroses, 1:128
Syndactyly, 1:54
Syndesmoses, 1:128
Synophthalmos, 1:411f
Synovial bursae, 1:155-156
Synovial cell sarcoma, 1:159
Synovial chondromatosis, 1:162, 1:162f
Synovial cysts, 1:162-163
566 Index
Synovial fluid, 1:131
purulent arthritis, 1:147-148
synovial cysts, 1:162-163
Synovial fossae, 1:130, 1:130f
goats, 1:130, 1:130f
horses, 1:130, 1:130f
Synovial joints, 1:129-131
degenerative diseases of, 1:137-143
fibrinous arthritis, 1:146-147
Synovial membrane, 1:130
Synovial myxoma, 1:160-162, 1:161f
Synovial pad proliferation, 1:163
Synoviocytes, 1:131
Syringomyelia, 1:278, 1:278f
Systemic arterial lesions, 2:386
Systemic cardiac responses, 3:6
Systemic granulomatous disease, 2:306
Systemic hypertension, 3:59
Systemic inflammation and neoplasia,
3:267-268
Systemic lupus erythematosus (SLE),
1:158-159, 1:605
polymyositis and, 1:227
Systemic reactive histiocytosis (SRH), 1:729,
3:249-250, 3:249f
T dental attrition, 2:7-8
Taenia krabbei, 1:240
Taenia multiceps, 1:389
Taenia ovis, 1:239-240
Taenia saginata, 1:239, 1:389
Taenia solium, 1:239, 1:389
Taeniid tapeworms, 2:223-225
Tail gland hyperplasia, 1:549
Tail tip necrosis, 1:560
Tamm-Horsfall mucoproteins, 2:421-423,
2:456, 2:458-459
Tanapox virus, 1:616
Tannerella forsythia, 2:9
Tapeworms, 2:222-225, 2:222f
Target cell response failure, 3:274
Targetoid fibers, 1:185
Tarsal joint, spavin of, 1:142
Tartar, tooth, 2:9
Tartrate resistant acid phosphatase (TRAP),
1:18, 1:27
Taurine-deficiency retinopathy, 1:471
Taylorella equigenitalis, 3:445
T-cell receptor (TCR), 2:107-108
T-cells
anaplastic large T-cell lymphoma (ALTCL),
3:230
angioimmunoblastic T-cell lymphoma,
3:230
cutaneous epitheliotropic lymphoma,
1:733-734
cutaneous T-cell lymphoma (CTCL),
3:232-235
enteropathy-associated T-cell lymphoma
(EATL), 3:230-232, 3:231f,
3:232.e1f
epitheliotropic T-cell tumors, 2:107-108
extranodal T-cell lymphoma, 3:232
graft-versus-host disease and, 1:608-609
hepatocytotropic T-cell lymphoma
(HC-TCL), 3:232
hepatosplenic T-cell lymphoma (HS-TCL),
3:232
immunodeficiency, 3:141
Langerhans cells and, 1:513
large granular lymphocytic leukemia, 3:235
large granular lymphocytic lymphoma,
3:231, 3:231f
T-cells (Continued)
in masticatory myositis, 1:226-227
mature (peripheral) T-cell neoplasms,
3:228-229
mycosis fungoides (MF), 3:232,
3:233f
nodal T-cell lymphoma, 3:229-230
pagetoid reticulosis (PR), 3:232-234,
3:233f
PCR for antigen receptor rearrangements
(PARR) assay, 3:215, 3:216f
-rich B-cell lymphoma, 1:734, 3:221-222,
3:222f
skin-homing memory, 1:515
subcutaneous “panniculitis-like” T-cell
lymphoma, 3:234, 3:234f
t-zone lymphomas (TZL), 3:229-230,
3:230f
unspecified, peripheral T-cell lymphomas,
3:229, 3:229f
Tears, muscle, 1:213-214
Technetium labeling, 1:30
Teeth
abnormal wear, 2:8
buds, 2:4
degenerative conditions, 2:7-9
infectious and inflammatory diseases,
2:9-12
odontodystrophies, 2:8-9
pigmentation, 2:7
development, 2:4-12
anomalies of, 2:6-7
fluorosis and, 1:84-86
mandibular osteomyelitis and, 1:103,
1:103f
undernutrition and, 1:65
vitamin A deficiency and, 1:82-83
pituitary dwarfism and, 3:281
structure of, 2:4-12
subnormal wear, 2:8
Teladorsagia, 2:54-55
Teladorsagia circumcincta, 1:66, 2:205
Telangiectasis, 3:99
adrenal cortex, 3:340
liver, 2:299-300, 2:299f-300f, 2:299.e1f
Telangiectatic osteosarcoma, 1:111, 1:111f,
1:114, 1:114f
Telemark lethal bovine chondrodysplasia,
1:38-39
Telepathology, 1:3-4, 1:3f
Telogen phase, hair, 1:516
Temporal odontomas, 1:502
Temporohyoid osteoarthropathy,
1:500
Tendons, 1:130, 1:246-249. See also
Muscle(s)
aging and injury, 1:247
aponeuroses and, 1:247-249
fibromatous disorders of tendons and
aponeuroses, 1:248-249
fibrodysplasia ossificans progressiva,
1:248-249, 1:249f
musculoaponeurotic fibromatosis, 1:248,
1:248f
general considerations, 1:246-247
parasitic diseases of, 1:247-248
Tension lipidosis, 2:275-276, 2:276f
Tephrosia cinerea, 2:342
Teratomas
ovaries, 3:377, 3:378f
testes, 3:496
Terminal acinus, 2:467
Terminal deoxynucleotide transferase-
mediated dUTP nick-end labeling
(TUNEL) technique, 2:280
Terminal hepatic venules, 2:260-261
Terminalia oblongata, 2:428
Terminal ileitis of lambs, 2:115
Terminal pulmonary edema, 2:386
Testes and epididymis
abdominally retained, 3:470f
atrophy and degeneration, 3:481-485,
3:482b, 3:482f-483f
circulatory disturbances, 3:491-492
epididymitis, 3:473-474, 3:474f, 3:487-
