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A Color Atlas

Pathology : A Color Atlas

3XEOLVKHUC.V. Mosby (November 1999)


Cardiovascular shunts and septal defects, 2
Conotruncal anomalies, 4
Cardiovascular obstructions, 6
Rheumatic heart disease, 9
Infective endocarditis, 11
Other valvular lesions, 13
Myocarditis, 14
Cardiomyopathy, 17
Coronary atherosclerosis, 20
Myocardial infarction, 22
Complications of myocardial infarction, 22

Immune-mediated vasculitis, 38



Pulmonary emboli, 57
Pulmonary hypertension, 58
Bronchiectasis, 60

Chronic obstructive pulmonary disease, 60



Bone marrow changes, 74
Peripheral blood smears, 74
Tissue changes in anemia, 77
Acute leukemias, 78
Chronic leukemias, 80
Histopathologic subtypes of Hodgkin disease, 87


Dental cysts, 105
Oral and salivary gland lesions, 108
Esophageal lesions, 110
Oral tumors, 112
Salivary gland tumors, 112
Esophageal tumors, 118


LUMEN, 125


Gastritis and peptic ulcer, 126
Small intestinal diseases that cause malabsorption, 129
Inflammation of the appendix and the large intestine,
Inflammatory bowel disease (IBD), 132
Gastric tumors, 134
Tumors of the small intestine, 136
Tumors of the appendix, 136
Intestinal polyps, 136
Carcinoma of the large intestine, 139
Anal tumors and related lesions, 140


Viral hepatitis, 147
Hepatitis caused by pathogens other than hepatitis
viruses, 149
Biliary infections, 150
Tumor-like conditions, 159
Epithelial tumors, 161
Mesenchymal tumors, 163
Metastatic tumors, 163

Benign tumors and tumors of borderline malignancy,
Carcinoma of the pancreas, 174


Hypopituitarism, 182
Reactive changes, 183
Tumors, 183


Thyroid hyperplasia, 185
Thyroiditis, 186
Benign thyroid tumors, 188
Malignant thyroid tumors, 190
Adrenocortical insufficiency, 198
Adrenocortical hyperplasia and hyperfunction, 199
Adrenocortical tumors, 201


Agenesis, malposition, exstrophy, and related defects,
Polycystic kidney disease, 212
Hereditary glomerular and tubular diseases, 213
Membranoproliferative glomerulonephritis, 219
Membranous glomerulonephritis, 220
IgA nephropathy and Henoch-Schonlein purpura, 222
Postinfectious glomerulonephritis, 223
Crescentic glomerulonephritis, 224
Systemic lupus erythematosus (SLE), 225
Tumors of the kidney and renal pelvis, 234
Tumors of the urinary bladder, 235


Germ cell tumors, 242
Sex cord stromal tumors, 246
Mixed germ cell stromal tumors, 247
Tumors of rete testis, epididymis, and tunica vaginalis
testis, 248
Benign prostatic hyperplasia, 248
Carcinoma of the prostate, 250




Endometrial adenocarcinoma, 268
Endometrial stromal tumor,s 270
Tumors of the myometrium, 271
Serous tumors, 273
Mucinous tumors, 275
Endometrioid carcinoma, 277
Clear cell carcinoma, 278
Transitional cell tumors, 278
Sex cord stromal tumors, 278
Germ cell tumors, 282
Unclassified and metastatic tumors of the ovary, 284
Abnormal implantation and separation of the placenta
and rupture of membranes, 289
Infections, 289
Gestational trophoblastic disease, 290

Fibroadenoma, 298
Adenoma, 298
Phyllodes tumor, 299
Intraductal papilloma, 300
Atypical hyperplasia, 301
Noninvasive carcinoma, 302
Invasive breast carcinoma, 303
Variants of invasive carcinoma 306
I mmunohistochemistry of breast carcinoma, 308

SKIN, 310
Bacterial infections, 313
Fungal infections, 314
Viral infections, 314
I mmune-mediated dermatoses, 316
Granulomatous diseases, 319
Idiopathic skin disease, 321
Pigmentary lesions, 323
Epidermal tumors, 328
Adnexal tumors, 331
Mesenchymal tumors, 333


Benign fibroblastic tumors and tumor-like lesions, 336
Fibromatoses, 337
Benign neural tumors, 347
Malignant neural tumors, 348


Metabolic bone diseases, 357
Hyperparathyroidism, 359
Paget disease of bone, 359
Crystal-induced arthritis, 360
Osteonecrosis, 361
Degenerative joint disease, 361
Infections of bones and joints, 363
Noninfectious arthropathies, 364
Benign bone-forming tumors, 367
Malignant bone-forming tumors, 369
Fibrous lesions of bone, 377
Giant cell tumor of bone, 378
Marrow tumors, 379
Vascular tumors, 380
Miscellaneous tumors and tumor-like conditions, 380
Tumors and tumor-like lesions of joints, 383


Carbohydrate storage diseases, 392
Lipid storage myopathies, 393
Mitochondrial myopathies, 394


Intracranial hemorrhages, 405
Cerebral ischemia, 408
Inborn errors of metabolism, 414
Astrocytic tumors, 422
Oligodendroglioma, 422
Ependymoma, 422
Neuronal, mixed neuronal-glial, and neuroendocrine
neoplasms, 424
Pineal tumors, 424
Meningioma, 425
Vascular neoplasms, 425
Malformative and nonneoplastic mass lesions, 426
Peripheral neuropathies, 426
Hereditary neuropathies, 428
Ischemic neuropathies, 430
Inflammatory neuropathies, 430
Neoplasms of peripheral nerves, 432


Glaucoma, 438
Diseases of the cornea, 440
Retinal degenerative diseases, 441
Cataracts, 442
Melanoma, 443
Retinoblastoma, 445
Medulloepithelioma, 446

EAR, 448
Tumors of the outer ear, 455
Tumors of the middle ear, 455
Tumors of the inner ear, 455


Color Atlas


Cardiovascular Shunts and Septa! Defects

Congenital heart disease encompasses disorders of the cardiovascular system that result from faulty embryogenesis
and are present at birth. The most common cardiac malformations in descending order of frequency are
1.Ventricular septal defect (VSD)
2. Atrial septal defect
3. Pulmonary stenosis
4. Tetralogy of Fallot (including pulmonary atresia)
5. Patent ductal artery (ductus arteriosus)
6. Aortic stenosis
7. Coarctation of the aorta
8. Complete transposition of the great arteries
9. Atrioventricular septal defect
10.Tricuspid atresia
11.Aortic atresia (hypoplastic left ventricular syndrome)
12.Total anomalous pulmonary venous connection
13.Persistent truncal artery (truncus arteriosus)

Shunts result either from patency of normal fetal structures

that fail to close postnatally or from incomplete formation
of one or more septa during cardiac embryogenesis. Persistent fetal structures include a patent oval foramen and a
patent ductal artery (Fig. 1-1). In contrast, shunts that result
from faulty embryogenesis involve defects at the level of the
atrial, atrioventricular, ventricular, ventriculoarterial, or aortopulmonary septa (Diagram 1-1).
Atrial septal defects occur at the oval fossa in 85% of cases
and are known as fossa or secundum atrial septal defects (Fig.
1-2). Ventricular septal defects involve the membranous part
of the septum in 75% to 80% of cases seen at operation or
autopsy (Fig. 1-3). Outlet defects located beneath the right
and left cusps of both semilunar valves account for 5% to
10% of all VSD. Inlet defects that involve the inlet septum beneath the septal tricuspid leaflet account for 5% of all VSD.
Defects of the muscular part of the septum account for only
10% to 20% of cases at operation or autopsy, even though
they actually represent the most common form of VSD. Most
of them are small and close spontaneously.

Diagram I-I. Cardiac and vascular shunts. Upper panel shows various levels of intracardiac
shunts. Lower panel shows various levels of shunts involving the great arteries.

Fig. I -I. Patent ductal artery (*), connecting the aorta with the
pulmonary artery, in adult with plexogenic pulmonary hypertension.

Fig. 1-2. Atrial septal defect, fossa (secundum) type, as seen in

an adult (*).

Fig. 1-3. Ventricular septal defects (*). A, Membranous defect; B, Outlet defect; C, Muscular
defect; D, Muscular defect that has undergone spontaneous closure (arrows).

Conotruncal Anomalies
Conotruncal anomalies are related to abnormal development
of ventricular outflow tracts (Diagram 1-2). Most are associated with an overriding great artery; in some cases one or
both arteries arise from the contralateral ventricle. Many patients have a VSD of the membranous or outlet type, as well
as valvular or subvalvular pulmonary stenosis. Clinically
these defects are associated with right-to-left shunts and peripheral cyanosis.

Tetralogy of Fallot is the most common conotruncal

anomaly, accounting for 8% to 10% of all congenital heart
defects. It comprises subpulmonary stenosis, a VSD, an overriding aorta, and right ventricular hypertrophy (Fig. 1-4).
Pulmonary atresia with a VSD is considered the most severe form of tetralogy of Fallot (Fig. 1-5).
The persistent truncal artery (Fig. 1-6) accounts for 1% of
all congenital heart defects and complete transposition ofgreat
vessels (Fig. 1-7) accounts for 5%.

Diagram 1-2. Conotruncal anomalies.

Fig. 1-4. Tetralogy of Fallot. A, Hypoplastic pulmonary trunk and enlarged ascending aorta
(anterior view); B, Displaced outlet septum (*) with pulmonary stenosis (probe), a ventricular septal
defect (arrow probe), and an overriding aorta (opened, hypertrophied right ventricle).

Fig. I-S. Pulmonary atresia with ventricular septal defect. A, Atretic cordlike pulmonary trunk
(arrow) and dilated ascending aorta (anterior view). B, Ventricular septal defect, overriding aorta,
and ductal origin of the left pulmonary artery (arrow).

Cardiovascular Obstructions
Cardiovascular obstructions can occur congenitally at the
level of cardiac chambers (e.g., hypoplastic ventricle), valves
(e.g., bicuspid semilunar valves), or great vessels (e.g., coarctation of aorta) (Diagram 1-3).
Aortic stenosis may be valvular, subvalvular, or supravalvular. Bicuspid aortic valves occur in 1% to 2% of the general population. Such abnormal valves usually remain
asymptomatic until late in adult life. In approximately 80%
of patients bicuspid valves undergo calcification, causing
aortic stenosis (Fig. 1-8). Pure regurgitation occurs in 20%
of patients and is the result of annular dilatation, prolapse
of the conjoined cusp, or infective endocarditis. Congenital
hypoplasia or nodular thickening of a unicommissural valve,
or less commonly a bicuspid valve, may cause critical aortic
stenosis in the neonate (Fig. 1-9).

Fig. 1-6. Persistent truncal artery is located over a ventricular

septa) defect (*). The overriding truncal artery gives rise to
ascending aorta and both pulmonary arteries (opened right

Fig. 1-7. Complete transposition of great arteries. A, Anterior view. B, Long axis view showing
ventriculoarterial discordance.

Diagram 1-3. Valvular and arterial stenosis. Upper panel shows aortic stenosis. Lower panel
shows pulmonary stenosis and aortic coarctation.

Fig. 1-8. Congenitally bicuspid aortic valves (surgical specimens). A, The valve is calcified and
stenotic. B, Regurgitation resulting from cuspid prolapse and annular dilatation. C, Regurgitation
resulting from healed infective endocarditis with cusp perforation.

Fig. 1-9. Congenital aortic stenosis. A, Critical stenosis of a unicommissural valve in an infant.
B, and C, represent mild stenosis of a unicommissural valve in a young adult (opened and closed

Fig. 1-10. Pulmonary stenosis. A, Poststenotic dilatation of the pulmonary trunk (anterior view).
B, Dome-shaped acommissural valve. C, Pronounced right ventricular hypertrophy (four-chamber

Pulmonary stenosis, like its left-sided counterpart, may be

valvular, subvalvular, or supravalvular. It often is associated
with other cardiac anomalies. Isolated pulmonary stenosis is
associated with a dome-shaped acommissural valve in approximately 45%, a dysplastic tricuspid pulmonary valve in
25%, unicommissural valve in 15%, a bicuspid valve in 10%,
and a hypoplastic annulus in 5% of patients (Fig. 1-10).
Coarctation of the aorta is the most common form of congenital vascular obstruction (Fig. 1-11). It is associated with
a V-shaped invagination of the aorta, just opposite the ductal
artery. It is associated with a patent ductal artery in 50%, a
biscuspid aortic valve in 50%, a membranous VSD in 30%,
subaortic stenosis in 25%, and mitral valve anomalies in 25%
of cases.

Cardiac valves may be congenitally deformed or they may
undergo secondary changes due to infections, hemodynamic
stress, or age-related degeneration accompanied by calcifications.

Rheumatic Heart Disease

Rheumatic fever is an immune-mediated systemic inflammatory disease related to sensitization of the body to beta
hemolytic group A streptococci. Even though rheumatic
heart disease may involve all parts of the heart and is thus a
pancarditis, endocarditis accounts for most important
pathologic changes and most of the morbidity. Rheumatic
carditis is less common today than it was in the preantibiotic
An active rheumatic fever causes typical lesions, the most
pathognomonic of which are the Aschoff bodies (Fig 1-12).
In the granulomatous stage, which is reached three to four
weeks after the infection, these bodies consist of macrophages, giant cells (Aschoff cells), lymphocytes, and occasional neutrophils. Aschoff bodies heal by scarring. They
most often are found in the myocardium and the subendocardial connective tissue, and only rarely in the valves.

Fig. I-I I. Coarctation of the aorta, with a typical indentation of

the aortic wall (arrow) opposite the ductal arterial ligament (*).

Fig. I-12. Rheumatic carditis in an active phase. A, Aschoff body composed of macrophages and
lymphocytes is found in the interstitial plane of the myocardium. B, At higher magnification one
can see that the Aschoff body is composed of macrophages, which have caterpillar (arrow) or owl's
eye-shaped nuclei (curved arrow).

Rheumatic valvulitis presents in the form of verrucous

endocarditis characterized by the formation of tiny translucent nodules on the atrial side of atrioventricular valves
and on the ventricular surfaces of semilunar valves (Fig.
1-13). Deposits of fibrin and underlying inflammation may
extend onto the left atrial parietal endocardium and less often
onto the chordae tendineae or papillary muscles. Histologically the vegetations are composed of fibrin covering the
valve, which are focally infiltrated with lymphocytes. The
valves, which are normally avascular, become vascularized
soon after the onset of inflammation. Within 6 to 8 weeks the
valves contain relatively thick-walled blood vessels, which
may persist indefinitely. Resolution of this inflammation results in scarring, thickening of the cusps, and obliteration of
valve commisures. The chordae tendineae become shortened, thickened, and fused to each other. Mitral valves (Fig.
1-14) and aortic valves (Fig. 1-15) are involved more often
than the valves of the right heart. The deformed valves tend
to calcify and become infected. Clinically chronic valvular
changes present as stenosis or insufficiency.

Fig. 1-13. Acute rheumatic endocarditis. A, Acute endocarditis presents with small translucent
vegetations. B, Histologically the lesion is composed of fibrin covering a valve that is infiltrated
with mononuclear inflammatory cells. C, Higher magnification of the vegetation and the inflamed


Fig. 1-14. Chronic rheumatic endocarditis of mitral valve. A, View from the opened left heart.
B, Stenotic orifice seen from the left atrium.

Infective Endocarditis
Inflammation may involve the valves or mural endocardium.
Accordingly, infective endocarditis is classified as either valvular or mural. It most often is caused by gram-positive bacteria such as Streptococcus pneumoniae and Staphylococcus
aureus. Valvular infection is more common and clinically
more important. The infected valves are covered with luscious, friable vegetations and are composed of fibrin, bacterial colonies, and inflammatory cells (Figs. 1-16 and 1-17).

Fig. I-15. Chronic rheumatic endocarditis of aortic valve. The

valves are deformed fused and the orifice is stenosed.

Fig. 1-16. Acute bacterial endocarditis. The valve is covered

with large, friable, irregular vegetations (arrow).

Fig. I-17. Acute bacterial endocarditis. The vegetation consists

of fibrin and bacteria.

Infective endocarditis affects valves of the left heart more

often than those of the right heart. Factors that predispose to
infection include congenitally deformed valves and preexisting valvular lesions such as those caused by rheumatic
fever (Figs. 1-18 and 1-19). Sepsis, intravenous drug abuse,
cardiovascular surgery, and insertion of prosthetic valves also
are associated with an increased risk for infective endocarditis.
Infective endocarditis of immunosuppressed persons
may be caused by uncommon bacteria and even fungi (Fig.
1-20), which may cause extensive local destructive lesions
(Fig. 1-21). Other complications of infective endocarditis are
listed in Table 1-1.

Potential Complications of Infective


Fig. 1-18. Acute bacterial endocarditis superimposed on chronic

rheumatic endocarditis. Valvular deformities and thickened
chordae tendineae are evidence of the chronic process.

Direct Damage to Heart

Perforation of valve cusps and/or leaflet causing insufficiency
Valve ring or myocardial abscess and fistula formation
Suppurative and obliterative pericarditis
Dehiscence of prosthetic valves, conduits, and patch components
Late valve fibrosis causing stenosis (accompanied by insufficiency)
Septic Embolization with Abscess Formation
Cerebral abscess
Mycotic aneurysm
Lung abscess
Infectious Arteritis with Thrombotic Occlusion
Infarctsbrain, myocardium, spleen, kidneys, other viscera
Ischemia in distribution of ileofemoral or other major arteries
Circulating Immune Complexes
Focal or diffuse glomerulonephritis
Fig. 1-19. Acute bacterial endocarditis superimposed on chronic
healing endocarditis. The arrow points to a microabscess formed
in the central part of the vegetation.

Fig. 1-20. Fungal endocarditis. Fungal hyphae can be demonstrated in the vegetation by Gomori methenamine-silver stain.

Fig. 1-21. Infective endocarditis with extensive destruction of

the valve.


Other Valvular Lesions

Nonbacterial thrombotic endocarditis, which is also known as
marantic endocarditis, typically occurs in terminally ill, emaciated patients who have cancer or other chronic diseases.
Small vegetations typically are found along the line of closure on otherwise normal valves (Fig. 1-22). Histologically
such vegetations resemble bland fibrin thrombi (Fig. 1-23).
Floppy mitral valves are common but they rarely cause
clinically significant changes unless they are associated with
myxomatous transformation. In floppy valve syndrome the
valve cusps expand, chordae lengthen, and one or both cusps
billow " or prolapse into the atrium during systole (Fig.

Carcinoid heart disease is a complication of intestinal carcinoids metastatic to the liver. It is characterized by fibrotic

changes in the endocardium of the right ventricle. The tricuspid and pulmonary valves have focal or diffuse plaques of
glycosaminoglycan-rich, elastin-free connective tissue (Fig.
1-25). The left ventricle also is involved in one third of patients examined at autopsy, but the changes are mild and
cause no clinically significant hemodynamic abnormalities.
Degenerative calcific aortic stenosis represents an agerelated lesion that typically is found in the elderly. The
valves are deformed by nodular calcifications within the
cusps (Fig. 1-26). Aortic insufficiency may result from the dilatation of the aortic valve annulus caused by a variety of diseases such as rheumatic fever, syphilis, or atherosclerosis,
which is the most common cause of this disease in the elderly
(Fig. 1-27).

Fig. 1-22. Nonbacterial thrombotic endocarditis. The line of

closure is covered with fine uniform vegetations.

Fig. 1-23. Nonbacterial thrombotic endocarditis. Histologically

the vegetations are composed of fibrin attached to a normal

Fig. 1-24. Floppy mitral valve. The valve appears irregularly

thickened and deformed. The greatest redundancy and gelatinous change are noted in the posterior leaflet (to the right), but
there also is localized thickening along the free margin of the
anterior mitral leaflet. Chordae tendineae are variably thickened
and focally fused.

Fig. 1-25. Carcinoid heart syndrome. Greatly thickened tricuspid valve and chordae show a whitish "onlay." The right
upper portion of the valve is relatively spared and appears

Fig. I -26. Degenerative calcific aortic stenosis. A, Superior view of tricuspid, fibrocalcific,
stenotic valve. The calcific nodules are most prominent inside the cusps (arrow). The commissures
are focally fused, most prominently on the posterior side. B, Similar case with more prominent

Fig. 1-27. Aortic insufficiency due to dilatation of the aortic root. The aorta has a thickened wall
and its luminal surface is covered with fibrous plaques and focal ulcerative calcific changes, most
consistent with healed aortitis. Focal endocardial thickening below the aortic valve is indicative of
regurgitation. B, Close-up view.
Causes of Myocarditis

The most important myocardial diseases are myocarditis and

Inflammations of the myocardium are classified as (1) infectious, (2) immune-mediated, or (3) idiopathic (Table
1-2). Pathologically myocarditis is classified as acute or
chronic, focal or diffuse. Histologically it is classified descriptively according to the predominant cell type infiltrating
the myocardium or the pattern of reaction, such as lymphocytic, eosinophilic, or giant cell (Fig. 1-28). Pathogens rarely


Fig. 1-28. Microscopic appearances of myocarditis. A, Active myocarditis of the predominantly

lymphocytic type. Isolated myocytes are surrounded by the infiltrate in a background of what
appears to be edema. B, Ventricular myocardium with myocarditis and clusters of cells immunoreactively identified as macrophages. C, Ventricular myocardium with active myocarditis and myocytolysis (arrows). The cytolysis is associated with an infiltrate of activated immune cells in a child
with suspected viral myocarditis. D, Ventricular myocardium with influenza A-related myocarditis
in a young child. The "punched-out" lesions of myocyte necrosis are best defined by lack of
positive staining (arrows) with monoclonal antibody to muscle-specific a-actin. E, Giant cell myocarditis with multinucleated giant cells positive for muscle-specific a-actin monoclonal antibody
staining. Some of the giant cells in the same heart were derived from muscle cells, whereas others
expressed macrophage markers. F, Giant cell myocarditis with multinucleated giant cell and neighboring macrophages stained brown with an antibody CD68. Although this multinucleated cell is
immunonegative, others in this case were immunopositive with the same antibody.

if ever are identified by routine histologic examination of the

myocardium with a few exceptions such as Chagas disease,
in which the myocytes typically contain Trypanosoma cruzi
(Fig. 1-29). Myocardial abscess caused by sepsis rarely contains identifiable bacteria (Fig. 1-30). Myocardial cell
necrosis with myophagocytosis in a patient with diphtherial
pharyngitis is by inference classified as diphtherial; the cardiac lesions actually are caused by a toxin released by C. diphtheriae, which hematogenously reaches the myocardium
(Fig. 1-31).

Transplant rejection is accompanied by an immunemediated myocarditis (Fig. 1-32). The type of rejection may
be classified by endocardial biopsy as: lafocal mild; lb
diffuse mild; 2focal moderate; 3amultifocal moderate;
3bdiffuse moderate or severe; or 4severe (Figs. 1-32 and
Idiopathic myocarditis is the most common type of myocardial inflammation identified at autopsy. It may present
histologically as lymphocytic, eosinophilic, giant cell, or
granulomatous inflammation (Fig. 1-34).

Fig. 1-29. Chagas disease. Myocytes contain Trypanosoma cruzi.

Fig. 1-30. Myocardial abscess. Myocardium contains aggregates

of neutrophils.

Fig. 1-31. Diphtherial myocarditis. Necrosis of cardiac

myocytes is more prominent than the inflammatory infiltrate.

Fig. 1-32. Cardiac transplant rejection. Focal, moderate

(grade 2).


Fig. 1-33. Cardiac transplant rejection. Multifocal, moderate

(grade 3a).

Fig. 1-34. Eosinophilic myocarditis. The interstitium contains

infiltrates of lymphocyte and eosinophils.

Cardiomyopathies are diseases characterized by cardiac dysfunction in which the main abnormality lies in the working
myocardium. Cardiomyopathies are divided into two
groups: primary (idiopathic, due to unknown causes) and
secondary (due to known causes). Both the primary and the
secondary categories have three possible functional states:
(1) dilated, congestive; (2) hypertrophic, hyperdynamic; and
(3) restrictive, constrictive (Diagram 1-4, p. 18).

Dilated cardiomyopathy (systolic disorder) is found in patients with hemochromatosis, chronic anemia, alcoholic cardiomyopathy, sarcoidosis, and many other diseases. Typically
it is found in the end stages of ischemic heart disease and in
hypertensive heart disease, in which it is accompanied by
hypertrophy of all four cardiac chambers (Fig. 1-35). The dilated heart shows foci of scarring ( "replacement fibrosis" )
(Fig. 1-36). Thrombi tend to form in the dilated ventricle and
there typically is functional mitral insufficiency.

Fig. 1-35. Dilated cardiomyopathy. Ventricles and atria are

dilated. There is a mural thrombus in the left ventricle.

Fig. 1-36. Dilated cardiomyopathy. There is replacement

fibrosis in the myocardium.

Diagram 1-4. Specific and less specific causes of dilated, hypertrophic, and restrictive

Hypertrophic cardiomyopathy (diastolic disorder) is found

in patients with Friedreich ataxia, glycogen storage disease,
congenital cardiomyopathies such as those related to mutations of gene for beta-myosin heavy chain, and in infants of
diabetic mothers (Figs. 1-37 and 1-38). The most common
cause of left ventricular hypertrophy is arterial hypertension.
Cor pulmonale causes right ventricular hypertrophy. In all
these diseases there is marked hypertrophy of the cardiac
myocytes, often accompanied by interstitial fibrosis.
Restrictive cardiomyopathy (diastolic and systolic disorder) may be caused by pathologic processes involving the
endocardium (e.g., endomyocardial fibrosis), myocardium
(e.g., cardiac amyloidosis), or pericardium (e.g., constrictive
pericarditis). These diseases typically impede the diastolic
filling of the cardiac chambers and reduce systolic ejection
of blood. The pathologic changes depend on the process that
has caused the disturbance, so the ventricles can be of normal
size (as in pericarditis) or markedly thickened (as in amyloidosis) (Figs. 1-39 and 1-40).

Fig. 1-37. Congenital hypertrophic cardiomyopathy with asymmetric septa) hypertrophy.


Fig. 1-38. Congenital hypertrophic cardiomyopathy. Histologically the cardiac myocytes are hypertrophied and show
branching and disarray. There also is considerable interstitial

Fig. 1-39. Amyloidosis of the heart. The ventricular myocardium

appears thickened but pale.

Fig. 1-40. Amyloidosis. A, The cardiac myocytes are surrounded by hyalinized material.
B, Electron microscopy shows pericellular amyloid fibers.


Atherosclerosis of coronary arteries is clinically the most important heart disease. Narrowing or occlusion of coronary
arteries typically causes myocardial ischemia, which clinically presents as angina pectoris, myocardial infarction, or
chronic ischemic heart disease.

Coronary Atherosclerosis
Atherosclerotic plaques of coronary arteries have the same
morphologic features as plaques in other sites, that is, they
have an atheromatous, cholesterol-rich core surrounded by
a fibrous cap (Fig. 1-41). Some lesions are composed only of

fibrous tissue and are calcified. Plaques may be eccentric (Fig.

1-42) or may concentrically narrow the lumen of the coronaries (Fig. 1-43). Soft lipid-rich atherosclerotic plaques tend
to rupture and provoke thrombus formation in the lumen of
the coronary (Fig. 1-44). Rupture of atheroma also may cause
microemboli and fibrin thrombi in the distal small branches
of the coronary artery system (Fig. 1-45).
Coronary thrombi may be lysed through the action of fibrinolytic enzymes. The presence of multiple vascular channels inside a coronary artery indicates recanalization (Fig.
1-46). Consequences and potential outcomes of coronary
atherosclerotic plaque rupture are outlined in Diagram 1-5.

Fig. 1-41. Coronary artery with a fibrolipid plaque. In cross

section the plaque, which was stained by Sudan red, had a core
of lipid separated from the lumen by a white fibrous cap. The
plaque projects outward rather than inward, so the artery
appeared normal on angiography.

Fig. 1-42. Eccentric plaque causing narrowing of the coronary

artery, estimated to be over 95 percent.

Fig. 1-43. Concentric plaque causing narrowing of the coronary

artery, estimated to be over 70 percent.


Fig. 1-44. Coronary thrombus. In this picro-Mallory

trichomestained slide, collagen is blue and the thrombus is red.
There is a small tissue in the plaque, which provoked the
intraluminal thrombosis.

Fig. 1-45. Microemboli in small intramyocardial vessels. This

small artery is occluded by a mass composed of platelets (blue),
red cells (yellow), and cholesterol (clefts).

Fig. 1-46. Coronary artery recanalization. The lumen of the

coronary artery has been subdivided into several channels by
fibrous strands.

Diagram 1-5. Potential outcomes of coronary plaque rupture.

Myocardial Infarction
Myocardial infarction represents the major consequence of
coronary artery occlusion; it frequently is fatal. Myocardial
infarcts can be localized or diffuse, transmural or subendocardial (Figs. 1-47 to 1-49). On gross examination the infarcted myocardium initially is redder than the surviving adjacent tissue at 12 hours after occlusion of the coronary and
then becomes paler; by day 3 it is yellow (Fig. 1-47). The pattern of infarction is best appreciated at autopsy by staining
slices of cross-sectioned heart enzyme histochemically to
demonstrate dehydrogenase activity. Infarcted areas appear
pale 12 hours after the onset of necrosis due to loss of enzyme activity in necrotic cells (Figs. 1-48 and 1-49).
Histologic changes indicative of myocardial infarction appear approximately 6 to 12 hours after occlusion but the definite signs of necrosis can be identified only after 24 hours.
The myocardial cells become hypereosinophilic, lose their
cross-striations, and show coalescence of myofibrils (Fig.

Fig. 1-47. Myocardial infarct. By clinical history this infarct was

six days old. The yellow necrotic area is surrounded by a
hemorrhagic red rim.

Fig. 1-49. Subendocardial infarct. The tissue was stained to

demonstrate succinic dehydrogenase activity. The subendocardial pale areas correspond to the infarct, which extends
across the areas supplied by at least three coronary arteries.

1-50). Contraction band necrosis in which the cytoplasm of

myocardial cells contains densely eosinophilic bands also
may be seen but it is more typical of reperfusion injury (Fig.
1-51). The infarcted area is invaded by neutrophils two to
three days after the coronary occlusion (Fig. 1-52).
Macrophages appear three to five days after the onset of ischemia and a fully established granulation tissue develops
over a few days. Granulation tissue gives rise to fibrotic scars,
which form three to six weeks thereafter.

Complications of Myocardial Infarction

The outcome of myocardial infarction depends on many
variables and includes a spectrum of clinical pictures from
sudden death to complete recovery. External cardiac rupture,
a complication of transmural infarcts, occurs during the first
10 days and typically is accompanied by hematopericardium
(Figs. 1-53 and 1-54). Rupture of the septum can cause an
acute left-to-right shunt and the rupture of papillary muscle

Fig. 1-48. Transmural myocardial infarct. The transverse

section of ventricles was stained to demonstrate succinic dehydrogenase activity. Normal myocardium is blue. The pale areas
involving the anterior and septal wall of the left ventricle represent the infarct caused by occlusion of the anterior branch of
the left coronary artery.


Fig. 1-50. Myocardial infarct 24 hours after occlusion of the

coronary artery. The necrotic myocytes have deeply eosinophilic amorphous cytoplasm. Adjacent surviving cells appear pale
and vacuolated.

Fig. I-5I. Contraction band necrosis. The cytoplasm of myocytes contains deeply eosinophilic bands.

Fig. 1-52. Myocardial infarct. In this three-day-old infarct the

necrotic myocardial cells are surrounded by neutrophils.

Fig. 1-53. Rupture of a transmural infarct.

Fig. 1-54. Hematopericardium. Pericardium is filled with blood

as a complication of cardiac rupture.

may cause acute mitral insufficiency (Figs. 1-55 and 1-56).

Mural thrombi form over the infarcted areas (Fig.1-57). Ventricular aneurysms form at the site of large scars replacing
infarcted myocardium of the left ventricle (Fig. 1-58).

Fig. 1-55. Rupture of the interventricular septum.

Fig. 1-57. Mural thrombus overlying a massive myocardial


Fig. 1-56. Papillary muscle rupture. (Courtesy of Dr. Fred

Bosman, Lausanne, Switzerland.)

Fig. 1-58. Ventricular aneurysm. The bulging aneurysm has a

thin fibrotic wall.


The pericardium may be affected by a variety of infectious,
i mmune-mediated, and metabolic diseases, as well as by adverse external influences such as -y-radiation, all of which can
cause pericarditis and pericardial fibrosis or both (Table 1-3).
Hydropericardium is a common complication of congestive
heart failure and generalized edema. Hematopericardium is a
complication of heart rupture. The pericardium often is involved, together with myocardium in myocarditis of viral
origin or in any form of pancarditis such as rheumatic fever.
Pericarditis also is a common complication of myocardial infarction.
Pericardial diseases present in several pathologic forms:
(1) serous effusion; (2) hematopericardium; (3) fibrinohemorrhagic or fibrinopurulent pericarditis; or (4) constrictive fibrosing pericarditis, which can be accompanied by
calcifications or adhesive mediastinitis (Figs. 1-59 to 1-64).

Fig. 1-59. Fibrinous pericarditis. The surface of the heart is

covered with a layer of fibrin.

Causes of Pericarditis



Coxsackievirus B
Staphylococcus aureus
Mycobacterium tuberculosis
Histoplasma capsulatum

I mmune-mediated
Rheumatic fever
Systemic lupus erythematosus
Dressler syndrome

Myocardial infarction


Open heart surgery


Chronic renal failure

Fig. 1-60. Fibrinous pericarditis. The surface of the epicardium

is covered with fibrin. There is granulation tissue under the layer
of fibrin.


Fig. 1-6 I. Fibrinohemorrhagic pericarditis. The heart is covered

with blood-tinged fibrin.

Fig. 1-62. Fibrinohemorrhagic pericarditis. The layer on the

surface of the epicardium consists of fibrin and granulation

Fig. 1-63. Tuberculous pericarditis. The inflammatory infiltrate

is composed of macrophages, lymphocytes, and multinucleated
giant cells.

Fig. 1-64. Constrictive pericarditis. The heart is encased in a

thick layer of white fibrous tissue.


Primary tumors of the heart are rare. The most common
tumor is myxoma (Fig. 1-65). Typically myxomas are benign
tumors, located in the left atrium. Less often they occur in
the right atrium or attached to the valves. Rhabdomyomas
are cardiac tumors of infancy and childhood (Fig. 1-66). Primary tumors of the pericardium are histologically classified

as benign or malignant mesotheliomas or hemangiosarcomas (Fig. 1-67).

Metastases to the heart are more common than primary
tumors. They may be found on the epicardial surface, within
the cardiac chambers, or invading the myocardium (Fig.

Fig. 1-65. Cardiac myxoma in the left atrium. A, The tumor may occlude the mitral orifice as a
"ball valve." B, The external surface is smooth and the tumor appears lobulated and myxomatous.
C, The tumor is composed of elongated cells surround by myxomatous matrix that stains pink.
There also are thin-walled blood vessels. D, High-power view of stellate and elongated (lepidic)
cells and hemosiderin laden macrophages.


Fig. 1-66. Rhabdomyoma. A, The tumor presents as a myocardial mass. B, The tumor is composed of glycogen-rich cells that have clear cytoplasm.

Fig. 1-67. Hemangiosarcoma of the pericardium. This hemorrhagic tumor was found encasing the heart.

Fig. 1-68. Metastatic melanoma of the epicardium.


Further Reading
Adenle AD, Edwards JE: Clinical and pathologic features of metastatic
neoplasms of the pericardium. Chest 81:166-169, 1982.
Altrichter PM, Olson LJ, Edwards WD et al: Surgical pathology of the
pulmonary valve. A study of 116 cases spanning 15 years. Mayo
Clin Prot 64:1352-1360, 1989.
Aretz HT: Myocarditis. The Dallas criteria. Hum Pathol 18:619-624,
Burke AP, Cowan D, Virmani R: Primary sarcomas of the heart. Cancer
Burke AP, Virmani R: Cardiac myxoma. A clinicopathologic study. Am
J Clin Pathol 100:671-680, 1993.
Burke AP, Virmani R: Cardiac rhabdomyoma. A clinicopathologic
study. Mod Pathol 4:70-74, 1991.
Davies MJ: Coronary artery remodeling and the assessment of stenosis
by pathologists. Histopathology 33:497-500, 1998.

Davies MJ: Review: the investigation of sudden cardiac death. Histopathology 34:93-98, 1999.
Klacsmann PG, Bulkley BH, Hutchins GM: The changed spectrum of
purulent pericarditis. An 86 year autopsy experience in 200 patients. Am J Med 63:666-673, 1977.
Lam KY, Dickens P, Chan AC: Tumors of the heart. A 20-year experience with a review of 12,485 consecutive autopsies. Arch Pathol Lab
Med 117:1027-31, 1993.
Maron BJ: Hypertrophic cardiomyopathies. Lancet 350:127-133, 1997.
Pardo-Mindan FJ, Lazano MD, Contreras-Mejuto F, de Alava E: Pathology of heart transplant through endomyocardial biopsy. Semin
Diagn Pathol 9:238-48, 1992.
Silver MD: Cardiac pathology. A look at the last five years. II. The pathology of cardiovascular prostheses. Hum Pathol 5:127-38, 1974.
Winters GL: The challenge of endomyocardial biopsy interpretation in
assessing allograft rejection. Curr Opin Cardiol 12:146-152, 1997.

Arteriosclerosis is an inclusive generic term that is used to describe thickening and hardening of arteries. Included under
this term are four pathologic entities: (1) arteriosclerosis,
(2) hypertensive arteriosclerosis, (3) Monckeberg medial calcific sclerosis, and (4) atherosclerosis.
Arteriolosclerosis, or thickening of the wall of arterioles,
occurs in two forms: hyaline arteriolosclerosis (arteriolar
hyalinosis) and hyperplastic (proliferative) arteriosclerosis.
In hyaline arteriolosclerosis the wall of arterioles appears
thickened by homogeneously glassy pink material ( " hyaline" ) (Fig. 2-1). It may accompany hypertension or diabetes
and is a common feature of involutional atrophy (e.g., postmenopausal ovaries) and aging. It often is prominent in the
Hyperplastic arteriolosclerosis is characterized by narrowing of the lumen of arterioles due to the concentric proliferation of smooth muscle cells in the vessel wall (Fig. 2-2).
It typically is found in malignant hypertension, progressive

systemic sclerosis (scleroderma), chronic transplant rejection, and after radiotherapy (Fig. 2-3).
Hypertensive arteriosclerosis may be divided clinically and
to some extent pathologically into chronic (benign) and accelerated (malignant) types.
Chronic (benign) hypertension affects all arteries and arterioles. In the large elastic arteries it causes changes indistinguishable from those of atherosclerosis; in arterioles it causes
hyaline arteriolosclerosis; in muscular arteries it causes
thickening of the media due to increased amounts of collagen, elastic tissue, smooth muscle cells, and fibroblasts (Fig.
2-4). Malignant hypertension is characterized by hyperplastic
arteriolar changes that often are accompanied by fibrinoid
necrosis of the vessel wall (Fig. 2-5).
Monckeberg medial calcific sclerosis is an age-related degenerative process in which the media of large and mediumsized muscular arteries undergoes calcification (Fig. 2-6). It
has little or no clinical significance.


Fig. 2-I. Hyaline arteriolosclerosis. A, Thickened arterioles in

kidney of a diabetic man appear homogeneously pink. B, Splenic
arterioles in an elderly nondiabetic man.

Fig. 2-2. Hyperplastic arteriolosclerosis. A, The lumen of the

arteriole is narrowed due to concentric proliferation of smooth
muscle cells in the vessel wall ("onionskin lesion"). B, Arterioles
have narrow lumen due to layers of fibrous tissue.


Fig. 2-3. Systemic sclerosis. The vessels show hyperplastic

changes and narrowing of the lumen.

Fig. 2-4. Hypertensive change in muscular arteries. The arterial

wall is thickened and contains increased amounts of collagen and
elastic tissue.

Fig. 2-S. Fibrinoid necrosis. A, The wall of the arteriole is infiltrated with fibrin and
appears magenta red. B, Immunofluorescence microscopy shows deposits of fibrin in the
vessel wall.

Fig. 2-6. Monckeberg medial calcific sclerosis. Media of this

elastic artery shows a discrete area of calcification.

Fig. 2-7. Fatty streaks in the aorta of an adolescent boy.

Fig. 2-8. Fatty streak. The intima contains fat-laden foam cells
that stain with oil red O.

Fig. 2-9. Severe atherosclerosis of aorta.

Fig. 2-I I. Atherosclerosis. Atheroma consists of amorphous

cellular debris and cholesterol crystals walled off by fibrous

Fig. 2-10. Atheroma. It contains yellow, porridge-like material.

Fig. 2-12. Atherosclerotic aneurysm. Ulcerated atheromas are

seen in the aorta above the renal arteries, whereas the lower
aneurysm contains thrombi.



Atherosclerosis is a multifactorial disease involving primarily the aorta and its major branches. The earliest
changes, which are considered to be reversible, are fatty dots
and fatty streaks of the intima (Figs. 2-7 and 2-8). These
changes lead to diffuse intimal thickening followed by eccentric intimal thickening and ultimately to formation of fibrous plaques. Atheromatous plaques, the typical lesions of
atherosclerosis, consist of an irreversibly altered softened
central area filled with cholesterol crystals and cell debris
( "atheroma") surrounded by collagenous fibrous tissue
(Figs. 2-9, 2-10, and 2-11). Weakening of the arterial wall
may lead to aneurysm formation, often complicated by
thrombosis (Fig. 2-12).

An aneurysm is a dilatation of the aorta or any other major

artery. Atherosclerotic aneurysms most often are located in the
abdominal aorta. Atherosclerosis, especially if it is combined
with hypertension, predisposes to the formation of dissecting
aneurysms of the aorta (Fig. 2-13). Hypertension combined
with cystic medial necrosis may lead to the formation of dissecting aneurysms even in the absence of atherosclerosis (Fig.
2-14). Atherosclerosis of the splenic artery leads to formation of cirsoid aneurysms (Fig. 2-15). Berry aneurysms are related to a defect in the muscle layer of cerebral arteries (Fig.
2-16). Syphilitic aneurysms are a consequence of infection
with Treponema pallidum. They typically occur in the thoracic aorta (Fig. 2-17).

Fig. 2-13. Dissecting aneurysm of the thoracic aorta. The blood

has filled the space formed by the forcible separation of intima
and media of the aorta.

Fig. 2-14. Dissecting aneurysm of the aorta. Layers of the aortic

wall are loose and have been separated by blood.

Fig. 2-I5. Cirsoid aneurysm of splenic artery. The calcified

blood vessels appear serpentine.

Fig. 2-16. Berry aneurysm of the circle of Willis (arrow).

Fig. 2-17. Syphilitic aneurysm. A, The aortic arch is dilated.

B, Intima has a "tree-bark" appearance.

Vasculitis, or inflammation of blood vessels, may be caused
by infections or may be immune mediated (Table 2-1).
Infection-induced vasculitis is an inflammation caused by
invasion of the vessel wall by pathogens. Pathogens can gain
entry into the vessel wall from outside (i.e., through extension of infection from the perivascular tissue) or from inside
(i.e., from the blood). Fungal vasculitis is a common complication of pneumonia caused by Aspergillus or Rhizopus in
which these fungi invade the pulmonary arteries and veins
from outside. Fungal meningitis can spread to the cerebral
vessels (Fig. 2-18).

Hematogenous dissemination of viruses, bacteria, or

fungi during sepsis or by means of infected thromboemboli
is a common cause of infectious vasculitis. Viruses are considered to cause granulomatous vasculitis of the central nervous system (Fig 2-19). Rickettsia have a predilection for the
endothelial cells of capillaries, postcapillary venules, arterioles, and to a lesser extent small arteries (Figs. 2-20 and 2-21).
Aortic lesions typical of tertiary syphilis are caused by a tendency of Treponema pallidum to cause inflammation of vasa
vasorum of the aorta (Fig. 2-22). Injury of these small nutrient vessels of the aorta results in scarring of media, weakening of vessel wall, and aneurysm formation (see Fig. 2-17).

Fig. 2-18. Fungal vasculitis. Histoplasma capsulatum has invaded

the meningeal arteries.

Fig. 2-19. Granulomatous giant cell vasculitis of cerebral

arteries. This patient had a herpes zoster virus infection.


Types of Vasculitis Categorized on the Basis of Proposed Pathogenic Mechanisms

Direct Infection of Vessels
Bacterial vasculitis (such as neisserial)
Mycobacterial vasculitis (such as tuberculous)
Spirochetal vasculitis (such as syphilitic)
Rickettsia) vasculitis (such as Rocky Mountain spotted fever)
Fungal vasculitis (such as aspergillosis)
Viral vasculitis (such as herpes zoster)

I mmunologic Injury
Immune complex-mediated vasculitis
Henoch-Schonlein purpura
Cryoglobulinemic vasculitis
Lupus vasculitis
Rheumatoid vasculitis
Serum sickness vasculitis
Infection-induced immune-complex vasculitis
Viral (such as hepatitis B and C)
Bacterial (such as group A streptococci)
Paraneoplastic vasculitis

Behcet disease
Some drug-induced vasculitides (e.g., sulfonamide-induced vasculitis)
Direct antibody attack-mediated vasculitis
Goodpasture syndrome (anti-collagen IV)
Kawasaki disease (possibly mediated by antiendothelial antibodies)
Antineutrophil cytoplasmic autoantibody-mediated vasculitis
Wegener granulomatosis
Microscopic polyangiitis (microscopic polyarteritis)
Churg-Strauss syndrome
Some drug-induced vasculitides (such as thiouracil-induced vasculitis)
Cell-mediated vasculitis
Allograft cellular vascular rejection
Giant cell (temporal arteritis)
Takayasu arteritis
Polyarteritis nodosa
Behcet disease

Fig. 2-20. Rocky Mountain spotted fever. Infection with

Fig. 2-21. Rocky Mountain spotted fever. Immunofluorescence

Rickettsia ricketsii causes segmental necrosis, inflammation, and

thrombosis in small blood vessels.

microscopy performed on this skin biopsy specimen demonstrates dotlike Rickettsia ricketsii in the wall of small dermal

pallidum infection caused infiltrate around vasa

vasorum composed of lymphocytes and plasma cells. B, The media of the aorta shows focal loss
of elastic fibers and scarring caused by ischemia.
Fig. 2-22. Syphilitic aortitis. A, Treponema

Immune-mediated Vasculitis
Vasculitis may be caused by antibody-mediated and cellmediated mechanisms elicited by a variety of antigens. The
causative antigens cannot be identified in many cases and the
exact pathogenesis of many lesions is only partially understood. For practical reasons it is best to classify vasculitides
in three groups according to the type of blood vessel involved:

(1) large vessel vasculitis, (2) medium-sized vessel vasculitis,

and (3) small vessel vasculitis (Diagram 2-1).
Takayasu arteritis involves the aorta and its major
branches. Histologically it presents as a granulomatous inflammation, causing necrosis and disruption of the media
(Fig. 2-23). The infiltrate typically contains multinucleated
giant cells.

Diagram 2-I. Vasculitis clinical syndromes. (Modified from Jennette JC et al: Arthritis Rheum
37:187, 1994.)

Fig. 2-23. Takayasu arteritis. Destruction of the media of the

aorta is a consequence of a granulomatous inflammation. The
infiltrate contains multinucleated giant cells.

Fig. 2-24. Kawasaki disease. Right lateral view of the heart of an

infant who died of Kawasaki disease. There is pronounced
thickening and immense prominence of all coronary arteries due
to a combination of ectasia and intimal thickening, as well as
adventitial fibrosis.


Fig. 2-25. Polyarteritis nodosa. A small subcutaneous artery

shows focal fibrinoid necrosis and transmural inflammation
extending into the perivascular tissue.

Fig. 2-26. Polyarteritis nodosa. The pancreatic artery forms an

aneurysm that is filled with a thrombus.

Fig. 2-28. Henoch-Schinlein purpura. Small dermal vessels

are infiltrated with IgA as demonstrated by immunofluorescence
microscopy in this slide stained with antibodies to IgA.

Fig. 2-27. Small vessel vasculitis. Dermal venules show signs

of leukocytoclastic vasculitis.

Kawasaki disease often involves coronary arteries, causing

segmental mural necrosis and acute inflammation. Such lesions predispose to thrombosis, vascular ectasia, and aneurysm formation (Fig. 2-24).
Polyarteritis nodosa is a necrotizing inflammation of
medium-sized or small arteries (Fig. 2-25). Destruction of
the vessel wall often leads to formation of microaneurysms
(Fig. 2-26).
Henoch-Schonlein purpura ( HSP) and drug-induced vasculitis are examples of small vessel vasculitis, typically involving postcapillary venules, capillaries, and arterioles (Fig.
2-27). In HSP this leukocytoclastic vasculitis typically is associated with a deposition of immunoglobulin A (IgA) in the
wall of small vessels (Fig. 2-28).

Further Reading
Jennette JC, Falk RJ, Andrassy K et al: Nomenclature of systemic vasculitides: proposal of an international consensus conference.
Arthritis Rheum 37:187-201, 1994.
Klima T, Spjut HJ, Coelho A et al: The morphology of ascending aortic
aneurysms. Hum Pathol 14:810-817, 1983.
Ledford DK: Immunologic aspects of vasculitis and cardiovascular disease. JAMA 278:1962-1971, 1997.
Lie JT: Histopathologic specificity of systemic vasculitis. Rheum Dis
Clin NAm 21:883-909, 1995.
Parums DV: The arteritides. Histopathology 25:1-20, 1994.
Pretre R, von Segesser LK: Aortic dissection. Lancet 349:1461-1464,
Ross R: Rous-Whipple Award Lecture. Atherosclerosis. A defense
mechanism gone awry. Am J Pathol 143:987-1002, 1993.
Stary HC, Chandler AB, Dinsmore RE et al: A definition of advanced
types of atherosclerotic lesions and a histological classification
of atherosclerosis. A report of the Committee on Vascular Lesions
of the Council on Atherosclerosis, American Heart Association.
Circulation 92:1355-1374, 1995.

Inflammation of the upper respiratory tract may present as
isolated rhinitis, sinusitis, pharyngitis, or laryngitis, or as a
combined upper respiratory tract inflammation. These
pathologic processes can be caused by infectious agents, most
often by common respiratory viruses, and by bacteria or allergies. The pathologic findings in such conditions are banal
and nondiagnostic. Uncommon infections such as nasal infection caused byKlebsiella rhinoscleromatis (Fig. 3-1) or Rhinosporidium seeberi (Fig. 3-2) produce more distinct tissue
changes, which can be recognized in biopsy specimens.
Allergy is a common cause of rhinitis, which usually presents as " hay fever " or rhinorrhea ( " runny nose " ). Chronic
inflammation may result in the formation of nasal polyps.

Histologically nasal polyps represent edematous mucosa infiltrated with inflammatory cells, especially eosinophils and
plasma cells, and dilated vessels (Fig. 3-3). Occasionally the
stroma of nasal polyps may contain atypical stromal cells
with dysplastic or bizarre nuclei. Such changes usually are
found in polyps with ulcerated surface epithelium, and it is
i mportant not to mistake them for malignancy.
Inflammation may be caused by chronic strain or irritation, or by foreign material. For example, chronic laryngitis
may be seen in professional speakers or singers (Fig. 3-4).
Myospherulosis is a form of inflammation related to packing
of nasal cavities with gauze that contains petroleum jelly
(Fig. 3-5).

Fig. 3-1. Rhinoscleroma. A, Granulation tissue is seen in the nasal cavity. (Courtesy of Dr. M.
Fred, Houston, Texas.) B, CT scan of paranasal sinus in 43-year-old man with rhinoscleroma.
Right nasal cavity and posterior wall of left maxillary sinus are involved. C, Nasal biopsy showing
numerous foamy histiocytes (Mikulicz cells). D, Slides stained with Warthin-Starry stain show
numerous intracellular coccobacilli corresponding to Klebsiella rhinoscleromatis.


Fig. 3-2. Rhinosporidiosis. A, The inflamed nasal mucosa contains round sporangia of RhinoSporangium filled with spores and surrounded by multinucleated giant cells.

sporidium seeberi. B,

Fig. 3-3. Nasal polyp. The edematous stroma contains scattered

bizarre cells between the dilated blood vessels.

Fig. 3-5. Myospherulosis. The central sac, containing a

multinucleated foreign body giant cell and a cluster of sporelike
bodies representing altered erythrocytes, is surrounded by
chronic inflammatory cells and fibrous tissue.

Fig. 3-4. Chronic laryngitis. As seen through the laryngoscope,

the lesion appears as thickening of vocal cords. (Courtesy of Dr.
V. Kambic, Ljubljana, Slovenia.)


Benign tumors of the upper respiratory tract are mostly of
epithelial origin and present as papillomas or nodules projecting into the lumen. They also may be located inside the
wall of each organ or may cause focal thickening, which
cannot be distinguished with certainty without biopsy from
nonneoplastic nodules inflammatory lesions, cysts, and
masses such as amyloidoma. Nonepithelial tumors are less
Papillomas most often originate from nasal or laryngeal
epithelium. Nasal papillomas, which are also known as
schneiderian papillomas, are of three histologic types: (1) exophytic (fungiform), (2) endophytic (inverted), and (3) oncocytic (cylindrical cells). Exophytic and endophytic papillomas together account for 95 percent of all nasal lesions (Fig.
3-6). These papillomas are lined by basaloid cells that occasionally show squamous differentiation, which may spare
isolated mucin-containing respiratory cells as "microcysts "
(Fig. 3-7). There is no reliable way to histologically predict
recurrence, which occurs in 30 percent to 60 percent of surgically treated patients. Laryngeal papillomas are lined by
nonkeratinizing squamous epithelium. Multiple papillomas
are usually found in preschool children. These lesions typically contain human papilloma virus type 6 and 11.
Juvenile nasopharyngeal angiofibroma is a benign mesenchymal tumor restricted to adolescent boys and young

men (Fig. 3-8). Histologically these tumors are composed of

gaping, irregular vessels surrounded by fibrous stroma
(Fig. 3-9).
Vocal cord nodules and solitary laryngeal polyps of adults
are common nonneoplastic tumefactions related to strain
and abuse of voice (Fig. 3-10). These lesions represent edema
of connective tissue, which often contains hyaline material
that should not be confused with amyloid (Fig. 3-11).

Fig. 3-6. Schneiderian papilloma. The tumor involves the nasal

cavity extending onto the septum and lateral wall. (Courtesy of
Dr. R. Sirota, Oak Park, IL.)

Fig. 3-7. Schneiderian papilloma. A, The tumor is exophytic but focally it shows features of an
inverted papilloma. B, Proliferation of monotonous, bland, basaloid cells with a few clear spaces
("microcysts") representing mutinous cell remnants.


Fig. 3-9. Juvenile nasopharyngeal angiofibroma. The irregularly

shaped, dilated, thin-walled vessels are surrounded by
fibroblastic cells.

Fig. 3-8. Juvenile nasopharyngeal angiofibroma. As viewed

through the nasal speculum, the mass filling the nasal cavity
shows prominent surface vascularity.

Fig. 3-10. Bilateral polypoid nodules of vocal cords. (Courtesy

of Dr. V. Kambic, Ljubljana, Slovenia.)

Fig. 3-I I. Vocal cord nodule ("singer's node"). The polypoid

mass consists of edematous, hyalinized stroma covered by an
intact epithelium.


Olfactory neuroblastoma is a rare but important nasal

tumor. It may show typical features of neuroblastoma of
other sites such as fibrillary stroma; alternatively, it may present as a poorly differentiated small cell tumor (Fig. 3-13).
Both variants stain with antibodies to neurofila:nents and
S-100 protein, and also paradoxically with antibodies to
Nasopharyngeal carcinoma accounts for 85 percent of all
malignant tumors of this site. Three histologic subtypes are

Malignant tumors of the upper respiratory tract are mostly

of epithelial origin and histologically represent squamous
cell carcinomas.
Nasal tumors, which are usually found in elderly men, typically present as mass lesions or nonbleeding ulcers, which
may require radical surgery such as nasal amputation (Fig.
3-12). Histologically these tumors show prominent keratinizations and tend to invade the underlying tissues.

Fig. 3-12. Squamous cell carcinoma of the nasal vestibule. A, The friable exophytic and invasive
tumor. B, Invasive squamous cell carcinoma of the nasal vestibule encroaching on the hyaline
cartilage of the septum.

Fig. 3-13. Olfactory neuroblaStoma. A, Nests of tumor cells beneath the epithelium. B, The
tumor is composed of small cells surrounded focally by fibrillar stroma.

WHO Histologic Classification of

Nasopharyngeal Carcinoma
Squamous cell carcinoma
Keratinization or intercellular bridges or both

Nonkeratinizing carcinoma
Defined cell borders, pavement like pattern

Undifferentiated carcinoma
Syncytial growth, large polygonal cells or spindle-shaped cells,
prominent nucleoli, lymphoid stroma

Fig. 3-14. Nasopharyngeal carcinoma. The tumor is composed

of polygonal cells with vesicular nuclei enclosed in a sea of


Fig. 3-I5. Keratinizing intraepithelial dysplasia of larynx.. Such

lesions are often aneuploid even though they show some degree
of "surface maturation" into keratinized squamous cells.

Fig. 3-16. Squamous cell carcinoma of the larynx. Laryngectomy

specimen showirig recurrent carcinoma of the right vocal cord.

Carcinoma of the larynx is a squamous cell carcinoma in

95 percent of patients. It may begin as squamous cell dysplasia or carcinoma in situ (Fig. 3-15). Invasive carcinomas
show variable degrees of keratinization (Figs. 3-16 and 3-17).

Further Reading

Fig. 3-17. A, Vertical section through a carcinoma localized to

the true vocal cord. False cord and ventricle are free of tumor.
B, Vertical section through a supraglottic squamous carcinoma.
The true cord is involved.

recognized (Table 3-1). The undifferentiated carcinoma,

which occurs as a large polygonal cell tumor or as a spindleshaped cell tumor, accounts for 60 percent to 80 percent of
all tumors (Fig. 3-14). Tumor cells are surrounded by lymphocytes, which accounts for the fact that these tumors previously were called lymphoepitheliomas.

Abbondanzo SL, Wenig BM: Non-Hodgkin's lymphoma of the sinonasal tract. A clinicopathologic and immunophenotypic study of
120 cases. Cancer 75:1281-1291, 1995.
Compagno J, Hyams VJ: Hemangiopericytoma-like intranasal tumors.
A clinicopathologic study of 23 cases. Am J Clin Pathol 66:672-683,
Devaney K, Wenig BM, Abbondanzo SL: Olfactory neuroblastoma and
other round cell lesions of the sinonasal region. Mod Pathol 9:658663, 1996.
Franquemont DW, Mills SE: Sinonasal malignant melanoma. A clinicopathologic and immunohistochemical study of 14 cases. Am J
Clin Pathol 96:689-697, 1991.
Heffner DK, Gnepp DR: Sinonasal fibrosarcomas, malignant schwannomas, and "Triton" tumors. A clinicopathologic study of 67 cases.
Cancer 70:1089-1101, 1992.
Helliwell TR: "Risky" epithelium of the larynx-a practical diagnosis?
Histopathology 34:262-265, 1999.
Helquist H, Cardesa A, Gale Net al: Criteria for grading in the Ljubljana
classification of epithelial hyperplastic laryngeal lesions. A study by
members of the Working Group on Epithelial Hyperplastic Laryngeal Lesions of the European Society of Pathology. Histopathology
34:226-233, 1999.
Lloreta-Trull J, Mackay B, Troncoso Petal: Neuroendocrine tumors of
the nasal cavity. An ultrastructural and morphometric study of 24
cases. Ultrastruct Pathol 16:165-175, 1992.
Michaels L: Benign mucosal tumors of the nose and paranasal sinuses.
Sem Ding Pathol 13:113-117, 1996.
Slavin RG: Nasal polyps and sinusitis. JAMA 278:1849-1854, 1997.

The respiratory system develops as a derivative of the primitive foregut. It is therefore not surprising that developmental
anomalies involving one system are accompanied by abnormalities in the other. The most important of these conjoined
anomalies is tracheoesophageal fistula ( Diagram 4-1), which
may be associated with abnormal or incomplete development of trachea or tracheal agenesis. Bronchial anomalies include abnormal branching patterns, abnormalities in size,
abnormal connections with other structures, and cartilage
plate abnormalities.
Bronchogenic cyst develops from an accessory fetal lung
bud that becomes isolated from the rest of the tracheobronchial tree, producing a solitary midline cyst lined by
bronchial epithelium (Figs. 4-1 and 4-2).
Pulmonary anomalies range from minor variations in the
lobar configuration to major developmental defects such as
unilateral pulmonary agenesis or hypoplasia (Fig. 4-3). Pulmonary hypoplasia has been identified in 10 percent to 15
percent of all neonatal autopsies and in 50 percent of neonates who have other significant congenital anomalies.
Anomalies limited to parts of a lung may remain asymptomatic until adult life. The most important of these anomalies are congenital cystic adenomatoid malformation and
extralobar bronchopulmonary sequestration or accessory lobe
(Figs. 4-4 and 4-5). So-called intralobar sequestration, which
is mentioned here for the sake of completeness and differential diagnosis, is considered to be an acquired abnormality
that is caused by recurrent pulmonary inflammation and
scarring (Fig. 4-6).

Fig. 4-I. Bronchogenic cyst. This posterior midline subpleural

cyst was compressing the esophagus, causing only minor

Fig. 4-2. Bronchogenic cyst. This resected cyst has a rugged

internal surface.

Diagram 4-I. Tracheoesophageal fistulas. Type C malformations account for 85 percent of all


Fig. 4-3. Pulmonary hypoplasia in a neonate.

Fig. 4-4. Congenital cystic adenomatoid malformation. This

mass, which is composed of abnormal bronchiolar structures,
consists of a large cyst with several smaller cysts in the

Fig. 4-5. Congenital cystic adenomatoid malformation. A, The lung is composed of cystic bronchi
and air spaces. B, The wall of the cyst is lined by pseudostratified or tall columnar epithelium
resembling the lining of proximal bronchioli or small bronchi.

Fig. 4-6. Intralobar sequestration. A, The mass consists of markedly dilated bronchi filled with
mucus and surrounded by fibrous tissue. B, Histologically, the mass consists of bronchi and air
spaces lined by cuboidal cells. The interstitium is fibrosed and contains inflammatory cells.


Failure of the lungs to fully expand and remain expanded is
a common complication of pulmonary immaturity encountered in neonates who are born preterm. Clinically it presents
as neonatal respiratory distress syndrome or hyaline membrane
disease. The lungs show patchy atelectasis (Fig. 4-7). Histologically pulmonary alveoli are collapsed and atelectatic,
whereas the alveolar ducts are dilated and lined by fibrin-rich
hyaline membranes (Fig. 4-8). Secondary changes such as
intraalveolar hemorrhage, dilatation of bronchioles proximal to atelectatic parenchyma, and dilatation of lymphatics
are common. Resorption of hyaline membranes, i.e., cleanup
by macrophages, begins 48 to 72 hours after birth and is associated with proliferation of bronchiolar reserve cells.
Oxygen therapy and mechanical ventilation cause additional
changes that cannot be separated from those caused by the
disease itself. Severe hyaline membrane disease that is treated
aggressively may result in development of chronic lung
changes known as bronchopulmonary dysplasia (Fig. 4-9).
Histologically it can be divided sequentially into three overlapping phases: (1) early reparative phase, (2) subacute fibro -

proliferative phase, and (3) chronic fibroproliferative phase.

The process is dominated by organization of hyaline membranes by granulation tissue, ongoing peribronchial fibrosis
and luminal obliteration (bronchiolitis obliterans), and interstitial fibrosis (Fig. 4-10). Pulmonary interstitial air, or pulmonary interstitial emphysema, which is characterized by the
presence of air in the connective tissue planes of the lungs, is
yet another complication of treatment of hyaline membrane
disease with ventilatory support (Fig. 4-11).
Neonatal pneumonia typically is a complication of:
(1) transplacental spread of maternal infection, (2) intrauterine ascending amniotic fluid infection, (3) intrapartum
infection with microorganisms in the birth canal, or (4) postnatal airborne infection.
Most neonatal pneumonias are acquired during labor and
delivery. Aspiration of infected amniotic fluid by the fetus accounts for 20 percent to 40 percent of early-onset neonatal
sepsis and pneumonia. The lungs of such neonates contain
amniotic fluid with squamous and inflammatory cells (Fig.

Fig. 4-7. Neonatal atelectasis. The atelectatic parenchyma

appears dark red in contrast to the paler areas of normally
aerated lung (right upper corner).

Fig. 4-8. Neonatal respiratory distress syndrome. A, Alveoli are collapsed and the alveolar ducts
and respiratory bronchioli are dilated and lined by hyaline membranes. B, Hyaline membranes
are brown due to staining with meconium.


Fig. 4-9. Bronchopulmonary dysplasia. Lungs are in part

consolidated and in part cystic.

Fig. 4-10. A, Bronchopulmonary dysplasia. The alveoli are partially obliterated by ingrown
granulation tissue. B, The lungs are consolidated except for a few cystic and slit-like spaces.

Fig. 4-I I. Pulmonary interstitial air. Air-filled spaces extending

the interlobular septa are seen through the pleura.

Fig. 4-I2. Amniotic fluid aspiration with early pneumonia.

The alveoli contain nucleated squamous cells and scattered
inflammatory cells.

Pneumonia, or pulmonary infection, can be classified (1) etiologically, as viral, bacterial, fungal, and so forth; (2) topologically, depending on the gross distribution, as lobar or lobular, focal or diffuse, one-sided or bilateral; (3) histologically,
depending on the distribution of the inflammatory cells, as
intraalveolar or interstitial and characterized by a neutrophilic, lymphocytic or mixed inflammatory infiltrate.
Bacterial infection presents as lobar or lobular pneumonia
(also known as bronchopneumonia). In lobar pneumonia entire lobes of one or both lungs are involved (Fig. 4-13).
Bronchopneumonia presents in the form of more circumscribed infiltrates (Fig. 4-14). These infiltrates are initially
composed of neutrophils and are predominantly inside the
alveoli (Fig. 4-15). Without treatment, consolidation of the
lungs progresses through several phases known as: (1) red
hepatization, in which the lungs appear red due to congestion; (2) gray hepatization, in which the exudate of neutrophils and fibrin, combined with reduced blood flow through
the compressed capillaries, imparts a gray color to the lungs;
and (3) resolution phase, in which the exudate is removed and
the air spaces become patent again. In severe cases the abundant fibrin cannot be removed and it stimulates the ingrowth
of granulation tissue into the alveoli (organizing pneumonia)
(Fig. 4-16). Pneumonia caused by Staphylococcus aureus may
result in massive tissue breakdown (Fig. 4-17) and suppuration resulting in abscess formation (Fig. 4-18).
Pulmonary tuberculosis presents with a spectrum of
changes. Primary tuberculosis, which is characterized by a
solitary parenchymal nodule and hilar lymph node involvement, usually heals spontaneously by undergoing fibrosis
and calcification (Fig. 4-19). Secondary tuberculosis results
in widespread dissemination of mycobacteria and the formation of multiple small nodules (miliary tuberculosis), consolidation of parenchyma (tuberculous pneumonia), or extensive destructive lung lesions (cavitary tuberculosis) (Fig.
4-20). Histologically all tuberculous lesions contain granulomas (Fig. 4-21). Similar changes can be caused by fungi
such as Histoplasma capsulatum.

Fig. 4-15. Lobar pneumonia in the stage of gray hepatization.

The alveoli are filled with neutrophils. The alveolar walls are of
normal thickness and do not contain red blood cells.

Fig. 4-13. Lobar pneumonia. The entire lung appears

consolidated and the parenchyma is bulging on cross section.

Fig. 4-14. Bronchopneumonia. The lungs appear only focally

consolidated. The infiltrates are peribronchial and appear
distinct from the surrounding parenchyma.


Fig. 4-16. Organizing pneumonia. The alveoli contain abundant

fibrin, which is being organized by inflammatory cells and an
ingrowth of fibroblasts.

Fig. 4-17. Necrotizing pneumonia. The exudate is accompanied

by necrosis of alveolar septa. The bluish material represents
bacterial colonies.

Fig. 4-18. Lung abscess. The large subpleural abscess contains

brownish-yellow pus. The surrounding parenchyma appears consolidated and contains scattered smaller whitish-yellow abscesses.

Fig. 4-19. Pulmonary tuberculosis. The primary lesion appears

as a sharply demarcated subpleural nodule.

Fig. 4-20. Secondary pulmonary tuberculosis. The parenchyma

and hilar lymph nodes contain numerous, often confluent
tubercles. (Courtesy of Cathy Looby, M.D., Philadelphia, PA.
From Woods CL, Gutierrez Y: Diagnostic pathology of infectious
diseases, Philadelphia, 1993, Lea & Febiger.)

Fig. 4-21. Pulmonary tuberculosis. Granulomas of tuberculosis

consist of lymphocytes, epithelioid macrophages, and
multinucleated giant cells arranged around a central area of
caseating necrosis.

Pneumocystis carinii pneumonia, an opportunistic fungal

infection that occurs in immunocompromised persons, presents histologically with an acellular intraalveolar exudate
(Fig 4-22). Fungal cysts can be seen in slides impregnated
with silver according to Gomori.
Viral infections cause alveolar cell injury, which is usually
accompanied by a predominantly interstitial mononuclear
cell infiltrate (Fig. 4-23). The alveoli contain well-developed
fibrin-rich hyaline membranes and some edema fluid. In

most instances the causative virus is not visible except in

some infections that are caused by herpes simplex virus 1
( HSV- 1) or cytomegalovirus (CMV). CMV inclusions appear as basophilic (blue) material in the nucleus and the cytoplasm, and are accompanied by enlargement of the infected
cells (Fig. 4-24). Alveolar cell injury caused by viruses such
as influenza or adenovirus produce histologically nonspecific changes. Such changes are indistinguishable from
other forms of diffuse alveolar damage ( DAD).

Fig. 4-22. Pneumocystis carinii pneumonia. A, The alveoli contain proteinaceous acellular floccular
material. B, Pneumocystis carinii cysts are seen in silver-impregnated cytologic smear prepared
. from bronchial brushings.

Fig. 4-23. Viral pneumonia. The alveolar septa are widened.

The alveoli contain edema fluid, fibrin-rich hyaline membranes,
and a few scattered mononuclear cells.

Fig. 4-24. Viral pneumonia caused by the cytomegalovirus

(CMV). Typical intranuclear inclusions are seen in desquamated
pneumocytes, which appear enlarged.


Blood flow through the lungs depends on proper cardiac
function. Acute left heart failure results in passive pulmonary
congestion and intraalveolar hemorrhage. Chronic heart
failure results in brown induration of the lungs.
Circulatory collapse that occurs in shock and multiple
organ failure often is clinically associated with adult respiratory distress syndrome (ARDS). Lungs . show signs of diffuse
alveolar damage accompanied by focal atelectasis, intraalveolar hemorrhage, and hyaline membrane formation (Fig.
Pulmonary Emboli
Pulmonary thromboembolism is one of the leading causes of

death, although it often is clinically unrecognized. Pulmonary emboli may involve the main pulmonary artery, its
major branches, or small intrparenchymal vessels. Clinically
they may cause sudden death, episodes of dyspnea and
hemoptysis, or only minor discomfort and thoracic pain.
Saddle emboli of the main pulmonary artery and the emboli occluding the major branches of the pulmonary artery
usually cause sudden death (Fig. 4-26). In patients who survive, the thromboemboli become lysed, organized, or recanalized. Thromboemboli that lodge in peripheral pulmonary arteries cause infarcts, but only in patients whose
pulmonary circulation is compromised by heart failure or
atherosclerotic obstruction of the nutrient pulmonary circulation through the bronchial arteries. On gross examination pulmonary infarcts appear red, as they do in other organs with dual circulation (Fig. 4-27). Histologically, the
alveoli of the infarcted area have necrotic septa and are filled
with blood (Fig 4-28).

Fig. 4-25. Diffuse alveolar damage. Air spaces contain hyaline

membranes, red blood cells, and desquamated cells.

Fig. 4-26. Pulmonary thromboembolism. The main branches of

the pulmonary artery are occluded with thromboemboli.

Fig. 4-27. Pulmonary infarct. Infarct is triangular and


Fig. 4-28. Pulmonary infarct. The septa are necrotic and the
alveoli contain blood.

Pulmonary Hypertension

episodes of wheezing and increased resistance to expiratory

air flow. The principal pathologic changes occur in the
bronchi and bronchioli, which show hyperplasia of mucussecreting cells, hypertrophy and hyperplasia of smooth
muscle cells, and signs of chronic inflammation (Fig. 4-30).
The mucus inthelumen o f thebronchi may contain CharcotLeyden crystals derived from the granules of eosinophils and
Curshman spirals.
Hypersensitivity pneumonia (extrinsic allergic alveolitis)
can be induced by a number of allergens or drugs (Fig. 4-31).
Clinically it may present under several conditions such as
farmer's lung, mushroom worker 's lung disease, bagassosis,
and suberosis. Foreign antigens usually induce a cellmediated reaction in the form of granulomas (Fig. 4-32).
Focal cellular infiltrates composed of lymphocytes and a few
plasma cells are less common. In advanced cases buds of organizing fibrovascular tissue (Masson bodies) fill the respiratory bronchioli and alveolar ducts (Fig. 4-33). Ultimately the
disease may progress to diffuse pulmonary fibrosis.
Pulmonary infiltration and eosinophilia (PIE) is a syndrome that could have many causes, such as visceral larva migrans syndrome related to infestation with nematodes, cestodes, or filarial worms. Many drugs may induce the same
syndrome. Eosinophilic pneumonia often is found in such
cases by lung biopsy (Fig. 4-34).

Pulmonary hypertension can be classified as primary or secondary. The causes of primary or idiopathic hypertension are
not known. Secondary pulmonary hypertension is a consequence of left heart failure, mitral valve lesions, or chronic
thromboembolism of the pulmonary vascular system. Congenital heart disease with left-to-right shunting of blood also
causes pulmonary hypertension, which can be graded on a
scale from 1 to 6 according to the Heath-Edwards classification (Fig. 4-29).

The lungs are exposed to numerous potential allergens inhaled daily and are thus a common site for a variety of
i mmune-mediated diseases. The most important in this
group of diseases are asthma, hypersensitivity pneumonia,
eosinophilic pneumonia, sarcoidosis, and Wegener granulomatosis. The lungs also may be affected by systemic autoi mmune diseases such as systemic lupus erythematosus,
Sjogren syndrome, and systemic sclerosis (scleroderma).
Other immune-mediated diseases such as Goodpasture syndrome and Churg-Strauss syndrome are less common.
Asthma is a disorder characterized by increased responsiveness of the airways to various stimuli as manifested by

Fig. 4-29. Plexogenic pulmonary arteriopathy. A, Medial hypertrophy and muscularization of an

arteriole (grade I). B, Concentric intimal proliferation (grade 2). C, Concentric laminar intimal
fibroelastosis (grade 3). D, Fibrinoid degeneration (grade 6). E, Necrotizing arteritis (grade 6).
F, Plexiform lesion (grade 4). (A, C, and E, Elasticavan Gieson stain.)


Fig. 4-30. Asthma. A, The bronchiole has a hy erplastic epithelium, a thick basement membrane,
and prominent smooth muscle cells in its wall. The lumen contains mucus. Inflammatory cells are
present in variable amounts and often are not prominent. B, Charcot-Leyden crystals.
C, Curshman spiral.

Fig. 4-31. Allergic drug reaction. The alveolar septa are

thickened and infiltrated with mononuclear cells, which are also
found in the alveolar spaces.

Fig. 4-32. Hypersensitivity pneumonia. The air spaces contain

loosely structured granulomas with multinucleated giant cells.

Fig. 4-33. Hypersensitivity pneumonia. In later stages of the

disease the airways are obliterated by fibroblastic granulation

Fig. 4-34. Eosinophilic pneumonia. The alveoli and thickened

septa are infiltrated by eosinophils and lymphocytes.


Fig. 4-35. Wegener granulomatosis. A, The lung parenchyma contains two nodules showing
central necrosis. B, The section shows areas of vasculitis, inflammation, and necrosis.

Wegener granulomatosis is an immune-mediated disease

that involves the upper and lower respiratory tracts and kidneys. The lung lesions may present as pale infarcts or bulky
necrotic nodules (Fig 4-35). Histologic features include vasculitis accompanied by thrombosis and pulmonary infarcts,
and granulomas often superimposed on a background of
nonspecific chronic inflammation. These changes contribute
to a variegated ( " geographic map-like" ) appearance of tissues in histologic sections.


