Disorders of Cell Growth & Neoplasia

Normal tissue growth & non-neoplastic

growth disorders
NORMAL
NORMAL TISSUE
TISSUE GROWTH
GROWTH AND
AND CELL
CELL PROLIFERATION
PROLIFERATION

Body
Body /
/ Organ
Organ Size
Size
• total cell mass = number of cells (cell division - cell death) + size of cells

• controlled by genes and regulated

by extracellular signal molecules.

 stimulatory factors

 inhibitory factors

• Excess of stimulators or deficiency of

inhibitors  net growth

Source: Robbins and Cotran Pathologic Basis of Disease (2010), 8th ed., Elsevier, Inc.
NORMAL
NORMAL TISSUE
TISSUE GROWTH
GROWTH AND
AND CELL
CELL PROLIFERATION
PROLIFERATION

• most adult organs contain a mixture of cells with different capacities for cell division

 Continuously dividing (labile) cells

- proliferate throughout life; replace cells that are continuously lost
eg. blood, skin, surface epithelia.

 Quiescent (stable) cells

- low level of division; respond rapidly to stimuli
eg. parenchymal cells, fibroblasts, osteoblasts, chondroblasts, endothelia

 Nondividing (permanent) cells

- cannot undergo mitosis
eg. Neurons, skeletal* and cardiac muscle
* can regenerate if sarcolemmal sheaths intact
DISTURBANCES
DISTURBANCES OF
OF GROWTH
GROWTH

• Range from complete absence of tissue development (agenesis) to totally

unregulated growth (neoplasia).

Agenesis
Agenesis
• complete failure of an organ
/ tissue to develop with no
associated primordium. A

Renal agenesis, unilateral.

K = left kidney, A = adrenal glands
 Aplasia
Aplasia

• Failure of an organ / tissue to grow

due to failure of development of
the primordium.

Uterine aplasia, unilateral and segmental, pigs. Note the

remnants of connective tissue (primordium; p)
 Hypoplasia
Hypoplasia
• failure of an organ / tissue to reach its normal size (less severe than
aplasia)

Cerebellar hypoplasia (top), normal Unilateral renal hypoplasia, calf.

cerebellum(bottom), brain, cats
Pathologic Basis of Veterinary Disease (2006), 4th ed., Mosby-Elsevier
 Unilateral hypoplasia (right sided), testes, dog

Histo: A: Normal testis showing normal

spematogenesis (arrows). B: Hypoplastic testis. The
seminiferous tubules are lined only by Sertoli cells (s) and
there is no spermatogenesis. Leydig cells (L) are not
affected.

Source: Robbins and Cotran Pathologic Basis of Disease (2010), 8th ed., Elsevier, Inc.
 Dysplasia
Dysplasia
• in organ development: abnormal organization/maturation of cells (‘eg retinal
dysplasia, hip dysplasia, renal dysplasia, etc.)

Renal dysplasia, dog. The external surface is Tricuspid valve dysplasia, kitten. The free edges of the
lobulated. Cut surface reveals irregular thickness of tricuspid leaflets are directly attached to the papillary
the cortex and heterogeneous tissue. muscles(no chordae tendinae in between)
Causes of Developmental Anomalies

• failure of the progenitor cells to proliferate and differentiate appropriately.

 Genetic causes:
i) chromosomal (karyotypic) aberrations.
- XX/XO mosaicism, etc.
ii) gene mutation.
- chondrodysplasia, collagen dysplasia, etc.

 Environmental causes:
i) in utero infections
- BVD, FPV, etc
ii) in utero exposure to radiation and drugs / chemicals / toxins
- thalidomide, Veratrum plants, etc

 Mutifactorial causes:
• combination of hereditary and environmental factors.
Hyperplasia
Hyperplasia

• increased organ/tissue mass due to increased number of cells.

• recall, hypertrophy and hyperplasia are not mutually exclusive.

a) Etiology
i) Physiologic Hyperplasia
• physiologic hormonal stimulation
• compensatory hyperplasia

ii) Pathologic Hyperplasia

• excessive hormonal stimulation
• chronic irritation (via growth factors)
 Hyperplasia
Hyperplasia

b) Mechanisms / Biochemistry

• Increased production of growth factors /

hormones.
• Increased expression of growth factor receptors.
• Activation of specific intracellular signaling
pathways.