491, 3:488f-489f
equine fetal, 3:475, 3:475f
hemorrhage, 3:492, 3:492f
hypertrophy, 3:485
hypoplasia, 3:478-479, 3:478f
immune function, 3:467-468
inflammation, 3:485-491
mesonephric and paramesonephric
structure disorders, 3:480-481,
3:480f
neoplasms, 3:492-497
oxidative stress and, 3:467
size variations, 3:481-485
Test validation, 1:14
Tetanic/paretic syndromes, 1:318
Tetanus, 1:317
Tetrathyridia, 2:255
Tetrology of Fallot, 3:20, 3:20f-21f
Texas Brangus cattle, epidermolysis bullosa
in, 1:535
Texel sheep, 1:41, 1:41f-42f
Thallium, 3:34-35
Thallotoxicosis, 1:568-569, 1:569f
Thebesian veins, 3:56
Theileria equi, 3:119-120
Theileria spp., 3:176-178, 3:177f
Theiler’s disease, 2:313-314, 2:314f
Thelazia, 1:425
Thermal injury, 1:564-566, 1:564f-565f
Thiacetarsemide, 2:329
Thiamine deficiency, 3:34
nervous system and, 1:312-314,
1:313f
Thin filaments, 1:167, 1:168f
Thioamides, 3:324-325
Thiocyanate, 1:306
Third-degree burns, 1:564-566
Thoracic empyema, 2:521.e1f
Thoracolumbar spinal tumor of young dogs,
1:402-403, 1:403f
Thoroughbred horses, agammaglobulinemia
in, 3:139
3-methylindole (3-MI) toxicity, 2:519
Threlkeldia proceriflora, 2:425-426
Thrombi, 3:27, 3:90, 3:90f, 3:64.e1f
Thrombin, 3:55
formation, 3:260-261
amplification of thrombin generation,
3:261, 3:261f
fibrin formation, 3:262-263
inherited disorders, 3:263-264
laboratory evaluation, 3:262-263
functions of, 3:255, 3:256f
receptors, 3:256
Thrombin-activatable fibrinolysis inhibitor
(TAFI), 3:262, 3:262f
Thrombocytopenia, 3:258
Thrombocytopenic syndrome, 2:122
Thrombocytosis, 3:129
Thromboelastography (TEG), 3:258

Thromboembolism (TE), 3:63-66, 3:63f,
3:265
pulmonary, 2:489, 2:489b, 2:489.e1f
Thrombophlebitis, 3:89-91
caudal vena cava, 3:90.e1f
intracranial, 1:300
parasitic, 3:91-94
Thrombosis
aortic, 1:6f
aortic-iliac, 3:64, 3:64.e1f
arterial, 3:63-66, 3:63f, 3:63.e1f
balance between antithrombosis and,
3:53.e1f
caudal vena cava, 2:298, 2:299f
cerebrospinal arterioles, 1:299,
1:299f
portal vein, 2:297f
pulmonary, 2:489.e1f
splenic, 3:171f
testicular arteries, 3:491
Thrombotic microangiopathy, 2:421f,
2:419.e1f
Thromboxane A2 (TxA2), 3:256
Thrush, 2:14, 2:32
Thymitis, 3:148, 3:149f
Thymomas, 1:691-692, 3:153-157, 3:153f-
154f, 3:153.e1f
Thymus, 3:141-158
atrophy, 1:6f, 3:123, 3:144-147,
3:145f
carcinomas, 3:156-157, 3:157f
cortical lymphocytes, 3:143
cysts, 3:151, 3:152f, 3:151.e1f
developmental diseases, 3:144
fibrosis, 3:147f
germ cell tumors, 3:158
hematomas, 3:147-148, 3:147f-148f,
3:146.e2f
hemorrhage, 3:147-148, 3:146.e2f
hyperplasia, 3:150-151, 3:150f
hyperplastic and neoplastic diseases,
3:150-158
inflammatory diseases, 3:148-150
involution and atrophy, 1:6f, 3:123,
3:144-147, 3:145f-146f
lymphomas, 3:157-158, 3:157f-158f, 3:237,
3:240f, 3:157.e1f
medullary lymphocytes, 3:143
necrosis, 3:145-146, 3:146f, 3:145.e1f
neoplasms, 3:151-158, 3:152t
remnants, 3:147f, 3:153f
structure and function of normal,
3:141-144, 3:142f, 3:142.e1f
thymomas, 1:691-692, 3:153-157,
3:153f-154f, 3:153.e1f
with anaplasia, 3:157
Thyroglossal duct
cysts, 2:29, 3:310, 3:314
neoplasms, 3:332, 3:332f
Thyroid gland, 3:310-336
biosynthesis of thyroid hormones,
3:311-312
C cells, 3:296-297
tumors, 3:332-336, 3:333f, 3:335f
development, structure, and function,
3:310-314, 3:310f
diseases, 3:314-326, 3:314f
effects of drugs and chemicals on,
3:323-326
function evaluation, 3:319
hormones, 1:25t
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Thyroid gland (Continued)
action, 3:313-314
release blockage, 3:325
secretion, 3:312-313, 3:313f
-stimulating hormone (TSH), 3:276-277
thyroxine, 3:272
hyperplasia, 3:320-323, 3:320f
hypofunction, 3:315-319, 3:315f
location, 3:293f
neoplasms, 3:326-336
Thyroidization, 2:440f
Thyrotroph adenomas, 3:286
Thyrotropin-releasing hormone (TRH),
3:312-313
Thyroxine, 3:311
-binding globulin, 3:312
Thysanosoma actinoides, 2:319-320,
2:319.e1f
Tibetan Mastiffs, hypertrophic neuropathy in,
1:341-342
Tibetan Terrier dogs
canine atopic dermatitis, 1:591
diabetes mellitus, 2:373
Ticks, 1:152, 1:684
Babesia transmission by, 1:611, 3:117-120,
3:117f
-borne fever, 3:178
external ear, 1:506-507
flaviviral encephalitides, 1:373-376
Hepatozoon transmission by, 3:110
Tiger-stripe pattern, 2:125
Tissue-activatable fibrinolysis inhibitor
(TAFI), 3:266
Tissue factor pathway, 3:260-261
inhibitor (TFPI), 3:261, 3:266
Tissue samples. See Gross and histologic