Chronic and recurrent pulmonary infections typically occur
in persons who have congenitally reduced pulmonary defense (e.g., Kartagener syndrome, agammaglobulinemia) or
acquired immunodeficiency (e.g., AIDS or cancer therapy).
People who are exposed to chronic irritants such as cigarette
smoke also suffer from chronic pulmonary infections.

Bronchiectasis is an irreversible dilatation of bronchi accompanied by an infection of the bronchial wall and obliteration
of distal airways. It may occur in several clinical settings such
as: (1) damage of bronchi by an infection in early life; (2) recurrent infections in patients with congenital disorders such
as cystic fibrosis, immotile cilia syndrome, or agammaglobulinemia; (3) allergy to molds; (4) inhalation of toxic
gases; and (5) in a localized form distal to a tumor or other
lesions causing bronchial obstruction. The involved bronchi
and bronchioli are markedly dilated, filled with mucous or
mucopurulent plugs, and surrounded by peribronchial fibrosis. In cystic fibrosis, a common cause of bronchiectasis,
purulent bronchitis and pulmonary insufficiency are the
leading cause of death (Figs. 4-36 and 4-37).

Chronic Obstructive Pulmonary Disease

COPD is a clinical diagnosis that includes two closely related
entities that typically cause dyspnea and other respiratory
problems in chronic cigarette smokers: chronic bronchitis
and emphysema.
Chronic bronchitis is defined clinically as chronic lung disease presenting as cough with expectoration and lasting at
least three months during two consecutive years. The bronchi
show histologic signs of chronic inflammation and contain
mucus admixed with pus (Fig. 4-38). The bronchi typically
have thickened walls. The enlarged bronchial mucous glands
occupy more than 40 percent of the thickness of the wall, as
found under normal circumstances (Reid index).
Emphysema is a permanent loss of pulmonary parenchyma that leads to an enlargement of air space distal to the
terminal bronchioles, without evidence of fibrosis. It occurs
in two main forms: centriacinar (centrilobular) emphysema,
which involves the respiratory bronchioles and destroys the
alveolar septa around it (Fig. 4-39); and panacinar (panlobular) emphysema, which involves the entire acinus ( "cotton
candy lung" ) (Fig. 4-40). Centriacinar emphysema most
often is found in cigarette smokers and typically shows centriacinar deposition of black pigment (anthracosis).
Panacinar (panlobular) emphysema typically is encountered
in persons with a i -antitrypsin deficiency. Other forms of
emphysema such as paraseptal or irregular emphysema (usually associated with scarring) are less important clinically. All
forms of emphysema can give rise to pulmonary subpleural
bullae. Similar air-filled bullae, which often are unrelated to
emphysema, are a common cause of lung rupture and spontaneous pneumothorax (Fig. 4-41).


Fig. 4-36. Cystic fibrosis. This lung from a 20-year-old man

shows diffuse bronchiectasis.

Fig. 4-37. Cystic fibrosis. The bronchiole is filled with an

exudate composed of neutrophils.

Fig. 4-38. Chronic bronchitis. The wall of the bronchus is

thickened and inflamed.

Fig. 4-39. Centriacinar emphysema. Note that the large air

spaces are surrounded by a normal alveolar network. Also note
the pigmentation inside the cystic central spaces.

Fig. 4-40. Panacinar emphysema. The entire pulmonary

parenchyma has a delicate cotton candylike texture.

Fig. 4-41. Subpleural bullae.

The term pneumoconiosis was coined by the German pathologist Friedrich Zenker in 1866 for all diseases of the lung
parenchyma that are attributable to the inhalation of inorganic mineral dust. The most important pneumoconioses
are silicosis, silicatosis, asbestosis, coal workers' pneumoconiosis, hard metal disease, and berylliosis.
Silicosis is an inflammatory and fibrotic lung disease that
is caused by the inhalation of silica crystals, also known as
alpha quartz. Several clinical and pathologic forms of silicosis are known, such as acute silicosis, accelerated silicosis,
chronic silicosis, and progressive massive fibrosis. Typical lesions, silicotic nodules, are found in the latter two entities (Fig.
4-42). Silica crystals can be seen in these lesions by polarization microscopy.

Silicatosis is caused by inhalation of particulate nonfibrous silicate minerals in the absence of silica dust. Silicates
account for one third of all known mineral species and are
ubiquitous. Inhalation of silicates such as talc or kaolin produces peribronchial and perivascular aggregates of macrophages that are heavily laden with dust and associated with
fibrosis (Fig. 4-43). Polarization microscopy reveals birefringent particulate matter that appears granular, platy, or lancetshaped. Multinucleated giant cells are especially prominent
in talcosis.
Coal workers ' pneumoconiosis is a fibrosing lung disease of
coal workers. The lungs show grossly visible black pigmentation (Fig. 4-44). Typical histologic findings include macules (primary dust foci), which represent carbon particles
containing fibrotic patches of damaged alveolar septa; and
nodules (secondary dust foci), which represent larger stellate
anthracotic connective tissue scars measuring 0.5 to 3 mm in
diameter (Fig. 4-45). Larger nodules seen on radiographic
examination of the lungs of coal workers with rheumatoid
arthritis (Caplan lesion) show central necrosis surrounded by
palisading macrophages that are reminiscent of subcutaneous rheumatoid nodules (Fig. 4-46).
Siderosis applies to the deposition of iron oxide in the
lungs, as is seen in welders, iron and steel workers, and those
who work in iron mines. Reddish-brown macules composed
of hemosiderin-laden macrophages gradually develop in the
lungs (Fig. 4-47). Numerous nonfibrous ferruginous bodies
that have round or irregularly shaped black cores also are
Hard metal disease sporadically develops in workers who
are employed in industries in which synthetic hard metals
are produced or are used in cuttings and fabrication of metal
parts. The disease becomes evident within days or weeks after
exposure. Histologically the lungs show variable degrees of
fibrosis accompanied by infiltrates composed of macrophages and giant cells (Fig. 4-48).

Fig. 4-42. Silicosis. A, It is composed of concentrically layered

whorled collagen bands. Black pigment is evidence of anthracosis. The monocular cell infiltrate at the periphery represents a
response to nonquartz silicate particles. B, Progressive massive
fibrosis. The lung of a coal worker shows anthracosilicotic
lesions more prominent in the upper lobes.

Fig. 4-43. Silicatosis. This lung of a slate worker shows perivascular inflammation and fibrosis. The silicates not evident in this
slide could be seen by polarization microscopy.


Fig. 4-44. Coal workers' pneumoconiosis. The lungs show increased

black pigmentation.

Fig. 4-45. Coal workers' pneumoconiosis. A, Macule consists

of fibrous tissue impregnated with carbon particles. B, Nodule
represents a stellate heavily pigmented scar.

Fig. 4-46. Caplan lesion in coal workers' pneumoconiosis. The

nodule has a variegated appearance and contains zones of
necrosis, lamellar concentric fibrosis, and anthracosis.

Fig. 4-47. Siderosis. The lungs of this iron ore miner contain
aggregates of hemosiderin-laden macrophages.

Fig. 4-48. Hard metal disease. The lung parenchyma contains

aggregates of macrophages and multinucleated giant cells.
Variable degrees of fibrosis may be found.

Berylliosis is a granulomatous lung disease that develops

after exposure to aerosolized beryllium particles. Beryllium
has been used for the production of lamps, for the production of atomic energy, and in space exploration programs.
Histologically the disease is indistinguishable from sarcoidosis and presents in the form of noncaseating pulmonary
granulomas (Fig. 4-49 and Fig. 4-50).
Asbestosis is a fibrotic lung disease consequent to longterm exposure to all types of asbestos (Diagram 4-2). Asbestos bodies found in or adjacent to the walls of fibrotic res-

piratory bronchioles are the hallmark of this disease (Fig. 451). In addition to pulmonary fibrosis, exposure to asbestos
leads to the formation of fibrous plaques on visceral or parietal pleura (Fig. 4-52). The most serious consequence of asbestos exposure is mesothelioma, a malignant tumor of
serosal surfaces (Fig. 4-53). Histologically mesotheliomas
may be classified as epithelial, sarcomatous, or mixed including both epithelial and sarcomatous elements (Fig.
4-54). The incidence of bronchial carcinoma also is increased
after chronic exposure to asbestos.

Fig. 4-49. Berylliosis. The lung contains numerous noncaseating

granulomas composed of epithelioid macrophages and giant

Fig. 4-50. Sarcoidosis. Noncaseating granulomas are found in the

peribronchiolar parencyma.

Diagram 4-2. Commercial and noncommercial asbestos.


Fig. 4-51. Asbestosis. A, Air spaces contain beaded iron-encrusted brown asbestos bodies.
B, Asbestos body.

Fig. 4-52. Asbestosis. White plaques cover the parietal pleura.

Fig. 4-53. Malignant mesothelioma. This pleural tumor has

invaded the pericardial cavity encasing the heart.

Fig. 4-54. Malignant mesothelioma. A, This epithelial variant shows a glandulopapillary growth
pattern. B, Fibrosarcomatous mesothelioma is composed of spindle shaped cells.

Lungs may be affected by a number of chronic diseases of unknown etiology, which show common and overlapping
clinical features but nevertheless have distinctive histologic
characteristics. Dyspnea and deterioration of pulmonary
function is invariably related to a loss of pulmonary parenchyma and pulmonary fibrosis. The most important of these
diseases are listed in Table 4-1.
Idiopathic organizing pneumonia, which is also known as
bronchiolitis obliterans with organizing pneumonia
(BOOP), is a restrictive lung disease that begins with symptoms that are suggestive of viral pneumonitis. The symptoms
fail to resolve and the lung parenchyma undergoes patchy
consolidation (Fig. 4-55). Microscopic sections show numerous fibroblastic polypoid protrusions (Masson bodies)
obliterating the respiratory bronchioles, the alveolar ducts,
and even the alveoli. The epithelium of terminal bronchioles
proliferates, covering the surface of Masson bodies and lining
the restructured air spaces. These findings are, however, non-

specific and also can be found in other forms of chronic

Chronic idiopathic pulmonary fibrosis begins insidiously
and progresses to end-stage lung disease over a variable
period. The lungs are firm and fibrotic and the normal areas
alternate with foci of scarring (Fig. 4-56). Microscopic features include prominent fibrosis replacing focally the normal
lung parenchyma. The remaining air spaces are abnormal,
dilated, and often lined by cuboidal cells (Fig. 4-57). Most
cases of so-called usual interstitial pneumonia (UIP) show
this histologic pattern. Some cases, however, are classified as
desquamative interstitial pneumonia (DIP). In this variant
the thick-walled alveoli are filled with numerous macrophages (Fig. 4-58).
Pulmonary alveolar proteinosis is a disease of unknown etiology. It presents as progressive dyspnea and respiratory
insufficiency. Parts of the lungs become consolidated due to
the accumulation of lipid-rich proteinaceous material in the
alveoli (Fig. 4-59).

Fig. 4-55. Bronchiolitis obliterans. A, The obliterated bronchioli surrounded with

consolidated parenchyma impart a micronodular pattern to the cross section of the lung
parenchyma. B, Masson bodies obliterate the lumen of bronchioli. C, Masson bodies in the
alveolar ducts appear as oval shaped structures composed of fibroblasts and collagen.


Clinicopathologic forms of pulmonary fibrosis

Form (alternative name)
Acute interstitial pneumonia (Hamman-Rich syndrome)
Idiopathic organizing pneumonia (BOOP, COP)
Usual interstitial pneumonia
Desquamative interstitial pneumonia
Nonspecific interstitial pneumonia (CIP)

Weeks to months

Histologic appearance


BOOP, bronchiolitis obliteransorganizing pneumonia; CIP, cellular.interstitial pneumonia; COP, cryptogenic organizing pneumonitis.

Fig. 4-56. Idiopathic pulmonary fibrosis. Cross section of the

lung shows fibrosis with microcystic dilatation of air spaces.

Fig. 4-57. Idiopathic pulmonary fibrosis. The lung parenchyma

has a simplified structure because of a loss of alveoli, which have
been replaced by fibrous tissue.

Fig. 4-58. Desquamative interstitial pneumonia. The alveoli have

thick walls and are filled with numerous macrophages.

Fig. 4-59. Pulmonary alveolar proteinosis. The alveoli are filled

with granular, eosinophilic, lipid-rich, proteinaceous material.

Tumors of the lungs can be classified as central (hilar) or peripheral. Several microscopic categories are recognized
(Table 4-2). Hilar tumors originate from the epithelium of
the main bronchi (Fig. 4-60). Histologically they present as
squamous cell, small (oat) cell, large cell carcinoma, or adenocarcinoma (Figs. 4-61 and 4-62). Peripheral subpleural tumors, which often arise in anthracotic fibrous scars, have his -

tologic features of adenocarcinoma (Fig. 4-63). Bronchioloalveolar carcinoma is a form of peripheral adenocarcinoma that grows along the alveolar septa, filling the alveoli
and causing pneumonia-like consolidation of the lung
parenchyma (Figs. 4-64 and 4-65).
Carcinoids are low-grade malignant tumors of endocrine
cells (Figs. 4-66 and 4-67). Other primary malignant tumors
are less common.

Fig. 4-60. Hilar squamous cell carcinoma. The tumor originates

from the main bronchus.
Fig. 4-61. Squamous cell carcinoma of the bronchus. A focus of
carcinoma (left) is seen adjacent to an area of squamous

Fig. 4-62. Small cell carcinoma. A, The tumor is composed of

small blue cells that have elongated or round nuclei, depending
on the plane of sectioning. The tumor contains areas of necrosis
(right upper corner). B, Neuroendocrine granules can be seen by
electron microscopy.

Fig. 4-63. Peripheral adenocarcinoma. The tumor contains

areas of black discoloration, which suggest that it originated in
an anthracotic scar.


Fig. 4-64. Bronchioloalveolar carcinoma. The tumor infiltrates

the parenchyma and produces lesions that resemble pneumonia.
Fig. 4-65. Bronchioloalveolar carcinoma. The cuboidal mucussecreting tumor cells grow along the alveolar septa.
Lung neoplasms
I. Epithelial tumors
A. Benign tumors
I. Papillomas
2. Adenomas
a. Pleomorphic adenoma
b. Monomorphic adenoma
B. Dysplasia/carcinoma in situ
C. Malignant tumors
I. Squamous cell carcinoma (epidermoid carcinoma)
2. Small cell carcinoma
a. Oat cell carcinoma
b. Intermediate cell type
c. Combined oat cell carcinoma
3. Adenocarcinomas
a. Acinar adenocarcinoma
b. Papillary adenocarcinoma
c. Bronchioloalveolar carcinoma
d. Solid carcinoma with mucus formation
4. Large cell carcinoma variants
a. Giant cell carcinoma
b. Clear cell carcinoma
5. Adenosquamous carcinoma
6. Carcinoid tumor
7. Bronchial gland carcinoma
8. Others
II. Soft tissue tumors primary in the lung
III. Pleural tumors
A. Benign mesothelioma
B. Malignant mesothelioma
IV. Miscellaneous tumors
A. Benign tumors
B. Malignant tumors
I. Carcinosarcoma
2. Pulmonary blastoma
3. Malignant melanoma
4. Malignant lymphoma
5. Others
V. Unclassified tumors
VI. Tumor-like lesions
Modified from Colby TV, Koss MN, Travis WD: Tumors of the lower
respiratory tract. Atlas of tumor pathology, series 3, fasc. 13, Washington,
D.C., 1995, Armed Forces Institute of Pathology; and the World Health
Organization Histological Typing of Lung Tumors, Am J Clin Pothol 77:I23126, 1982.

Fig. 4-66. Bronchial carcinoid. The tumor presented as a small

nodule in the wall of the bronchus.

Fig. 4-67. Carcinoid tumor. The tumor is composed of uniform

cells that have round nuclei.

Sarcomas of the lung present as bulky solid masses (Fig.

4-68). Histologically they resemble sarcomas of soft tissues.
Pulmonary blastoma is an organ-specific malignant tumor
composed of cuboidal epithelial cells that form branching
ducts surrounded by mesenchymal stroma that resemble
fetal lungs (Fig. 4-69).
Benign tumors and tumor-like conditions present as coin
lesions on radiographic examination. Pulmonary hamartomas are composed of cartilage, bronchial epithelium, and

smooth muscle cells. On gross examination hamartomas appear as clefted cartilaginous nodules (Fig. 4-70). Sclerosing
hemangioma, also called papillary pneumocytoma, is a benign tumor of controversial histogenesis (Fig. 4-71). Inflammatory pseudotumor is an inflammatory lesion that may resemble tumors (Fig. 4-72).
Metastatic tumors appear on radiographic examination as
sharply demarcated multiple round nodules ( " cannonball"
lesions). Equivalent autopsy findings are typical (Fig. 4-73).

Fig. 4-68. Sarcoma of the lung. The tumor forms a bulky mass.

Fig. 4-69. Pulmonary blastoma. The tumor is composed of

branching epithelium-lined ducts surrounded by spindle-shaped
stromal cells.

Fig. 4-70. Pulmonary hamartoma. A, The nodule has a prominently clefted appearance on cross
section. B, It is composed of cartilage and cleft-like spaces lined by cuboidal cells.


Fig. 4-71. Sclerosing hemangioma. Vascular papillae are lined by

cuboidal cells.

Fig. 4-73. Metastatic carcinoma. The parenchyma contains

several round nodules.

Further Reading
Bjornsson J, Edwards WD: Primary pulmonary hypertension. A
histopathologic study of 80 cases. Mayo Clin Proc 60:16-25, 1985.
Blumenfeld W. McCook 0, Grississ JM: Detection of antibodies to
Pneumocystic carinii in bronchoalveolar lavage fluid by immunoreactivity to Pneumocystis carinii within alveoli, granulomas,
and disseminated sites. Mod Pathol 5:107-113, 1992.
Colby TV: Bronchiolitis: pathologic considerations. Am J Clin Pathol
109:101-109, 1998.
Dunnill MS: Pulmonary fibrosis. Histopathology 16:321-329, 1990.
Hagan JL, Hardy JD: Lung abscess revisited. A survey of 184 cases. Ann
Surg 197:755-762, 1983.

Fig. 4-72. Inflammatory pseudotumor. The lesion is composed

of a variety of cell types. Plasma cells and fibrosis predominate.

Hasleton PS, Roberts TE: Review: adult respiratory distress syndrome

an update. Histopathology 34:285-294, 1999.
Jeffery PK: Structural and inflammatory changes in COPD: a comparison with asthma. Thorax 53:129-136, 1998.
Marchevsky A, Rosen MJ, Chrystal G, Kleinerman J: Pulmonary complications of the acquired immunodeficiency syndrome. A clinicopathologic study of 70 cases. Hum Pathol 16:659-670, 1985.
Mark EJ, Ramirez JF: Peripheral small-cell carcinoma of the lung resembling carcinoid tumor. A clinical and pathologic study of 14
cases. Arch Pathol Lab Med 109:263-269, 1985.
Porter HJ: Pulmonary hypoplasia-size is not everything. Virchow Arch
432:3-6, 1998.
Takemura T and others: Pulmonary vascular involvement in sarcoidosis. A report of 40 autopsy cases. Hum Pathol 23:1216-23,
Travis WD, Gal AA, Colby TV et al: Reproducibility of neuroendocrine
lung tumor classification. Hum Pathol 29:272-279, 1998.
Travis WD, Rush W, Flieder DB et al: Survivial analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for
atypical carcinoids and its separation from typical carcinoid. Am J
SurgPathol22:934-944, 1998.
Uner AL, Rozum-Slota B, Katzenstein AA: Bronchiolitis obliteransorganizing pneumonia (BOOP)-like variant of Wegener's granulomatosis. A clinicopathologic study of 16 cases. Am J Surg Pathol
20:794-801, 1996.
Winn WC Jr, Myerowitz RL: The pathology of the Legionella pneumonias. A review of 74 cases and the literature. Hum Pathol 12:40142, 1981.
Yousem SA, Lohr RH, Colby TV: Idiopathic bronchiolitis obliterans organizing pneumonia/cryptogenic organizing pneumonia with unfavorable outcome: pathologic predictors. Mod Pathol 10:864-871,
1997.ganizing pneumonia/cryptogenic organizing pneumonia
with unfavorable outcome: pathologic predictors. Mod Pathol
10:864-871, 1997.

Anemia is a reduction in the hemoglobin concentration in
the blood, which decreases its oxygen-carrying capacity. The
pathologic changes related to anemias can be seen primarily
in the bone marrow, which is the site of red blood cell (RBC)
production; the circulating blood; and the spleen, which is
the primary site of RBC destruction.
Pathophysiologically anemias can be classified into those
attributable to (1) impaired production of erythrocytes;
(2) inherited quantitative and structural abnormalities of
hemoglobin synthesis; (3) increased rate of erythrocyte destruction, that is, hemolytic anemias; and (4) acute blood
loss. On the basis of RBC morphology, anemias are classified
as (1) microcytic, (2) normocytic, or (3) macrocytic (Table

Morphologic Classification of Anemias

Microcytic hypochromic anemias
Iron deficiency
Chronic disease
Sideroblastic anemia
Normocytic normochromic anemias
Aplastic anemia
Chronic disease
Myelophthisic conditions
Hemolytic anemia
Macrocytic anemias
Vitamin B12 deficiency
Folic acid deficiency
Chronic liver disease
Myelodysplastic syndrome

Bone Marrow Changes

Hematopoietic cells constitute 40 percent of normal bone
marrow (Fig. 5-1). Hemolytic anemia results in compensatory erythroid hyperplasia (Fig. 5-2). In aplastic anemia the
bone marrow is acellular and contains few or no hematopoietic cells (Fig. 5-3). Anemia can result from the replacement of the normal hematopoietic cells as a result of sarcoidosis or other inflammatory conditions and tumors (Fig.
5-4). Specific causes of anemia such as parvovirus B19 occasionally may be identified by bone marrow biopsy (Fig. 5-5).
Many other forms of anemia are characterized by specific
bone marrow findings. For example, pernicious anemia
shows megaloblastic changes (Fig. 5-6).

Peripheral Blood Smears

Peripheral blood smears are important for assessing anemia.
Morphology of red blood cells may be used to classify anemias into general categories (e.g., microcytic versus macrocytic) or to obtain specific information about the nature of
the underlying defect, as in spherocytosis,.elliptocytosis,
pyropoikilocytosis, or acanthocytosis (Figs. 5-7 to 5-9).

Fig. 5-I. Normal bone marrow of an adult. Hematopoietic cells

account for approximately 40 percent of marrow's cellularity.

Fig. 5-2. Erythroid hyperplasia. Markedly hypercellular bone

marrow from a patient with hemolytic anemia contains an
increased number of erythroid precursors. Megakaryocytes and
granulocyte at all stages of maturation are present.

Fig. 5-3. Aplastic anemia. There is a marked reduction in

hematopoietic cells with expansion of fat cells.


Fig. 5-4. Parvovirus BI9induced erythroid hypoplasia. The

bone marrow smear shows a reduced number of erythroid
precursors. A giant proerythroblast with a prominent
intranuclear inclusion is seen in the middle of the field.

Fig. 5-5. Sarcoidosis. The bone marrow contains several

confluent noncaseating granulomas.

Fig. 5-6. Pernicious anemia. Bone marrow aspirate smear

contains megaloblastic red cell precursors and giant

Fig. 5-7. Spherocytosis. Spherical RBCs may be seen in

peripheral blood smears of patients who have hereditary
spherocytosis or immune hemolytic anemia, or after RBC

Fig. 5-8. Elliptocytosis and pyropoikilocytosis. A, In hereditary elliptocytosis, elliptocytes

constitute more than 25 percent of all cells in peripheral blood smears. Elliptocytes also are seen
in iron deficiency anemia and various myeloproliferative and/or myelodysplastic disorders.
B, Pyropoikilocytosis may be hereditary, but similar morphology of RBCs can be seen in severe
burns, clostridial sepsis, and snake venom poisoning.

Fig. 5-9. Acanthocytosis. Acanthocytes, or RBCs

with numerous irregular surface spikes, are seen
in peripheral blood smears of patients with
severe liver disease, but also in abetalipoproteinemia, McLeod phenotype, and several other

Fig. 5-10. Hemolytic anemia with Heinz bodies. A, The

peripheral blood smear of this patient with low glucose-6phosphate dehydrogenase activity treated with dapsone contains
numerous "bite cells." B, Neutral redbrilliant green shows
Heinz bodies inclusions. Reticulocytes contain red, delicate,
granular deposits of ribonucleic acid.

Fig. 5-1 I. Sickle cell anemia. The red blood cells vary in size
and shape and are often deformed, that is, sickle-shaped.

Fig. 5-12. Thalassemia. The peripheral blood smear contains numerous target
cells. A, Thalassemia minor. B, Thalassemia major.


Certain forms of hemolytic anemia such as sickle cell anemia

or thalassemia also have typical morphologic features (Figs.
5-10 to 5-12).

Tissue Changes in Anemia

Anemias produce a variety of tissue changes, which vary depending on the severity and duration of the disease and its
pathogenesis. Some tissue changes such as atrophic gastritis
in pernicious anemia reflect the causes of anemia. Replacement of blood cell precursors in the marrow by fibrous tissue
is seen in anemia of myelofibrosis (Fig. 5-13). It may be as -

Fig. 5-13. Myelofibrosis. The hematopoietic bone marrow has

been replaced with fibroblastic tissue.

sociated with extramedullary hematopoiesis, usually in the

spleen and the liver (Fig. 5-14). Intrasplenic hemolysis of
hereditary spherocytosis is accompanied by splenomegaly
(Fig. 5-15). Histologically such enlarged spleens have dilated
sinuses filled with blood (Fig. 5-16). In sickle cell anemia prolonged pooling of red blood cells and obstruction of the
blood flow may cause infarcts, which ultimately lead to fibrotic shrinkage of the spleen ( " autosplenectomy " ) (Fig. 5-17).
The fibrous scars in these abnormally small spleens often are
i mpregnated with iron and calcium salts and thus appear
black (Fig. 5-18).

Fig. 5-14. Extramedullary hematopoiesis. Erythroid and myeloid

cells in various stages of maturation and megakaryocytes are
seen in the liver and spleen.

Fig. 5-15. Hereditary spherocytosis. Spleen is markedly

enlarged. The cut surface is homogeneously red.
Fig. 5-16. Hereditary spherocytosis. Spleen shows prominent
congestion of the red pulp sinuses.

Fig. 5-17. Sickle cell anemia. Spleen is shrunken and has a gray,
nodular external surface.

Fig. 5-18. Sickle cell anemia. The spleen contains fibrotic scars,
which are impregnated with iron and calcium salts and therefore
appear black.

Leukemias are neoplastic diseases of hematopoietic cells presenting primarily with changes in the blood and bone marrow. They are classified as two major cytologic types, myeloid
and lymphocytic, based on the primary cell of origin. Within
each cytologic type, the leukemias are further classified as
acute or chronic, based on the degree of maturation of the
major cell population.

Acute Leukemias
Acute myeloid leukemias (AML) are classified into eight subgroups (Table 5-2). AML is characterized by the appearance
of blast cells in the bone marrow; the diagnosis of AML is
made if the bone marrow contains 30 percent or more blasts.
The major blast populations include myeloblasts, monoblasts, erythroblasts, and megakaryoblasts. Two types of
myeloblasts generally are recognized: type I and type II (Fig.
5-19). The monoblasts and promonocytes are the major immature cells in acute monocytic leukemia (Fig. 5-20). The
promyelocyte is the predominant abnormal cell in acute
promyelocytic leukemia (Fig. 5-21). In approximately 60

percent of cases of AML, myeloblasts contain linear

azurophilic structures known as Auer rods (Fig. 5-22).
Acute lymphoblastic leukemia is classified as L1, L2, or
L3, depending on the blast morphology. The L1 lymphoblast is a small cell, approximately twice the size of a normal
lymphocyte, with a high nuclear-cytoplasmic ratio, a homogeneous smooth nuclear chromatin, and inconspicuous or no identifiable nucleoli (Fig. 5-23).
L2 lymphoblasts are larger than L 1 lymphoblasts and have
moderate amounts of lightly basophilic cytoplasm and fine
nuclear chromatin with distinct and sometimes prominent
multiple nucleoli (Fig. 5-23). L3 lymphoblasts have a moderate amount of intensely basophilic cytoplasm that contains
sharply defined, clear vacuoles, which usually stain with oil
red O and are periodic acidSchiff (PAS) negative (Fig. 5-24).



Classification of Acute Myeloid Leukemias

Acute myeloblastic leukemia, minimally differentiated' (AML-MO)
Acute myeloblastic leukemia without maturation (AML-M I)
Acute myeloblastic leukemia with maturation (AML-M2)
Acute promyelocytic leukemia (AML-M3)
Hypergranular type
Microgranular variant
Acute myelomonocytic leukemia (AML-M4)
Increased marrow eosinophils (AML-M4-EO)
Acute monocytic leukemia (AML)
Acute monoblastic leukemia (AML-M5A)
Acute monocytic leukemia, differentiated (AML-M5B)
Erythroleukemia (AML-M6)
Acute megakaryoblastic leukemia (AML-M7)

Fig. 5-19. Acute myeloid leukemia. The type I myeloblast (I)

is agranular. The type II myeloblast (II) has a few azurophilic
granules in the cytoplasm at the lower right. The promyelocyte (Pro) has numerous azurophilic granules in the cytoplasm.


Fig. 5-20. Acute monoblastic leukemia (M5A). The bone

marrow contains monoblasts, which are larger than normal
myeloblasts and usually have abundant cytoplasm, frequently
with delicate, scattered, azurophilic granules.

Fig. 5-22. Acute myeloblastic leukemia with maturation (M2).

Variation in size and amount of cytoplasm is shown in this
bone marrow smear. The blast at the upper right is small with
sparse cytoplasm and coarser nuclear chromatin and
inconspicuous nucleoli. All of the blasts contain Auer rods.

Fig. 5-24. Acute lymphoblastic leukemia. The cytoplasm of L3

lymphoblasts in a marrow aspirate contains sharply outlined
cytoplasmic vacuoles.

Fig. 5-21. Promyelocytic leukemia. Cells with multiple

intertwining Auer rods ("faggot" cells) are characteristic of
hypergranular promyelocytic leukemia.

Fig. 5-23. Acute lymphoblastic leukemia. LI and L2

lymphoblasts show characteristic morphology in
marrow aspirates.

Chronic Leukemias
Chronic myeloid leukemia (CML) is a myeloid stem cell disorder. Together with several other closely related diseases of
the bone marrow, it forms a group if disorders known as primary myelodysplastic syndromes (Table 5-3). In CML the
bone marrow is markedly hypercellular and contains an increased number of neutrophils and megakaryocytes and
their precursors (Fig. 5-25). The peripheral blood leukocytosis exceeds 100 X 10 9/L in 70 percent to 90 percent of patients. Neutrophils at the myelocyte and segmented stages
predominate; myeloblasts do not exceed 2 percent to 3 percent of all cells (Fig. 5-26).
Chronic lymphoproliferative disorders are a heterogeneous
group of diseases that are characterized by a proliferation of
small well-differentiated lymphocytes. On the basis of immunohistochemical markers these disorders represent
either B-cell or T-cell neoplasms (Table 5-4).
Chronic B-cell lymphocytic leukemia is characterized by
lymphocytosis that varies from 4 X 10 9 /L to more than 400
X 109 /L. Peripheral blood smears contain numerous relatively uniform lymphocytes that have condensed nuclear
chromatin and sparse cytoplasm (Fig. 5-27).
In hairy cell leukemia the peripheral blood contains
medium-sized lymphocytes with an oval or lobated nucleus
and shaggy cytoplasm extending into surface projections
(Fig. 5-28). In adult T-cell leukemia, a disease associated with
human T-cell leukemia/lymphoma virus (HTLV-1) infection, peripheral blood smears contain abnormal lymphocytes, which are described as having " flower-shaped,"
markedly convoluted nuclei (Fig. 5-29). In granulated cell
lymphocytic leukemia peripheral blood smears contain
medium-sized to large lymphocytes with abundant cytoplasm that is rich in coarse azurophilic granules (Fig. 5-30).

Fig. 5-25. Chronic myeloid leukemia. Bone marrow is markedly

hypercellular and infiltrated with numerous myeloid cells.

Fig. 5-26. Chronic myeloid leukemia. The peripheral blood

smear shows marked leukocytosis and basophilia.

Classification of Primary Myelodysplastic Syndromes

Refractory anemia (RA)

Anemia refractory to hematinic therapy; dyserythropoiesis 6; granulocytes and megakaryocytes usually normal; marrow blasts less than 5%; no blasts in blood

Refractory anemia with ringed sideroblasts (BARS)

More than 15% of red cell precursors in marrow "ringed" sideroblasts; less than 5% blasts
in marrow

Refractory anemia with excess blasts (RAEB)

5% to 20% blasts in marrow; less than 5% blasts in blood

Refractory anemia with excess blasts in

transformation (RAEB-T)

I. 20% to 29% blasts in marrow;

2. 5% to 29% blasts in blood
3. Auer rods
(any one criterion suffices)

Chronic myelomonocytic leukemia (CMML)

> I X I09/L monocytes in blood; <20% blasts in marrow; dysgranulopoiesis -!-

Chronic myelomonocytic leukemia in

> I X I09/L monocytes in blood and one of the criteria listed for RAEB-T

transformation (CMML-T)
Myelodysplastic syndrome, unclassified

Less than 5% blasts in marrow; significant dysplasia in two or more myeloid cell lines


Chronic Lymphoproliferative Disorders

B-cell lymphoproliferative disorders
Chronic lymphocytic leukemia
Mixed cell type
Prolymphocytic leukemia
Chronic lymphocytic leukemia/prolymphocytic leukemia
Hairy cell leukemia
Splenic lymphoma with villous lymphocytes
T-cell chronic lymphoproliferative disorders
T prolymphocytic leukemia
Granulated T-lymphocyte leukemia
Sezary syndrome
Adult T-cell leukemia

Fig. 5-27. Chronic lymphocytic leukemia. The smear contains

numerous well-differentiated lymphocytes with a high nuclearcytoplasmic ratio and condensed nuclear chromatin.

Fig. 5-28. Hairy cell leukemia. A, The blood smear contains lymphoid cells that have a shaggy
cytoplasm. B, Electron microscopy shows slender surface villi.

Fig. 5-29. Adult T-cell leukemia/lymphoma. The smear contains

lymphoid cells with lobulated ("flower-shaped") nuclei.

Fig. 5-30. Granulated lymphocyte leukemic CD8+ lymphocytes

have abundant cytoplasm filled with coarse azurophilic granules.



Plasma cell dyscrasias are proliferations of B immunocytes
accompanied by the production of monoclonal immunoglobulin. This group of diseases includes several closely
related entities (Table 5-5).
Multiple myeloma is a neoplastic proliferation of plasma
cells associated with a monoclonal gammopathy. The criteria
for the diagnosis are summarized in Table 5-6. Plasma cell
Plasma Cell Dyscrasias and Related
Monoclonal gammopathy of undetermined significance (MGUS)
Solitary plasmacytoma
Multiple myeloma
Waldenstrom macroglobulinemia
Heavy chain disease
Primary amyloidosis

infiltrates cause lytic punched-out lesions in the bones (Fig.

5-31). Bone marrow aspirates of these lesions contain plasma
cells, which can be classified as mature, immature, or plasmablastic (Fig. 5-32). The neoplastic infiltration of the bone
marrow seen in trephine biopsies may be diffuse, focal, interstitial, or a combination of these patterns (Fig. 5-33).
Immunohistochemistry typically shows that the cells are
light chain restricted (i.e., monoclonal), expressing either
kappa (K) or lambda (K) light chains (Fig. 5-34). Light chains
of immunoglobulin are excreted in urine as Bence Jones protein. Renal amyloidosis is a common complication (Fig.
Waldenstrom macroglobulinemia is a monoclonal gammopathy of the immunoglobulin M class. It is associated with
plasmacytoid lymphoma cells infiltrating the bone marrow
or the lymph nodes (Fig. 5-36). The bone marrow is involved
focally or diffusely in 85 percent of patients. Tumor cells appear as either small or plasmacytoid lymphocytes.

Fig. 5-3 I. Multiple myeloma. A, The radiograph shows lytic lesions. B, The skull contains lytic
("punched-out") lesions.

Fig. 5-32. Multiple myeloma. Bone marrow aspirate contains

mostly plasma cells.

Fig. 5-33. Multiple myeloma. Bone marrow is infiltrated with

atypical plasma cells.


Diagnostic Criteria for Multiple Myeloma

Modified from Durie BG: Staging and kinetics of multiple myeloma, Semin
Oncol 13:300, 1986.

Fig. 5-34. Multiple myeloma. The bone marrow biopsy was

stained immunohistochemically with antibodies to kappa (K) and
lambda (X) light chains. The plasma cells are kappa light chain

Fig. 5-35. Amyloidosis. A, Renal

amyloidosis affecting the glomeruli and
blood vessels is a common complication of monoclonal gammopathies.
B, Congo red stained amyloid
examined under polarized light appears

Fig. 5-36. Waldenstrom macroglobulinemia. The infiltrate

consists of small lymphocytes, lymphoplasmacytic cells, and
plasma cells. Arrow shows intranuclear inclusions (Dutcher
bodies), which are known to be composed of immunoglobulin.


The term lymphadenopathy is used to describe nonneoplastic
enlargement of lymph nodes caused either by infection or by
any other antigenic stimulation. Five histologic patterns are
recognized: (1) follicular, (2) interfollicular, (3) mixed follicular and interfollicular, (4) diffuse, and (5) sinusoidal (Table
Follicular hyperplasia, the most common form of reactive
lymphoid proliferation, is characterized by an increased
number and size of follicles. Fusion of adjacent germinal
clusters may take place, resulting in a histologically bizarre
geographic pattern" (Fig. 5-37). The hyperplastic follicles
contain expanded germinal centers composed of small and
large cleaved and noncleaved cells (Fig. 5-38).
Castleman disease, or angiofollicular lymph node hyperplasia, occurs in two forms: the more common hyaline vascular type (Fig. 5-39) and plasma cell variant (Fig. 5-40). The
histologic findings are diagnostic.
Histiocytic necrotizing lymphadenitis, or Kikuchi disease,
is a benign self-limited disease that predominantly affects
young women. Histologically the enlarged lymph nodes contain patchy areas of necrosis confined to paracortical and cortical areas, surrounded by macrophages, immunoblasts, and
plasma cells (Figs. 5-41 and 5-42).
Human immunodeficiency virus (HIV) infection leads to
lymph node enlargement, a condition known as persistent
generalized lymphadenopathy (Fig. 5-42). The enlarged
lymph nodes contain hyperplastic germinal centers with
little intervening interfollicular tissue. In other cases the
sinuses are distended by monocytoid B-cells and scattered

Fig. 5-37. Follicular lymph node hyperplasia. Fusion of adjacent

germinal centers results in bizarre structures.

Patterns of Reactive Lymphadenopathies

Follicular pattern
Nonspecific follicular hyperplasia
Rheumatoid arthritis/Sjogren syndrome
Angiofollicular hyperplasia (Castleman disease)
Progressive transformation of germinal centers
Interfollicular pattern
Nonspecific interfollicular hyperplasia
Dermatopathic lymphadenitis
Histiocytic necrotizing lymphadenitis (Kikuchi disease)
Granulomatous lymphadenitis
Mixed follicular and interfollicular pattern
Toxoplasmosis lymphadenitis
Cat-scratch disease
Lymphogranuloma venereum
Mesenteric lymphadenitis
Kimura disease
Diffuse pattern
Infectious mononucleosis and other viral lymphadenitis
Abnormal immune response/angioimmunoblastic lymphadenopathy
Drug-induced hypersensitivity reactions
Systemic lupus erythematosus
Mucocutaneous lymph node syndrome (Kawasaki disease)
Sinus pattern
Sinus histiocytosis
Hemophagocytic syndrome
Sinus histiocytosis with massive lymphadenopathy
Lymphangiography effect
Whipple disease
HIV, Human immunodeficiency virus.

Fig. 5-38. Follicular hyperplasia. The hyperplastic germinal

center contains small and large cleaved and noncleaved germinal
center cells, tingible body macrophages, and scattered plasma


Fig. 5-39. Castleman disease, hyaline vascular type. Two

follicles with progressively transformed germinal centers are
surrounded by concentrically arranged mantle zone lymphocytes. "Lollipop" appearance of a follicle (right) is evident.
Interfollicular vascularity is prominent.

Fig. 5-40. Castleman disease, plasma cell variant. Part of a follicle

is seen adjacent to a dense interfollicular plasma cell infiltrate.

Fig. 5-41. Kikuchi disease. A, An irregular patchy focus of paracortical necrosis devoid of neutrophils is characteristic of this disease. B, Higher magnification shows that the necrotic area is
surrounded by a mixture of large cells, such as macrophages, immunoblasts, and plasmacytoid

Fig. 5-42. A, HIV-related lymphoadenopathy. Most of the node is replaced by large germinal
centers in which there is a prominent starry sky appearance. B, Monocytoid B-cells occupy the
paracortex between two large germinal centers.


Fig. 5-43. Diagnostic Reed-Sternberg cells and variants. A, Diagnostic Reed-Sternberg cell: a
large multinucleated or multilobated cell with inclusion bodylike nucleoli surrounded by a halo of
clear nucleoplasm. There is a moderate amount of amphophilic cytoplasm. B, L&H variant. A large
cell with a polyploid nucleus and high nuclear-cytoplasmic ratio. The nucleolus is not large and
prominent. C, Lacunar variant: the cell has a lobated nucleus with small-to moderately prominent
nucleoli in a clear lacuna produced by the retraction of cytoplasm from the plasm membrane. A
small amount of cytoplasm often is observed around the nucleus. D, Mononuclear variant. This
cell has the characteristics of a diagnostic Reed-Sternberg cell but with a single round or oval
nucleus. E, Mummified (necrobiotic) cells frequently seen in nodular sclerosis type HD with
pyknotic nucleus and darkly eosinophilic cytoplasm. F, Electron microscopy of a typical ReedSternberg cell.



Histopathologic Subtypes of
Hodgkin Disease

Hodgkin disease (HD) is a neoplastic disease of lymph nodes.

Current evidence suggests that HD may be a syndrome that
comprises several entities, which nevertheless show some
common pathologic and clinical features that distinguish
them from non-Hodgkin lymphomas. Histologically the
tumor consists of neoplastic Reed-Sternberg (R-S) cells that
typically are found in a background of reactive cells such as
small lymphocytes, macrophages, eosinophils, neutrophils,
and plasma cells. R-S cells have characteristic features and are
pathognomonic of HD (Fig. 5-43). In addition to classic R-S
cells the tumors contain varying numbers of large pleomorphic neoplastic cells known as R-S variants (Fig. 5-43).
Hodgkin disease tends to involve cervical and axillary
lymph nodes in a contiguous manner (Fig. 5-44). The spleen,
thymus, bone marrow, and liver also may be involved (Fig.

The pathologic classification of Hodgkin disease (HD) in

current use continues to be the one proposed by Lukes and
Butler in 1966. The relationship of this classification to the
older classification by Jackson and Parker and the simplified
version adopted at the Rye conference is shown in Table 5-8
Lymphocyte predominance type HD is characterized by a
dense lymphocytic infiltrate with some histiocytes, which occasionally may be abundant. It occurs in a diffuse and a
nodular form (Fig. 5-45). The L&H variants of R-S cells are
scattered in this infiltrate, occasionally even in the form of
small aggregates. Diagnostic R-S cells are very difficult to
Nodular sclerosis type HD is characterized by a thickened
lymph node capsule. Bands of collagen extend inward from


The Pathologic Classification of Hodgkin Disease

Jackson & Parker


Lukes & Butler

I. Lymphocytic and histiocytic
a. Nodular
b. Diffuse
2. Nodular sclerosis

Rye Conference
Lymphocytic predominance

Frequency (%)*

Nodular sclerosis


3. Mixed cellularity
4. Diffuse fibrosis
5. Radicular

Mixed cellularity


Lymphocytic depletion

From Colby TV, Hoppe RT, Warnke RA Cancer 49:1848-1856, 1981. Copyright 1981 American Cancer Society. Reprinted by permission of Wiley-Liss,
Inc., a subsidiary of John Wiley & Son, Inc.
*Two percent of the cases were considered unclassifiable.

Fig. 5-44. Hodgkin disease. Axillary lymph nodes are enlarged.

Fig. 5-45. L&H Hodgkin disease, nodular type. Large nodules

with small round lymphocytes, macrophages, and scattered L&H
cells are seen.


the capsule and separate the tumor into nodules composed

of a variety of reactive cells and R-S variants called lacunar
cells (Fig. 5-46). Areas of necrosis or microabscess formation
may be prominent (Fig. 5-47).
Mixed cellularity type HD is characterized by a mixed cellular background of lymphocytes, histiocytes, eosinophils,
and plasma cells (Fig. 5-48). Typical R-S cells and mononuclear variant R-S cells are readily identified.
Lymphocyte depletion type HD occurs as diffuse fibrosis
type (Fig. 5-49) or reticular type (Fig. 5-50). In the former
R-S cells are not necessarily numerous. In the latter there is
marked proliferation of R-S cells, which may be pleomorphic
and bizarre.

Fig. 5-46. Nodular sclerosis type HD. Bands of thick collagen

extend from the thickened capsule to divide the lymph node
into smaller nodules.

Fig. 5-47. Nodular sclerosis type HD. Microabscess is

surrounded by a ri m of R-S variant cells.

Fig. 5-48. Mixed cellularity type HD. Mononuclear R-S variant

cells are scattered in a mixed cellular background.

Fig. 5-49. Lymphocyte depletion type HD. Diffuse fibrosis type.

Much of the lymph node has been replaced by a pink, eosinophilic, amorphous material with depletion of lymphocytes.
Scattered R-S variant cells are seen.

Fig. 5-50. Reticular type. The lymph node is largely replaced by

a proliferation of R-S cells and R-S variant cells.


The term non-Hodgkin lymphoma includes all malignant
lymphomas other than Hodgkin disease. Non-Hodgkin
lymphomas can be classified according to the Working Formulation developed by the National Cancer Institute; a
German system, called the Kiel classification, which is widely
used in Europe; or the new classification developed by the

International Lymphoma Study Group, which is referred to

as REAL (Revised European-American Lymphoma; Table
Small lymphocytic lymphoma is a low-grade B-cell neoplasia that diffusely infiltrates the lymph nodes (Fig. 5-51).
Morphologically the tumor cells resemble small mature lymphocytes (Fig. 5-52).

Comparison of Working Formulation (WF) and

Revised European-American Lymphoma (REAL) Classification
WF Category*
A. Small lymphocytic consistent with CLL


B. Follicular, predominantly small cleaved cell

B-cell Neoplasms

REAL Classification
T-cell Neoplasms

Marginal zone/MALT
Mantle cell



Follicle center, follicular, grade I

Mantle zone
Marginal zone

C. Follicular, mixed small cleaved and large cell

Follicle center, follicular, grade II

Marginal zone/MALT

D. Follicular, large cell

Follicle center, follicular, grade III

E. Diffuse, small cleaved cell

Mantle cell
Follicle center, diffuse small cell
Marginal zone/MALT

Peripheral T-cell, unspecified

F. Diffuse, mixed small and large cell

Large B-cell lymphoma (rich in T-cells)

Follicle center, diffuse small cell
Marginal zone/MALT
Mantle cell

Peripheral T-cell, unspecified



Diffuse large B-cell lymphoma


Peripheral T-cell, unspecified

H. Large cell

Diffuse large B-cell lymphoma

Peripheral T-cell, unspecified

Anaplastic large-cell



Precursor B-lymphoblastic

Precursor T-lymphoblastic

Small noncleaved cell


High-grade B-cell, Burkitt-like

Peripheral T-cell, unspecified

G. Diffuse, large cell

From Skarin AT, Dorfman DM: Non-Hodgkin's lymphoma: current classification and management, CA Cancer /.


47:351-372, 1997. Reproduced with

*Categories AC = low-grade (survival 5 to 10 or more years untreated); DG = intermediate grade (survival 2 to 5 years untreated); H J = high grade
(survival 0.5 to 2.0 years untreated). Categories DH are also called aggressive lymphomas. ATUL, Adult T-cell lymphoma/leukemia; CLL, chronic lymphocytic leukemia; LGL, large granular lymphocyte leukemia; MALT, mucosa-associated lymphoid tissue; PLL, prolymphocytic leukemia; SLL, small lymphocytic lymphoma.


Fig. 5-5I. Small lymphocytic lymphoma. The normal lymph

node architecture has been completely effaced.

Marginal zone lymphoma is a low-grade lymphoma composed of cells that resemble normal B cells of the marginal
zones. These B cells are normally present external to follicular mantle cells and are particularly prominent in the spleen.
They are thought to be capable of differentiating into reactive monocytoid B cells and plasma cells. Cases involving
lymph nodes are often referred to as monocytoid lymphoma,
whereas those arising in mucosa-associated lymphoid tissue
are called maltomas. Involved lymph nodes show a variety of
architectural patterns. In early stages lymphoma cells infiltrate the marginal zone surrounding reactive germinal centers, with occasional colonization of the germinal center (Fig.
5-53). In later stages lymphoma cells diffusely infiltrate the
lymph nodes or the mucosa (Fig. 5-53). The infiltrate typically is composed of intermediate-sized monocytoid B cells
(Fig. 5-54). Lymphoma cells tend to invade epithelia, forming
lymphoepithelial lesions " (Figs. 5-55 and 5-56). In approximately 40 percent of cases monoclonal plasma cells or plasmacytoid cells also are found in the infiltrate.
Mantle cell lymphoma is a low- to intermediate-grade lymphoma. There are several architectural patterns. The normal
architecture of the lymph node may be completely effaced or
a vaguely vascular pattern may be retained. Mantle zone pattern results from a broad infiltrate around the reactive germinal centers (Fig. 5-57). The infiltrate is composed of small
to medium-sized lymphocytes with a mature chromatin pattern and slightly irregular nuclear membranes. Nucleoli are
inconspicuous and the cytoplasm is scant (Fig. 5-58).
Follicular lymphoma is a low- to intermediate-grade lymphoma that grows in a follicular pattern. It represents the
neoplastic counterpart of germinal center B lymphocytes
(Fig. 5-59). Cytologically several variants have been recognized: small cleaved cell (Fig. 5-60), mixed small cleaved and
large cell (Fig. 5-61), and predominantly large cell (Fig. 5-62).
Occasionally the neoplastic cells take unusual forms, such as
signet ringlike cells, or they may show plasmacytoid differentiation.

Fig. 5-52. Small lymphocytic lymphoma. The lymph node is

composed of loosely packed cells of intermediate size with
discernible nucleoli.

Fig. 5-53. Marginal zone lymphoma. There is preferential

infiltration of the marginal zone of splenic white pulp.

Fig. 5-54. Marginal zone lymphoma. The lymph node is

infiltrated by a uniform population of small to intermediate-sized
lymphocytes with bland nuclei and a moderate rim of clear
cytoplasm. Note the presence of scattered neutrophils.


Fig. 5-55. Marginal zone lymphoma of salivary gland. The

epithelial gland is infiltrated with lymphocytes, forming a socalled "lymphoepithelial lesion."

Fig. 5-56. Marginal zone lymphoma of the stomach ("maltoma").

Small to medium-sized lymphocytes, many of which have a clear
perinuclear halo, invade gastric glands.

Fig. 5-57. Mantle cell lymphoma. Germinal center is surrounded

by a broad zone ("mantle").

Fig. 5-58. Mantle cell lymphoma. The infiltrate consists of a

monotonous population of small lymphocytes. The nuclei of
these cells have a mature chromatin pattern and slightly irregular

Fig. 5-59. Follicular lymphoma. Many crowded nodules of relatively even size and lacking well-defined mantle zones are present.

Fig. 5-60. Follicular, predominantly small cleaved cell lymphoma. The infiltrate is composed of a monotonous population of
small cells with contorted nuclei (cleaved cells).


Fig. 5-61. Follicular, mixed small cleaved and large cell lymphoma.
Two cell populations are clearly seen.

Fig. 5-62. Follicular, predominantly large cell lymphoma. The

infiltrate is composed predominantly of large noncleaved cells.

Fig. 5-63. Diffuse large cell lymphoma. Large tumor cells have
vesicular nuclei in contrast to occasional normal lymphocytes
that have condensed chromatin.

Fig. 5-64. Large cell immunoblastic lymphoma. The tumor cells

are large, with vesicular nuclei containing a single prominent
nucleolus. The cytoplasm is abundant and shows plasmacytoid

Diffuse, mixed large cell and large cell immunoblastic lymphomas of B-cell lineage are classified according to the
Working Formulation as intermediate- or high-grade lymphomas, respectively. The neoplastic cells infiltrate the lymph
node, causing partial or complete effacement of the lymph
node architecture. The hallmark of these lymphomas is the
presence of a significant number of large lymphoid cells (Fig.
5-63) or immunoblasts (Fig. 5-64). In diffuse mixed lymphomas there is a significant admixture of small lymphoid
cells, such that neither element dominates (Fig. 5-65). In
other cases the small round cells represent reactive T cells that
are not part of the neoplastic process. These tumors usually
are designated T-cell rich B-cell lymphomas (Figs. 5-66 and
5-67). Necrosis or sclerosis may be prominent in large cell
lymphomas (Fig. 5-68). Typically there is an admixture of reactive cells, such as epithelioid and nonepithelioid histio -

cytes, small lymphocytes, eosinophils, and plasma cells.

Peripheral T-cell lymphomas (PTCL), also known as postthymic T-cell lymphomas, are intermediate- or high-grade
malignancies composed of T cells, morphologically and immunophenotypically equivalent to mature T cells. The term
PTCL encompasses several clinicopathologic entities, includipg mycosis fungoides/Sezary syndrome, adult T-cell
leukemia/lymphoma; angioimmunoblastic lymphadenopathy with dysproteinemia-like (AILD-like) T-cell lymphoma, lymphoepithelioid T-cell lymphoma, angiocentric
T-cell lymphoma, intestinal T-cell lymphoma, T-cell lymphoma associated with erythrophagocytosis, hepatosplenic
T-cell lymphoma, erythrophagocytic T- y lymphoma, and
many cases of CD30+ lymphoma. Peripheral T-cell lymphomas are difficult to recognize morphologically because
they can assume a variety of histologic appearances. They


Fig. 5-65. Diffuse mixed small and large cell lymphoma. A

relatively even admixture of small and large atypical lymphoid
cells is seen.

Fig. 5-66. T-cell rich B-cell lymphoma. The large tumor cells are
embedded in a background of smaller T cells.

Fig. 5-67. T-cell rich B-cell lymphoma. The large cells stain with
antibodies to CD20, a B cell marker.

Fig. 5-68. Large cell lymphoma. The tumor contains prominent

areas of sclerosis.

never show a follicular architecture but may show effacement, preferential paracortical infiltration, or preferential
sinusoidal involvement. The cell infiltrate usually is composed of a mixture of atypical intermediate-sized to large
lymphoid cells (Fig. 5-69). The atypical cells often have irregular nuclear contours, which may vary from one cell to
another and may include highly pleomorphic forms, some
of which have multilobated nuclei (Fig. 5-70).
AILD-like T-cell lymphoma is characterized by cell-poor
diffuse effacement of lymph node architecture, numerous
arborizing vessels, and absence or repression of germinal
centers. Deposits of intercellular PAS-positive amorphous
material may be prominent. In early stages of the disease the
definitive diagnosis of this lymphoma cannot be made easily.
When the neoplastic cells increase in number and cells with
clear cytoplasm appear, often forming clusters around the

Fig. 5-69. Peripheral T-cell lymphoma. The perivascular infiltrate is composed of both large and intermediate-sized atypical
lymphoid cells. Scattered eosinophils are present.


Fig. 5-70. Peripheral T-cell lymphoma. The tumor consists of a

mixed population of small, intermediate-sized, and large lymphoid cells. Many of the large lymphoid cells have hyperlobated

Fig. 5-71. AILD-like T-cell lymphoma. The infiltrate contains

prominent intermediate-sized atypical lymphoid cells with pale
cytoplasm. These cells often form small groups.

Fig. 5-72. Lymphoepithelioid T-cell (Lennert) lymphoma. Atypical lymphoid cells are admixed to epithelioid histiocytes, which
represent the most abundant cells in the tissue. Eosinophils and
plasma cells also may be present.

Fig. 5-73. Angiocentric lymphoma. A small artery in the center

is infiltrated with atypical lymphoid cells that occlude its lumen.

vessels, the diagnosis of AILD-like T-cell lymphoma can be

made readily (Fig. 5-71).
Lymphoepithelioid T-cell lymphoma, or Lennert lymphoma, is characterized by a proliferation of atypical T lymphocytes surrounded by epithelioid histiocytes (Fig. 5-72).
Plasma cells and eosinophils usually are present.
Angiocentric T-cell lymphoma is a term that encompasses
a group of previously poorly characterized entities, such as
lymphomatoid granulomatosis and polymorphic reticulosis. It
occurs in extranodal sites, particularly the upper and lower
respiratory tracts and the skin. The unifying feature of the
various forms of this lymphoma is the infiltration of small
arteries and veins (Fig. 5-73). The infiltrates consist of atypical T cells, small lymphocytes, plasma cells, macrophages,
and eosinophils.

Lymphoblastic lymphoma is a high-grade malignant lymphoma; it represents the tissue equivalent of acute lymphoblastic leukemia. A lymphoblastic lymphoma typically presents as a mediastinal mass, often with pleural or pericardial
effusion. The atypical small to medium-sized lymphoid cells
tend to efface the lymph node architecture and spread into
the pericapsular tissue, evoking a fibrous response (Fig.
5-74). The mitotic rate is high and extensive single cell
necrosis may be present. The tumor cells have round or
highly irregular nuclear contours with finely dispersed chromatin and inconspicuous nucleoli.
Small noncleaved cell lymphoma (SNCL) is a high-grade
malignancy of two subtypes: Burkitt type and non-Burkitt
type. In Burkitt lymphoma the infiltrate begins in the germinal centers, subsequently leading to an effacement of the


Fig. 5-74. Lymphoblastic lymphoma. A single cell file pattern of

infiltration is seen in the perinodal tissue.

Fig. 5-75. Burkitt lymphoma. A starry sky pattern is seen at low


Fig. 5-76. Burkitt lymphoma. The tumor is composed of a uniform population of medium-sized lymphoid cells. The chromatin
is not dispersed as finely as it is in lymphoblastic lymphoma. Each
nucleus contains several nucleoli.

Fig. 5-77. Small noncleaved cell lymphoma, non-Burkitt type. A

population of intermediate-sized lymphoid cells with a high
mitotic rate is present. The cells are somewhat more pleomorphic than those typically seen in Burkitt lymphoma.

lymph node architecture (Fig. 5-75). There are numerous mitoses and tangible body macrophages, which impart to the
lymph node a starry sky appearance. The neoplastic cells are
B lymphocytes of intermediate size with round nuclei, coarse
chromatin, and multiple nucleoli (Fig. 5-76). The neoplastic
cells of the non-Burkitt subtype are similar to those in Burkitt
lymphoma except that the cells show more pleomorphism
and fewer but often more prominent nucleoli (Fig. 5-77).


Neoplasms that originate from other cellular components of

lymph nodes are much less common than lymphomas.
Langerhans cell histiocytosis presents with neoplastic infiltrates in lymph node sinuses (Fig. 5-78). The neoplastic

Fig. 5-78. Langerhans cell histiocytosis. The sinusoid of the

lymph node is distended by sheets of Langerhans cells and an
aggregate of eosinophils.


Fig. 5-79. Follicular dendritic cell sarcoma. The infiltrate consists

of spindle cells. A few scattered lymphocytes are still present.

Langerhans cells have grooved nuclei with complex, folded

delicate nuclear membranes, which give them a coffee
beanlike appearance.
Dendritic cell sarcomas include follicular dendritic cell sarcoma and interdigitating cell sarcoma. The neoplastic cells
have elongated nuclei and pale eosinophilic cytoplasm (Fig.
5-79). There are numerous small lymphocytes between the
tumor cells.
Myeloid leukemia may involve the lymph nodes or may
present as a soft tissue mass ( "chloroma " ). Tumors are composed of a uniform population of cells with vesicular nuclei
(Fig. 5-80). The mitotic rate is high and occasionally there is
a starry sky appearance.

Splenomegaly may be caused by a variety of neoplastic and
nonneoplastic diseases, which are listed in Table 5-10.
All leukemias, myeloproliferative diseases, and lymphomas may involve the spleen and cause splenomegaly (Fig.
5-81). The pattern of splenic involvement depends on the
type of the disease. In acute myeloid leukemia the cords and
sinuses are filled with blast cells (Fig. 5-82). In hairy cell
leukemia the neoplastic cells infiltrate the red pulp and surround the trabecular vessels of the white pulp (Fig. 5-83). Lowand intermediate-grade lymphomas involve the white pulp
and produce a "miliary" pattern (Fig. 5-84). High-grade
B-cell lymphomas, on the other hand, produce one or more
solid tumors or masses (Fig. 5-85). T-cell lymphomas are less
common in the spleen, where they usually involve the T zones
and the red pulp (Fig. 5-86). Splenic involvement is found in
approximately one third of cases of Hodgkin disease. The infiltrates are always in the white pulp.

Fig. 5-80. Acute myeloid leukemia involving a lymph node. A

diagnosis of "atypical" lymphoblastic lymphoma was favored histologically because this patient did not have a history of leukemia.

Causes of Splenomegaly
Myeloproliferative and myelodysplastic disorders, leukemia,
and lymphoma
Hemolytic anemias
Hereditary spherocytosis, elliptocytosis
Thalassemias, sickle cell anemia
Autoimmune disorders
Autoimmune hemolytic anemia
Thrombocytopenia, essential neutropenia
Systemic lupus erythematosus
Rheumatoid arthritis
Infectious mononucleosis, brucellosis, etc.
Malaria, toxoplasmosis, etc.
Cirrhosis of the liver
Budd-Chiari syndrome
Chronic congestive heart disease
Storage diseases
Gaucher disease, Niemann-Pick disease


Fig. 5-81. Chronic myeloid leukemia. Splenomegaly is a common

finding. Spleen also shows infarcts.

Fig. 5-82. Acute myeloid leukemia. The cords and sinuses are
filled with blast cells.

Fig. 5-83. Hairy cell leukemia. The tumor cells diffusely infiltrate
the red pulp. Replacement of normal sinus-lining cells by hairy
lymphocytes leads to pooling of blood and the formation of
"blood lakes," which are typical of this disease.

Fig. 5-84. Mantle cell lymphoma. The enlarged follicles of the

white pulp infiltrated with tumor cells impart a "miliary" pattern
to the cross section of the spleen.

Fig. 5-85. Lymphoblastic lymphoma. Tumor cells form a

discrete mass in the spleen.

Fig. 5-86. T-cell lymphoma, high-grade. The tumor involves the

sinusoids of the red pulp, simulating malignant histiocytosis.



The most important pathologic changes involving the
thymus are (1) developmental disorders such as thymic
aplasia, hypoplasia, or dysplasia; (2) accelerated involution
of the thymus; (3) thymitis and hyperplasia; and (4) thymic
In primary immunodeficiency states the thymus is very
small (Fig. 5-87). Histologically the thymus shows either
simple dysplasia (Fig. 5-88), dysplasia with stromal corticomedullary differentiation (Fig. 5-89), dysplasia with pseudoglandular appearance, or severe atrophy.
Lymphofollicular thymitis, also known as lymphoid follicular hyperplasia, is found in 50 percent to 70 percent of cases
of myasthenia gravis. The enlargement of the thymus is as-

sociated with an increased number of lymphoid follicles with

germinal centers (Fig. 5-90).
Tumors of the thymus originate from the thymic epithelium or lymphocytes. Thymomas are classified as benign or
malignant. Benign thymomas are well encapsulated (Fig.
5-91). They are composed of spindle-shaped epithelial
cells admixed to mature lymphocytes (Fig. 5-92). There are
three forms of thymic carcinomas: (1) low-grade, predominantly cortical (organoid), malignant thymoma; (2) welldifferentiated thymic carcinoma, which includes squamous
cell carcinoma, clear cell carcinoma, or carcinoid; and (3) anaplastic carcinoma (Fig. 5-93). Lymphomas are of B-cell or
T-cell type. Hodgkin disease also may involve the thymus.

Fig. 5-87. Thymic hypoplasia. A, A severely hypoplastic thymus (arrowheads) was found close to the aortic arch at the
autopsy of a six-month-old infant who died of sepsis superimposed on severe combined immunodeficiency (SCID).
B, Incomplete DiGeorge syndrome shows incompletely descended hypoplastic thymus. T, Thymus. L, Larnyx.

Fig. 5-88. Simple thymic dysplasia. Epithelial thymic lobules are

almost devoid of lymphoid cells, without corticomedullary
demarcation and with a lack of Hassall corpuscles.

Fig. 5-89. Thymic dysplasia with stromal corticomedullary differentiation. Rudimentary cortical medullary demarcation is
evident, but no Hassall corpuscles are seen. Patient had SCID
caused by purine nucleoside phosphorylase (PNP) deficiency.


Fig. 5-90. Follicular thymitis in myasthenia gravis. The thymus

contains numerous lymphoid follicles in the perivascular spaces
and the medulla.

Fig. 5-91. Thymoma. The tumor is encapsulated and appears

lobulated on cross section.

Fig. 5-92. Medullary thymoma. The tumor is composed of

spindle-shaped epithelial cells in a background of mature

Fig. 5-93. Thymic carcinoma. Epithelial tumor cells form solid

nests that contain only a few scattered lymphocytes. The
borders of the tumor nests may be scalloped or infiltrating.

Further Reading
Baddoura FK, Chan WC, Masih AS et al: T-cellrich B-cell lymphoma.
A clinicopathologic study of eight cases. Am J Clin Pathol 103:6575, 1995.
Burke JS: Splenic lymphoid hyperplasias versus lymphomas/leukemias.
A diagnostic guide. Am J Clin Pathol 99:486-493, 1993.
Chang KL, Kamel OW, Arber DA et al: Pathologic features of nodular
lymphocyte predominance Hodgkin's disease in extranodal sites.
Am J Surg Pathol 19:1313-1324, 1995.
Hammer RD, Glick AD, Greer et al: Splenic marginal zone lymphoma.
A distinct B cell neoplasm. Am J Surg Pathol 20:613-626, 1996.
Harris NL, Jaffe ES, Stein H et al: A revised European-American classification of lymphoid neoplasm: A proposal from the International
Lymphoma Study Group. Blood 84:1361-1392, 1994.
Isaacson PG: Recent developments in our understanding of gastric lymphomas. Am JSurg Pathol 20(suppl 1):S1-S7, 1996.
Kuo Ti': Kikuchi's disease (histiocytic necrotizing lymphadenitis). A
clinicopathologic study of 79 cases with an analysis of histologic
subtypes, immunohistology, and DNA ploidy. Am J Surg Pathol
19:798-809, 1995.

Lieberman PH, Jones CR, Steinman RM et al: Langerhans cell

(eosinophilic) granulomatosis. A clinicopathologic study encompassing 50 years. Am J Surg Pathol 20:519-552, 1996.
Ree HJ, Kadin ME, Kikuchi M et al: Angioimmunoblastic lymphoma
(AILD-type T-cell lymphoma) with hyperplastic germinal centers.
Am J Surg Pathol 22:643-655, 1998.
Siebert JM, Stuckey JH, Kurtin P1, Bank PM: Extranodal lymphocyte
predominance Hodgkin's disease. Clinical and pathologic features.
Am J Clin Pathol 103:485-491, 1995.
Skarin AT, Dorfman DM: Non-Hodgkin's lymphoma: Current classification and management. CA Cancer J Clin 47:351-372, 1997.
Suster S, Moran C: Primary thymic epithelial neoplasms showing combined features of thymona and thymic carcinoma. Am J SurgPathol
20:1469-1480, 1996.
Zarate-Osorno A, Madeiros LJ, Kingma DW et al: Hodgkin's disease
following non-Hodgkin's lymphoma. A clinicopathologic and immunophenotypic study of nine cases. Am' SurgPathol 17:123-132,


The upper digestive system develops from the embryonic
foregut through a sequence of highly regulated events. The
morphogenesis of the mouth and especially the lips, the maxilla, and the mandible is even more complex because it involves the fusion of anlagen that are symmetrically formed
on each side. The teeth primordia develop through an intricate interaction of epithelial-mesenchymal precursors of the
various layers of the teeth, the periodontal ligaments, and the
Cleft lip and cleft palate are dysraphic malformations of
polygenic origin that result from incomplete fusion of the facial embryonic structures (Fig. 6-1). Complex facial malfor-

mations maybe associated with incomplete formation of the

mouth, nose, and other parts of the face (Fig. 6-2). Micrognathia, with recessed mandible and low-set ears, is a feature
of Potter syndrome, in which the kidneys are not formed or
the fetal urinary tract is obstructed (Fig. 6-3). Prognathia is
abnormal protrusion of the mandible beyond the maxilla
(Fig. 6-4).
Anomalies of tongue include macroglossia (a common feature of Down syndrome, congenital hypothyroidism, and
several other conditions), fissured tongue, congenital tumors, and hamartomas such as giant hemangioma (Figs. 6-5
and 6-6).

Fig. 6-1. Cleft palate.

Fig. 6-2. Complex facial malformation in a stillborn infant.

Fig. 6-3. Potter syndrome. The receding chin is associated with

a hypoplastic mandible. The pregnancy was marked by
oligohydramnios related to renal agenesis.

Fig. 6-4. Prognathia.


Fig. 6-5. Macroglossia. It could have many causes.

Anomalies of teeth may be numerical or may involve positioning, eruption, size, shape, enamel, formation, dentinogenesis, and coloration.
Anomalies of the esophagus include congenital atresia,
stenosis, and tracheoesophageal fistula.

Stomatitis (inflammation of the mouth), sialadenitis (inflammation of the salivary glands), pharyngitis, and esophagitis may occur as isolated diseases or as a manifestation of
generalized infection and/or various systemic diseases. Because the upper digestive tract is lined by squamous epithelium from the oral orifice to the lower end of the esophagus,
all of these infections show a predictable, stereotypic pathol -

Fig. 6-7. Aphthous ulcer. Grayish fibrinous material covers the

ulcer on the ventral surface of the tongue.

Fig. 6-6. Giant congenital cavernous hemangioma of the tongue.

ogy, and typically are prone to ulceration, vesiculation, or

Stomatitis may be classified as acute or chronic and according to its etiology as viral, bacterial, or fungal. Acute
stomatitis presents in many forms such as erythematous,
vesicular, aphthous, suppurative, or pseudomembranous inflammation (Fig. 6-7). Chronic stomatitis often is seen in
smokers or may be caused by chronic irritation from illfitting dentures. Ill-fitting dentures may cause fibrous
hyperplasia or inflammatory papillary hyperplasia, which
typically occurs on the mucosa of the hard palate (Fig. 6-8).
Hyperplastic granulation tissue on the gingiva, presumably
caused by infection or trauma, may present in the form of
nodular masses known as pyogenicgranuloma or epulis (Fig.

Fig. 6-8. Inflammatory papillary hyperplasia. This hard palate

lesion, caused by ill-fitting denture, shows papillary hyperplasia
with numerous downward projections of epithelium and a
chronic submucosal inflammation.


6-9). In most instances oral infections can be treated effectively or may heal spontaneously. Severe bacterial infection
occasionally may spread to the neck and cause necrotizing
neck gangrene known as Ludwig angina (Fig. 6-10). Oral lesions are common features of acquired immunodeficiency
syndrome (AIDS) (Table 6-1).
Pharyngitis is a common manifestation of numerous viral
and bacterial infections ( " strep throat " ). Presenting symptoms include erythema, swelling or suppuration, and pseudomembrane formation.
Sialadenitis may be caused by bacteria or viruses, such as
mumps virus. Bacterial infections typically ascend through
Stensen's excretory duct from the mouth, whereas viral infections are hematogenous. Sialadenitis also may be immune
mediated (Fig. 6-11).

Esophagitis usually is found in immunosuppressed persons who have AIDS, those who are receiving treatment for
cancer, or those who are debilitated. In most instances
esophagitis is caused by viruses, such as herpes simplex and
cytomegalovirus (CMV), or fungi, such as Candida and Aspergillus (Fig 6-12).
Oral Manifestation of AIDS
Chronic thrush
Hyperplastic stomatitis
Recurrent apthae
Condyloma acuminatum
Necrotizing ulcerative gingivitis
Kaposi sarcoma

Angular cheilitis
Erythematosus stomatitis
Hairy leukoplakia
Submandibular cellulitis

Fig. 6-9. Pyogenic granuloma of gingiva. The lesion presents as a

sharply demarcated nodule.

Fig. 6-10. Ludwig angina. Necrosis and ulceration are

accompanied by marked inflammation and edema of underlying
neck tissue.

Fig. 6-11. Chronic sialaderiitis. The salivary gland is infiltrated

focally by mononuclear cells. The infiltrates are most prominent
around the small ducts.


Fig. 6-12. Esophagitis. A, Herpes simplexinfected cells have multinucleated "ground

glass" nuclei. B, Viral particles can be demonstrated by immunohistochemistry.

Dental Cysts

keratinizing squamous epithelium that resembles the enamel

epithelium. Mucous or ciliated cells may be present and the
wall of dentigerous cysts may contain foci of ameloblastoma
(Fig. 6-13). Such unicysticameloblastomas occur in teenagers
and are readily cured by enucleation.
Odontogenic keratocyst ( OKC) accounts for 5 percent to
10 percent of all jaw cysts. It occurs in two types: the more
common parakeratotic OKC and the orthokeratotic OKC.
The parakeratotic OKC is lined by a layer of squamous epith-

Dental cysts are classified as developmental or inflammatory

(Table 6-2, Diagram 6-1). True cysts are lined by epithelium,
in contrast to pseudocysts, which are cavities in bone that are
surrounded by granulation tissue or fibroosseous tissue.
Dentigerous cyst is the most common developmental
odontogenic cyst. It usually is associated with the crown of
an impacted or unerupted tooth. It is lined by a thin non-

Fig. 6-13. Dentigerous cyst. A, The cyst usually is lined by nonkeratinizing, stratified squamous
epithelium. B, The stratified squamous epithelium lining the cyst shows mucous metaplasia.
C, The wall of this dentigerous cyst contains foci of ameloblastoma penetrating into the
connective tissue wall of the cyst.

10 6

WHO Classification of Cysts of the Jaws


Gingival cysts of infants (Epstein pearls)
Odontogenic keratocyst (primordial cyst)
Dentigerous (follicular cyst)
Eruption cyst
lateral periodontal cyst
Gingival cyst of adults
Glandular odontogenic cyst; sialood

Nasopalatine duct (incisive canal) cyst

Nasolabial (nasoalveolar) cyst
Radicular cyst
Apical and lateral cysts
Residual cyst
Paradental (inflammatory collateral, mandibular infected buccal) cyst

From Kramer IRH, Pindborg JJ, Shear M: Histological typing of odontogenic tumors, ed 2, Berlin, 1992, Springer-Verlag.

Diagram 6-I. Diagrams of the site of odontogenic, A, and fissural (nonodontogenic) cysts,
B, in the mandible and maxilla respectively. A: I, gingival; 2, eruption; 3, lateral periodontal; 4,
residual; 5, periapical (radicular); 6, dentigerous; 7, primordial. B: I, nasolabial cyst; 2, nasoalveolar
cyst, 3, globulomaxillary cyst; 4, nasopalatine cyst; 5, cyst of palatine papilla; 6, median palatal cyst.
(From Batsakis JG: Tumors of the head and neck: clinical and pathological considerations, ed 2,
Baltimore, 1979, Williams & Wilkins.)

Fig. 6-14. Parakeratotic cyst. A, The cyst is lined by partially detached,

corrugated, squamous epithelium. Daughter cysts are present in the connective
tissue capsule. B, The squamous epithelium shows palisaded basal cell
proliferation and surface parakeratosis. C, Higher power view shows typical


Fig. 6-I S. Orthokeratotic cyst. A, The cyst is lined by
keratinizing epithelium covered with a keratin layer. B, The
wall of the cyst is lined by keratinizing epithelium, with
flattened basal layer, prominent granular layer, and surface

Fig. 6-16. Radicular cyst. A, Radioluscent area is seen in association with the remaining roots of
the right maxillary bicuspid and first molar. B, Cyst wall contains inflammatory cells, extravasated
blood, hemosiderin pigment, and cholesterol clefts. C, Rushton bodies and remnants of squamous
epithelium are found in the inflamed cyst wall.

elium that is five to eight cells thick and shows maturation

from the palisading basal layer toward the lumen (Fig. 6-14).
The luminal surface is corrugated and is at least partially
lined by parakeratotic cells. The connective tissue capsule
may contain daughter cysts. The orthokeratotic OKC does not
have a palisading basal layer, and the epithelial lining appears
flattened. The surface keratin layer lies on a prominent granular cell layer but without surface corrugation (Fig. 6-15).
The lumen is filled with keratin.