• It is reversible, it regresses when stimulus is

removed (unlike neoplasia).
• Pathologic hyperplasia is a “fertile soil” for
the development of neoplasia.
Histo: Regenerative nodules:
Nodules (N) are surrounded
by thick bands of fibrous
tissue (F)

F
Hyperplasia
Hyperplasia

Cirrhotic liver with multiple hyperplastic (regenerative)

nodules, dog. From Noah’s arkive
 Goiter, thyroid gland, goat fetus. Marked
enlargement of the gland (T) due to diffuse
T
proliferation of follicular cells.

Cortical hyperplasia (c) of adrenal glands

stimulated by an ACTH secreting tumor (T) of
the pituitary gland. C
 Metaplasia
Metaplasia

• One adult cell type is replaced

by another adult cell type (e.g.,
squamous, intestinal, or bone
metaplasia)

• An adaptive substitution; cells

sensitive to stress are replaced
by a more resistant cell type

• causes:
• chronic inflammation
• vitamin A deficiency

Metaplasia of columnar to squamous epithelium. A, Schematic

diagram. B, Metaplasia of columnar epithelium (left) to squamous
• Usually reversible (if persists can epithelium (right) in a bronchus.
lead to cancer development)
Source: Robbins and Cotran Pathologic Basis of Disease (2010), 8th ed., Elsevier, Inc.
 Dysplasia
Dysplasia

• in mature tissues, it refers to disordered growth of cells.

• loss of cell uniformity & architectural disorganization.

• primarily in epithelium; early indicator of neoplastic transformation.

• characterized by cellular atypia:

 pleomorphism.

 nuclei often hyperchromatic,

enlarged (↑ N/C ratio) & large
nucleoli.

 more mitotic figures; in

abnormal locations.

 tissue architecture is often

disorganized.
Adaptive changes in epithelium
Pathologic Basis of Veterinary Disease (2006), 4th ed., Mosby-Elsevier
 C Robbins and Cotran Pathologic Basis of Disease (2010), 8th ed., Elsevier, Inc.

Normal squamous epithelium. Stratum basale (B), stratum

spinosum /lucidum (S), stratum corneum (C). Dysplastic squamous epithelium. There is no differentiation
(maturation), so most cells look like basal cells.

Dysplastic squamous
epithelium. Dysplastic cell
show large (karyomegaly)
hyperchromatic nuclei
(arrows) .
Hamartoma

• A benign tumor-like mass composed of an overgrowth of mature cells

and tissues normally present in the affected organ

• Present at birth (an overgrowth of progenitor cells in the fetus)

Vascular hamartoma (i.e. consisting of well differentiated blood vessels) on the dorsal surface of the tongue, 2-day-
old bovine.
 Joseph Merrick photographed in 1889
"The Elephant Man”

Proteus syndrome, a complex hamartomatous

disorder characterized by asymmetrical gigantism,
epidermal nevi, vascular malformations, hamartomas,
lipomas and hyperostosis. Proteus syndrome (named for the shape-shifting god Proteus)
 Choristoma
Choristoma

• a mass of histologically normal tissue in an abnormal location (ectopic rest).

Dermoid, cornea. A mass consisting of mature skin

and its appendages

Ectopic pancreatic tissue (choristoma),

small intestine (arrow). http://w3.vet.cornell.edu/nst/nst.asp
 NEOPLASIA

Definitions
Definitions

Neoplasia/Neoplasm = new growth (a purposeless, heritable altered growth of tissue

that tends to be atypical, autonomous and aggressive)
Tumor = historically referred to any swelling; now synonymous with neoplasm.

Oncology = the study of neoplasia.

Oncogenesis = the causation or production of neoplasia.

Cancer (“crab”) = common term for all malignant neoplasms (human medicine). “cancers
adhere to any part that they seize on in an obstinate manner, similar to a crab”
“infiltrative growths that extend crab-like feet into adjacent tissues”
“radiating dilated veins often do appear over and around a bulging tumor resembling the claws of a
crab”

"A tumor is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated
with that of the normal tissue and persists in the same excessive manner after cessation of the
stimuli which evoked the change." (Willis, 1952)
Terminology

• Inconsistencies persist in the classification of neoplasms

• The term for a neoplasm must convey whether it is:

Benign or Malignant

Mesenchymal versus epithelial origin.