examinations
T lymphoblasts, 2:64
Tobramycin, 2:424
Toluidine blue stains, 1:29
Tongue abnormalities, 2:4, 2:4f
Tonsillar crypts, 2:20
Tonsillar diseases, 2:19-20
Tonsillitis, 2:13-19, 2:13f
pigs, 2:13f
Tonsillophilus, 2:20
Tonsils, 2:20
Torsion, 2:78
bladder, 2:451
liver lobe, 2:268
lung lobe, 2:485-486, 2:485f
testis, 3:491-492
Total myeloschisis, 1:279
Toxascaris canis, 2:219
Toxascaris leonina, 2:219-220
Toxemia, pregnancy, 2:275
Toxic bone diseases, 1:84-91
fluorosis, 1:84-86
lead toxicity, 1:86, 1:87f
molybdenosis, 1:84
plant toxicities, 1:90-91
vitamin A toxicity, 1:67, 1:86-89
vitamin D toxicity, 1:89-90
Toxic epidermal necrolysis (TEN), 1:607-
615, 1:610f
Toxic hepatic disease, 2:325-344
agents, 2:328
Toxic insult, acute, 2:425
Toxicities, plant, 1:90-91, 1:219-220
avocado, 3:38
fluoroacetate, 3:38
Index 567
Toxicities, plant (Continued)
gousiekte, 3:38
hepatogenous photosensitization and,
1:580
horses, 1:91
liver and, 2:329-344
myocardial necrosis and, 3:34-41, 3:35f
parathyroid suppression associated with,
3:301-302, 3:301f
sheep, 1:90-91
Toxic lung injury, 2:518-520
Toxic metabolite-dependent idiosyncrasies,
2:327
Toxic myocardial degeneration, 3:34-35
Toxic myopathies, 1:218-220
ionophore toxicosis, 1:219
Toxicology, 1:11
Toxicopathology, 1:3
anoxia and nervous system, 1:305-307
thyroid gland, 3:323-326
Toxicosis. See Poisoning
Toxic retinopathies, 1:471-472
Toxic shock syndrome (TSS), 1:636-637
Toxocara canis, 2:219, 2:220f, 2:442
Toxocara vitulorum, 2:220
Toxoplasma gondii, 1:451, 1:664,
2:236-238
abortion and, 3:420-424, 3:420f-421f
adrenal cortex and, 3:340
central nervous system and, 1:389
myositis, 1:237
respiratory system and, 2:590, 2:590f,
2:590.e3f
Toy Manchester Terrier dogs, dilated
cardiomyopathy in, 3:48
Trabecular adenomas, 3:326-327
Trabecular meshwork, 1:461-462, 1:462f
Trabecular trichoblastomas, 1:716
Trachea, 2:467-469, 2:482-483
bronchus, 2:467
collapse, 2:483f, 1:192.e1
smoke inhalation and, 2:483, 2:483f
transitional metaplasia, 2:501, 2:501.e1f
Tracheal puddle, 2:571-572
Trachyandra poisoning, 1:292
Traction alopecia, 1:560
Traction diverticulum, 2:31
Transepidermal elimination, 1:524
Transglutaminases, 1:513
Transitional cell carcinoma, 1:736
nasal, 2:478-479, 2:479f
Transitional metaplasia of trachea, 2:501,
2:501.e1f
Transmissible gastroenteritis virus (TGEV),
2:113, 2:147, 2:148f
Transmissible genital papilloma, 3:508-509,
3:509f
pig, 3:449
Transmissible mink encephalopathy (TME),
1:349
Transmissible spongiform encephalopathies
(TSEs), 1:347
Transmural granulomatous enteritis, 2:97
Transphyseal blood vessels, 1:27-28, 1:28f
Transposition complexes, 3:22
Trans-synaptic degeneration, 1:254
Transverse ridge arthrosis, 1:142
Trapped neutrophil syndrome, 3:110
Trauma
abdominal, 2:246-247, 2:246f
acute conjunctival, 1:424
568 Index
Trauma (Continued)
articular cartilage response to, 1:131-132
blood loss anemia and, 3:112-114
central nervous system, 1:301-303
chronic conjunctival, 1:424
corneal, 1:429-432, 1:430f, 1:431t,
1:432f
deposits secondary to, 1:434, 1:434f
deafness caused by, 1:493-494
head, 1:301-303
hemolytic anemia due to, 3:125-126
infectious arthritis and, 1:149
ischemic damage to muscle fibers, 1:211,
1:211f
liver, 2:285-290, 2:287f, 2:326
hepatic artery, 2:296
portal vein, 2:296-297
lung, 2:500-520, 2:500f, 2:500.e1f
toxic, 2:518-520
ventilator-induced, 2:511
mammae, 3:451
muscle, 1:180-182, 1:180f, 1:213-214
myocardial necrosis secondary to neural,
3:39
neurons response to, 1:252-256, 1:252f
osteochondrosis, 1:132
peritoneal, 2:245-246
response of gastric mucosa to, 2:46-48
retinal, 1:473
skin, 1:559-561
mechanical, frictional, and traumatic,
1:559-566
psychogenic, 1:561-562, 1:561f
spinal cord, 1:128
tendon, 1:247
tracheal, 2:483
Traumatic lens rupture, 1:444
Traumatic neuroma, 1:724-725
Traumatic pericarditis, 2:39
Traumatic reticuloperitonitis of forestomachs,
2:38-39
Traumatic synovitis, 1:141
Trematodes, 1:391, 2:320-324
Trema tomentosa, 2:331
Tremor, congenital, 1:338
Tremorgenic mycotoxicoses, 1:318,
1:322
Trianthema portulacastrum, 2:425-426
Tribulosis, 2:338-340
Trichiasis, 1:421
Trichinella spiralis, 2:19
myocarditis and, 3:44
Trichinellosis, 1:237-238
Trichobezoars, 2:38, 2:50, 2:76f
Trichobezoars, 2:50
Trichoblastomas, 1:716, 1:716f
Trichoepitheliomas, 1:714-715, 1:715f
Trichofolliculomas, 1:705
Tricholemmoma, 1:715-716