Radicular cyst is the most common cyst of the jaws. It develops from a periapical abscess or granuloma. The persistent inflammation stimulates the proliferation of the epithelium derived from odontogenic residues in the periodontal
ligament, the rests of Malassez, which provide partial lining
of the cavity (Fig. 6-16). The epithelium lining the radicular
cysts is squamous but it shows no tendency toward keratinization. The surrounding connective tissue is heavily inflamed and may be hyalinized.



Oral and Salivary Gland Lesions

Salivary gland enlargement and chronic inflammation may
be caused by sialolithiasis. This term applies to a variety of
calcified masses that form in larger or smaller ducts. Large
calcifications cannot be sectioned; smaller ones are seen in
histologic sections and are composed of a proteinaceous core
undergoing concentric calcification (Fig. 6-17).
Obstruction of the duct of small salivary glands located
in the oral mucosa leads to the formation of mucoceles.
Mucoceles are small lesions, 1 cm in diameter in average, that
most often are located on the lower lip of young adults.
Microscopically they show extravasation of mucus, which is
transformed into eosinophilic granular material surrounded
by inflammatory cells (Fig. 6-18). Granulation tissue in the
wall of mucoceles typically contains mucus-laden
macrophages (Fig. 6-19).
Mucous retention cysts are less common than mucoceles
and occur in older people. These cysts result from the
obstruction of salivary gland ducts. They are lined by stratified squamous or mucinous columnar epithelium containing mucus (Fig. 6-20). The wall of these cysts is inflamed
or fibrotic.
Sjgren syndrome is an autoimmune disease that typically
affects the salivary and lacrimal glands. The salivary glands

show signs of chronic inflammation (see Fig. 6-11). As the

disease advances the lymphoid infiltrate destroys the acinar
portion of the gland. The epithelial and myoepithelial cells
of the ducts and ductules remain as islands in a sea of
lymphocytes (Fig. 6-21). This lymphocytic myoepithelial
sialadenitis maybe seen in primary Sjgren syndrome or secondary Sjgren syndrome (sialadenitis that occurs in the
course of multisystemic autoimmune disease such as systemic lupus erythematosus), or it may be unrelated to any
autoimmune process.
Necrotizing sialometaplasia is a benign lesion of unknown
cause that affects the minor salivary glands. It most often is
located on the palate but it may be found in other sites, including extraoral sites in the upper aerodigestive tract. It presents as an ulcer, which occasionally may be bilateral. Microscopically it consists of nests of metaplastic squamous
epithelium representing residual ducts surrounded by inflamed loose connective tissue that may contain pools of
mucus (Fig. 6-22). The acini usually are not evident and those
that remain show necrosis. The squamous epithelium may
show some nuclear atypia, which should not be mistaken for
mucoepidermoid carcinoma. The distinct lobular pattern of
the epithelial islands is the best clue that this is an inflammatory lesion, and not a neoplasm.

Fig. 6-17. Sialolithiasis. The early sialoliths consist of a proteinaceous core that undergoes gradual calcification.

Fig. 6-18. Mucocele. A band of inflammatory cells and granulation tissue is surrounding the inspissated mucus.


Fig. 6-19. Mucocele. Mucus is infiltrated with inflammatory cells.

Fig. 6-20. Mucous retention cyst. The cyst is lined by squamous


Fig. 6-21. Sjogren syndrome. A, Focal chronic sialoadenitis.

B, Myoepithelial sialoadenitis of Sjogren syndrome. The myoepithelial nests are surrounded by lymphoid cells in a follicular

Fig. 6-22. Necrotizing sialometaplasia. The epithelial nests

represent ducts that have undergone squamous metaplasia. The
nests are surrounded by loose connective tissue.

11 0

Diagram 6-2. Diverticula and hernia. A, Outpouchings of the esophagus may occur in the upper,
middle, or lower esophagus and are either of traction or pulsion type. B, Sliding hernia. C, Rolling

Esophageal Lesions
Dysphagia, the most common esophageal symptom, usually
is caused by dysmotility syndromes related to spasms (e.g.,
"nutcracker esophagus" ). These syndromes do not have a distinct anatomic substrate and show no pathologic changes except in rare instances, such as in systemic sclerosis, in muscle
diseases such as myotonic dystrophy, or in Chagas disease
involving autonomic ganglia. Diaphragmatic hernia and
esophageal diverticula can be diagnosed best by radiograph
(Diagram 6-2). The wall of these lesions may show nonspecific inflammation.
Esophageal varices are a complication of portal hypertension, which typically is caused by cirrhosis. The dilated veins
are located in the lower third of the esophagus (Fig. 6-23).
Lacerations at the level of the gastroesophageal junction,
which typically are caused by prolonged vomiting in alcoholics, is a cause of bleeding in Mallory-Weiss syndrome (Fig.
Reflux esophagitis is an inflammatory disease that is
caused by the reflux of acidic gastric juice into the esophagus.
The epithelium shows basal cell hyperplasia, elongation of
the papillae beyond the normal 50 percent extension into the
epithelium, capillary proliferation in the papillae, and congestion (Fig. 6-25). Eosinophils have been described as characteristic but they rarely are actually seen. Prolonged reflux
leads to ulceration and glandular metaplasia (Barrett esophagus) (Fig. 6-26). Mucosal ulceration maybe extensive in terminally ill patients, even in those who have not previously
had reflux esophagitis (Fig. 6-27).

Erosive or corrosive esophagitis may be caused by accidental

or suicidal ingestion of lye, strong acids, and corrosive chemicals. The mucosa typically is eroded, hemorrhagic, or blackened (Fig. 6-28). Rupture of the esophagus, fistulas, and
stenosis are common complications.

Fig. 6-23. Esophageal varices. A, Dilated tortuous veins are

seen bulging underneath the intact epithelium of the lower
esophagus. B, Dilated veins filled with blood are seen in the wall
of the esophagus.

Fig. 6-25. Reflux esophagitis. The papillae are elongated and

congested. There also is basal cell hyperplasia.

Fig. 6-24. Mallory-Weiss syndrome. Hematemesis in this

chronic alcoholic was caused by deep mucosal tears at the
gastroesophageal junction.

Fig. 6-27. Ulcerative esophagitis. The normal squamous

epithelium (white) is missing over broad areas.

Fig. 6-26. Barrett esophagus. The mucosa replacing the normal

squamous epithelium is composed of glands rich in goblet cells.

Fig. 6-28. Corrosive esophagitis and gastritis caused by ingestion of

hydrochloric acid. Mucosa appears black.


Oral Tumors
Most tumors of the mouth originate from the squamous epithelium lining the oral cavity. Tumors also can originate
from the tooth-related structures and primordia and from
minor salivary glands. Histologically tumors that originate
from minor salivary glands are identical to those seen in
major salivary glands.
Tumors of the squamous epithelium present clinically as
white or red plaques (leukoplakia and erythroplakia), indurations, or ulcerations (Fig. 6-29). Histologically the tumors have the usual features of squamous cell carcinoma
(SCC), beginning as carcinoma in situ and progressing to
invasive carcinoma that shows varying degrees of keratinization. Important variants are (1) poorly differentiated
nonkeratinizing SCC, (2) basaloid SCC, (3) papillary SCC,
and (4) verrucous SCC (Fig. 6-30).
Dental tumors occur in several forms (Table 6-3). Benign
tumors are more common than malignant tumors.

Fig. 6-29. Erythroplakia of the hard palate.

Fig. 6-3 I. Ameloblastoma. The interdigitating cords of

palisading epithelial cells surround areas composed of stellate
reticulum cells.

Ameloblastoma is the most common odontogenic tumor.

Ameloblastomas originate mostly in the mandible from the
rests of enamel organ epithelium, epithelial lining of
dentigerous cysts, or occasionally from the basal layer of the
oral mucosa. Most patients are in the third to fifth decade of
life. Most ameloblastomas present in a follicular or plexiform
histologic pattern; other patterns are less common (Fig.
Other odontogenic tumors such as odontogenic adenomatoid tumor (Fig. 6-32), calcifying epithelial odontogenic
tumor (Fig. 6-33), and ameloblastic fibroma (Fig. 6-34) are
less common.
Salivary Gland Tumors
Salivary gland tumors occur in several histologic forms (Table
6-4). They can occur in the major or minor salivary glands.
The parotid gland is the most commonly involved site,
mostly because of its size . Benign tumors are more common
than malignant tumors. Pleomorphic adenoma is the most

Fig. 6-30. Verrucous carcinoma. The neoplastic epithelium

forms rounded nests extending into the underlying stroma.

Fig. 6-32. Odontogenic adenomatoid tumor. Cuboidal or

columnar tumor cells form ductlike structures.


Fig. 6-33. Calcifying epithelial odontogenic tumor. The islands

of polyhedral epithelial cells are surrounded by extracellular
eosinophilic material with foci of calcification.

Fig. 6-34. Ameloblastic fibroma. Odontogenic epithelium forms

islands surrounded by highly cellular stroma.

Odontogenic Tumors
Odontogenic adenomatoid tumor
Calcifying epithelial odontogenic tumor
Odontogenic fibroma
Cemental tumors
Mixed epithelial and mesenchymal origin
Ameloblastic fibroma
Ameloblastic fibroodontoma
Complex and compound odontomas

Malignant ameloblastoma
Ameloblastic carcinoma
Ameloblastic fibrosarcoma

Classification of Epithelial Salivary Gland Tumors

Pleomorphic adenoma (mixed tumor)
Papillary cystadenoma lymphomatosum (Warthin tumor)
Monomorphic adenoma
Basal cell
Ductal papilloma
Sialadenoma papilliferum
Sebaceous adenoma
Sebaceous lymphadenoma
Malignant Arising from Preexisting Benign Tumor
Ex pleomorphic adenoma
Ex monomorphic adenon
cell a


NOS, Not otherwise specified.

Ex Warthin tumor
Ex myoepithelioma
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Acinic cell carcinoma
Epimyoepithelial (clear cell) carcinoma
Salivary duct carcinoma
Papillary and nonpapillary adenocarcinoma
Mucinous adenocarcinoma
Adenocarcinoma, NOS
Epidermoid (squamous cell) carcinoma
Sebaceous carcinoma
Basal cell adenocarcinoma
Undifferentiated carcinoma
Large cell lymphoepithelial
Small cell lymphoepithelial


common tumor, accounting for 60 percent to 70 percent of

all parotid tumors and for 40 percent to 70 percent of tumors
in other glands.
Pleomorphic adenoma is a benign tumor that presents as
a sharply demarcated mass. Histologically it consists of an
epithelial component forming ducts, nests, sheets, or interlocking cords (Fig. 6-35). Epithelial cells are intermixed or
surrounded by mesenchymal stroma that may be myxoid,
chondroid, or fibrous, and may even show ossification. In approximately 5 percent of patients mixed tumors give rise to
adenocarcinomas (Fig. 6-36).
Myoepithelioma is a benign tumor composed of myoepithelial cells (Fig. 6-37). Papillary cystadenoma lympho-

matosum is a benign slow-growing tumor of older adults. It

is composed of columnar and cuboidal cells covering papillae
embedded in a lymphocyte-rich stroma. Basal cell adenoma
is a benign tumor composed of bluish basaloid cells that form
solid sheets or nests that have a palisaded outer layer (Fig.
Oncocytoma is an uncommon benign tumor composed of
mitochondria-rich cells with eosinophilic or clear cytoplasm,
(Fig. 6-39).
Sialadenoma papilliferum is a benign tumor composed of
an exophytic and an endophytic component. Neoplastic
papillae, which are typical of the tumor, can be lined by oncocytic cuboidal or squamous cells (Fig. 6-40).

Fig. 6-35. Pleomorphic adenoma of the parotid

gland. The interlacing epithelial nests form
occasional lumina and are surrounded by fibrous

Fig. 6-36. Adenocarcinoma arising in pleomorphic adenoma. A, The tumor has an invasive
growth pattern. B, Histologically it is an adenocarcinoma.


Fig. 6-37. Myoepithelioma: Tumor is composed of spindleshaped myoepithelial cells.

Fig. 6-38. Basal cell adenoma. The tumor nests are composed
of small basaloid cells. The cells at the periphery of these nests
are cuboidal and palisaded.

Fig. 6-39. Oncocytoma. A, Eosinophilic cells form solid nests. B, Clear cells are arranged in
an alveolar pattern.

Fig. 6-40. Sialadenoma papilliferum. The papillae

are lined by a double layer of oncocytic cells.

11 6

Fig. 6-41. Acinic cell adenocarcinoma. A, Well-differentiated serous acinar cells form solid sheets
(solid pattern). B, Cells form follicles that vary in size and shape (follicular pattern).

Fig. 6-42. Adenoid cystic carcinoma. A, Cribriform pattern. B, Solid pattern. C, Tubular pattern.

Malignant tumors of salivary glands are less common. The

ratio of benign to malignant tumors is 4:1. Mucoepidermoid
carcinoma is the most common malignancy, accounting for
10 percent of major salivary gland tumors and 90 percent of
minor salivary gland tumors. This tumor has the general features of squamous cell carcinoma but it also contains mucous cells, usually in the center of epithelial nests.
Acinic cell carcinoma accounts for 2 percent to 3 percent
of salivary gland tumors. The tumor may be composed of
several cell types including serous, vacuolated, clear or-granular, acinar, and intercalated ductlike cells arranged in a solid,
cystic, papillary, or follicular pattern (Fig. 6-41).

Adenoid cystic carcinoma accounts for 3 percent to 10 percent of all salivary gland tumors, more often arising in minor
than major glands. Microscopically these tumors are composed of rather uniform populations of basaloid tumor cells
with little cytoplasm. The cells grow in three patterns: cribriform, solid, and tubular (Fig. 6-42). Other malignant tumors,
such as epithelial-myoepithelial carcinoma (Fig. 6-43), polymorphous low-grade adenocarcinoma (Fig. 6-44), sebaceous
carcinoma (Fig. 6-45), and salivary duct carcinoma (Fig.
6-46), are less common.

Fig. 6-43. Epithelial-myoepithelial carcinoma. Numerous

ductlike structures are lined by eosinophilic and clear cells.

Fig. 6-44. Polymorphous low-grade carcinoma. Cytologically

bland and uniform basaloid cells grow in an infiltrating manner.

Fig. 6-45. Sebaceous carcinoma. Atypical basaloid cells show

central sebaceous differentiation . Such cells have clear

Fig. 6-46. Salivary duct carcinoma. Tumor nests are composed

of cells arranged in a cribriform pattern that resembles breast


Esophageal Tumors
Carcinoma of the esophagus is the most important tumor in
this anatomic site (see Diagram 6-2).
Squamous cell carcinoma is the predominant form of
esophageal tumor. It usually presents as ulcerated or indurated lesions (Figs. 6-47 and 6-48).

Fig. 6-47. Carcinoma of the esophagus. The tumor appears


Fig. 6-49. Barrett esophagus with early carcinoma.

Adenocarcinomas arise from the glandular epithelium of

Barrett esophagus and often are located at the gastroesophageal junction (Figs. 6-49 and 6-50) and are preceded
by dysplasia (Fig. 6-50). Such adenocarcinomas do not differ
from those in the stomach (Figs. 6-51 and 6-52). Other malignant tumors of the esophagus, such as small cell carcinoma,
sarcoma, or melanoma, are extremely rare (Fig. 6-53).
Benign tumors of the esophagus are less common than
malignant tumors. The most common are leiomyomas,
which typically present as intramural subepithelial masses,
sharply demarcated from the surrounding tissues.

Fig. 6-48. Carcinoma of the esophagus. Squamous tumor cells

form solid nests.

Fig. 6-50. Barrett's esophagus with dysplasia. Nuclei in

dysplastic glands appear crowded and are not restricted to the
basal parts of the cells.


Fig. 6-5I. Adenocarcinoma of the esophagus. The tumor at the

gastroesophageal junction appears bulky and ulcerated.

Fig. 6-52. Adenocarcinoma. Some squamous epithelium remains

between the neoplastic gland-like structures.

Fig. 6-53. Melanoma of esophagus. A, A black mass is seen protruding into the lumen. B, Tumor
is composed of polygonal cell with a large nuclei. Brown pigment is seen focally.
Further Reading
Brandwein MS, Huvos AG: Oncocytic tumors of the major salivary
glands. Amer J Surg Pathol 15:514-528, 1991.
Cameron AJ, Carpenter HA: Barrett's esophagus, high-grade dysplasia,
and early adenocarcinoma: A pathologic study. Am J Gastroenterol
92:586-591, 1997.
Dawsey SM, Lewin KJ: Histologic precursors of squamous esophageal
cancer. Pathol Annu 30:209-226, 1995.
Delgado R, Vuitch F, Albores-Saavedra J: Salivary duct carcinoma.
Cancer 72:1503-1512, 1993.
Ellis GL: Clear cell neoplasms in salivary glands: clearly a diagnostic
challenge. Ann Diag Pathol 2:61-78, 1998.
Eveson JW: Granulomatous disorders of the oral mucosa. Semin Diagn
Pathol 13:118-127, 1996.
Haggitt RC: Barrett's esophagus, dysplasia and adenocarcinoma. Hum
Pathol 25:982-993, 1994.

Klimstra D: Pathologic prognostic factors in esophageal carcinoma.

Semin Oncol21:425-430, 1994.
Lieberman MD, Shriver CD, Bleckner Set al: Carcinoma of the esophagus; prognostic significance of histologic type. J Thor Cardiovasc
Surg 109:130-138, 1995.
Paraf F, Fl@jou J-F, Pignon J-P et al: Surgical pathology of adenocarcinoma arising in Barrett's esophagus: Analysis of 67 cases. Am J Surg
Pathol 19:183-191, 1995.
Sarbia M, Bittinger F, Porschen R et al: Prognostic factors in esophageal
squamous carcinoma: A study of histologic parameters of
esophageal squamous cell carcinoma. Cancer 76:922-927, 1995.
Simpson RH: Classification of salivary gland tumorsa brief histopathological review. Histol Histopathol 10:737-746, 1995.
Wenig BM, Hitchcock CL, Ellis GL, Gnepp DR: Metastasizing mixed
tumor of salivary glands. A clinicopathologic and flow cytometric
analysis. Am J Surg Pathol 16:845-858, 1992.


Developmental disorders of the gastrointestinal tract include
positional anomalies, persistent embryonic rests, duplications, congenital atresias, stenoses, dilatations, diverticula,
and malrotations.
Positional anomalies include conditions, such as diaphragmatic hernia or omphalocele, in which the normal body
compartments have not been formed and parts of the gastrointestinal system are located outside their normal abdominal
location (Fig. 7-1).
Meckel diverticulum is an example of a persistent embryonic structure. It represents a remnant of the fetal vitelline
duct (Fig. 7-2).
Intestinal duplications are cystic structures included in the
intestinal wall or attached to it (Fig. 7-3). The cysts are lined
by intestinal epithelium.

Pyloric stenosis is the most common form of congenital

gastrointestinal stenosis (Fig. 7-4). Projectile vomiting in the
first weeks of life is the presenting symptom. Males are affected four times more often than females.
Inappropriate development of innervation in the distal
colon is the main cause of proximal dilatation of the large intestine in Hirschsprung disease. Microscopically the intestinal
wall is devoid of ganglion cells (aganglionosis) but it contains
numerous hypertrophic nerves. Proliferation of small nerves
may be demonstrated immunohistochemically using antibodies to acetylcholinesterase (Fig. 7-5).
Intestinal lymphangiectasia is a rare developmental disorder that is associated with protein-losing enteropathy. It
may be limited to the bowel or it may be part of generalized
familial lymphedema (Milroy disease). The dilated lymphatics may be seen by the naked eye as cystic spaces that distort segments of the intestine (Fig. 7-6).

Fig. 7-I. Omphalocele. As a result of incomplete formation of the

anterior abdominal wall, a sac forms at the site of the insertion of the
umbilical cord. It contains intestinal loops, which protrude through
the defect of the abdominal wall.

Fig. 7-2. Meckel diverticulum. This blind intestinal loop of the

il eus is found in 2 percent of the population, two feet proximal
to the cecum. It usually is two inches long and causes clinical
symptoms in 2 percent of those who have it.

Fig. 7-3. Intestinal duplication. It forms a cystic mass protruding

into the intestinal lumen.


Fig. 7-4. Pyloric stenosis. The pylorus of this adult who was
operated on for congenital pyloric stenosis still shows muscular
hypertrophy. (Courtesy of Dr. Fred Bosman, Lausanne, Switzerland.)

Fig. 7-5. Hirschsprung disease. A, Dilated sigmoid colon tapers off toward the
lower stenotic part. B, The lamina propria of the colon contains numerous
proliferated fine nerve fibers visualized immunohistochemically with the antibody to
acetylcholinesterase. (Courtesy of Dr. James Dimmick, Vancouver, Canada.)

Fig. 7-6. Congenital lymphangiectasia. Cystic spaces distorting

the wall of the resected intestinal loop represent dilated
lymphatics. (Courtesy of Dr. W.V. Harrer, Camden, NJ.)


Circulatory disturbances are common in the gastrointestinal
tract. Acute systemic circulatory collapse as typically seen in
shock is commonly associated with gastrointestinal mucosal
bleeding ulcerations. Acute stress erosions and ulcers found in
the proximal duodenum or stomach following burns or
trauma traditionally are called Curling ulcers, and those
found in the stomach and associated with brain lesions are
called Cushing ulcers (Fig. 7-7).
Occlusion of the mesenteric arteries or veins by thrombi
or thromboemboli causes intestinal infarcts, which typically
are hemorrhagic (Figs. 7-8 and 7-9). Chronic intestinal ischemia,which typically is related to the progressive stenosis

Fig. 7-7. Curling ulcers. Surface ulcerations of gastric mucosa

appear as dark red defects.

Fig. 7-9. Acute ischemia of large bowel. The mucosa shows

hemorrhagic discoloration.

and gradual occlusion of smaller branches of the arterial

system, causes focal ischemic necrosis and ulceration of intestinal mucosa. Hypoperfusion of intestinal mucosa in shock
causes similar ischemic mucosal ulcers (Fig. 7-10).
Vascular anomalies, both congenital and acquired, are important causes of gastrointestinal hemorrhage. Typically seen
in Osler-Weber-Rendu disease, they include mucosal aneurysmal dilatations of small vessels (congenital hemorrhagic
telangiectasia) and multiple congenital hemangiomas (Fig.
7-11). Dieulafoy ulcer, a bleeding ulcer of the stomach, forms
over an arteriovenous malformation (Fig. 7-12). Intestinal
angiodysplasia is another important cause of gastrointestinal
blood loss.

Fig. 7-8. Mesenteric artery thrombosis. The intestinal loops

have undergone hemorrhagic infarction. Thrombosed artery
attached to the aorta (arrow).

Fig. 7-10. Ischemic colitis. Necrotic epithelium has been

sloughed off and only a few crypts remain.


Fig.7 - 1I . Intestinal hemangiomas.

Fig. 7-12. Dieulafoy ulcer. The ulcer contains ruptured superficial tortuous arteries.


The gastrointestinal tract may be obstructed by a number of
intraluminal foreign bodies, such as trichobezoars, gallstones,
or fecaliths (Fig. 7-13). Inspissated meconium, which is found
in children who have cystic fibrosis, also may cause intestinal
obstruction (Fig. 7-14). Histologically viscous mucus may be
seen filling the crypts. Rupture of the obstructed intestine
leads to meconium peritonitis.
Protrusions of the intestines or any other abdominal
organ into another body cavity, or new cavities formed by
defects or weakening of the abdominal wall, are called hernias. Herniated intestinal loops may become obstructed and
may require surgery. Other causes of intestinal obstruction
are volvulus, intussusception, peritoneal adhesions, tumors,
and tumor-like lesions such as endometriosis (Figs. 7-15 to

Fig. 7-13. Trichobezoar. This large mass removed from the

stomach was composed of hair.


Fig. 7-14. Meconium ileus. A, The

dilated intestine of this neonate is
obstructed by thick meconium, which
appears as a black intestinal plug.
B, Intestinal crypts contain viscid

1 26

Fig. 7-15. Volvulus. Intestinal loops twisted around mesocolon

have undergone hemorrhagic necrosis.

Fig. 7-16. Intussusception. Loops of bowel invaginating one

into another.

Fig. 7-17. Endometriosis. The serosa of this intestinal loop is

covered with hemorrhagic tissue specks.

Diverticula are outpouchings of the mucosa through

weakened muscularis propria. Diverticula may occur in any
part of the intestine but are most common in the sigmoid
colon. The outpouchings typically occur between the anti mesenteric taeniae (Fig. 7-18).

Each of the anatomic parts of the gastrointestinal tract may
be affected by a site-specific type of inflammation or other
organ-specific diseases.

Gastritis and Peptic Ulcer

Inflammation of the gastric mucosa is classified as acute or
chronic. Acute gastritis is subclassified as infectious (e.g., bacterial, viral, or fungal) or chemical, which most often is caused
by nonsteroidal antiinflammatory drugs, irritants in food, or
alcohol (Figs. 7-19 and 7-20).

Fig. 7-18. Diverticulosis. A, Subserosal protrusions. B, The

mucosa protrudes through a defect of the muscle layer, as seen
on cross section blackened.

Chronic gastritis is classified as autoimmune atrophic

(type A) gastritis or chronic nonatrophic (type B) gastritis
Type A gastritis preferentially involves the fundus and
oxyntic corpus and is characterized by inflammatory cell infiltrates and progressive replacement of the normal mucosa
by patches of antral, pseudoantral, or intestinal epithelium
(Fig. 7-21).
Type B gastritis is associated with Helicobacter pylori infection and is characterized by pronounced inflammatory
infiltrates. The normal mucosal architecture is preserved and
there is no atrophy (Fig. 7-22). Neutrophils and H. pylori may


Fig. 7-19. Chemical gastritis caused by aspirin. The mucosa

shows multiple hemorrhagFc erosions.

Fig. 7-20. Fungal gastritis. The fungi form slightly raised mucosal

Fig. 7-21. Gastritis type A (autoimmune), associated with

pernicious anemia. The oxyntic mucosa shows atrophy and
is replaced to a large extent by pseudoantral metaplasia.
There also is mild edema and chronic inflammation.

Fig. 7-22. Gastritis type B (nonatrophic).

A, The lamina propria is expanded by
inflammatory cells. The foveolae show mild
reactive changes. B, The inflammatory cells are
prominent in the lamina propria and the lumen
contains H. pylori organisms, which are stained
black. Neutrophils are invading the epithelium of
gastric pits.


Fig. 7-23. Peptic ulcer. Two ulcers appear as sharp, deep

hemorrhagic defects of gastric mucosa.

Comparison of Type A and Type B

Gastric acidity
Cancer risk

ype A (atrophic)

Type B (nonatrophic)
Helicobacter pylori




Fig. 7-24. Menetrier disease. The gastric mucosal folds are

markedly thickened.

be seen in the mucosal pits. Infection with H. pylori also is

associated with gastric and duodenal peptic ulcers (Fig.
7-23). Other less common forms of gastritis include
eosinophilic, granulomatous, lymphocytic, and xanthomatous gastritis.
Hypertrophic gastritis (gastropathy) includes so-called
Menetrier disease and gastric mucosal hyperplasia/hypertrophy resulting from an excess of gastrin in Zollinger-Ellison
syndrome. It is associated with marked rugal thickening and
histologically characterized by variable degrees of hyperplasia of foveolar or glandular compartments (Fig. 7-24).

Fig. 7-25. Celiac disease A, Intestinal biopsy specimen shows atrophy of the villi and lengthening
of the crypts. B, Biopsy specimen of the same patient shows that the mucosa has recovered
almost completely after 6 months of gluten-free diet.


Small Intestinal Diseases That

Cause Malabsorption
According to small intestinal mucosal biopsy findings the
diseases that cause malabsorption syndrome are classified
into four major groups (Table 7-2).
Celiac disease is a multifactorial disease of uncertain
pathogenesis; it is related to hypersensitivity to gluten. Small
intestinal mucosa shows atrophy of the villi and lengthening
of the crypts (Fig. 7-25). These changes are reversible. Complete recovery is possible if a patient follows a gluten-free diet,
and the intestinal mucosa resumes its normal morphology.
Infectious enteritis caused by bacteria, viruses, or fungi
may cause diarrhea and malabsorption (Fig. 7-26). In many
instances the causative pathogens are recognized by biopsy
of the small intestine. The best examples are infections
caused by Mycobacterium avium-intracellulare and Tropheryma whippelii (Figs. 7-27 and 7-28).
Several diseases of neoplastic or unknown etiology such
as Waldenstrom macroglobulinemia, amyloidosis, or lipoid

Classification of Malabsorption Syndromes

According to the Small Intestinal Biopsy
Normal histologic features
Gastric, pancreatic biliary disease
Inborn errors of metabolism
(disaccharidase deficiency)
Short bowel syndrome
Alcohol abuse
Drug induced enteropathy

Nonspecific inflammatory
mucosal changes
Celiac disease (sprue)
Tropical sprue
Graft versus host disease
Intraluminal bacterial overgrowth

Identifiable pathogens
Viruses (e.g., rota virus)
Bacteria (e.g., MAI, Whipple
Fungi (e.g., Cryptococcus
Protozoa (e.g., Giardia lamblia)
Metazoa (e.g., Strongyloides
Diagnostic tissue changes
Waldenstr6m macroglobulinemia
Lipoid proteinosis

MAI, Mycobacterium avium-intracellulare.

Fig. 7-26. Fungal enteritis in an immunosuppressed person. Patches

of mucosa infiltrated with fungi appear raised and necrotic.

Fig. 7-27. Intestinal infection with Mycobacterium avium-intracellulare ( MAI). A, The lamina propria
contains numerous foamy macrophages. B, Macrophages are filled with MAI, which are acid fast in
this Ziehl-Neelsenstained slide.

13 0

Fig. 7-28. Whipple disease. A, Light microscopy shows prominent macrophages and dilatation of
lacteals in the lamina propria. B, Detail of lamina propria with macrophages. C, Electron
microscopy shows the pathogenic bacteria in the cytoplasm of these macrophages. (Courtesy of
Dr. N. Ectors, Leuven, Belgium.)

proteinosis are characterized by deposition of proteinaceous

extracellular material, which maybe recognized on histologic
examination of the intestines (Fig. 7-29).

Inflammation of the Appendix and

the Large Intestine

Fig. 7-29. Lipoid proteinosis. The lamina propria contains

deposits of fibrillar proteinaceous material. (Courtesy of Dr.
D. Caccamo, Detroit, MI.)

Acute appendicitis is one of the most common infections of

the gastrointestinal tract that requires surgical intervention.
The appendix appears swollen and congested and histologically shows signs of transmural inflammation (Fig. 7-30).
The lumen of the appendix may be obstructed with inspissated feces or worms such as Enterobius vermicularis (Fig.
Infectious colitis presents as localized or diffuse inflammation and often is associated with ulceration or pseudomembrane formation. Pseudomembranous colitis typically is
a complication of Clostridium difficile infection. Segments of
the intestine are covered with yellow or brown flat-topped
plaques (Fig. 7-32). Histologically the pseudomembranes
consist of fibrin, mucin, neutrophils, and cellular debris covering the surface of the damaged mucosa (Fig. 7-33). Amebic
colitis typically produces ulcers in the cecum. The necrotic
cell debris in the bottom of ulcers contains pathogenic
Entamoeba histolytica (Fig. 7-34).


Fig. 7-30. Acute appendicitis. A, Inflammation extends to the serosa, which appears hyperemic.
B, Cross section shows transmural inflammation (blue) and foci of hemorrhange (red).

Fig. 7-3I. Acute appendicitis. The lumen of the appendix contains Enterobius vermicularis in cross section.

Fig. 7-32. Pseudomembranous colitis. The surface of the large

intestine is covered with yellow, flat-topped plaques.

13 2

Fig. 7-33. Pseudomembranous colitis. A, Volcano-like appearance of early lesions. B, The exudate
covering the damaged mucosa consists of mucus, fibrin, inflammatory cells, and cell debris. The
pseudomembrane has a layered appearance.

Fig. 7-34. Amebiasis. The trophozoites of Entamoeba histolytica

are found in the area of "dirty necrosis" scraped from the
bottom of a colonic ulcer.

Fig. 7-35. Collagenous colitis. Broad bands of collagen are seen

underlying the surface epithelium in this trichrome-stained slide.

There are several histologic forms of noninfectious colitis

of uncertain etiology. Eosinophilic colitis is an occasional
manifestation of food allergy that presents with mucosal
eosinophilia. Collagenous colitis, which is characterized by
intermittent diarrhea unrelated to a known pathogen, appears on colonic biopsy specimen as typical subepithelial
collagen bands (Fig. 7-35). Lymphocytic colitis is characterized by lymphocytic infiltration of colonic mucosa.

itis and Crohn disease. The morphologic features that distinguish ulcerative colitis from Crohn disease are listed in
Table 7-3.
Ulcerative colitis begins as acute inflammation of the mucosa, producing crypt abscesses (Fig. 7-36). As the disease
progresses the inflammation spreads over the surface of the
entire large intestine (Fig. 7-37). In chronic colitis the luminal
surface may be flat and featureless, or it may be ulcerated,
alternating with pseudopolypous transformation of the intervening mucosa that has not been destroyed (Fig. 7-38).
Ulcerative colitis is characterized by superficial inflammation that is limited to colonic mucosa and does not extend

Inflammatory Bowel Disease (IBD)

The term inflammatory bowel disease (IBD) includes two
closely related entities of unknown etiology: ulcerative col -


Fig. 7-36. Ulcerative colitis. Crypt abscesses (aggregates of

neutrophils in the intestinal crypts) are early signs of the disease.

Fig. 7-37. Ulcerative colitis. The entire colon is involved; there

are no skip areas.

Comparison of Ulcerative Colitis and

Crohn Disease
Mucosa in chronic

Ulcerative colitis

Crohn disease

Flat or pseudopolyposis

Ileum and colon

Patchy with skip areas







into the deeper layers of the intestinal wall. The weakened intestine may undergo massive dilatation ( "toxic megacolon " ).
The small intestine is not involved, although the terminal
ileum may show signs of " backwash ileitis."
Crohn disease is a transmural inflammation of the terminal ileus and segments of the colon. Because of the segmental nature of the disease the inflamed areas alternate with
uninvolved " skip areas." The intestinal wall is thickened (Fig.
7-39). The thickened ulcerated mucosa has a "cobblestone "
appearance (Fig. 7-40). The inflammation extends into the
deeper layers of the intestine up to the serosa and in approximately 50 percent of cases there are granulomas (Fig. 7-41).

Fig. 7-38. Ulcerative colitis. In the chronic stages of the disease

there is inflammatory polyposis. Pseudopolyps represent
hyperplastic mucosa surrounded by ulcers.

Fig. 7-39. Crohn disease. The intestine has a thick wall and
narrowed lumen. Fat tissue covers the antimesometrial serosal


Fig. 7-40. Crohn disease. The ulcerated thickened inflamed

mucosa has a "cobblestone" appearance.

Tumors of the gastrointestinal tract are clinically classified as
benign or malignant. These tumors most often arise from the
epithelium but also may be derived from the smooth muscle
and other stromal cells, and from the mucosa-associated
lymphoid tissue (MALT).

Gastric Tumors
Carcinoma of the stomach is the most important gastric neoplasm. Several types are recognized on gross examination

Fig. 7-41. Crohn disease. Foci of chronic inflammation are seen

in the muscle layers of the large intestine.

( Diagram 7-1, Fig. 7-42). Histologically these tumors are adenocarcinomas of two types: intestinal or diffuse (Fig. 7-43).
The stomach is the site of origin of approximately 50 percent of all gastrointestinal stromal tumors. These submucosal
tumors may be benign, of borderline malignancy, or malignant, and are composed of either smooth muscle cells,
Schwann cells, or nondescript stromal cells (Figs. 7-44 and
7-45). Carcinoids and lymphomas are less common but nevertheless important tumors of the stomach.


Fig. 7-42. Carcinoma of the stomach. A, Fungating tumor has a cauliflower-like appearance.
B, Ulcerated tumor. The irregularly shaped ulcerated area appears indurated and shows
areas of necrosis.




Diagram 7-I. Gastric carcinoma. Type I, protruding; Type Ila,
superficial elevated; Type Ilb, superficial flat; Type IIc, superficial
depressed; Type III, excavated.

Fig. 7-44. Leiomyoma of the stomach. The tumor forms a

submucosal mass.

Fig. 7-43. Adenocarcinoma of the stomach. A, Intestinal type.

The neoplastic glands are composed of stratified pleomorphic cells.
B, Diffuse type. The tumor is composed of scattered individual
cells that have a clear and sometimes vacuolated cytoplasm and
appear signet ringlike.

Fig. 7-45. Spindle cell leiomyoma. The tumor cells have

elongated nuclei with round tips and eosinophilic cytoplasm.


Tumors of the Small Intestine

Overall, tumors of the small intestine are rare. Approximately
60 percent to 75 percent of all tumors are thought to be benign and are classified as epithelial (adenomas) or mesenchymal neoplasms such as leiomyoma, lipoma, hemangioma, and so forth. (Fig. 7-46). Malignant tumors include
adenocarcinomas, carcinoids, malignant stromal tumors
(sarcomas), and lymphomas (Figs. 7-47 to 7-49). Histologically these tumors have the same features as the more
common colonic neoplasms of the same type.

Tumors of the Appendix

The most important tumors of the appendix are (1) adenoma, colonic-type, noncystic; (2) cystadenoma or circumferential adenoma; (3) adenocarcinoma, which may be
colonic, mucinous, or signet ring-type; and (4) carcinoid and
its most important variant, the goblet cell carcinoid (Figs.
7-50 and 7-51).

Fig. 7-47. Carcinoid tumors. Most tumors are small and appear
as I to 2 cm submucosal nodules.

Intestinal Polyps
Polyp is a term used to describe any mass that projects into

the lumen of the intestine. Polyps are classified as nonneoplastic or neoplastic (Table 7-4).

Fig. 7-48. Carcinoid. The tumor is composed of uniform cells

with round nuclei forming nests and strands.

Fig. 7-46. Lipoma of the small intestine. The submucosal tumor

appears yellow, resembling normal fat tissue. (Courtesy of Dr.
W.V. Harrer, Camden, NJ.)

Fig. 7-49. Mantle cell lymphoma of the intestine. The tumor

presented in the form of multiple small mucosal nodules
(lymphomatous polyposis). (Courtesy of Dr. Rachel Cherian,
Kansas City, MO.)


Fig. 7-50. Mutinous cystadenoma of the appendix. A, The cystic tumor is filled with mucus. B, Villi
lined by mucous cells protrude into the lumen.

Fig. 7-51. Goblet cell carcinoid. The tumor is composed of uniform mucin-rich cells that
form small nests.

Intestinal Polyps
Neoplastic polyps

Nonneoplastic polyps
Hyperplastic polyp
Hamartomatous polyp
Juvenile polyp
Peutz-Jeghers polyp
Inflammatory polyps
IBD-related pseudopolyps
Inflammatory fibroid polyp


Lymphoid hyperplasia
Mucosal prolapse
Solitary rectal ulcer syndrome
Diverticular disease
Pneumatosis intestinalis

Inflammatory bowel disease; GIST, gastrointestinal stromal tumor.

_ cinoid

Stromal tumor


Fig. 7-52. Hyperplastic polyp. The polyp is lined by glands that

have a serrated lumen.

Fig. 7-53. Juvenile polyp. The surface is ulcerated and the

stroma is congested and inflamed. The glands, which are lined by
normal epithelium, are focally dilated.

Fig. 7-54. Peutz-Jeghers polyp. The polyp is composed of

normal glands and strands of smooth muscle.

Fig. 7-55. Tubular adenoma. The tumor protrudes into the

lumen of the large intestine.

Fig. 7-56. Tubular adenoma. Histologically the tumor is

composed of dysplastic but nevertheless uniform glands.

Fig. 7-57. Villous adenoma. The finger-like villi are lined by

mucin-secreting columnar cells.


Hyperplastic polyps are minute dewdrop-like lesions, approximately 5 mm in diameter and composed of glands that
have a serrated luminal surface (Fig. 7-52). Juvenile polyps are
hamartomas, which usually are diagnosed during the first
five years of life. Histologically they consist of stroma that
contains dilated crypts lined by normal intestinal epithelium
(Fig. 7-53).
Peutz-Jeghers polyps are sessile arborizing lesions that
most commonly are found in the small intestine. The polyps
have a smooth muscle core covered with normal mucosal
epithelium (Fig. 7-54).
Tubular adenomas are the most common neoplastic
polyps. They typically are pedunculated and often are multiple (Fig. 7-55). Polyps are composed of dysplastic columnar
epithelium forming tubular glands (Fig. 7-56). Villous
adenomas are sessile lesions composed of finger-like villous
projections lined by columnar mucin-secreting cells (Fig.
7-57). Mixed tubulovillous polyps show both growth patterns.

Carcinoma of the Large Intestine

Carcinoma of the large intestine may arise in preexisting
tubular or villous adenomas or may appear de novo. Familial
adenomatous polyposis coli, an autosomal dominant disorder,
is the best defined premalignant condition; it invariably leads
to colon cancer. Patients with this condition have multiple
neoplastic colonic polyps (Figs. 7-58).
Adenocarcinomas of the colon that arise in tubular adenomas invade the stalk and thereafter the submucosa of the
underlying bowel (Fig. 7-59). On gross examination adenocarcinomas of the cecum and the right colon have the appearance of endophytic fungating or ulcerated masses,
whereas the carcinomas of the sigmoid colon and rectum
tend to produce circumferential narrowing ( "napkin ringlike lesions " ) (Figs. 7-60 and 61). Histologically the tumors
are adenocarcinomas; they may be well differentiated or
poorly differentiated. Many colorectal carcinomas have a
mucinous component but the designation mucinous carci-

Fig. 7-58. Familial adenomatous polyposis coli. Numerous

polyps cover the luminal surface of the colon.

Fig. 7-59. Adenocarcinoma arising in a tubular adenoma. The

malignant glands have more irregular contours and are lined by
cells that show marked nuclear irregularities and pleomorphism.

Fig. 7-60. Adenocarcinoma of the right colon. The fungating

endophytic mass shows central ulceration.

Fig. 7-61. Adenocarcinoma of the sigmoid colon. The tumor

forms a circumferential mass narrowing the intestinal lumen.


noma is reserved for those neoplasms that have at least a 60

percent mucinous component. Other forms of carcinoma
such as adenosquamous, pure squamous, spindle cell, clear
cell, and choriocarcinomatous are less common. Neuroendocrine tumors include hindgut carcinoids, goblet cell carcinoids, combined adenocarcinoma-carcinoids, and neuroendocrine cell carcinomas (Fig. 7-62).

Anal Tumors and Related Lesions

Condyloma acuminatum, which may present clinically as a

wartlike intraluminal mass, is a human papillomavirusinduced tumor-like epithelial lesion that occurs in the anus
(Fig. 7-63). Benign tumors are rare. Malignant tumors originate from the epithelium and represent mostly as squamous
cell neoplasms. The earliest lesions are intraepithelial and re-

semble the more common cervical lesions (Fig. 7-64). Two

thirds of anal invasive cancers are keratinizing squamous cell
carcinomas. The remaining one third are nonkeratinizing
and are classified as basaloid (cloacogenic) (Fig. 7-65). An
important variant is the so-called verrucous carcinoma, which
macroscopically resembles condyloma acuminatum. Histologically the tumor is composed of well-differentiated squamous epithelial cells (Fig. 7-66).
Anal gland carcinomas are of three histologic types: (1) welldifferentiated adenocarcinoma, (2) mucinous carcinoma,
and (3) mucoepidermoid carcinoma (Fig. 7-67). Paget disease associated with carcinoma of the anal glands or rectum
may affect the anus or the perianal skin (Fig. 7-68). It resembles genital extramammary Paget disease.

Fig. 7-62. Neuroendocrine tumors of the colon. A, Carcinoid is composed of groups of cells
with uniform round nuclei. B, Small cell neuroendocrine carcinoma is composed of undifferentiated small blue cells that have oval nuclei and very little cytoplasm.

Fig. 7-63. Anal condyloma acuminatum. The lesion is composed

of finger-like protrusions of keratinizing squamous epithelium
covering fibrovascular cores.

Fig. 7-64. Anal intraepithelial neoplasia. The entire thickness of

the disorganized epithelium contains dysplastic atypical epithelial


Fig. 7-65. Anal carcinoma of the basaloid type. The small hyperchromatic tumor cells form - nests that show peripheral palisading.

Fig. 7-66. Verrucous carcinoma. The tumor is composed of

well-differentiated, relatively uniform squamous cells.

Fig. 7-67. Anal gland carcinoma. Adenocarcinoma cells surround an obstructed anal duct.

Further Reading
Antonioli DA: Precursors of gastric carcinoma. A critical review with a
brief description of early (curable) gastric cancer. Hum Pathol
25:994-1005, 1994.
Carr NJ, McCarthy WF, Sobin LH: Epithelial noncarcinoid tumors and
tumor-like lesions of the appendix. A clinicopathologic study of
184 patients with a multivariate analysis of prognostic factors.
Cancer 75:757-768, 1995.
Correa P: Helicobacter pylori and gastric carcinogenesis. Am J Surg
Pathol 19:S37-S43, 1995.
Dixon MF, Genta RM, Yardley JH et al: Classification and grading of
gastritis. The updated Sidney system. Am J Surg Pathol 20:11611181, 1996.
Franquemont DW: Differentiation and risk assessment of gastrointestinal stromal tumors. Am I Clin Pathol 103:41-47, 1995.
Galperin C, Gershwin ME: Immunopathogenesis of gastrointestinal
and hepatobiliary diseases. JAMA 278:1946-1955, 1997.
Ghadially FN, Walley VM: Pigments of the gastrointestinal tract. A
comparison of light microscopic and electron microscopic findings. Ultrastruct Pathol 19:213-220, 1995.
Goldstein NS, Lewin KJ: Gastric epithelial dysplasia and adenoma: historical review and histological criteria for grading. Hum Pathol
28:127-133, 1997.
Isaacson PG: Recent developments in our understanding of gastric lymphomas. Am J Surg Pathol 20(suppl)S1-S7, 1996.

Fig. 7-68. Paget disease of the anus. The basal portion of the
squamous epithelium contains nests of mucin-rich carcinoma cells.

Kleer CG, Appelman HD: Ulcerative colitis. Patterns of involvement

in colorectal biopsies and changes with time. Am J Surg Pathol
22:983-989, 1998.
Lewin KJ: Nomenclature problems of gastrointestinal epithelial neoplasia. Am J Surg 22:1043-1047, 1998.
Offner FA, Jao RV, Lewin KJ: Collagenous colitis: A study of the distribution of morphological abnormalities and their histologic detection. Hum Pathol 30:451-457, 1999.
Pascal RR: Dysplasia and early carcinoma in inflammatory bowel disease and colorectal adenomas. Hum Pathol 25:1160-1171, 1994.
Riddell RH: Premalignant and early malignant lesions in the gastrointestinal tract: definitions, terminology, and problems. Am J Gastroenterol 91:864-872, 1996.
Stemmermann GN: Intestinal metaplasia of the stomach. A status report. Cancer 74:556-564, 1994.
Suster S: Gastrointestinal stromal tumors. Sem Diagn Pathol 13:297313, 1996.
Torres C, Antonioli D, Odze RD: Polypoid dysplasia and adenomas in
inflammatory bowel disease. A clinical, pathologic and follow-up
study of 89 polyps from 59 patients. Am J Surg Pathol 22:275-284,
Willenbucher RF: Inflammatory bowel disease. Semin Gastrointest Dis
7:94-104, 1996.



Numerous hereditary diseases of carbohydrate, lipid, or protein metabolism affect the liver. Liver changes are prominent
in diseases that involve the metabolism of heavy metals such
as copper or iron. Diseases of bilirubin conjugation and the
excretion of bile also may be hereditary. All of these diseases
may become clinically evident in infancy and childhood or
may present clinically in adult life.
Glycogen and lipid storage diseases typically are accompanied by hepatomegaly and intrahepatic accumulation of intermediate metabolites. Glycogen-rich hepatocytes have
clear cytoplasm (Fig. 8-1).
Hereditary tyrosinemia is associated with steatosis and
cholestasis. Pseudoglandular transformation of hepatocytes,
intraacinar and periportal fibrosis, and nodular regeneration
develop early in childhood (Fig. 8-2).
Hereditary hyperbilirubinemias reflect defects in bilirubin
conjugation or excretion, or both (Table 8-1). Hepatocellular
changes are most pronounced in the Dubin-Johnson syndrome. The liver appears brown-black on gross examination
and the hepatocytes contain large amounts of cytoplasmic
brown pigment (Fig. 8-3).
Alpha j -antitrypsin deficiency is characterized by the presence of cytoplasmic globules, mostly in the periportal hepatocytes. These globules are round, eosinophilic, and periodic
acid-Schiff (PAS) positive. They contain a l -antitrypsin, which
may be demonstrated immunohistochemically (Fig. 8-4).
Wilson disease is characterized by an accumulation of
copper in liver cells. Liver changes include steatosis, glycogenated nuclei, and rare foci of necrosis or apoptotic bodies.
Like many other storage diseases such as a,-antitrypsin deficiency or hemochromatosis, Wilson disease may progress
to cirrhosis (Fig. 8-5).
Genetic hemochromatosis is characterized by an accumulation of hemosiderin, the iron-rich, Prussian blue-positive,
brown pigment in hepatocytes, Kupffer cells, and bile duct
cells (Fig. 8-6).

Fig. 8-1. Glycogen storage disease. Glycogenosis type I (von

Gierke disease) is characterized by an accumulation of glycogen
in liver cells. Liver cells have clear cytoplasm.

Fig. 8-2. Hereditary tyrosinemia. The liver shows steatosis,

cholestasis, lobular disorganization, and giant cell transformation
of hepatocytes.

Fig. 8-3. Dubin Johnson syndrome. Hepatocytes contain coarse brown granules in their
cytoplasm, which give the liver a black or dark brown appearance. A, Gross. B, Microscopic.


Histopathology of Viral Hepatitides

Crigler-Najjar, type I
Crigler-Najjar, type II
Dubin Johnson

Principal Defect in Bilirubin Metabolism

Conjugation and/or uptake
Unknown but may include uptake, conjugation, or excretion

Fig. 8-4. a i -Antitrypsin deficiency. The liver cells contain typical

PAS-positive round cytoplasmic bodies.

Histopathologic Changes in the Liver

Canalicular cholestasis
None or excess lipofuscin in zone 3 and 2 hepatocytes
Pigmented brown granules in hepatocytes

Fig. 8-5. Wilson disease. Hepatocytes of this cirrhotic liver have

glycogenated nuclei, which appear clear. Some hepatocytes have
clear cytoplasm, whereas cytoplasm in other hepatocytes is


Fig. 8-6. Hemochromatosis. A, Brown pigment (hemosiderin) accumulates in hepatocytes,

Kupffer cells, and bile ductular cells. B, Hemosiderin granules in bile ductular cells appear blue
after the Prussian blue reaction.


The liver, which has a dual blood supply in that it receives
blood from both the hepatic artery and the portal vein, often
is affected by circulatory disorders. Sudden heart failure
causes acute passive congestion with or without centrilobular
(zone 3) hepatocellular necrosis (Fig. 8-7). Chronic passive
congestion leads to zone 3 liver cell atrophy and loss, and replacement of liver cells by fibrous tissue. On gross examination such livers have a nutmeg-like appearance (Fig. 8-8).
Venous outflow obstruction of Budd-Chiari syndrome is
reminiscent of changes produced by congestive heart disease,
but the liver typically shows a spectrum of changes. Those
acini with acute changes show severe sinusoidal dilatation
and congestion, which is most pronounced in zone 3 but
sometimes extends to the portal tracts. Coagulative necrosis

commonly is seen. Progressive sinusoidal dilatation is accompanied by atrophy of hepatocytes and zone 3 fibrosis. In
other areas the central hepatic venules and intercalated veins
may contain thrombi or recanalized thrombi, or may show
fibrous mural thickening (Fig. 8-9). These thrombotic
changes are not seen in congestive heart failure.
Venoocclusive disease maybe a consequence of irradiation,
cytotoxic drug therapy, or drinking bush tea produced from
Senecio or Crotalaria alkaloids. The changes resemble those
seen in Budd-Chiari syndrome but are limited to the intrahepatic veins. In typical cases intimal edema of the terminal
hepatic venules is followed by the subendothelial deposition
of reticulin and collagen fibers, and progressive narrowing
and complete obliteration of their lumen (Fig. 8-10). Inflammation is sparse and thrombi are not seen.

Fig. 8-7. Acute passive congestion. The terminal hepatic venule

and the sinusoids of zone 3 are filled with blood. Many
hepatocytes have been lost from those areas or are ischemic
and are undergoing necrosis.

Fig. 8-8. Chronic passive congestion. The fixed liver has a

nutmeg-like appearance. A nutmeg is included for comparison.

Fig. 8-9. Budd-Chiari syndrome. The vein containing an

organized thrombus is surrounded by areas of necrosis of zone
3 hepatocytes.

Fig. 8-10. Venoocclusive disease caused by Senecio alkaloids.

Terminal hepatic venule (center) is almost completely occluded
and is surrounded by areas devoid of hepatocytes, which have
undergone necrosis.

1 47

Peliosis hepatis is a consequence of endothelial cell injury

leading to an accumulation of blood in the spaces of Disse
and sinusoids that become transformed into blood-filled
cavities (Fig. 8-11). Peliosis most often is induced by drugs
or steroid hormones, but it also may be a complication of infection with Rochalimaea henselae in acquired immunodeficiency syndrome (AIDS) or chronic debilitating infections such as tuberculosis.
Fibrin thrombi in sinusoids typically are found in toxemia
of pregnancy and severe disseminated intravascular coagulation (DIC) syndromes. Deposits of fibrin may be accompanied by spotty hepatocellular necrosis and liver cell dropout, most prominently in the periportal areas. Portal vein
thrombosis is a common complication of hepatocellular carcinoma (Fig. 8-12).

Hepatitis most often is caused by hepatotropic viruses, but it
also may be found in patients infected with other pleiotropic
viruses such as herpes simplex virus, cytomegalovirus
(CMV), and others. Bacterial hepatitis is a feature of biliary
tract infection or sepsis. Infections with protozoa and parasites occur in tropical countries.

Viral Hepatitis
Unless otherwise specified, the term viral hepatitis denotes
an infection caused by one of the hepatotropic viruseshepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C
virus (HCV), hepatitis D virus (HDV), hepatitis E virus
( HEV ), or hepatitis G virus (HGV). The severity of the acute
disease and its histology vary from case to case. In acute viral
hepatitis the liver shows acinar disarray, variable degrees of
ballooning of hepatocytes, scattered apoptotic bodies, and
prominence of Kupffer cells (Figs. 8-13 and 8-14). Various
viruses induce different changes, which are not always
predictable. The comparative histopathologic features of the
major forms of acute viral hepatitis are listed in Table 8-2.

Fig. 8-11. Peliosis hepatis. Blood-filled cavities do not have

endothelial lining. Blood also contains leukemia cells.

Fig. 8-12. Portal vein thrombosis. The cirrhotic liver contains

hepatocellular carcinoma (left).

Fig. 8-13. Viral hepatitis. The liver shows marked lobular

disarray, focal necrosis of hepatocytes, and prominence of
Kupffer cells.

Fig. 8-14. Viral hepatitis. Prominent apoptotic cells are being

pushed into the sinusoids. Hepatocytes appear swollen and the
Kupffer cells are prominent. Sinusoids appear narrow.


Histopathology of Viral Hepatitides

*Includes apoptosis, unicellular acidophilic and ballooning degeneration, and focal necrosis.
tMicrovesicular steatosis; seen only in posttransplantation "reinfection."
$E, Eosinophils; L, lymphocytes; N, neutrophils; P, plasma cells.

Fig. 8-15. Massive hepatic necrosis caused by HBV. Only some

periportal hepatocytes have survived the infection.

Fig. 8-16. Chronic HBV infection. Fibrous bands bridge the

space between neighboring portal tracts. There also is
considerable chronic inflammation and piecemeal necrosis.

Fig. 8-17. Chronic HCV infection. The bile ducts are inflamed
and surrounded by a dense lymphocytic infiltrate.

Fig. 8-18. HBV carrier state. The cytoplasm of hepatocytes has

a "ground glass " appearance.


Hepatitis Caused by Pathogens

Other Than Hepatitis Viruses

Complications of acute viral hepatitis include massive

necrosis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Severe viral infection may cause massive hepatic
necrosis (Fig. 8-15). Chronic hepatitis, a complication of all
viral hepatitides except those caused by HAV, is characterized by portal and/or lobular inflammation and fibrosis (Fig.
8-16). Entrapment of isolated hepatocytes or small groups of
liver cells by the expanding portal fibrous tissue is highly typical of chronic hepatitis. Extension of strands of fibrous tissue
and inflammatory cells from portal tracts into the acini with
focal liver cell necrosis and dropout ("piecemeal necrosis")
commonly is present. HCV causes steatosis and bile duct inflammation and destruction (Fig. 8-17). Hepatocytes with a
finely granular "ground glass " cytoplasm (Fig. 8-18) are the
hallmark of the chronic carrier state of hepatitis B. Serology
is the best way to diagnose specific forms of hepatitis virus

Herpesvirus hepatitis is characterized by foci of necrosis with

a relatively sparse inflammatory response (Fig. 8-19).
Cowdry type A intranuclear inclusions typically are present
(Fig. 8-20).
CMV infection causes enlargement of bile ductal cells,
which typically contain basophilic intranuclear inclusions.
Infectious mononucleosis is characterized by sinusoidal
lymphocytic infiltrates and prominence of Kupffer cells (Fig.
8-21). The hepatocellular changes are relatively mild and include focal apoptosis and only mild ballooning.
Q fever hepatitis is characterized by noncaseating granulomas with a fibrin ring often surrounding a centrally located
fat vacuole (Fig. 8-22).
Hematogenous hepatic infection occurs in many acute
bacterial diseases, such as typhoid, brucellosis, tularemia, and

Fig. 8-19. Herpesvirus hepatitis. Coagulative liver cell necrosis

with almost no inflammation.

Fig. 8-20. Herpesvirus hepatitis. The hepatocytes contain

Cowdry type A intranuclear inclusions.

Fig. 8-21. Infectious mononucleosis. The liver shows sinusoidal

Iymphocytosis and prominence of Kupffer cells.

Fig. 8-22. Q fever. Fibrin rings are typical, albeit not diagnostic
of this disease.


so forth, and causes foci of hepatic necrosis and inflammation (Fig 8-23). Mycobacterium avium-intracellulare ( MAI)
infection presents in the form of granulomas composed of
MAI-filled macrophages (Fig. 8-24).

Fig. 8-23. Typhoid fever. Liver contains sharply demarcated foci

of necrosis.

Biliary Infections
Ascending biliary infection is a common complication of bile
stone impaction in the common bile duct and other diseases
of the biliary system. Hematogenous infections may reach
the liver through arteries, usually in sepsis, or through portal
veins from the intestines.
Acute bacterial cholangitis often is a suppurative infection
(Fig. 8-25). Histologically there is bile ductal dilatation with
infiltrates of neutrophils. Biliary hepatic abscesses may persist as encapsulated pus-filled cavities inside the liver (Fig.

Fig. 8-24. MAI infection. A, Macrophagic granulomas. B, Ziehl-Neelsen stain shows

numerous acid-fast bacilli inside macrophages.

Fig. 8-25. Bacterial cholangitis. Pus is oozing from bile ducts on

a cross-sectioned liver.

Fig. 8-26. Cholangitic abscesses. Abscesses contain bile-tinged



Hepatic amebiasis, a complication of amebic colitis, is

characterized by hepatic lesions called amebomas. Although
these lesions are also known as amebic abscesses, they do not
contain pus but are filled with putty-like material formed
from necrotic liver cells (Fig. 8-27). Infections with parasites
such as Echinococcus granulosus lead to the formation of hep-

atic cysts (Fig. 8-28). Infections with Schistosoma haematobium and Opisthorchis sinensis are accompanied by granulomas and periportal hepatic fibrosis of "pipe stem " type
(Fig. 8-29). Malaria is accompanied by pronounced hypertrophy of Kupffer cells, which contain black hemozoic pigment (Fig. 8-30).


Fig. 8-27. Amebic abscess. A, The cavitary lesion is filled with yellow putty-like material.
It does not contain pus and thus is not a true abscess but rather a localized area of hepatic
necrosis. (From Damjanov I: Pathology for the health related professions, Philadelphia, 1996,
WB Saunders; with permission.) B, Necrotic material occupies space surrounded by
fibrous tissue.

Fig. 8-28. Echinococcus granulosus cyst. A, Cyst has a hyaline fibrotic wall. B, Cyst
contains cross-sectioned scolices of the parasite.


Fig. 8-29. Schistosomiasis. The parasite in tissue is surrounded

by chronic inflammation and fibrosis.


Most drugs absorbed into the portal or systemic circulation
are metabolized in the liver. During this metabolic process
the liver cells may be injured as a result of the direct toxicity
of the drug or its metabolites. These substances also may
produce an immune response, and such a hypersensitivity
reaction also may indirectly affect the liver. Some drugs may
induce an unpredictable idiosyncratic adverse response in

Fig. 8-30. Falciparum malaria. The enlarged Kupffer cells

contain black hemozoic pigment.

the liver. In general, the morphologic features of drug-induced liver injury parallel those of viral hepatitis but also include fatty change, pure cholestasis, vascular changes, and
hyperplastic and/or neoplastic lesions (Table 8-3, Figs. 8-31
to 8-36).

Drug-induced Liver Diseases


Drug Examples
= `ds-like
Spotty necrosis Methyldopa
Halothane, acetaminophen
necrosis, zone 3
Paraaminosalicylic acid,
necrosis, zone I
Massive necrosis Isoniazid, halothane,
Methyldopa, sulfonamides
Chlorpromazine, oral
Fatty change
Tetracycline, salicylates

Vascular changes


Peliosis hepatis

Anabolic steroids, tamoxifen

Oral contraceptives

Cytotoxic drugs


copper sulfate
ferrous sulfate

Fig. 8-31. Drug-induced hepatitis. This patient developed a

hepatitis-like disease after treatment for tuberculosis with


Senecio or

Fig. 8-32. Massive hepatic necrosis induced by acetaminophen.


Fig. 8-33. Drug-induced chronic hepatitis. Liver changes in this

patient treated with methyldopa resemble those of chronic

Fig. 8-35. Hepatic granulomas. These granulomas were found in

a patient treated with phenylbutazone.

Fig. 8-34. Drug-induced fatty change.

Fig. 8-36. Cholestasis. Androgen-related jaundice was

associated with bile plugs and cholestatic rosettes.


Fig. 8-37. Fatty liver. The liver appears yellow.

Chronic abuse of alcohol may produce a spectrum of overlapping hepatic changes, which are classified morphologically as (1) fatty change, (2) alcoholic hepatitis, and (3) alcoholic cirrhosis. Fatty change often is associated with
hepatomegaly, but in essence it causes no clinical symptoms
and is reversible. Microscopically it presents with macrovesicular steatosis (Fig. 8-37). In a minority of chronic alcoholics the liver injury presents as alcoholic hepatitis. The most
prominent changes are seen in zone 3, which shows pronounced unrest (pleomorphism) of hepatocytes. Many hepatocytes show cytoplasmic dissociation (clumping of part of
the cytoplasm around the nucleus with rarefaction of the
remainder) and Mallory body formation (Fig. 8-38). Mallory


Fig. 8-38. Alcoholic hepatitis. There is noticeable unrest of

hepatocytes, some of which contain Mallory bodies (arrows).

bodies may be demonstrated immunohistochemically with

antibodies to ubiquitin (Fig. 8-39). Groups of neutrophils
tend to surround hepatocytes with Mallory bodies ( "neutrophilic satellitosis " ). Steatosis usually is mild to moderate
but may even be absent. Fibrosis tends to occur around the
terminal hepatic venules extending into the spaces of Disse
and sinusoids enveloping individual hepatocytes or groups
of hepatocytes ( "chicken wire " fibrosis) (Fig. 8-40). The connective tissue may become confluent, replacing zone 3 hepatocytes and obliterating efferent veins ( " sclerosing hyaline
necrosis " ). Venoocclusive lesions may be associated with
variable degrees of periportal fibrosis. In some biopsy specimens of patients with portal hypertension, perivenular fibrosis of zone 3 and steatosis may be the only findings (Fig.
8-41). Fibrosis may progress, dissecting acini into small segments, which ultimately leads to cirrhosis (Fig. 8-42). In typical cases alcoholic cirrhosis is micronodular and the liver is
yellow and fatty. However, in many cases the liver is devoid
of fat and appears macronodular or mixed micro- and

Fig. 8-39. Mallory bodies. In this immunohistochemical preparation Mallory bodies stain brown with antibodies to ubiquitin.

Fig. 8-40. Alcoholic hepatitis. In this Mallory trichromestained

slide zone 3 shows periventricular fibrosis extending between

Fig. 8-41. Alcoholic liver disease. The liver shows steatosis and
fibrosis of zone 3 in the center of the field.

Fig. 8-42. Alcoholic cirrhosis. Cirrhosis typically is micronodular and the liver appears yellow because of a high fat



Autoimmune hepatitis and primary biliary cirrhosis are the
best known autoimmune diseases of the liver. It should be
noted that some drug reactions also are immune mediated.
Primary sclerosing cholangitis, a disease of unknown pathogenesis, is mentioned here only because many patients with
this disease have perinuclear antineutrophil cytoplasmic antibodies (pANCA) and may have an altered immune system.
Autoimmune chronic hepatitis includes three subgroups:
(l a) lupoid hepatitis (antinuclear antibody-positive, with or
without actin antibody) and (lb) which is only actin antibodypositive; (2) liver-kidney microsomal antibodypositive; and (3) liver-pancreas antibodypositive (with or
without other antibodies). There are no histologic findings
that reliably distinguish autoimmune chronic hepatitis from
chronic hepatitis B or drug-induced chronic hepatitis. Some
authors believe that hypocellular areas of collapse, severe
intraacinar necrosis, and inflammation with rosettes and
multinucleated hepatocytes are more suggestive of autoi mmune hepatitis than other forms of chronic hepatitis;
many other investigators do not find any specificity in these
findings. The presence of plasma cells is considered to be

useful for distinguishing autoimmune chronic hepatitis from

chronic hepatitis C, in which the portal infiltrates consist predominantly of lymphocytes (Fig. 8-43). However, plasma
cells may be abundant in viral hepatitis B and in some druginduced lesions.
Primary biliary cirrhosis is an autoimmune disease that is
characterized by destruction of intrahepatic bile ducts, which
leads to biliary cirrhosis. An increased titer of antimitochondrial antibodies is seen in 90 percent of patients, and the
disease often is associated with other autoimmune disorders
such as Hashimoto thyroiditis or atrophic gastritis. Histologically, in early stages of the disease, the chronic inflammatory cells in the portal tracts infiltrate and destroy the bile
ducts ( "chronic nonsuppurative destructive cholangitis")
(Fig. 8-44). As the disease progresses the bile ducts are replaced by fibrosis, which extends from one portal area to another (Fig. 8-45). In liver biopsy specimens more than half
the portal tracts lack bile ducts, in contrast to the normal liver
in which 87 percent or more portal tracts have bile ducts. The
presence of lteriportal cholestasis and foci of pseudoxanthomatous cells is useful for diagnosis but is not pathognomonic of primary biliary cirrhosis (Fig. 8-46). Cholangi-

Fig. 8-43. Autoimmune hepatitis. The inflammatory infiltrate in

this chronic hepatitis contains numerous plasma cells.

Fig. 8-44. Primary biliary cirrhosis. The bile duct is distorted by

inflammatory cells, which surround and invade it.

Fig. 8-45. Primary biliary cirrhosis. Connective tissue bridges

connect portal areas, which typically are devoid of bile ducts in
advanced stages of the disease.

Fig. 8-46. Primary biliary cirrhosis. Clusters of xanthomatous

cells are found in the dilated sinusoids.


Fig. 8-47. Primary sclerosing cholangitis. A, The medium-sized bile ducts are surrounded by
collagenous fibrous tissue. B, Bile ducts have been replaced by round scars. Ductopenia is
accompanied by residual chronic inflammation.

olar proliferation may be prominent. Hepatocytes are relatively spared except in advanced cirrhotic stages of the disease, which are characterized by prominent piecemeal
necrosis and nodular regeneration. Periportal Mallory
bodies are found in approximately one fourth of all cases.
Cirrhosis usually is micronodular and maybe associated with
marked cholestasis.
Primary sclerosing cholangitis usually is idiopathic and occurs sporadically. In some cases it may be associated with ulcerative colitis or retroperitoneal fibrosis. The disease affects
the intrahepatic bile ducts, which show focal stenosis alternating with dilatation ( " beading" on cholangiography). Histologic changes in the liver resemble those caused by other
forms of extrahepatic biliary obstruction and include
periductal fibrosis and variable cholestasis (Fig. 8-47). Intrahepatic bile ducts compressed by concentric.(` onionskin " )
fibrosis ultimately disappear and are replaced by round fibrotic scars (Fig. 8-48). Extrahepatic ducts also are narrowed
and fibrotic and ultimately are transformed into fibrous
strands devoid of any lumen. Biliary cirrhosis develops terminally in most patients.

Obstruction of extrahepatic biliary ducts causes jaundice
and is associated with typical hepatic changes. Possible causes
of biliary obstruction such as bile stones are readily identified clinically (Fig. 8-49). Other causes of obstruction are
listed in Table 8-4.
In acute biliary obstruction the first changes are seen in
acinar zone 3 and sometimes in zone 2. Zone 3 hepatocytes
show slight unrest (Fig. 8-50). Portal tract infiltrates of neutrophils and acute cholangiolitis, edema, and cholangiolar
proliferation are typical but not diagnostic (Fig. 8-51). The
epithelium of the intraacinar bile ducts may show irregularity, hyperplasia, or edema. Bile plugs sometimes are present in the bile ducts. In severe cases the bile ducts rupture
and cholangitic abscesses form (Fig. 8-52). These abscesses
contain remnants of disrupted biliary epithelium, and bile
mucin admixed with neutrophils in various stage of disintegration. Xanthomatous cells and foreign body giant cells with
phagocytosed bile may be present. Extravasated bile ("bile
lakes " ) and dissolution of liver cells resulting from the detergent action of bile ( " bile infarcts" ) are seen only in advanced cases, usually at autopsy, and are of limited diagnostic
value in liver biopsies (Figs. 8-53 and 8-54).

Causes of Biliary Obstruction

Fig. 8-48. Biliary cirrhosis. The liver is nodular and shows greenish nodular discoloration.

Primary sclerosing
Bacterial cholangitis
Surgical stricture

Carcinoma of head of pancreas
Carcinoma of ampulla of Vater
Carcinoma of common bile ducts
Lymphoma of hilar lymph nodes


Fig. 8-49. Gallstones in the hepatic ducts. Pigmented stones

were found in dilated ducts.

Fig. 8-50. Extrahepatic biliary obstruction. The acinar zone 3

shows unrest and canalicular cholestasis.

Fig. 8-5 I. Extrahepatic biliary obstruction. The portal tract is

inflamed and there is cholangiolar proliferation.

Fig. 8-52. Cholangitic abscess. The dilated and ruptured bile

duct is filled with neutrophils and bile.

Fig. 8-53. Bile lake. Darkly stained extravasated bile surrounded

by xanthomatous cells is found in late stages of biliary

Fig. 8-54. Bile infarct. Dissolution of liver cells is a late

consequence of chronic biliary obstruction.


Cirrhosis, a term used as a synonym for advanced liver disease
or end-stage liver disease, is characterized by replacement of
normal liver parenchyma by abnormal liver cell nodules and
fibrosis. Morphologically it is classified as (1) micronodular
if the nodules are smaller than 3 mm in diameter; (2) macronodular if the nodules are larger than 3 mm in diameter; and
(3) mixed if the liver contains an equal number of large and
small nodules (Figs. 8-55 and 8-56). The most important
causes of cirrhosis are listed in Table 8-5.
Histologic features of cirrhosis are typical and usually reflect the gross findings. In all instances groups of liver cells
are arranged into nodules surrounded by fibrous septa (Fig
8-57). These septa may contain proliferating bile ducts and
chronic inflammatory cells. Dilated branches of portal veins,
which reflect intrahepatic vascular obstruction and portal
hypertension, are found in most cases (Fig. 8-58). Septa contain reticulin fibers that extend between the liver cells, accentuating their abnormal structure (Fig. 8-59). The hepatocellular nodules are composed of pleomorphic liver cells
arranged into groups, strands, and nests that lack normal sinusoidal blood supply (Fig. 8-60).

Fig. 8-55. Micronodular cirrhosis. The nodules are small and of

approximately even size.

Causes of Cirrhosis

Viral hepatitis
Alcohol abuse
Metabolic diseases
Wilson disease
a,-antitrypsin deficiency
Immune-mediated hepatic diseases
Primary biliary cirrhosis
Primary sclerosing cholangitis
Autoimmune ("lupoid") hepatitis
Toxic and drug-induced hepatitis
Biliary obstruction
Cryptogenic cirrhosis

Fig. 8-57. Cirrhosis. Nodules of liver cells are surrounded by

fibrous septa.

Fig. 8-56. Macronodular cirrhosis. Large nodules, which vary in

size and shape, are surrounded by broad areas of fibrosis.

Fig. 8-58. Cirrhosis. The fibrous septa contain proliferating bile

ducts, chronic inflammatory cells, and dilated veins.


Fig. 8-59. Cirrhosis. Reticulin stain highlights broad septa giving

rise to fine fibers that extend into the hepatocellular nodules.
Reticulin fibers of this kind are not seen in hepatocellular

Tumor-Like Conditions
Extensive cystic changes in the liver are uncommon. Cysts
usually occupy only part of the liver, but occasionally the
change may be widespread (Fig. 8-61). Cysts of the liver are
found in several hereditary conditions such as Caroli disease,

Fig. 8-60. Cirrhosis. Hepatocellular nodules lack normal

sinusoidal blood supply and are composed of pleomorphic liver
cells arranged into groups rather than plates.

autosomal recessive polycystic kidney disease (ARPKD), or

autosomal dominant polycystic kidney disease (ADPKD).
The hepatic changes vary from mild to severe. The most
common finding in mild hepatic forms of ADPKD are
minute nodules, measuring 1 to 3 mm in diameter, composed
of small bile ductules embedded in collagenous stroma (von
Meyenburgcomplexes) (Fig. 8-62).

Fig. 8-61. Polycystic liver disease. A, The liver contains numerous large cysts. B, The cyst wall
contains small bile ducts surrounded by fibrous tissue. (Courtesy of Dr. Paramjit Bhatia, Kansas
City, Kansas.)


Fig. 8-62. von Meyenburg complex. Groups of small bile ducts

are enclosed in connective tissue stroma.

Fig. 8-63. Focal nodular hyperplasia. The lobular mass has a

central fibrotic scar.

Fig. 8-64. Focal nodular hyperplasia. The central scar extends

peripherally into thinner septa.

Fig. 8-65. Nodular transformation. The nodules are composed

of hepatocytes that are larger and paler than those of the
surrounding normal liver.

Fig. 8-66. Nodular transformation. Reticulin stain shows the

difference between the nodule composed of two cellthick
plates and the compressed normal liver to the right.

Focal nodular hyperplasia may present as solitary or multiple nodules in noncirrhotic livers of adults: It is twice as
common in women as in men, and it most often is asymptomatic and is discovered accidentally. The average mass
measures 5 cm in diameter. On cross section it appears lobulated and is well demarcated from the rest of the liver (Fig.
8-63). The nodule typically has a central fibrous scar radiating toward the periphery ("wagon wheel" pattern). Histologically, focal nodular hyperplasia is composed of normalappeanng hepatocytes arranged into two cell-thick plates
between septa of fibrous tissue (Fig. 8-64).
Nodular transformation, also known as nodular regenerative hyperplasia, represents diffuse hepatic nodularity
without fibrosis or cirrhosis. It has been associated with a
number of diseases such as autoimmune diseases, including
CREST (calcinosis, Raynaud 's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) syndrome and
polyarteritis nodosa; inflammatory bowel disease; lymphoma and myeloproliferative diseases; or bacterial endo -


carditis. Some cases have been related to prolonged intake of

anabolic steroids or oral contraceptives. It usually is asymptomatic, but morphologically it may be confused with cirrhosis. The nodules are composed of hyperplastic hepatocytes arranged into two cellthick plates compressing the
adjacent liver without any intervening fibrous tissue (Fig.
8-65). Reticulin stain clearly shows the differences between
the nodule and the compressed atrophic normal liver cells
(Fig. 8-66).