The suffix -oma is almost always present.

Mesenchymal = embryonic mesoderm (connective tissue, bone,

cartilage, muscle and hematopoietic / lymphatic systems)
Epithelial = cells that line surfaces or lumina of organs and form glands
 Benign
Mesenchymal (structural / connective tissues, vessels):

TUMOR NAME ORIGIN

Lipoma (lipocyte),
Fibroma (fibrocyte),
Osteoma (osteocyte),
Chondroma (chondrocyte),
Leiomyoma (leios, smooth; mys, muscle),
Rhabdomyoma (rhabdos, rod [striated]; mys, muscle),
Hemangioma (endothelial cells), etc.
Benign

Epithelial:

i) Non-glandular epithelial proliferations papilloma (squamous epithelium)

trichoepithelioma (hair follicles),
pilomatrixoma (hair follicles), etc.

Esophageal papilloma, bovine.

Note finger-like projections from
the surface.
Benign

Skin papilloma, bovine. In this low power histologic section note the finger-like projections
(fronds or papillae) from the surface of the mass.
Source: Pathologic Basis of Veterinary Disease (2006), 4th ed., Mosby-Elsevier
 Benign

 Epithelial:

ii) Adenoma (adenos = gland):

- Cells form recognizable glandular structures: Mammary adenoma

(e.g., tubules / acini)
Pulmonary adenoma

Intestinal adenoma

Renal tubular adenoma

- Cells derived from glandular tissue: Pituitary adenoma
(but no tubular / acinar arrangement) Hepatocellular
adenoma
Adrenal cortical adenoma
 Benign

 Epithelial:
• Polyp = Club-shaped hyperplastic growth or benign tumor protruding from a mucosal surface.

Polyp, small intestine, mouse. The neoplastic growth arises

from the mucosa and extends into the lumen of the
intestine. It is supported by a stalk (peduncle) of
Inflammatory polyps, urinary bladder, dog. Note
fibrovascular tissue (s). P = polyp
the multiple dark-red protrusions.
Source: Pathologic Basis of Veterinary Disease (2006), 4th ed., Mosby-Elsevier
Malignant

 Mesenchymal:

- Sarcomas: liposarcoma,
fibrosarcoma,
osteosarcoma,
chondrosarcoma,
leiomyosarcoma,
rhabdomyosarcoma,
hemangiosarcoma, etc.
Epithelial / Parenchymal:
- Carcinoma: squamous cell carcinoma
(no glandular patterns) pituitary carcinoma
hepatocellular carcinoma
adrenal cortical carcinoma

- Adenocarcinomas: bronchoalveolar adenocarcinoma

(glandular patterns) mammary adenocarcinoma
intestinal adenocarcinoma

Karkinos (crab)  karkinoma  epithelial cancer

Malignant

Lymphoma (or lymphosarcoma) = malignant tumor of lymphoid tissue.

Leukemia = malignant neoplasm of blood-forming tissues.

Melanoma (or malignant melanoma) = a malignant tumor of melanocytes.

Melanocytoma = benign tumor of melanocytes.

Melanoma, skin, horse.

Mixed Tumors
• The majority of neoplasms are composed of cells representative of a single germ layer, and
a single cell type.
• Mixed tumors contain more than one cell type, but all derived from one germ layer.
 Mixed Mammary Tumor
• Relatively common in dogs.
• Contains both epithelial and mesenchymal elements.

Benign mixed tumor of mammary gland, canine.

 Teratomas
• A variety of tumor cell types representative of more than one germ layer.
• Possibly arise from pluripotential embryonic cells; in the gonads.
• These cells differentiate into various types of tissues.