Trichomegaly, 1:421
Trichophytobezoars, 2:50
Trichophyton, 1:652, 1:652f
Trichostrongylus axei, 2:54-55, 2:208-209
Trichostrongylus colubriformis, 1:66, 2:212
Trichostrongylus rugatus, 2:212
Trichostrongylus spp., 3:112-114
Trichostrongylus vitrinus, 2:212
Trichothecene toxicoses, 1:573-574
Trichuriasis, 2:115-116
Trichuris spp., 2:220-221, 2:221f
Trichuris vulpis, 2:98
Trifolium hybridum, 2:341-342, 2:341f
Trifolium subterraneum, 2:458
Triiodothyronine, 3:272, 3:311
Trimethoprim-sulfonamides, 2:329
Trimming of fixed autopsy and biopsy
specimens, 1:8-9
Tritrichomonas foetus, 2:98, 2:243, 3:423-424
Troglostrongylus acutum, 1:391
Troglostrongylus brevior, 2:591
Troglostrongylus subcrenatus, 2:591
Trombiculiasis, 1:682-683
Trueperella pyogenes, 2:19
Trueperella (Arcanobacterium) pyogenes,
1:102, 1:230, 3:507
abortion in cattle and sheep and, 3:412
endocarditis and, 3:30-31, 3:31f
infectious arthritis and, 1:148
oral cavity lesions, 2:19
splenic abscesses, 3:183-184
True retinal dysplasia, 1:420
Trypanosoma brucei brucei, 3:124, 3:473-474
Trypanosoma cruzi, 3:44, 3:121, 3:124
Trypanosoma equinum, 3:124
Trypanosoma equiperdum, 3:121, 3:445-447,
3:508
Trypanosoma evansi, 3:124
Trypanosoma simiae, 3:124
Trypanosomatidae, 3:174
Trypanosoma vivax, 3:121f, 3:491
Trypanosomiasis, 3:121-124, 3:121f
Trypanosom suis, 3:124
T-2 toxin, 1:573
Tuberculoid granuloma, 2:549
Tuberculoid leprosy, 1:641
Tuberculoproteins, 2:548
Tuberculosis, 1:639. See also Mycobacterial
infections
bovine, 2:547-551, 2:549f
caseous, 3:389
dogs and cats, 2:550
horses, 2:550
liver and, 2:315f
lymph nodes and, 3:204f-205f, 3:203.e1f
mastitis, 3:456-457
pigs, 2:550
Tubular backleak, 2:423
Tubular basement membranes, 2:422-423
Tubular cells, degeneration and swelling of,
2:421-422
Tubular diseases, 2:421-431
acute tubular injury (ATI), 2:421-428
ischemic tubular necrosis, 2:423f
with karyomegaly, 2:428f
epithelial injury, 2:428.e3f
myoglobin-induced acute tubular injury,
2:423f
nephrotoxic, 2:423
amaranthus, 2:427
aminoglycosides, 2:424
amphotericin B, 2:424-425
chelation of calcium, 2:426
cyanuric acid, 2:426-427
degeneration and swelling, 2:421-422
ethylene glycol, 2:425
grapes and raisins, 2:428
marked acute tubular necrosis, 2:428.e1f
melamine acid, 2:426-427
mycotoxins, 2:427
nephrotoxic in domestic animals, 2:424b
oxalate poisoning, 2:425-426
plant toxicoses, 2:427-428
primary renal glucosuria, 2:429
specific tubular dysfunctions, 2:428-429
sulfonamides, 2:424
tetracyclines, 2:424
Tubular epithelial injury, acute, 2:428.e3f,
2:421.e2f
Tubular genitalia development, 3:360-361,
3:361f
Tubular injury, acute, 2:427f-428f,
2:433f
Tubular necrosis, acute, 2:398-399
caused by ethylene glycol intoxication,
2:426f, 2:425.e2f
Tubular protein casts, 2:407
Tubules, 2:383
Tubule segment, structure, 2:381
Tubuloglomerular feedback, 2:379
Tubulointerstitial diseases, 2:431-443
chronic interstitial nephritis, 2:431
Encephalitozoon cuniculi, 2:431
histologic features, 2:431
Leptospira interrogans, 2:431
nonsuppurative interstitial nephritis,
2:431-432
Tubulointerstitial nephritis, chronic,
2:433.e1f
Tubulointerstitium, from proteinuric dog,
2:407f
Tubulorrhectic ATI, 2:422-423
Tularemia, 3:184-186, 3:185f
Tumoral calcinosis, 1:127, 1:127f
Tumor-like proliferative lesions, 2:101t
Tumor necrosis factor-α, 2:548-549
Tumors, 2:447-448. See also Lymphomas;
Metastases, tumor; Non-neoplastic
lesions
adrenal medullary, 3:349-352
benign cortical fibromas, 2:447
bone, 1:107-127
cartilage-forming, 1:116-121
fibrous, 1:121-122, 1:121f
forming, 1:109-116, 1:109f
giant cell, 1:122
secondary, 1:124-125
vascular, 1:122
brain, 1:296f
carcinoma, 2:447
cholangiocellular, 2:348-349, 2:348f
dental tissue, 2:22-25
endocrine gland, 3:271-272
epithelial
pulmonary, 2:495
skin, 1:703
thymic, 3:152-153
granular cell, 1:245, 2:27
heart, 3:52-53
laryngeal, 2:482
pulmonary, 2:498
hemangioma, 2:447
hepatocellular, 2:345-348, 2:346f
hypersecretion of hormones by,
3:274
interstitial cell, 2:447
intestinal stromal tumors, 2:110-111
gastrointestinal, 2:110
leiomyoma, 2:110
leiomyosarcoma, 2:110
-like lesions
of bones, 1:125-127
of joints, 1:159-163
liver mesodermal, 2:349-351, 2:350f
lymphoma, 2:447
male genital system
germ cell, 3:495-496, 3:495f
interstitial testicular, 3:493, 3:493f
Sertoli cell, 3:494-495, 3:494f
sex cord-gonadal stromal, 3:492-495

Tumors (Continued)
mast cell, 2:27