Epithelial Tumors
Hepatocellular adenoma is the most important benign liver

tumor. It occurs as a yellow, congested or hemorrhagic

nodule in an otherwise normal liver (Fig. 8-67). The tumor
is composed of hepatocytes resembling those of the normal
liver. Tumor cells usually are larger, are arranged into two
cellthick plates, and contain glycogen, which makes their
cytoplasm appear clear (Fig. 8-68).
Hepatocellular carcinoma is a malignant liver cell tumor
that most often originates in a cirrhotic liver. It maybe pathogenetically related to hepatitis B or hepatitis C virus infection. The tumor may be classified on gross examination as
solitary, multinodular, massive, or diffuse (Figs. 8-69 and
8-70). Histologically, hepatocellular carcinoma occurs in several patterns such as trabecular, compact, pseudoglandular

Fig. 8-67. Hepatocellular adenoma. The tumor appears as a

partially hemorrhagic yellow mass.

Fig. 8-68. Hepatocellular adenoma. The tumor is composed of

clear cells arranged into two cellthick plate. The cells have a
low nuclear-cytoplasmic ratio, and the nuclei appear uniform.

Fig. 8-69. Hepatocellular carcinoma. This cirrhotic liver

contains a solitary malignant nodule, which appears yellow.
Smaller satellite nodules are seen left of the main mass.
(Courtesy of Dr. James Fishback, Kansas City, Kansas.)

Fig. 8-70. Hepatocellular carcinoma. The massive tumor is

poorly demarcated from the remaining liver.


(acinar), and scirrhous (Figs. 8-71 and 8-72). Irrespective of

its growth pattern, hepatocellular carcinoma has a poor
Fibrolamellar hepatocellular carcinoma is a distinct subtype of hepatocellular carcinoma that occurs in adolescents
and young adults. It is not associated with hepatitis virus infection and occurs in normal rather than cirrhotic livers. The
five-year survival rate is in the range of 60 percent to 80 percent. On gross examination the tumor presents as a mass that
is demarcated from the remaining liver and crisscrossed with
fibrous scars. Histologically the tumor is composed of large
polygonal cells with intensely eosinophilic cytoplasm (Fig.
8-73). The cytoplasm of tumor cells appears granular because the cells contain numerous mitochondria. Tumor cells
also may contain globular PAS-positive inclusions and socalled pale bodies.
Hepatoblastoma is a tumor of childhood. It often is associated with a variety of congenital anomalies such as

Fig. 8-71. Hepatocellular carcinoma. The tumor has a trabecular pattern.

Fig. 8-72. Hepatocellular carcinoma. The tumor has a pseudoglandular pattern.

Fig. 8-73. Fibrolamellar hepatocellular carcinoma. The tumor is

composed of large cells with well-developed eosinophilic
cytoplasm. Connective tissue scars also are seen.

Fig. 8-74. Hepatoblastoma. The tumor has a lobular appearance

with areas of necrosis.

Fig. 8-75. Hepatoblastoma. The tumor is composed of cuboidal

cells that resemble fetal hepatocytes.


Fig. 8-76. Cholangiocellular carcinoma. A, The tumor appears grayish-white. B, Histologically the
tumor has a tubular pattern.

hemihypertrophy, congenital absence of the portal vein,

Beckwith-Wiedemann syndrome, or familial adenomatous
polyposis coli. On gross examination the tumor usually is
well circumscribed with foci of cystic degeneration, necrosis,
or hemorrhage (Fig. 8-74). Histologically it consists of cells
that resemble embryonic fetal hepatocytes embedded in a
mesenchymal matrix. Embryonal type cells are small
fusiform cells with hyperchromatic nuclei. Fetal type cells are
larger and have more eosinophilic or clear cytoplasm filled
with fat and glycogen (Figs. 8-75).
Cholangiocellular carcinoma is a malignant epithelial
tumor derived from the intrahepatic bile ducts. Two thirds
of these tumors are solitary and one third are multifocal. In
Southeast Asia this tumor has been associated with liver fluke
infestation, but in the rest of the world it seems to be sporadic. Histologically the tumors are adenocarcinomas, often
of a tubular pattern evoking a strong desmoplastic reaction.
(Fig. 8-76).

Fig. 8-77. Epithelioid hemangioendothelioma. Tumor cells,

which typically show cytoplasmic vacuoles (lumens), are
supported by delicate stroma. Sinusoidal vascular spaces are
seen as clefts between tumor cells.

Mesenchymal Tumors
Hemangioma is the most common benign mesenchymal
tumor. It usually is asymptomatic and clinically insignificant.
Other benign tumors such as lipoma and fibroma are rare.
Malignant mesenchymal tumors are rare. They most often
originate from vascular cells. The most important are epithelioid hemangioendothelioma, angiosarcoma, and undifferentiated sarcoma (Fig. 8-77).

Metastatic Tumors
Metastases to the liver are the most common malignancy in
this organ. On gross examination metastases appear as multiple spherical nodules with a central indentation ("umbilication") (Fig. 7-78). They most often originate from primary
tumors in the colon, lung, or breast.


Fig. 8-78. Metastatic carcinoma. The liver contains numerous

spherical nodules, many of which show central indentation
("umbilication") corresponding to the areas of necrosis.

Fig. 8-79. Gallstones. The gallbladder is filled with multifaceted



The most important diseases of the gallbladder and biliary
ducts are biliary stones (cholelithiasis), inflammation of the
gallbladder (cholecystitis), and tumors.
Gallstones are predominantly composed of cholesterol
and bile pigment. They may be solitary or multiple, firm or
soft, and radiographically opaque or translucent (Fig. 8-79).
Gallstones often are accompanied by inflammation, which
may be related to mechanical or chemical irritation of the
mucosa or to bacterial infection.
Cholecystitis may be classified as acute or chronic (Figs. 880 and 8-81). Histologically the wall of the gallbladder shows
signs of inflammation, which in chronic cholecystitis may be
accompanied by fibrosis and epithelial metaplasia. If extensive lymphoid hyperplasia is found, the term follicular cholecystitis is used. If infiltrates of neutrophils are found in
chronic cholecystitis, the term chronic active cholecystitis is
used (Fig. 8-82). Porcelain gallbladder is a term that is used
for fibrosed and/or calcified gallbladders in chronic states of
Hydrops of the gallbladder typically is caused by impacted
gallstones. The gallbladder is distended and filled with clear
fluid. Its wall may be fibrosed (Fig. 8-83).
Carcinoma of the gallbladder is clinically the most important tumor of the gallbladder. It often is found in association
with gallstones even though there is no pathogenetic link between these two diseases. It is more common in women than
in men and is especially common in Native Americans. The
tumor grows into the lumen or through the wall and infiltrates the liver (Fig. 8-84). Histologically most tumors are
adenocarcinomas, but some appear as mixed adenosquamous or squamous cell carcinomas. Carcinoids, endocrine
carcinoma, or carcinosarcomas are rare. Sarcomas are extremely rare.

Fig. 8-80. Acute cholecystitis. The mucosa appears red and

swollen. The gallbladder contained stones, which were removed
after surgery.

Fig. 8-81. Chronic cholecystitis. Transmural Iymphocytic

infiltrates in a follicular pattern account for the term follicular


Fig. 8-82. Chronic active cholecystitis. The wall of the

gallbladder is infiltrated with chronic inflammatory cells, whereas
the surface mucosa is infiltrated with neutrophils.

Fig. 8-84. Carcinoma of the gallbladder. The gallbladder is

partially filled and infiltrated with neoplastic tissue
Further Reading
Albores-Saavedra J, Nolberg K, Henson DE: Unusual malignant epithelial tumors of the gallbladder. Sem Diag Pathol 13:326-338, 1996.
Batts KP, Ludwig J: Chronic hepatitis. An update on terminology and
reporting. Am J Surg Pathol 19:1409-1417, 1995.
Brewer GJ, Yuzbasiyan-Gurkan V: Wilson disease. Medicine (Baltimore) 71:139-164, 1992.
Carriaga MT, Henson DE: Liver, gallbladder, extrahepatic bile ducts,
and pancreas. Cancer 75:175-190, 1995.
Chevallier M, Guerret S, Chossegross P et al: A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle
liver biopsy specimens. Comparison with morpholometric studies.
Hepatology 20:349-355, 1994.

Fig. 8-83. Hydrops of the gallbladder. Dilated gallbladder contains an impacted stone in its neck region.

Desmet VI, Gerber M, Hoofnagle JH et al: Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology 19:1513-1520,
Edmonson HA, Steiner PE: Primary carcinoma of the liver. A study of
100 cases among 48,900 necropsies. Cancer 7:462-503, 1954.
Gold JH, Guzman IJ, Rosai J: Benign tumors of the liver. Pathologic examination of 45 cases. Am J Clin Pathol 70:6-17, 1978.
Heintges T, Wands JR: Hepatitis C virus: epidemiology and transmission. Hepatology 3:521-526, 1997.
Hoofnagle JH, Carithers RL Jr, Shapiro C et al: Fulminant hepatic
failure. Summary of a workshop. Hepatology 21:240-252, 1995.
International Working Party. Terminology of nodular hepatocellular
lesions. Hepatology 22:983-993, 1995.
Ishak KG: Chronic hepatitis. Morphology and nomenclature. Mod
Pathol 7:690-713, 1994.
James 0, Day C: Non-alcoholic steatohepatitis: another disease of affluence. Lancet 353:1634-1636, 1999.
Lee WM: Hepatitis B virus infection. NEngl JMed 337:1733-1745, 1997.
Maeda T, Adachi E, Kajiyama K et al: Combined hepatocellular and
cholangiocarcinoma. Proposed criteria according to cytokeratin
expression and analysis of clinicopathologic features. Hum Pathol
26:956-964, 1995.
Meyer zum Buschenfelde K-H, Dienes H-P: Autoimmune hepatitis.
Definitionclassificationhistopathologyimmunopathogenesis. Virchows Arch 429:1-12, 1996.
Ojeda VJ, Shilken KB, Walters MNI: Premalignant epithelial lesions of
the gallbladder. A prospective study of 120 cholecystectomy specimens. Pathology 17:451-454, 1985.
Seeff LB: Natural history of viral hepatitis, type C. Semin Gastrointest
Dis 6:20-27, 1995.
Weiss JB Jr, Persing DH: Hepatitis C. Advances in diagnosis. Mayo Clin
Proc 70:296-297, 1995.
West AB, Chatila R: Differential diagnosis of bile duct injury and ductopenia. Sem Diag Pathol 15:270-284, 1998.



Developmental disorders of the exocrine pancreas include
(1) anatomic anomalies such as annular pancreas, pancreas
divisum, and ectopic pancreas (e.g., in the stomach, small intestine, or Meckel diverticulum); and (2) hamartomas, cysts,
and heterotopic inclusions or choristomas, which most often
are composed of splenic or intestinal tissue (Figs. 9-1 and
9-2). These abnormalities occur sporadically and usually are
asymptomatic, but an annular pancreas occasionally causes
intestinal obstruction.
Nesidioblastosis is an anomaly of the endocrine pancreas
that is characterized by persistent neonatal hyperinsulinemic
hypoglycemia. It occurs in both focal and diffuse forms. In
the focal form islet cells form small nodules. In the diffuse
form there are distinct insular changes, which are widespread. Histologically the main criteria for establishing the
diagnosis are (1) distinct 13-cell hypertrophy with nuclear enlargement, often resulting in giant and bizarre nuclei; (2) the
presence of islets of variable size, often of somewhat irregular outline; (3) irregularly sized and poorly defined endocrine cell clusters scattered in the acinar parenchyma; and
(4) endocrine cell complexes, often intimately connected
with small or larger ducts (ductuloinsular complexes) (Figs.
9-3 and 9-4).
Cystic fibrosis is one of the most common autosomal recessive diseases of man and it always involves the pancreas.
The disease is related to mutations of the gene encoding the
cystic fibrosis transmembrane conductance regulator
(CFTR). Dysfunction of the CFTR is associated with increased viscosity of the mucus of many exocrine glands, including the pancreas. The viscous mucus stagnates and accumulates in the pancreatic ducts (Fig. 9-5). In advanced
stages of the disease chronic obstruction of the pancreas is
associated with compression and atrophy of acini, which
then are replaced by fibrous tissue (Fig. 9-6).

Fig. 9-3. Diffuse nesidioblastosis. Many cells in this enlarged islet

have hypertrophic nuclei.

Fig. 9-I. Annular pancreas. The narrowed duodenum is only

probe patent.

Fig. 9-2. Cyst of the pancreas. A, These cysts, which may be

multiple, usually are asymptomatic. B, Cyst is lined by cuboidal

Fig. 9-4. Diffuse nesidioblastosis. The irregularly shaped islet is

attached to a small duct, forming a ductuloinsular complex.


Fig. 9-5. Cystic fibrosis. Dilated ducts contain inspissated

proteinaceous material.

Fig. 9-6. Cystic fibrosis. In later stages of the disease the dilated
ducts filled with eosinophilic material are surrounded by fibrotic
parenchyma and atrophic acini.

Acute interstitial pancreatitis occurs in the course of many
systemic diseases. It may be associated with elevated blood
amylase or lipase but usually causes no symptoms. Histologically it presents as interstitial edema accompanied by a
sparse inflammatory infiltrate (Fig. 9-7). Viral pancreatitis
may be caused by the mumps virus, cytomegalovirus (CMV),
and some other viruses (Fig. 9-8).
Acute hemorrhagic pancreatitis, which is the most important clinical form of pancreatitis, results from acinar cell injury and intrapancreatic activation of pancreatic lytic enzymes (Diagram 9-1). Proteolytic enzymes digest the walls
of blood vessels, which leads to massive hemorrhagic necrosis
of the pancreas and adjacent tissues (Fig. 9-9). Blood-filled
cavities (pseudocysts) form in the pancreas (Fig. 9-10). Fat
necrosis characterized by saponification of fatty acids re -

Fig. 9-8. Viral pancreatitis. The pancreas appears disorganized,

and some pancreatic cells contain CMV nuclear inclusions. The
loose connective tissue stroma contains scattered inflammatory

Fig. 9-7. Interstitial pancreatitis. The interstitial spaces, which

appear dilated because of edema, contain a few inflammatory

Fig. 9-9. Acute hemorrhagic pancreatitis. The pancreas has

been completely obliterated by blood.

17 0

Diagram 9-I. A, Pathogenetic relationships of acinar cell injury and duct obstruction to
pancreatitis. B, Intrapancreatic mechanisms of enzyme activation in pancreatitis

Fig. 9-10. Acute hemorrhagic pancreatitis. Hemorrhage, fat

necrosis, and a pseudocyst filled with blood are seen on cross

Fig. 9-1 I. Acute pancreatitis. Foci of fat necrosis appear as

white opaque patches.

Fig. 9-12. Acute pancreatitis. In the areas of fat necrosis the fat
cells have left their normal outlines and appear eosinophilic. The
necrotic pancreatic acinar cells have been transformed into
amorphous bluish granular material.

Fig. 9-13. Peritonitis complicating acute pancreatitis. The

mesentery shows foci of fat necrosis and hemorrhage. The
bloody ascites has been removed.


leased from damaged fat cells through the action of pancreatic lipase is a typical finding (Figs. 9-11 and 9-12).
Complications of acute pancreatitis are massive bloody
peritonitis, which typically is accompanied by shock and
massive necrosis of mesenteric and omental fat tissue (Fig.
9-13). Large pseudocysts may form at the site of pancreatic
tissue destruction (Fig. 9-14). These pseudocysts typically
are filled with pancreatic enzymes, which act on the adjacent tissue, continuously promoting necrosis and inflammation (Fig. 9-15). Treatment by marsupialization (i.e., exteriorization of the cyst, allowing its drainage to the outside
of the body) may eliminate the enzymes, but the fibrous capsule remains (Fig. 9-16).
Chronic pancreatitis may be a late consequence of acute
pancreatitis, but more often it is the end result of clinically
undetected bouts of recurrent pancreatitis. The disease is a
well-known complication of chronic alcoholism. Clinically
it is marked by chronic pancreatic insufficiency and malabsorption. The pancreas usually is firm, fibrotic, and focally

calcified. Its obstructed and dilated ducts contain calculi (Fig.

9-17). Histologically the acini are replaced by fibrous tissue
and chronic inflammatory cells, which surround the few remaining ducts and islets of Langerhans (Fig. 9-18). Diabetes
is seen in approximately 25 percent to 35 percent of cases.

Fig. 9-14. Pancreatic pseudocyst. Cyst filled with hemorrhagic

fluid in the tail is extending into the hilum of spleen.

Fig. 9-I5. Pancreatic pseudocyst. The lumen is lined by necrotic

material that lacks an epithelial layer.

Fig. 9-16. Pancreatic pseudocyst. After drainage of its content,

the pseudocyst appears as a fibrous sac.

Fig. 9-17. Chronic pancreatitis. The main pancreatic duct is

dilated and contains calculi. The normal lobular architecture of
the pancreas has been lost because most acini have been
replaced by fibrous tissue.

Fig. 9-18. Chronic pancreatitis. Connective tissue and foci of

chronic inflammatory cells are found surrounding a few
scattered ducts and remnants of acini and islets.



Benign or malignant neoplasms of the exocrine pancreas
may arise from ductal, acinar, and stromal cells. Malignant
tumors predominate; ductal adenocarcinoma accounts for
80 percent to 85 percent of pancreatic neoplasms. The World
Health Organization histologic classification of tumors of
the exocrine pancreas is presented in Table 9-1.

Benign Tumors and Tumors

of Borderline Malignancy

Cystadenomas of the pancreas are multicystic tumors that are

classified as serous or mucinous (Fig. 9-19). The cystic spaces
in serous cystadenoma are filled with clear fluid and lined by
flattened cuboidal epithelium (Fig. 9-20). Mucinous cystadenomas are lined by cuboidal mucinrich epithelium. These
tumors are either benign or borderline malignant, and some
from the latter group may give rise to invasive cancer.
Intraductal papillary mucinous neoplasms represent a
group of closely related neoplasms, including benign, borderline malignant, and malignant neoplasms. Overall, they
grow slowly and measure from 2 to 4 cm in diameter at di-

agnosis. The benign variant, also called intraductal papilloma, papillary adenoma, or villous adenoma of the pancreatic
ducts, is composed of papillae lined by well-differentiated
mucin-rich epithelium (Fig. 9-21). Intraductal papillary mucinous tumors of borderline malignancy have complex papillae
lined by tall columnar epithelium with moderate nuclear
dysplasia (Fig. 9-22). Malignant tumors of this group are indistinguishable from other mucinous adenocarcinomas (Fig.
9-23). Some of these tumors contain foci of borderline and
even benign mucinous epithelium, indicating that the malignancy arose through an adenoma-carcinoma sequence
similar to the histogenesis of carcinoma of the colon in familial adenomatous polyposis coli.
Solid pseudopapillary tumor, also known as solid cystic
tumor, refers to a group of tumors that may be benign, borderline, or malignant. These tumors typically occur in young
women and present in the form of a solid or partially cystic
mass. They measure from 2 to 20 cm in diameter. Histologically they are composed of solid nests of cuboidal cells that
have clear or eosinophilic cytoplasm and round to oval nuclei (Fig. 9-24). Tumor cells contain both zymogen and neuroendocrine granules. The tumor is traversed by fibro-

Histologic Classification of Tumors of the Exocrine Pancreas

Proposed by the World Health Organization


Fig. 9-19. Serous cystadenoma. A, The tumor is well circumscribed. B, On cross section it
appears microcystic.


Fig. 9-20. Serous cystadenoma. Small cystic spaces are lined by

flattened cuboidal epithelium.

Fig. 9-22. Intraductal papillary-mucinous tumor of borderline

malignancy. The long papillary folds are lined by tall columnar
epithelium showing nuclear crowding, hyperchromasia, and mild
to moderate atypia.

Fig. 9-21. Intraductal papillary mucinous adenoma. The duct

epithelium forms intraluminal folds lined by well-differentiated
mucin-rich epithelium.

Fig. 9-23. Intraductal papillary-mucinous carcinoma.

Fig. 9-24. Solid pseudopapillary tumor. A, Solid areas are composed of uniform cuboidal cells.
B, In the pseudopapillary part of the tumor, cells line or are attached to fibrovascular cores that
project into the cystic space.


vascular septa. Necrosis occurs in more than half of all tumors. In this process only the cells close to the vasculature
remain viable, which gives the tumor a pseudopapillary histologic appearance. Invasion and metastases are found in 10
percent to 20 percent of cases, most of which also show a
high degree of nuclear atypia.

classified as mucinous (Fig. 9-28), adenosquamous (Fig.

9-29), undifferentiated (Fig. 9-30), or undifferentiated with
osteoclast-like multinucleated giant cells (Fig. 9-31).
Acinar cell carcinomas are rare tumors composed of cells
that resemble acinar cells. Acinar cells may form acini and
lobules or solid sheets (Fig. 9-32).
Pancreatoblastoma is a tumor of children and adolescents.
It is composed of primitive undifferentiated cells that differentiate into epithelial and neuroendocrine cells, occasionally
arranged into organoid structures (Fig. 9-33). Other tumors
are extremely rare.

Carcinoma of the Pancreas

Carcinoma of the pancreas not otherwise specified is a term that
usually is reserved for malignant tumors that originate from
ductal epithelium. Approximately 60 percent of these tumors
are located in the head of the pancreas, 10 percent are in the
tail, and the remaining 30 percent are in the body or are diffuse (Figs. 9-25 and 9-26). Histologically most tumors are
adenocarcinomas that are graded on a scale from Ito III or
are described as well-differentiated, moderately differentiated, or poorly differentiated (Fig. 9-27). Some tumors are

Fig. 9-25. Carcinoma of the body of the pancreas. The tumor

has metastasized to the liver.

Fig. 9-26. Carcinoma of the tail of the pancreas. The tumor invades the spleen.

Fig. 9-27. Adenocarcinoma of ductal origin. A, Well-differentiated carcinoma (grade I). Columnar
hyperchromatic cells form irregular glands with a "gland within gland" and "back to back " growth
pattern. B, Moderately differentiated carcinoma. (grade II). Cuboidal cells form irregular glands
that vary in size and shape, eliciting a strong desmoplastic reaction. C, Poorly differentiated carcinoma (grade III). It is composed of a few poorly formed ducts and scattered anaplastic or signet
ringlike cells in small clusters. There is a moderate desmoplastic reaction.


Fig. 9-28. Mucinous (noncystic) carcinoma. Mucin-filled spaces

are partially lined by columnar mucin-secreting epithelium.

Fig. 9-29. Adenosquamous carcinoma. Both glandular and squamous elements are evident.

Fig. 9-30. Undifferentiated carcinoma. The tumor is composed

of pleomorphic and spindle-shaped cells.

Fig. 9-3I. Undifferentiated carcinoma. The tumor contains

numerous osteoclast-like multinucleated giant cells.

Fig. 9-32. Acinar cell carcinoma. A, Well-differentiated acinar carcinoma is composed of uniform
cells with well-developed eosinophilic cytoplasm arranged into acini or acinar tubules. B, Solid
acinar carcinoma. The tumor is composed of uniform cells that have round nuclei and welldeveloped eosinophilic cytoplasm. The cells form solid sheets.


Fig. 9-33. Pancreatoblastoma. A, The tumor is composed predominantly of primitive cells and
only occasional ductlike structures. B, The tumor is composed of duct-like and endocrine cells.


Islet cell tumors are rare neoplasms that are found in the general population at a rate of 1 per 100,000. Because the tumors
have the features of neuroendocrine cells and presumably
have the same origin as islets of Langerhans, they are referred
to as neuroendocrine tumors of the pancreas. Clinically they
are either benign or malignant. It is not possible to determine
on the basis of histology whether a particular tumor is benign or malignant, and the presence of metastases is the only
definitive sign that a tumor is malignant.
On gross examination neuroendocrine tumors appear as
well-circumscribed nodules (Fig 9-34). Some tumors are
multiple, and malignant tumors may have local metastases

Fig. 9-34. Islet cell tumor. The tumor presented as a small

mass, which was sharply demarcated from the remainder of the

in the lymph nodes or liver. Histologically, islet cell tumors

resemble neuroendocrine tumors (carcinoids) of the intestine or the bronchi and present in several patterns such as
trabecular, insular, glandular, or solid (Fig. 9-35). Some tumors are composed of endocrine and exocrine cells. In some
patients with multiple endocrine neoplasia type 1 (MEN 1),
islet cell tumors are seen only on microscopic examination
and are classified as microadenomas (Fig. 9-36).
Islet cell tumors are classified functionally according to
which hormone they produce as: (1) insulinoma; (2) glucagonoma; (3) somatostatinoma; (4) PPoma (pancreatic
polypeptidesecreting tumor); (5) gastrinoma; (6) VIPoma
(vasoactive intestinal polypeptide-secreting tumor); (7) nonfunctioning tumors; and (8) ectopic hormonesecreting tumors. By light microscopy all of these tumors have the same
features and cannot be distinguished one from another. Somatostatinomas may contain calcifications (Fig. 9-37), but

Fig. 9-35. Islet cell tumor. Uniform tumor cells with round
nuclei are arranged in solid sheets.


Fig. 9-36. Microadenoma in MEN I. The tumor cells are

arranged in a trabecular pattern.

Fig. 9-37. Somatostatinoma. The tumor has a trabecular

pattern with focal calcifications.

Fig. 9-38. Islet cell tumor. Immunohistochemically this insulinoma reacted strongly with antibodies to insulin.

this finding does not have enough specificity to allow one to

make a definitive diagnosis. Immunohistochemistry and electron microscopy are essential for diagnosis and in most cases
provide morphologic confirmation and correlation with the
clinical and biochemical laboratory data (Figs. 9-38 and
9-39). Many neuroendocrine tumors of the pancreas are,
however, composed of more than one cell population and are
i mmunohistochemically polyhormonal.

Fig. 9-39. Islet cell tumor. Immunoelectron microscopy with

antibodies to insulin proves that the tumor is an insulinoma.

refers to a group of disorders characterized
by hyperglycemia that is related to either absolute or relative
insulin deficiency. On the basis of clinical, genetic, and immunologic features diabetes is classified as (1) type 1, insulindependent diabetes mellitus (IDDM); (2) type 2, non
insulin-dependent diabetes mellitus (NIDDM); (3) diabetes
Diabetes mellitus

secondary to pancreatic disease; (4) diabetes related to overproduction of hormones that antagonize the action of insulin; and (5) gestational diabetes (Table 9-2).
Type I diabetes is characterized by an immune-mediated
injury of the islets of Langerhans. Infiltrates of T lympho -


Features of the Main Types of Diabetes Mellitus

Fig. 9-40. Type I diabetes (IDDM). Islet of Langerhans is

infiltrated with lymphocytes on the left. On the right side the
islet still contains many cells that stain brown with the
antibody to insulin.

Fig. 9-41. Type I diabetes (IDDM). The islet cells stain with
fluorescein-labeled anti-islet autoantibodies typically found in
patients with IDDM.

Fig. 9-42. Type I diabetes (IDDM). A, After 21 years of disease

this patient shows few remaining 13 cells staining with antibodies
to insulin (INS). B, There is hyperplasia of a cells staining with
antibodies to glucogen (GLU).

Fig. 9-43. Type I diabetes (IDDM). The islets have been

replaced to a great extent by fibrous tissue.


Fig. 9-44. Type 2 diabetes-(NIDDM). Amyloid deposits are

seen in the stroma of the islet.

Fig. 9-45. Chronic pancreatitis with diabetes. Fibrous tissue has

replaced the acini but has spared the islets, which appear in

Diabetes of chronic pancreatitis is related to destruction of

the pancreas, with fibrosis replacing the lost parenchyma
(Fig. 9-45). Although fibrosis preferentially replaces acini,
many islets also are destroyed and the number of f3-cells is
reduced (Fig. 9-46). The remaining islets usually form irregular clusters surrounded by fibrotic tissue, which impedes the
release of insulin into the circulation.
Further Reading

Fig. 9-46. Pancreas in advanced chronic pancreatitis. Islets with

reduced 13 cell number. (Immunostaining for insulin.)

cytes are seen in early stages of the disease (Fig. 9-40). Affected patients typically develop autoantibodies to islet cells
(Fig. 9-41). In the course of the disease the islets lose R cells,
an event that maybe accompanied by a hyperplasia of a cells
(Fig. 9-42). In some fulminant cases islets may be destroyed
(Fig. 9-43). In such cases patients survive only by receiving
daily injections of insulin.
Type 2 diabetes usually is not associated with specific insular changes. Some patients show hyalinization and/or amyloid deposition in islets (Fig. 9-44).

Klimstra DS: Pancreatoblastoma. A clinicopathologic study and review

of the literature. Am J Surg Pathol 19:1371-1389, 1995.
Kloppel G, Maillet B: Chronic pancreatitis. Evaluation of the disease.
Hepatogastroenterology 38:408-412, 1991.
Le Bodic M-F, Heyman M-F, Lecomte M et al: Immunohistochemical
study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type 1. Am J Surg Pathol 20:1378-1384, 1996.
Marshall JB: Acute pancreatitis. A review with an emphasis on new developments. Arch Intern Med 153:1185-1198, 1993.
Oertel JE: The pancreas. Nonneoplastic alterations. Am J Surg Pathol
13(suppl 1):50-65, 1989.
Pettinato G and others: Papillary cystic tumor of the pancreas. A clinicopathologic study of 20 cases with cytologic, immunohistochemical, ultrastructural and flow cytometric observations, and a
review of the literature. Am I Clin Pathol 98:478-488, 1992.
Steer ML, Waxman I, Freedman S: Chronic pancreatitis. NEngl JMed
332:1482-1490, 1995.
Steinberg W, Tenner S: Acute pancreatitis. NEngl JMed 330:1198-1210,
Talamini MA, Pitt HA, Hruban RH et al: Spectrum of cystic tumors of
the pancreas. Am )"Surg 163:117-124, 1992.
Warshaw AL, Fernandez-del Castillo C: Pancreatic carcinoma. N Engl
J Med 326:455-65, 1992.


Diseases of the endocrine glands present clinically as hypofunctional or hyperfunctional states or as space-occupying
lesions caused by neoplastic or nonneoplastic enlargement
of the glands. The hypofunction of endocrine glands may be
traced to a destruction of parenchymal cells by inflammation, circulatory disturbances, or tumors; hyperfunction may
be related to hyperplasia or neoplasia. Major endocrine
glands are interrelated, and changes in one gland may produce reactive changes in another gland.


Hypofunction of the pituitary gland maybe related to (1) agen-

esis or congenital hypoplasia; (2) circulatory disturbances;

(3) inflammatory disease caused by infections or autoimmune disorders; (4) compression or destruction of the pituitary gland or hypothalamus by space-occupying lesions such
as tumors, abscesses, or hematomas; (5) trauma, irradiation,
or surgical procedures (Fig. 10-1). Pathologic changes de -

Diagram 10-I. Primary empty sella syndrome. The pituitary is

compressed as a result of the increased cerebrospinal fluid
pressure. CSF, Cerebrospinal fluid.

Fig. 10-1. Pituitary necrosis caused by ischemia.

Fig. 10-2. Lymphocytic hypophysitis. The anterior pituitary is

infiltrated with lymphocytes.

Fig. 10-3. Craniopharyngioma. The tumor is located at the base

of the brain and consists of nests of epithelial cells. Calcifications
are prominent.

Fig. 10-4. Histiocytosis X. The pituitary gland is infiltrated with

Langerhans cells (histiocytes) and eosinophils.

1 83

pend on the primary disease, but ultimately the entire content of the sella turcica may be destroyed, resulting in the socalled empty sella syndrome. Empty sella syndrome related
to incomplete or absent sellar diaphragm is called primary
empty sella syndrome (Diagram 10-1). If the cause of empty
sella syndrome is traced to a destructive disease, it is classified as secondary.
Lymphocytic hypophysitis is thought to be an autoimmune
disease (Fig. 10-2). Granulomas may be infectious or-idiopathic, as in sarcoidosis. Tumors such as craniopharyngioma
or Langerhans cell histiocytosis (histiocytosis X) may destroy
the pituitary gland or the hypothalamus, causing hypopituitarism (Figs. 10-3 and 10-4).

Reactive Changes
Reactive changes may be seen in the pituitary gland (1) under
physiologic conditions, as in pregnancy; (2) as a result of hypofunction of other endocrine glands, as in hypothyroidism
or adrenocortical hypofunction (Addison disease); (3) as a
result of hypefunction of other endocrine glands, as in
hyperadrenocorticism; or (4) as a consequence of a drug effect. The reactive cells enlarge or decrease in size, or show
typical cytoplasmic changes such as Crooke hyaline in hyperadrenocorticism (Figs. 10-5 and 10-6).
Tumors of the pituitary gland are mostly benign and are composed of cells equivalent to those normally seen in the pituitary gland. Immunohistochemically they are classified as
prolactinomas, or as adrenocorticotropic hormone (ACTH),
growth hormone (GH), thyroid-stimulating hormone,
(TSH), or gonadotropic hormones (FSH or LH) secreting
adenomas. If the immunochemical results are negative or inconclusive, pituitary adenomas are designated null cell adenomas or unclassified adenomas. Tumors composed of oncocytic cells are called oncocytomas. The frequency of
various types of pituitary adenomas is listed in Table 10-1.

Fig. 10-5. Reactive hyperplasia of thyrotroph cells in

hypothyroidism. The enlarged thyrotroph cells are arranged into

Fig. 10-6. Crooke hyaline. In hyperadrenocorticism adrenocorticotropic cells enlarge because of an accumulation of intermediate filaments in their cytoplasm. These cytoplasmic bodies
displace the secretory granules to the subplasmalemmal
periphery of cell cytoplasm.

Frequency of Pituitary Adenomas

Adenoma Type
GH cell adenoma, densely granulated
GH cell adenoma, sparsely granulated
PRL cell adenoma, densely granulated
PRL cell adenoma, sparsely granulated
Mixed (GH cellPRL cell) adenoma
Mammosomatotroph adenoma
Acidophil stem cell adenoma
Corticotroph adenoma
Silent "corticotroph" adenoma, subtype I
Silent "corticotroph" adenoma, subtype 2
Silent adenoma, subtype 3
Thyrotroph adenoma
Gonadotroph adenoma
Null cell adenoma
Unclassified adeno


GH, Growth hormone; PRL, prolactin.

*Based on unselected surgical material involving 1910 cases.

Fig. 10-7. Pituitary adenoma. The tumor protrudes from the

sella turcica.


On the basis of their size, pituitary tumors are classified

as microadenomas (if they are smaller than 10 mm in diameter) or macroadenomas (if they are larger than 10 mm in diameter) (Figs. 10-7 and 10-8). On the basis of their morphology on routine hematoxylin-eosinstained slides,
pituitary adenomas traditionally were classified as acidophilic, basophilic, or chromophobic (Fig. 10-9). This classification did not provide useful correlates with clinical or
biochemical data, and it has been replaced by a functional
classification based on immunohistochemical and electron
microscopic typings of tumor cells (Figs. 10-10 and 10-11).
Pituitary carcinomas are rare, locally invasive tumors that
account for 2 percent to 3 percent of all pituitary neoplasms.
Histologically it is not possible to distinguish with confidence
adenomas from carcinomas, except in rare cases in which the
malignant tumor is highly anaplastic.

Fig. 10-8. Pituitary adenoma. On cross section the tumor

nodule is sharply demarcated from the normal pituitary.

Fig. 10-9. Pituitary adenomas A, Acidophilic. B, Basophilic. C, Chromophobic.


Fig. 10-10. Prolactin cell adenoma. A, Small tumor cells are staining with antibody to prolactin.
B, By electron microscopy the tumor cells show extrusion of small granules at the lateral cell
membranes ("misplaced exocytosis").


Fig. 10-I I. Corticotroph adenoma. A, ACTH-positive tumor cells form solid nests.
B, By electron microscopy the tumor cells contain 250 to 450 nm granules.


Disorders of thyroid function are commonly diagnosed in
clinical practice. Hypothyroidism or hyperthyroidism may
be associated with distinct morphologic changes, but in most
instances it is not possible to predict functional thyroid abnormalities from the morphologic data alone.

Thyroid Hyperplasia
Hyperplasia typically causes enlargement of the thyroid
gland (goiter), which may be either nodular or diffuse. Hyperplasia of the thyroid gland may result from hyperstimulation by (1) TSH, (2) antibodies to TSH receptor, (3) iodine
deficiency, (4) goitrogens in food, or (5) drugs.
Idiopathic nodular goiter is the most common cause of thyroid enlargement, affecting 3 percent to 5 percent of the population at large. In one form or another it is found in ap-

proximately 50 percent of autopsies in adults. It presents as

a mass that causes enlargement of the thyroid gland without
hormonal abnormalities. The thyroid gland is asymmetrically nodular and may compress surrounding structures (Fig.
10-12). Histologically it is composed of colloid-filled follicles
that vary in size and shape. Follicles are lined by cuboidal or
flattened epithelium, which may show focal papillary hyperplasia (Fig. 10-12). Secondary degenerative changes are
common and include fibrosis, hyalinization, calcification,
foci of hemorrhage, cholesterol crystals, and cystic degeneration. Foci of secondary proliferation composed of cells arranged in a microfollicular or solid pattern may be seen in
some nodules, which otherwise are composed only of large
dilated follicles. Some nodules may acquire adenoma-like
properties, but in general nodular goiter is not a direct precursor of thyroid cancer.

Fig. 10-12. Nodular goiter. A, The thyroid gland is enlarged and consists of nodules that vary in
size and shape. B, The thyroid gland is composed of follicles arranged into clusters, imparting a
nodular appearance to the gland. Foci of hemorrhage and chronic inflammation are present.

18 6


Fig. 10-13. Graves disease. A, The thyroid gland is symmetrically enlarged. B, On cut section the
thyroid gland appears moist and hyperemic and lacks normal colloidal appearance.

Graves disease is an autoimmune disorder caused by stim-

ulation of the thyroid gland by antibodies to the receptor for

TSH (Diagram 10-2). The thyroid gland is diffusely enlarged,
and on cross section it appears hyperemic, moist, and soft
(Fig. 10-13, B). Histologically the follicles are lined by hyperplastic, tall columnar, vacuolated cells with basally located
nuclei. The epithelium often projects into the lumen of follicles in the form of small papillary infoldings. Oncocytic
changes may be evident but usually are not prevalent. The
colloid is pale and often shows peripheral scalloping (Fig.
10-14). The stroma is vascular and mildly fibrotic and may
contain lymphoid cell aggregates.


Diagram I0-2. Pathophysiologic mechanism of Graves disease.

A defect in suppressor T-lymphocytes is responsible for the
excessive production of autoantibodies to TSH receptor causing
enlargement of the thyroid gland and excessive production of
triiodothyronine (T 3 ) and thyroxine (T 4). The excess of T 3 and
T4 results in the suppression of thyrotropin-releasing hormone
(TRH) and thyroid-stimulating hormone (TSH) production.

Nonspecific lymphocytic thyroiditis is a disease of no clinical

significance, commonly diagnosed at autopsy (Fig. 10-15).
Other forms of thyroiditis that may cause clinical symptoms
are less common but may be associated with specific clinical
symptoms (Table 10-2).
Subacute thyroiditis, also known as granulomatous or
de Quervain thyroiditis, is characterized by painful enlargement of the thyroid gland, low-grade fever, and hyperthyroidism of sudden onset, usually following a viral infection.
Histologically it is characterized by a granulomatous giant
cell and lymphocytic reaction around the colloid released
from ruptured follicles. (Fig. 10-16).
Hashimoto thyroiditis is an autoimmune thyroid disease
that may occur either in an isolated form or conjointly with
other autoinunune diseases such as atrophic gastritis or primary biliary cirrhosis. It most often occurs in women, and
the female-male ratio is 8:1. Most patients initially are euthyroid, but as destruction of the thyroid gland advances they
may develop signs of hypothyroidism. Occasionally there is


Fig. I0-14. Graves disease. A, Follicles are lined by tall columnar epithelium. The colloid adjacent
to the epithelium appears vacuolated and scalloped. Some follicles contain very little colloid.
B, Marked hyperplasia of the epithelium is seen, and the follicles contain almost no colloid. The
stroma contains lymphocytes.

Fig. 10-15. Nonspecific lymphocytic thyroiditis. The thyroid

gland is infiltrated focally with lymphocytes and plasma cells. The
follicular epithelium shows no significant changes.

hyperthyroidism ( " hashitoxicosis"). The thyroid gland typically is enlarged to three or four times its normal size (Fig.
10-17). Histologically the gland is infiltrated with lymphocytes and plasma cells, which form lymphoid follicles with
germinal centers. Thyroid follicles are destroyed and replaced
in part by the infiltrate. The remaining follicles are atrophic
and often devoid of colloid. Widespread oncocytic change
(i.e., transformation of epithelium into cuboidal cells with
mitochondria-rich, eosinophilic, granular cytoplasm) is typical. Other epithelial changes such as nodular hyperplasia or
squamous metaplasia are less common. Hashimoto thyroiditis is associated with an increased risk for lymphoma.
Several histologic and clinical variants of Hashimoto thyroiditis have been recognized. The most common is the fibrous variant, which accounts for 10 percent of cases (Fig.

Fig. 10-16. Subacute granulomatous thyroiditis. Multinucleated

giant cells surround residual colloid in a follicle.

Forms of Thyroiditis
Type of Thyroi
Nonspecific lymphocytic
Acute bacterial
Subacute (granulomatous)


Clinical Features
Common finding at autopsy;
Rare; related to head and neck
infections, sepsis, or surgery
Rare; probably related to viral disease;
sudden onset of painful swelling
Clinically the most important
autoimmune thyroiditis; leads to
hypothyroidism but often euthyroid;
"hashitoxicosis" rare
Rare; fibrosing destruction of thyroid
extending into adjacent tissue
("ligneous" thyroiditis)


Fig. 10-17. Hashimoto thyroiditis. A, The enlarged thyroid has a multinodular, whitish
appearance, which stems from lymphoid infiltrates and loss of colloid-filled follicles. B, A lymphoid
follicle with a germinal center and diffuse lymphocytic infiltrates replace the thyroid follicles. The
epithelium of the remaining follicles shows oncocytic transformation. C, Thyroid follicles devoid
of colloid are lined by oncocytic cells that have eosinophilic granular cytoplasm and round
vesicular nuclei.

10-18). It is characterized by fibrosis and prominent hypothyroidism, even though the thyroid gland is enlarged. Atrophic thyroiditis (idiopathic myxedema) is characterized by
a loss of follicles and atrophy of the gland, and although its
etiology is not known this disease might represent an outcome of Hashimoto disease. Juvenile thyroiditis is a variant
that occurs in children and young women. In contrast to
classic Hashimoto thyroiditis, the epithelium does not show
oncocytic changes but may be hyperplastic. Closely related
to it is the so-called painless thyroiditis, also known as silent
thyroiditis or self-resolving lymphocytic thyroiditis with hyperthyroidism. Histologically it may present as lymphocytic
or granulomatous inflammation but without multinucleated
giant cells. The epithelium shows either oncocytic or hyperplastic changes.
Riedel thyroiditis, also known as invasive fibrous thyroiditis, is a rare cause of hypothyroidism that is characterized by extensive fibrosis, which replaces most of the thyroid
parenchyma and extends into adjacent neck structures. The
process may be focal or diffuse. Histologically, collagenous
bands are found replacing thyroid follicles. The remaining
follicles are atrophic. Lymphocytes and plasma cells are
found between the strands of connective tissue, around the
blood vessels, and typically in the walls of small veins (Fig.

Benign Thyroid Tumors

Most thyroid tumors are of epithelial origin; a minority arise
from stromal cells or lymphoid tissue. Benign tumors are
more common than malignant tumors, which, however, present a more formidable challenge from both the diagnostic
and the therapeutic point of view.
Follicular adenoma is a benign encapsulated tumor that
shows evidence of follicular differentiation (Figs. 10-20 and
10-21). It presents as a solitary " cold" nodule on isotopic
scanning with radioactive iodine - and is surrounded by
normal or compressed thyroid follicles. It should not be confused with nodular hyperplasia, which typically produces
multiple nodules. Microscopically the tumor may present in
one of several patterns and is classified as trabecular, solid
(embryonal), microfollicular (fetal), normofollicular
(simple), or macrofollicular (colloid) adenoma. These descriptive terms have no biologic or clinical implications. Hyperplastic changes in the form of papillary or pseudopapillary structures may occur (Fig. 10-22).
Variants of follicular adenoma that deserve additional
studies are (1) atypical follicular adenoma; (2) hyalinized
trabecular adenoma; (3) adenoma with bizarre nuclei; and
(4) oncocytic (HUrthle cell) adenoma. Atypical follicular adenomas show less regular architectural and cytologic features
than typical adenomas. Hyalinized trabecular adenoma shows


Fig. 10-18. Fibrous variant of Hashimoto thyroiditis. Fibrous

tissue infiltrated with lymphocytes is replacing the follicles, few
of which remain.

Fig. 10-19. Riedel thyroiditis. Diffuse fibrosis and inflammatory

cells such as lymphocytes and plasma cells have replaced the
thyroid follicles. A medium-sized vein shows signs of vasculitis

Fig. 10-20. Follicular adenoma. The well-circumscribed nodule

has a fibrous capsule separating it from the normal parenchyma.
On cross section the tumor appears yellow-tan with focal

Fig. 10-22. Follicular adenoma with papillary hyperplasia. Short

papillary projections lined by follicular cells have almost no
fibrovascular cores.

Fig. 10-21. Follicular adenoma, microfollicular pattern. Tumor

cells form small follicles.


Fig. 10-23. Follicular adenomas, hyalinizing trabecular pattern.

Tumor cells are arranged into nests reminiscent of the
"Zellballen" of paraganglioma.

Fig. 10-24. Follicular adenoma with bizarre nuclei. Clusters of

cells with huge, irregularly shaped nuclei are admixed with
smaller cells that have a solid growth pattern.

prominent perivascular hyalinization and collagenous

strands that subdivide the parenchyma into trabeculae or
solid nests reminiscent of " Zellballen" of paragangliomas
(Fig. 10-23). Adenoma with bizarre nuclei is characterized by
clusters of cells that have gigantic hyperchromatic nuclei
(Fig. 10-24). Oncocytic (Hurthle cell) adenoma consists of
solid nests of cuboidal cells that have round uniform nuclei
and eosinophilic granular or clear cytoplasm (Fig. 10-25).

Malignant Thyroid Tumors

Fig. 10-25. Hurthle cell adenoma. Tumor cells arranged into

solid sheets have abundant eosinophilic cytoplasm, large nuclei,
and prominent nucleoli.

Malignant thyroid tumors include carcinomas, sarcomas,

and lymphomas. The salient features of carcinomas, which
account for the vast majority of tumors, are given in Table
Papillary carcinoma is the most common malignant
tumor of the thyroid gland. It occurs more often in women
than in men, with a ratio of 2.5:1. It may occur at any age,

Natural History of Different Types of Thyroid Carcinoma Arising from Follicular Cells


Fig. 10-26. Papillary carcinoma. This large tumor, which almost

completely replaces one thyroid lobe, appears solid with some
unevenness on cross section.

Fig. 10-27. Papillary carcinoma. Tumor cells line branching

papillae. Numerous blue-stained psammoma bodies are seen in
the connective tissue stroma.

Fig. 10-28. Papillary carcinoma. Tumor cell nuclei have a clear

"ground glass appearance.

but the mean age of patients at diagnosis is 35 to 40 years.

The size of the tumor varies from microscopic to several centimeters in diameter, with the mean being 2.5 cm. It may be
solid or cystic, and multicentric foci are seen in 20 percent of
cases on gross examination (Fig. 10-26).
The microscopic diagnosis of papillary carcinoma is made
on the basis of architectural features, such as papillae, and
nuclear features, such as optically clear nuclei ( "ground glass"
or "Orphan Annie " nuclei), or nuclear pseudoinclusions and
grooves (Figs. 10-27 and 10-28). In addition to papillary proliferation, almost all tumors also show a follicular component. Metastases to local lymph nodes are common.

Fig. 10-29. Papillary carcinoma, follicular variant. Cuboidal

tumor cells with clear cytoplasm line colloid-filled spaces. Wide
fibrous strands incompletely divide the tumor into lobules.

Variants of papillary carcinoma include (1) papillary microcarcinoma, (2) encapsulated variant, (3) follicular
variant, (4) diffuse sclerosing variant, (5) tall cell variant, and
(6) columnar cell variant (Figs. 10-29 to 10-31).
Follicular carcinoma is a tumor composed of neoplastic
cells that form follicles. It occurs more often in women than
in men, and the average age at diagnosis is 10 years more than


Fig. 10-30. Papillary carcinoma, solid growth pattern. The tumor

has a predominantly solid pattern.

Fig. 10-31. Papillary carcinoma, diffuse sclerosing variant. The

tumor contains prominent connective tissue strands infiltrated
with lymphocytes and psammoma bodies. Papillae lined by
tumor cells project into the lumen of endothelium-lined spaces.

Fig. 10-32. Follicular carcinoma, minimally invasive type. On

gross examination this tumor appears well circumscribed.

Fig. 10-33. Follicular carcinoma, minimally invasive type. The

neoplastic cells extend across the full thickness of the capsule into
the normal parenchyma.

Fig. 10-34. Follicular carcinoma, widely invasive type. Tumor

cells form irregular, almost solid sheets.

Fig. 10-35. Follicular carcinoma. Follicles are lined by cells that

have clear cytoplasm.

1 93

Fig. 10-36. Oncocytic (Hiirthle cell) carcinoma. This encapsulated tumor has a tan color with central areas of necrosis and

Fig. 10-37. Oncocytic carcinoma. Tumor cells invade capsular


for papillary carcinomas (i.e., 45 to 50 years). Two subtypes

are recognized: a minimally invasive or encapsulated form
and a widely invasive form. Minimally invasive follicular carcinoma grows as an encapsulated nodule that usually exceeds
1 cm in diameter (Fig. 10-32). Histologically it resembles follicular adenoma, especially the embryonal, fetal, and atypical
types. Tumor cells penetrate the capsule and extend into the
surrounding thyroid tissue (Fig. 10-33). Widely invasive follicular carcinoma usually is not encapsulated but shows
widespread invasion of the adjacent thyroid parenchyma and
blood vessels. A solid or trabecular growth pattern is seen
(Fig. 10-34). Nuclear atypia, hyperchromasia, numerous mitoses, and areas of necrosis are prominent. Clear cell change
may occur focally but also may be widespread (Fig. 10-35).
Metastases, which usually are blood borne, most often are
seen in the lungs and bones.

Oncocytic carcinomas are more aggressive than classic follicular carcinomas and are thus a distinct entity. They may
be encapsulated, but they also may invade the adjacent
parenchyma, usually in a multinodular manner (Fig. 10-36).
Histologically the tumors are composed of oncocytic cells arranged in a follicular pattern (Fig 10-37). Rarely, some tumors show a trabecular pattern, and a papillary pattern is
even more rare.
Medullary carcinoma is composed of cells that show differentiation into C cells. These tumors occur in sporadic and
familial forms in the context of multiple endocrine neoplasia
( MEN) syndromes types 2A and 2B. They account for 10 percent of all thyroid malignancies (Table 10-4). Medullary carcinomas range in size; they may be barely visible or may replace the entire thyroid. The larger lesions are sharply
circumscribed but not encapsulated (Fig. 10-38). Individual

Type 2 Multiple Endocrine Neoplasia (MEN) Syndromes*

*Rarely, familial forms of medullary carcinoma may occur in the absence of other endocrine abnormalities.
tin a small number of families, type MEN 2A has occurred in association with hereditary cutaneous lichen amyloidosis.


Fig. 10-38. Medullary carcinoma. The thyroid gland contains

well-demarcated tan nodules.

Fig. 10-39. Medullary carcinoma. Groups of cells form lobules,

which are surrounded by stroma containing deposits of amyloid
that stain red with Congo red.

Fig. 10-40. Medullary carcinoma. A, Solid growth pattern. B, Lobular growth pattern.

tumor cells may be round, polygonal, oval, or spindleshaped. The stroma is abundant and typically contains amyloid (Fig. 10-39). Histologically the tumor may have a solid,
lobular, or insular growth pattern (Figs. 10-40).
Variants of medullary carcinoma include (1) follicular
or tubular, (2) papillary, (3) pseudopapillary, (4) small cell,
(5) giant cell, (6) oncocytic, (7) clear cell, (8) melanocytic,
(9) squamous, and (10) amphicrine types (Fig. 10-41).
Undifferentiated (anaplastic) carcinomas are rare, accounting for 10 percent to 25 percent of thyroid malignancies. These
tumors typically occur in old age and are as common in
women as in men. They present as a rapidly enlarging mass,
with broad areas of necrosis that invade the surrounding neck
structures. Histologically they show three distinct patterns
known as spindle cell, giant cell, and squamoid. These different cell types often are intermixed (Fig. 10-42). Cellular
pleomorphism, high mitotic activity, areas of necrosis, and in-

vasion into adjacent structures typically are found. These tumors grow fast, metastasize widely, and have a poor prognosis.
Poorly differentiated carcinoma is a recently described type
of thyroid cancer that occupies an intermediate position between well-differentiated follicular and papillary carcinomas
and undifferentiated (anaplastic) carcinomas. Histologically
these tumors show a solid trabecular or microfollicular pattern (Fig. 10-43). Solid nests tend to retract from the connective tissue stroma, imparting an " insular" pattern. As a result of widespread necrosis that spares only the perivascular
cells, a "peritheliomatous " pattern may be prominent. In
most cases these tumors represent poorly differentiated follicular carcinomas, but occasionally they may arise from papillary carcinomas. Immunohistochemically the tumors are
positive for thyroglobulin and keratin and negative for calcitonin, which distinguishes them from medullary carcinoma. Metastases are common and occur hematogenously.


Fig. 10-41. Medullary carcinoma. A, Follicular variant. B, Small cell variant.

Fig. 10-42. Undifferentiated carcinoma. The tumor is composed

of spindle-shaped and giant cells.


Hypoparathyroidism is a rare disease that most often is related to inadvertent removal of the parathyroid glands
during neck surgery or radiotherapy. Other causes include
genetic diseases such as DiGeorge syndrome, metabolic disorders that destroy the parathyroid glands such as hemochromatosis, and pluriglandular endocrine autoimmune
Hyperparathyroidism is classified clinically as primary if
the cause lies primarily in the parathyroid glands or secondary if the cause is outside the parathyroid glands. In the
latter case the glands become hyperfunctioning in response
to the altered homeostasis of calcium and phosphate caused

Fig. 10-43. Poorly differentiated carcinoma. The neoplastic cells

form solid nests surrounded by connective tissue stroma that
shows artificial retraction from tumor nests.

by a kidney, bone, or intestinal diseases (Diagrams 10-3 and

Parathyroid hyperplasia, whether primary or secondary,
shows the same morphologic changes. All four glands are enlarged, although not to the same extent (Fig. 10-44). Histologically the glands are composed of a mixture of chief,
oxyphil, and transitional oxyphil cells arranged into cords,
sheets, and follicles (Fig. 10-45). Hyperplastic glands composed exclusively of clear cells rarely are found but usually
are associated with severe hypercalcemia.
Parathyroid adenoma usually presents in the form of
nodular enlargement of one parathyroid gland while the
other three glands are of normal size (Fig. 10-46). Histologically most parathyroid adenomas are composed of chief cells


Diagram I0-3. Control of calcium metabolism. Parathyroid

hormone (PTH) acts primarily on the bone and kidneys,
whereas vitamin D (D) metabolites act on the intestines, bone,
and parathyroid glands. Calcium-ion concentration acts on the
parathyroid glands and the thyroid C cells. In humans calcitonin
appears to play a relatively insignificant role in the rapid
regulation of calcium metabolism. All effects of PTH and vitamin
D (+) tend to elevate the ionic serum calcium, and such
elevation results in a negative feedback on PTH. Calcitonin acts
in opposition to PTH in most experimental conditions.

Diagram I 0-4. Human calcium balance in a young adult in

calcium balance. Of the total dietary calcium 200 mg per day is
actually absorbed and excreted through the kidneys and sweat
glands. The bone exchange is 640 mg per day.

Fig. 10-45. Parathyroid hyperplasia. Indistinct nodules

composed of chief and oxyphil cells are surrounded by loose
connective tissue stroma. Only a few fat cells remain inside the

Parathyroid carcinoma is a rare tumor, accounting for 1

Fig. 10-44. Parathyroid hyperplasia. All four glands are enlarged,
albeit not to the same extent.

that form solid sheets, nests, or acini (Fig. 10-47). Adenomas

of oxyphil cells are less common. Nuclei of tumor cells usually are of normal size and uniform, but in 10 percent of adenomas there are multinucleated cells and even giant cells (Fig.

percent to 2 percent of all cases of primary hyperparathyroidism. The tumor has an invasive growth pattern and tends
to metastasize. Histologically it is composed of cells that resemble watermelon seeds arranged into solid sheets rimmed
by thick ocellular fibrous bands (Fig. 10-49). Cells tend to be
uniform. The presence of nuclear atypia, variation, and giant
cells speaks against the diagnosis of malignancy; such cellular
changes more often are found in adenomas than in carcinomas of the parathyroid glands.


Fig. 10-47. Parathyroid adenoma. The tumor is composed

almost entirely of chief cells arranged into uniform sheets, cords,
and pseudofollicles, which are best seen in the left lower portion
of the photograph.

Fig. 10-46. Parathyroid adenoma. The enlarged gland (3 X 2.5 cm)

is teardrop-shaped, nodular, and yellow-tan beneath its thin translucent capsule.

Fig. I 0-48. Parathyroid adenoma. Tumor cell nuclei vary in size and

Fig. 10-49. Parathyroid carcinoma. A, Solid sheets of tumor cells are traversed by thick fibrous
septa, as seen in this trichrome-stained specimen. B, Large watermelon-shaped cells have regular
nuclei. Cells show palisading around a centrally placed vessel.



Adrenocortical Insufficiency
Insufficiency or hypofunction of the adrenal cortex may be
diagnosed in any age group and may be related to (1) congenital disorders, such as congenital adrenal hypoplasia,
familial glucocorticoid deficiency, or adrenoleukodystrophy;
(2) deposition of amyloid in amyloidosis or hemosiderin in
hemochromatosis; (3) circulatory disorders such as massive
bilateral hemorrhage in Waterhouse-Friderichsen syndrome; (4) infections, such as tuberculosis, histoplasmosis,
and viral infections with cytomegalovirus (CMV), herpes
simplex, or varicella-zoster virus; (5) autoimmune
adrenalitis, which may be limited to the adrenal glands or
may be part of a pluriglandular syndrome. Schmidt syndrome, which includes adrenocortical insufficiency and hypothyroidism, probably is such an autoimmune disease. If no
obvious causes are found, adrenocortical insufficiency is designated idiopathic Addison disease.

Fig. 10-50. Adrenoleukodystrophy. The cytoplasm of large

ballooned cortical cells contains cleftlike spaces caused by
extraction of lipid.

Fig. 10-52. CMV infection. Adrenal cells appear enlarged and

contain viral inclusions. Infection is associated with necrosis.

Adrenoleukodystrophy is an inborn defect of metabolism

of fatty acids that affects peroxisomes. Three clinical forms
are recognized: infantile, juvenile (childhood onset), and
adult. Adrenocortical insufficiency accompanies the more
prominent central nervous system symptoms. The adrenal
glands are small, but the cortical cells appear enlarged and
have a striated or ballooned cytoplasm (Fig. 10-50). Lipid accumulation is thought to have cytotoxic defects in both the
adrenal glands and the brain.
Amyloidosis is a rare cause of adrenocortical insufficiency.
Amyloid deposits are found in the sinusoids and in the walls
of larger blood vessels. Amyloid deposits cause atrophy of
adrenal cells, and ultimately the entire gland may be replaced
by amyloid (Fig. 10-51). Such deposits usually are found in
secondary amyloidosis and represent AA amyloid.

Fig. 10-51. Amyloidosis. Eosinophilic hyaline material has

replaced most of the cortical cells.

Fig. 10-53. Histoplasmosis. Histiocytes filled with round to oval

structures are found between adrenocortical cells.


Infectious adrenalitis caused by bacteria, viruses, or fungi

is accompanied by adrenocortical cell loss. CMV has a distinct tropism for adrenocortical cells, and adrenal involvement is found in 50 percent of patients with acquired immunodeficiency syndrome (AIDS) (Fig. 10-52). In systemic
histoplasmosis the adrenal glands often are involved (Fig.
10-53). In severe cases the entire adrenal gland may be destroyed. In tuberculosis the gland is replaced to a large extent
by caseating granulomas, and in advanced stages it often is
accompanied by calcifications (Fig. 10-54).
Immune-mediated adrenalitis is currently the most
common cause of adrenal inflammation. The adrenal glands
are infiltrated with lymphocytes that destroy the adrenocortical cells until no cortex remains (Fig. 10-55). In chronic
stages of Addison disease the adrenal glands have almost no
cortex and are reduced to only the medulla.

Fig. 10-54. Tuberculosis. Caseating granulomas are partially

replacing the parenchyma of the adrenal gland.

Fig. 10-55. Autoimmune adrenalitis. A, Adrenal gland is infiltrated with lymphocytes arranged
into a follicle. B, Most of the cortex has been destroyed.

Adrenocortical Hyperplasia and

Hyperfunction of the adrenal cortex may present as several
clinical syndromes: (1) hyperaldosteronism (Conn syndrome),
(2) hypercortisolism (Cushing syndrome), or (3) adrenogenital syndrome. Hypercortisolism is considered primary if it
is caused by adrenocortical hyperplasia or neoplasia; secondary hyperplasia develops as a result of overstimulation of
the adrenal cortex by the pituitary gland or ACTH-secreting
tumors (Diagram 10-5).

Adrenocortical hyperplasia may be diffuse or nodular

(Figs. 10-56 and 10-57). In typical Cushing disease caused by
an ACTH-secreting pituitary adenoma, the cortex is thicker
than 2 mm because of an increase in the thickness of the zona
fasciculata (Fig. 10-58).Adrenocortical cells of the inner zona
fasciculata have eosinophilic cytoplasm as a result of the conversion of lipid-rich cells to more compact lipid-depleted
cells. Hyperplastic cells may extend into periadrenal fat,
forming microscopic nodules. Macronodular hyperplasia
rarely occurs. Macronodular hyperplasia more often is a sign


Fig. 10-56. Diffuse adrenocortical hyperplasia.

Fig. I 0-57. Nodular adrenocortical hyperplasia on cross section.

The adrenal gland shows several yellow nodules that measure up
to I cm in diameter.

Fig. I0-58. Adrenocortical hyperplasia in Cushing disease. The

cortex appears thickened. The zona fasciculata consists of clear
and lipid-depleted compact cells.

Fig. I0-59. Macronodular hyperplasia of adrenal in Cushing

syndrome. The nodules are composed of pale lipid-rich cells.

Fig. 10-60. Primary pigmented nodular adrenocortical disease

(PPNAD). The adrenal contains darkly pigmented nodules.

Fig. 10-6I. PPNAD. Adrenal cells have eosinophilic cytoplasm

that is rich in lipofuscin (brown). There also is an area of lipomatous metaplasia.


Ectopic ACTH (or CRF) Syndrome

Diagram 10-5. A, Pituitary-dependent form of hypercortisolism (Cushing disease) is usually
caused by an ACTH-producing microadenoma of the pituitary gland. ACTH levels may be in the
normal range or only mildly elevated. B, Autonomous secretion of cortisol by an adrenocortical
neoplasm. ACTH levels tend to be very low or undetectable. C, With ectopic secretion of ACTH
(or rarely corticotropin-releasing factor) levels of circulating ACTH typically are higher than in
Cushing disease and sometimes are greatly elevated. Some tumors may secrete corticotropinreleasing factor (CRF)

of primary adrenal disease in which the Cushing syndrome

is caused by autonomous hyperfunction of adrenocortical
cells (Fig. 10-59).
Primary pigmented nodular adrenocortical disease
(PPNAD) is a rare ACTH-independent hypercortisolism.
PPNAD is a descriptive term that has no particular reference
to underlying pathogenesis. The adrenal glands are enlarged
and show pigmented nodules on their surface and on cross
section (Fig. 10-60). Histologically the micronodules appear
to reside in the zona reticularis and may encroach slightly on
the medulla (Fig. 10-61). Most of the cells in these nodules
have compact eosinophilic cytoplasm and contain variable
amounts of lipochrome pigment.

Adrenocortical Tumors
Adrenocortical tumors are classified as benign (adenomas)
or malignant (carcinomas). These tumors may secrete one
or more hormones and are classified clinically as inactive or
active. Hormone-producing tumors may be associated with
typical adrenocortical syndrome (Cushing, Conn, or adrenogenital syndrome) or with generalized adrenocortical hyperfunction that combines some features of all three syndromes.
Adenomas are benign, sharply circumscribed nodules that
are attached to the adrenal gland or more often completely
replace it. Tumors removed from patients with Cushing syndrome usually weigh less than 50 g and measure 3 to 4 cm in
diameter (Fig. 10-62). On cross section most tumors are

Fig. 10-62. Adrenal adenoma on cross section. The tumor appears deep orange with tan-brown geographic areas composed
of lipid-depleted cells that are rich in lipofuscin.

Fig. 10-63. Adrenal adenoma. The tumor is composed of pale

li pid-rich cells.


yellow, but some are brown and may have a variegated appearance. Histologically they are composed of pale lipidladen cells resembling those of normal zona fasciculata (Fig.
10-63). Aldosterone-secreting adenomas of Conn syndromes usually are small intraadrenal nodules that measure
less than 3 cm in diameter (Fig. 10-64). On cross section these
tumors are homogeneously yellow-orange or canary-yellow,
but larger tumors may show degenerative changes. Histologically they are composed of alveolar ducts, short cords, or
anastomosing trabeculae (Fig. 10-65). Cells may have clear
or granular eosinophilic cytoplasm, and occasional intranuclear pseudoinclusions are seen. Nuclei are round and uniform, but sometimes there is considerable nuclear variation.

Fig. 10-65. Aldosterone-producing adrenocortical adenoma.

The tumor is composed of cortical cells that have granular cytoplasm. Spironolactone bodies appear as round cytoplasmic
inclusions. Inset shows spironolactone bodies stained with Luxol
fast blue.

Fig. 10-64. Aldosterone-producing adrenocortical adenoma.

The tumor is yellow-orange and sharply circumscribed.

Fig. 10-66. Adrenocortical carcinoma resected from a teenaged girl with virilization. The tumor weighs more than 1000 g,
and on cross section it is coarsely nodular with extensive areas
of necrosis.

Fig. 10-67. Adrenocortical carcinoma. A, Histologically the tumor is composed of cells arranged
into broad trabeculae. B, Tumor cells have voluminous compact eosinophilic cytoplasm and large
pleomorphic nuclei with prominent pseudoinclusions.


Some tumor cells contain round cytoplasmic bodies that are

known as spironolactone bodies. The histologic appearances
may vary from one microscopic field to another.
Adrenocortical carcinomas are rare malignant tumors that
occur at a rate of 2 per million. These tumors may be found
in any age group, and functionally they are either active or
inactive. Tumors vary in size, typically measuring over 12 cm
in diameter and weighing on average 1000 g (Fig. 10-66).
Areas of necrosis, cystic degeneration, hemorrhage, and invasion of adjacent tissues are apparent in large tumors,,Histologically the cells show considerable pleomorphism, and
atypical mitoses may be seen (Fig. 10-67). Growth patterns
have been described as trabecular, alveolar, or diffuse.
There are no reliable differences between adrenocortical
adenomas and carcinomas. Empiric data indicate that in
adults most tumors that weigh less than 50 g are benign,
whereas those that weigh more than 95 g tend to be malignant. On microscopic examination the following features
are most predictive of malignancy: (1) broad fibrous bands,
(2) diffuse growth pattern, (3) vascular invasion, (4) mitotic
rate greater than 5 per 50 high-power fields, and (5) atypical
mitoses. In a small but significant number of cases, it is not
possible to predict the biologic behavior of tumors, most of
which weigh between 100 and 400 g. Adrenocortical carcinomas are highly malignant tumors that metastasize through
the lymphatics or hematogenously. In most cases they cause
death within 12 months of diagnosis.


Hyperplasia of adrenal medullary cells is seen most convincingly in patients with MEN syndrome type 2 (Fig. 10-68). It
also occurs in Beckwith-Wiedemann syndrome and in some
patients with paroxysmal attacks of hypertension that are
suggestive of pheochromocytoma. The distinction between

Fig. I0-68. Adrenal medullary hyperplasia. There is nodular

expansion of the medulla.

hyperplasia and small pheochromocytomas is, however, arbitrary. By convention most nodules larger than 1 cm in diameter are considered to represent true neoplasms.
Pheochromocytoma is a tumor composed of cells that resemble normal adrenal medullary cells. Pheochromocytomas occur in the general population at a rate of 8 per
million. As a general rule, 90 percent of tumors are functional, causing hypertension, and 10 percent are nonfunctional; 90 percent are located in the adrenal, and 10 percent
are located in sympathetic ganglia; 90 percent are unilateral
and 10 percent are bilateral; 90 percent are benign and 10
percent are malignant. On gross examination the tumors are
sharply circumscribed, grayish or brownish-tan nodules that
may resemble adrenocortical neoplasms (Fig. 10-69). Most
surgically resected tumors weigh approximately 100 g and
measure 3 to 5 cm in diameter. On cross section they appear
grayish or dusky red. Degenerative changes such as fibrosis,
necrosis, cystic degeneration, and hemorrhage are seen in
larger tumors. Invasive growth is a feature of malignant
types. Histologically three major architectural patterns are
seen: (1) trabecular, in which cells form anastomosing cords;
(2) alveolar, in which groups of cells are surrounded by connective tissue septa; and (3) diffuse, in which cells grow in
solid sheets (Fig. 10-70). A spindle cell pattern occasionally
is seen.
Individual tumor cells are polygonal with a lightly
eosinophilic granular cytoplasm. The cytoplasm of tumor
cells may be lavender, resembling normal medullary chromaffin cells. Nuclei are round and vesicular. In larger tumors
there is considerable nuclear variation and pseudoinclusions,
but this should not be considered a sign of malignancy. Intracytoplasmic hyaline globules are found in 45 percent of
pheochromocytomas. Such globules are periodic acidSchiff
positive and diastase resistant. By electron microscopy tumor
cells contain typical neurosecretory granules (Fig. 10-71).

Fig. 10-69. Pheochromocytoma. The cross-sectioned surface of

this encapsulated tumor appears grayish or red because of areas
of congestion and hemorrhage.

20 4

Fig. 10-70. Pheochromocytoma. A, Trabecular pattern. Tumor cells form anastomosing cords
partially surrounded by fibrous septa. B, Diffuse pattern. Cells form solid sheets. Their lavender
cytoplasm contains fine pinpoint granules. C, A few tumor cells have unclear pseudoinclusions,
which are intranuclear invaginations of the cytoplasm.

Fig. 10-71. Pheochromocytoma. A, By electron microscopy tumor cell cytoplasm contains

numerous dense granules. B, Dense-core neurosecretory granules vary in size and shape.
Norepinephrine is stored in granules that have an eccentric dense core surrounded by a wide halo
(straight arrow). Epinephrine is stored in granules that appear more symmetric, lacking the wide
halo around the dense core (curved arrow).


Scattered neuronal or ganglion cells often are present, and

approximately 5 percent of tumors have composite features
of pheochromocytoma, neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. Pheochromocytomas are sporadic in 90 percent of cases, but 10 percent occur in the context of MEN 2A or 2B conjointly with medullary carcinoma
of the thyroid gland. Patients with MEN 2B have typical oral
neuromatous nodules (Fig. 10-72).
Neuroblastoma is a tumor of neural crestderived neuroblastic precursors of adrenal medullary cells and sympathetic
ganglia. It is the most common malignancy in infants under
the age of one year, with an incidence of 9.6 per million. The
tumor presents as a partially encapsulated, soft ("encephaloid" ) adrenal mass that often invades the surrounding tissues (Fig. 10-73). On cross section the tumor is lobulated and
shows prominent areas of necrosis and hemorrhage. Metastases through the lymphatics or blood vessels are common,

Fig. 10-72. MEN 2B. The tongue is studded with neuromatous


Fig. 10-73. Neuroblastoma. The bisected tumor attached to the kidney appears lobulated
and blood-stained.

Fig. 10-74. Neuroblastoma. The tumor is composed of sheets of

closely packed cells that have very little cytoplasm. Pale fibrillar
areas are composed of neuritic processes.


Fig. 10-75. Neuroblastoma. A, Nests of small cells are enclosed by fibrous septa with foci of
calcification. B, Cells appear loosely arranged. The spaces between the nuclei contain pink fibrillar
material that represents neuritic processes. C, Tumor cells form Homer Wright rosettes.

Fig. 10-76. Ganglioneuroblastoma. The tumor consists of ganglion cells that have eosinophilic cytoplasm. Stroma is inconspicuous.

Fig. 10-77. Ganglioneuroma. The tumor consists of spindleshaped Schwann cells and round ganglion cells.

with a predilection for the cortex of long bones and short

bones. Other sites of metastasis are the lymph nodes, liver,
skin, bone marrow, and skull. The dura may be involved, but
brain metastases are unusual. Histologically the tumors are
composed of small blue cells that are separated focally by
eosinophilic fibrillar material representing neuritic processes
(Fig. 10-74). These neuritic processes extend between cells,
may be arranged around vessels or connective tissue cores,
and form so-called Homer Wright rosettes, which are the
most characteristic feature of neuroblastomas (Fig. 10-75).
As differentiation or maturation of neuroblasts proceeds,
neoplastic cells develop neuronal or ganglion-like features,
with more distinct cell borders and more pronounced

eosinophilia of the cytoplasm. Such tumors are called ganglioneuroblastomas (Fig. 10-76). Ultrastructurally the fibrillar matrix of neuroblastoma and ganglioneuroblastomas
consisfs of a tangled Skein of neuritic process that contains
arrays of microtubles and intermediate filaments. An important diagnostic feature is the presence of small, densecore, membrane-bound neurosecretory granules.
Ganglioneuromas are benign tumors that are composed of
ganglion cells and Schwann cells (Fig. 10-77). Approximately
10 percent to 15 percent of ganglioneuromas originate in the
adrenal glands, usually in school-aged children (average age
seven years). Most ganglioneuromas are, however, found in
the posterior mediastinum.


Further Reading
Attie JN, Auguste LJ: Multiple parathyroid adenomas: Report of thirtythree cases. Surgery 108:1014-1019, 1990.
Brodeur GM: Molecular pathology of human neuroblastomas. Semin
Diagn Pathol 11:118-125, 1994.
Grimelius L, Bondeson L: Histopathological diagnosis of parathyroid
diseases. Path Res Pract 191:353-365, 1995.
Kane LA, Leinung MC, Scheithauer BW et al: Pituitary adenomas in
childhood and adolescence. A clinicopathologic study of the Mayo
Clinic experience. Endocr Pathol 3:517-518, 1992.
Kontogeorgos G, Kovacs K, Horvath E et al: Null cell adenomas, oncocytomas, and gonadotroph adenomas of the human pituitary. An
i mmunocytochemical and ultrastructural analysis of 300 cases. Endocr Pathol 4:20-27, 1993.
Lamovec J, Frkovic-Grazio S, Bracko M: Nonsporadic and unusual
morphologic features in pheochromocytoma and paraganglioma.
Arch Pathol Lab Med 122:63-68, 1998.
Lin BT-Y, Bonsib SM, Mierau GW et al: Oncocytic adrenocortical neoplasms. A report of seven cases and review of the literature. Am J
Surg Pathol 22:603-614, 1998.
Mizukami Y, Michigishi T, Nonomura A et al: Autonomously functioning (hot) nodule of the thyroid gland. A clinical and
histopathologic study of 17 cases. Am I Clin Pathol 101:29-35,1994.

Oelkers W: Adrenal insufficiency. NEngl J Med 335:1206-1212, 1996.

Ohta TI et al: Cortico-medullary mixed tumor (pheochromocytoma
and cortical adenoma) of the adrenal gland. J Urol Pathol 3:157164, 1995.
Ostrowski ML, Merino MJ: Tall cell variant of papillary thyroid carcinoma. A reassessment and immunohistochemical study with comparison to the usual type of papillary carcinoma of the thyroid. Am
J Surg Pathol 20:964-974, 1996.
Samaan NA, Hickey RC: Pheochromocytoma. Semin Oncol 14:297-305,
Schlumberger MJ: Papillary and follicular thyroid carcinoma. N Engl J
Med 338:297-306, 1998.
Shortell CK, Andrus CH, Phillips CE Jr, Schwartz SI: Carcinoma of the
parathyroid gland. A 30-year experience. Surgery 110:704-708,
Singer PA: Thyroiditis. Acute, subacute and chronic. Med Clin North
Am 75:61-77, 1991.
Thapar K, Kovacs K, Muller PJ: Clinical-pathological correlation of pituitary tumours. Bailliere's Clin Endocrin Metab 9:243-270, 1995.
Westra WH, Pritchett DD, Udelsman R: Intraoperative confirmation
of parathyroid tissue during parathyroid exploration. A retrospective evaluation of the frozen section. Am J SurgPathol 22:538-544,



The kidneys and the urinary tract form during prenatal life
in a complex sequence of interrelated morphogenetic processes. The urethra and the urinary bladder form from the
cloaca, which gives rise to ureteric buds. Ureteric buds grow
upward and interact with the primordium of the kidney,
which has passed through three sequential stages: pronephros, mesonephros, and metanephros. Metanephric blastema
establishes contact with the ureteric bud and is induced to
form the definitive kidney. Developmental disorders of the
kidneys and the urinary tract reflect disturbances of this
complex morphogenesis.