Ovarian teratoma, canine. Grossly the tumor consists

mostly of fibrous-like tissue with several cyst like structures
evident. Note the aggregates of hair some cavitated areas of
Ovarian teratoma. Cystic (cavitated) mass containing the mass.
hair usually admixed with sebaceous material and
keratin. Dental structures may be present sometimes (not
in this case).
Downloaded from: http://www.righthealth.com/topic/Teratoma_Pictures?p=l&as=goog&ac=404
Benign vs Malignant Neoplasms

Benign “After they have been removed, the patients can forget about them”
• well differentiated cells & architecture (closely resemble the tissue of origin)
• Cohesive & expansile masses that remain localized
• Grow slowly; may cause compressive atrophy of adjacent parenchyma.

• May have a fibrous capsule (from the surrounding compressed stroma)

Thyroid (follicular cell) adenoma, equine. Note: well demarcated (arrows) and compression atrophy of adjacent
thyroid tissue (A) is evident on histology (right). T = tumor
Subcutaneous lipoma, dog.
 Benign

• Some benign tumors may regress; eg cutaneous papillomas, cutaneous

histiocytoma.
• Other benign tumors may slowly progress to malignancy eg colonic adenomas.

Colonic adenomatous polyps are relatively common in humans and

dogs. If not removed, these can progress to colonic
adenocarcinoma.

Colonic polyp. This benign glandular tumor

(adenoma) is projecting into the lumen.

Source: Robbins and Cotran Pathologic Basis of Disease (2010), 8th ed., Elsevier
 Malignant

• Designation of malignancy indicates an aggressive, life-threatening tumor.

• Malignancy is characterized by:

 anaplasia

 rapid rate of growth

 local invasion of tissue

 metastasis
Splenic hemangiosarcoma
• Most common malignant tumour of the canine spleen

Histology:
• Blood-filled vascular spaces lined by
anaplastic endothelial cells
 Anaplasia Abnormal nuclei
• nuclei often large (high N/C ratio)
• chromatin often coarsely clumped and marginalized.
• nucleoli often large and/or multiple.

Hepatocellular carcinoma, chimpanzee. The cells show nuclear pleomorphism and marked
anisokaryosis. Some cells are multinucleated or show multilobulated nuclei. Their nucleoli are
often prominent and magenta.
 Anaplasia Mitoses
• increased numbers of mitotic figures.
• ± abnormal (atypical to bizarre) mitotic figures.

Fibrosarcoma, dog. Several mitotic figures evident. The two marked with large arrows have the chromosomes
aligned at the equatorial plane (metaphase plate), the three marked with small arrows have the chromosomes at
the cellular poles (anaphase / telophase). Inset: Atypical mitotic figures
 Anaplasia Loss of Polarity
• cells lose their nuclear polarity & grow in an disorganized fashion.

Normal
polarity

Uterine adenocarcinoma, bovine. Two acini, surrounded by smooth muscle, are present. The neoplastic cells show
features of anaplasia including anisokaryosis and particularly, loss of polarity; ie in many cases the nuclei are not in the
normal basal location and also the cells tend to pile up on each other (pseudostratification) instead of forming a single
layer of cuboidal epithelium along the basement membrane of the acinus. The photo in the left shows normal polarity of
nuclei with a basal location (prostatic glands).
Malignant Other
• ischemic necrosis / hemorrhage

Metastatic carcinoma, liver, dog. The cut surface of the tumor shows areas of hemorrhage
(red ) and numerous white-yellow areas of necrosis (arrows), good indications that the
tumor is growing rapidly and is malignant .
Malignant

 Rate of Growth (Tumor Cell Kinetics)

• in general, growth rates of neoplasms correlate with
their level of differentiation / anaplasia.

i) doubling time of tumor cells

• after clinical detection, doubling times can range from 1-12

months (average 2-3 months)

Robbin’s fig 7-12. Biology of tumor growth. Minimal estimates of tumor

cell doublings that precede the formation of a clinically detectable tumor
mass. By the time a solid tumor is detected, it has already completed a
major portion of its life cycle as measured by cell doublings.
 Malignant  Local Invasion of Tissue
• cancer growth is characterized by progressive infiltration (invasion) and
destruction of surrounding tissues.