mesenchymal, 2:44
metastatic, 2:447
nasomaxillary, 2:480, 2:560, 2:560f
neuroendocrine, 2:497-498
pedicles of, 2:76-77
pituitary gland, 3:281-289, 3:289f
plasmacytomas, 2:27-28
primary mesenchymal, 2:447
pulmonary adenocarcinoma, 2:447
renal oncocytomas, 2:447
skin, 1:703, 1:705
adnexal differentiation, 1:714-720
epidermis, 1:706-714
mast cell, 1:730-733
melanocytic, 1:720-722, 1:720f
metastasis to, 1:736
sebaceous gland, 1:717-718, 1:717f
spindle cell, 1:722-726
sweat gland, 1:718-720
vascular, 1:726-728
stomach and intestine, 2:100-111, 2:101t
thymic epithelial, 3:152-153
thyroid, 3:327-329
urothelial papilloma, 2:447
Tumor(s)
embryonal, 1:401-403
mengingeal, 1:396-398
neuroepithelial tissue, 1:398-403
sellar region, 1:403-404
Tumor(s), peritoneal, 2:256-257
Tunica vaginalis, indirect inguinal hernia,
2:80
Turning sickness, 3:178, 3:178f
25- hydroxycholecalciferol-1-α-hydroxylase,
3:295
2,8-DHA urolithiasis, 2:430.e1
2,8-dihydroxyadenine, 2:272
Tylecodon toxicosis, 1:345
Tympanic cavities, 1:495
otitis media, 1:496-498
Tympanic cavity inflammation. See Otitis
media
Tympanic membrane, 1:491, 1:495
Tympanic ring, 1:495, 1:495.e2f
Tympanokeratoma, 1:499, 1:499f
Type AB thymomas, 3:156, 3:156f
Type 2A histochemical fiber type, 1:169
Type A thymomas, 3:154, 3:154f
Type 2B histochemical fiber type, 1:169
Type B2 thymomas, 3:155-156, 3:155f-156f
Type B3 thymomas, 3:156, 3:156f
Type 1 histochemical fiber type, 1:169,
1:170f
Type I collagen, 1:19
Type II pneumocytes, 2:470
Type I pneumocytes, 2:469-470
Type 2X histochemical fiber type, 1:169
Typhlitis, 2:97
Typhlocolitis, 2:97-98, 2:98f
horses, 2:99-100
pigs, 2:100
Tyrosine, 3:311
Tyzzer’s disease, 2:317, 2:317f-318f
T-zone lymphomas (TZL), 3:229-230,
3:230f
U Uremic toxins, 2:385
Uasin Gishu disease, 1:621
Ulcerating fibrosarcoma, 2:35f
Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510
Index 569
Ulceration, 2:385f Ureters
BVDV, 2:123-124, 2:124f anomalies, 2:449-450
corneal, 1:429-432, 1:430f, 1:431t, 1:432f displacements, 2:451
decubitus, 1:559 duplication of, 2:392
gastroduodenal, 2:55-60 Urethra, 2:448
indolent, 1:694, 1:694f Urethral atresia, 2:450
laryngeal, 2:481 Urethral caruncles, 2:452
mucosal protective mechanisms, 2:55 Urethral hypoplasia, 2:450
of squamous mucosa, 2:59f Urethral plugs, 2:452
Ulcerative balanitis, 3:508 Urethrorectal, 2:450
Ulcerative colitis, 2:86f Urinary bladder, 2:448
Ulcerative dermatosis of sheep, 1:618 duplication, 2:450
Ulcerative duodenitis, 2:59 Urinary hydroxyproline, pyridinoline (PYD),
Ulcerative esophagitis, 2:31-32 1:27
Ulcerative keratitis, 1:436 Urinary system
Ulcerative lymphangitis, 3:97 calculi, 2:453t
Ulcerative mural endocarditis, 3:32, 3:33f defenses, 2:439
Ulcerative posthitis infections. See Urinary tract infection
bulls, 3:507 (UTI)
of wethers, 3:508 kidneys. See Kidney(s)
Ulcerative stomatitis, chronic, 2:16 neoplasms, 2:462
Ulegyria, 1:268 obstruction, 2:399
Ulex europaeus agglutinin I, 2:445 pH, 2:452-453
Ulmaceae, 2:331 urea excretion, 2:73
Ultimobranchial body, 3:296 Urinary tract, lower, 2:448-464
Ultimobranchial gland, 3:296 anomalies of, 2:449-452
Ultimobranchial tumors of thyroid, acquired anatomic variations, 2:451-452
3:334-336 ectopic ureter, 2:450
Ultrastructure, muscle, 1:167 renal dysplasia in pig, 2:449.e2f
Umbilical hernia, 2:80 ureteral duplication in pig, 2:449.e2f
Uncinaria stenocephala, 2:214 ureters, 2:449-450
Undifferentiated carcinomas, 2:463 urethra, 2:450-451
nasal, 2:478-479 urinary bladder, 2:450
Undifferentiated diarrhea of neonatal circulatory disturbances, 2:452
animals, 2:111, 2:112f clover stones, 2:458
Undifferentiated neonatal diarrhea, 2:112f cystine calculi, 2:458
Undifferentiated pleomorphic sarcomas, cystitis, 2:459-461
1:725-726 enzootic hematuria, 2:461-462
Undifferentiated thyroid carcinomas, inflammation of, 2:458-462
3:330-331 mycoplasmas, 2:459
Unexpected death, causes of, 1:4t neoplasms of, 2:462-464
Unfolded protein response (UPR), 2:280 epithelial tumors, 2:462-463
Unilateral agenesis of adrenal gland, 3:338 mesenchymal tumors, 2:463-464
Unilateral papular dermatosis, 1:695 obstructive urolithiasis, 2:455f
Unilateral renal hypoplasia, 2:392f oxalate calculi, 2:456-457
Unipyramidal, 2:378 oxalate uroliths, in cats, 2:457
Unspecified, peripheral T-cell lymphomas ruminants, 2:456
(PTCL), 3:229, 3:229f silica calculi, 2:455