Agenesis, Malposition, Exstrophy, and

Related Defects
The definitive kidney results in incomplete induction (renal
hypoplasia) or aplasia (renal agenesis), which may be unilateral or bilateral (Fig. 11-1). Bilateral agenesis results in a developmental sequence called Potter syndrome, in which renal
agenesis is accompanied by oligohydramnios, pulmonary hypoplasia, and a small recessed mandible and low-set ears (see
also Fig. 5-4).
Ectopia of one or both kidneys results from malpositioning of the kidneys (Diagram 11-1). Ectopic kidneys usually are located caudal to their normal lumbar position but
may be cranial to their normal location or even in the thorax
(thoracic ectopia or dystopia). Both kidneys may be on the
same side of the vertebra (crossed ectopia). Ectopia also may
be associated with abnormal rotation of the kidney, and in
such cases the hilum may face anteriorly or posteriorly (Fig.
11-2). Horseshoe kidney results from the fusion of left and
right renal anlage into a simple kidney (Fig. 11-3).

Fig. 11-1. Renal agenesis. Urinary bladder, adrenal, and testes

are normally developed, but the ureters and kidneys are missing.

Diagram 11-1. Positional renal abnormalities. A, Pelvic kidney.

B, Crossed ectopia. The right kidney has crossed the left ureter
and has migrated only part of the normal distance. (From Carlson
BM: Human embryology and developmental biology, St. Louis, 1994,

Fig. 11-2. Ectopia and malrotation of the kidney. The right kidney is located lower than the left one, and its hilum is facing


The ureters may form incompletely and may show focal

stenosis or atresia. Congenital megaureters are dilated and
tortuous and usually are associated with abnormal urinary
conduit (Fig.l1-4)
Exstrophy of the urinary bladder represents incomplete
formation of the urinary bladder combined with a defect of
the anterior abdominal wall (Fig. 11-5).
Developmental defects of the urethra include agenesis
and stenosis. In males these anomalies maybe associated with
abnormal development of the penis. An abnormal opening
of the urethra on the lower side of the penile shaft is called

hypospadia (Fig. 11-6). Epispadia, which is less common than

hypospadia, is an opening of the urethra on the dorsum of
the penis. Abnormalities of the penis such as agenesis or micropenis are rare and usually are associated with other urogenital anomalies or chromosomal changes.

Fig. I 1-4. Megaureters. The ureters are dilated and tortuous. The
kidneys are multicystic and dysplastic.

Fig. 11-3. Horseshoe kidney.

Fig. I I-S. Exstrophy of the urinary bladder. Red mucosa of the

urinary bladder may be seen through the defect of the anterior
abdominal wall. (Courtesy of Dr. Roger D. Smith, Cincinnati,
Ohio, and GRIPE.)

Fig. I 1-6. Hypospadia. The urethra opens on the lower side of

the shaft of the penis rather than on the tip of the glans penis.


Polycystic Kidney Disease

Abnormal morphogenesis of nephrons, which are the basic
anatomic and functional units of the kidneys, results in
polycystic kidney disease. Several clinicopathologic subtypes
are recognized, the most important of which are (1) autosomal dominant polycystic kidney disease; (2) autosomal
recessive polycystic kidney disease; (3) familial juvenile
nephronophthisis-medullary cystic disease complex; and
(4) renal dysplasia (Diagram 11-2).
Autosomal dominant polycystic kidney disease (ADPKD) is
a genetic disease that occurs at a rate of 1 per 1000. Symptoms of renal disease appear in the third or fourth decade,
and the disease therefore is known as adult polycystic kidney

disease. Both kidneys are enlarged, weighing up to 2000 to

3000 g and measuring up to 40 cm in length. Kidney
parenchyma typically is replaced by fluid-filled cysts that vary
in size and shape (Fig. 11-7). These cysts are lined by nondescript flattened cells derived from the epithelium of
tubules, collecting ducts, or Bowman capsule (Fig. 11-8).
Autosomal recessive polycystic kidney disease (ARPKD) is
less common than ADPKD. Because symptoms of ARPKD
appear in infancy and childhood, both infantile and childhood forms are recognized. Both kidneys are enlarged but retain their normal shape. The cysts are small and elongated,
extending in the form of slits from the corticomedullary
junction toward the subcapsular cortex (Fig. 11-9). The cysts

Diagram 11-2. Cystic developmental kidney diseases. A, Autosomal dominant polycystic kidney
disease is characterized by widespread cystic dilatation of all parts of the nephron. B, Childhood
polycystic disease is autosomal recessive, but also shows microcystic changes in all parts of the
nephron. C, Medullary sponge kidney shows cystic dilatation of collecting ducts of the papillae.
D, Nephronophthisis shows cystic dilatation of juxtacortical medullary tubules. E, Cystic dysplasia
contains solid and cystic areas. The solid areas comprise homologous renal and heterologous
(nonrenal) elements. (From Damjanov I: Histopathology. A color atlas and textbook, Baltimore, 1996,
Williams & Wilkins.)

Fig. 11-7. ADPKD. The enlarged kidneys consist of cysts that

have replaced the normal parenchyma.

Fig. 11-8. ADPKD. The cysts are lined by flattened epithelium

and contain proteinaceous fluid.


represent dilated collecting ducts, which compress the remaining tubules, causing either atrophy or dilatation of the
remaining parts of the nephron (Fig. 11-10).
Renal dysplasia is a disorder of differentiation of the
metanephros, often in association with other developmental
disorders. It may be bilateral, but more often it is unilateral,
causing an abdominal mass in neonates and infants. The enlarged kidney consists of cysts ( " multicystic dysplasia " ) and
solid tissue replacing to a variable extent the normal renal
parenchyma (Fig. 11-11). Histologically the cysts varyin size
and shape and are lined by cuboidal or flattened epithelium.
The solid areas consist of primitive ducts lined by columnar

epithelium surrounded by concentric layers of fibromuscular stroma that often contains islands of cartilage (Fig.

Hereditary Glomerular and Tubular Diseases

Many multisystemic genetic disorders affect the kidneys, but
only in certain disorders do renal symptoms represent the
main clinical manifestation of such diseases.
Alport syndrome is a form of hereditary nephritis that is
caused by a defect in the synthesis of collagen type IV. The
biochemical defect is associated with morphologic changes
of the glomerular basement membrane (GBM), which show

Fig. 11-9. ARPKD. The kidneys are enlarged because of diffuse

dilatation cystic transformation of tubules and collecting ducts,
which appear as dilated channels crossing from the cortex to the

Fig. 11-10. ARPKD. The cortex contains numerous dilated collecting ducts lined by flattened epithelium. The remaining portions
of the nephrons are either compressed or dilated.

Fig. I 1-I I. Multicystic renal dysplasia. The deformed kidney consists of several large cysts and solid tissue replacing the normal
renal parenchyma.

Fig. 11-12. Renal dysplasia. The normal parenchyma has been

almost completely replaced by fibromuscular tissue and cartilage. Remnants of two fetal glomeruli are seen surrounded by
atrophic tubules.


focal thinning, thickening, and layering. These changes are

best appreciated by electron microscopy (EM) (Fig. 11-13).
Presenting symptoms include proteinuria, hematuria, and
slowly evolving but progressive renal failure. The disease is
more common, has an earlier onset, and is more severe in
men than in women.
Thin basement membrane nephropathy may occur in familial and sporadic forms. By light microscopy the glomeruli
are normal. By EM the glomeruli have membranes that measure 80 to 250 nm in width, which is much thinner than
normal (340 to 360 nm) (Fig. 11-14). Thinning is caused by
the reduction of the width of the lamina densa. Clinically the
disease presents with mild hematuria with or without proteinuria. Renal function remains preserved, and the disease
has a good prognosis.
Fabry disease is an X-linked hereditary disease caused by
the mutation of the gene for a-galactosidase A. The disease
has renal, neurologic, and cutaneous manifestations. The en-

zyme deficiency results in accumulation of the glycosphingolipid ceramide trihexoside in plasma and many tissues. In
the kidneys ceramide trihexoside accumulates in glomerular
epithelial cells, which become vacuolated (Fig. 11-15). EM
reveals accumulation of lipid-rich myelin figures in the cytoplasm of these cells (Fig. 11-16). Similar changes are seen in
arteries and arterioles, and occasionally in interstitial cells.
Damage of the glomeruli ultimately leads to proteinuria.
Chronic renal failure evolves over 10 to 20 years.
Nail-patella syndrome is a hereditary disease whose presenting symptoms include typical nail changes, congenital
absence of the patella, and renal symptoms. Glomerular
changes are prominent and are related to changes in the
glomerular membrane, which contains strands of banded
collagen (Fig. 11-17).
Many inborn errors of metabolism affect the renal
tubules. In glycogenosis type I the renal tubules are vacuolated and filled with glycogen (Fig. 11-18).

Fig. 1 I-13. Alport syndrome. A, The glomerulus appears unremarkable by light microscopy. The tubules appear atrophic and
there are foam cells in the interstitium. B, By EM the thickened
basement membrane consists of alternating dense and lucent
segments. There also is subepithelial scalloping of the basement
membrane and partial effacement of the epithelial cell foot

Fig. I 1-14. Thin basement membrane nephropathy. A, The capillary wall is very thin, measuring 90 nm in width. The epithelial cell
foot processes are discrete and show no effacement. B, Normal
basement membrane, shown here for comparison, measures 360
nm in width.


Fig. 11-15. Fabry disease..The visceral epithelial cells are enlarged and have vacuolated cytoplasm.

Fig. I 1-16. Fabry disease. The cytoplasm of epithelial cells is

filled with dense myelin figures representing stored sphingolipid.

Fig. I 1-17. Nail-patella syndrome. A, Abnormal nails. B, GBM

contains banded collagen fibrils.

Fig. 11-18. Glycogenosis type I. Renal tubules have clear cytoplasm as a result of glycogen accumulation.


The most important vascular disease that affects the kidneys
is atherosclerosis. Atherosclerosis most prominently involves
the main renal arteries, but it also is associated with intimal
and medial fibrosis of the intrarenal arteries, arteriolosclerosis, and glomerulosclerosis. Because the entire kidney is
affected, the term nephroangiosclerosis (nephrosclerosis) is
used as a synonym for ischemic changes in the kidney caused
by prolonged ischemia in atherosclerosis. On gross examination the kidneys are smaller than normal and show cortical atrophy and V-shaped indentations that correspond to
small infarcts (Fig. 11-19). Larger cortical infarcts may cause
more profound multiple scarring, which may be indistinguishable from scars caused by pyelonephritis (Fig. 11-20).
Histologically the glomeruli are hyalinized, and the tubules
appear atrophic and are replaced by fibrous tissue and scattered lymphocytes (Fig. 11-21). Atrophic tubules filled with
colloid ( " thyroidization " ) typically are found as evidence of
blocked flow of solutes through nephrons that have been dis -

rupted or obstructed by interstitial scarring (Fig. 11-22).

Clinically nephrosclerosis is accompanied by a loss of renal
function, which slowly progresses to renal failure. Nephrosclerosis accounts for 15 percent of end-stage kidney disease
worldwide. It is especially prevalent among the elderly.
Thrombotic microangiopathy is a term that encompasses
several diseases, including hemolytic uremic syndrome,
thrombotic thrombocytopenic purpura, scleroderma, and
malignant hypertension. All thrombotic microangiopathies
are characterized by intravascular deposition of fibrin and
lesions that primarily involve arterioles and glomerular capillaries (Fig. 11-23). Two types of glomerular changes are
seen: those that result from fibrin deposition and those that
result from ischemia (Fig. 11-24). Capillary walls are thickened because of endothelial cell swelling and widening of
subendothelial spaces, which sometimes gives the capillaries
a double contour. Capillary lumens may contain fibrin
thrombi. Mesangial regions are widened, with increased cytoplasmic volume. Mesangiolysis (dissolution of matrix)

Fig. 11-19. Nephroangiosclerosis. Kidneys have , scarred and

granular external surface. Aorta shows marked atherosclerosis.
The kidney on the right contains a cyst.

Fig. 11-20. Nephroangiosclerosis. Severe surface scarring may

be indistinguishable from changes caused by pyelonephritis.

Fig. 11-21. Nephroangiosclerosis. The glomeruli are hyalinized,

and the atrophic tubules are surrounded by fibrous tissue.

Fig. 11-22. Nephroangiosclerosis. Atrophic tubules are filled

with eosinophilic proteinaceous casts that resemble thyroid
follicles ("thyroidization of the kidney").


may produce microaneurysms. During the healing process

there is sclerosis of glomeruli, which often has a lobular pattern that is reminiscent of membranoproliferative glomerulonephritis type I. Lesions of interlobar and arcuate arteries
may be present and are most prominent in scleroderma.
Clinically all of these disorders are characterized by diminished renal function and oliguria. Hypertension is evident in
50 percent of cases.


Fig. 11-23. Thrombotic microangiopathy. The arteriole contains

a thrombus that extends into the glomerulus.

Fig. 11-24. Thrombotic microangiopathy. Double contours of

glomerular capillaries are seen in segments of the glomerulus.
Some capillary loops have wrinkled membranes.

I mmune-mediated glomerular diseases may involve any part

of the kidney but most often they present as glomerulonephritis. The pathogenesis of some glomerulopathies, such
as poststreptococcal glomerulonephritis, has been elucidated
to a great extent, whereas the pathogenesis of others, such as
minimal change disease, remains obscure. Clinically glomerulopathies present with proteinuria, hematuria, or both,
and are diagnosed as nephrotic or nephritic syndromes.
Glomerular disease may occur in an isolated form or as part
of a systemic disease, such as systemic lupus erythematosus
(SLE). Some glomerulopathies, such as minimal change disease, respond well to treatment with corticosteroids, whereas
others, such as membranous nephropathy, are slowly progressive and unresponsive to treatment.
Minimal change disease, also known as nil disease, lipoid
nephrosis, or visceral epithelial cell disease, is a disease of unknown etiology and poorly understood pathogenesis. It is
one of the "primary" glomerulopathies responsible for
nephrotic syndrome (Table 11-1). By light microscopy the
glomeruli appear normal (Fig. 11-25). There are no diagnostic immunofluorescence (IF) microscopy findings. By
EM the GBMs are normal, but the epithelial foot processes
show complete effacement (Fig. 11-26).
Focal and segmental glomerulosclerosis (FSG) is a term
used to describe two entities: a glomerulopathy that causes
nephrotic syndrome, and morphologic changes that may
occur in association with a variety of systemic diseases that
affect the kidneys (Table 11-2). The etiology and pathogenesis of FSG are not known. Segmental sclerosis (i.e., obliteration of segments of a single glomerulus) is seen affecting
some glomeruli (hence called focal). The sclerotic lesions
may correspond to an occluded capillary obliterated with
plasma protein deposits ( " hyalinosis " ) or may represent expanded mesangium associated with collapsed capillary base-

"Primary" Glomerulopathies Responsible

for Nephrotic Syndrome
Minimal change disease
Mesangial injury glomerulonephritis with IgM deposits
Focal and segmental glomerulosclerosis
Membranous glomerulonephritis
Membranoproliferative glomerulonephritis
Fig. 11-25. Minimal change disease. In this slide stained with PAS
methenamine silver the glomeruli appear normal.

IgM. Immunoglobulin.


ment membrane (Figs. 11-27 and 11-28). Except for deposits

of immunoglobulin (IgM) and third component of complement (C3) in the areas of hyalinosis, there are no other findings by IF microscopy. Hyaline material appears finely granular by EM and may contain lipid droplets.
Human immunodeficiency virus (HIV)associated nephropathy may present as FSG, but in many cases the glomeruli
also show changes that might represent precursor lesions of
typical hyalinosis. The most typical is the so-called collapsing
glomerulopathy, in which there is complete collapse of the
capillary loops (Fig. 11-29). The tubules contain proteinaceous casts and may undergo microcystic dilatation. Numerous tubuloreticular structures are seen by EM in the
cytoplasm of endothelial cells but also in other cells (Fig.

Focal and Segmental Glomerulosclerosis

Parts of minimal change disease spectrum
Unique disease
Heroin-associated nephropathy
HIV-associated nephropathy
Complicating Other Renal Disorders
Reflux nephropathy and other sclerotic interstitial disorders
Glomerulonephritis (many types)
Familial-metabolic diseases
Chronic transplant rejection
Collapsing glomerulopathy
Tip lesions
HIV, Human immunodeficiency virus.

Fig. I 1-27. Focal and segmental glomerulosclerosis. The hyalinized portions of the glomerulus appear blue in this Masson
trichromestained slide.

Fig. I 1-26. Minimal change disease. There is complete effacement of the foot processes of the visceral epithelial cell. A normal
mesangial cell is seen to the right.

Fig. I 1-28. Focal and segmental glomerulosclerosis. "Hyaline"

occludes the lumen of the hilar capillaries.


Fig. 11-29. HIV-associated nephropathy. The glomerulus in the

center shows collapse of capillary loops, and the tubules filled
with proteinaceous casts show microcystic dilatation.

Fig. I 1-30. HIV-associated nephropathy. The cytoplasm of this

endothelial cell contains a large tubuloreticular structure.

Fig. 11-31. MPGN-I. The glomerulus has a lobular configuration

with mesangial widening and hypercellularity. Peripheral capillary
loops have double contours.

Fig. 11-32. MPGN-I. Glomerular capillary has a narrow lumen

because of peripheral extension of mesangial cell cytoplasm,
which is interposed between the layers of basement membrane.

Membranoproliferative Glomerulonephritis
Membranoproliferativeglomerulonephritis ( MPGN) is a renal

Fig. 11-33. MPGN-I. Granular deposits of C3 are seen along the

capillary loops and in the mesangium by IF microscopy.

lesion that may represent different disease entities, which are

grouped here for historical reasons. Three subtypes (I, II,
and III) are recognized. MPGN-1 is an immune complex
mediated disease that is characterized by mesangial hypercellularity, lobular appearance of glomeruli, and prominent
reduplication (double contours) of basement membranes
(Fig. 11-31). These double contours are better seen by EM,
which shows interposition of mesangial cell cytoplasm between the original basement membranes and the newly
formed basement membranes (Fig. 11-32). IF microscopy
shows granular deposits of C3 along the peripheral capillary
loops and in the mesangium (Fig. 11-33). IgG and IgM deposits are present focally but may be missing entirely. IgA
maybe found in a few patients. Immune deposits seen by EM


are located in the basement membranes or inside the capillaries in a subendothelial location.
MPGN-II, or dense deposit disease, involves activation of
the alternate complement pathway, which results in consumption of complement. Circulating C3 typically is decreased. C3 nephritic factor, an IgG that enhances clearance
of C3, may be demonstrated in the blood. The basement
membranes of the glomeruli are biochemically abnormal,
which may contribute to glomerular pathology. By light microscopy the glomeruli appear lobular and show mesangial
expansion and hypercellularity. The basement membranes
appear thickened and may have double contours (Fig. 11-34).
Dense deposits are seen along the basement membranes by
EM (Fig. 11-35). By IF microscopy deposits of C3 are seen in
a finely granular pattern along the GBMs and in the mesangial areas (Fig. 11-36). MPGN-III is a heterogeneous group
of diseases that produce changes similar to MPGN-I.

Fig. I 1-34. MPGN-II. The glomerular capillary basement membranes are thickened and have a ribbon-like quality. Double
contours are seen segmentally. The mesangial areas are expanded and hypercellular segmentally and show some nodularity.

Membranous Glomerulonephritis
Membranous glomerulonephritis (GN), also known as membranous nephropathy, is an immune complex mediated disease that presents with proteinuria and nephrotic syndrome.
It may occur as a primary kidney disease or secondary to
other systemic diseases (Table 11-3). By light microscopy the
glomeruli show thickening of basement membranes, which
become more prominent in the course of disease progression
(Fig. 11-37). Silver impregnation techniques show subepithelial projections ( " spikes ") of the basement membrane between the deposits of immune complexes, which may be seen
as fuchsinophilic material in Masson trichromestained
slides. By EM the early deposits (stage I) are epimembranous
and subepithelial. In stage II the deposits are larger and are
located between the spikes of the basement membrane. In
stage III or IV of the disease the deposits may be completely
covered with the basement membrane (Fig. 11-38). Dense

Fig. I 1-35. MPGN-II. EM shows segmental replacement of the

lamina densa by electron-dense finely granular material. A resorbing subendothelial deposit is indicated by an arrow.

Common Associations with Secondary

Membranous Glomerulonephritis
Hepatitis B
Autoimmune Diseases
Systemic lupus erythematosus
Rheumatoid arthritis
Sjogren syndrome
Diabetes mellitus
Renal transplantation

Fig. I 1-36. MPGN-II. Glomerulus shows coarse granular staining

of mesangial regions, capillary walls, and tubules.


Fig. 11-37. Membranous glomerulonephritis. A, In this slide stained with PASmethenamine

silver the thickened basement membranes have fine spikes along their subepithelial surface.
B, In this Masson trichromestained slide immune complexes appear red ( " fuchsinophilic").

Fig. 11-38. Membranous glomerulonephritis. A, Early (stage I) disease shows small subepithelial
electron-dense deposits (arrows). B, Stage II is characterized by larger deposits between the
intervening projections of newly formed basement membrane ("spikes"). C, Stage IV disease is
characterized by large lucent spaces enclosed by basement membrane. The lucent areas
correspond to partially resorbed immune complexes.


deposits may become lucent, which usually is a sign of their

resorption. By IF microscopy the immune complexes appear
as finely granular deposits along the basement membrane
(Fig. 11-39).

IgA Nephropathy and

Henoch-Schonlein Purpura
IgA nephropathy (Berger disease) is an immune complex

Fig. 11-40. IgA nephropathy. IF microscopy shows that the

mesangial areas contain diffusely finely granular deposits of IgA.

mediated glomerulonephritis with IgA as the sole or dominant antibody in the complexes, which localize preferentially
in the mesangium. It is the most common primary immunemediated glomerulopathy worldwide, with an exceptionally
high incidence in Asia and in Mediterranean countries. Its
etiology and pathogenesis are not known. The disease presents with widening of mesangial areas, increased mesangial
cellularity, and mesangial or paramesangial deposits of IgA
(Figs. 11-40 to 11-43). Clinically, presenting symptoms of the
disease are asymptomatic proteinuria and hematuria but it
also may manifest in the form of other renal syndromes and
thus is considered to have a protean nature. Approximately
one third of all patients develop end-stage renal disease over
20 years and require renal transplantation. IgA mesangial deposits recur in transplanted kidneys but are clinically insignificant in most cases.
Henoch-Schonlein purpura ( HSP), also known as anaphylactoid or rheumatoid purpura, is a clinical syndrome that
comprises renal, dermal, and gastrointestinal lesions. The
primary abnormality is a small vessel vasculitis in the IgA
deposits of affected vessels. The renal changes result from
deposition of immune complex, which contains IgA. The
glomerular changes vary from mild to severe. In mild cases
there are only mesangial deposits of IgA. In severe cases the
deposits also are found in the glomerular capillaries. In extreme cases the damaged capillaries rupture, and a crescentic
glomerular nephritis ensues. Accordingly, on the basis of
glomerular lesions, HSP glomerulonephritis is classified as

Fig. I 1-41. IgA nephropathy. Several widened mesangial and

paramesangial areas contain large, round, fuchsinophilic deposits
in this Masson trichromestained slides. The number of mesangial cells is not increased.

Fig. I 1-42. IgA nephropathy. The glomerulus shows mesangial

widening and segmental mesangial hypercellularity in this slide
stained with PASmethenamine silver. A capsular adhesion and
an area of sclerosis are seen at 12 o'clock.

Fig. I 1-39. Membranous glomerulonephritis. By IF microscopy

the capillary loops are covered with granular, partially confluent
deposits of IgG and C3.

22 3

Fig. 11-43. IgA nephropathy. The paramesangial areas are

widened by round electron-dense deposits. The capillary loops
appear unremarkable.

Fig. 11-44. Henoch-Schonlein purpura. A, Some mesangial areas

appear expanded and hypercellular, whereas others appear normal. The capillary loops are normal in this Masson trichromestained slide. B, EM shows electron dense deposits in the
mesangial area.

(1) mesangiopathic, (2) focal and segmental, (3) diffuse proliferative (endocapillary), and (4) endocapillary/extracapillary (crescentic). If microscopy is required for diagnosis; it
shows IgA predominance. By light microscopy there always
is mesangial widening and hypercellularity (Fig. 11-44, A).
EM demonstrates mesangial deposits, which usually are
more diffuse and not as round as in IgA nephropathy (Fig.
11-44, B). In more severe cases hump-shaped subepithelial
and subendothelial capillary deposits are seen, and in such
cases HSP resembles SLE. Clinically, renal disease occurs in
10 percent to 25 percent of affected children and young
adults. Symptoms vary, but in general the outcome of the disease correlates with the severity of glomerular changes.

Postinfectious Glomerulonephritis
Postinfectious glomerulonephritis is a form of immune com-

plexmediated acute glomerulonephritis that occurs as a sequela of certain bacterial infections. Certain strains of group
A streptococci, usually belonging to types 12, 4, and 1, are the
most common cause. It is believed that the antigens of these
microorganisms are planted in the glomeruli, where they
form immune complexes with the antibodies deposited into
the glomeruli from circulation. Immune complexes attract
neutrophils and evoke a proliferative response by glomerular
cells. Histologically the glomeruli appear hypercellular and
typically contain inflammatory cells in the capillaries (Fig.
11-45). Deposits of IgG and complement are seen in the capillaries and mesangial areas (Fig. 11-46). Large subepithelial
deposits of osmiophilic material ( " lumps" ) are seen by EM.


Clinically, poststreptococcal glomerulonephritis usually presents as a transient self-limited nephritic syndrome of childhood. Most children recover, and end-stage kidney disease
occurs in less than 2 percent to 3 percent of all patients. Unfavorable outcome is more common in adults, 50 percent of
whom may ultimately show signs of chronic kidney disease.
In such cases the kidneys are uniformly shrunken and small
(Fig. 11-47). There is extensive glomerular hyalinization and
tubular atrophy accompanied by interstitial fibrosis (Fig.
11-48). These morphologic findings are, however, nonspecific and also are seen in a variety of other kidney diseases
that progress to end-stage renal disease.

Crescentic Glomerulonephritis
Fig. 1 I-45. Acute poststreptococcal glomerulonephritis. The
glomerulus appears hypercellular and contains numerous
intracapillary neutrophils.

Glomerular crescents are a sign of severe glomerular injury

associated with rupture of GBMs and exudation of fibrin and
macrophages into the glomerular urinary space. Crescents
may be seen in several diseases (Table 11-4).
Anti glomerular basement membrane disease is an
i mmune-mediated disease that is characterized by destructive glomerular lesions caused by antibodies to GBM antigens, such as the globular noncollagenous domain of type IV
collagen. The disease may be limited to the kidneys or may

Diseases That May Present as Crescentic


Fig. I 1-46. Acute postinfectious glomerulonephritis. IF microscopy shows irregular deposits of C3 in the mesangium and the

Fig. 11-47. Chronic glomerulonephritis. Symmetrically shrunken

kidneys have a uniformly granular surface.

Anti-GBM disease
Idiopathic glomerulonephritis with anti-GBM antibodies
Goodpasture disease
Wegener granulomatosis
Polyarteritis nodosa
Systemic lupus erythematosus
Henoch-Schonlein purpura
Essential cryoglobulinemia
Postinfectious glomerulonephritis

Fig. 11-48. Chronic glomerulonephritis. Glomeruli are hyalinized

and surrounded by atrophic tubules, interstitial fibrosis, and
scattered mononuclear cells.


be part of a renal-pulmonary syndrome (Goodpasture disease). The glomeruli show typical extracapillary exudation
of fibrin into the urinary space between the Bowman capsule and the capillary loops (Fig. 11-49). In addition to fibrin,
such "crescents " also contain exudated macrophages and
proliferated epithelial cells compressing the collapsed capillary loops. IF microscopy shows linear staining of the capillaries with antibodies to IgG or IgM . (Fig. 11-50). Fibrin is
seen in the crescents. Damaged glomeruli undergo scarring,
and end-stage kidney disease may evolve over a few weeks or
months. Clinically this is recognized as rapidly progressive
glomerulonephritis (RPGN) characterized by relentless loss
of renal function.
Typical Goodpasture disease, presenting with pulmonary
hemorrhage and RPGN, is rare. Crescentic glomerulonephritis of the type found in Goodpasture disease may be found
in other kidney diseases that present as RPGN, which are

World Health Organization Classification

of Lupus Nephritis


No abnormalities by light, electron, and
immunofluorescence microscopies
Mesangial (injury, proliferative glomerulonephritis)
No increased cellularity
Mild increases in mesangial cellularity
Focal and segmental glomerulonephritis
Diffuse proliferative glomerulonephritis
Membranous glomerulonephritis
"Pure" membranous glomerulonephritis
With mesangial glomerulonephritis
With focal proliferative glomerulonephritis
With diffuse proliferative glomerulonephritis

listed in Table 11-4. Wegener granulomatosis probably is the

most common cause of crescentic glomerulonephritis. Because all of these diseases produce the same morphologic
changes, additional immunologic data, such as tests for antinuclear antibody (ANA) and antineutrophil cytoplasmic antibody (ANCA), are essential for proper diagnosis.

Systemic Lupus Erythematosus (SLE)

SLE glomerulonephritis is an immune complexmediated
renal disease that occurs in more than 75 percent of patients
who have this systemic autoimmune disease. According to
the World Health Organization classification, the renal lesions are graded on a scale from mild to severe and are classified into five categories (Tables 11-5 and 11-6).
In mesangial lupus glomerulonephritis there is mild
mesangial widening accompanied by mild mesangial hypercellularity (Fig. 11-51). In focal and segmental proliferative

Lupus Nephritis Scoring System of Renal


Active Lesions
Leukocytic infiltration
Necrosis, karyorrhexis*
"Wire loops"
"Hyaline thrombi"

Chronic Lesions
Fibrous crescents


Active Lesions
Mononuclear leukocyte infiltration

Chronic Lesions
Interstitial fibrosis
Tubular atrophy

Each lesion is assigned a grade of 0, I, 2, or 3; those with an asterisk are

doubled. Add all active lesions for activity index (maximum number 27)
and chronic lesions for chronicity index (maximum number 12).

Fig. 11-49. Antiglomerular basement membrane nephritis. In

this slide stained with PASmethenamine silver the collapsed
capillary loops are compressed by a crescent composed of fibrin
and macrophages. Some tubules contain red blood cells as
evidence of severe glomerular injury and glomerular hematuria.

Fig. 11-50. Antiglomerular basement membrane nephritis. The

capillary loops stain in a linear manner with antibodies to IgG.


GN and diffuse proliferative GN, deposits of immune complexes are accompanied by proliferation of mesangial cells,
expansion of mesangial areas, and obliteration of capillary
lumina (Figs. 11-52 and 11-53). Deposits of immune complexes may be found by IF microscopy in the mesangial areas,
along the GBM, and in capillaries (Figs. 11-54 and 11-55).
Capillary deposits are classified by EM as subendothelial,

intramembranous, or subepithelial. Endothelial cells typically contain tubuloreticular structures (Fig. 11-54). Deposits of immune complexes also may be seen in the interstitial peritubular spaces (Fig. 11-55). In membranous GN the
glomeruli show subepithelial deposits like in any other membranous GN, but they also contain mesangial deposits (Fig.

Fig. I 1-51. Lupus nephritis, mesangial proliferative. Mesangial

areas are widened and contain an increased number of mesangial
cells in this slide stained with PASmethenamine silver.

Fig. I 1-52. Lupus nephritis, focal proliferative. Glomerulus

shows segmental loss of normal architecture of the tufts because
of deposition of eosinophilic material and cell proliferation. The
lower part of the glomerulus is relatively spared.

Fig. I 1-53. Lupus nephritis, diffuse proliferative. The glomerulus

is hypercellular and has expanded mesangial areas and partially
obliterated capillary lumens. Intracapillary eosinophilic hyaline
thrombi and wire loops are seen segmentally.

Fig. 11-54. Lupus nephritis, diffuse proliferative. EM shows a

large subendothelial electron-dense deposits and "hyaline capillary thrombus."


Fig. 11-55. Lupus nephritis. Numerous interstitial deposits are

located around a peritubular capillary.

Fig. 11-56. Lupus nephritis, membranous. Deposits of dense

material corresponding to immune complexes are seen in a subepithelial location along the capillaries and in the mesangium.


Acute interstitial nephritis, also known as acute tubulointerstitial nephritis, may have many causes (Table 11-7). The
kidneys typically are enlarged and edematous and show extensive interstitial infiltrates composed of lymphocytes,
macrophages, plasma cells, or eosinophils (Fig. 11-57). Interstitial nephritis also may present as a granulomatous reaction (Fig. 11-58).

Tubulointerstitial diseases are classified etiologically as (1) immune-mediated, (2) infectious, (3) metabolic and/or toxic,
and (4) ischemic. These diseases have many common morphologic features, and their etiology is not always apparent.
Clinically and pathologically they are classified as acute or

Fig. 11-57. Acute interstitial nephritis. A, In this Masson trichromestained slide the edematous
interstitium is infiltrated with mononuclear cells. Tubules show focal signs of injury. B, The interstitium contains a dense infiltrate of lymphocytes, macrophages, and eosinophils.

22 8

Pyelonephritis is a term that refers to bacterial tubulointerstitial infections. Infections may be caused by hematogenous spread of bacteria or reflux of infected urine. In acute
pyelonephritis the kidney is infiltrated with neutrophils,
which may fill the tubules or form interstitial abscesses (Fig
11-59). The kidneys are enlarged and swollen and may contain abscesses. In chronic pyelonephritis, which often is associated with urinary obstruction, the loss of renal parenchyma
typically results in shrinkage of the kidneys and hydronephrosis (Fig. 11-60). Histologically the kidneys are infiltrated with lymphocytes, macrophages, and plasma cells,
which tend to replace the tubules (Fig. 11-61). Pyelonephritis
may be unilateral or bilateral. Bilateral chronic pyelonephritis is associated with end-stage kidney disease.
Metabolic and/or toxic disorders that affect the kidneys
cause tubular injury, which may or may not be associated
with glomerular and vascular changes. Acute tubular necrosis
(ATN) is a reversible lesion of the tubular epithelium that is
associated clinically with acute renal failure. It may be caused

Etiologies of Acute Interstitial Nephritis

Allergic (hypersensitivity)
Antitubular basement membrane disease
Immune complex deposition
T cellmediated (sarcoid, idiopathic)
Reactive (viral, bacterial)
Direct (viral, leptospiral, rickettsial, mycobacterial)
Hereditary and metabolic
Crystal formation

Fig. 11-58. Granulomatous interstitial nephritis. The interstitium

contains epithelioid granulomas.

Fig. 11-59. Acute pyelonephritis. Neutrophils are found in the

tubules and the edematous interstitium.

Fig. 11-60. Chronic pyelonephritis. This kidney from a patient

with urinary obstruction shows dilatation of calices and pelvis and
loss of renal parenchyma.

Fig. 1 1-61. Chronic pyelonephritis. Extensive mononuclear

infiltrates have replaced most of the tubules, but the glomeruli
appear preserved in this Masson trichromestained slide.


Causes of Toxic Acute Tubular Necrosis

Fig. 11-62. ATN. The tubules are lined by flattened epithelium,

which is focally missing altogether. Some tubules contain granular casts.

Fig. 11-63. ATN. The medullary tubules contain casts, and the
congested vasa recta contain nucleated red blood cells.

by a variety of toxins (Table 11-8). Ischemia may also cause

ATN, which typically is found in various forms of shock, in
multiple organ failure, and in essentially all conditions that
are associated with anoxia or hypoperfusion of the kidneys.
The kidneys are enlarged and have a pale cortex and congested medulla. Histologically the earliest changes are those
in which the proximal tubules lose their brush borders, which
is best seen in slides stained with period acidSchiff reagent.
Necrosis of tubular cells leads to widening of the tubules,
which contain cellular debris in the form of granular proteinaceous material. The epithelium of the tubules is flattened, and focally cells are missing altogether (Fig. 11-62).
The desquamated cells fragment and form granular casts that
are most prominent in the medullary tubules, accounting for
the term lower nephron nephrosis, which previously was used
to describe ATN in autopsy specimens. The vasa recta of the
medulla typically are congested and contain nucleated blood
cell precursors (Fig. 11-63). Renal tubular epithelium may
regenerate, and in the recovery phase of ATN the tubules are
lined by cells that have basophilic cytoplasm. Recovery is associated with normalization of renal function.
Diabetes mellitus is a major cause of kidney disease.
Typical renal lesions include (1) diabetic glomerulosclerosis,
(2) hyalinization of arterioles (hyaline arteriolosclerosis),
(3) pyelonephritis, and (4) papillary necrosis. Diabetic
glomerulosclerosis occurs in diffuse and nodular forms (Figs.
11-64 and 11-65). In diffuse glomerulosclerosis the GBMs
are uniformly thickened and the amount of mesangial matrix is increased. In nodular glomerulosclerosis there is nodular expansion of the mesangial regions. By microscopy the
basement membranes and mesangial areas appear to be impregnated with IgG and albumin, which imparts to them a
pseudolinear " staining pattern (Fig. 11-66). By EM the
basement membranes of the capillary loops appear uniformly thickened. The expanded mesangial areas and the nodular
material also consist of basement membranelike material.

Fig. 11-64. Diabetic glomerulosclerosis. The glomerulus contains a mesangial nodule composed of basement membranelike


Fig. I 1-65. Diffuse diabetic glomerulosclerosis. The basement

membranes are diffusely thickened, and the mesangial areas
appear widened. Bowman capsule thickening ("hyaline drop") also
is seen. The arterioles show hyalinization.

Fig. 11-66. Diabetic glomerulosclerosis. Antibody to IgG stains

the GBM and Bowman capsule in a linear way.

Fig. 11-67. Papillary necrosis. Papillae missing their tips appear

blunted and partially calcified (arrows).

Fig. 11-68. Urinary stone. The dilated pelvis contains irregular


Papillary necrosis is characterized by an infarction of the

renal papillae, which may slough off into the pelvis (Fig.
11-67). This complication is not unique to diabetes. It is especially common in diabetic patients who have obstruction
of urine flow or pyelonephritis. Papillary necrosis also occurs
in women who abuse aspirin and phenacetin ( " analgesic
abuse nephropathy " ).
Metabolic changes associated with the excretion of calcium and phosphates often result in the formation of urinary
stones. Urolithiasis (urinary stones) also occurs in gout, in
several other metabolic diseases such as hyperoxaluria and
cystinosis, and in urinary tract infections. Biochemically, uri-

nary stones are composed of (1) calcium (oxalate or phosphate,, (2) magnesium ammonium phosphate, (3) uric acid,
and (4) cysteine. The stones may be small or large, and clinical symptoms depend on their size and location. Small
stones that obstruct the ureter cause colic. Large stones that
are impacted in the pelvis cause obstructive hydronephrosis
and progressive renal failure (Fig. 11-68). Calcium phosphate
crystals may precipitate in renal tubules or renal interstitium,
especially in end-stage kidney disease (nephrocalcinosis). Deposits of other metabolites that may be found in the kidneys
include uric acid crystals in gout and oxalate crystals in oxalosis or ethylene glycol poisoning (Figs 11-69 and 11-70).


Fig. I 1-69. Gout. A, Deposits of uric acid crystals have caused yellowish discoloration of the papilla.
B, Uric acid crystals appear as birefringent deposits in the medulla.

Fig. 11-70. Oxalosis. Birefringent crystals in the tubules are seen

under polarized light.

Fig. 11-71. Amyloid. Amyloid fibrils have a typical appearance

by EM.


Fig. 11-72. Multiple myeloma. Tubular proteinaceous casts

elicit a giant cell reaction.

Renal deposits of amyloid are found in both primary and

secondary amyloidosis. These deposits are seen in the glomeruli, blood vessels, and tubular basement membranes (Fig.
11-71). Besides amyloid, multiple myeloma kidney disease is
characterized by tubular casts of immunoglobulin light
chains, which may cause urinary obstruction (Fig. 11-72).
Deposition of cryoglobulins, plasma proteins that precipitate at low temperature, predominantly occurs in renal vessels. Cryoglobulinemia typically is associated with glomerulonephritis, which usually leads to lobular transformation of
the hypercellular glomerular tufts reminiscent of MPGN
(Fig. 11-73).

Fig. 11-74. Acute cystitis. The mucosa of the urinary bladder is

congested and shows foci of hemorrhage.

Fig. 11-73. Cryoglobulinemia. The glomerulus shows lobular

expansion and hypercellularity. Many capillary loops have double
contours, and some contain pink-staining plasma protein casts in
their lumen.


Infections of the lower urinary tract may occur as an isolated
form, such as urethritis or cystitis, but most often the pathogens do not respect the anatomic boundaries and the inflammation involves the major part of the lower urinary
tract. In males it may spread to the prostate, vas deferens, or

Fig. 11-75. Chronic cystitis caused by prostatic hyperplasia. The

wall of the bladder is thickened. The mucosa is focally


Cystitis is a very common disease. Acute cystitis usually is

caused by coliform bacteria. It is less common in men than
in women, who have shorter urethra and are more likely to
develop an ascending urinary tract infection. The urinary
bladder appears congested and may show shallow bleeding
ulcerations that result in hematuria (Fig 11-74). Chronic cystitis may result from recurrent bouts of acute infection. It
often is associated with predisposing conditions such as urinary stones or prostatic hyperplasia. The urinary bladder has
a thick wall and may show trabeculation as a result of smooth
muscle hypertrophy and hyperplasia (Fig. 11-75).
Several pathologic variants of chronic cystitis are recognized, and they do not necessarily have distinct clinical symptoms. Interstitial cystitis is a persistent form of cystitis of unknown etiology that typically affects women. It presents with
thickening of the wall of the urinary bladder and mucosal ulceration (Hunner ulcer) (Fig. 11-76).
Pseudomembranous cystitis may be a complication of chemotherapy. In this disease the urinary bladder undergoes
necrosis of the epithelium, and the surface of the bladder subsequently is covered with a pseudomembrane that is composed of fibrin and cell debris. The mucosa of the urinary
bladder of patients receiving chemotherapy may necrotize
and the urinary bladder may fill with blood and necrotic debris (Fig. 11-77).
Histologic features of chronic cystitis generally are nonspecific and provide few if any clues to the etiology of the disease. In interstitial cystitis the chronic inflammatory infil-

trate contains an increased number of mast cells, but these

cells also may occur in other forms of cystitis. Histologically
pseudomembranes may be recognized by their content of
fibrin and amorphous cell debris. Granulomatous cystitis has
been observed in patients treated by intravesical instillation
of bacille Calmette-Guerin (BCG) vaccine. Malacoplakia
(see Chapter 12) is characterized by the presence of
Michaelis-Gutmann bodies and von Hansemann histiocytes.
Chronically inflamed epithelium of the lower urinary
tract may show hyperplastic and metaplastic changes, which
are known in the urinary bladder as (1) von Brunn nests,
(2) cystitis cystica, (3) cystitis glandularis, (4) nephrogenic
metaplasia, and (5) squamous metaplasia (Figs. 11-78).

Fig. 11-76. Interstitial cystitis. The wall of the contracted bladder is edematous and thickened and the mucosa shows hemorrhagic ulceration.

Fig. I 1-77. Massive hemorrhagic cystitis. Urinary bladder of this

patient treated for Burkitt lymphoma is filled with clotted blood
and necrotic detritus.

Fig. I 1-78. Chronic cystitis. Inflammation and glandular metaplasia are seen.


The most important tumors of the kidney and the urinary
tract are (1) renal cell carcinoma, (2) Wilms tumor, and
(3) urothelial carcinoma. In comparison with these tumors,
which account for most neoplasms at this site, all other benign and malignant tumors are rare.

Tumors of the Kidney and Renal Pelvis

the most common renal tumor. It occurs in several histologic subtypes (Table 11-9). Most tumors
are of clear cell type. On gross examination tumors appear
as well-circumscribed, solid lobulated masses, of yellow
color, and with areas of necrosis or hemorrhage (Fig. 11-79).
Histologically the tumors are composed of clear cells arranged in an alveolar or diffuse pattern (Fig. 11-80). The tuRenal cell carcinoma is

Classification of Renal Cell Tumors

Benign Neoplasms
Renal oncocytoma
Renal cell carcinoma
Clear cell
Collecting duct carcinoma
Neuroendocrine tumors
Small cell carcinoma

mors are graded on a scale from 1 to 4 according to size, the

contour of nuclei, and the appearance of nucleoli (Table
Wilms tumor, or nephroblastoma, is a tumor of infancy
and childhood that arises from nephrogenic nests. The tumors may be unilateral or bilateral. On gross examination
nephroblastomas may replace the whole kidney, but often
they appear as circumscribed multinodular masses. On cross
section they are solid, soft, and grayish-white (Fig. 11-81).
Areas of hemorrhage, necrosis, or cystic degeneration are
common. Histologically they are composed of a mixture of
blastema-like epithelial and stromal cells and cells forming
tubules and cords (Fig. 11-82). The stroma component is
composed of loose connective tissue that occasionally may
show differentiation into skeletal muscle or cartilage. On the
basis of histologic features and the presence or absence of
anaplasia, nephroblastomas are classified as tumors of a favorable or an unfavorable nature. Unfavorable features are
large hyperchromatic nuclei and multipolar mitotic figures.
Nephroblastomas, which account for 80 percent of the renal
tumors of childhood, must be differentiated from mesoblastic nephroma, clear cell sarcoma, rhabdoid tumor, and
cystic nephroma.

Grading of Nuclei of Renal Cell Tumors

Grade I Rund, uniform nuclei approximately 10 p.m in diameter
with minute or absent nucleoli
Grade 2
Slightly irregular contours and diameters of approximately
I5 p.m with nucleoli visible at 400x
Grade 3
Moderately to greatly irregular nuclear contours and diameters of approximately 20 p.m with large nucleoli visible at
Grade 4
Nuclei similar to those of grade 3 but also multilobular or
multiple nuclei or bizarre nuclei and heavy clumps of chromatin

Fig. 11-80. Renal cell carcinoma. The tumor is composed of

Fig. I 1-79. Renal cell carcinoma. A relatively well demarcated
yellow tumor occupies the upper pole of the kidney.

clear cells arranged into alveoli surrounded by thin fibrovascular



Fig. 11-81. Wilms tumor. The multinodular tumor is replacing a

large portion of the renal parenchyma.

Fig. I 1-82. Wilms tumor. The tumor is composed of blastema,

primitive tubules, and loose stroma.

Fig. I 1-83. TCC of the renal pelvis. Wartlike tumor masses

protrude into the lumen of the pelvis.
Fig. I 1-84. TCC of the renal pelvis. The tumor is composed of
papillary and solid components.
Classification of Urinary Bladder Tumors
(Epithelial Neoplasms)
Transitional cell (urothelial) neoplasms
Nonpapillary (solid)
Carcinoma in situ and possible precursor lesions
Variants of TCC
TCC, nested type
TCC with glandlike lumens
Lymphoepithelial carcinoma
Squamous cell carcinoma, conventional type
Verrucous squamous cell carcinoma
Villous adenoma
Papillary, glandular, mucinous, signet-ring cell, and clear cell
Small cell carcinoma (neuroendocrine carcinoma)
Mixed carcinoma
Other epithelial neoplasms
Carcinoid tumor

Urothelial carcinomas of the renal pelvis and ureter present as exophytic and papillary masses that often fill the pelvis
and obstruct the ureter (Fig. 11-83). Histologically most
tumors are transitional cell carcinomas (TCC) (Fig. 11-84).
Approximately 10 percent of tumors are squamous cell carcinomas, and 1 percent to 2 percent of tumors show glandular differentiation and are classified as adenocarcinomas.
In all respects these tumors resemble the more common urinary bladder tumors.

Tumors of the Urinary Bladder

Most tumors of the urinary bladder arise from the urothelium; only a small fraction of all bladder tumors are of mesenchymal origin, arising from the smooth muscle or stromal
cells. A histologic classification of epithelial bladder tumors
is given in Table 11-11.


Fig. I 1-85. Carcinoma of the urinary bladder. This exophytic

tumor protrudes into the lumen of the bladder.

Fig. 11-86. Transitional cell papilloma, everted type. The central fibrovascular core is lined by transitional epithelium that has
a surface umbrella cell layer.

Fig. I 1-87. TCC. A, Grade I TCC is composed of slightly atypical cells forming a thickened transitional epithelium-like layer. B, Grade II TCC is composed of cells showing mild nuclear pleomorphism, hyperchromasia, and loss of polarity. C, Grade III TCC is composed of pleomorphic cells
showing variation in the size and shape of their nuclei and a complete loss of polarity.


Fig. 11-88. Carcinoma in situ of the urinary bladder. Pleomorphic cells have completely lost polarity, and the epithelium appears disorganized throughout its entire thickness.

Fig. 1 1-89. Small cell carcinoma of the urinary bladder with foci
of TCC.

Bladder tumors appear on gross examination as polyps or

exophytic cauliflower-like masses that protrude into the
lumen of the bladder (Fig. 11-85). Some tumors appear as
flat plaquelike lesions, whereas others show both an exophytic and an endophytic invasive component. Approximately 25 percent of bladder tumors are multifocal.
Papillomas are benign lesions of transitional epithelium
that occur in two forms: everted and inverted papillomas. Everted papillomas have a connective tissue core lined by seemingly normal transitional epithelium that is less than seven
cells thick and a surface umbrella cell layer (Fig. 11-86). Inverted papillomas are composed of similar cells that form
solid nests. They are rare and represent less than 1 percent of
all bladder tumors.
Transitional cell carcinomas (TCC) occur in three grades
(Fig. 11-87). Grade I tumors are papillary lesions that are
lined by slightly disorganized epithelium showing minimal
nuclear abnormalities and measuring more than seven layers
in thickness. Grade II lesions are multilayered, and to a large
extent the cells have lost their polarity. Grade III tumors are
composed of nests of disorganized cells that show marked
nuclear polymorphism. Adjacent epithelium may contain
carcinoma in situ (Fig. 11-88).
Pathologic findings are of prognostic significance. In
addition to the stage of the tumor, which is determined by
its size and the extent of local and metastatic spread, the
recurrence or progression and a clinically unfavorable outcome are related to (1) high tumor grade, (2) interruption of
basement membrane, (3) invasion into or below the muscularis mucosae, (4) detrusor muscle involvement, (5) invasion of blood vessels or lymphatics, (6) tentacular invasion,
(7) associated carcinoma in situ in adjacent epithelium, and
(8) multiple tumors.

Approximately 90 percent of urinary bladder tumors are

TCC, 9 percent are squamous cell carcinomas, and the remaining 1 percent are adenocarcinomas and small cell carcinomas. Sarcomas, most of which are leiomyosarcomas, are
Rhabdomyosarcoma is the most common malignancy of
the urinary bladder in children. The tumor presents in the
form of multiple, glistening, polypoid masses or a solitary
large mass that replaces the wall of the bladder. Histologically
it shows features of embryonal rhabdomyosarcoma (Fig.
Further Reading
Berden JHM: Lupus nephritis. Kidney hit 52:538-558, 1997.
Bostwick DG, Eble IN, Murphy GP: Conference summary: Diagnosis
and progression of renal cell carcinoma: 1997 workshop,
Rochester, Minnesota. Cancer 80:975-976, 1997.
Couser WG: Glomerulonephritis. Lancet 353:1509-1515, 1999.
Emancipator SN: IgA nephropathy: Morphologic expression and
pathogenesis. Am J Kidney Dis 23:451-460, 1994.
Epstein JI, Amin MB, Reuter VR et al: The World Health Organization/
International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of urinary bladder.
Am J Surg Pathol 22:1435-1448, 1998.
Lynch CF, Cohen MB: Urinary system. Cancer 75:316-329, 1995.
Pearson JM, McWilliams LJ, Coyne JD, Curry A: Value of electron microscopy in diagnosis of renal disease. J Clin Pathol 47:126-132,
Rennke HG: Secondary membranoproliferative glomerulonephritis.
Kidneylnt 47:643-651, 1995.
Reichert LJM, Koene RAP, Wetzels JFM: Prognostic factors in idiopathic membranous nephropathy. Am 'Kidney Dis 31:1-11, 1998.



The abnormal development of the testis may result in (1) abnormal positioning of one or both testes, including cryptorchidism, testicular ectopia, or dystopia; (2) numeric aberrations, including anorchia, monorchidism, or polyorchidism;
(3) structural malformations of the testes or epididymis;
(4) gonadal dysgenesis, which almost always is associated
with sex chromosome abnormalities and intersexuality; and
(5) abnormal spermatogenesis, including germ cell aplasia,
hypospermatogenesis, and various forms of maturation arrest associated with oligospermia or azoospermia.
Klinefelter syndrome is a chromosomal anomaly that usually is associated with a 47,XXY karyotype. The testes are atrophic and show no signs of spermatogenesis (Fig. 12-1).
Cryptorchidism, a term derived from Greek words
meaning "hidden testis, " is generally used as a synonym for
undescended testes, which may be unilateral or bilateral. Undescended testes are smaller than normal and remain small
even after orchidopexy. The histologic features vary depending on the age of the patient, the location of the testis,
and the treatment that has been carried out. Histologic
changes are minimal in 26 percent of patients. Marked germinal hypoplasia is found in 24 percent, diffuse tubular hypoplasia in 33 percent, and severe atrophy in 17 percent of
patients (Fig. 12-2). Approximately 25 percent of contralateral descended testes show similar changes, and in many cases
there also are epididymal abnormalities.

Fig. 12-1. Klinefelter syndrome. The seminiferous tubules have

been replaced by fibrous tissue. The remaining tubules have
thick hyalinized basement membranes and contain no
spermatogenetic cells (Courtesy of Drs. N. Skakkebaek and A.
Giwercman, Copenhagen, Denmark.)

Fig. 12-2. Cryptorchidism. The tubules appear dilated and show


Fig. 12-3. Germ cell aplasia. The tubules contain only Sertoli

Fig. 12-4. Maturation arrest of spermatogenesis. Spermatogenesis has not progressed beyond the stage of spermatocytes.
(Courtesy of Drs N. Skakkebaek and A. Giwercman,
Copenhagen, Denmark.)


Fig. 12-6. Hypogonadotropic hypogonadism. The small seminiferous tubules contain immature (fetal) Sertoli cells and a few

Fig. 12-5. Hypospermatogenesis. Only one seminiferous tubule

contains spermatozoa.

Disturbances of spermatogenesis occur in several forms.

The most severe form is aplasia of germ cells, in which the
seminiferous tubules contain only Sertoli cells (Fig. 12-3).
Maturation arrest may occur at any stage of spermatogenesis. The arrest typically is at the level of spermatocytes or
round spermatids (Fig. 12-4). Hypospermatogenesis is associated with hypoplasia of germinal epithelium, dilatation of
seminiferous tubules, and reduced sperm counts (Fig. 12-5).
Spermatogenesis also may be reduced as a result of hypothalamic or pituitary disorders that are characterized by a
lack of gonadotropin and hypogonadotropic hypogonadism.
This form of hypogonadism is typical of Prader-Willi prepubertal syndrome, Kallmann syndrome, pituitary apoplexy,
or hypothalamic tumors. Follicle-stimulating hormone and
luteinizing hormone deficiencies result in incomplete maturation of the testes. The testes are small and never attain
normal adult size. The seminiferous tubules are small and are
lined by immature Sertoli cells that have round nuclei and
inconspicuous nucleoli (Fig. 12-6). The germ cells are sparse,
and there is no evidence of spermatogenesis.

Infections of the male genital organs may occur in a localized form as orchitis, epididymitis, prostatitis, urethritis, or

Fig. 12-7. Suppurative epididymoorchitis. The testis contains


balanoposthitis, or in a diffuse form that involves all of the

genital organs and the lower urinary tract. Infections most
often are acquired through sexual transmission or from ascending urinary tract infections. Pathogens may reach the
genital organs hematogenously. Gonorrhea, syphilis, and
herpesvirus infection are typical sexually transmitted diseases. Mixed infections with uropathogens such as Escherichia coli or Pseudomonas aeruginosa are common causes of
infection in older men over the age of 60 years. Viruses such
as the mumps virus reach the testes hematogenously.
Ascending bacterial infections that reach the testes usually also affect the epididymis and cause a suppurative epididymoorchitis (Fig. 12-7). In contrast to bacterial infections,
viral infections cause an interstitial orchitis, which usually is
associated with spermatogenetic arrest (Fig. 12-8). Chronic
infections cause severe testicular destruction. The best
known example of such chronic infection is malacoplakia,
also known as granulomatous orchitis. In this disease the seminiferous tubules are infiltrated with numerous macro -


phages, lymphocytes, and plasma cells (Fig. 12-9). The macrophages have a prominent cytoplasm filled with residues of
phagocytosed bacteria and concentrically calcified round inclusions called Michaelis-Gutmann bodies. These bodies
have a characteristic targetoid appearance by electron microscopy (EM).
The testes may be damaged by a variety of systemic infections even if there is no direct invasion of testicular tissue
by pathogens. In acquired immunodeficiency syndrome
(AIDS) the testes show atrophy of germinal epithelium,
tubular hyalinization, interstitial fibrosis, a reduced number
of Leydig cells, and focal lymphocytic infiltrates (Fig. 12-10).

In most patients who histologically show extensive tubular

atrophy, hyalinization and loss (so-called end-stage testis disease), the cause of testicular injury usually cannot be determined (Fig. 12-11).


Testicular tumors account for approximately 1 percent of all
tumors of the internal organs in men. Germ cell tumors account for 92 percent to 95 percent of all neoplasms. Sex cord
cell tumors such as Leydig cell and sertoli cell tumors account
for 2 percent to 5 percent of all tumors, whereas the remainder are tumors of nonspecific stromal cells and metastases.
Malignant tumors are more common than benign tumors.
All age groups may be affected, but the peak incidence for
germ cell tumors typically is in the range of 25 to 40 age years
(Table 12-1).

Germ Cell Tumors

Fig. 12-8. Mumps orchitis. Mononuclear infiltrate is associated

with spermatogenic arrest.

The histogenesis of germ cell tumors has not been entirely

clarified, which reflects our ignorance about the initiation
and promotion of malignancy in this cell system. With an exception of some tumor types, such as spermatocytic seminoma and yolk sac tumor of infancy and childhood, all other
germ cell tumors pass through a preinvasive carcinoma in
situ (CIS) stage (Diagram 12-1). CIS, also known as intratubular testicular neoplasia (ITTN), appears in the form of
large atypical cells inside the tubules, which are devoid of
spermatogenesis (Fig. 12-12). CIS cells give rise to seminoma
or embryonal carcinoma (EC), cells, which are developmentally pluripotent cells that resemble early embryonic cells. EC
cells may mimic normal embryonic cells and form embryo-

Fig. 12-9. Malacoplakia A, The tubules are obliterated by a mononuclear infiltrate. B, By EM this
typical Michaelis-Gutmann body has a dark calcified center surrounded by a halo and a distinct rim.


Fig. 12-I I. End-stage testis disease. Most tubules are hyalinized,

and the interstitial spaces are dilated and fibrotic.

Fig. 12-10. AIDS. The seminiferous tubules are dilated hypocellular and show reduced spermatogenesis.

Fig. 12-12. CIS. Large neoplastic cells with centrally located

nuclei and clear cytoplasm are located along the basement

Classification of Testicular and

Epididymal Neoplasms
Germ cell tumors
Tumors of sex cord cells
Leydig cell tumors
Sertoli cell tumors
Mixed germ cellsex cord cell tumors
Tumors of the rete testis
Tumors of the epididymal epithelium
Tumors of mesothelial origin
Tumors of nonspecific stromal cells
Tumors derived from epithelial rests and choristomas
Tumors of hematopoietic cells

Diagram 12-1. Pathogenesis of germ cell tumors.


like structures, which are called embryoid bodies (Fig.

12-13). EC cells also may differentiate into various somatic
tissues, such as nerve, muscle, or glands, or into extraembryonic tissues, such as trophoblast or yolk sac epithelium. Tumors composed of EC cells and their derivatives are called
teratocarcinomas. For clinical purposes germ cells are divided
into two groups: seminomas and nonseminomatous germ
cell tumors (NSGCT). The latter is a heterogeneous group
that encompasses embryonal carcinoma, teratocarcinoma,
i mmature and mature teratomas, choriocarcinoma, and yolk
sac carcinomas. The histologic components of these tumors
most often are intermixed, and after a diagnosis of malignant

NSGCT has been established, it is only of academic interest

to enumerate all elements identified in the tumor. It is, however, important to note that the malignancy of NSGCT tumors resides primarily with EC cells. An abundance of EC
cells in a given tumor and extensive invasion of EC cell into
the blood vessels and lymphatics are related to an unfavorable prognosis.
Seminoma is the most common germ cell tumor. The
tumor appears lobulated and homogeneously yellowish on
cross section (Fig. 12-14). Histologically it is composed of
clear glycogen-rich cells arranged into nests that are surrounded by fibrous septa (Fig. 12-15). Fibrous septa are infiltrated with lymphocytes, macrophages, plasma cells, and occasionally multinucleated giant cells. The tumor cells are
positive for placental alkaline phosphatase (PLAP) and negative for keratin, which distinguishes them from EC cells,
which are PLAP-negative and keratin-positive. In approximately 20 percent to 30 percent of tumors there are scattered
trophoblastic giant cells. Seminomas are radiosensitive and
have a good prognosis.
Embryonal carcinoma is a tumor that grows much faster
than a seminoma. On gross examination it has a variegated
appearance because of broad areas of necrosis and hemorrhage (Fig. 12-16). Histologically it is composed of a single
population of undifferentiated cells, which have vesicular, irregularly shaped nuclei, and scant cytoplasm with indistinct
borders (Fig. 12-17).

Fig. 12-13. Embryoid body. It consists of an embryonic shield

and primitive amniotic and yolk sac cavities, and resembles early
human embryo.

Fig. 12-14. Seminoma. The tumor is homogeneously yellow and


Fig. 12-15. Seminoma. A, Clear tumor cells form nests surrounded by fibrous strands infiltrated with lymphocytes.
B, Placental alkaline phosphatase is demonstrated in tumor cells.


Teratocarcinoma is a tumor that is composed of EC cells

and their somatic and extraembryonic derivatives (Figs.
12-18 to 12-20). Extraembryonic tissues include trophoblastic and yolk sac elements. Trophoblastic cells secrete
human chorionic gonadotropin (hCG), and yolk sac carcinoma cells secrete alpha-fetoprotein (AFP). Antibodies to
hCG and AFP are used to demonstrate these tumor components immunohistochemically in tissue sections. In some tumors these cells may proliferate and overshadow all others.
Pure yolk sac carcinomas and choriocarcinoma are rare in
the testis (Fig. 12-21). Teratoma of adult testis ostensibly is a
histologically benign tumor composed of somatic tissues
that are devoid of EC cells. Such teratomas develop from teratocarcinomas in which all EC cells have differentiated into
histologically benign somatic tissues (Fig. 12-20). However,
one can never be sure that all malignant cells have disappeared from such tumors, many of which actually are capable

Fig. 12-16. Embryonal carcinoma. On cross section the tumor has

an inhomogeneous texture.

Fig. 12-17. Embryonal carcinoma. The tumor is composed of

undifferentiated cells with scant cytoplasm. The nuclei appear
crowded and overlap.

Fig. 12-18. Teratocarcinoma. On cross section the tumor shows

irregular nodularity and appears to be composed of heterogeneous

Fig. 12-19. Teratocarcinoma. The tumor is composed of hyperchromatic EC cells and other loosely arranged elements.

Fig. 12-20. Teratoma. The tumor is composed of neural tissue,

squamous epithelium, and connective tissue stroma.


Fig. 12-21. Choriocarcinoma. Clear cytotrophoblastic and

multinucleated syncytiotrophoblastic cells are surrounded by
extravasated blood.

Fig. 12-22. Yolk sac tumor. The tumor is composed of epithelial cells forming solid nests and strands lining irregular cavities.

ranged into dense sheets. Medium-sized principal cells with

round nuclei and scant cytoplasm predominate. Small cells
that resemble lymphocytes are scattered at random or form
small clusters. Giant cells, which measure up to 100 pm in
diameter, are the least common (Fig. 12-23). Spermatocytic
seminoma generally is a benign tumor, although a few malignant ones have been described.

Sex Cord Stromal Tumors

Fig. 12-23. Spermatocytic seminoma. The tumor consists of

three types of cells: medium-sized principal cells, small cells, and
giant cells.

of progressive growth and metastasis. Teratomas of infancy

and childhood are benign tumors, which probably have a histogenesis entirely different from that of tumors of adult testis.
Yolk sac tumor, a neoplasm composed of pure yolk sac elements, is the most common tumor of infancy. Histologically it consists of yolk saclike tissue that is similar to the
yolk sac components of teratocarcinoma (Fig. 12-22). Yolk
sac tumors of infancy have a good prognosis.
Spermatocytic seminoma is a germ cell tumor of older
adults. It apparently is unrelated to NSGCT tumors and is
not associated with CIS. It is composed of three cell types ar-

Tumors of specialized gonadal stroma include Leydig cell tumors, Sertoli cell tumors, and granulosa cell tumors.
Leydig cell tumors are composed of cells that resemble
normal Leydig cells and therefore may be hormonally active.
These tumors account for 2 percent to 3 percent of testicular
neoplasms. They most often occur in the 30- to 60-year age
group, but approximately 20 percent of Leydig cell tumors
are found in children. Most Leydig cell tumors are benign,
but 10 percent are malignant. On gross examination they
appear as well-circumscribed brown nodules. Histologically
they are composed of polyhedral cells that have welldeveloped eosinophilic cytoplasm and vesicular round nuclei (Fig. 12-24). The cytoplasm may be vacuolated because
of fat droplets or may contain brown pigment (lipofuscin).
Typical Reinke crystals are sparse and are found in only one
third of tumors. There are few mitoses, even in those tumors
that are clinically malignant and metastasize. Hormonally inactive tumors do not differ from those that are hormonally
active; androgen-secreting tumors are not different from
estrogen-secreting tumors. Benign Leydig cells cannot be histologically distinguished from malignant Leydig cells, and
the presence of metastases is the only reliable sign of malignancy.


Fig. 12-24. Leydig cell tumor. The tumor is composed of solid

nests of uniform cells that have vesicular round nuclei,
prominent nucleoli, and well-developed eosinophilic cytoplasm.

Fig. 12-25. Sertoli cell tumor. Tumors form cords and groups
that resemble tubules.

Fig. 12-26. Sertoli cell, large cell calcifying type. Tumor is

composed of tubules lined by Sertoli cells. It contains prominent
foci of calcification.

Fig. 12-27. Gonadoblastoma. Tumor nests composed of germ

cells and sex cord cells are surrounded by dense stroma that
contains lymphocytes. Foci of calcification may be seen in epithelial nests, often replacing them.

Sertoli cell tumors are composed of cells that resemble

adult or fetal Sertoli cells. Sertoli cells account for 1 percent
of all testicular tumors. They occur in all age groups. Clinically they are benign or malignant. Histologically Sertoli cell
tumors are composed of cells that form nests and cords reminiscent of seminiferous tubules (Fig. 12-25). Other variants
are (1) tubular, which are known as tubular adenoma of Pick;
(2) large cell calcifying; (3) sclerosing; (4) sex cord tumor
with annular tubules; and (5) anaplastic, which may invade
and metastasize (Fig. 12-26).

tumor of the adult testes. The latter tumor is benign and resembles such tumors in the dysgenetic ovary, the most common site of their occurrence.
Gonadoblastomas are tumors of dysgenetic gonads and are
found in infants, children, and adolescents. Almost all gonadoblastomas described so far were found in persons who have
a Y chromosome. Histologically they are composed of nests
of germ cells and sex cord cells surrounding round bodies
composed of basement membranelike material (Fig.
12-27). Areas of calcification are common. The abundant
stroma surrounding these nests may contain lymphocytes.
Invasive germ cell tumors may evolve from gonadoblastomas.

Mixed Germ Cell Stromal Tumors

Tumors composed of germ cells and sex cord stromal cells
occur in two forms: gonadoblastoma and mixed germ cell


Fig. 12-29. Adenomatoid tumor. Tissue spaces are lined by

flattened epithelial cells surrounded by cords of cuboidal cells in
connective tissue stroma.
Fig. 12-28. Adenocarcinoma of rete testis. Cuboidal tumor cells
form tubules and papillae that project into their lumen.

Tumors of Bete Testis, Epididymis, and Tunica

Vaginalis Testis
Tumors of rete testis are very rare. These lesions may be benign or malignant. Carcinoma of rete testis is a tumor that occurs in men over the age of 40 years. Histologically it appears
as adenocarcinoma with papillary and tubular features (Fig.
12-28). Epithelial tumors of the epididymus resemble
miillerian serous or mucinous adenomas and adenocarcinomas of the female genital system.
The mesothelium of the tunica vaginalis may give rise to
benign and malignant tumors. Benign tumors are called adenomatoid tumors; malignant tumors are called malignant
mesotheliomas and are similar to peritoneal or pleural mesotheliomas.
Adenomatoid tumors are small nodules that measure from
a few millimeters to 5 to 6 cm in diameter. Histologically these
tumors are composed of epithelial cells arranged into cords
or strands in dense connective stroma, lining glandlike or
cystic spaces (Fig. 12-29).


The two most important diseases of the prostate are benign
prostatic hyperplasia (BPH) and carcinoma of the prostate.

Benign Prostatic Hyperplasia

BPH is a disease of old age that results from proliferation of
epithelial and stromal cells of the periurethral and transitional zone of the prostate. BPH is a common disorder, accounting for approximately 400,000 partial prostatectomies
per year in the United States. The pathogenesis of BPH is not
understood, but it is apparent that it is hormonally mediated
and that androgens play an important role in its development. The enlarged prostate contains rubbery, yellow-gray

Fig. 12-30. Benign prostatic hyperplasia (BPH). Shelled-out prostate contains numerous nodules.

nodules that bulge from the surface (Fig. 12-30). The prostate
nodules may compress and deform the urethra (Fig. 12-31).
The enlarged median bar may protrude into the urinary
bladder, acting as a ball valve.
Microscopically BPH typically is nodular and is composed of varying proportions of epithelium and stroma comprising fibrous connective tissue and smooth muscle (Fig.
12-32). In addition to this most prevalent form of hyperplasia, several histologic variants are recognized (Figs. 12-33
to 12-35). The most important histologic variants are
1. Atrophy, which is characterized by small distorted
glands.lined by flattened epithelium, hyperchromatic nuclei,
and stromal fibrosis. The incidence of atrophy increases with
2. Postatrophic hyperplasia, in which clear cells proliferate in an atrophic background. Such cells often show nuclear atypia, and the glands contain mucin.
3. Basal cell hyperplasia, which is characterized by several layers of basal cells at the periphery of the prostatic
glands and acini. The hyperplastic basal cells usually are
larger than normal, elongated or spindled basal cells; they
often show nuclear enlargement.


Fig. 12-3I. BPH. Periurethral prostate appears nodular.

Fig. 12-32. BPH. The lesions typically are composed of hyperplastic glands and stroma.

Fig. 12-33. BPH, atrophic variant. The distorted glands are

lined by flattened epithelium.
Fig. 12-34. Cribriform hyperplasia. The glands have a cribriform

4. Atypical basal cell hyperplasia, which is composed of

large basal cells with prominent nucleoli.
5. Basal cell adenoma, which consists of large, circumscribed nodules composed of basal cells arranged into solid
nests or cystically dilated glands. Stromal connective tissue
often traverses the adenomatous nodule, creating incomplete
6. Adenoid cysticlike tumor (adenoid basal cell tumor),
which is composed of nests of basaloid cells that infiltrate the
stroma. In contrast to basal cell adenoma, this lesion is not
circumscribed. The cell nests frequently are large and round
to angular. Peripheral basaloid cells have elongated nuclei
and often show palisading. Cell crowding is prominent, and
the lumina surrounded by such cells vary in size and shape.
Peripheral invasion may be seen, but there are no metastases.
7. Cribriform hyperplasia, including clear cell cribriform
hyperplasia, which usually presents as a nodule composed of
glands that have a distinctive cribriform pattern. The cells
from such glands usually have pale to clear cytoplasm and
small uniform nuclei with inconspicuous nucleoli.

Fig. 12-35. Stromal hyperplasia with atypia. Stromal cell nuclei

vary in size and shape and appear hyperchromatic.

25 0

8. Atypical adenomatous hyperplasia (adenosis), in which

a localized but circumscribed proliferation of small glands
within the prostate may be mistaken for carcinoma.
9. Sclerosing adenosis, in which there is striking myoepithelial metaplasia of the basal cell compartment, and the
stroma is exuberant and contains loose ground substance
surrounding fibroblasts. The basal cells react positively with
antibodies to S-100 protein and smooth musclespecific
actin, as evidence of myoepithelial metaplasia.
10. Stromal hyperplasia with atypia composed of hypercellular nodules that show crowding of cells, hyperchromasia, and nuclear enlargement with atypia. There are,
however, no mitoses or necrosis, and such stromal nodules
should not be considered malignant. Solid stromal nodules
composed of smooth muscle cells are referred to as atypical
11.Phyllodes tumor, which is a rare benign tumor that has
the features of a fibroadenoma and resembles the more
common breast tumors. The glandular epithelium is distorted, lining slitlike spaces. The stroma, which is composed

of fibroblasts and smooth muscle cells, appears proliferative.

Benign and malignant phyllodes tumors are differentiated
on the basis of a number of factors, including the ratio of
stroma to epithelium and the degree of stromal cellularity,
mitotic activity, and cytologic atypia.

Carcinoma of the Prostate

Prostatic intraepithelial neoplasia (PIN) represents the putative precancerous end of the morphologic continuum of cellular proliferations that occur within prostatic ducts, ductules, and acini (Diagrams 12-2 and 12-3). The cells show
nuclear atypia but are enclosed by a basement membrane
(Fig. 12-36). Several architectural patterns, such as flat,
tufting, micropapillary, or cribriform, are recognized. Adenomatous hyperplasia, a localized proliferation of small glands
with varying degrees of nuclear atypia, is another possible
preinvasive lesion (Fig. 12-37).
Carcinoma of the prostate is the most common form of
cancer among men in the United States. Estimates are that in
1998 more than 45,000 men will die of prostate cancer and

Diagram 12-2. The architectural patterns assumed by high-grade PIN. A, Tufting pattern.
B, Micropapillary pattern. C, Cribriform pattern. D, Flat pattern. (From Bostwick DG et al: Hum
Pathol24:298, 1993.)

Diagram 12-3. Morphologic continuum from normal prostatic epithelium through increasing grades of PIN to early
invasive carcinoma, according to the disease continuum concept. Low-grade PIN (formerly grade I) corresponds to
very mild to mild dysplasia. High-grade PIN (formerly grades 2 and 3) corresponds to moderate to severe dysplasia and
CIS. The precursor state ends when malignant cells invade the stroma; this invasion occurs where the basal cell layer is
disrupted. Notice that the dysplastic changes occur in the superficial (luminal) secretory cell layer, perhaps in response
to lumina) carcinogens. Disruption of the basal cell layer accompanies the appearance of the architectural and cytologic
features of high-grade PIN and appears to be a necessary prerequisite for stromal invasion. (From Bostwick DG,
Brawer MK: Cancer 59:788, 1987.)

Fig. 12-36. PIN. This high-grade lesion has a flat pattern.

Fig. 12-37. Atypical adenomatous hyperplasia. Small proliferating

atypical glands form a cluster adjacent to the normal prostatic


Fig. 12-38. Carcinoma of the prostate. A, The main tumor appears as a circumscribed, yellowwhite mass in the lateral peripheral zone of the prostate. Additional microscopic foci were found
bilaterally in the periphery. B, Transition zone cancer is characterized by a bulging asymmetric
mass that is present in association with BPH (arrow).

Fig. 12-39. Carcinoma of the prostate. Cross section of tumor

shows that it has invaded the seminal vesicles and the fat tissue.