Osteosarcoma of the nasal cavity, dog. The neoplasm has invaded the adjacent nasal sinuses, the hard
palate (white arrows), and the calvarium / brain (black arrow)
 Malignant

 Local Invasion of Tissue

Osteosarcoma, distal region of the right femur,

dog. This tumor has destroyed and distorted
the femur (f); it is also invading the surrounding
soft tissues. Hemorrhages within the neoplastic
mass are also consistent with a malignant
process.
Malignant  Metastasis
• Metastasis refers to tumor implants discontinuous with the primary tumor.
• Unequivocally indicates malignancy & what kills the majority of cancer patients.
Lymphatic spread

Metastatic osteosarcoma,
axillary lymph node, dog.
Several metastatic foci of
osteosarcoma (arrows) are
scattered throughout a local
lymph node.
 Metastasis Hematogenous spread
Mammary gland carcinoma, dog. Hematogenous
dissemination involving the liver and spleen.
.

Same liver, cut surface

 Malignant  Metastasis

Hematogenous spread

Hemangiosarcoma of the right atrium (left, arrow) with

metastases to the lungs (right). These tumors contain
irregular vascular channels filled with blood which
explains its dark red color. They are very common in the
heart, friable and prone to rupture. Hemopericardium
and dissemination to the lungs are common
complications.
Benign vs Malignant Neoplasms

Robbin’s Figure 7-22 Comparison between a benign tumor of the myometrium

(leiomyoma) and a malignant tumor of similar origin (leiomyosarcoma).
Carcinogenic
Carcinogenic Agents
Agents

Viruses, chemical carcinogens, chronic inflammation and radiation

Oncogenic Viruses

• HPV, HBV, EBV, HTLV responsible for ~15% human cancer incidence.

• Oncogenic viruses are the 2nd most important risk factor (exceeded only by tobacco
consumption)

• Oncogenic viruses documented more extensively in veterinary than human medicine.

General features of viral replication

Oncogenic DNA viruses
i) Papilloma viruses
• large number of host-specific papilloma viruses produce papillomas in vertebrates.
• HPV’s cause condyloma acuminata (genital warts) & cervical carcinoma
• PV’s infections are common in vet med (mostly self-limited); exceptions

Skin papilloma, dog. Note the finger-like projections

(fronds) on this mass’s cut surface.

Several cutaneous papillomas in a horse

Multiple papillomas (papillomatosis) due to papilloma
virus infection are most commonly seen in young dogs,
cattle & horses. The size and number vary considerably
and they are typically found on the skin or on the
mucosal surfaces of the upper GI tract. It is generally a
self-limiting disease, of varying duration. Images to the
right shows single (top) and multiple (bottom)
papillomas projecting from the mucosal surface of the
esophagus.

Images from Noah’s arkive

 Bracken fern (Pteridium aquilinum)

Malignant neoplasms of the esophagus (right,

top) and forestomachs (right, bottom) in
ruminants are very rare. However, in several
localities, squamous cell carcinoma (right) is
relatively common in cattle, when an interaction
between Bovine papillomavirus and ingestion of
bracken fern (Pteridium aquilinum) occurs.

Images from Noah’s arkive

  Oncogenic DNA viruses
ii) Herpesviruses
• Marek's disease virus + genetically susceptible chickens  T-cell lymphoma

The lymphoma of Marek’s disease often shows an early “homing” for sciatic nerves often leading to paralysis (top, left). Compare
affected left sciatic nerve (arrows) with the grossly unaffected right sciatic nerve. The liver shows multiple nodular lesions (top, right).
Chemical Carcinogenesis

• mutagenic chemicals that initiate carcinogenesis are either:

 direct acting carcinogens; do not require chemical transformation.
 indirect-acting carcinogens; require metabolic activation  ultimate carcinogens.

Direct-acting carcinogens
some anticancer drugs (eg cyclophosphamide), β-propiolactone,
Alkylating agents dimethyl sulfate, etc
Acylating agents 1-acetyl-imidazole, dimethylcarbamyl chloride

Indirect-acting carcinogens
Polycyclic & Heterocyclic many produced in combustion of tobacco & also in broiled /
Aromatic Hydrocarbons smoked meats, eg benzo(a)pyrene

Aromatic Amines, Amides, Azo aniline dye & rubber industries (eg β-naphthylamine), food dyes
Dyes (eg dimethylaminoazobenzene)

Natural Plant and Microbial Aflatoxin B1, Griseofulvin, Cycasin, Safrole, Betel nuts
Products
Others (often occupational chromium, nickel, arsenic, asbestos, vinyl chloride, polychlorinated
exposures) biphenyls (PCB’s), etc
Radiation Carcinogenesis

• Ionizing radiation, either weak (UV rays) or strong (medical) can induce
neoplasia.
• Many skin tumors are induced by UV light exposure.