Upper airway, 2:466-467, 2:466f staghorn calculus in renal pelvis of dog,
disease, 2:500-504, 2:500.e1f 2:454f
Upper respiratory tract, 2:473 struvite calculi, 2:455-456
immunology, 2:474 types of calculi, 2:458
Urate calculi, 2:385f urate calculi, 2:457
Ureaplasma diversum, 1:154, 2:554 ureters, urinary bladder, and urethra, 2:448
abortion and, 3:411-412, 3:412f uric acid, 2:457
Ureaplasma spp., 3:401 urinary calculi, composition and
Urea-splitting organisms, 2:457 importance, 2:453t
Urea toxicity, 2:35-36 urinary pH and reduced water intake,
Uremia, 2:16-17, 2:384-388, 3:60, 3:260 2:452-453
diffuse tissue mineralization, pathogenesis urolithiasis, 2:452-458
of, 2:387 dog, 2:454f
nonrenal lesions of, 2:385 urothelium, 2:448-449
renal lesions of, 2:387 xanthine calculi, 2:457-458
Uremic acidosis, 2:384 Urinary tract infection (UTI), 2:458-459
Uremic encephalopathy, 2:387 predisposition, 2:458-459
Uremic gastritis, 2:51 risk factors, 2:458-459
Uremic pneumonitis, 2:386, 2:387.e1f Urine
Uremic pneumonopathy, 2:494-495, 2:494f osmolality, 2:459
in peritoneal cavity, 2:452
Ureteral duplication, 2:449.e2f protein to urine creatinine (UPC), 2:401
Ureterocele, 2:450 supersaturation, 2:452-453
570 Index
Uriniferous pseudocyst, 2:451
Urolithiasis, 2:454f
Urolith initiation
crystallization-inhibition theory, 2:453
matrix-nucleation theory, 2:453
Uroperitoneum, 2:247
Uroplakins, 2:462.e1
Urothelial cell carcinomas, 2:447f, 2:462-463,
2:462f, 2:447.e1f
metastasize, 2:462-463
Urothelial papilloma, 2:447
Urothelium, 2:448
Urticaria, 1:594
Uterine (fallopian) tubes pathology,
3:379-380
Uterus
abscess, 3:390
accumulation of secretory or inflammatory
exudates, 3:386-387
carcinoma, 3:449-450, 3:450f
cysts arising from, 3:366-367
inflammatory diseases of, 3:387-393
mucometra, 3:374, 3:374f
neoplasia, 3:449-450, 3:450f
pathology, 3:380-382, 3:380f, 3:393-398
postpartum, 3:440-441
rupture, 3:381, 3:381f
UVA/UVB radiation. See Solar radiation
Uvea, 1:445-465
degenerations, 1:445-446
glaucoma, 1:459-465
melanocytoma, 1:482-483, 1:483f
uveitis, 1:446-459
bacterial endophthalmitis, 1:449
significance of, 1:447-448, 1:447f-448f
Uveitis, 1:446-459
bacterial endophthalmitis, 1:449
bovine malignant catarrhal fever-associated,
1:453
canine adenovirus I, 1:452-453
equine recurrent ophthalmitis, 1:455-456
feline infectious peritonitis-associated,
1:453, 1:453f
histologic classification, 1:448-449
idiopathic immune-mediated, 1:453-455,
1:454f
idiopathic lymphocytic, in dogs, 1:456
idiopathic lymphonodular, of cats, 1:456
lens-induced, 1:453-454, 1:457-459
mycotic endophthalmitis, 1:449-451
protozoal endophthalmitis, 1:451
significance of, 1:447-448, 1:447f-448f
uveodermatologic syndrome, 1:453-454,
1:456-457, 1:457f
viral endophthalmitis, 1:452
Uveodermatologic syndrome, 1:453-454,
1:456-457, 1:457f
V photoactivated, 1:580
Vaccinal fibrosarcomas, 1:725
Vaccine administration and injection-site
reactions, 1:560
Vaccine-induced polyarthritis, 1:158
Vaccinia virus, 1:616, 1:620
Vacuolar degeneration, 1:185, 1:185f, 1:254,
1:254f, 1:522
Vacuolation, 2:272-273, 2:272f
Vagal indigestion, diagnosis of, 2:39
Vagal lesions, 2:39
Vagina
anomalies, 3:369-370, 3:370f
inflammatory diseases, 3:443
pathology of, 3:442-447, 3:442f
Vaginal eventration, 2:78
Vaginal stenosis, 3:369, 3:370f
Vaginal tunics, 3:473-474, 3:473f-474f
Vaginitis, necrotic, 3:445, 3:445f-446f
Vagus indigestion, 2:39
Valgus deformity, 1:31
Valvular cysts, 3:30
Valvular endocarditis, 3:30-31, 3:31.e1f
Vanishing bone disease, 1:54
Varicocele, 3:497-498, 3:498f
Varicose tumor of the scrotum, 3:99
Variola virus, 1:616
Varus deformity, 1:31
Vascular anomalies
heart, 3:23-24, 3:23f
liver, 2:266-268
Vascular endothelial growth factor (VEGF)
receptors, 2:421
Vascular-epithelial structure, 2:379-380
Vascular hamartomas of ovary, 3:366,
3:378-379
Vascular malformation, 3:99
Vascular neoplasia, 3:98-101
Vascular nevus, 1:727
Vascular occlusive syndrome, 1:212,
1:212f
Vascular ring anomalies, 2:33
Vascular smooth muscle cells, 3:55-56
Vascular system
arteries, 3:56-88
congenital abnormalities, 3:14-24
dermal, 1:514-515
diseases, 3:54-101
hemodynamic effects of valvular
abnormalities, 3:4.e1f
leakage, 1:298f
liver, 2:266-268, 2:296-300
lungs, 2:467-468, 2:468f
neoplasms, 3:98-101
retina, 1:466
spleen, 3:161, 3:161f
tumors
bone, 1:122
dogs, 1:122
oral cavity, 2:28
skin, 1:726-728
veins, 3:88-94