Fig. 12-40. Carcinoma of the prostate. It extends into the

rectum and urinary bladder.


more than 250,000 cases will be diagnosed. Approximately

80 percent of all 80-year-old men have been found to have
prostate cancer at autopsy, indicating that only a fraction of
these tumors become clinically apparent. Carcinoma of the
prostate tends to occur in peripheral parts of the gland (Figs.
12-38 and 12-39) but also may occur in the transition zone.
Carcinoma invades the seminal vesicles (Fig. 12-39) and may
extend into other pelvic organs (Fig. 12-40).

Microscopically, prostatic carcinoma most often consists

of small glands that exhibit a myriad of patterns. The diagnosis is dependent on confirmation of architectural and cytologic findings (Fig. 12-41).
Several histologic variants of prostatic carcinoma are recognized. The clinical and pathologic features of these variants are summarized in Table 12-2, and the salient features
are shown in Fig. 12-42.

Fig. 12-41. Carcinoma of the prostate. A, Gleason pattern I. B, Gleason pattern 2. C, Gleason
pattern 3, small gland subtype. D, Gleason pattern 3, cribriform subtype. E, Gleason pattern 4,
with fused glands. F, Gleason pattern 5, with little or no glandular differentiation.


Carcinoma of the prostate is graded according to the

system developed by Gleason (Table 12-3, Diagram 12-4).
The Gleason system takes into account the degree of
glandular differentiation, accommodating tumor heterogeneity by assigning a primary pattern for the dominant

grade and a secondary pattern for the nondominant grade;

the composite histologic score is derived by including the
scores for the dominant and secondary patterns. Typical
histologic patterns used for Gleason grading are shown in
Fig. 12-41.

Fig. 12-42. Variants of prostatic carcinoma. A, Ductal (endometrioid) carcinoma. B, Small cell
carcinoma. C, Mucinous (colloid) adenocarcinoma. D, Signet-ring cell carcinoma. E, Urothelial
carcinoma of the prostate. F, Adenocarcinoma after androgen deprivation therapy.

25 4

Variants of Prostate Adenocarcinoma

Ductal (endometrioid) adenocarcinoma
Histologic features: Florid papillary, cribriform, or solid epithelial proliferation in large periurethral prostatic ducts
Clinical features: Often presents at an advanced stage without elevation of serum PSA level

Histologic features: Adenocarcinoma with sarcomatous elements (for
example, cartilage, bone, and smooth muscle)
Clinical features: Poor prognosis, apparently the same as sarcomatoid

Small cell, undifferentiated carcinoma (high-grade neuroendocrine carcinoma)

Histologic features: Identical to counterpart in lung and other sites
Clinical features: Very poor prognosis, with mean survival less than 2
years; may be associated with paraneoplastic syndromes such as
Cushing syndrome, inappropriate antidiuretic hormone secretion,
and others

Transitional cell carcinoma of the prostate

Histologic features: May be primary in the prostate or prostatic urethra but usually is secondary to bladder involvement. Tumor may
be in situ or invasive within the prostate; look for pagetoid spread,
which rarely may extend along the ejaculatory ducts through the
prostate to the seminal vesicles
Clinical features: Unfavorable prognosis; important to distinguish from
adenocarcinoma because tumor is refractory to androgen deprivation therapy

Mutinous (colloid) carcinoma

Histologic features: At least 25 percent of tumor is composed of
extracellular mucin, some with extraglandular mucin and mucin
lakes. Rare variant includes colonic-type carcinoma of the prostate,
but this pattern usually is a result of contiguous spread from rectal
Clinical features: Similar or slightly worse than those of conventional
Signet-ring cell carcinoma
Histologic features: Typical signet-ring cell features, with tumor cells
showing PAP and PSA immunoreactivity; mucin may or may not be
present; usually mixed with typical acinar adenocarcinoma
Clinical features: Very rare in pure form; very poor prognosis
Squamous cell carcinoma of the prostate
Histologic features: Most commonly seen as mixed adenosquamous
carcinoma but may be pure squamous cell carcinoma with typical
malignant features
Clinical features: Mixed adenosquamous and pure squamous cell carcinoma pattern may appear after irradiation or hormonal therapy
for typical acinar adenocarcinoma. Pure squamous cell carcinoma is
rare and carries a very poor prognosis; it is refractory to androgen
deprivation therapy

Adenoid basal cell tumor (adenoid cystic carcinoma or basal

cell carcinoma)
Histologic features: Nests of basaloid round to oval cells, often with a
cribriform pattern; look for luminal mucin and eosinophilic basement membranelike material
Clinical features: Very rare, with no definite metastatic tumors or
Lymphoepithelioma-like carcinoma
Histologic features: Islands of closely packed glands set in a dense lymphocytic stroma
Clinical features: Only one reported case; unknown prognostic significance
Adenocarcinoma after androgen deprivation therapy
Histologic features: Shrunken, closely packed glands with optically clear
cytoplasm and inconspicuous nucleoli
Clinical features: Unknown; no long-term follow-up studies of this histologic pattern

Sarcomatoid carcinoma of the prostate

Histologic features: Spindle cell carcinoma, usually with typical acinar
carcinoma; immunohistochemical results may be positive for PSA,
keratin proteins, and other epithelial markers; main differential
diagnosis is carcinosarcoma, and some authors do not make this
Clinical features: Poor prognosis, death in less than 48 months
PAP, Prostatic acid phosphatase; PSA, prostate-specific antigen.

Further Reading
Blute ML, Bostwick DG, SeayTM et al: Pathologic classification of prostate carcinoma. The impact of margin status. Cancer 82:902-908,
Bostwick DG, Amin MB, Dundore Petal: Architectural patterns of highgrade prostatic intraepithelial neoplasia. Hum Pathol 24:298-310,
Bostwick DG, Dousa MK, Crawford BG, Wollan PC: Neuroendocrine
differentiation in prostatic intraepithelial neoplasia and adenocarcinoma. Am J Surg Pathol 18:1240-1246, 1994.
Bostwick DG: Grading prostate cancer. Am J Clin Pathol 102:S38-S56,

Cheville JC, Dundore PA, Bostwick DG et al: Transitional cell carcinoma of the prostate. Clinicopathologic study of 50 cases. Cancer
82:703-707, 1998.
Cubilla AL, Barreto JE, Ayala G, Riveros M: Pathologic features of epidermoid carcinoma of the penis. Am J Surg Pathol 17:753-776,
Cubilla AL, Reuter VE, Gregoire L et al: Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm: a report of 20 cases. Am J Surg Pathol 22:755-761, 1998.
Eble JN: Spermatocytic seminoma. Hum Pathol 25:1035-1042, 1994.
Eble JN: Variants of prostatic hyperplasia that resemble carinoma. J Urol
Pathol 8:3-20, 1998.


Gleason Grading System for Prostatic Adenocarcinoma: Histologic Patterns

Diagram 12-4. Gleason grading system of prostatic adenocarcinoma

Epstein JI: Diagnostic criteria of limited adenocarcinoma of the prostate

on needle biopsy. Hum Pathol 26:223-229, 1995.
Epstein JI: Pathology of prostatic intraepithelial neoplasm and adenocarcinoma of the prostate. Prognostic influences of stage, tumor,
volume, grade, and margins of resection. Semin Oncol 21:527-541,
Grignon DJ: Minimal diagnostic criteria for adenocarcinoma of prostate. J Urol Pathol 8:31-44, 1998.
Heidenreich A, Sesterhenn IA, Mostofi FK, Moul JW: Prognostic risk
factors that identify patients with clinical stage I nonseminomatous germ cell tumors at low risk and high risk for metastasis.
Cancer 83:1002-1011, 1998.
Jones MA, Young RH, Scully RE: Malignant mesothelioma of the tunica vaginalis. A clinicopathologic analysis of 11 cases with review
of the literature. Am J Surg Pathol 19:815-825, 1995.
Murphy WM: Prognostic factors in the pathological assessment of
prostate cancer. Hum Pathol 29:427-430, 1998.
Ohori M, Egawa S, Wheeler TM: Nodules resembling nodular hyperplasia in the peripheral zone of the prostate gland. J Urol Pathol
2:223-234, 1994.
Piaton E, Fendler J-P, Berger Net al: Clinical value of fine-needle aspiration cytology and biopsy in the evaluation of male infertility. A
comparative study of 48 infertile patients. Arch Pathol Lab Med
119:722-726, 1995.
Randolph TL, Amin MB, Ro JY, Ayala AG: Histologic variants of adenocarcinoma and other carcinomas of prostate: pathologic criteria
and clinical significance. Mod Pathol 10:612-629, 1998.
Ulbright TM: Germ cell neoplasm of the testis. Am J Surg Pathol
17:1075-1098, 1993.
van de Voorde W, Baldewijns M, Lauweryns J: Florid basal cell hyperplasia of the prostate. Histopathology 24:341-348, 1994.
Young RH, Koelliker DD, Scully RE: Sertoli cell tumors of the testis,
not otherwise specified. A clinicopathologic analysis of 60 cases.
Am J Surg Pathol 22:709-721, 1998.


The development of the female genital organs is complex
for two main reasons: various parts of the system develop
from distinct embryonic primordia such as genital ridges,
mullerian ducts, and cloaca; and proper development de -

pends on genetic and hormonal regulation. Clinically important conditions that involve abnormal sexual development are listed in Table 13-1, and some of these conditions
are illustrated in Figs. 13-1 to Fig. 13-6.

Intersex Syndromes Affecting Females, Apparent Females, or Female Genitalia

Courtesy of Dr. Robert H. Shikes, Denver, Colorado.


Fig. 13-2. Turner syndrome. Streak gonad consists of ovarian

type of stroma without follicles. Hilar vessels and rete ovarii are
seen in the lower portion of the figure.
Fig. I3-I. Turner syndrome and gonadal dysgenesis. A, Streak
gonad is attached to a hypoplastic uterus. B, The dysgenic gonad
contains a gonadoblastoma that appears like a small nodule.

Fig. 13-3. External genitalia in mixed gonadal dysgenesis. Left

testis has descended into the scrotum; the right gonad was a
streak in the abdomen.

Fig. 13-4. Androgen insensitivity (testicular feminization) syndrome. Bisected testis appears dark brown and contains hamartomatous nodules.

Fig. 13-5. Androgen insensitivity (testicular feminization) syndrome. Histologically the testis consists of immature solid tubules
lined by Sertoli cells.

Fig. 13-6. Persistent miillerian duct syndrome (hernia uteri inguinalis) secondary to deficiency of miillerian inhibitory substance
( MIS). The hernia sac of this phenotypic male contains endomyometrium.


Infections of the female reproductive system may be localized to external or internal genital organs and occur in an isolated form such as vulvitis, vaginitis, cervicitis, endometritis,
salpingitis, or oophoritis; or they may involve the entire reproductive system as a chronic inflammation known as pelvic inflammatory disease (PID). The infections may be acute
or chronic and are caused by various pathogens. Most of
these infections are sexually transmitted or are related to infections in other parts of the body.
Herpes simplex virus 2 is a very common cause of infection of the vulva. Infection tends to occur in the form of vesicles, which ulcerate and then heal spontaneously (Fig. 13-7).
Condyloma acuminatum, or giant genital warts, are found on
the vulva but also may occur on the cervix. These lesions are
caused by several types of human papillomavirus (HPV) and
present as whitish-gray, wartlike excrescences (Fig. 13-8).
Histologically these lesions are squamous cell papillomas
composed of cells that show typical nuclear and cytoplasmic
changes (koilocytosis), which may be recognized in histologic sections and Papanicolaou (Pap) smears (Fig. 13-9).
Trichomas vaginalis is the most common cause ofvaginitis
in sexually active women. The flagellate protozoan resides in
the lumen of the vagina and maybe recognized in Pap smears
(Fig. 13-10, A). Infection with the bacterium Gardnerella
vaginalis is yet another cause of vaginitis and leukorrhea. In
Pap smears the bacteria tend to adhere to squamous cells,
which assume a peculiar appearance and are known as "clue
cells " (Fig. 13-10, B).
PID, which is an infection of the internal genital organs,
may occur in the form of a recurrent acute infection or as a
chronic infection. Infections tend to center on the fallopian
tubes, and salpingitis is almost a sine qua non for the diagnosis of PID. The fallopian tubes are distorted, swollen, and
thick-walled (Fig. 13-11). These infections, which are caused

Fig. 13-8. Condyloma acuminatum. Exuberant keratotic papillary processes cover and obliterate large areas of the vulva.

by a mixed flora, including gram-negative coliform bacteria,

gram-positive bacteria, Chlamydia, and Ureaplasma, may
cause tumor-like periovarian and peritubal abscesses or may
spread to the peritoneal cavity. Intraluminal fibrosis and adhesions impart the tube's complex and multiglandular appearance on cross section (Fig. 13-12).

Fig. 13-7. Herpesvirus infection of the vulva. Mucosa shows

numerous vesicles, some of which have ruptured. (Courtesy of
Dr. Cynthia Caputo, Kansas City, Missouri.)

Fig. 13-9. Condyloma acuminatum. Papillary processes are

covered by orderly squamous epithelium, each supported by a
fibrovascular connective tissue stalk.


Fig. I3-I0. Vaginal infections. A, A Trichomonas vaginalis infection. Protozoans are seen between
the epithelial cells. B, Gardnerella vaginalis showing "clue cells."

Fig. 13-I I. Chronic salpingitis. Both fallopian tubes are retortshaped and swollen and show adhesions to the ovaries.

Fig. 13-12. Chronic follicular salpingitis. The lumen of the fallopian tube is partially obliterated by deformed, swollen villi infiltrated with mononuclear cells. Epithelial hyperplasia may be
prominent and may simulate adenocarcinoma.


Fig. 13-13. Anovulatory cycle. Endometrium has failed to enter

the secretory phase and shows ischemic stromal necrosis.

The entire female reproductive system normally is under the

influence of female sex hormones, but it also may respond to
male hormones, hormone-like drugs, and hormone antagonists. During the reproductive life of a woman, estrogen and
progesterone act in a cyclic manner. This cycle ends at the
time of menopause but also is interrupted by pregnancy and
lactation and may be perturbed by exogenous hormones,
contraceptive pills, and various drugs.
Lack of sex hormones or their excess may cause typical
changes, most prominently in the uterus. Anovulatory cycles
result in prolonged estrogenic stimulation, and when the endometrial mucosa exceeds its capacity to respond, it undergoes necrosis and a hemorrhage ensues (Fig. 13-13). Excess
of endogenous or exogenous estrogens leads to endometrial
hyperplasia, which is classified histologically as simple, corn -


Fig. 13-14. Simple (cystic) hyperplasia. Endometrial glands are

dilated and cystic. There are thrombosed vessels in the abundant
stroma between the glands.

Fig. 13-15. Complex hyperplasia (adenomatous hyperplasia).

Glands are fairly widely separated by stroma but exhibit architectural complexity. Cytologic atypia is absent.

Fig. 13-16. Complex hyperplasia with atypia. Cells within these

closely packed glands lack polarity and show stratification and
nuclear atypia resembling to some extent well-differentiated

Fig. 13-17. Polycystic ovarian disease (PCOD). A, On cross section the enlarged
ovary has abundant central stroma and subcapsular follicles. B, Prominent stroma
and follicles are seen in the histology section. The follicles show theca cell
hyperplasia and atrophy of the granulosa cells.


plex, or complex with atypia (Figs. 13-14 to 13-16). Endometrial hyperplasia is a reversible benign lesion, but in some
cases, especially if it is associated with atypia, it may progress
to endometrial carcinoma.
The ovaries function as part of the hypothalamicpituitary-ovarian and adrenal system. Disturbances of this
system are considered to be the major cause of polycystic
ovarian disease (PCOD). In this relatively common hor-

monal disorder, which is associated with menstrual irregularities and infertility, the dysfunctioning ovaries are enlarged and contain numerous follicular cysts (Fig. 13-17).
The follicles, which are composed of nonluteinized granulosa cells and an outer layer of luteinized theca cells, are surrounded by dense cortical stroma that may form an external
fibrous capsule. Hyperthecosis may be seen in deeper parts
of the cortex. PCOD may be treated hormonally, albeit with
varying results.
Endometriosis is a disease of unknown etiology. It is characterized by the appearance of ectopic endometrial tissue on
the serosal surface of the fallopian tube, ovary, pelvic peritoneum, and less often on other sites. Most foci of endometriosis are small, measuring only a few millimeters in diameter. Larger nodules (endometriomas), which usually are
found on the ovary, are filled with old blood and are colloquially called " chocolate cysts " (Fig. 13-18). Histologically
endometriosis consists of endometrial glands and stroma,
which respond to hormonal stimulation and tend to become
hemorrhagic at the time of normal menstruation. Endometriosis may be treated hormonally, but large endometriomas and some complications (e.g., intestinal adhesions)
may require surgery.


Squamous cell carcinoma and its precursor lesions, vulvar in-

Fig. 13-18. Ovarian endometriosis. A, "Chocolate cyst."

B, Histologically the nests are composed of endometrial glands
and stroma.

Fig. 13-19. VIN. Lesion is white and well circumscribed. It involves the left labium minus.

traepithelial neoplasia (VIN), represent the most important

neoplastic vulvar lesions. These lesions must be distinguished clinically and pathologically from viral warts (condyloma acuminatum) and nonneoplastic vulvar dystrophies,
such as lichen plan us et acuminatus atrophicans, which may
present clinically as leukoplakia or kraurosis vulvae.
Carcinoma of the vulva is believed to begin as an intraepithelial malignancy that progresses over time to invasive
cancer (Fig. 13-19). VIN, a term that has replaced older terms
such as carcinoma in situ, Bowen disease, and erythroplasia of

Fig. 13-20. VIN with anal interepithelial neoplasia (VIN-AIN).

Many atypical cells are scattered through all layers of the epidermis.


Queyrat, may be graded histologically on the basis of the

extent of cytologic atypia. The neoplastic process tends to
spread horizontally. It may involve large portions of the vulva
and may even extend to the anus (Fig. 13-20). Vertical growth
with invasion of the underlying stroma ensues in untreated
cases (Fig. 13-21). Invasive cancer usually presents as indurated ulcers (Fig. 13-22). Metastases are found first in inguinal lymph nodes, but they also occur in the pelvic and
abdominal lymph nodes and hematogenously may reach distant organs.
Extramammary Paget disease is an intraepidermal neoplasm that has features of adenocarcinoma. Grossly it appears as an eczematoid patch with discrete borders and white
keratotic areas and typically begins on the labia majora. Histologically the epidermis contains pale vacuolated adenocarcinoma cells scattered between the compressed but otherwise normal squamous cells (Fig. 13-23). The epithelium of
hair follicles and apocrine glands also is typically involved.
An underlying adenocarcinoma is found in approximately
one third of all cases. In the presence of invasive growth and
metastasis the tumor has a poor prognosis.
Other tumors of the vulva, such as melanoma, adenocarcinoma of Bartholin glands, and stromal neoplasms, are
rare. Locally invasive aggressive angiomyxoma is a rare but
i mportant lesion of the labia. It usually affects women under
the age of 40 years. The lesion appears as a soft, circumscribed, myxoid mass that is composed of hypocellular myxoid tissue with numerous muscular medium-sized arteries
(Fig. 13-24). The tumor cells are fibroblasts and myofibroblasts that lack significant nuclear atypia but nevertheless
have a propensity to invade local tissues. The tumor may
recur locally but metastases have not been reported.

Fig. 13-22. Invasive squamous cell carcinoma of vulva. The

tumor appears ulcerated.

Fig. 13-21. Carcinoma of the vulva. Radical vulvectomy and bilateral inguinal lymphadenectomy were performed for this squamous cell carcinoma of the left labia.

Fig. 13-23. Vulvar Paget disease. Neoplastic cells infiltrate the

epidermis in small clumps. Squamous cells of the epidermis itself
are histologically benign and compressed by tumor, and the
underlying dermis is not involved by cancer cells.



The most common malignant tumor of the vagina is squamous cell carcinoma, which has the same features as the more
common carcinomas of the vulva and the cervix. Other tumors are less common but deserve to be mentioned because
of their unique features.
Vaginal adenosis is a benign condition that has been reported in young women who were exposed to diethylstilbestrol (DES) during fetal life. On gross examination foci of
vaginal adenosis appear red and velvety, in contrast to the
more opaque, pale pink normal vagina. Histologically the
lesions are composed of glands lined by mucinous columnar
epithelium (Fig. 13-25). Invasive adenocarcinoma may
evolve from some of these lesions (Fig. 13-26). Histologically
these tumors are clear cell adenocarcinomas and are similar
to those in the ovary or uterus (Fig. 13-27). Tumor cells are
rich in glycogen, and electron microscopy (EM) shows that
they have prominent apical microvilli.
Benign mixed tumor of the vagina is a rare tumor that may
be confused with sarcoma. The tumor occurs in young
women (median age 30 years) and is located in or just above
the hymenal ring. Histologically this small (1 to 5 cm in di-

Fig. 13-24. Aggressive angiomyxoma. A, The tumor presented

as a large, soft, myxoid, well-circumscribed mass. B, Hypocellular myxoid tissue surrounds numerous medium-sized blood

Fig. 13-25. Vaginal adenosis. Mucosa of the exocervix and adjacent vagina contains mucinous glands in place of normal squamous epithelium. Mucus is PAS-positive (red).

Fig. 13-26. Clear cell adenocarcinoma of the vagina subsequent

to in utero exposure to diethylstilbestrol. Carcinoma appears as
an ulcerated nodule (right). The cervix (left) shows an abnormal


ameter) tumor is composed of bland spindle-shaped " stromal" elements admixed with epithelial foci (Fig. 13-28). Both
the spindle-shaped cells and the epithelial cells appear to be
of epithelial origin.
Embryonal rhabdomyosarcoma (botryoid sarcoma) is the
most common malignant vaginal tumor in girls under the
age of five years. The tumor presents as a grapelike polypoid
mass protruding from the vagina (Fig. 13-29). Histologically
it is composed of malignant spindle-shaped cells that
forming dense aggregates that are separated from the surface
squamous epithelium by a lucent loosely textured zone
( "cambium layer " ) (Fig. 13-30). Tumor cells may show crossstriations and react with antibodies to desmins, indicating
that they represent rhabdomyoblasts.


Fig. 13-27. Clear cell adenocarcinoma arising in vaginal adenosis

from a young women exposed in utero to diethylstilbestrol. The
tumor is composed of tubulocystic glands.

Fig. 13-28. Benign mixed tumor of the vagina. A mixture of stromal and squamous cells is seen in the submucosa. Cells show no
significant atypia.

Fig. 13-29. Embryonal rhabdomyosarcoma of the vagina (botryoid sarcoma). A fleshy mass protrudes into the lumen of the

Fig. 13-30. Embryonal rhabdomyosarcoma of vagina (botryoid

sarcoma). The tumor is composed of embryonic rhabdomyoblasts.

Most tumors of the cervix originate from the squamocolumnar junction between the squamous epithelium of the
exocervix and the glandular epithelium of the endocervix
(transitional zone). Tumors also originate from the squamous epithelium itself, but the neoplastic transformation of
the glandular epithelium of the endocervix is less common.
Most tumors are classified as squamous cell carcinomas; adenocarcinomas are considerably less common.
Carcinoma of the cervix begins as an intraepithelial neoplasm that is termed cervical intraepithelial neoplasia (CIN).
It is graded on the basis of cellular and architectural atypia
as CIN I, CIN II, or CIN III. These lesions maybe recognized
by colposcopy (Fig. 13-31).


The National Cancer Institute recently proposed a new

terminology (Bethesda System) according to which the
three-grade CIN scheme was reduced to two grades of squamous intraepithelial lesion (SIL). The lesions that formerly
were designated CIN I, mild koilocytic dysplasia, and simple
koilocytotis now are grouped under one heading, low-grade
squamous intraepithelial lesion (LSIL) (Fig. 13-32). Lesions
that previously were classified as CIN II and CIN III are called
high-grade squamous intraepithelial lesion (HSIL) (Figs.
13-33 and 13-34). The main reason for the change in terminology is the apparent differential distribution of HPV in
these lesions. HPV 6 and HPV 11 account for 70 percent to
90 percent of HPV associated with flat and exophytic condy-

lomas; HPV 16 is found in nearly one half of CIN III and invasive carcinomas. Low-grade lesions usually are diploid or
polyploid and tend to regress. High-grade lesions are aneuploid and are more likely to progress. It is becoming increasingly obvious that LSIL represents a productive viral infection, whereas HSIL is a true neoplastic intraepithelial lesion,
and the two entities do not appear to be related.
Invasive carcinoma of the cervix may appear as an ulcer, an
indurated mass, or a polypoid cauliflower-like lesion (Fig.
13-35). Staging and grading of cervical cancer are important
for clinical assessment, therapy, and prognosis. Carcinoma
of the cervix spreads by direct invasion of contiguous tissues
and lymphogenously to local lymph nodes. Distant metastases are found at autopsy in the lungs and liver in 25 percent
of patients.
Adenocarcinoma of the cervix occurs in several histologic
patterns. Clear cell carcinoma of the cervix may be similar to

Fig. 13-31. HSIL. Colposcopy shows a mosaic pattern and accentuated punctate vessels against a background of white-red
opaque epithelium.

Fig. 13-32. LSIL (CIN I) of the cervix. This lesion, also known
as flat condyloma, is characterized by koilocytotic atypia and
usually is related to HPV 6 or HPV I I infection.

Fig. 13-33. HSIL (CIN II) of the cervix. Abnormal squamous

epithelial cells appear atypical, but they vary considerably in size
and shape and have a relative abundance of cytoplasm. Maturation is evident at the surface.

Fig. 13-34. HSIL (CIN III) of the cervix. Abnormal cells have
uniform size and shape and relatively scant cytoplasm. There is
no evidence of maturation.


Fig. 13-35. Invasive squamous cell carcinoma of the cervix. Ulcerated invasive lesion extends into the endocervix.

Fig. 13-36. Villoglandular adenocarcinoma of the cervix. The

tumor resembles a colonic polyp. No stromal invasion is seen.

the clear cell carcinoma of the vagina or endometrium. A

well-differentiated mucinous adenocarcinoma may be difficult to distinguish from reactive changes in the normal endocervix.
Villoglandular papillary adenocarcinoma is a newly recognized variant. It is characterized by exophytic growth, elongated fibrovascular papillae that are lined by well-differentiated, slightly atypical cuboidal cells (Fig. 13-36). Malignant
mixed miillerian tumors, carcinosarcomas, and smooth
muscle tumors similar to those in the body of the uterus
rarely are found in the cervix.

velop endometrial cancer during her life span. Estrogenic

stimulation plays an important pathogenetic role in lowgrade ( "endometrioid") cancer of post menopausal women
and cancer that is associated with endometrioid hyperplasia.
The more aggressive forms of endometrial cancer (serous,
adenosquamous, and clear cell carcinoma) that occur in
women of reproductive age do not seem to be related to hyperestrinism.
Endometrial carcinoma presents as an intrauterine lesion
that invades the myometrium and extends into the cervix
(Fig. 13-37). Several histologic patterns are recognized (Table
13-2). Endometrioid carcinoma, the most common subtype,
is graded histologically according to the scheme adopted by
the International Federation of Gynecology and Obstetrics
(FIGO) (Figs. 13-38 and 13-39). Other variants, such as
serous papillary carcinoma, clear cell carcinoma, and adenocarcinoma with squamous differentiation, have typical histologic features (Figs. 13-40 to 13-42). Histologic features have
prognostic implications, but the stage of the tumor is the
most important prognostic parameter (Table 13-3).


Tumors of the body of the uterus may arise from endometrial glands, endometrial stroma, or the myometrium.

Endometrial Adenocarcinoma
Adenocarcinoma of the uterus occurs in menopausal and
postmenopausal women. In industrialized countries its incidence has surpassed the incidence of cervical cancer, and in
the United States it is estimated that 1 in 100 women will de -

Classification of Endometrial Carcinoma*

With squamous differentiation
Secretory carcinoma
Ciliated carcinoma
Serous papillary adenocarcinoma
Clear cell adenocarcinoma
Mucinous adenocarcinoma
Squamous cell carcinoma
Mixed carcinomat
Un_ i
_;tiated carcinoma

Fig. 13-37. Adenocarcinoma of the endometrium. The tumor

*Modified from the World Health Organization and International Society

of Gynecological Pathologists classifications of endometrial carcinoma.

fills the endometrial cavity. Obvious myometrial invasion in seen.

t o carcinoma containing more than 10 percent of a second cell type.


Fig. 13-38. Endometrial adenocarcinoma, FIGO grade I. Glands

show back to back and gland within gland arrangement.

Fig. 13-39. Endometrial adenocarcinoma, FIGO grade I, secretory type. Tumor cells have cytoplasmic vacuoles.

Fig. 13-40. Serous papillary adenocarcinoma of the endometrium.

Thick connective strands forming papillae are lined by stratified
anaplastic cells.

Fig. 13-41. Clear cell carcinoma. Glands are lined by clear

hobnail-like cells.

International Federation of Gynecology

and Obstetrics (FIGO) Staging of
Endometrial Adenocarcinoma (1988)

Fig. 13-42. Adenocarcinoma with squamous differentiation

(adenoacanthoma). The glands are malignant but the squamous
epithelium appears benign.


Endometrial Stromal Tumors

Tumors that originate from the endometrial stromal cells include benign endometrial stromal nodules, low-grade endometrial stromal sarcomas (ESS), and high-grade ESS.
Benign endometrial stromal nodules form single, well-circumscribed masses that often resemble leiomyomas but
differ from them by their yellow color and softer consistency.
They most often are located in the myometrium, but some
nodules protrude into the endometrial cavity (Fig. 13-43).
Histologically these nodules resemble endometrial stroma,
with numerous evenly distributed small vessels. Stromal lesions of distinct trabecular architecture may form a variety
of glandlike structures and may mimic sex cord stromal
ovarian tumors. The lesions often are found under the serosa
of the uterus and are called plexiform tumorlets. Similar his-

tologic elements may be found in typical endometrial

stromal nodules and ESS.
Low-grade ESS occur as grossly circumscribed nodules
with or without extensive intravascular extension (endolymphatic stromal myosis). The most characteristic feature is the
presence of numerous wormlike masses that protrude from
the vascular spaces on cut surface. Microscopically these tumors also are composed of endometrial stromal cells that resemble the stroma of proliferative stage endometrium or that
of benign endometrial stromal nodules. In contrast to these
benign lesions, the cells of ESS infiltrate the adjacent myometrium (Fig. 13-44). Mitotic figures may be prominent.
High-grade ESS are malignant tumors that form one or
more nodules and polypoid masses that protrude into the
lumen and invade the myometrium. These tumors are composed of cells that resemble endometrial stromal cells even
less than those of the low-grade ESS (Fig. 13-45). There are

Fig. 13-43. Endometrial stromal nodule. A well-circumscribed

nodule protrudes into the endometrial cavity. The tumor was
limited to the endometrium. (From Lloreta J, Prat J: Int J Pathol
11:293, 1992)

Fig. 13-44. Low-grade ESS. The myometrium appears infiltrated

with irregularly contoured aggregates of tumor cells that resemble endometrial stromal cells.

Fig. 13-45. Low-grade ESS. Tumor cells resemble endometrial

cells of proliferative endometrium and are separated by a network of small blood vessels.

Fig. 13-46. Malignant mixed miillerian tumor. The large multinodular tumor has a variegated cross section with areas of
hemorrhage and necrosis.


prominent small blood vessels between the cells, and mitotic

figures are prominent; usually there are more than 10 mitotic
figures per 10 high-power fields (HPFs). The histologic appearance of the tumor is, however, more reliable than its mitotic rate as a predictor of the biologic behavior of ESS.
Mixed mullerian tumors are composed of both epithelial
and mesenchymal cells and are classified as carcinosarcomas.
Typical lesions protrude into the endometrial cavity as large
irregular polypoid masses (Fig. 13-46). Histologically they
are composed of poorly differentiated, often papillary endometrial adenocarcinoma and homologous or heterologous
malignant stromal cells (Fig. 13-47). Homologous stromal
cells resemble endometrial stroma, whereas the heterologous
elements include cells that resemble chondrosarcoma,
rhabdomyosarcoma, or osteosarcoma cells. These tumors
have a poor prognosis. .

Fig. 13-47. Malignant mixed miillerian tumor. Carcinomatous

component is of the papillary serous type, and the stroma consists of large pleomorphic spindle cells.

Fig. 13-48. Adenosarcoma. Apparently benign glands are surrounded by neoplastic stromal cells.

Miillerian adenosarcoma is a variant in which the homologous stromal elements form a sarcomatous stroma and the
glandular epithelium is benign (Fig. 13-48).

Tumors of the Myometrium

Tumors of the myometrium originate from smooth muscle
cells and thus are classified as leiomyomas or leiomyosarcomas.
Leiomyoma is the most common benign tumor of the
uterus. It presents in the form of well-circumscribed, firm
nodules that appear gray-white and have a characteristic
whorled appearance on cross section. These nodules often
are multiple and vary considerably in size and shape (Fig.
13-49). By location they may be submucosal, intramural, or
subserosal. Histologically they are composed of smooth
muscle cells that have typically elongated "cigar-shaped" nuclei and eosinophilic cytoplasm that has no distinct borders
(Fig. 13-50).
Several histologic variants are recognized. Lipoleiomyomas contain a sizable adipose tissue component. Cellular
leiomyomas are highly cellular and may resemble endometrial stromal nodules. Nevertheless, the fusiform nuclei, fascicular growth pattern, and lack of extensive vascular network provide clues to the leiomyomatous nature of these
lesions. Bizarre (symplastic) leiomyomas have a frightening
appearance on microscopy because of many giant cells with
very large, cytologically malignant-looking nuclei, which
may be multiple. Mitotic figures are sparse. This lesion occurs in premenopausal women and occasionally is associated
with exogenous progestin intake. Epithelioid leiomyoma
(leiomyoblastoma) is composed of cells that have clear
glycogen-rich cytoplasm and resemble leiomyoblastomas of
the gastrointestinal tract. They show low mitotic activity and
generally are benign. A few more aggressive tumors of this
type have been reported, but they contained more numerous

Fig. 13-49. Multiple leiomyomas. In sagittal section there are

numerous, well- circumscribed, solid, light gray nodules distorting the uterus.


Fig. 13-5 I . Intravenous leiomyomatosis. Intravascular cast of

smooth muscle cells contains prominent blood vessels.

Fig. 13-50. Leiomyoma. A, Spindle cells are arranged in a typical interlacing pattern. B, Elongated nuclei have rounded ends
and are described as "cigar-shaped."

Fig. 13-52. Leiomyomatosis peritonealis disseminata. Omentum

contains multiple nodules of smooth muscular tissue, grossly
simulating metastatic leiomyosarcoma.

Fig. 13-53. Leiomyosarcoma of the uterus. Intramural, solitary

mass shows foci of necrosis.

Fig. 13-54. Leiomyosarcoma. Spindle-shaped nuclei show marked

hyperchromasia. Mitotic figures are present.


Some smooth muscle cell tumors may behave aggressively,

belying their benign microscopic appearance. These variants
include intravenous leiomyomatosis, metastasizing leiomyomatosis, and peritoneal leiomyomatosis. Intravenous leiomyomatosis is characterized by the presence of grossly visible
intravenous proliferation of benign smooth muscle cells,
usually found in the pelvic veins. Such intravascular masses
usually consist of benign smooth muscle cells and prominent
blood vessels (Fig. 13-51). Peritoneal leiomyomatosis refers to
extensive proliferation of histologically benign smooth
muscle cells, typically limited to peritoneal cavity. Such intravascular masses usually consist of benign smooth muscle
cells that form microscopic or macroscopic nodules on the
peritoneal surfaces (Fig. 13-52). These lesions most often
occur in pregnancy or under hormonal stimulation and tend
to regress after the hormonal stimulus is withdrawn. Metastasizing leiomyoma is a term used to describe a benign uterine
leiomyoma that is associated with secondary nodules in the
lymph nodes or the lungs. These lesions are composed of benign smooth muscle cells and have no mitotic activity. Some
of them are related to hormonal stimulation or pregnancy
and may regress following cessation of hormonal stimulation or termination of pregnancy.
Leiomyosarcomas are rare malignant tumors of smooth
muscle cells. They account for one third of all uterine sarcomas. Estimates are that 1 in 800 smooth muscle cell tumors
of the uterus is malignant. On gross examination they usually appear as solitary, soft, intramural masses that distort the

uterus. On cross section they appear yellow or brown and

show numerous areas of hemorrhage and necrosis (Fig.
13-53). Histologically they are composed of spindle-shaped
cells arranged into fascicles (Fig. 13-54). There typically is
focal or diffuse hypercellularity and marked nuclear atypia.
Mitotic figures are found at a rate of more than 10 per 10
HPFs. Tumors that are mitotically less active may pose diagnostic problems. It has been recommended that tumors that
have more than 5 mitotic figures per 10 HPFs and show nuclear atypia should be designated leiomyosarcoma; those that
have the same mitotic rate but show no nuclear atypia are
designated mitotically active leiomyomas.


Ovarian tumors occur in many forms and generally are classified as originating from the surface epithelium, sex cord
stromal cells, and germ cells (Table 13-4).
Serous Tumors
Serous tumors are classified as benign, borderline malignant,
and malignant. Serous cystadenoma is a benign cystic mass
that has one or multiple cavities filled with clear serous fluid
(Fig. 13-55). Histologically the cavities are lined by cuboidal
or low columnar uniform epithelium, which may be ciliated
or pseudostratified as in the fallopian tube (Fig. 13-56). Papillary processes are common and may be complex. Similar
epithelium may cover the external surface of the cysts. Borderline malignant tumors more often are multilocular and

World Health Organization Classification of Ovarian Tumors


Fig. 13-55. Serous cystadenoma. The cystic mass has a smooth

surface. It is filled with clear serous fluid and appears translucent.

Fig. 13-56. Serous cystadenoma. A, Fluid has flowed out from the main cyst. There still are
several smaller unopened cysts. B, Cyst is lined by cuboidal cells that have round or elongated
regular nuclei with evenly distributed chromatin.

Fig. 13-57. Borderline serous tumor of ovary, a multilocular cystic mass with spaces lined by papillary epithelial masses.

Fig. 13-58. Serous borderline tumor of the ovary. Prominent

papillae lined by cuboidal epithelium project into the lumen of
the cystic tumor.


form complex papillae on their internal surface (Fig. 13-57).

Papillae are lined by cells that show atypia, mitotic activity,
and stratification (Fig. 13-58). Microinvasion of the stroma
may be present, and in approximately 30 percent of cases
there are peritoneal implants. Peritoneal implants are classified as invasive or noninvasive; the former are further divided
into epithelial and desmoplastic subtypes (Fig 13-59). The
cells of these implants resemble the original tumor and may
show mild to moderate atypia. Similar.tumors may arise from
the peritoneum without ovarian neoplasia. Malignant serous
tumors (serous cystadenocarcinomas) form papillae, invade
stroma, and contain many solid areas (Fig. 13-60). Peritoneal
seeding and ascites often are present.

Mutinous Tumors
Mucinous tumors typically are large, cystic, mucus-filled

masses, which on cross section may be classified as unilocular or multilocular (Fig. 13-61). The cavities are lined by tall
columnar epithelium that resembles endocervical glands.
Such cells have basally located nuclei and apical cytoplasm
filled with mucus (Fig. 13-62). More often the epithelium
may contain goblet cells, interspersed with neuroendocrine
and even Paneth cells, and resembles intestinal epithelium.
Borderline mucinous tumors account for 40 percent to 50
percent of all mucinous malignant tumors. Such tumors
differ from benign cystadenomas in that they show more nuclear unrest, atypia, and focal invasion (Figs. 13-63 and

Fig. 13-59. Serous borderline tumor of the ovary. A, Paratubal implant of serous borderline
tumor of noninvasive epithelial type. Papillae fill submesothelial invaginations. B, Invasive implant
of serous borderline tumor. Tumor nests resemble low-grade serous carcinoma but are composed of cells that show no atypia and are devoid of mitotic figures.

Fig. 13-60. Serous carcinoma of the ovary. This carcinoma is

composed of glands that contain papillary projections lined by
cuboidal cells.

Fig. 13-61. Mucinous cystadenoma of the intestinal type. Mucus

was removed from the main cavity, but it still shines through the
wall of smaller cysts.


Fig. 13-62. Mucinous cystadenoma of the intestinal type. Mucinrich goblet cells line the central cavity of this cystic tumor.
Fig. 13-63. Mucinous intestinal cystadenoma of borderline malignancy. Irregular glands are lined by relatively uniform mucus-rich
cells. There is no stromal invasion.

Fig. 13-64. Mucinous endocervical (miillerian) cystadenoma of

borderline malignancy. Mucin-rich tumor cells line edematous
papillae that are infiltrated with neutrophils.

Fig. 13-65. Mucinous intestinal cystadenocarcinoma. The tumor

appears as a solid mass.

Fig. 13-66. Mucinous intestinal cystadenocarcinoma, FIGO

grade II. Mucin-rich cells pile up within atypical glands invading
the stroma.

Fig. 13-67. Endometrioid adenocarcinoma. The tumor is a solid



13-64). In 85 percent of cases cysts are lined by intestinal-like

epithelium. Borderline tumors of the endocervical type have
a better prognosis than those of the intestinal type.
Mucinous cystadenocarcinomas are obviously malignant
tumors that contain large solid parts or may be composed
entirely of solid tissue (Fig. 13-65). Histologically such tumors are adenocarcinomas lined by mucus-producing cells.
The solid area may contain anaplastic carcinoma or rarely
sarcoma. Sarcoma-like stromal reaction occasionally is seen,
but it is inconsequential from the clinical point of view. The
distinction between borderline malignant and low-grade
malignant mucinous tumors may be difficult. The main
reason for this diagnostic dilemma lies in the nature of
stromal reaction to the tumor. Instead of being desmoplastic,
the stroma of the tumor may be luteinized and may resemble
ovarian stroma, which.makes it almost impossible to determine whether there is any true invasion (Fig. 13-66). Empiric
criteria have been proposed, and carcinoma is diagnosed if
the tumor forms layers that are four or more cells thick; if it

forms finger-like projections of solid cellular masses without

connective tissue support; or if the neoplastic glands have a
cribriform growth pattern. Recently it was proposed that intestinal mucinous borderline tumors may be separated from
well-differentiated carcinomas by quantitative nuclear morphologic analysis.
Extraovarian spread of mucinous tumors results in peritoneal seeding and mucinous ascites known as pseudomyxoma peritonei. There often is a simultaneous mucinous
tumor of the appendix, and there is controversy over whether
these represent two independent primary tumors, that is,
multifocal primaries, a metastasis of the ovarian tumor to the
appendix, or vice versa.
Endometrioid Carcinoma

Fig. 13-68. Well-differentiated endometrioid adenocarcinoma

of the ovary. Histologically it is identical with uterine endometrial adenocarcinoma.

Endometrioid carcinomas account for 20 percent to 30 percent of all ovarian cancers. They are so named because of
their histologic resemblance to uterine adenocarcinomas.
The similarity is most evident in well-differentiated tumors.
Less-differentiated lesions may have a typical endometrioid
appearance only focally, which together with additional foci
of squamous differentiation may be the only clue to the true
nature of such tumors.
Endometrioid adenocarcinomas present as solid or partially cystic ovarian masses (Fig. 13-67). Histologically they
resemble endometrioid adenocarcinomas of the uterus and
are graded the same way (Fig. 13-68).
The criteria for borderline malignant endometrioid tumors are not well established. Such criteria are most easily
applied to endometrioid tumors that have a prominent stromal component. These tumors are called adenofibromas and
may be classified as benign, borderline malignant, or malignant (Fig. 13-69). Endometrioid tumors that have a malignant stromal component are classified as carcinosarcomas
and are equivalent to uterine malignant mixed mullerian tumors. Adenosarcomas and endometrial stromal sarcomas also
occur in the ovary, but they are rare.

Fig. 13-69. Endometrioid adenofibroma of borderline malignancy. The tumor contains glands and squamous morules with
central necrosis.

Fig. 13-70. Clear cell adenocarcinoma. Tubulocystic pattern is

identical to that found in clear cell carcinomas of the vagina, cervix, and endometrium.


Clear Cell Carcinoma

Clear cell carcinomas account for approximately 10 percent
of all ovarian cancer. On gross examination they appear as
solid or partially cystic masses. Microscopically they are
characterized by masses of large epithelial cells with clear cytoplasm arranged into glands or solid nests. The most
common pattern is that of small tubules and cysts lined by a
single layer of cuboidal hobnailed cells (Fig. 13-70). Benign
and borderline clear cell tumors rarely occur, usually as adenofibromas. The association between clear cell carcinoma
and endometriosis is six times greater than that of ovarian
carcinomas in general.

Transitional Cell Tumors

Transitional cell tumors include benign Brenner tumors,
transitional cell carcinomas that originate from Brenner tumors (malignant Brenner tumor), and transitional cell carcinomas that are of surface epithelial origin and are unrelated to a preexisting Brenner tumor.

Brenner tumor is a benign lesion that accounts for 2 percent to 3 percent of all ovarian tumors. In 25 percent of cases
Brenner tumors are found within mutinous ovarian tumors.
Tumors typically appear as small, fibrotic nodules, which histologically are composed of nests of transitional epithelium
surrounded by dense fibrous stroma (Fig. 13-71). The epithelial nests may be solid or may have a central lumen that contains dense eosinophilic material or mucus. The tumor cells
are polygonal and have grooved nuclei and clear cytoplasm.
The cells lining the central lumen may be filled with mucin.
The surrounding stroma often is hyalinized and may contain
foci of calcification. Less than 2 percent of all Brenner tumors
are classified as borderline malignant or overtly malignant.
The epithelial component of borderline malignant Brenner
tumors resembles grade I papillary carcinomas of the urinary bladder, and no invasion of the stroma is seen. In malignant Brenner tumors the nests have features of higher grade
transitional cell malignancy (Fig. 13-72). Similar tumors may
originate from the surface epithelium unrelated to Brenner
tumors, but such transitional carcinomas of the ovary are

Sex Cord Stromal Tumors

Fig. 13-71. Brenner tumor. Solid tumor nests are enclosed by

fibroblastic stroma.

Fig. 13-72. Malignant Brenner tumor. Cells in the nest to the

left show significant atypia.

Sex cord stromal tumors originate from specialized and nonspecific stroma of the ovary. Accordingly, the tumors are
composed of cells that resemble granulosa cells, theca cells,
luteinized and nonluteinized fibroblastic stromal cells, and
hilar luteinized cells. Sex cord stromal tumors account for
most hormonally active ovarian tumors.
Granulosa cell tumors usually present as solid masses with
some cystic parts. On cross section solid areas appear brown
or grayish-yellow and typically contain blood clots. Approximately 75 percent of all granulosa cell tumors are estrogenic,
whereas others are either nonfunctioning or androgenic. Less
than 5 percent are bilateral. Granulosa cell tumors are composed of cells that resemble normal granulosa cells. Tumor
cells have oval nuclei with prominent clefts (coffee bean
shaped nuclei) and often are arranged into rosette-like structures, known as Call-Exner bodies, which are reminiscent of
those found in normal graafian follicles (Fig. 13-73).
Several microscopic patterns are recognized. Microfollicular and macrofollicular patterns recapitulate the histologic features of graafian follicles. Tumors may have a trabecular, insular, or gyriform pattern, but these descriptive
terms do not have significant clinical implications. Diffuse or
sarcomtoid tumors may behave more aggressively.
Juvenile granulosa tell tumor, a variant that is found in
girls, has a distinct histologic appearance. It consists of cells
that often are luteinized and form rudimentary follicles or
solid masses (Fig. 13-74). All granulosa cell tumors should
be considered potentially malignant, although 90 percent of
patients survive 10 years after surgery. Late recurrences may
occur even beyond that period. The most consistent indicator of aggressive behavior is the presence of metastases or
invasion of surrounding tissues outside the ovary. Other unfavorable signs, which are not consistently reliable predictors


Fig. 13-73. Granulosa cell tumor. A, Microfollicular pattern. B, Tumor cells have clefted, coffee
beanshaped nuclei.

Fig. 13-74. Juvenile granulosa cell tumor. Cells form rudimentary follicles. Tumor cell nuclei show some atypia, and their cytoplasm appears luteinized and clear.

of malignancy, are large tumor size, tumor rupture, and high

mitotic rate. Tumors of older patients appear to be more aggressive than those of younger women.
Fibromas of the ovary account for 6 percent of all ovarian
tumors. These hormonally nonfunctioning tumors are composed of fibroblasts that form solid masses. On cross section
the masses are white and have a whorled appearance (Fig.
13-75). Fibromas are benign, even if they are classified as cellular and mitotically active. Fibrosarcomas are rare and resemble equivalent soft-tissue tumors. Thecomas are similar
to fibromas, but they are hormonally active and are composed of luteinized stromal cells. Because of the luteinization
of tumor cells, theca cell tumors appear yellow on cross section (Fig. 13-76). Histologically they consist of fibroblast-like
tumor cells, which may have a somewhat more abundant cy -

Fig. 13-75. Fibroma. On cross section this lipid-rich tumor appears white and fibrotic.

Fig. 13-76. Thecoma. On cross section this lipid-rich tumor appears yellow.

28 0


Fig. 13-77. Thecoma. A, The tumor is composed of spindle-shaped cells. B, Fat stain (oil red 0)
shows lipid droplets in the cytoplasm of tumor cells.

Fig. 13-78. Sclerosing stromal tumor of the ovary'. Spindleshaped and clear cells form nests surrounded by loosely structured stroma and thin-walled vessels.

Fig. 13-79. Sertoli-Leydig cell tumor. The tumor is yellow on

cross section.

Fig. 13-80. Sertoli-Leydig cell tumor. The well-differentiated

tumor consists of tubules and groups of Leydig cells.

Fig. 13-81. Sertoli-Leydig cell tumor. This tumor shows intermediate differentiation, and its cells form cords.


toplasm than the cells of fibromas. Such cells typically contain fat droplets that may be demonstrated by special stains
(Fig. 13-77). Thecomas are benign tumors of older women
(80 percent are postmenopausal), and malignant variants are
extremely rare.
Sclerosing stromal tumor of the ovary belongs to the general category of fibroblastic stromal tumors, but it differs
from fibromas and thecomas both clinically and morphologically. These tumors occur in women under the age of 30
years and are composed of distinct nests of spindle-shaped
stromal and clear cells separated from other similar nests by
loosely structured stroma (Fig. 13-78). The tumor typically
contains thin-walled vessels. Luteinization of cells occurs at
a variable rate, and occasional tumors may be hormonally
Sertoli-Leydig cell tumors occur in all age groups, but their
peak incidence is in younger women (average age 25 years).
These tumors typically are solid, yellow, and often lobulated
N(Fig. 13-79). They secrete androgenic hormones and cause
virilization. Histologically Sertoli-Leydig cell tumors have
features of a developing testis and are composed of cells that
resemble Sertoli cells and Leydig cells. Five histologic patterns are recognized:
1. Well-differentiated tumors in which Sertoli cells form
tubules surrounded by nests of Leydig cells
2. Tumors of intermediate differentiation, which are composed of cords, abortive tubular structures, and nests of
luteinized Leydig cells and spindle-shaped stromal cells
3. Sarcomatoid variant, which is composed of spindleshaped cells with focal formation of vague tubular structures
and only sparse Leydig cells, which maybe missing altogether
4. Retiform tumors, which mimic rete ovarii or rete testis
5. Sertoli-Leydig cell tumors with heterologous elements,
such as neoplastic mucous glands, cartilage, or skeletal
muscle cells (Figs. 13-80 to 13-82). Almost all Sertoli-Leydig
cell tumors are benign. The rare malignant tumors were
poorly differentiated and had mesenchymal heterologous elements. Intraabdominal spread but not extraabdominal
metastases were recorded in such cases.

Fig. 13-83. Sex cord tumor with annular tubules. Eosinophilic

globules are surrounded by spindle-shaped cells.

Sex cord stromal tumor with annular tubules (SCTAT) is a

unique tumor composed of cells that have intermediate features of granulosa cells and Sertoli cells. These tumors occur
in patients with Peutz-Jeghers syndrome. They have a favorable prognosis in most instances. Histologically they are
composed of tubules lined by spindle-shaped cells arranged
around centrally located globules of eosinophilic basement
membrane likematerial (Fig. 13-83). Gynandroblastoma is
a term that is used to describe Sertoli-Leydig cell tumor cognates that also contain incontrovertible granulosa cells.
Steroid lipid (cell) tumors are distinctive tumors that appear as yellow or brown nodules or larger masses. They include three entities: stromal luteomas, hilar cell tumors, and
steroid cell tumors not otherwise specified (NOS). These tumors are hormonally active and usually are benign, except
for steroid cell tumors NOS, which may be malignant. Histologically they are composed of polyhedral luteinized cells
with round nuclei and well-developed eosinophilic, lipidrich cytoplasm (Fig. 13-84).

Fig. 13-82. Sertoli-Leydig cell tumor, sarcomatoid variant. The

tumor is composed of spindle-shaped cells.

Fig. I3-84. Stromal luteoma. The tumor is composed of polyhedral cells that have round centrally located nuclei and welldeveloped eosinophilic cytoplasm.


Germ Cell Tumors

Germ cell tumors of the ovary originate from the oocytes and
are histologically equivalent to testicular and extragonadal
germ cell tumors.
Dysgerminoma is the most common malignant germ cell
tumor of the ovary. It occurs in young women and is considered to be an ovarian equivalent of testicular seminoma.
Grossly it appears as a gray-white or yellowish lobulated solid
mass (Fig. 13-85). Histologically it is composed of polygonal
clear cells arranged into nests that are surrounded by stroma
infiltrated with lymphocytes (Fig. 13-86). Dysgerminomas
are extremely radiosensitive and have a good prognosis; the
five-year survival rate is approximately 95 percent.
Embryonal carcinoma of the ovary is rare. Choriocarcinoma is composed of cytotrophoblastic and human chorionic gonadotropin (hCG)positive syncytiotrophoblastic
cells. Yolk sac carcinoma is an alpha-fetoproteinsecreting
tumor of women under the age of 20 years. Histologically the

tumor may present in several patterns, including reticular,

microcytic, tubular, and so forth (Figs. 13-87 and 13-88).
Glomeruloid Schiller-Duval bodies are typical. Tumors also
contain periodic acid-Schiffpositive, diastase-resistant hyaline globules.
Benign cystic teratoma (dermoid) is the most common
germ cell tumor of the ovary. It typically occurs after puberty
and early reproductive life, but in some cases it is diagnosed
later in life. On gross examination it presents as a cystic structure that is filled with hair and sebaceous material (Fig.
13-89). Histologically the tumor is composed of various mature somatic tissues, including skin, glandular epithelium,
neural tissue, bone, and teeth (Fig. 13-90). Teratomas are benign, although they may undergo malignant transformation
if they are left inside the body. Most of these secondary malignancies are squamous cell carcinomas, but a few sarcomas
also have been reported.

Fig. 13-85. Dysgerminoma. This large lobulated tumor was removed from a six-year-old girl.

Fig. 13-86. Dysgerminoma. Tumor cells have clear cytoplasm.

These cells form' solid nests by septa infiltrated with

Fig. 13-87. Yolk sac carcinoma. Tumor cells form glomeruloid

structures, nests, and strands.

Fig. 13-88. Yolk sac carcinoma. Tumor cells are positive for


Immature teratomas are malignant tumors that present as

solid masses, parts of which appear encephaloid (Fig. 13-91).

Histologically they may contain many kinds of tissues, but

their malignancy derives predominantly from the immature
neural tissue. Neural components of immature teratomas are
graded on a scale from Ito III (Fig. 13-92 to 13-94). Tumors
tend to spread throughout the peritoneum, and the histologic evaluation of metastases is important for prognostic
purposes. Benign glial implants are innocuous, but those that
are composed of neuroblasts are ominous. Overall five-year
survival is in the range of 70 percent, mostly because of the
efficient use of modern chemotherapy.
Specialized teratomas may represent one-sided differentiation of an overgrowth of a specific tissue or tumor type in
a previously benign teratoma. Struma ovarii is composed of
thyroid tissue, which may be highlighted with antibodies to
thyroglobulin (Fig. 13-95). Neuroendocrine tumors may resemble carcinoids as in other parts of the body, but they also
may originate in thyroid tissue (Fig. 13-96).
Fig. 13-89. Benign cystic teratoma (dermoid cyst). The cavity is
filled with sebaceous material and hair.

Fig. 13-90. Benign teratoma. The tumor is composed of squamous epithelium, neural tissue, and glands.

Fig. 13-91. Immature teratoma. Solid areas appear encephaloid

and bulge from the cross section.

Fig. 13-92. Immature teratoma, grade I . The tumor consists of

differentiated neuropil with only occasional immature neural

Fig. 13-93. Immature teratoma, grade 2. The tumor contains

mature and immature neural tissue.


Unclassified and Metastatic Tumors

of the Ovary
Small cell carcinoma with hypercalcemia is a highly malignant tumor of young women. It is composed of small undifferentiated cells that form solid compact sheets and nests
with areas of necrosis (Fig. 13-97). Tumor cells may form
abortive rosettes and follicles, but they do not show any distinct differentiation.

Fig. 13-94. Immature teratoma, grade 3. The tumor consists

mostly of immature neuroblastic cells that form rosettes.

Fig. 13-95. Struma ovarii. The tumor consists of thyroid-like


Fig. 13-97. Small cell carcinoma with hypercalcemia. The

tumor is composed of closely compacted small cells, focally surrounding spaces filled with proteinaceous fluid.

Fig. 13-96. Strumal carcinoid. The tumor consists of small neuroendocrine cells surrounding

Fig. 13-98. Krukenberg tumor. Metastatic carcinoma from the

primary tumor in the stomach has symmetrically enlarged the
ovaries, which appear lobulated and have a smooth surface.


Krukenberg tumor represents bilateral metastases of adenocarcinoma of the gastrointestinal tract to the ovaries. The
ovaries typically are enlarged and have a smooth, usually lobulated external surface (Fig. 13-98). Histologically the ovary
is permeated with tumor cells, which maybe signet ringlike
or cuboidal (Figs. 13-99 and 13-100). Ovarian stromal cells
often are luteinized and hyperplastic. Nodular metastases on
the surface of the ovary may mimic primary ovarian tumors,
and mucinous adenocarcinomas of the large intestine may

produce lesions that are indistinguishable from primary

ovarian tumors of the same histologic type. Nevertheless,
metastases tend to be composed of more anaplastic cells, and
the tumors often show extensive necrosis (Fig. 13-101). Lymphoma may involve the ovary, usually in the advanced stages
of the disease. Burkitt lymphoma occasionally may present
as a primary ovarian mass. Histologically such tumors are indistinguishable from equivalent lymphomas in other sites
(Fig. 13-102).

Fig. 13-99. Krukenberg tumor. The ovary is infiltrated with

signet-ring cancer cells.

Fig. I3-100. Krukenberg tumor. Stromal cells of the ovary infiltrated with cancer appear hyperplastic.

Fig. 13-101. Metastasis from colonic adenocarcinoma. The neoplastic glandlike structures are partially necrotic.

Fig. 13-102. Burkitt lymphoma. Ovary infiltrated by undifferentiated lymphoid cells has a starry sky appearance.

28 6

Diagram 13-I. A, B, Drawing of a frontal section of the uterus showing the elevation of the
decidua capsularis caused by the expanding chorionic sac of a 4-week embryo. C-F, Drawings of
sagittal sections of the gravid uterus from the fifth to twenty-second weeks, showing the changing
relationship of the fetal membranes to the decidua. In F, the amnion and chorion are closely approximated but never quite fuse with each other and the decidua parietalis, thereby obliterating
the uterine cavity. Note in D to F that the chorionic villi thrive only where the chorion is associated with the decidua asalis; here they form the chorion frondosum, and the chorion laeve will
show persistence of ghostlike atrophic villi seen even at term on the free membranes. (Modified
from Moore KL, Persaud TVN: The developing human, clinically oriented embryology, ed 5, Philadelphia,
1993, Saunders.)



The placenta develops from embryonic trophoblastic cells at
the site of implantation of the embryo, which occurs at the
blastocyst stage. The fully functioning placenta, which provides the essential support to the developing fetus, develops
over a period of weeks and remains in place in utero until the
end of pregnancy.
The mature placenta consists of the placental disk, the
chorioamniotic membranes, and the'umbilical cord (Diagrams 13-1 and 13-2). The placental disk consists of trophoblastic cells, including mononuclear cytotrophoblastic and
-multinucleated syncytiotrophoblastic cells arranged into
chorionic villi. Villi, like the entire placenta, contain numerous blood vessels filled with fetal blood, which carries
nutrients and oxygen to the fetus from the mother. In pregnancies with multiple fetuses the placenta varies from the
normal in that it maybe composed of a single disk or entirely

separate disks. In twin pregnancy, which is the most common

multiple pregnancy, a single-disk placenta is classified as
monochorionic, diamniotic, or dichorionic diamniotic
(Figs. 13-103 and 13-104). Such variations are of limited clinical significance in most cases.
Placental abnormalities include (1) abnormal implantation, which may occur in the uterus (e.g., placenta previa) or
outside the uterus, which results in extrauterine pregnancy;
(2) abnormal separation of the placenta from the pregnant
uterus, such as placenta accreta; (3) abnormal morphology
of the placental disk, which may be multilobated, succenturiate, and so forth, or may show abnormal insertion of the
umbilical cord and the chorioamniotic membranes (e.g.,
circummarginate or circumvallata placenta); (4) abnormal
differentiation of trophoblastic cells, which results in gestational trophoblastic disease, such as hydatidiform mole and

Diagram 13-2. Recommended minimum sections include a membrane roll, which included the
zone of rupture and a marginal portion of the placental disk for orientation. There are two
sections of umbilical cord, one from the fetal end and the other from the placental end, 2 to 3 cm
from the insertion. (Computer-generated diagram by Martin E. Nau.)

Fig. 13-103. Monochorionic diamniotic placenta. The fetal surface of the placenta shows the thin dividing membrane. Fetal
vessels were injected with milk-barium solution to illustrate the
vascular anastomoses. (Courtesy of Dr. Milton J. Finegold,
Houston, Texas.)

Fig. 13-104. Dichorionic diamniotic placenta. The fetal surface

shows a very thick dividing membrane.

28 8


Fig. 13-105. Ectopic pregnancy. A, The fetus was found in the fallopian tube. B, Chorionic villi
and blood are found inside the fallopian tube.

Fig. 13-106. Placenta accreta. A hysterectomy was performed

because the placenta could not be removed from the pregnant

Fig. 13-107. The early amnion rupture sequence (TEARS). Fetal abnormalities usually are related
to placental changes. A, Fetus shows abnormalities of the head and extremities. B, The fetal surface of the placenta shows a dull denuded chorionic surface with thin bands of tissue extending
from it. C, Microscopically the epithelial layer of the amnion is absent and the chorion is thickened and cellular. (A and B, courtesy Sherrie A. Caldwell, MD, The Children's Hospital, Denver,


Abnormal Implantation and Separation of the

Placenta and Rupture of Membranes
Extrauterine implantation results in ectopic pregnancy, usu-

ally in the fallopian tubes (Fig. 13-105). Chorionic villi of an

abnormally implanted ovum tend to invade the underlying
tissue. Destruction of the muscle layer of the fallopian tube
typically is associated with a hematosalpinx, and tubule rup,ture may ensue.
Abnormal invasion of chorionic villi at an intrauterine
site results in placenta accreta. Placenta accreta is firmly anchored in the uterus, and it does not separate normally
during delivery. It may be removed with difficulty, and until
recently many patients with placenta accreta required hysterectomy (Fig. 13-106). Histologically placenta accreta shows
invasion of chorionic villi into the myometrium, without an
intervening decidua and Nitabuch fibrinoid layer. In the third
trimester premature separation of the placenta from the
uterus, such as abruptio placentae, or rupture of the fetal

membranes, results in premature delivery. Premature rupture of the membranes also may cause infection.
The early amnion rupture sequence (TEARS), which occurs in early pregnancy, is associated with a variety of fetal
malformations that usually affect the head and the extremities (Fig. 13-107).

On the basis of the route of entry, fetoplacental infections are
classified as secondary to (1) hematogenous spread, (2) endometrial infection, including descending infection of the
fallopian tubes or the peritoneum, (3) ascending infection of
the vagina, and (4) iatrogenic infection of the amniotic fluid
during amniocentesis or fetal surgery. The infection may
cause inflammation in the umbilical cord (funisitis),
chorion, amnion (chorioamnionitis), or chorionic decidua
(Figs. 13-108 and 13-109). Histologically the inflammatory
response may include neutrophils, which may be sprinkled

Fig. 13-108. Acute chorioamnionitis. A, The row of membranes sectioned crosswise shows more
inflammation at the center nearest the cervical os. B, Bacterial polymorphonuclear leukocytes
extend from the maternal intervillous space at the subchorionic space into the chorion. C, Fusobacterium, a common cause of preterm labor, is seen "standing on end" in the amnion, which was
impregnated with silver according to the Warthin-Starry method. D, A "bacterial cloud" is seen
without much inflammation, a feature suggestive of inadequate maternal response.


at random or may form abscesses. Lymphocytes and plasma

cells may be found together with macrophages, which occasionally are arranged into granulomas. Histologic findings
are not reliable indicators for the onset of inflammation, and
often one cannot determine whether the inflammatory response was elicited by infective pathogens or by an immune
response. Pathogens such as bacteria, viruses, or fungi may
be demonstrated, sometimes with the use of special stains,
but in most cases they are not obvious. Many cases of chronic
inflammation identified histologically and interpreted
without additional clinical or microbiological data often are
classified as villitis of undetermined etiology ( WE) (Fig.

Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) has been defined by
the World Health Organization and International Society of

Fig. 13-109. Villitis caused by Listeria monocytogenes. An infiltrate composed of neutrophils involves microvilli,extending into
the intervillous spaces.

Gynecological Pathologists as a group of closely related diseases that includes (1) complete hydatidiform mole, (2) partial hydatidiform mole, (3) invasive mole, (4) placental site
trophoblastic tumor, (5) choriocarcinoma, and (6) other trophoblastic lesions. The salient features of these lesions are
summarized in Table 13-5 and are compared with changes
in hydropic abortus. Representative gross and microscopic
aspects of GTD are shown in Figs. 13-111 to 13-115.
Hydropic abortus must be included in the differential diagnosis of molar gestation. The classic features are amphophilia of the villous stroma and atrophy of the trophoblasts.
Trophoblastic proliferation, if present at all, is polar, representing a normally implanting villus (Fig. 13-116).
The differential diagnosis of placental site trophoblastic
tumor includes the "exaggerated implantation site " and the
placental nodule (Fig. 13-117).

Fig. 13-I 10. Chronic villitis. This predominantly intervillous

inflammation ("intervillositis") may have been caused by infection, but it also might represent an immune response.

Fig. 13-III. Complete hydatidiform mole. A, Nearly all villi are enlarged and are interconnected
by thin nonedematous cordlike structures. B. Greatly enlarged edematous villus with incompletely
formed central cistern. There also is circumferential cellular obliteration of syncytiotrophoblast,
cytotrophoblast, and intermediate trophoblast, some of which show eosinophilic necrosis.


Gestational Trophoblastic Disease: Clinical, Gross, Microscopic, and Flow Cytometric Features

From Popek EJ: ASCP check sample AP 94-7 (AP-241), "Partial hydatidiform mole," American Society of Clinical Pathologists, 1994.
Copyright ASCP Chicago.
AB, Abortion; CHM, complete hydatidiform mole; CT, cytotrophoblast; I-I A, hydropic abortus; IT, intermediate trophoblast; n/a, not applicable; n/r, none
reported; NRBC, nucleated red blood cells; PHM, partial hydatidiform mole; PSTT, placental site trophoblastic tumor; SAB, spontaneous abortion; ST,


Fig. 13-112. Partial hydatidiform mole. A, Less than 20 percent of villi are cystic. A macerated
fetus is attached to the placenta. B, Enlarged villus shows pronounced scalloping, which results in
pseudoinclusions (i.e., islands of trophoblast in the stroma of the villus). "Knuckles" of proliferating syncytiotrophoblast have undergone eosinophilic necrosis.

Fig. I3-1 13. Invasive CHM showing enlarged villi with trophoblastic proliferation deeply invasive into the myoretrium.

Fig. 13-1 14. Placental site trophoblastic tumor (PSTT). Uniform

polygonal cells form sheets of intermediate trophoblast, with
only rare multinucleated cells invading the myometrium.

Fig. 13-I 15. A, Choriocarcinoma. Cytotrophoblastic and syncytiotrophoblastic cells show foci of
necrosis and are admixed with extravasated blood. B, Immunohistochemically, human chorionic
gonadotrophin can be demonstrated in the syncytiotrophoblastic cells.


Fig. 13-116. Hydropic abortus (HA) with enlarged edematous villi with amphophilic stroma, few residual blood vessels, and polar trophoblastic proliferation of anchoring villi.

Fig. 13-1 17. Lesions easily confused with PSTT. A, Exaggerated implantation site with numerous
mononuclear cells within the maternal myometrium. Normal invasion of the uterus by trophoblasts is extensive in early pregnancy and may be underappreciated. B, Placental nodule is residua
from a previous pregnancy; well circumscribed, it has a central acellular or sclerotic region surrounded by a few viable intermediate trophoblasts. The last documented pregnancy in this case
was several years before this curettage.

Further Reading
Benda JA: Pathology of cervical carcinoma and its prognostic implications. Semin Oncol 21:3-11, 1994.
Clement PB: Pathology of the uterine corpus. Hum Pathol 22:776-791,
Cramer SF, Patel A: Myometrial hyperplasia. Proposed criteria for a discrete morphological entity. Mod Pathol 8:71-77, 1995.
Eichhorn JH, Bell DA, Young RH, Scully RE: Ovarian serous borderline tumors with micropapillary and cribriform patterns. A study
of 40 cases and comparison with 44 cases without these patterns.
Am J Surg Pathol 23:397-409, 1999.
Gordon MD, Ireland K: Pathology of hyperplasia and carcinoma of the
endometrium. Semin Oncol 21:64-70, 1994.
Hoerl HD, Hart WR: Primary ovarian mucinous systadenocarcinomas.
A clinicopathologic study of 49 cases with long-term follow-up.
Am J Surg Pathol 22:1449-1462, 1998.
Longacre TA, Hendrickson MR: Diffusely infiltrative endometrial adenocarcinoma. An adenoma malignum pattern of microinvasion.
Am J Surg Pathol 23:69-78, 1999.

Manson CM, Hirsch PJ, Coyne JD: Post-operative spindle cell nodule
of the vulva. Histopathology 26:571-574, 1995.
Merino MJ: Vaginal cancer. The role of infectious and environmental
factors. Am J Obstet Gynecol 165:1255-1262, 1995.
Riopel MA, Ronnett BM, Kurman RJ: Evaluation of diagnostic criteria
and behavior of ovarian intestinal-type mucinous tumors. Atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinoma. Am J Surg Pathol
23:617-635, 1999.
Young RH: New and unusual aspects of ovarian germ cell tumors. Am
J Surg Pathol 17:1210-1224, 1993.
Zaino RJ, Kurman RJ, Brunetto VL et al: Villoglandular adenocarcinoma of the endometrium: a clinioopathologic study of 61 cases.
A Gynecologic Oncology Group Study. Am J Surg Pathol 22:13791385, 1998.



Epithelial proliferative lesions occur in several histologic

forms, including (1) sclerosing adenosis, (2) ductal hyperplasia, (3) radial scar formation, and (4) lobular hyperplasia.
Sclerosing adenosis presents as enlargement of one or more
lobular units, which is caused by an increased number of
alveolar ducts along with an increase in the density of interlobular fibrous tissue. Occasionally a mass is produced by aggregation of adjacent lobules or less commonly by massive
enlargement of a single lobule. The normal double cell layer
structure of ductules is preserved, but their lumina may be
compressed or narrowed. In some cases the lumen is dilated,
and this change is termed blunt duct adenosis or microglandular adenosis.
Ductal hyperplasia occurs predominantly in terminal
ducts and lobular units and is characterized by an increased
number of cells inside the lumen of these structures. Ductal
hyperplasia includes a continuum of changes that range from
trivial changes to changes similar to those of ductal carcinoma in situ (CIS), which is termed atypical ductal hyperplasia. In mild hyperplasia the ducts are lined by one or two
additional cell layers. If there are more cells layers, hyperplasia is considered to be moderate; if it is quite prominent,
the term florid hyperplasia is used (Fig. 14-2). Irregular proliferation of ductlike epithelial structures around a centrally
located focus of connective tissue is called radial scar formation. Ductal hyperplasia may be associated with lobular
hyperplasia. Occasionally lobular hyperplasia may be more
prominent, and the hyperplastic cells may extend into the

The mammary tissue develops from the ingrowth of epithelial strands that differentiate into ducts, ductules, and acini
arranged into lobules (Diagram 14-1). Once the breasts reach
their adult form, they remain sensitive to hormonal stimulation and undergo typical cyclic changes during each menstrual cycle. However, female breasts reach their full differentiation only under proper hormonal stimulation during
pregnancy and lactation. The breasts involute to some extent
after the cessation of lactation, but they remain capable of assuming their full functional potential again. The breasts involute after menopause.
If the normal hormonal response of breasts is disrupted
or partially altered, the breast tissue undergoes fibrocystic
change, a complex set of changes characterized by fibrosis,
epithelial proliferation, and cyst formation (Figs. 14-1 and
14-2). Cysts are the most common feature of fibrocystic disease. Cystic dilatation begins at the level of terminal ducts
and lobules, but over time microscopic cysts enlarge and
transform into fluid-filled macroscopic cysts. The largest
cysts are associated with atrophy of the remaining lobular elements, whereas small cysts typically develop as multiple dilatations within the same lobule. Solitary cysts are lined by
simple cuboidal or flattened epithelium, whereas multiple
cysts are lined by apocrine type of epithelium (apocrine
metaplasia). Fibrosis leads to the expansion of the dense perilobular connective tissue, which encroaches on the lobules
and ultimately replaces the loose interlobular stroma. As part
of the fibrocystic change, fibrosis typically occurs in younger
women, and fibrotic nodules are the sole lesions in approximately 5 percent of benign breast biopsy specimens.

Diagram 14-I. A, Development of mammary ducts and lobules. Upper, birth; middle, early adolescence;
lower, adult. B, Adult breast illustrating typical variability in size and development of lobules. (A from Russo
J, Russo IH: Development of the human mammary gland. In Neville MC, Daniel CW, editors: The mammary
gland: development, regulation, and function, New York and London, 1987, Plenum Press.)


Fig. 14-I. Fibrocystic change. A, Dilated terminal duct and lobules are lined by epithelium that
either is flattened or shows apocrine metaplasia (evidenced as cuboidal cells with eosinophilic
cytoplasm). The overall lobular structure is preserved. B, Fibrosis leads to merging of perilobular
and intralobular connective tissue. C, Sclerosing adenosis involves hyperplasia of alveolar ductules,
along with an increase in the density of intralobular fibrous tissue. Ductules show swirling and
collapse of their lumina. D, Focal adenosis shows similarity of proliferated ductules to those in the
adjacent uninvolved normal lobule.

Fig. 14-2. Fibrocystic changes. A, Florid duct hyperplasia. The epithelial nests inside the ducts are
partially solid and partially cystic but lack fibrovascular stalks. B, Radial scar. Central fibrosis is
surrounded in a radiating manner by ductlike structures.


Tumors of the breast may be benign or malignant. Adenomas
are benign epithelial tumors. However, because they also entail proliferation of stromal cells, most of them are classified
as fibroadenomas. Most malignant tumors originate from
the mammary epithelium and accordingly are called carcinomas. Breast tumors represent the most common malignancy in women, accounting for 30 percent of all newly diagnosed cancers in 1998. Breast cancer is responsible for 16
percent of cancer-related deaths in women.

Fibroadenoma is the most common breast mass encountered

Fig. 14-3. Fibroadenoma. This spherical tumor surgically shelled

out from the breast of a young women appears myxoid, translucent, grayish white, and lobulated on cross section.

in young women, constituting the majority of lesions found

at biopsy or in surgically removed specimens in women
under the age of 25 years. On gross examination fibroadenomas are sharply circumscribed, rubbery nodules that are
distinct from the surrounding tissue (Fig. 14-3). They may
range in size from less than 1 mm to several centimeters in
diameter. Histologically they are composed of proliferating
ducts and stroma. Two patterns of growth, intracanalicular
and pericanalicular, are recognized (Fig. 14-4). Most breast
lesions show both of these growth patterns.


Considering the relative frequency of fibroadenomas and

mammary carcinoma, it is surprising that pure epithelial tumors , or adenomas, are so infrequent. Adenomas are benign
circumscribed tumors (Fig. 14-5). Histologically classified,
they are as tubular or lactating (Fig. 14-6). Both of these
tumor types are composed of closely packed terminal ducts
with little surrounding stroma. Myoepithelial cells surround
the cuboidal ductal epithelium. In lactating adenomas the
ductlike structures are dilated and show cytoplasmic vacuolization and enlargement that is typical of lactation.