Degree of risk associated with:

A Type of UV rays (esp UV-B),
B Intensity of exposure
C Amount of protective pigmentation (esp white regions)
The tumor most frequently associated with prolonged exposure to UV light in domestic animals is
squamous cell carcinoma. They typical occur in non-pigmented locations with sparse hair coat.
Effects
Effects of
of Neoplasms in the host

Local Effects: Compression of Adjacent Structures

• Expansile growth of benign pituitary / brain tumors can compress adjacent structures.

SC
Adenoma, pituitary gland (sagittal section), dog. A large pituitary
adenoma (A) has extended dorsally and compresses the overlying
brain. The optic chiasm (arrow) is also severely compressed. The
adenohypophysis, neurohypophysis, and hypothalamus have been
destroyed by the neoplasm.
Compression of the spinal cord (SC) by a
subdural lymphoma (L), bovine. Noah’s arkive.
Pathologic Basis of Veterinary Disease(2006), 4th ed.
Local Effects: Obstruction, ulceration and
infection

• Benign or malignant tumors can cause local

obstruction of tubular organs (intestinal or
urinary tract).
• Tumors on organ surfaces can have ulceration,
bleeding, 2o infections.

Intestinal lymphoma (top) and intestinal adenocarcinoma

Squamous cell carcinoma, skin, ventral thorax / abdomen (bottom). There is obstruction due to luminal obliteration or
dog. The tumor is completely ulcerated stenosis (arrows). The intestinal segment proximal to the site of
obstruction is dilated (d).
Local effects: Rupture or Infarction of Tumor

Hemangiosarcomas are frequently often found on

the right atrium / auricle (right). They are prone to
rupture with subsequent hemopericardium and
cardiac tamponade (left).
Systemic
Systemic Effects
Effects of
of Neoplasms
Neoplasms
Pathologic Basis of Veterinary Disease(2006), 4th ed..
Hormonal effects

From Noah’s arkive

The two most common causes of hyperadrenocorticism (excess glucorticoids) in the dog are illustrated by the two lesions
above. A pituitary adenoma (right) autonomously secreting ACTH will cause bilateral diffuse adrenal cortical hyperplasia
and an accompanying excess in glucocorticoids. Alternatively, an adrenal cortical adenoma (left) can autonomously secrete
excess glucocorticoids without regard to decreased ACTH levels.
Hormonal effects
Sertoli cell tumor, testicle, dogs. This tumor is usually
benign but commonly associated with the production of
estrogens and a feminization syndrome in dogs.
Symmetrical alopecia and hyperpigmentation,
hyperestrogenism, skin, dog. Note the symmetrical
alopecia (hair loss) and hyper­pigmentation over the caudal
dorsal trunk and caudolateral hind legs. In male dogs, the
symmetrical alopecia in conjunction with enlargement of
nipples, pendulous prepuce, and attraction of other male
dogs suggest the possibility of hyperestrogenism.
Pathologic Basis of Veterinary Disease(2006), 4th ed.
Cachexia

• progressive weight loss due to decreased muscle mass and fat stores.
 can be the first clinical sign noticed; its degree may not correlate with the size of
the tumor.
 some types of cancer are more prone than others to induce cachexia.

• result of cytokines produced by tumor cells or host cells in response to the tumor.
Anemia

• Common manifestation of chronic disease (infections / malignancies).

• Decreased production of rbc’s by the bone marrow (from ↓ availability of iron)

• A mild decrease in the life-span of erythrocytes also occurs.

• Chronic blood loss from hemorrhages within the tumor or adjacent tissues.

Disseminated (multicentric?)
hemangiosarcoma omentum, German
Shepherd. Note multiple dark-red
nodules in the omentum. The dog
developed chronic hemoperitoneum
and anemia.
Best wishes in your final exam