Vasculitis, 1:525-526, 1:526f, 1:607, 3:67-88,
3:68b, 3:68.e1f
cerebrospinal, 1:298-299, 1:298f-299f
chronic fibrosing, 3:71, 3:71f
cutaneous, 1:611-612, 1:611f
lymphocytic, 1:526, 1:611
male genital system, 3:498
necrotizing, 1:200, 1:200f, 3:69, 3:69f
neutrophilic, 1:526, 1:611
nodular eosinophilic, 1:612
pastern leukocytoclastic, 1:612
pulmonary, 2:494, 2:494.e2f
rabies vaccine-induced, 1:612-613, 1:613f
Vasoactive intestinal polypeptide, 2:368
Vasogenic edema, 1:294, 1:295f
Vasopressin. See Antidiuretic hormone
(ADH)
Veins, 3:54, 3:88-94
drainage, 2:18
hepatic, 2:260
infarction, 2:82f
inflammation. See Phlebitis
invasion by neoplasms, 3:89, 3:89f
obstruction of cerebrospinal, 1:300
pulmonary, 2:467-468, 2:468f
Vena caval syndrome, 3:85
Venom, 1:568
Venous drainage, 2:18
Venous infarction, 2:82f
Ventilator-induced lung injury, 2:511
Ventral hernia of abdominal wall,
2:80
Ventricles, heart, 3:2
restricted filling, 3:6
wall thickness, 3:5
Ventricular pre-excitation, 3:51
Ventricular septal defect (VSD), 3:17,
3:17f-18f
Veratrum californicum, 1:90, 1:269-270,
2:3
cleft palate and, 2:3
Verminous arteritis, 3:83-88
Verminous endoarteritis, 2:84
Verminous granulomas, 3:498
Vernonia rubricaulis, 2:331
Verotoxin-producing E. coli (VTEC),
2:162
Verrucous sarcoids, 1:708, 1:709f
Vertebrae
congenital abnormalities, 1:57
diskospondylitis, 1:156, 1:156f
osteomyelitis, 1:101-102, 1:102f
subluxations, 1:303
Very low-density lipoproteins (VLDLs),
2:273, 2:276-277
Vesicle, 1:524
Vesicoureteral reflux, 2:439
Vesicular adenitis, 3:499-500, 3:499f
Vesicular cutaneous lupus erythematosus,
1:607
Vesicular exanthema (VE), of swine,
2:120-121
Vesicular exanthema of swine virus (VESV),
2:121
Vesicular stomatitis (VS), 2:14-15, 2:117-
158, 2:120f
Vestibular membrane, 1:489
Vestibular window, 1:489
Vestibulocochlear nerve, 1:489-491
Vetch toxicosis, 1:574
Vicia villosa, 3:36
Villaneuva’s bone stain, 1:29
Villus, 1:524
Villus atrophy, 2:67-68, 2:96
Villus fusion, 2:146
Vimentin, 1:261
Viral agents, 2:57
Viral antigen, 2:22
Viral arthritis, 1:154
Viral endophthalmitis, 1:452
Viral inclusion bodies, 1:255
Viral infections
abortion and stillbirth due to, 3:398,
3:399b
alimentary tract, 2:117-158
bone, 1:104-105
central nervous system and, 1:365-385
developmental defects of central nervous
system and, 1:280-284
liver, 2:309-325
lobular necrosis and, 2:282
lymphomagenesis and, 3:235
myocarditis and, 3:42, 3:43f
parvo-, 1:628
pregnant uterus, 3:424-440
respiratory system, 2:523-531
cats, 2:587-589
cattle, 2:537-542
 Index 571

Viral infections (Continued) Vogt-Koyanagi-Harada syndrome, 1:453-454, Whippet dogs

dogs, 2:574-577 1:456-457, 1:457f, 1:613 color dilution alopecia, 1:539-540
horses, 2:567-569 Volvulus, 2:83 muscle hypertrophy, 1:191, 1:191f
sheep and goats, 2:557-562 abomasal, 2:49-50, 2:50f myxomatous valvular degeneration, 3:27
skin, 1:615-628 gastric, 2:49, 2:49f Whipworms, 2:220-221, 2:221f
thymic atrophy and, 3:145 splenic, 3:167, 3:167f White pulp, spleen, 3:161-162
Viral vasculitides, 3:71-80 Von Hippel-Lindau (VHL) gene, 2:444-445 White-spotted kidneys, 2:431f, 2:436,
Virology, 1:10-11 Von Kossa stains, 1:29 2:431.e1f
Virtual microscopy, 1:3-4, 1:3f Von Meyenburg complex, 2:264, 2:265f White-tailed deer, osteopetrosis in, 1:52
Virulent footrot (VFR), 1:644 Von Willebrand disease (vWD), 3:258-259 Whorled muscle fibers, 1:185, 1:185f
Virus-induced fibrosarcomas, 1:725 Von Willebrand factor (vWF), 3:256 WHO system of classification of
Virus titers, 2:121 Vulva, 3:442-447 hematopoietic neoplasms, 3:217,
Visceral larva migrans, 1:452 fibropapilloma, 3:449 3:217t
Visceral leishmaniasis, 3:174-175 inflammatory diseases, 3:443 Wild black cherry, 1:90
Visna-maedi virus (VISNA), 1:378-380 swelling, 3:442-443 Wildebeest-associated MCF, 2:132
Vitamin A Vulvitis Wild lupins, 1:90
deficiency, 1:82, 1:581-582, 1:582f, 2:8, granular, 3:443, 3:443f Winchester syndrome, 1:54
2:29-30 necrotic, 3:445, 3:445f-446f Winter dysentery, 2:149, 2:150f
hydrocephalus, 1:271, 1:271f Vulvovaginitis, infectious pustular, 3:443-445, Wohlfahrtia magnifica, 1:668
odontodystrophies and, 2:8 3:444f Wolff’s law, 1:30
pigs, 1:82-83 Wolfhound dogs, gastric volvulus in, 2:49
salivary gland inflammation, 2:29-30 W Wooly haircoat and cardiomyopathy, 3:50
excess, 1:89 Waardenburg syndrome, 1:555-556 Worms. See Helminthic infections;