Fig. 14-4. Fibroadenoma. A, Intracanalicular type. Myxoid stroma

distorts the elongated ducts. B, Pericanalicular type. Cellular
fibrous stroma shows periductal layering.

Fig. 14-5. Lactating adenoma. The lobulated tumor appears

fleshy brown on cross section. Its margins are less distinct than
those of typical fibroadenoma or juvenile fibroadenoma.


Fig. 14-6. Adenoma. A, Tubular adenoma consists of tubules surrounded by stroma similar to
that of normal breast. B, Lactating adenoma is composed of tubules that show lactational
changes. The presence of interlobular duct suggests focal hyperplasia rather than neoplasia.

Phyllodes Tumor
Phyllodes tumors are composed of proliferating epithelial
and stromal cells. At presentation phyllodes tumors are on
average larger than fibroadenomas or adenomas, and a history of rapid tumor growth is a common presenting symptom. The excised specimen is firm and rubbery and may separate into leaflike structures, which account for its name
(Greek phyllon, meaning leaf).

Phyllodes tumors are classified clinically as low-grade or

high-grade neoplasms. On gross examination low-grade tumors tend to have a variegated pale appearance, and highgrade tumors appear more fleshlike (Fig. 14-7). Stroma of
low-grade tumors is composed of loosely arranged cells that
have bland nuclei. High-grade tumors have a more cellular
stroma, and the nuclei of these tumor cells show atypia, hyperchromasia, and mitotic figures (Fig. 14-8).

Fig. 14-7. Phyllodes tumor. A, Low-grade tumor lacks encapsulation and shows a variegated redtan and white cut surface. B, High-grade tumor has a fleshy appearance.


Intraductal Papilloma

Fig. 14-8. Phyllodes tumor. A, Low-grade tumor shows low cellularity, which is more pronounced around the elongated ducts.
B, High-grade tumor consists of densely arranged stromal cells
showing nuclear atypia.

Papillomas are benign intraductal tumors that usually reach

clinical attention primarily because of nipple discharge or
bleeding, although a few may present as a palpable mass.
Most papillomas measure 0.5 to 2 cm in diameter and are located in the main collecting ducts, but 20 percent to 25 percent occur more peripherally and appear to be multiple. Microscopically the hallmark of papillomas is intraductal
proliferation of epithelial cells arranged into fronds that have
a fibrovascular core (Fig. 14-9). Large subareolar lesions may
be quite cellular and are composed predominantly of glandlike structures (Fig. 14-10).
Papillomas display a propensity for degeneration and
necrosis and often are accompanied by periductal fibrosis
and sclerosis, which may obscure their papillary nature. Epithelial elements trapped in the fibrous scar may be mistaken
for invasive carcinoma, but the absence of intraductal carcinoma in adjacent ducts is a clue to their benign nature. Papillomas must be differentiated from papillary carcinoma, an
indolent malignancy of older women that also is largely intraductal but displays definitive signs of malignancy, including a cribriform pattern of epithelial growth, nuclear
anaplasia, and intraductal papillary proliferation without fibrovascular cores. The presence of papillary carcinoma in an
intraductal papilloma may present a difficult diagnostic
Papillomas as a group confer a slightly elevated risk for
the subsequent development of invasive mammary carcinoma. Some authors believe that the risk is largely confined to
patients who have multiple papillomas. Multiple lesions
more commonly are associated with atypical patterns of epithelial proliferative disease, and their biologic behavior and
tendency to progress to invasive cancer should be predicted
more accurately by evaluating the degree of cellular atypia
rather than their architectural features.

Fig. 14-9. Ductal papilloma. Epithelial cells are arranged on fibrovascular stalks that project into the ductal lumen.

Fig. 14-10. Ductal papilloma, subareolar type. The lesion shows

florid proliferation of epithelial cells with focal nuclear atypia.


Atypical Hyperplasia
Atypical hyperplasia occurs in two forms: atypical intraductal
hyperplasia (ADH) and atypical intralobular hyperplasia
(ALH). Atypical hyperplasia is the only finding in approximately 3 percent of breast biopsy specimens; nevertheless, it
must be recognized and treated appropriately. Diagnostic
criteria for ADH and ALH have been defined, but their reproducibility has been a matter of discussion. There also is
controversy over whether atypical hyperplasia is only a risk
factor or a definitive precursor to invasive carcinoma. Several studies have shown that atypical hyperplasia is associ -

ated with a four- to fivefold higher risk for carcinoma than

that for age-matched controls.
ADH usually is an incidental finding in biopsy specimens
that show mostly benign changes. Microscopically ADH is
characterized by intraductal proliferation of cells showing either the growth pattern or the cytologic features that are
characteristic of noninvasive carcinoma, but neither in a fully
developed form. ADH may mimic noncomedo type ductal
CIS growing in a cribriform, partially cribriform, micropapillary, fenestrated, solid, or mixed pattern (Fig. 14-11). Regularity of the pattern, regardless of the specific cellular ar-

Fig. 14-I I. Atypical ductal and lobular hyperplasia. The most common patterns of ADH include
A, Cribriform intraductal pattern, B, Partial cribriform intraductal pattern, C, Fenestrated intraductal pattern, and D, Micropapillary intraductal pattern. E, ALH appears as distention of lobules
filled with atypical cells.


rangements, is an important theme of ADH. The cytologic

features also resemble those of noncomedo type intraductal
carcinoma and include relatively small, round cells with distinct borders; moderate to scant cytoplasm; and uniform, occasionally hyperchromatic, round-to-oval nuclei with delicate chromatin and small nucleoli. Mitotic figures are rare.
Because of their perplexing similarity to intraductal carcinoma, these lesions represent a diagnostic problem and there
is no consensus regarding therapy.
ALH is found in 1 percent of breast biopsy specimens,
mostly in premenopausal women. ALH has no distinguishing clinical or mammographic features and usually is
an incidental finding on histologic examination. It also carries a four- to fivefold higher risk for invasive cancer. The microscopic features are distinctive and include intralobular
proliferation of cells distending the lobules. The cells are uniform, small, and round to polygonal. The cells have moderate
to scant cytoplasm, round regular nuclei, delicate chromatin,
and small nucleoli. ALH often is multicentric. It is not always
possible to distinguish ALH from intralobular carcinoma.

Noninvasive Carcinoma
Noninvasive carcinoma of the breast is diagnosed in approximately 10 percent of breast biopsy specimens. Two
major categories are recognized: ductal carcinoma in situ
( DCIS) and lobular carcinoma in situ (LCIS). DCIS is further divided into (1) comedo, (2) cribriform, (3) micropapillary, (4) solid, and (5) papillary subtypes.
Comedo type DCIS accounts for 3 percent to 5 percent of
all breast carcinomas and 35 percent to 50 percent of solitary
noninvasive carcinomas. The majority of comedo DCIS present as palpable masses that are 2 to 3 cm in diameter, but
some may be as large as 5 cm or more. On gross examination
they are well circumscribed, and a cheesy "comedo-like "
necrotic material may be expressed from the dilated ducts.
Microscopically comedo DCIS grows inside the ducts, distending them to as much as 10 times their normal diameter.

The atypical neoplastic cells form solid masses that typically

show central necrosis (Fig. 14-12). The cytoplasm of most
tumors is well developed. Nuclear features are those of highgrade tumors, and mitoses are common. Retrograde extension of the tumor cells into the acini (cancerization of the
lobules) is common. Such an extension of tumor should not
be confused with invasion, which should be diagnosed only
if the neoplastic cells extend across the borders of the loose
intralobular connective tissue.
Noncomedo DCIS accounts for 5 percent to 8 percent of
all breast carcinomas and 50 percent to 70 percent of solitary
noninvasive carcinomas. It is considered to be less aggressive
than comedo type DCIS, with a lower short-term recurrence
rate (less than 5 percent) after local excision. Other favorable
biologic features, such as the presence of hormone receptors,
low proliferation rates, and diploid DNA content, also are
also usually found. However, the unequivocal malignant potential of these lesions is underscored by a 30 percent recurrence rate after incomplete surgical excision and the invasiveness of cancer found in 50 percent of these recurrences.
Noncomedo DCIS rarely produces palpable masses and usually is diagnosed by biopsy of microcalcific breast lesions recognized by mammography. Several histologic subtypes are
found, but the patterns often are intermixed and usually are
present in the same lesion. On the basis of histologic growth
patterns, these tumors are subtyped as (1) cribriform, (2) micropapillary, (3) solid, and (4) papillary (Fig. 14-13).
Lobular carcinoma in situ (LCIS) accounts for 1 percent
to 3 percent of all breast carcinomas and 10 percent to 30 percent of solitary noninvasive carcinomas. It usually is not detected by palpation but rather incidentally in breast biopsy
tissue of premenopausal women. Histologically it presents as
multifocal interlobular proliferation of atypical neoplastic
cells (Fig. 14-13). Pagetoid spread beneath the epithelium of
larger ducts is common. Tumor cells typically have round or
oval nuclei with homogeneous chromatin and inconspicuous nucleoli. The risk of developing invasive carcinoma of

Fig. 14-12. DCIS, comedo type. A, The distended ducts are lined by atypical cells that have
undergone necrosis in the central portion. B, Cancerization of the lobule presents as extension of
the malignant cells into the acini.


Fig. 14-13. DCIS, noncomedo type, and LCIS. Typical growth patterns of ductal carcinoma in situ
include A, Cribriform ductal, B, Solid ductal, and C, Papillary ductal pattern. D, Lobular
carcinoma in situ presents in the form of distended acini filled with atypical cells. The lobular
pattern is preserved.

the breast after excision of LCIS increases by approximately

1 percent per year, a rate that translates to a greater than tenfold relative risk and a 20 percent absolute risk over 20 years.
The risk is bilateral, and most invasive carcinomas that develop are ductal rather than lobular. This indicates that LCIS
may be a marker for the development of invasive breast
cancer rather than its precursor.

Major Histologic Types of Breast

Carcinoma and Their Relative Incidence
for All Stages Combined

Invasive Breast Carcinoma

Invasive breast carcinoma accounts for approximately 90 percent of all breast cancers. Modern taxonomic attempts to
subdivide these lesions into categories with distinct morphologic, biologic, and clinical features have not produced
definitive results because breast carcinomas are a heterogeneous group of tumors. The system of nomenclature used
here is a compromise derived from several studies and proposed classifications (Table 14-1).
Infiltrating ductal carcinoma not otherwise specified (IDCNOS) is a heterogeneous group of lesions characterized by a
relative absence of histologic features that define other special forms of breast carcinoma, and in this sense it is a diagnosis of exclusion. It accounts for approximately 60 percent
of all breast carcinomas and 70 percent of invasive breast can -

NOS, Not otherwise specified.


Fig. 14-14. Infiltrating ductal carcinoma, NOS. A, Typical scirrhous tumor presents as a stellate
scar in the fat tissue of the breast. B, Irregularly shaped fibrotic tumor does not have definite
borders even though it seems to have been removed in toto, with adequate normal peritumoral
breast tissue. The foci of hemorrhage are due to previous biopsy.

Fig. 14-15. Infiltrating ductal carcinoma, NOS. Common growth patterns include A, Solid
hypercellular, B, Solid desmoplastic, C, Acinar and tubular, and D, Acinar and solid.


cers. It is clinically and biologically more aggressive than the

special types of cancer separated from it. The median fiveyear survival rate for IDC-NOS is only approximately 60 percent, compared with 80 percent to 95 percent for the special
types of cancer.
IDC-NOS usually presents as a firm mass that is gritty on
cross section. It may vary in size and shape and may present
as a small stellate mass with indistinct borders or as larger fibrotic masses that are relatively distinct from the remainder
of the breast (Fig. 14-14). Histologically IDC-NOS is ap adenocarcinoma that has no distinctive features. It may be cellular, paucicellular, or desmoplastic, or it may consist of solid
strands or acini (Fig. 14-15).
Several grading systems for IDC-NOS have been developed over the years. Table 14-2 shows the widely used Elston
modification in which numeric scores are assigned to each
of three major histologic features: the percentage of tubule
formation, the degree of nuclear pleomorphism, and the
number of mitoses per 10 high-power fields based on microscopic evaluation of the entire lesion. Nuclear grading is
based on assessing the lesionis size and shape, chromatin pattern, and nucleoli (Fig. 14-16). Using this grading system in
prospective studies, median 10-year survival rates of 90 percent, 60 percent, and 40 percent were associated with grade
I, grade II, and grade III lesions, respectively.
Infiltrating lobular carcinoma (ILC) accounts for approximately 15 percent of all invasive breast carcinomas. In addition to the classic type, which shows single file ( " Indian file " )
cell arrangement, the tumor may present in several histologic
variants, such as (1) solid, (2) alveolar, (3) mixed, or (4) pleomorphic (Fig. 14-17). The cytologic features of these subtypes are the same as those of classic ILC.

Histologic Grading of Breast Carcinoma

*The percentage of tubule formation is based on assessment of the entire

tumor. However, nuclear pleomorphism is assessed in the worst area,
and mitotic counts are assessed at the leading edge of tumor growth.
HPF, High power field.

Fig. 14-16. Nuclear atypia in infiltrating ductal breast carcinoma. A, Grade I, mild atypia.
B, Grade II, moderate atypia. C, Grade III, severe atypia.

30 6

Fig. 14-17. Infiltrating lobular carcinoma. Common growth patterns include A, Classic ("Indian
file"), B, Solid, C, Alveolar, and D, Pleomorphic.

Variants of Invasive Carcinoma

Several variants of breast carcinoma that differ biologically
from IDC-NOS and ILC have been described, the most important of which are (1) medullary carcinoma, (2) mucinous
carcinoma, (3) tubular carcinoma, (4) cribriform carcinoma,
(5) Paget disease, and (6) metaplastic carcinoma. For the
most part these variants occur in a typical form, but they also
may have subtypes.
Medullary carcinoma accounts for approximately 7 percent of all breast cancers. Typical medullary carcinoma has a
better prognosis than IDC-NOS, with a 10-year survival rate
of 80 percent to 90 percent. It presents as a palpable mass,
which usually is circumscribed and measures 2 to 3 cm in
diameter. On cross section it appears lobulated, wellcircumscribed, tan-white, relatively soft, and homogeneous
in consistency. Microscopically the tumor has blunt, pushing
borders, and the cells are arranged into solid nests that have
a syncytium-like appearance (Fig. 14-18). The tumors contain a lymphocytic infiltrate, which is most prominent in the
loose connective tissue stroma and at the margins of nests of
neoplastic cells. Bizarre tumor giant cells and foci of squamous metaplasia may be seen in some tumors. There may be
a minor intratubular component, which usually is of the
comedo type.

Mucinous carcinoma, also known as colloid carcinoma, accounts for approximately 2 percent to 3 percent of all breast
cancers. Typical mucinous carcinomas have a very good
prognosis with a 10-year survival rate in the range of 85 percent to 90 percent. Tumors present as soft palpable masses
that produce vague, nonspecific findings on mammography.
On cross section they appear circumscribed, glistening, tan,
soft, and gelatinous. Histologically the tumors are composed
of small islands of malignant cells in a contiguous pool of
extracellular mucinous material (Fig. 14-19).An in situ component is rare. Cytologic and nuclear features are those of a
low- to intermediate-grade malignant tumor. The mucinous
part must constitute 90 percent of the total lesion if the tumor
is to be classified as mucinous. If the mucinous parts account
for only 75 percent or less, the tumor should be classified as
Tubular carcinoma accounts for approximately 5 percent
of all breast cancers. It has a favorable prognosis, with a fiveyear survival rate of 95 percent to 100 percent. However, concurrent or subsequent contralateral breast cancer maybe present in up to 20 percent of patients. Tubular carcinoma
usually presents as a small mass, 1 cm in diameter or smaller,
and usually is detected by mammography. The lesions appear firm, white, and stellate. Microscopically these tumors


Fig. 14-18. Medullary carcinoma. Tumor cells form syncytia-like

solid nests with pushing circumscribed margins surrounded by

Fig. 14-19. Mucinous carcinoma. Clusters of well-differentiated

cells appear suspended in pools of mucin-filled spaces between
thin strands of fibrovascular stroma.

Fig. 14-20. Tubular carcinoma. Tumor cells form small angular

glands evenly distributed in the dense fibrous stroma.

Fig. 14-21. Cribriform carcinoma. Low-grade tumor cells form

islands that contain round lumina.

are composed of small glands or tubules that have round,

oval, or angular ( " teardrop" ) shapes (Fig. 14-20). The glands
are uniformly distributed in centrally dense fibrous stroma
with prominent elastosis. The peripheral stroma is less dense,
and in these places the glands may invade the adjacent tissue.
Cribriform or micropapillary DCIS may be present in up to
65 percent of tubular carcinomas.
Cribriform invasive carcinoma is a recently described histologic entity that has biologic properties similar to those of
tubular carcinoma (Fig. 14-21).
Paget disease of the nipple presents as an eczematous rash
or as a red oozing lesion of the nipple. It represents the intraepidermal spread of malignant cells that reach the skin
through ducts that are involved with DCIS or high-grade
ductal carcinoma (Fig. 14-22).

Fig. 14-22. Paget disease of the nipple. Groups of tumor cells

with clear cytoplasm form nests in the epidermis of the nipple.


Figure 14-23. Invasive papillary carcinoma. The tumor grows

in a micropapillary pattern.

Figure 14-24. Adenocystic carcinoma. This breast tumor is

indistinguishable from equivalent carcinoma in the salivary

Figure 14-26. Metaplastic carcinoma. Tumor shows chondroid

Fig. 14-25. Metaplastic carcinoma. Metaplastic bone is formed
between sheets of carcinoma cells.

Rare forms of breast carcinoma account for less than 1

percent of all breast cancers. Included among these cancers
are signet-ring carcinoma, invasive papillary carcinoma, salivary glandlike carcinoma, secretory carcinoma, and clear cell
carcinoma (Figs. 14-23 to 14-25). .
Metaplastic carcinoma is a rare cancer that may present as
squamous cell carcinoma and pseudosarcomatous carcinoma. Pseudosarcomatous metaplastic carcinomas contain at
least 20 percent of metaplastic elements, such as areas that
resemble fibrosarcoma, chondrosarcoma, or osteogenic sarcoma (Figs. 14-25 to 14-27). Such tumors grow fast and have
a poor prognosis.

I mmunohistochemistry of Breast Carcinoma

Figure 14-27. Metaplastic carcinoma. Tumor has features of


Immunohistochemical analysis is being increasingly employed by pathologists to measure unreported prognostic

factors, including estrogen and progesterone receptors (ER,
PgR), pS2, Ki-67, HER-2/neu, and p53 (Fig. 14-28). Although
these tests will undoubtedly play an important role in the future, they have yet to be technically and clinically validated
before they become part of routine practice.


Figure 14-28. Immunohistochemistry of breast cancer. A, Estrogen receptors; B, progesterone

receptors; C, estrogen-induced protein pS2; D, Proliferation-associated marker Ki-67;
E, HER-2/neu oncoprotein; and F, p53 tumor-suppressor gene product.

Further Reading
Andersen JA: Lobular carcinoma in situ. A histological study of 52 cases.
Acta Pathol Microbiol Scand (A) 82:735-741, 1974.
Andersen JA, Gram JB: Radial scar in the female breast. A long-term
follow-up study of 32 cases. Cancer 53:2557-2560, 1984.
Bannayan GA, Hajdu SI: Gynecomastia. Clinicopathologic study of 351
cases. Am J Clin Pathol 54:431-437, 1972.
Bobrow LG, Happerfield LC, Gregory WM et al: The classification of
ductal carcinoma in situ and its associations with biological
markers. Semin Diagn Pathol 11:199-207, 1994.
Dawson AE, Mulford DK, Sheils LA: The cytopathology of proliferative breast disease. Am J Clin Pathol 103:438-442, 1995.
Di Costanzo D, Rosen PP, Gareen I, Franklin S, Lesser M: Prognosis in
infiltrating lobular carcinoma. An analysis of "classical" and
variant tumors. Am J Surg Pathol 14:12-23, 1990.
Elston CW: Pathological prognostic factors in breast cancer. The value
of histological grade in breast cancer: experience from a large study
with long-term follow-up. Histopathology 19:403-411, 1991.
Eusebi V, Feudale E, Foschini MP et al: Long-term follow-up of in situ
carcinoma of the breast. Semin Diagn Pathol 11:223-235, 1994.
Fechner RE: Frozen section examination of breast biopsies. Practice parameter. Am J Clin Pathol 103:6-7, 1995.
Gaffey MJ, Mills SE, Frierson HR Jr et al: Medullary carcinoma of the
breast. Interobserver variability in histopathologic diagnosis. Mod
Pathol 8:31-38, 1995.

Hensen DE, Oberman HA, Hutter RVP et al: Practice protocol of the
examination of specimens removed from patients with cancer of
the breast. A publication of the Cancer Committee, College of
American Pathologists. Arch Pathol Lab Med 121:27-33, 1997.
Hertzel BF, Zaloudek C, Kempson RL: Breast adenomas. Cancer
37:2891-2905, 1976.
Lefkowitz M, Lefkowitz W, Wargotz ES: Intraductal (intracystic) papillary carcinoma of the breast and its variants. A clinicopathological study of 77 cases. Hum Pathol 25:802-809, 1994.
Love SM, Gelman RS, Silen W: Fibrocystic "disease" of the breast. A
nondisease? N Engl J Med 307:1010-1014, 1982.
Merino MJ, Carter D, Berman M: Angiosarcoma of the breast. Am J
Surg Pathol 7:53-60, 1983.
Moffat CJC, Pinder SE, Dixon AR, Elston CW, Blamey RW, Ellis I0:
Phyllodes tumours of the breast: a clinicopathological review of
thirty-two cases. Histopathology 27:205-218, 1995.
Oberman HA: Hamartomas and hamartoma variants of the breast.
Semin Diagn Pathol6:135-145, 1989.
Rosen PP, Caicco JA: Florid papillomatosis of the nipple. A study of 51
patients, including nine with mammary carcinoma. Am J Surg
Pathol 10:87-101, 1986.
Tavassoli FA: Ductal carcinoma in situ: introduction of the concept of
ductal intraepithelial neoplasia. Mod Pathol 11:140-154, 1998.
Telesinghe PU, Anthony PP: Primary lymphoma of the breast.
Histopathology 9:297-307, 1985.



Hereditary skin diseases (genodermatoses) present in many
forms, such as recurrent bullae in epidermolysis, bullosa, or
diffuse or localized keratoses.
Ichthyosis is a term used to describe a complex group of
disorders of keratinization characterized by formation of
scales on the skin surface. The diseases usually are hereditary
(e.g., ichthyosis vulgaris, lamellar ichthyosis, X-linked
ichthyosis) but there also is an acquired form. Ichthyosis vulgaris, a common autosomal dominant disease, involves in a
symmetric manner the exterior surfaces of the limbs and the
trunk (Fig. 15-1). Histologically all forms of ichthyosis are
characterized by hyperkeratosis.
Porokeratosis is a disease that is characterized by the formation of small papules with surface scale that progressively
enlarge to form a sharply demarcated ring of hyperkeratosis,
often with an atrophic center. It affects men more often than

women. Autosomal dominant transmission has been suggested for the variant known as porokeratosis of Mibelli. Histologically the ring of hyperkeratosis is represented by a discrete parakeratotic column of hyperkeratosis, known as
cornoid lamella (Fig. 15-2). The dermis beneath the cornoid
lamella contains a lymphocytic infiltrate.
Darier disease, or keratosis follicularis, is an autosomal
dominant disease whose presenting symptoms include lesions of the scalp, neck, and upper chest in a distribution resembling that of seborrheic keratosis. It may be more
widespread and also may involve mucosal surfaces and nails.
The basic lesion is a papule that is 1 to 3 mm in diameter,
with a dirty gray-tan, keratotic surface (Fig. 15-3). These
papules become confluent, forming scales. Secondary infection is common. Histologically the basic lesion consists of a
broad zone of hyperkeratosis with parakeratosis, suprabasal
acantholysis, and formation of rounded cells (corps ronds)
and oval, individually keratinized cells (grains) (Fig. 15-4).
In well-developed lesions, the basal layer forms villi that project into the clefts.
Hailey-Hailey disease, or familial benign pemphigus, is an
autosomal dominant disease that presents with small vesicles
on an erythematous base. These lesions become confluent,
forming erythematous plaques (Fig. 15-5). Plaques often are
found in the axillae, neck, or intertriginous zones that are
predisposed to friction and excessive moisture. Superficial
bacterial infections exacerbate or trigger the development of
these lesions, which become crusted and fissured. Histologically the lesions show prominent partial acantholysis of the
lower stratum spinosum (Fig. 15-6). A suprabasal cleft is
formed, leading to detachment of groups of cells and a few
individual cells, which are found floating in the cavity.
Dermal inflammation is minimal.

Fig. 15-I. Ichthyosis vulgaris. The extensor surface of the arm is
covered with polygonal scales.

The skin often is infected by viruses, bacteria, fungi, protozoa,

and other pathogens.

Fig. 15-2. Porokeratosis. Cornoid lamella is formed by a column

of parakeratosis overlying slightly vacuolated keratinocytes that
have migrated centrifugally, here from right to left.

Fig. 15-3. Darier disease. Brown scaly papules form aggregates

on the lateral surface of the shoulder.


Fig. 15-4. Darier disease. A cleft is formed as a result of acantholysis of the lower strata of epidermis. The clefts contain
rounded cells (corps ronds) and oval individually keratinized cells

Fig. 15-5. Hailey-Hailey disease. The papules and vesicles have

fused to form a fissured plaque with a scaly surface.

Fig. 15-7. Impetigo. The lesions are erythematous and covered

with yellow-white purulent crusts.

Fig. 15-6. Hailey-Hailey disease. A suprabasal cleft is formed as

a result of acantholysis of deeper parts of the epidermis.

Bacterial Infections
Impetigo is a clinical diagnosis that denotes superficial bac-

terial infection of the epidermis. Impetigo contagiosa (nonbullous type) most often is caused by streptococci. The bulbous form is caused by Staphylococcus aureus. The infection
begins in the form of small papules that become thin-roofed
vesicles. Vesicles rupture to produce a yellow or honeycolored surface crust (Fig. 15-7). Staphylococci cause extensive cleavage of epidermis in the upper layers, which results

Fig. 15-8. Impetigo. In this bullous lesion a blister containing pus

has formed below the stratum granulosum.


in the formation of bullae or extensive exfoliation. Histologically impetigo contagiosa shows collections of neutrophils
in the epidermis beneath the stratum corneum. In bullous
impetigo the blister is below the level of the granular layer
(Fig. 15-8). Deeper bacterial infections may involve both the
epidermis and the dermis (pyoderma) and may extend into
the subcutis, causing widespread cellulitis.

Fungal Infections
Tinea is the name for epidermal infections caused by fungi,
known as dermatophytes, which usually belong to the genera
Microsporum, Trichophyton, Epidermophyton, or Malassezia.
The lesions vary in appearance and may present as papules,
plaques, or blisters. Lesions often are annular and show
scaling with central clearing (Fig. 15-9). Histologically there
usually is a superficial infestation with fungal yeast and hyphae with variable inflammation in the dermis (Fig. 15-10).
Fungal infection of hair follicles may cause deep folliculitis
and abscesses, which have been named kerion or Majocchi
granuloma (Fig. 15-11). Histologically the skin shows acute
and chronic inflammation surrounding cellular debris and
fragments of hair and fungi (Fig. 15-12).

Fig. 15-9. Tinea. This superficial fungal infection (ringworm) appears as a round scaly erythema with central clearing.

Viral Infections
Human papillomaviruses ( HPV) of several types may infect
the skin and cause warts (verruca vulgaris or verruca plana),
condyloma acuminatum, bowenoid papulosis, or epidermodysplasia verruciformis. These chronic skin lesions present as localized, often multiple papules or larger excrescences, except for verruca plana, which leads to minimal
elevation of the skin (Figs. 15-13 and 5-14).
Herpes simplex virus (HSV) infections of the skin may be
caused by any of the several HSV viruses, but they most often
are caused by HSV- 1 and HSV-2, herpes zoster virus (HZV),
varicella-zoster virus (VZV), and less commonly cytomegalovirus (CMV). Clinically HSV and VZV present in the form
of a vesicular exanthema on erythematous skin (Fig. 15-15).
Keratinocytes infected with herpesviruses show ballooning
degeneration and often become multinucleated (Fig. 15-16).
Intranuclear viral particles account for their " ground glass "
appearance. Vesicles formed as the result of acantholysis of
epidermis are associated with a variable inflammatory response in the dermis. Secondary bacterial infections are
Molluscum contagiosum is a DNA virus (deoxyribovirus)
of the pox family. The skin infection may present as a solitary lesion or as umbilicated papular lesions, some of which
are surrounded by an erythematous ring. Histologically the
papule shows striking acanthosis of the epidermis with some
extension into the dermis (Fig. 15-17). Viruses grow in keratinocytes, filling their cytoplasm in the form of eosinophilic
inclusions. As the viral aggregates are extruded into the
stratum corneum, they become basophilic. In ruptured lesions the dermis shows a strong inflammatory response.
Human immunodeficiency virus ( HIV), type I and type II,
may cause a psoriasiform dermatitis. This skin lesion in part
is caused by the uptake of HIV into the Langerhans cells and

Fig. 15-10. Tinea versicolor. Fungal hyphae and spores are evident in the stratum corneum.

Fig. 15-11. Majocchi granuloma. This fungal infection of the hair

follicles presented as a dermal abscess.


Fig. I 5-12. Majocchi granuloma. Neutrophils surround a

centrally located hair covered with fungal spores and hyphae.

Fig. 15-13. Verruca plana. Human papillomavirus type 3 has

caused hyperpigmented, only slightly elevated, multiple skin

Fig. 15-14. Verruca plana. The keratinocytes in the upper spinous layer show typical vacuolization.

Fig. 15-15. Herpes simplex virus infection. Perioral skin shows

grouped vesicles.

Fig. 15-16. Herpes zoster. Early changes include ballooning degeneration of midepidermal keratinocytes, which have pale nuclei
and multinucleation.

Fig. 15-17. Molluscum contagiosum. Acanthotic invaginations of

the epidermis contain cytoplasmic inclusions of viral particles.


Fig. 15-18. HIV infection. This psoriasiform dermatitis of AIDS

shows acanthosis of the epidermis and a scant dermal lymphocytic infiltrate. Necrotic keratinocytes and fragments of lymphocytes are seen focally.

Fig. 15-19. Pemphigus vulgaris. An acantholytic cleft separates

the basal cell layer, which is still attached to the basement membrane, from the superficial layers of the epidermis.

in part is a reflection of immune, metabolic, and other

changes in the body. Histologically the lesions differ from
classic seborrheic dermatitis or psoriasis in that they show
necrosis of keratinocytes, and leukocytoclasis of lymphocytes but lack suprapapillary thinning (Fig. 15-18).

Acute and chronic dermatoses may be related to an immune
or metabolic injury, but most often they have a complex
pathogenesis. In many cases the pathogenesis of such dermatoses is not known.

Immune-mediated Dermatoses
Pemphigus is a term that encompasses several diseases that
are characterized by the formation of intraepidermal blisters
caused by the binding of antibodies to the cell membrane of
keratinocytes. In the most common form, pemphigus vulgaris, flaccid blisters form and rupture, leaving behind reddened, eroded skin. Histologically the blisters present as clefts
just above the basal row of keratinocytes with minimal
necrosis (Fig. 15-19). Immunoglobulin G (IgG) may be
demonstrated by immunofluorescence (IF) microscopy on
the surface of keratinocytes in the lower layers of the epidermis (Fig. 15-20).
Bullous pemphigoid is a chronic blistering disease that occurs in several forms. It is characterized by a split in the
lamina lucida portion of the basement membrane, which results in the formation of subepidermal bullae. It is the most
common blistering disease of the elderly, preferentially
affecting the legs, thighs, and lower trunk. The initial erythematous lesions show spongiosis and an infiltrate in the
epidermis that contains many eosinophils as well as lymphocytes and neutrophils. The dermal infiltrate usually is superficial and is located around the blood vessels and diffusely in
the papillary dermis. Vesicles and bullae form at the dermoepidermal junction (Fig. 15-21). The blister cavity contains

Fig. 15-20. Pemphigus vulgaris. IF microscopy shows linear

deposits of IgG along the cell membrane of basal keratinocytes.

eosinophils and neutrophils. IgG deposits may be demonstrated along the dermoepidermal basement membrane by
IF microscopy (Fig. 15-22).
Dermatitis herpetiformis ( Duhring disease) is a rare, IgAmediated, blistering disease that often is accompanied by a
sensitivity to gluten in the diet. Small pruritic vesicles that resembl.herpetic lesions appear on the extensor aspects of the
legs and arms. Histologically the blisters start at the tips of
dermal papillae and then become confluent, forming larger
bullae. The dermal inflammatory infiltrate contains neutrophils and scattered eosinophils (Fig. 15-23). Granular deposits of IgA may be seen by IF microscopy in the tips of dermal
Erythema multiforme is a common immune-mediated
disease that represents a hypersensitivity response to a variety of antigens. The disease occurs at any age, although it is
more common in children and young adults. There are two


Fig. 15-21. Bullous pemphigoid. The blister is subepidermal and

its cavity contains proteinaceous fluid and inflammatory cells.

Fig. 15-22. Bullous pemphigoid. A band of IgG is found along the

dermoepidermal junction.

Fig. 15-23. Dermatitis herpetiformis. The subepidermal blister

contains neutrophils, which show a tendency to aggregate at the
tips of dermal papillae.

Fig. 15-24. Erythema multiforme. The targetoid lesions on the

palms have a central, dusky gray, necrotic center.

forms: erythema multiforme minor and Stevens-Johnson syndrome, which is related to hypersensitivity to drugs. The same
type of immune reaction may result from hypersensitivity to
microbes or from malignant tumors. It also may be part of a
systemic autoimmune disease, such as systemic lupus erythematosus. Both forms present with distinctive skin lesions,
which are called iris lesions or target lesions. These skin lesions consist of a zone of erythema with a pale center or a
central vesicle (Fig. 15-24). In the minor form erythema multiforme tends to occur on the extremities or on the trunk.
Stevens-Johnson syndrome presents as a generalized blistering disease that involves the entire body and the oral and
ocular mucosae. Histologically the disease is characterized by
perivascular dermal infiltrates of lymphocytes. During the
first 24 hours deposits of IgM are found in the walls of small
blood vessels of dermal papillae by IF microscopy. Blisters
form as a result of necrosis of basal keratinocytes, but ulti -

mately the entire epidermis becomes necrotic. The early blisters contain fragmented lymphocytes and necrotic keratinocytes, and the underlying dermis usually shows a lymphocytic infiltrate. Secondary infection is common,
especially in the most severe systemic form of the disease,
which is known as toxic epidermal necrolysis. In contrast to
classic erythema multiforme, this disease is characterized by
a rather sparse lymphocytic dermal infiltrate. By definition
more than 30 percent of the skin surface is involved.
Lupus erythematosus is an autoimmune disorder that may
present as a systemic disease (SLE) or in a localized form as
discoid lupus erythematosus (DLE). SLE is associated with
arthritis, kidney disease, and many other disorders. A third,
often mild form that is intermediate between SLE and DLE
is called subacute lupus erythematosus. In all forms of lupus
erythematosus there are autoantibodies to DNA virus and a
variety of other antigens. Skin lesions appear atrophic and


tend to occur on sun-exposed skin. Malar erythema ( " butterfly rash") is common in SLE (Fig. 15-25). Nonspecific but
disease-related manifestations include urticaria, telangiectasia, necrotizing vasculitis, Raynaud phenomenon, and
bullous eruptions. Histologically DLE differs from SLE, although in the beginning both diseases have many common
features. Early changes include infiltrates of lymphocytes at
the dermoepidermal junction with foci of necrosis of ker-

atinocytes and surface parakeratosis (Fig. 15-26). Epidermal

atrophy is common. Infiltrates of lymphocytes in the deeper
dermis are found around the skin appendages and blood vessels. The reticular dermis appears edematous and contains
increased amounts of hyaluronic acid. Chronic discoid lupus
is characterized by prominent epidermal atrophy and prominent infiltrates of lymphocytes in the superficial and deep
dermis (Fig. 15-27). Infiltrates of lymphocytes center around
blood vessels and skin appendages. Advanced lesions have
thick basement membranes and a dermis that is sclerotic,
eosinophilic, and hypocellular (Fig. 15-28). Appendages
often are destroyed, and if this destruction extends into the
subcutis, the disease is called lupus erythematosus profundus.
If the lesions are concentrated in the subcutis, the term lupus

Fig. 15-25. SLE. This patient with acute lupus erythematosus has
a classic red "butterfly rash" over her malar areas. The eroded
erythematous surfaces weep fluid.

Fig. 15-26. Lupus erythematosus, acute systemic disease. Lymphocytic infiltrates are found at the dermoepidermal junction.
Hydropic changes of the basal layer are accompanied by necrosis
of keratinocytes.

Fig. 15-27. DLE. Atrophic epidermis covers sclerotic dermis,

which contains superficial and deep perivascular appendages and
infiltrates of lymphocytes around blood vessels and skin appendages. Hyperkeratosis of patulous hair follicles is prominent.

Fig. 15-28. DLE. Periodic acidSchiff method stains a thickened

basement membrane. The dermis contains scattered
lymphocytes and melanophages.


Fig. 15-29. SLE. Granular deposits of immunoglobulin and complement are seen along the dermoepidermal junction.

panniculitis is applied. Immune complexes, which form gran-

ular deposits along the epidermal basement membrane, on

the hair follicles, and occasionally diffusely spread in the papillary dermis and in the blood vessels, are typical (Fig. 15-29).
Early lesions contain IgM and complement, but later there
also are deposits of IgG, IgA, and fibrin. Deposits of immunoglobulins without complement are found in the sunprotected skin in approximately 50 percent of patients with
SLE, and sun-exposed skin shows deposits in 70 percent of
these patients.
Mixed connective tissue disease is an autoimmune disorder
that has some features in common with SLE, scleroderma,
and polymyositis. It is characterized by antibodies to nuclear
riboproteins and a lack of antibodies to native DNA. Skin lesions resemble those of SLE and scleroderma. Dermatomyositis is an autoimmune disease in which the primary
target organs are the skin and skeletal muscle. In both the
childhood and the adult forms of dermatomyositis, patients
develop symmetric erythematous skin lesions on the face
(Fig. 15-30). Skin lesions are most prominent on the upper
eyelids and cheeks. Lesions also appear on the elbows and
knees, nail folds, and dorsal surface of the knuckles. There is
slight hyperkeratosis, edema, telangiectasia, and occasional
hypopigmentation. Skin atrophy develops over time. Histologically the skin lesions are subtle, with some similarity to
those of acute SLE. In contrast to SLE, there are no deposits
of immunoglobulin along the dermoepidermal junction.

Fig. 15-30. Dermatomyositis. Diffuse erythema symmetrically

involves the cheeks and upper eyelids.

granulomatous diseases according to their clinical and histopathologic features. The most important noninfectious
granulomatous diseases are (1) sarcoidosis; (2) granulomatous vasculitis, as typically found in Wegener granulomatosis, Churg-Strauss syndrome, and giant cell arteritis; (3) granuloma annulare; (4) necrobiosis lipoidica; (5) erythema
nodosum; (6) erythema induratum; and (7) rheumatoid
Granuloma annulare presents in the form of papules arranged in an annular manner (Fig. 15-31). The cause of this
disease is not known. Histologically the lesions show foci of
mucin and fibrin deposition in the superficial dermis surrounded by macrophages (Fig. 15-32).

Granulomatous Diseases
Granulomatous reactions in the dermis may be elicited by
mycobacteria, such as M. tuberculosis or M. leprae, or by fungi.
The causative pathogen may be demonstrated by special
Granulomas also typically form in the skin as part of a
type IV, cell-mediated hypersensitivity reaction. However, in
many instances it is not possible to identify an inciting
antigen, and thus it is more convenient to classify various

Fig. 15-3I. Granuloma annulare. Papules are distributed on the

extremities in an annular manner.


Fig. 15-32. Granuloma annulare. Deposits of fibrin and mucin in

the upper dermis are surrounded by macrophages penetrating
between the collagen bundles.

Fig. 15-35. Erythema induratum. Deep erythematous nodules

are typically found on the legs. Depressed areas reflect tissue
necrosis caused by the underlying vasculitis.

Fig. 15-33. Erythema nodosum. The shin, which-is the favored

site for these lesions, show erythematous deep subcutaneous

Fig. 15-34. Erythema nodosum. The connective tissue septa of

the subcutis are widened, fibrotic, and infiltrated at their edges
with lymphocytes. Multinucleated giant cells and eosinophils may
be present.

Erythema nodosum is an inflammatory lesion of the subcutis that typically presents in the form of erythematous
painful nodules on the anterior shin (Fig. 15-33). The lesions
may spread to other parts of the legs, the hands, and even the
face. Erythema nodosum may have many causes, but most
often it is a reaction to streptococcal or other infection. It may
be part of generalized sarcoidosis, and in such cases it is considered to be a type IV hypersensitivity reaction. Histologically it involves the connective tissue septa of the subcutis.
Initially the septa are widened by infiltrates of lymphocytes,
neutrophils, and eosinophils. Focal hemorrhages are common. Later, as the lesions evolve, the-septa become infiltrated
with lymphocytes and macrophages, and the amount of collagen increases (Fig. 15-34). Small compact granulomas
often are present, and the infiltrates may extend into the fat
Erythema induratum is one of the classic tuberculoids,
that is,, it represents a hypersensitivity reaction to mycobacterial infection in some other part of the body. The skin lesions present as painful, firm, erythematous nodules, most
often on the posterior calf (Fig. 15-35). The lesions may ulcerate and heal by scarring. They respond favorably to tuberculostatic therapy. Lesions of this type that develop in patients who are not infected with M. tuberculosis are called
nodular vasculitis. Histologically there are signs of necrotizing vasculitis with neutrophilic infiltrates affecting arteries
and veins in the fat lobules of the subcutis (Fig. 15-36). Lymphocytic infiltrates extend into the fat lobules.


Fig. 15-37. Psoriasis. The skin shows deep erythema and is

covered with silvery scales.

Fig. 15-36. Nodular vasculitis. The inflammation is centered

around medium-sized arteries in the fat lobules of the subcutis.
Lymphocytic infiltrates extend into the fat tissue.

Idiopathic Skin Disease

Psoriasis is a common skin disease of unknown etiology. It
affects 1 percent to 2 percent of the entire population in the
United States. The skin lesions appear as relapsing and remitting papulosquamous plaques and silvery scales (Fig.
15-37). The skin lesions most often are found over the elbows, knees, scalp, intergluteal groove, and the nails.
Psoriasis is considered to be a disorder of proliferation and
differentiation of keratinocytes that results in irregular acanthosis of the epidermis. The epidermis typically has thickened rete ridges that extend into the dermis (Fig. 15-38). The
intervening dermal papillae are edematous and contain dilated capillaries surrounded by scattered lymphocytes. The
epidermis overlying the dermal papillae is thin. The epidermis lacks stratum granulosum and typically is covered with
alternating zones of keratotic and parakeratotic scales. Parakeratotic layers may contain nuclear debris (Munro microabscesses). Foci of spongiosis of the upper epidermal layers
infiltrated with neutrophils and occasional lymphocytes are
known as spongiform pustules of Kogoj.
Seborrheic dermatitis is a chronic scaling spongiotic and
psoriasiform dermatitis of unknown etiology that affects approximately 3 percent of the total population in the United
States. It ranges in severity from common minimal dandruff
of the scalp to the severe but rare Leiner disease (erythro-

Fig. 15-38. Psoriasis. The acanthotic epidermis shows bridging

of thickened rete ridges. It is covered with a crust of parakeratosis and many neutrophils. The dermal papillae are edematous and contain dilated vessels surrounded by scattered lymphocytes and some extravasated red blood cells.

derma desquamativum) of neonates. The disease affects skin

that has prominent sebaceous follicles, such as the scalp,
supraorbital region, face, and central chest. The early skin lesions present histologically with spongiosis with neutrophils
and lymphocytes at the orifices of hair follicles (Fig. 15-39).
With the progression of the disease the interfollicular epidermis becomes involved, and the lesions may resemble psoriasis, although they typically show much more spongiosis.
Pityrosporum yeasts may be seen in the parakeratotic surface
Pityriasis rosea is a rather common transient papulosquamous disease that presents in the form of erythematous
papules or small plaques, often arranged in the axes of skin
lines. Histologically the lesions show a surface scale of parakeratosis with slight spongiosis but without microvesicula-


tion or neutrophilic infiltration (Fig. 15-40). The scale is focal

and loosely attached, and the amount of acanthosis may be
variable. Lymphocytic infiltrates and hemorrhages may be
seen in the dermis extending into the epidermis.
Small plaque parapsoriasis is a chronic macular to papular
scaling disorder of unknown etiology. It is also known as digitate dermatosis, xanthoerythroderma perstans, or chronic
superficial dermatitis. This disorder may include several disease entities that present with slightly scaly, erythematous

macules and plaques that have a fine scale and orange-red

color. The histologic changes are very subtle and often do not
allow for a definitive diagnosis. The dermis shows sparse
lymphocytic infiltrates around the vessels of the superficial
plexus, and the epidermis is spongiotic and covered with thin
parakeratotic scales (Fig. 15-41).
Pityriasis lichenoides et varioliformis acuta (PLEVA), or
Mucha-Habermann disease, typically affects children and
young adults. It is more common in males than in females,

Fig. 15-39. Seborrheic dermatitis. Spongiosis and parakeratosis

of the epidermis of the orifice of the hair follicle is associated
with mild inflammatory infiltrates.

Fig. 15-40. Pityriasis rosea. The unit lesion is a papule with

slight spongiosis, surface parakeratosis, and a lymphocytic infiltrate with a few small hemorrhages extending from the papillary
dermis into the epidermis.

Fig. 15-41. Parapsoriasis. A superficial perivascular lymphocytic

infiltrate is accompanied by slight hyperkeratosis, slight spongiosis, and early fibrosis of the papillary dermis.

Fig. 15-42. Pityriasis lichenoides and varioliformis acuta (PLEVA).

Foci of hemorrhage and lymphocytic infiltrates in the upper
dermis extend into the epidermis, which shows hyperkeratosis
and necrosis of individual keratinocytes.


with a 3:1 ratio. It presents with small round to oval, slightly

scaly macules or papules, and occasionally small plaques,
which appear in crops and disappear spontaneously. These
lesions typically are found on the arms, legs, buttocks, or
trunk. Histologically the lesions show a superficial and deep
perivascular lymphocytic infiltrate that extends into the epidermis (Fig. 15-42). The epidermis shows slight acanthosis
and parakeratosis, as well as single cell necrosis associated
with invading lymphocytes. Hemorrhages in the papillary
dermis extend into the dermis. Ulceration may result from
extensive epidermal necrosis.

ically it is characterized by elongation of rete ridges, increased

pigmentation of basal keratinocytes, and an increased number of melanocytes (Fig. 15-44). Lentigo may be associated
with sun damage (solar lentigo), but it also occurs in association with hypertrichosis on the shoulders of young men
(Becker nevus), or with polyps of the gastrointestinal tract


Tumors of the skin are classified according to their site of
origin as epidermal, dermal, or subcutaneous, and according
to their biologic characteristics as benign or malignant.

Pigmentary Lesions
Benign pigmentary lesions include ephelis, lentigo, and
nevus; malignant pigmented lesions are called malignant
melanomas (Table 15-1).
Ephelis or freckle is a small, discrete, nearly round, pigmented macule that is less than 5 mm in diameter and has a
uniform brown color. Freckles appear on sun-exposed skin.
The tendency to form freckles is transmitted in an autosomal
dominant manner. Histologically freckles are characterized
by an increased amount of melanin in the basal keratinocytes. Melanocytes are not increased in number.
Lentigo is a discrete, round to oval, hyperpigmented lesion
that is not limited to sun-exposed skin (Fig. 15-43). Histolog-

Fig. 15-43. Lentigo. The palms show multiple pigmented lesions.

Comparison of Melanocytic Lesions*

*, Meaning of scale: =absent; +/=rare or uncommon; + = common; ++ = present in almost all lesions; +++ =very striking feature in almost all lesions.
, At birth, occasionally in acral nevi in young patients, and in some recurrent junctional components of nevi after surgery or trauma.
, Nodular melanomas, small melanomas, and metastatic melanomas may have symmetry.
, Melanoma in situ does not have a dermal component.
I Regression of the dermal portion of a lesion can lead to fibrosis.
I, Lamellar fibroplasia at the tips of rete ridges can be a residual component in melanomas that arise in disordered nevi.


Fig. 15-44. Lentigo. The epidermis shows slight thickening of

rete ridges, increased prominence of a few melanocytes, and
hyperpigmentation of basal keratinocytes at the rete ridges.

Fig. 15-45. Junctional nevus with architectural disorder

(dysplastic nevus). This lesion is larger than 6 mm in diameter. It
is irregularly pigmented and shows inflammatory erythema at its

Fig. 15-46. Lentiginous junctional nevus with minimal architectural disorder and cytologic atypia (MIN-I). Nests of nevus cells
are present, as are individual melanocytes on slightly distorted
rete ridges. The papillary dermis is fibrotic. The nevus cell nuclei
are small, and nucleoli are not visible.

Fig. 15-47. Lentiginous junctional nevus with moderate

architectural disorder and cytologic atypia (MIN-II). The nests of
nevus cells distort the rete ridges more than those in MIN-I. The
nuclei are larger, and a few cells have visible nucleoli.

and pigmentation of mucosae of the mouth and other body

ostia (Peutz-Jeghers syndrome).
When the melanocytes form rounded nests of nevus cells
on the elongated rete ridges, the preferred term is lentiginous
junctional melanocytic nevus. In some enlarged nevi there is
grossly visible irregular pigmentation (Fig. 15-45). Histologically such lesions show architectural disorder such as elongation and distortion of rete ridges and fibrosis of the papillary dermis (Fig. 15-46). Melanocytes show atypia that may
be mild, moderate, or severe. These lesions, formerly called
dysplastic junctional melanocytic nevi, now are called junctional melanocytic nevus with architectural disorder and
atypism of melanocytes, and are graded from mild to severe.

Numeric grades may be applied, and the lesions are designated melanocytic intraepidermal neoplasm ( MIN), grade I,
II, or III (see Figs. 15-46 to 15-48).
Lentiginous lesion may be static and unchanging or they
may progress from simple lentigo to lentiginous nevi. However, all of these lesions involve keratinocytes, which form
elongated rete ridges, in contrast to malignant melanomas,
which do not show proliferation of keratinocytes. Melanomas also show upward proliferation of melanocytes. Nevertheless. histologic distinction between atypical lentiginous
lesions and melanoma may be difficult.
Compound melanocytic nevus is formed by the proliferation of nevus cells in the epidermis, followed by the exten -


Fig. 15-48. Junctional melanocytic nevus with severe

architectural disorder and cytologic atypia (MIN-III). The nests
of nevus cells are almost confluent on the distorted rete ridges.
The nuclei are enlarged, and nucleoli are prominent. There is no
intraepidermal upward migration of individual atypical melanocytes.

Fig. 15-49. Congenital compound melanocytic nevus. This

intermediate-sized lesion shows peripheral speckling of

Fig. 15-50. Compound melanocytic nevus. Each nest of melanocytic nevus cells is surrounded by a fibrillar basement membrane. The cells in the deeper reticular dermis are dispersed and
smaller than those at the dermoepidermal junction.

Fig. 15-51. Compound melanocytic nevus with architectural

disorder. The epidermal component extends several rete ridges
beyond the dermal component. The nests of nevus cells appear
irregular and distort the rete ridges.

sion of these cells, with certain cytologic modifications, into

the dermis. Most compound nevi are acquired after birth,
and only 1 percent of whites are born with a congenital compound melanocytic nevus. Congenital compound melanocytic nevi often have a slightly irregular outline with peripheral speckling of the pigmentation. They vary in size and
occasionally may cover segments of the skin as so-called giant
congenital nevi (Fig 15-49). Compound melanocytic nevi are
slightly raised. They remain less that 6 mm in diameter, have
a smooth outline, and are round-to-oval, symmetric, with
rather uniform brown pigmentation.
Histologically compound melanocytic nevi have sharply
circumscribed lateral borders. Proliferated melanocytes

(nevomelanocytes) form nests at the dermoepidermal junction (Fig. 15-50). Some compound melanocytic nevi have
prominent individual melanocytes on elongated rete ridges,
as in lentiginous nevi. As the nevus cells extend into deeper
reticular dermis, their nuclei and cytoplasm diminish in size.
The size of nevus cell nests also decreases in size, and the cells
tend to become dispersed in a fine collagenous matrix.
Compound melanocytic nevus with architectural disorder
differs from the typical compound melanocytic nevus in that
the junctional component extends for many rete ridges beyond the region that contains the dermal component (Fig.
15-51). The epidermal changes of such lesions (see Fig. 15-46
to 15-48) are accompanied by dermal changes. Dermal


changes include fibrosis at the tips of rete ridges, arranged

parallel to the skin surface (lamellar fibroplasia), or condensation of eosinophilic collagen bundles around the tips of rete
ridges (concentric eosinophilic fibrosis) (Fig. 15-52).
Spitz nevus is a variant of compound nevi that is found in
children and young adults. It has all the features of compound nevi, but in addition it contains large cells with large
nuclei and finely dispersed delicate chromatin, sharp nuclear
envelope, and a single large round nucleolus (Figs. 15-53 and
15-54). There usually is a mixture of spindle-shaped and
epithelioid melanocytes. Mitoses are common in the upper
part of the lesion but not in the deeper dermal parts. The cells
become smaller as they descend into the dermis and are less
cohesive. Variant Spitz nevus, which shows pigmentation and

is restricted to the epidermis and papillary dermis, is called

pigmented spindle cell nevus of Reed. Spitz nevus and its variants occasionally may be difficult to distinguish from malignant melanoma.
Malignant melanoma is a malignant tumor of melanocytes, estimated to affect 1 in every 70 whites in the United
States. Malignant melanomas may occur in any age group,
but they tend to be more common in the older age groups.
Certain patterns of clinical presentation have been defined.
Lentigo maligna melanoma (LMM) most often occurs on the
face of elderly persons with very sun-damaged skin and accounts for approximately 15 percent of cases of malignant
melanoma (Fig. 15-55). It characteristically has a long intraepidermal growth phase, and it forms a spindle cell nodule

Fig. 15-52. Compound melanocytic nevus with architectural

disorder. The junctional lesion is accompanied by dermal lamellar fibroplasia in the form of collagen layers parallel to the surface of the skin.

Fig. 15-53. Spitz nevus. Epidermal hyperplasia is associated with

a proliferation of large epithelioid and spindle-shaped melanocytic nevus cells that form nests at the dermoepidemal junction.
Smaller groups of cells have descended into the dermis.

Fig. 15-54. Spitz nevus. At the base of the lesion, the cells
decrease in size, become dispersed between the collagen bundles,
and cease mitotic activity.

Fig. 15-55. Lentigo maligna, malignant melanoma.


in the dermis (Fig. 15-56). Superficial spreading melanoma

accounts for 60 percent of cases of malignant melanoma. It
presents as an irregularly shaped maculopapular lesion with
varied pigmentation (Fig. 15-57). Histologically it has an intraepidermal and a dermal component (Fig. 15-58). Nodular
melanoma accounts for 15 percent of all cases of malignant
melanoma and presents as a well-circumscribed hyperpigmented nodule. It has mostly a dermal neoplastic component with relative sparing of the adjacent epidermis. Acral
lentiginous melanoma accounts for approximately 5 percent
of all cases of malignant melanoma. It originates in the skin
of distal extremities that often are protected from the sun. It
may have a prolonged epidermal phase.
Malignant melanoma cells vary in size and shape and may
proliferate as individual cells or in small groups. The cytoplasm may be well developed and pigmented or scant and

Fig. 15-56. Lentigo maligna melanoma. The invasive nodule is

composed of spindle-shaped atypical melanocytes.

Fig. 15-58. Malignant melanoma. This superficial spreading

melanoma has invaded the dermis. Atypical melanocytes may be
seen in the superficial stratum corneum and the granular layer of
the epidermis.

nonpigmented. The nuclei usually contain prominent nucleoli. Desmoplastic melanoma, a distinctive histologic variant that is associated with minimal lentiginous proliferation
of atypical melanocytes in the epidermis, typically presents
in the form of spindle-shaped amelanotic cells in a fibrous
and myxoid stroma (Fig. 15-59). It may be difficult to distinguish it from scar. When desmoplastic melanomas form
structures that resemble nerves or invade nerves in the dermis, the term neurotropic melanoma is applied. Acral lentiginous melanoma has the growth pattern of lentigo maligna melanoma or a superficial spreading melanoma, but
characteristically it contains highly dendritic cells and often
small melanoma cells (Fig. 15-60).

Fig. 15-57. Malignant melanoma. A, Superficial spreading malignant melanoma with invasion. The lesion appears multinodular
and shows pale gray scaly foci of atrophy or regression. B, Nodular melanoma. A well-circumscribed nodule is protruding above
the skin surface.

Fig. 15-59. Desmoplastic melanoma. Spindle-shaped cells

showing nuclear atypia are intermixed with fibroblasts and bundles of collagen. There is no pigment.


Fig. 15-60. Acral lentiginous melanoma, invasive. This slide was

stained with the antibody HMB45 to show the dendritic
melanocytes in the epidermis and the nodule of tumor cells in
the dermis.

Fig. 15-6I I. Seborrheic keratosis. A, Exophytic slightly yellowish

skin lesion. B, Pigmented lesion with a corrugated surface. Such
lesions may be mistaken for malignant melanoma.

The histologic diagnosis of malignant melanoma may be

fraught with difficulties. The important histologic features
that are useful in distinguishing malignant melanomas from
other pigmented lesions are listed in Table 15-1. The prognosis of melanomas depends on the extent of tumor spread.
Histologically the extent of invasion maybe expressed in millimeters, or it is designated by levels Ito IV according to the
systems developed by Breslow and Clark, respectively.

Epidermal Tumors
Seborrheic keratosis is a very common benign epidermal lesion that is known as verruca seborrheica. It occurs mostly
in the elderly as a well-demarcated, flat to raised papule or
plaque that is flesh-colored or yellow-pigmented with a rugose surface (Fig. 15-61). It occurs in several histologic patterns, all of which show acanthosis of the epidermis without
cytologic atypia (Fig. 15-62).
Actinic keratosis, also known as solar keratosis or senile
keratosis, is one of the most common neoplasms in whites.
It presents as a scaly, erythematous patch on sun-exposed
skin. It may be hyperpigmented and confluent and tends to
bleed or ulcerate (Fig. 15-63). Histologically the affected skin
contains atypical keratinocytes with enlarged hyperchromatic nuclei arranged in an irregular pattern. According to
the degree of atypia, these lesions are called squamous intraepithelial neoplasia (SIN), grade I, II, or III (Figs. 15-64 and
15-65). In SIN I cytologic atypia is restricted to the basal layer;
in SIN II the entire lower half of the epidermis contains atypical cells; and in SIN III the entire thickness of the epidermis
is involved. The surface of the epidermis usually is keratinized, and the suprabasal region may show acantholysis,
mimicking acantholytic bullous disorders.
The dermis shows signs of solar injury. Several histologic
variants are recognized, including pigmented actinic keratosis, lichenoid actinic keratosis, hyperplastic actinic ker -

Fig. 15-62. Seborrheic keratosis. The epidermis is acanthotic,

with interconnected rete ridges, and the dermal papillae are
fibrotic. Small collections of keratin form "horn pseudocysts."

atosis, and large cell acanthoma. Actinic keratosis is a precursor of invasive squamous carcinoma.
Squamous carcinoma in situ of sun-protected skin is known
by several names, including Bowen disease or erythroplasia
of Queyrat if it is found on the penis. As in typical Bowen
disease, this neoplasia is characterized by cytologic atypia of
cells, which appear in the basal layer but spread through all
layers of the epidermis (Fig. 15-66). Bowen disease also is
graded SIN-I, SIN-II, and SIN-III.
Squamous cell carcinoma most often occurs on sunexposed skin and presents as a nodular or ulcerated lesion
(Fig. 15-67). Histologically it is composed of nests and
strands of squamous cells. Tumors may differ with regard to
the level of differentiation and keratinization (Fig. 15-68).


Fig. 15-63. Actinic keratosis. Confluent lesions on sun-damaged

skin. Foci of ulceration and hemorrhage occur because of the
increased fragility of the skin.

Fig. 15-64. Actinic keratosis (SIN-I). Atypical keratinocytes

replace almost the entire basal layer. Decreased cohesiveness of
the cells cause suprabasal cleavage.

Fig. 15-65. Actinic keratosis (SIN-II). The lower half of the epidermis has been replaced by atypical keratinocytes. The surface
shows extensive keratosis and parakeratosis.

Fig. I5-66. Bowen disease (SIN-III). Atypical keratinocytes are

found in all layers of the epidermis.

Fig. 15-67. Squamous cell carcinoma. The irregularly shaped

plaque on the forehead has a hyperkeratotic and hemorrhagic

Fig. 15-68. Squamous cell carcinoma. The tumor is composed

of invasive nests of keratinizing squamous cells.


Histologically this tumor resembles squamous cell carcinoma from other sites. Metastases of squamous cell carcinoma
of the internal organs to the skin may be difficult to distinguish from primary tumors, especially because the metastatic
tumors also may establish contact with the epidermis, and
thus mimic a primary skin neoplasm.
Keratoacanthoma is a solitary, round, symmetric, nodular
lesion with a central keratotic plug (Fig. 15-69). It typically
grows rapidly, and most lesions fully develop over several
weeks or months. Histologically keratoacanthomas are symmetric, crater-like lesions that have a central keratotic plug
and folds of keratinized epithelium (Fig. 15-70). Because of
the expansile growth of the lesion, it compresses the adjacent
epidermis, which forms a collarette around the central craterlike tumor. The keratinocytes are large and pale and remain
closely adherent to one another, in contrast to acantholysis

Fig. 15-69. Keratoacanthoma. The tumor is round and symmetric and has a visible central keratotic plug.

Fig. 15-71. Basal cell carcinoma. This nodular tumor has a

depressed center and is surrounded by telangiectatic blood

in squamous cell carcinoma. Intraepidermal neutrophils are

present and may form abscesses. The adjacent epidermis
shows no signs of atypia. The intradermal portion of the
tumor is sharply demarcated, and there is no invasion or extension beyond its margins.

Fig. 15-70. Keratoacanthoma. Central area consists of a keratotic plug with papillary projections of keratinized epithelium.
The lesion has a spherical contour compressing the lateral epidermis and the dermis.

Fig. 15-72. Basal cell carcinoma. The tumor is composed of

basaloid cells that form compact nests. Peripheral cells show palisading. Clefts are seen between the tumor nests and the stroma.
Mitoses are prominent. There also are scattered apoptotic cells.


Basal cell carcinoma is the most common malignant tumor

in whites. It typically occurs on the sun-exposed skin of the
elderly and is directly related to excessive ultraviolet light
exposure. Clinically there are three types of tumors: (1) nodular type, which is an opalescent gray nodule that often is associated with telangiectasia; (2) superficial type, which is a
scaly, erythematous, flat lesion with distinct, sometimes
pearly borders; and (3) morpheic type, which is a flat, someti mes depressed, white plaque with adjacent erythema (Fig.
15-71). Each of these types of tumor grows slowly, but. they
also may enlarge quickly and ulcerate. Inexorable local lesions are common, but metastases are extremely rare. Histologically, basal cell carcinoma presents in several forms, but
most of them have at least four of the following six features:
(1) basaloid cells that resemble the basal layer of the epidermis; (2) peripheral palisading at the margins of cell nests;
(3) mitotic figures; (4) individual cell apoptosis, balancing
the proliferation; (5) cellular stroma composed of spindleshaped cells in a mucinous matrix with fine collagen fibrils
and scattered mast cells; and (6) cleft formation that separates nests of neoplastic cells from the stroma (Fig. 15-72).
The only exception is the morpheic basal cell carcinoma,
which often lacks peripheral palisading and shows very little
cleft formation. The stroma of morpheic basal cell carcinoma
is dense and collagenous. Furthermore, these tumors may
show foci of keratinization. Keratinization maybe seen in the
typical basal cell carcinomas, which are called keratotic basal
cell carcinomas. Extensive keratinization makes basal cell
carcinomas resemble squamous cell carcinoma, and those tumors are termed basosquamous carcinoma. There also may
be focal sebaceous differentiation and even formation of
ducts that resemble sweat ducts. Pigmentation of tumor cells
may be found, and this is attributed to the proliferation of
dendritic, heavily pigmented melanocytes, which transfer the
pigment to tumor cells. Pigmentation most often is seen in
superficial basal cell carcinomas. Basal cell carcinomalike
changes occur in the epidermis overlying dermatofibromas.

Fig. 15-73. Trichoepithelioma. Multiple small papular lesions

appear flesh-colored.

Fig. 15-74. Trichoepithelioma. The tumor is composed of

groups of basaloid cells in a cellular stroma. They differ from
basal cell carcinoma in that they lack clefts between nests of
tumor cells and stroma, have low mitotic count, and show no
areas of confluent necrosis.

Adnexal Tumors
Many histologically distinct tumors are found in the dermis
and subcutis. These tumors originate from cells that form
hair follicles, sebaceous glands, apocrine glands, and many
others. These tumors usually are solitary and benign, but they
may be multiple and malignant. Only some tumors, which
have been chosen to illustrate this heterogeneity, are presented here.
Trichoepithelioma is a tumor of the hair follicles that presents in the form of solitary or multiple skin nodules (Fig.
15-73). Histologically this tumor varies with regard to the degree of its differentiation, but most tumors contain both keratotic and basaloid areas (Fig. 15-74).
Syringocystadenoma papilliferum is a tumor that typically
occurs on the face or the scalp as a crusty, exophytic, papillary lesion (Fig. 15-75). Histologically the tumor cells line
connective tissue papillae that project into the lumen of a
cystic cavity (Fig. 15-76).

Fig. 15-75. Syringocystadenoma papilliferum. The tumor presented as a solitary crusted papillary lesion.


Fig. 15-76. Syringocystadenoma papilliferum. Papillary fronds

lined by epithelial layers project into a cystic cavity.

Fig. 15-77. Sebaceous carcinoma. The tumor is composed of

epithelial cells that differentiate focally into lipid-laden, sebaceous
cells that have clear cytoplasm.

Fig. 15-78. Merkel cell carcinoma. Tumor cells that have round
nuclei of uniform size and very little cytoplasm form compact
nests in the dermis.

Fig. 15-79. Blue nevus. A, Common blue nevus appears as a

black, slightly raised papule. B, Cellular blue nevus is larger and
may resemble malignant melanoma.

Fig. 15-80. Cellular blue nevus. The dermis is replaced by

densely packed spindle cells that contain variable amounts of
brown melanin pigment.

Fig. 15-81. Juvenile xanthogranuloma. Typical lesions present as

slightly orange-colored papules or nodules.


Fig. 15-82. Juvenile xanthogranuloma. This well-developed

lesion consists of Iipidized macrophages and scattered multinucleated Touton giant cells.

Fig. 15-83. Kaposi sarcoma. Purplish nodules, many of which

have ulcerated, cover large parts of the body. Between the
larger lesions there still are many smaller ones that resemble

Sebaceous carcinoma is a rare form of malignancy that

originates from the sebaceous glands. The epithelial cells of
this tumor differentiate into fat-laden sebaceous cells (Fig.
Merkel cell carcinoma is a malignant skin tumor that is
composed of neuroendocrine cells. The tumor is composed
of dense aggregates of uniform cells that have round nuclei
and little cytoplasm (Fig. 15-78).

Mesenchymal Tumors
Mesenchymal tumors of the dermis and epidermis most
often are benign but may be malignant. They correspond histologically to equivalent tumors of soft tissues. Only some of
these tumors are illustrated here.
Blue nevus is a dermal lesion composed of dendritic and
spindle-shaped highly pigmented cells that produce blueblack skin nodules (Figs. 15-79 and 15-80). In addition to the
common type, there is a cellular blue nevus, which may show
Juvenile xanthogranuloma is a nodular lesion composed
of macrophages. It presents in the form of solitary or multiple skin nodules (Fig. 15-81). This lesion typically is found
in children. Infiltrates of macrophages are found in the
dermis (Fig. 15-82). In fully developed lesions these macrophages have lipid-rich cytoplasm. Scattered multinucleated
cells with a wealth of nuclei also are present. Kaposi sarcoma
is a low-grade, often multifocal malignant vascular tumor
that involves the skin and the internal organs. It has been
linked to infection with herpesvirus type 8. It occurs both in
a sporadic form and epidemically in patients who are infected
with HIV. Patients present with purplish macules of the skin,
which evolve over time `ipto hemorrhagic nodules (Fig.
15-83). Histologically this tumor is composed of spindleshaped cells lining clefts that contain red blood cells (Fig.
15-84). Nuclear atypia is minimal, but mitoses are present.

Fig. 15-84. Kaposi sarcoma. The tumor is composed of spindleshaped cells, and the clefts between the tumor cells contain red
blood cells.

Further Reading
Carlson AJ, Mihm MC Jr, LeBoit PE: Cutaneous lymphocytic vasculitis:
a definition, a review, and a proposed classification. Sem Diagn
Pathol 13:72-90, 1996.
Kohler S, Rouse RV, Smoller BR: The differential diagnosis of pagetoid
cells in the epidermis. Mod Pathol 11:79-92, 1998.
LeBoit PE: Minimal deviation melanoma: concept or quagmire? Adv
Dermatol 13:289-304, 1997.
Leung DYM, Diaz LA, DeLeo V, Soter NA: Allergic and immunologic
skin disorders. ]AMA 278:1914-1923, 1998.
Murphy GF, Mihm MC Jr: Recognition and evaluation of cytological
dysplasia in acquired melanocytc nevi. Hum Pathol 30:506-512,
Rippey JJ: Review: Why classify basal carcinomas? Histopathology
32:393-398, 1998.


Benign Fibroblastic Tumors and
Tumor-Like Lesions
Fibroblastic tumors encompass a variety of lesions ranging
from purely reactive conditions secondary to injury and benign fibromas to fibrosarcomas that have the ability to both
recur and metastasize. Fibromatoses fall midway in the spectrum in that they have the ability to recur locally but do not
metastasize (Table 16-1).
Nodular fasciitis is a tumor-like spindle cell proliferation
that may be confused with sarcoma. It is more common in
young adults, but it also occurs in older adults. Typically it
first appears as a small (1 to 2 cm in diameter), rapidly enlarging, mildly painful, subcutaneous nodule in the upper
extremity, especially the forearm. Although most lesions are
superficial, they may extend to the fascia and form an intramuscular mass that may be confused with soft-tissue sarcoma.
Histologically, nodular fasciitis is composed of enlarged
spindle-shaped to round cells in a richly vascular myxoid
background that contains extravasated erythrocytes, variable
lymphocytic infiltration, and newly formed collagen fibers
(Fig. 16-1). The cells resemble tissue culture fibroblasts in
that they have enlarged but regular nuclei with prominent
nucleoli. Multinucleated giant cells may be present. Mitotic
figures may be numerous, but atypical forms seldom are present. The histologic appearance changes as the lesion ages.
Younger lesions are cellular, whereas older lesions contain
more collagen and may be hyalinized or cystic.
Proliferative fasciitis and proliferative myositis are reactive
fibrous lesions that have similar histologic features. The
former arises at the fascial level, the latter within the muscles, typically in middle-aged persons. These lesions resemble
nodular fasciitis in their proliferative spindle cell component
and myxoid background, but they also contain ganglion
celllike cells with large nuclei and prominent nucleoli (Fig.

Fig. 16-I. Nodular fasciitis. The lesion is composed of spindleshaped cells in a myxoid background.

Elastofibroma is a nonneoplastic condition that probably

is degenerative. It typically and almost exclusively occurs on
the thoracic wall at the lower end of the scapula. The lesion
is seen in adults, most of whom are elderly women. Histologically it consists of scattered fibroblasts, collagen fibers, fat
cells, and large amounts of coarse, serrated elastic fibers of
variable sizes that maybe highlighted with elastin stains (Fig.
Fibrous hamartoma of infancy usually occurs in the axillary soft tissue or in the proximal parts of the extremities

Fibrous Tissue Tumors

Fig. 16-2. Proliferative fasciitis. In addition to spindle-shaped

cells, there are polygonal ganglion celllike cells that have more


during the first year of life. It is more common in boys. The

lesion is poorly circumscribed and usually measures 3 to 5
cm in diameter. Histologically it consists of collections of cellular fibrous tissue traversing fibroadipose tissue and of nodules of immature-appearing fibroblasts in a myxoid stroma
(Fig. 16-4).

broblastic lesions with locally infiltrative features. Fi gromatoses in adults are divided into two types: a deep form (desmoid tumor) and a superficial form (palmar and plantar
fibromatoses); the two forms vary in their clinical presentation and biologic behavior.
Desmoid tumor (aggressive or musculoaponeurotic fibromatosis) previously was commonly classified as low-grade
fibrosarcoma. Approximately half of all cases are abdominal

desmoids, which typically occur in the rectus abdominis

muscles of young women. Extraabdominal desmoids occur
in both women and men, most commonly between 30 and
40 years of age. The most common locations include the
shoulder girdles, chest wall, and thigh.
Desmoids typically arise within muscles but extend into
fat tissue and the subcutis. On sectioning they are firm graywhite masses that have a rubbery consistency and a trabeculated surface. The periphery may have an infiltrating or
sharply demarcated appearance (Fig. 16-5). Histologically all
desmoids are composed of long, sweeping fascicles of differentiated fibroblastic cells with ill-defined cytoplasmic borders, delicately staining nucleoli, and only rare mitoses.
Broad bands of collagen, similar to those seen in keloids, may
be present. The microscopic tumor infiltration beyond the
margins explains the common recurrence of locally excised

Fig. 16-3. Elastofibroma. Fibrofatty tissue contains fragmented

elastic fibers.

Fig. 16-4. Fibrous hamartoma of infancy. Fibrofatty tissue contains groups of loosely arranged immature-appearing fibroblasts.

Fibromatosis is the term given to a group of differentiated fi-

Fig. 16-5. Desmoid tumor. A, Abdominal wall desmoid appears as a gray-white mass measuring 4
cm in diameter. B, Broad bands of fibroblastic collagenous tissue infiltrate the space between
muscle cells.


The generally accepted category of fibrohistiocytic tumors has
been retained for historic reasons to facilitate the communication between clinicians and pathologists who have been
using this term for more than 30 years. Immunohistochemical data indicate, however, that these tumors are composed
of fibroblastic cells, which show no evidence of histiocytic
differentiation. This category includes benign tumors, such
as benign fibrous histiocytoma; tumors of intermediate malignancy, such as dermatofibrosarcoma protuberans; and
malignant tumors, such as malignant fibrous histiocytoma
(Table 16-2).
Dermatofibrosarcoma protuberans ( DFSP) is a superficial
tumor of intermediate (low-grade) malignancy. This tumor
occurs primarily in young adults and develops as a cutaneous
mass, most commonly on the chest wall or trunk (Fig. 16-6).
Initially developing as a plaque or small nodule, it may become large, ulcerate, and give rise to satellite nodules.
Histologically DFSP is composed of slender fibroblastic
cells that often are arranged in a repetitive storiform pattern.
Although most of the lesions are quite cellular, hyalinization
or a myxoid change of the stroma may supervene to obscure
the typical appearance. The cells seldom display significant
mitotic activity. The tumors show an infiltrative pattern of
growth into subcutaneous fat, a feature that accounts for the
high frequency of recurrences after conservative local excision.
Malignant fibrous histiocytoma ( MFH) is a malignant
tumor composed of cells that resemble fibroblasts and histiocytes. Immunohistochemical data indicate that these cells are
fibroblasts and that there is no evidence of differentiation
into histiocytes (macrophages). The term MFH is retained
for historical reasons.
MFH occurs in soft tissues of extremities, in the retroperitoneum, and in other sites. On gross examination the tumor
appears as a fibrotic, often multinodular, white mass with
areas of necrosis and hemorrhage (Fig. 16-7). There are four
histologically distinct subtypes of MFH: (1) storiformpleomorphic, (2) myxoid, (3) giant cell, and (4) inflammatory. Storiform-pleomorphic MFH is the most common

subtype. Histologically this tumor consists of large spindleshaped or polygonal cells arranged into sheets or short intersecting fascicles. The cells typically are pleomorphic. Mitoses are prominent and often atypical. Myxoid MFH is the
second most common subtype. As its name implies, it has a
myxoid component, which occupies more than 50 percent of
the entire mass. Giant cell MFH is composed of spindle and
round cells, with an abundant infiltrate of osteoclast-like
multinucleated giant cells. Inflammatory MFH is the least
common subtype and usually is found in the retroperitoneum. It consists of parts that resemble the conventional
MFH and parts that show poor cellular cohesion and infiltrates of inflammatory cells, including neutrophils and
macrophages, which often transform into xanthoma cells.