function, 1:82 Wallerian degeneration, 1:256-257, Nematodes
-responsive dermatosis, 1:552 1:257f Woven bone, 1:21, 1:21f, 1:78-79, 1:79f,
toxicity, 1:86-89 Warbles, 1:668-669 1:108f
cats, 1:88, 1:88f Warts. See Papillomas
cattle, 1:88 Warty dyskeratomas, 1:705 X
horses, 1:89 Water Xanthine calculi, 2:457
osteoporosis and, 1:67, 1:87 diuresis, 2:381 Xanthium pungens, 2:331
pigs, 1:88 salinity, 1:314 Xanthomas, 1:641
Vitamin B deficiency, 1:582 urolithiasis and, 2:454f cutaneous, 1:700
Vitamin C Waterhouse-Friderichsen syndrome, 3:65 Xanthosis, 3:34
deficiency, 1:83, 1:582-583 “Watery mouth”, 2:167 Xenobiotics, 3:324-326, 3:326f
cataract and, 1:443 Wattles, 1:532 liver and, 2:325
scurvy and, 1:83, 1:83f Wave mouth, 2:8 Xipapillomavirus, 2:22
function, 1:83 Weaner colitis of sheep, 2:180-181 Xiphoid, 2:39
Vitamin D Wedelia glauca, 2:331 X-linked hypohidrotic ectodermal dysplasia
cholecalciferol, 3:295-296 Weighting of competing etiologies, cut-offs, (XHED), 1:539, 1:539.e1f
deficiency, 1:61 explanation, 1:12-13 X-linked ichthyosis, 1:530
cats, 1:68 Weimaraner dogs X-linked myotubular myopathy in Labrador
cattle, 1:68 canine hypomyelinogenesis, 1:337-338 Retrievers, 1:197
dogs, 1:68 follicular dysplasia, 1:540-541 X-linked severe combined immunodeficiency,
pigs, 1:68 hydromyelia, 1:278 3:140
rickets and, 1:68 hyperestrogenism, 1:589 Xnathium pungens, 2:329-330
-dependent rickets type I, 1:69-70 malignant oral tumors, 2:21 XXY chromosomes, 3:469
metabolism disorders. See Rickets subvalvular aortic stenosis, 3:20 XY disorders of sexual development, 3:365,
parathyroid hormone and, 1:62 syringomyelia, 1:278, 1:278f 3:365f
parathyroid suppression associated T-cell immunodeficiency, 3:141 Xylitol, 2:329
with intoxication of, 3:301-302, Weisses Alpenschaf sheep, epidermolysis
3:301f bullosa in, 1:535 Y
poisoning, 3:61 Werdnig-Hoffman disease, 1:331 Yaba monkey tumor virus, 1:616
-resistant rickets, 1:70 Wesselsbron virus (WESSV), 1:281, 2:312, Yatapoxvirus, 1:616
toxicity, 1:89-90 2:313f, 3:428-429 Y chromosome, 3:365, 3:469
cats, 1:89 West Highland White Terrier dogs Yeast bodies
transport, 1:62 canine atopic dermatitis, 1:591 Blastomyces dermatitidis, 1:104, 1:449,
Vitamin E chronic hepatitis, 2:304 2:580, 3:491
deficiency, 1:583, 2:86-87 cochleosaccular degeneration, 1:492 Coccidioides immitis, 1:449-450, 2:583-584,
nutritional myopathy, 1:214-215, globoid cell leukodystrophy, 1:339 2:584f
1:217 hyperplastic dermatosis, 1:553 Yellow fat disease. See Steatitis
Vitamin K, 1:19 interstitial fibrosis, 2:514-515, 2:515f Yersinia enterocolitica, 2:176, 3:210
antagonism, 3:264 keratoconjunctivitis sicca in, 1:436 Yersinia pestis, 3:210, 3:210f
-dependent γ-glutamyl carboxylase polycystic kidney and liver disease, Yersinia pseudotuberculosis, 2:176, 2:177f,
deficiency, 3:264 2:265 3:209-210, 3:209f
Vitamins. See also specific vitamins seborrhea, 1:548 liver and, 2:314-315
imbalances, 1:82-84 sick sinus syndrome, 3:51 Yersinia spp. and abortion, 3:401, 3:413-414,
lipid malabsorption, 2:90 spongy enceophalomyelopathies, 3:413f
Vitiligo, 1:555, 1:556f, 1:556.e1f 1:346 Yersiniosis, 2:176-177
Vizsla dogs West Nile virus, 1:281 Yorkshire Terrier dogs
afibrinogenemia, 3:265 encephalomyelitis, 1:374-375, 1:375f color dilution alopecia, 1:539-540
sebaceous adenitis, 1:551 Wheal, 1:524 pancreatic necrosis, 2:358

Volume 1  •  pp 1–736  •  Volume 2  •  pp 1–592  •  Volume 3  •  pp 1–510

572 Index
Yorkshire Terrier dogs (Continued)
primary portal vein hypoplasia,
2:267-268
rabies vaccine-induced vasculitis and
alopecia, 1:612, 1:613f
spongy encephalomyelopathies, 1:346-347
Yucatan minipigs, 1:604
Z Z-line streaming, 1:190, 1:193-194,
Zalophus californianus, 2:121
Z bands, 1:167
in muscular dystrophy, 1:193-194, 1:194f
Zenker’s degeneration, 1:181-182
Zenker’s fixative, 1:408, 1:449, 3:474-475
Zinc
chemical abomasitis and, 2:52
deficiency, 1:583-585, 1:584f
dogs, 1:585-586, 1:585f
hereditary, 1:532-533
toxicity and pancreas, 2:356, 2:357f
1:194f
Zollinger-Ellison syndrome, 2:55-56,
2:375
Zona fasciculata, 3:336
Zona glomerulosa, 3:336
hyperplasia, 3:343, 3:344f
Zona reticularis, 3:336-337
Zone of degeneration, growth plate, 1:23
Zonisamide, 2:329
Zoophilic dermatophytes, 1:649
Zoospores, 1:632, 2:203
Zoo ungulates, 1:214-215
Zygomycetes, 1:659, 2:42, 2:324, 2:324f,
2:573
Zygomycosis, 1:659-660
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