Fibrohistiocytic Tumors


Fig. 16-6. Dermatofibrosarcoma protuberans. A, This 3 cm mass located in the dermis and subcutis appears grayish-white on cross section. B, Fibroblasts arranged in whorls infiltrate the
subcutaneous fat.

33 9

Fig. 16-7. Malignant fibrous histiocytoma (MFH). A, This large fleshy mass was removed from the
deep soft tissue of the calf. B, Storiform-pleomorphic MFH consists of spindle-shaped and larger
pleomorphic cells. C, Myxoid MFH consists of myxoid tissue surrounding prominent blood vessels.
D, Giant cell MFH consists of fibroblastic and multinucleated giant cells.

Lipomatous tumors are composed of fat cells and their precursors (Table 16-3).
Lipoma probably is the most common soft-tissue tumor.
This benign tumor typically occurs in subcutaneous tissue
but may be found elsewhere. It is composed of mature fat

Lipomatous Tumors

cells that may be admixed with connective tissue, blood vessels, and other elements (Fig. 16-8). Several subtypes are recognized, including (1) angiolipoma, (2) angiomyolipoma,
(3) spindle cell lipoma, (4) pleomorphic lipoma, (5) intramuscular lipoma, (6) perineural fibrolipoma, and (7) myelolipoma.


Fig. 16-8. Spindle cell lipoma. In addition to fat cells, the tumor
contains spindle-shaped fibroblastic cells.

Hibernoma is a benign tumor of brown fat (Fig. 16-9).

This tumor most often develops on the back or the shoulder
and less often appears on the thigh.
Lipoblastoma is a benign tumor of infancy and childhood
that is composed of lobules of immature fat cells (Fig. 16-10).
Liposarcoma is a common soft-tissue malignancy that almost exclusively occurs in adults. Approximately 50 percent
of liposarcomas occur on the lower extremities; 20 percent
are intraabdominal. On gross examination liposarcoma appears as a yellow mass that may be relatively circumscribed
or invasive (Fig..16-11). Several histologic subtypes are recognized: (1) well-differentiated (lipoma-like and sclerosing),
(2) myxoid, (3) round cell, (4) pleomorphic, and (5) dedifferentiated. The first two forms are low-grade sarcomas,
whereas the latter three are high-grade sarcomas that have a
tendency to metastasize.
Well-differentiated liposarcomas resemble mature fat
tissue or lipomas, and the only indication that the tumor is
malignant stems from the hyperchromatic atypical cells in
the widened connective tissue septa and the presence of scattered lipoblasts. The latter are immature fat cells that contain
one or more fat vacuoles, which indent or scallop the nucleus. Lymphocytic infiltrates are common, especially in abdominal liposarcomas of this type.
Myxoid liposarcoma is the most common type. Histologically it has a typical pattern with abundant branching fine
capillaries surrounded by uniform small tumors cells suspended in hyaluronic acidrich matrix (Fig. 16-11, B).
Varying numbers of lipoblasts are present. Lipoblasts vary in
size and shape and typically contain vacuoles of lipid in their
Round cell liposarcoma represents the cellular or poorly differentiated variant of myxoid liposarcoma. It may coexist as a
minor component of otherwise typical myxoid liposarcoma;
in such cases the tumor shows more pronounced aggressiveness. Histologically it consists of uniform, primitive round
cells with a high nuclear-cytoplasmic ratio (Fig. 16-11, C).

Fig. 16-9. Hibernoma. The tumor is composed of multivacuolated cells that resemble normal brown fat cells.

Fig. 16-10. Lipoblastoma. Immature, richly vascular fat tissue has

a lobular appearance.

There often is a hemangiopericytomatous pattern in which

the cells surround branching blood vessels.
Pleomorphic liposarcoma is a relatively rare tumor that
typically is found in the elderly. Histologically it is composed
of pleomorphic tumor cells, including highly atypical multinucleated giant cells, many of which have multiple cytoplasmic vacuoles (Fig. 16-11,D).
Dedifferentiated liposarcoma consists of areas that resemble well-differentiated liposarcoma and areas that resemble
high-grade MFH.


Fig. 16-1 I. Liposarcoma. A, On gross examination this liposarcoma appears as a yellow, deepseated circumscribed mass. B, Myxoid liposarcoma consists of small lipoblasts in a loose myxoid
stroma arranged around prominent branching blood vessels. C, Round cell liposarcoma consists
of compact sheets of round cells, some with fat vacuoles. D, Pleomorphic liposarcoma consists of
large pleomorphic and multinucleated cells, many of which contain lipid vacuoles in their cytoplasm.

Endothelial Tumors of Blood and Lymph Vessels

Vascular tumors composed of endothelial cells of blood and
lymph vessels are very common lesions of the skin and subcutaneous tissue, but they also occur in many other tissues
and in internal organs. Most vascular tumors are benign.
Low-grade malignant tumors such as hemangioendothelioma and highly malignant angiosarcomas are less common
(Table 16-4).

Benign tumors of endothelial cells occur in all age groups

and may present in many clinical and pathologic forms.
Some congenital hemangiomas actually are hamartomas,
whereas others, such as bacillary angiomatosis or pyogenic
granuloma, maybe reactive lesions (Fig. 16-12). On the basis
of histology it is difficult and often impossible to determine
the true nature of such vascular lesions.


Fig. 16-12. Pyogenic granuloma. A, The lesion is a well-circumscribed, red nodule that bleeds
easily on trauma. It forms fast and tends to recur rapidly if it is incompletely excised. B, The lesion
is composed of thin-walled vessels with edematous stroma that is rich in inflammatory cells and
capillaries that have collapsed lumina.

Fig. 16-13. Lymphangioma. The dilated vascular spaces lined by

flattened endothelial cells contain proteinaceous lymph and a
few lymphocytes.

Fig. 16-14. Epithelioid hemangioendothelioma. The tumor

consists of endothelial cells arranged into cords and clusters. The
vacuoles represent microlumina.

Fig. 16-15. Angiosarcoma. A, The tumor forms a hemorrhagic mass in the deep soft tissue.
B, The tumor is composed of endothelial cells lining irregular channels, some of which contain
blood. (Gross specimen photograph courtesy of Dr. Steven I. Hajdu, Manhasset, New York.)


Benign tumors of blood vessels are called hemangiomas,

and those that originate from endothelial cells of lymphatics
are called lymphangiomas (Fig. 16-13). Several clinical and
pathologic variants are recognized, including (1) capillary
hemangioma, (2) cavernous hemangioma, (3) intramuscular hemangioma, (4) epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia or Kimura disease),
(5) angiomatosis, 6) bacillary angiomatosis, (7) pyogenic
granuloma, (8) intravascular papillary endothelial cell hyperplasia (Masson hemangioma), (9) cystic lymphangioma,
(10) lymphangiomyoma, and (11) lymphangiomyomatosis.
Hemangioendothelioma is an endothelial cell neoplasm
of intermediate (borderline) malignancy that occurs in several forms, such as (1) epithelioid hemangioendothelioma,
(2) spindle cell hemangioendothelioma, and (3) Kaposiform
Epithelioid hemangioendothelioma is composed of endothelial cells that have abundant eosinophilic cytoplasm and
thus resemble histiocytes (Fig. 16-14). More than one half of
all soft-tissue tumors of this type arise from the wall of identifiable vessels, which usually are thrombosed. Neoplastic endothelial cells have cytoplasmic vacuoles, representing miniature vascular lumens, which may contain erythrocytes.
These cells are arranged into cords and clusters in a loose fibromyxoid stroma.
Spindle cell hemangioendothelioma is a rare vascular tumor
of the subcutis of young adults, usually located on the hands.
Histologically it is composed of cavernous blood spaces juxtaposed with bland spindle cells, reminiscent of Kaposi sarcoma.
Kaposiform hemangioendothelioma is a rare childhood
tumor of superficial or deep soft tissues. Histologically it resembles Kaposi sarcoma.
Angiosarcoma is a term that encompasses four clinical entities: (1) cutaneous tumors that occur without preexisting
lymphedema, (2) cutaneous tumors that arise in lymphedematous extremities, (3) angiosarcomas of the breast, and
(4) angiosarcomas of deep soft tissues.
On gross examination tumors often are hemorrhagic and
poorly demarcated from normal tissue (Fig. 16-15,A). Histologically the tumors show a wide spectrum of differentiation.
The well-differentiated tumors show irregular anastomosing, blood-filled vascular channels, lined by variably
atypical endothelial cells, which often show papillary intraluminal tufting. The less differentiated tumors may show
solid strands and sheets, resembling carcinoma or lymphoma
(Fig. 16-15, B). Immunohistochemically the cells express endothelial markers such as von Willebrand factor, CD31 and
CD34, and receptors for the lectin Ulex europaeus. WeibelPalade bodies are the electron microscopy (EM) markers of endothelial cells. Angiosarcoma also must be distinguished from
Kaposi sarcoma and benign vascular tumors, which may show
some nuclear unrest when irritated. Because angiosarcoma-like
areas occur in many hypervascular soft tissues and bone tumors, it is important not to diagnose such tumors as angiosarcomas. The same rule applies to hemangiopericytomas.

The new World Health Organization (WHO) classification
of soft-tissue tumors assigns glomus tumors and hemangiopericytomas to a separate category of perivascular tumors
(Table 16-5).
Glomus tumors are small painful nodules in superficial
soft tissues of adults. They recapitulate the basic features of
glomus bodies, that is, specialized arteriovenous anastomoses regulating the blood flow in distal parts of the body.
Most often they arise from the nailbeds or from the fingers,
palms, feet, legs, and forearms. Simple excision is curative in
most instances, albeit 10 percent of glomus tumors recur locally. Histologically the tumors are composed of uniform,
round to polygonal cells arranged into sheets and cords surrounding thin-walled dilated blood vessels (Fig. 16-16).Variants such as glomangioma, glomangiomyoma, and rare malignant glomus tumors have been described.
Hemangiopericytoma is a rare borderline malignant tumor that occurs in deep soft tissues of the extremities and
the retroperitoneum of adults. Tumor cells are arranged
around thin-walled blood vessels, and although they resemble pericytes, their true nature is subject to controversy;
it has not been proved that they truly are derived from normal
pericytes. Histologically hemangiopericytomas are composed of spindle-shaped or round cells embedded in a moderately dense stroma matrix arranged around dilated vas-

Perivascular Tumors

Fig. I6-16. Glomus tumor. Round and polygonal cells surround

thin walled blood vessels in a collar-like manner.


Fig. 16-17. Hemangiopericytoma. Thin-walled blood vessels in a

"staghorn"pattern are surrounded by spindle-shaped cells in a
collagenous matrix.

Fig. 16-18. Leiomyoma. This spherical nodule was shelled out

from subcutaneous soft tissue. It is brownish-red on cross
section because of an abundance of blood vessels in its stroma.

cular lumina (Fig. 16-17). Reticulin fibers surrounding each

tumor cell and arranged radially perpendicular to the lumen
of the vessel may be demonstrated with special stains. Mitotic activity usually is low, except in highly malignant tumors. There are no immunohistochemical stains that would
be typical of hemangiopericytoma. Most tumors react positively with antibodies to CD34 and are negative for endothelial cell markers, smooth muscle cell actin, and desmin.
However, some tumors of the same histologic appearance
react with antibodies to smooth muscle actin, which suggests
that some "hemangiopericytomas" are not of pericytic origin
but are leiomyosarcomas. Hemangiopericytomatous patterns of growth may be seen in other soft-tissue sarcomas,
most notably MFH and liposarcomas.


Smooth muscle cell tumors include leiomyomas and leiomyosarcomas, which histologically resemble the more common uterine and gastrointestinal tumors (Table 16-6).
Leiomyomas are benign soft-tissue tumors that are
grouped into four clinicopathologic categories: (1) piloleiomyoma arising from arrectores pilorum and presenting as
small 1 to 2 cm nodules; (2) genital leiomyoma commonly
found in the vulva or the scrotum; (3) angiomyoma presenting as vascular subcutaneous nodules with a predilection
for the lower extremities, especially the legs and ankles; and
(4) leiomyomas of deep soft tissue, which are rare tumors
that show considerable regressive changes, such as hyalinization.
Leiomyomas usually are well-demarcated nodules, which
on cross section appear grayish-tan or brown and red, depending on the extent of vascularization (Fig. 16-18). Histologically the tumors are composed of smooth muscle cells
that have uniform elongated nuclei with blunt tips and a welldeveloped eosinophilic cytoplasm (Fig. 16-19).
Leiomyosarcomas are malignant tumors composed of
atypical smooth muscle cells, arranged into fascicles that in -

Fig. 16-19. Leiomyoma. The tumor is composed of smooth

muscle cells that have uniform elongated nuclei and welldeveloped cytoplasm.

Smooth Muscle Tumors


Fig. 16-20. Leiomyosarcoma. A, Pleomorphic leiomyosarcoma is composed of atypical spindle-

shaped cells that vary in size and shape and often show considerable nuclear pleomorphism.
B, Epithelioid leiomyosarcoma consists of polygonal cells that often have clear cytoplasm. Nuclei
appear more uniform, but there are mitotic figures, which indicate that this is a malignancy.

Fig. 16-21. Adult rhabdomyoma. A, Tumor presented as a lobulated pharyngeal mass. B, Tumor

is composed of large polygonal cells that have ample eosinophilic cytoplasm and small nuclei.
(Gross specimen photograph courtesy of Dr. Antonio Racela, Overland Park, Kansas.)

tersect obliquely or perpendicularly with one another. Neoplastic cells have elongated nuclei that show hyperchromasia,
have irregular distribution of chromatin, and often are pleomorphic (Fig. 16-20, A). Areas of necrosis are prominent in
larger tumors. The number of mitoses varies, and the prognosis is determined by taking into account the size of the
tumor, its location, and the histologic findings.
Epithelioid leiomyosarcoma (leiomyoblastoma, bizarre
leiomyoblastoma) more often is found in the gastrointestinal
tract but also may occur in soft tissues. The most common
sites are the peritoneum, omentum, and mesentery. Tumors
that measure more than 6 cm in diameter and have more than
3 to 5 mitoses per 10 high-power fields are malignant. Histologically the tumors are composed of polygonal cells
arranged into sheets (Fig. 16-20, B). These cells have welldeveloped cytoplasm that may be clear or eosinophilic, and
some cells even have a signet ringlike appearance.


Tumors of striated muscle include rhabdomyomas and
rhabdomyosarcomas. Rhabdomyoma is a benign tumor that
shows striated muscle differentiation. Four clinicopathologic
entities are recognized: (1) adult rhabdomyoma, (2) rhabdomyoma of female genital organs, (3) fetal rhabdomyoma, and (4) cardiac rhabdomyoma. Strictly speaking, only
adult rhabdomyoma and fetal rhabdomyoma are soft-tissue
Adult rhabdomyoma is a rare tumor of adults that typically presents as a slow-growing mass in the oral cavity or nasopharynx. Grossly the tumor is a brown or red multilobular
mass that measures 1 to 5 cm in diameter (Fig. 16-21,A). Histologically it is composed of large polygonal cells that resemble skeletal muscle cells. Compared with normal or hyperplastic muscle cells, rhabdomyoma cells are larger and
show cytoplasmic vacuolization (Fig. 16-21, B).


Rhabdomyosarcoma is a malignant tumor that shows striated muscle differentiation and primarily affects children.
Five clinicopathologically distinct types are recognized:
(1) embryonal, (2) botryoid, (3) spindle cell, (4) alveolar, and
(5) pleomorphic, although some overlap exists among these
types. On gross examination rhabdomyosarcoma usually appears as a gray-white myxoid mass (Fig. 16-22,A). Histologically, embryonal rhabdomyosarcoma accounts for 75 percent of all cases. It has a peak incidence in the first year of life.
Urogenital and head and neck areas most often are involved.
Embryonal rhabdomyosarcoma are composed of a mixture
of small and large rhabdomyoblasts, which have prominent
eosinophilic cytoplasm (Fig. 16-22, B). The degree of rhabdomyoblastic differentiation correlates positively with the
prognosis. In some cases loose myxoid areas alternate with
cellular areas in a trabecular pattern.
Alveolar rhabdomyosarcoma accounts for 10 percent to 20
percent of all cases of rhabdomyosarcoma. It occurs predominantly in adolescents and preferentially involves the distal
parts of the extremities and the head and neck area. Histologically the tumor is composed of small cells that are separated into groups by fibrovascular septa.

Because of poor cohesiveness of the cells and areas of

necrosis, central parts of tumor nests transform into " alveolar spaces " (Fig. 16-22, C). In addition to the round undifferentiated cells, the tumor may contain larger multinucleated cells with abundant eosinophilic cytoplasm. Desmin,
which is the best marker of striated differentiation, may be
demonstrated even in the smaller cells (Fig. 16-22, D). EM is
useful for demonstrating myofibrils, which show Zbandlike condensations (Fig. 16-22, E).
Pleomorphic rhabdomyosarcoma, which previously was
considered to be a common soft-tissue sarcoma of the extremities in adults, now is considered to be rare. Most of these
tumors actually are desmin negative and represent pleomorphic MFH. Spindle cell rhabdomyosarcoma is a rare childhood
tumor that is composed of spindle-shaped rhabdomyoblasts.
Botryoid rhabdomyosarcomas are myxoid, " grapelike,"exophytic tumors of the urinary bladder, cervix, and vagina of
preschool-age girls (see Figs. 13-29 and 13-30). Similar tumors occasionally are found in the liver and upper respiratory tract.

Fig. 16-22. Rhabdomyosarcoma. A, On gross examination the tumor appears as a myxoid mass.
B, Embryonal rhabdomyosarcoma consists of small and large rhabdomyoblasts. C, Alveolar
rhabdomyosarcoma is composed of undifferentiated small round cells attached to fibrous septa.
Alveolar spaces are formed between discohesive cells. D, Rhabdomyosarcoma stains positively
with antibodies to desmin. E, EM shows thick and thin filaments and Z-bandlike densities.


Neural tumors include neoplasms that show nerve sheath
differentiation and are composed of Schwann cells, perineurial cells, and perineurial fibroblasts; and those that display neuronal feature ganglioneuroma. Most of these neural
tumors are benign, and many of them are quite common.
Malignant nerve sheath tumors are rare.

Benign Neural Tumors

Benign Neural Tumors

Benign neural tumors are listed in Table 16-7.
Schwannoma is a benign tumor that is composed of
Schwann cells. It typically originates from peripheral nerves
and often is recognized as a fusiform mass that focally expands the nerve or is attached to it (Fig. 16-23, A). Histologically it is characterized by cellular Antoni A areas alternating
with myxoid Antoni B areas. The cellular areas consist of
sheets of spindle cells with palisaded nuclei that form
columns around an amorphous matrix (Verocay bodies)
(Fig. 16-23, B).
Neurofibroma is a common benign nerve sheath tumor
that most often appears as an unencapsulated subcutaneous
nodule. It consists of haphazardly arranged fibroblasts, perineurial cells, and Schwann cells (Fig. 16-24). The spindleshaped tumor cells are intermixed with wavy collagen bundles. The stroma may be myxoid or densely collagenous.
Nerve sheath myxoma (neurothekeoma) is a benign nerve
sheath tumor of the subcutis that most often is found in children and young adults. Histologically it is composed of multiple lobules of spindle cells suspended in myxoid material
surrounded by dense fibrous bands (Fig. 16-25).

Fig. 16-24. Neurofibroma. Spindle-shaped cells are surrounded
by wavy matrix.

Fig. 16-23. Schwannoma. A, Tumor has produced a bulging

mass in the peripheral nerve. B, Spindle-shaped cells show palisading, which is evidenced by the alignment of nuclei at the margins of eosinophilic areas composed of cytoplasmic processes.

Fig. 16-25. Nerve sheath myxoma. Cellular myxoid lobules are

found enclosed in dense connective tissue septa.


Malignant Neural Tumors

Malignant neural tumors are listed in Table 16-8.
Malignant peripheral nerve sheath tumors (MPNST),
which include malignant schwannoma and neurofibrosarcoma, account for less than 10 percent of all soft-tissue sarcomas. Approximately 50 percent of these tumors arise in patients with neurofibromatosis type I through malignant
transformation of nerve trunk fibromas, whereas the remainder arise sporadically. Schwannomas almost never

Malignant Neural Tumors

undergo malignant transformation. Most patients are

middle-aged but some are young, especially those with neurofibromatosis. Multiple malignancies occasionally are
found, again mostly in the context of neurofibromatosis.
MPNST originating from nerves or from preexisting neurofibromas within a nerve expand the nerve in an irregular
manner and extend into the adjacent soft tissues (Fig. 16-26,
A). Histologically MPNST resembles fibrosarcoma except for
the fact that spindle cells tend to have an irregular buckled
shape that is reminiscent of normal Schwann cells (Fig.
16-26, B). Some tumors may be pleomorphic and resemble
MFH. Heterologous elements such as cartilage and bone may
be present. Malignant triton tumor is the designation used to
describe tumors that contain rhabdomyoblasts. Glandular
malignant schwannoma is the term used for those that contain glandular elements. Clear cell sarcoma shows melanocytic differentiation. Well-differentiated malignant neural
tumors stain with antibodies to S-100 protein (Fig. 16-26, C),
like normal Schwann cells, but many highly malignant ones
do not. Differentiation into Schwann cells may be detected
by EM in better differentiated tumors. These ancillary tests
are of no value in undifferentiated tumors. Precise diagnosis
of such tumors often is uncertain unless the tumor arose in
the context of neurofibromatosis type I or the mass was obviously attached to a peripheral nerve.

Fig. 16-26. Malignant peripheral nerve sheath tumor (MPNST). A, Tumor is arising from the
ulnar nerve. B, Histologically MPNST is composed of nondescript spindle-shaped cells. C, Some
tumor cells in the MPNST stain with the antibody to S-100 protein.



Cartilage and bone-forming tumors are listed in Table 16-9.
Histologically these tumors have the same features as their
more common equivalents in the bones.
Myositis ossificans is a pseudoneoplastic condition that is
marked by the formation of reactive bone inside the muscle.
It typically occurs in young adults and presents as a painful
mass, most often in the anterior muscle of the thigh. or the
buttocks (Fig. 16-2 7, A). The mature lesion is sharply demar-

cated from the surrounding muscle. The central part, which

consists of osteoblasts, osteoid, and osteoclasts, is rimmed by
mature bone at the periphery (Fig. 16-27, B and C).
Osteosarcoma of soft tissues is a tumor of adulthood, and
most patients are older than 40 years. Deep muscle compartments of the extremities and the retroperitoneum are the
most common sites. Histologically most tumors are highgrade sarcoma and may be indistinguishable from those in
MFH except that focally they show osteoblastic differentiation and produce trabecular osteoid (Fig. 16-28).

Cartilage and Bone-Forming Tumors of Soft Tissue


Fig. 16-27. Myositis ossificans. A, Sharply demarcated intramuscular lesion shows a distinct difference between the peripheral rim of bone and the central part. B, The peripheral part consists
of trabeculae of newly formed bone. C, The central part consists of osteoblasts surrounding
osteoid and osteoclast-like giant cells.


Fig. 16-28. Osteosarcoma of soft tissue. Tumor is composed of

high-grade malignant spindle-shaped cells surrounded by osteoid.

Fig. 16-29. Extraskeletal myxoid chondrosarcoma. Trabeculae

of spindle cells are suspended in myxoid matrix.

pended in a myxoid matrix (Fig. 16-29). Because of its resemblance to chordoma, it also is known as chordoid sarcoma. Hyaline cartilage, a typical finding in skeletal chondrosarcoma, is seen only occasionally.
Mesenchymal chondrosarcoma of soft tissues is a rare malignancy that is similar to its osseous counterpart. It occurs
in young patients in the thigh and the meninges and is prone
to metastasis, which may be found in the lungs at the time of
diagnosis. The tumor consists of primitive round cells in a
collagenous stroma demarcating islands of differentiated
cartilage (Fig. 16-30). These tumors usually are highly vascular and may have a hemangiopericytomatous appearance.



Fig. 16-30. Mesenchymal chondrosarcoma of soft tissue.

Primitive-appearing round cells in fibrous stroma are focally juxtaposed to differentiated cartilage. Vascularity of the tumor imparts
to it a hemangiopericytomatous pattern.

Chondrosarcomas of soft tissues may present as extraskeletal myxoid chondrosarcoma or mesenchymal chondrosarcoma. Extraskeletal myxoid chondrosarcoma is a highly
malignant tumor of middle-aged persons. It presents as a
gray gelatinous tumor of the extremities and the retroperitoneum. Histologically it consists of spindle-shaped cells sus -

Soft tissues may give rise to a variety of tumors of unknown

or incompletely known histogenesis (Table 16-10). Some of
these tumors are benign, others are malignant, and in all likelihood still others are not even neoplastic.
Small round cell tumors of soft tissues are grouped together
because of similar morphology, even though there is no
doubt that they may not be related one to another histogenetically. This group of tumors includes extraskeletal Ewing
sarcoma, peripheral neuroepithelial tumors (PNET, or peripheral neuroepithelioma), Askin tumor, and intraabdominal desmoplastic small round cell tumors (Figs. 16-31 and
16-32). Neuroblastomas and metastatic tumors such as
nephroblastoma or hepatoblastoma and lymphomas might
have the same morphology.


Miscellaneous Soft-Tissue Tumors

Fig. 16-3I. Peripheral neuroepithelioma (PNET). Tumor is

composed of nests of small cells arranged focally into rosettes.

Fig. 16-32. Intraabdominal desmoplastic small round cell tumor.

Nests of small blue cells are surrounded by dense collagenous

Fig. 16-33. Synovial sarcoma. A, Biphasic tumor consists of glandlike structures surrounded by
uniform spindle-shaped cells. B, Monophasic tumor is composed of nearly uniform spindle-shaped
cells with some whorling focally.


Fig. 16-34. A, Epithelioid sarcoma. Polygonal cells form compact

nests surrounded by spindle-shaped cells. B, The epitheliod sarcoma cells are uniformly positive for cytokeratin. C, The cells
show membrane staining for CD34.

Fig. 16-35. A, Alveolar soft-part sarcoma. Polygonal cells are

arranged into nests surrounded by connective tissue septa. The
central space gives the tumor an alveolar appearance. B, Electron
microscopy shows rhomboid crystals with a latticelike pattern
and regular periodicity.


Synovial sarcoma is a distinctive malignant tumor of soft

tissues that often shows a dual epithelial and spindle cell mesenchymal differentiation, which previously was believed to
reflect differentiation into synovium. Even though there is
no evidence that the tumor is related to the synovium, its
name was retained for historical reasons. Synovial sarcoma
occurs in young adults (25 to 35 years) and predominantly
involves the extremities. It accounts for 10 percent of softtissue sarcomas. Histologically it occurs in both biphasic and
monophasic forms. The biphasic form of synovial sarcoma
consists of glandlike epithelial structures and mesenchymal
spindle cells (Fig. 16-33, A). The monophasic synovial cell
sarcoma is composed only of spindle cells (Fig. 16-33, B).
Epithelial cells and some spindle-shaped cells react immunohistochemically with antibodies to keratins and epithelial
membrane antigen (EMA).
Epithelioid sarcoma is a rare soft-tissue sarcoma that affects young adults (average age 30 to 35 years). It tends to
arise from distal parts of the extremities and usually presents
as a superficial nodule. The neoplastic nature of the lesion
may elude the clinician and the pathologist alike, but during
histologic examination tumor cells usually extend beyond
the area that is assumed to be involved on the basis of gross
impression. Histologically the tumor is composed of epithelial-like cells arranged into sheets or groups surrounded by
connective tissue stroma (Fig. 16-34). Central necrosis is
common in larger clusters. The nuclei of tumor cells have
complex outlines, and the cytoplasm of most cells is well developed and eosinophilic. The tumor cells typically stain with
antibodies to vimentin, keratin, and EMA, but they also are
positive for CD34.
Alveolar soft-part sarcoma is an architecturally distinct,
rare soft-tissue sarcoma of unknown histogenesis. Most often
it is located in the deep soft tissue of the thigh, but it may
occur anywhere. Most patients are young. Histologically the
tumor has a distinctive organoid appearance (Fig. 16-35).
Tumor cells are polygonal and have an abundant granular
eosinophilic cytoplasm. Central areas of tumor nests tend to
necrotize, giving the nests an alveolar appearance. The cytoplasm contain PAS-positive crystals, which have a lattice-like
appearance on EM. Although it resembles paraganglioma,
there is no evidence of neuroendocrine or neural differentiation. The tumor does not contain keratin and is not epithelial.
Further Reading
Agamanolis DP, Dasu S, Krill CE: Tumors of skeletal muscle. Hum
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Aiba M. Hirayama A, Kuramochi S: Glomangiosarcoma in a glomus
tumor. An immunohistochemical and ultrastructural study.
Cancer61:1467-471, 1988.
Allen PW, Enzinger FM: Hemangioma of skeletal muscle. An analysis
of 89 cases. Cancer 29:8-22, 1972.
Allen PW: The fibromatoses. A clinicopathologic classification based
on 140 cases. Am J Surg Pathol 1977; 1:255-270, 1977.

Azzopardi JG, Iocco J, Salm R: Pleomorphic lipoma. A tumour simulating liposarcoma. Histopathology 7:511-523, 1983.
Bernstein KE, Lattes R: Nodular (pseudosarcomatous) fasciitis, a nonrecurrent lesion. Cancer 49:1668-1678, 1982.
Chase DR, Enzinger FM: Epithelioid sarcoma. Diagnosis, prognostic
indicators, and treatment. Am J Surg Pathol 9:241-263, 1985.
Churg AM, Kahn LB: Myofibroblasts and related cells in malignant fibrous and fibrohistiocytic tumors. Hum Pathol 28:205-218, 1997.
Coffin CM, Dehner LP: Vascular tumors in children and adolescents.
A clinicopathologic study of 228 tumors in 222 patients. Pathol
Annu 28(pt 1):97-120, 1993.
Enzinger FM, Smith BH: Hemangiopericytoma. An analysis of 106
cases. Hum Pathol 7:61-82, 1976.
Enzinger FM: Malignant fibrous histiocytoma 20 years after Stout. Am
J Surg Pathol 10(suppl 1):43-53, 1986.
Erlandson RA, Woodruff JM: Role of electron microscopy in the evaluation of soft tissue neoplasms, with emphasis on spindle and pleomorphic tumors. Hum Pathol 29:1372-1381, 1998.
Evans HL: Liposarcoma. A study of 55 cases with a reassessment of its
classification. Am J Surg Pathol 3:507-523, 1979.
Fields JP, Helwig EB: Leiomyosarcoma of the skin and subcutaneous
tissue. Cancer 47:156-169, 1981.
Fletcher CDM: Benign fibrous histiocytoma of subcutaneous and deep
soft tissue. A clinicopathologic analysis of 21 cases. Am JSurgPathol
14:801-809, 1990.
Goodlad JR, Fletcher CDM: Recent developments in soft tissue tumours. Histopathology 27:103-120, 1995.
Henricks WH, Chu YC, Goldblum JR, Weiss SW: Dedifferentiated liposarcoma: a clinicopathologic analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg
Pathol21:271-281, 1997.
Hibshoosh H, Lattes R: Immunohistochemical and molecular genetic
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24:515-525, 1997.
Hollowood K, Fletcher CDM: Soft tissue sarcomas that mimic benign
lesions. Sem Diag Pathol 12:87-97, 1995.
Hollowood K, Fletcher CDM: Malignant fibrous histiocytoma: morphologic pattern or pathologic entity? Sem Diag Pathol 12:210-220,
Jensen B, Schumacher B, Jesen OM et al: Extraskeletal osteosarcomas.
A clinicopathologic study of 25 cases. Am J Surg Pathol 22:588-594,
Lucas DR, Nascimento AG, Sanjay BK, Rock MG: Well differentiated
liposarcoma. The Mayo Clinic experience with 58 cases. Am J Clin
Pathol 102:677-683, 1994.
Meis-Kindblom JM, Bergh P, Gunterberg B, Kindblom L-G: Extraskeletal myxoid chondrosarcoma. A reappraisal of its morphologic spectrum and prognostic factors based on 177 cases. Am JSurg
Pathol 23:636-650, 1999.
Middleton LP, Duray PH, Merino JM: The histological spectrum of hemangiopericytoma: application of immunohistochemical analysis
including proliferative markers to facilitate diagnosis and predict
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Miettinen M, Lehto V-P, Virtanen I: Monophasic synovial sarcoma of
spindle-cell type. Virchows Arch [A] 44:187-199, 1983.
Miettinen M, Soini Y: Malignant fibrous histiocytoma. Heterogeneous
patterns of intermediate filament proteins by immunohistochemistry. Arch Pathol Lab Med 113:1363-1366, 1989.
Smith PS, Pieterse AS, McClure J: Fibroma of tendon sheath. J Clin
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Stemmermann GN, Stout AP: Elastofibroma dorsi. Am J Clin Pathol
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Developmental disorders that affect the bones most often are
based on a genetic defect that prevents the normal formation
of the osteon, the basic anatomic and functional unit of the
bone. Many of the genes responsible for these developmental
defects have already been cloned, and the pathogenesis of
many developmental bone disorders has been elucidated.
The basic nature of others remains obscure.
Achondroplasia is the most common cause of disproportionately short stature, affecting 1 in 40,000 newborns. It is
based on the mutation of the gene encoding the receptor for
the fibroblast growth factor, which is transmitted from one
generation to another in an autosomal dominant manner.
Nevertheless, 80 percent of cases are sporadic. The growth of
the long bones of the extremities has been stunted, which
accounts for dwarfism, the most prominent feature of this
disease (Fig. 17-1). Histologically the long bones show abnormalities of endochondral ossification at the epiphyseal
growth plate (Fig. 17-2).
Osteogenesis imperfecta is a name given to several clinical
syndromes, all of which are caused by mutations in the genes
encoding collagen type I. Four main forms of osteogenesis
imperfecta have been identified, all of which except the rare
type III are transmitted in an autosomal dominant manner.
The clinical and pathologic findings vary from mild to severe, depending on the type of the disease and the nature of
the genetic defect. Osteopenia is the main feature, and it may
be associated with dental defects and abnormalities of the
skin, ligaments, and sclerae, which typically are blue. Type II
osteogenesis imperfecta is lethal in infancy. Affected infants

Fig. 17-2. Achondroplasia. Epiphyseal growth plate is broad and


show minimal calvarial mineralization ( "rubber head " ) and

short compressed and fractured bones of the extremities
(Fig. 17-3). Histologically bones show irregular and inefficient osteogenesis and are composed of incompletely calcified, thin, and irregular trabeculae (Fig. 17-4).
Osteopetrosis, which is also called marble bone disease or
Albers-Schonberg disease, is a term used to describe four
clinical syndromes that are characterized by excessive thickness of bones. Despite this variability the pathogenesis of all
types involves defective osteoclast function that impairs bone

Fig. 17-I. Achondroplasia. Bones of the extremities are short

and have a disproportionately large cartilaginous epimetaphyseal
part, as compared with short diaphysis.

Fig. 17-3. Osteogenesis imperfecta type II. The infant, who died
shortly after birth, had a large, soft head, small thorax, and short
extremities, which by radiograph showed numerous fractures.


resorption. Carbonic anhydrase II deficiency has been identified in some cases. As a result, primary spongiosa of growing
bones is not removed but persists into adult life. The bones
remain sclerotic forever (Fig. 17-5). In severe forms of the
disease there is anemia because the thick bones do not contain enough space for hematopoiesis. Sclerotic bones tend to
fracture easily despite their thickness.
Sporadic nongenetic developmental anomalies of the
skeleton occur without obvious causes, and they present as
abnormalities of fingers and toes (syndactyly). Parts of extremities or the entire limb may be defective or missing. In
most severe cases such as amelia, li mbs are not formed at all
(Fig. 17-6).


Metabolic Bone Diseases

Fig. 17-4. Osteogenesis imperfecta type II. Neonatal long bones

show irregular osteogenesis. Cortex is incompletely mineralized
and the trabeculae are irregular.

In adults metabolic bone diseases are disorders of the bone

remodeling system, which is responsible for the maintenance
of the anatomic and functional integrity of the osteon, the
basic anatomic unit of bone. In some instances a genetic defect is found to be the cause of bone disease, as in hypophosphatasia or Marfan syndrome; in other cases bone disease is
secondary to a primary disease of the kidneys, endocrine
glands, or gastrointestinal tract. The pathogenesis of many
bone diseases such as osteoporosis remains, however, incompletely understood.
Osteoporosis is defined as a loss of normally mineralized
bone. Bones are structurally weak because of a loss of trabecular bone, cortical porosity, and reduced thickness of cortical
bone (Fig. 17-7). In states of low bone turnover, the rate of

Fig. 17-5. Osteopetrosis. The medullary spaces of the bone do

not contain fibrous tissue or hematopoietic marrow cells but are
filled with bone corresponding to primary spongiosa.

Fig. 17-6. Amelia. Extremities have not formed.

Fig. 17-7. Osteoporosis. Cortical bone and trabeculae are thin.


bone formation is normal to reduced and small amounts of

osteoid are present. Osteoid surface areas are decreased, and
the surface of the bone trabeculae appears smooth and " inactive" (Fig. 17-8). Bone resorption studies indicate decreased resorption surface areas and number of osteoclasts.
In high-turnover osteoporosis, the osteoid surface areas covered with osteoblasts are increased but the width of the osteoid is normal (Fig. 17-9). Bone resorption indices point to
an increased bone resorption.
Osteomalacia and rickets are diseases that result from defective mineralization of the trabecular and cortical bone
matrix. Rickets is a disease of childhood in which defective
mineralization occurs at the growth plate, thus inhibiting
normal bone growth. It usually is related to vitamin D defi-

ciency. Typically the epiphyseal growth plate is disorganized

and widened (Fig. 17-10). Affected bones are weak and tend
to become deformed (bowlegs). Other features of rickets,
such as craniotabes, rachitic rosary (thickening of the costochondral junction), pigeon breast, and lumbar lordosis, also
are related to basic defects in bone mineralization and
Osteomalacia is characterized by softening of bones,
which typically contain more osteoid than normal (Fig.
17-11). Inadequate mineralization of the osteoid, accompanied by inadequate reabsorption and remodeling of the peripheral rim of the trabeculae, results in their widening and
structural weakness. Such bones tend to be less resistant to
stress and are prone to deformities and fractures. Osteomalacia is a major component of renal osteodystrophy, which
typically is found in patients with end-stage kidney disease.
The affected bones show decreased mineralization of the os-

Fig. 17-8. Osteoporosis, inactive. The surface of the bone trabeculae is smooth and covered with flattened inactive cells. Very
little or no osteoid may be found.

Fig. 17-9. Osteoporosis, active. The trabeculae are rimmed with

osteoid, lined by osteoblasts.

Fig. 17-10. Rickets. Epiphyseal growth plate is disorganized and


Fig. 17-I I. Osteomalacia. Thick seams of osteoid cover the calcified core of bone trabeculae.


teoid but increased osteoclastic bone resorption and fibrosis

of the medullary spaces (Fig. 17-12).

Hyperparathyroidism is an important cause of metabolic
bone changes. Parathyroid hormone stimulates both osteoblasts and osteoclasts, which leads to accelerated remodeling
of the bone and loss of minerals from the osteon (Fig. 17-13).
The bone marrow shows fibrosis. Focal aggregates ofmultinucleated osteoclasts may result in lytic lesions (osteitis fibrosa cystica) or tumors ( " brown tumors of hyperparathyroidism"). These lesions may resemble giant cell tumors of
bones (Fig. 17-14). Weakened bones tend to fracture or bleed,
and these secondary changes are accompanied by additional
histologic changes that reflect replacement of damaged bone
and new bone formation. For unknown reasons hyperparathyroidism affects the cortical and subperiosteal bone more
than the trabeculae of the cancellous bone. Early diagnosis
of primary hyperparathyroidism and successful treatment of
chronic renal diseases have reduced the occurrence of severe

forms of renal osteodystrophy and osteitis fibrosa cystica, and

brown tumors of hyperparathyroidism rarely are seen today.
Minor bone changes similar to those seen in other forms of
osteomalacia are, nevertheless, often encountered. Such
changes respond well to treatment of the primary disease.

Paget Disease of Bone

Paget disease of bone, also known as osteitis deformans, is a
chronic osteolytic and osteosclerotic bone disease of uncertain cause. It may involve one or more bones, causing pain,
progressive deformities, fractures, and arthritis. It is a common disease that affects 3 percent of the white population
over 40 years of age. The incidence of Paget disease increases
with age. Most patients (80 percent to 90 percent) are asymptomatic. Deformities of weight-carrying bones of the extremities are the most common feature of polyostotic Paget
disease, which also tends to involve the hematopoietically active flat bones. Involvement of the skull is especially common
in monostotic Paget disease. Involved bones appear sclerotic
and dense (Fig. 17-15).

Fig. 17- 12. Renal osteodystrophy. Trabeculae are rimmed with

prominent osteoid, and the medullary spaces contain increased
amounts of dense fibrous tissue and scattered osteoclasts.

Fig. 17-13. Hyperparathyroidism. Osteoblasts form an almost

continuous line along the thick seams of osteoid rimming the
bone trabeculae. There also is marrow fibrosis, and groups of
osteoclasts are seen in lacunae of bone.

Fig. 17-14. Hyperparathyroidism. Brown tumor of hyperparathyroidism is composed of numerous multinucleated osteoclasts.

Fig. 17-I5. Paget disease of bone. The bone appears sclerotic

and dense.


Fig. 17-16. Paget disease of bones. A, Active resorptive phase is characterized by increased osteoclastic activity. B, Active osteogenic phase is characterized by new bone formation. C, In sclerotic
phase the bone has prominent seams that impart to it a jigsaw mosaic pattern.

Paget disease may be divided into three phases: (1) active

resorptive phase, (2) active osteogenic phase, and (3) quiescent sclerotic phase (Fig. 17-16). In the active resorptive
phase the bone marrow is replaced by richly vascular, loose
connective tissue and congregations of osteoclasts along the
existing trabeculae and within the cortex. The osteoclasts are
morphologically abnormal and many are very large, containing up to 100 nuclei. In the second phase osteoblastic
activity is triggered. Repeated episodes of bone removal, remodeling, and new bone formation finally result in a jigsaw
mosaic pattern, which is the hallmark of sclerotic Paget disease.
Crystal-induced Arthritis
Crystal-induced arthritis refers to a group of metabolic disorders that are characterized by deposition of crystals in and
around the joints. Arthritis may result from the deposition
of monosodium urate, calcium pyrophosphate, and basic
calcium phosphate (hydroxyapatite) and calcium oxalate.
Gout, which is caused by deposition of urate crystals, is
the most important and most common of these diseases, affecting approximately 0.5 percent of the population. Urate
crystals accumulate in the synovial fluid, eliciting an intraarticular inflammation. During an acute attack uric acid
crystals typically are seen in the cytoplasm of polymorphonuclear leukocytes obtained from the inflamed joint. As the
disease progresses deposits of urates form masses ( " tophi " )
that erode the adjacent bone and extend into the soft tissues.

In chronic tophaceous gout, tophi may be seen not only

around the joints but also in the subcutaneous tissue, tendons, earlobes, and even in some internal organs such as the
kidneys. Histologically tophi are characterized by deposits of
uric acid crystals with a central core of proteinaceous material (Fig. 17-17). Crystal deposits are surrounded by granulation tissue that often contains foreign body multinucleated
giant cells (Fig. 17-18). Because uric acid is soluble in water
that contains fixatives, it is washed out during tissue processing. However, in tissues fixed in absolute alcohol, uric
acid crystals appear birefringent when examined under
polarized light.
Pseudogout, which is caused by deposition of calcium
pyrophosphate crystals in articular cartilage, synovium, ligaments, menisci, and intervertebral discs, resembles gout. In
contrast to gout, most patients have a short history. In acute
phases the disease evokes an acute inflammatory response
followed by a chronic inflammation. Challdike deposits are
seen in chronic stages of the disease. These deposits are composed of typical biaxial crystals.
Ochronosis, also known as alkaptonuria, is an inborn error
of metabolism that is marked by a deficiency of homogentisic acid oxidase. Polymers of homogentisic acid accumulate in connective tissue, particularly cartilage, and cause
grossly visible blue-black discoloration. In histologic slides
these deposits appear brown (Fig. 17-19). Homogentisic acid
interferes with the normal metabolism of cartilage, which becomes brittle and easily abraded from the joint surface, which


Fig. 17-17. Gout. Tophus appears as a soft-tissue mass.

Fig. 17-18. Gout. Tophus consists of deposits of uric acid surrounded by granulation tissue that contain foreign body giant cells.

Fig. 17-19. Ochronosis. Polymers of homogentisic acid appear

as brown material in the connective tissue.

Fig. 17-20. Osteonecrosis of the head of femur. The necrotic

bone appears discolored and is demarcated from surrounding
normal bone.

leads to joint dysfunction. Severe spondylosis with chondrocalcinosis of intervertebral disks and degenerative arthropathy of weight-carrying joints develops at an early age.

blood vessels. In the head of the femur the necrotic area usually appears triangular, with a broad subchondral base and
the apex pointing inside (Fig. 17-20). The articular cartilage
may be intact because it receives nutrients from the synovial

Osteonecrosis, also known as aseptic or avascular necrosis, is

a term used to describe bone necrosis that occurs in many

sites but which most often is found in the femoral head of
the elderly. Many predisposing factors have been identified,
including systemic, metabolic, and autoimmune diseases;
drugs; and hormones. In most instances the exact cause
cannot be found and the condition is considered to be idiopathic. Corticosteroids are the most common identifiable
cause of osteonecrosis in younger persons. Treatment of endstage kidney disease by xenotransplantation and trauma is
another common cause. Morphologically the bone shows
typical signs of ischemic necrosis. The infarct usually involves
the medulla and the bone marrow.
The medullary bone and the bone marrow often are affected, sparing the cortex that receives blood from periosteal

Degenerative Joint Disease

Degenerative joint disease, also known as osteoarthritis, is a
common noninflammatory disease of movable joints that is
characterized by degeneration of articular cartilage and adjacent bone and new bone formation. Osteoarthritis may be
classified as primary, or as idiopathic and secondary when it
is related to identifiable causes. The pathologic changes include a variety of degenerative changes, associated with destruction of the bone and joint, and reparatory changes (Diagram 17-1). These changes typically include fragmentation
of cartilage, proliferation of chondrocytes, remodeling of
tidemark, subchondral pseudocysts, eburnation, subchondral bone sclerosis, and focal necrosis of subchondral bone
and osteophytes (Fig. 17-21).

36 2

Diagram I7-I. Possible insults to joint structure and function are numerous and result in a high
cumulative prevalence of joint disorders.

Fig. 17-21. Degenerative joint disease. A, Degeneration of cartilage leads to denuded articular
surface areas. B, Fragmentation of cartilage with proliferation of chondrocytes leads to remodeling
of the tidemark.


Inflammatory diseases of bones and joints include infections
of the bone (osteomyelitis), infections of the joints (infectious
arthritis), and immune-mediated inflammatory diseases of
the joints, such as rheumatoid arthritis.

Infections of Bones and Joints

Infections of bone and joints may occur in an isolated form
or together. Osteomyelitis may spread into the joint and
cause arthritis, and the primary infection of the joint may
spread into the underlying bone. Infectious arthritis may be
caused by viruses, bacteria, or fungi.
Viral arthritis usually is a short-lived acute infection that
heals spontaneously and leaves no consequences. Arthritis is
a common feature of human immunodeficiency virus (HIV)
infection, and the HIV virus may be isolated readily from the
affected joints. Epstein-Barr virus infection typically is associated with arthritis. The pathologic findings are nonspecific
and include synovial edema, chronic infiltrates of lymphocytes, and mild hyperplasia of synovial cells.
Bacterial arthritis maybe caused by a variety of pathogens,
including Streptococcus and Staphylococcus species, Neisseria
gonorrhoeae; spirochetes such as Treponema pallidum and
Borrelia burgdorferi; and mycobacteria such as Mycobacterium tuberculosis. Depending on the causative agent, the inflammatory response may be mediated by neutrophils or
macrophages and lymphocytes, which may form granulomas
(Fig. 17-22). Chronic granulation tissue forms a layer, known
as pannus, which also leads to destruction of the cartilage and
adjacent bone and formation of intraarticular free bodies
( " mice" ) (Fig. 17-23). Destructive lesions lead to ankylosis
and deformities of the joint.
Osteomyelitis typically results from bacterial infections
that may reach the bone by blood-borne means, from adjacent infected joints or soft tissues, or as a result of a bone fracture or bullet wound. Staphylococcus aureus is the most common pathogen, accounting for more than 80 percent of all

Fig. 17-23. Tuberculous synovitis. Articular surface is covered

with grapelike bodies ("rice bodies").

cases that are unrelated to bone fracture. Mixed infections

are especially common in posttraumatic osteomyelitis complicating open fractures or bullet wound.
Morphologic changes in bones affected by osteomyelitis
reflect its etiology and pathogenesis. Staphylococcus aureus
tends to produce abscesses and cavitary lesions, which may
be medullary or subperiosteal (Fig. 17-24). Deep-seated abscesses form sinus tracts lined by granulation tissue that does
not heal (Fig. 17-25). The bone fragments generated in this
process remain inside the cavity of the abscess and are known
as "sequestrum:" Reactive bone sclerosis forms around the
abscess, corresponding to the pseudocapsule of a chronic ab-

Fig. 17-22. Tuberculous arthritis. Pannus infiltrated with mononuclear cells covers the articular cartilage.

Fig. 17-24. Osteomyelitis. Infection has caused massive destruction of the bone shaft and has extended into the surrounding
soft tissue.


scess of soft tissues or parenchymal internal organs. Such a

walled-off abscess is called a Brodie abscess. Sclerotic bone
surrounding a sequestrum-containing abscess cavity is referred to as " involucrum." Extensive new bone formation
results in complete obliteration of medullary spaces and
high-density osteosclerotic lesions (Fig. 17-26). Chronic
osteomyelitis leads to deformities of the skeleton. Since the
advent of modern chemotherapy, deformities, such as severe
gibbous kyphoscoliosis (Pott disease), that result from tuberculosis of the spine are rare (Fig. 17-27).

Fig. 17-25. Osteomyelitis. Granulation tissue forms between the

bone trabeculae in response to persistent infection.

Noninfectious Arthropathies
Noninfectious arthritis and spondylitis are common diseases
that often are accompanied by other systemic symptoms. The
most important among these diseases is rheumatoid arthritis, which is a systemic, presumably autoimmune, chronic
disease that also involves the soft tissues, muscles, heart, and
lungs. The disease is accompanied by a set of immunologic
disturbances reflected in positive serologic tests such as the
test for rheumatoid factor. The groups of chronic arthritides
that do not have positive immunologic test results are, in contradistinction to rheumatoid arthritis, termed seronegative.
This group includes diseases such as ankylosing spondylarthritis, Reiter syndrome, psoriatic arthritis, enteropathic
arthritis, and some less common diseases.
Rheumatoid arthritis begins as a slowly evolving but persistent chronic inflammation that may lead to significant deformities of joints (Fig. 17-28). The inflamed synovium is
edematous and is infiltrated with lymphocytes and plasma
cells (Fig. 17-29). The infiltrates are most prominent around
the blood vessels, which are increased in number and often
show signs of endothelial proliferation and fibrinoid
necrosis. With time the synovium forms a cover over the joint
surfaces ( " pannus " ). Hypertrophic synovitis typical of advanced rheumatoid arthritis leads to erosion of the joint surfaces. It may obliterate the entire cavity and cause ankylosis
( Diagram 17-2). Hyperplastic synovium forms hypervascular fronds that are infiltrated with lymphocytes, plasma
cells, and macrophages. As a result of foci of necrosis and mechanical trauma, pannus tends to fragment and form loose
intraarticular bodies ( " rice bodies") (Fig. 17-30). All of these
changes are associated with joint deformities, reduced mobility, and often complete loss of joint function and ankylosis.
Rheumatoid arthritis is a systemic disease that may affect
many internal organs. Nodules form in the subcutaneous
tissue. These nodules consist of a central area of fibrinoid

Fig. 17-26. Chronic osteomyelitis. The bone appears sclerotic.

Fig. 17-27. Tuberculosis of spine (Pott disease). Destructive

lesion of vertebral bodies may result in kyphoscoliosis.

Fig. 17-28. Rheumatoid arthritis. Prominent deformities of hands

are features of long-lasting disease.


Fig. 17-29. Rheumatoid arthritis. A, Synovium is cellular and covered with fibrin. B, Prominent
synovial vessels are surrounded by plasma cells and lymphocyte.

Diagram 17-2. Complex multifactorial pathogenesis of rheumatoid arthritis involves genetic

susceptibility and environmental influences.


Fig. 17-30. Rheumatoid arthritis. A, Hyperplastic synovium and a rheumatoid nodule removed
from joint. B, Chronic synovitis results in the formation of fibrovascular structures lined on their
surface by synovial cells. C, Pannus invading the subchondral bone.

Fig. 17-31. Rheumatoid nodule. The subcutaneous nodule is composed of a

central zone of fibrinoid necrosis surrounded by palisaded histiocytes.


necrosis surrounded by palisaded macrophages and lymphocyte or plasma cells (Fig. 17-31). Vasculitis that involves small
vessels occasionally is seen in patients with a high titer of immunoglobulin M (IgM). Large vessel disease is even less common but may involve internal organs, which show signs of
infarction. Rheumatoid nodules, fibrosis, and chronic inflammation also may occur in internal organs, most notably
in the lungs of coal workers (Caplan lesion).


Neoplasms of bones are rare, accounting for only 0.2 percent

of all tumors of internal sites. Nevertheless, they are an important cause of morbidity and mortality, especially in children and young adults. Although neoplasms of bone are
quite heterogeneous, overall they tend to affect younger persons, with a peak incidence under the age of 20 years. Long
bones more often are involved than short bones, and the long
bones of legs are the most common site. Malignant neoplasms are distinctly rare in short bones. Primary tumors of
joints are even less common than bone tumors.
The evaluation of patients with bone tumors is based on
an interdisciplinary approach that includes a clinicianorthopedic surgeon, a radiologist, and a pathologist. Clinical
and radiologic data are essential for proper pathologic diagnosis, which should never be based on microscopic findings
alone. Typical anatomic locations of the most common bone
tumors and their radiographic features are shown in Diagram 17-3.

Benign Bone-forming Tumors

Osteoma is a benign slow-growing tumor that is composed

of mature bone (Fig. 17-32). Clinical symptoms are rare except in tumors that compress nerves or cause facial deformities.
Osteoid osteoma is a benign bone-producing tumor that
may occur at any age but most often is seen in the second and
third decades. Males are affected significantly more often
than females. This tumor most often is located within the
cortex of long bones or immediately beneath it (Fig. 17-33).

Fig. 17-32. Osteoma. The tumor is composed of mature bone.

Diagram 17-3. Anatomic locations of common benign and malignant bone neoplasms. Left, proximal end of tibia. Right, distal end of femur. (Modified from Madewell JE, Ragsdale ED, Sweet DE:
Radio) Clin North Am 19:715, 1981.)


It consists of a small nidus of bone-forming cells surrounded

by sclerotic bone. The nidus, which by definition measures
only 1 to 2 cm in diameter, is composed of osteoblasts, interlacing trabeculae of woven bone and osteoid, blood vessels,
and occasional osteoclasts.
Osteoblastoma is a benign bone-producing tumor that accounts for 1 percent of all bone neoplasms. It more often is
found in males than in females and most often is located in

the posterior parts (transverse and spinous processes) of the

vertebrae. Radiologically it is a mixed osteolytic and osteoblastic lesion that may cause cortical thinning and eventually cortical expansion (Fig. 17-34). On gross examination
osteoblastoma appears as a granular, hemorrhagic, gritty
mass that is sharply demarcated from the normal bone. Histologically it is indistinguishable from osteoid osteoma. The
tumor contains numerous interlacing trabeculae of osteoid

Fig. 17-33. Osteoid osteoma.A, Radiograph shows a dense blastic reaction of cortex with a
small lucent area. B, Nidus of osteoid osteoma measures approximately I cm in diameter and has
a finely granular lattice-like appearance. C, Bone spicules lined by osteoblasts are formed within
fibrovascular stroma.

Fig. 17-34. Osteoblastoma. A, Radiograph show an osteolytic lesion with foci of calcification.
B, Osteoblasts line newly formed spicules of osteoid and bone.


and woven bone that are lined by a nearly continuous population of osteoblasts, which may be likened to soldiers in a
row or crows on a fence. The stroma is highly vascular and
there are scattered osteoclasts. No other elements are seen,
although recently there have been reports that small foci of
cartilage occasionally are found. Osteoblastomas are benign
tumors but a rare aggressive variant may appear occasionally. These tumors are considered to be low-grade osteosarcomas and are treated accordingly. .

Malignant Bone-forming Tumors

Osteosarcoma is a complex family of biologically diverse

pathologic entities that share a single histologic finding: the

production of bone or osteoid by malignant cells. On the
basis of clinical and pathologic features, conventional
( "classic" ) osteosarcomas may be separated from several
variant forms. Variant forms of osteosarcoma have a different
prognosis from that of conventional osteosarcoma and need
to be recognized.
Conventional osteosarcomas account for 65 percent to 75
percent of all osteosarcomas. Although they may occur in any
age group, most tumors are diagnosed in persons between 10
and 30 years of age. Males are affected twice as often as females. Fewer than 1000 cases of conventional osteosarcoma
are diagnosed yearly. Although any bone may be involved,
most tumors arise in the distal part of the femur and in the
proximal parts of the tibia, fibula, femur, and radius. Approximately 90 percent of tumors arise in the metaphysis,
and 10 percent arise in the diaphysis. Epiphyseal involvement

almost always represents secondary extension or metastasis

from a metaphyseal primary tumor. Radiologically osteosarcoma presents as a highly aggressive and destructive lesion
that has a variegated appearance on radiograph (Fig. 17-35).
Most lesions contain both radiolucent and radiopaque areas,
and extension into the soft tissues is common. There are,
however, no specific diagnostic radiologic features or features
that would have special prognostic significance.
The gross and microscopic appearance of conventional
osteosarcoma is highly variable and depends on its histologic
composition. Lesions that are rich in osteoid and bone appear dense, granular, and sclerotic, and their color varies
from yellow-brown to ivory-white. Tumors that contain significant amounts of cartilage have an overall gray-blue, lobulated, chondroid appearance. If little matrix is present, the
tumors appear gray-tan; hemorrhage may account for the
brownish-red mottling of some lesions. Microscopically
osteosarcoma is composed of atypical spindle-shaped cells
(Fig. 17-36). The production of osteoid or bone by malignant cells represents the single diagnostic criterion of conventional osteosarcoma. Osseous matrix may be the dominant histologic finding or it may be quite inconspicuous.
Cartilage and collagenous stroma also may be present, and
accordingly tumors may be further subclassified as osteoblastic, chondroblastic, or fibroblastic. Most osteosarcomas
represent a mixture of these three patterns. Histologic subclassifications are impractical and have no clinical value.
Multidisciplinary protocols used in the treatment of osteosarcoma have dramatically improved the long-term survival


Fig. 17-35. Osteosarcoma, conventional. A, MRI shows a predominantly blastic lesion extending
into soft tissue. B, The mass in the distal femur has destroyed the cortex, extending into the soft
tissue. Whitish areas represent the sclerotic part of the tumor. Medullary cavity contains a "skip"
metastasis that appears as a whitish nodule.


Fig. 17-36. Osteosarcoma. conventional. Tumors may show several histologic patterns.
A, Hypercellular tumor forms only a few bone spicules. B, Osteoblastic tumor shows extensive
new bone formation. C, Chondroblastic tumor contains abundant cartilage. D, Fibroblastic osteosarcoma consists of heterogeneous spindle-shaped cells with focal bone formation.

of patients with conventional osteosarcoma from less than

20 percent in the past to approximately 80 percent as reported
in most recent studies.

Osteosarcoma Variants
Parosteal osteosarcoma is a low-grade malignant tumor that
arises from the surface of bones. It most often occurs in the
third to fifth decade of life, and women are affected twice as
often as men. It is almost exclusively a disease of long bones
and most often affects the posterior aspect of the distal femur
(Fig. 17-37). Radiologically it appears as a radiopaque, lobulated mass that seemingly is applied to the surface of the involved bone. The tumor generally grows along the surface of
the bone without involving the medullary cavity. On gross
examination the tumor arises from the bone surface and
tends to be large.
Microscopically, parosteal osteosarcoma is composed of
relatively innocuous spindle-shaped fibroblastic cells that
produce well-formed lamellar bone spicules. With appropriate treatment, the long-term survival rate is over 90 percent.
Periosteal osteosarcoma has a peak incidence in the second
and third decades of life. Men are affected more often than
women. This tumor most often arises in the diaphysis and

metadiaphysis of long bones, especially the femur and the

tibia. Radiologically it may involve part of the surface or may
extend into the soft tissues in a spiculated "sunburst " pattern
(Fig. 17-38). Like parosteal osteosarcoma, this tumor also
may circumferentially envelop tubular bones from which
they have arisen. On gross examination the tumor is located
in the metaphysis or metadiaphysis; it has a broad base, with
fusiform elevation of the periosteum. Microscopically it has
the features of high-grade chondroblastic osteosarcoma. The
five-year survival rate is 50 percent.
Intraosseous well-differentiated osteosarcoma is a rare variant that has a peak incidence in the third decade and affects
women more often than men. The tumor has a strong predilection for the long bones of the extremities, especially the
metaphysis, but it also may occur in the diaphysis. Radiologically it has no distinct features and may simulate fibrous
dysplasia or desmoplastic fibroma. Grossly it contains both
osteoblastic and osteolytic areas and often is confined to the
medullary cavity (Fig. 17-39), although older lesions may extend beyond the cortex. The tumor shares the innocuous histologic features of parosteal osteosarcoma. Microscopically
it is composed of relatively bland fibroblastic cells that form
mature bone spicules, resembling parosteal osteosarcoma. It
has a favorable prognosis.



Fig. 17-37. Parosteal osteosarcoma. A, Radiopaque lobulated

masses are found on the surface encircling the long bone.
B, Longitudinal section of the femur shows a superficial tumor
attached to the posterior side of the bone. C, Bland spindleshaped cells surround lamellar bone spicules.

Fig. 17-38. Periosteal osteosarcoma. A, Radiograph shows a

spiculated surface mass that has a "sunburst" appearance.
B, Surface tumor arising from the shaft of the femur has a broad
base. The medullary cavity is intact. C, Tumor cells form
cartilage. Nuclei show high degree of atypia.


Fig. I7-39. Intraosseous well-differentiated osteosarcoma. A, The medullary cavity contains

tumor tissue that is partially sclerotic. B, Bone spicules are associated with innocuous fibroblastic

37 2

Fig. 17-40. Telangiectatic osteosarcoma. A, Radiograph shows an invasive tumor with prominent
cystic areas. B, Multiple cystic areas involving the proximal metaphysis of the bone resected after
chemotherapy. C, Large hemorrhagic mass in the distal epimetaphysis of the femur has destroyed
the cortex and extended beyond the confines of the bone. D, High-grade osteoblastic cells are
surrounded by cystic dilated vascular spaces and extravasated blood.

Telangiectatic osteosarcoma has the same clinical features

as conventional osteosarcoma but differs in that it is cystic
and hemorrhagic and may resemble aneurysmal bone cyst
(Fig. 17-40). Microscopically the tumor is composed of highgrade osteoblastic cells that produce little osteoid and are surrounded by prominent dilated blood vessels.

Benign Cartilage-forming Tumors

Osteochondroma is the most common benign cartilaginous
tumor of bones, accounting for approximately one third of
all benign bone neoplasms. Most often it is found in children
and adolescents. It usually is located in the metaphysis of long
bones, growing away from the nearest joint. On gross examination the tumor apparently arises from the cortex and may
be sessile or pedunculated. The lesion consists predominantly of cancellous bone that is covered with a cartilaginous
cap (Fig. 17-41). Histologically the lesion is composed of ma -

ture bone and cartilage and is not resected unless it causes

compression, fracture, or other complications.
Enchondroma is a benign cartilaginous tumor of short
bones of the hand and foot of adults. When tumors are multiple and unilateral, the disorder is referred to as Oilier disease. If tumors are multiple and are associated with angiomas
of soft tissues, the condition is called Maffucci syndrome. Solitary enchondroma is the most common of all tumors that
occur in the short tubular bones of hands. Enchondromas
typically are located, in order of decreasing frequency, in
bones of the fingers, metacarpal bones, phalanges of toes, and
metatarsal bones. Tumors arise from the medullary cavity,
extending the bone longitudinally, expanding it, and causing
cortical thinning. Histologically the tumors consist of hyaline cartilage of variable cellularity. There often are numerous
binucleated chondrocytes with nuclei larger than the nuclei
of mature lymphocytes (Fig. 17-42). Finely dispersed chro-



Fig. 17-41. Osteochondroma. A, The lesion is composed of cancellous bone covered with a cartilaginous cap. B, A cartilaginous cap covers the cancellous bone. .

matin and nucleoli are seen, but mitoses are not apparent.
These tumors do not metastasize but may recur after curettage. Conservative treatment is recommended because only
a few tumors that have metastasized have been reported.
Periosteal chondroma is a rare, benign, slow-growing, cartilaginous tumor that arises from the surface of a bone under
the periosteum. Like enchondromas of the hand and feet, its
histologic features may be alarming, but its behavior is benign. The most common location is the metaphyseal region
of long tubular bones, such as the humerus and femur, proxi mal tibia, and phalanges of fingers (Fig. 17-43). Radiologically the lesion typically is small (1 to 3 cm in diameter) and
saucer-shaped on the surface of the bone with a dense rim of
reactive bone tissue. The lesion usually protrudes into the
soft tissue but is well delimited by the periosteum, which may
form a thin eggshell ossification around it. On gross examination periosteal chondroma is a lobulated cartilaginous
nodule surrounded by a rim of bone. Histologically it may
appear as an innocuous proliferation of hyaline cartilage, but
it is common to find binucleated cells and enlarged nuclei
with finely dispersed chromatin. This histologic pattern is
similar to that of a low-grade chondrosarcoma. The diagnosis is based on typical radiologic findings, and the histologic findings should not be a cause for alarm because the
tumor is invariably benign. Nevertheless, it should be distinguished from periosteal chondrosarcoma and periosteal
osteosarcoma, both of which show much more pronounced
nuclear atypia.
Chondromyxoid fibroma is a rare, locally aggressive but benign tumor of bone that accounts for less than 0.5 percent of
benign bone tumors. It may occur in any age group but is
more common in the second and third decades of life. The
most common sites of involvement are the metaphyses of
long bones, proximal tibia and fibula, and distal femur, which

Fig. 17-42. Enchondroma. The tumor is composed of cartilaginous cells that show mild nuclear variation.

is the site of origin of approximately one half of all cases. Radiographically the lesion has an eccentric radiolucent area
surrounded by a sclerotic rim of dense bone, which imparts
a geographic appearance (Fig. 17-44). In contrast to other
cartilaginous tumors, chondromyxoid fibromas rarely contain calcifications. Tumor may destroy the cortex, but generally it is well delimited by the periosteum. On gross examination the tumor is glistening, myxoid, lobulated, and
cartilage-like, and in resected specimens it is surrounded by
a rim of dense bone. Microscopically the tumor contains lobules of myxoid tissue surrounded by condensation of cells at
the periphery of the lobulated areas. The myxoid areas are
poorly cellular, containing stellate, triangular-shaped,
spindle-shaped, or round cells Hyaline cartilage differentiation is not seen even though some cells resemble chondroblasts. At the periphery of lobules there is condensation of

37 4

Fig. 17-43. Periosteal chondroma. A, Radiograph of the posterior surface of distal femur shows a
well-delineated nodule that has a saucer-like shape at the base and a rim of peripheral calcified
material. B, The tumor is composed of cartilage, which focally has lacunae with two nuclei.
C, Cartilage cells show signs of atypia.

Fig. 17-44. Chondromyxoid fibroma of bone. A, Tomogram of

the elbow shows a lytic lesion surrounded by a sclerotic border.
B, The tumor consists of lobulated cartilaginous tissue enclosed
by thick sclerotic rim of bone. C, Tumor cells are arranged into
lobules that have less cellular central areas and cellular periphery.


Fig. 17-45. Chondroblastoma. A, Epiphysis of femur contains a

lucent but demarcated lesion. B, Tumor is composed of small roue
chondroblasts. C, Chondroblasts are surrounded by amorphous
material ("chondroid").

medium-sized cells, many of which resemble chondroblasts.

Some osteoclast-like giant cells are seen, but mitoses are rare.
Immunohistochemically the cells are positive for S-100 proteins, which indicates their cartilaginous nature. Tumors are
treated by block resection because curettage alone is accompanied by an 80 percent recurrence rate.
Chondroblastoma is a rare, benign, cartilaginous tumor
that accounts for 1 percent of benign bone tumors. It may
occur at any age but most often it is diagnosed in the second
decade of life. It typically occurs in the epiphyses of long
bones but extends into the metaphyses as it grows. Radiologically the lesion is eccentric in 75 percent of cases. It has
a geographic pattern of bone destruction with a sclerotic rim
of dense bone at the periphery, consistent with the slow
growth of the tumor over prolonged periods (Fig. 17-45).
Grossly the lesion consists of reddish-brown hemorrhagic
tissue, with occasional small calcifications. Microscopically
the tumor consists of chondroblasts, islands of cartilage,
giant cells, and calcifications. The chondroblasts are polygonal or round cells with indented or grooved nuclei, without
nucleolus and abundant light tanpink cytoplasm. These
cells stain positive for S-100 protein. Mitotic figures are found
in most tumors and range from 1 to 3 per 10 high-power
fields. Nuclear atypia and focal necrosis may be found, but
these changes alone do not imply malignancy. Cartilage is
found in the form of small islands but appears as ill-defined
amorphous pink material that may resemble osteoid. It contains collagen but is depleted of proteoglycans and is referred
to as " chondroid." Giant cells, which may be sparse or abundant, represent osteoclasts. Calcifications are of two types:
small, irregular, and ill-defined; or lacy, " chicken wire " type,
i mparting to the lesions a honeycomb appearance. Ossification that simulates osteoblastoma is found in 5 percent of lesions. Aneurysmal bone cyst formation is a common secondary phenomenon that might be associated with a higher
degree of recurrences. Most tumors are benign and respond

well to conservative management with curettage. Recurrences are expected in 15 percent of cases. Metastasizing malignant chondroblastomas are extremely rare.

Malignant Cartilage-forming Tumors

Chondrosarcoma is the second most malignant bone tumor.
It is classified as central (medullary) if it is located in the
medullary cavity or peripheral (juxtacortical) if it is found
on the surface of the bone. Microscopically it is categorized
as classic chondrosarcoma or as chondrosarcoma variants .
Chondrosarcomas may arise de novo or as a secondary malignancy in a preexisting cartilage lesion, such as enchondromas of Oilier disease. Chondrosarcomas occur mostly in
adults, generally those between 20 and 70 years of age. The
most common sites of involvement are the pelvis, femur,
scapula, humerus, and ribs (Fig. 17-46). Radiographic findings are typical. Scattered calcifications, described as punctate, annular, popcorn-like, stippled, and so on, are indicative of cartilaginous tumors but do not help in distinguishing
benign from malignant tumors.
Classic chondrosarcoma is the most common type of this
malignancy. On gross examination the tumors have a glistening, lobulated cartilaginous appearance irrespective of
their intramedullary or surface location. As the tumors grow,
they tend to compress tissues or invade and trap adjacent
structures. Microscopically chondrosarcomas may be composed of morphologically benign cells or apparently malig-

37 6

Fig. 17-46. Chondrosarcoma. A, Humerus shows extensive

diaphyseal and metaphyseal involvement with scalloping of
endosteum. B, Cartilaginous mass originates from the surface of

nant and undifferentiated cells (Fig. 17-47). Histologic

grading of lesions, which usually is done on a scale from 1 to
3, is an important part of the evaluation of all cartilaginous
tumors. Low-grade lesions are made up of hyaline cartilage
showing sparse cellularity and rare lacunae with binucleated
cells. The nuclei of tumor cells are dark, round, and not larger
than the nuclei of lymphocytes. Higher grade lesions are
more cellular and are composed of tumor cells that have
larger nuclei with finely dispersed chromatin and occasional
nucleoli. There is increased variation in the size and shape of
nuclei, some of which are spindle-shaped, vesicular, or
bizarre. The number of lacunae with binucleated cells is increased. High-grade lesions show nuclear atypia, pleomorphism, and mitotic activity. Two or more mitoses per 10 highpower fields are found in grade 3 lesions. Grade 1 lesions have
an excellent prognosis and may be cured by local treatment,
in contrast to grade 3 lesions, which tend to metastasize and
have a 10-year survival rate of 55 percent.
Chondrosarcoma variants include (1) dedifferentiated
chondrosarcoma, (2) mesenchymal chondrosarcoma, and
(3) clear cell chondrosarcoma.
Dedifferentiated chondrosarcoma is a rare tumor that accounts for 1 percent to 2 percent of malignant bone tumors.
It has the worst prognosis of all chondrosarcomas and invariably is considered to be fatal. Most tumors occur in the
elderly and most often are located in the pelvis and femur.
Radiologically the tumors are speckled like other cartilaginous tumors, but they also have a large lytic component and
extend outside the bones. On gross examination they are
large infiltrative tumors, with variable foci of obvious cartilage. Histologically the diagnosis is made upon finding areas
of cartilage adjacent to high-grade sarcoma, which usually
appears like malignant fibrous histiocytoma or unclassified
spindle cell sarcoma or osteosarcoma. Despite radical surgery
survival rates are dismal.
Mesenchymal chondrosarcoma is a rare tumor that accounts for 0.3 percent to 0.5 percent of primary malignant

Fig. 17-47. Chondrosarcoma. A, Grade I tumor is composed of innocuous bland cells that have
nuclei the size of those of lymphocytes. B, Grade 2 tumors have enlarged nuclei, fine chromatin,
and occasional nucleoli. C, Grade 3 lesions show hypercellularity and nuclear anaplasia.


Fig. 17-48. Mesenchymal chondrosarcoma. The tumor consists
of small undifferentiated cells and foci of cartilage.

bone tumors. It has a peak incidence in the second decade,

and 80 percent of all patients are younger than 40 years old;
it is rare in children. Any bone may be involved. Radiologic
findings are nonspecific. On gross examination the tumor is
meaty, red-brown, and hemorrhagic. Histologically it consists of two components: a primitive small cell neoplasm and
hyaline cartilage that either appears benign or shows features
of low-grade malignancy (Fig. 17-48). The small cell component may simulate Ewing sarcoma or hemangiopericytoma. Management is surgical, although in some cases chemotherapy has been beneficial. The prognosis is poor.
Clear cell chondrosarcoma is an extremely rare tumor that
has a relatively good prognosis. It occurs in the epiphysis of
long bone, especially the head of the femur, which is the most
common location. Grossly it appears as calcified or ossified
foci alternating with cartilaginous-like material enclosed
within the bone but also extending into the surrounding tissues (Fig. 17-49). Microscopically it consists of clear polygonal cells with round nuclei. The stroma is scant and usually includes only fine capillaries juxtaposed to tumor cells.
Osteoclastic giant cells appear in clusters or are scattered
throughout the tumor. Osteoid and bone spicules may be
found, together with foci of calcification. En bloc resection
cures most lesions and the five-year survival rate is 85 percent.

Fibrous Lesions of Bone

Fibrous neoplasms of bone include benign lesions, locally
aggressive lesions, and frank malignancies. They are classified as (1) fibrous cortical defect and nonossifying fibroma
of bone, (2) fibrous histiocytoma, (3) xanthoma, (4) osteofibrous dysplasia and fibrous dysplasia, (5) desmoid tumor
of bone (desmoplastic fibroma), and (6) malignant fibrous
histiocytoma. Some of these lesions are unique to bones, but
others have the same morphology and biologic properties as
their equivalents in soft tissues.
Fibrous cortical defect and nonossifying fibroma are closely
related entities that differ in size but histologically are iden -

Fig. 17-49. Clear cell chondrosarcoma. A, The tumor in the

head of femur shows central calcification surrounded by darker
tissue. B, Tumor cells have clear cytoplasm. The blood vessels
have thin walls.

tical and have a tendency to self-heal. Both lesions are found

in children. They usually are asymptomatic and are discovered incidentally during radiographic examination. Radiologically, fibrous cortical defect presents as a small radiolucent defect in the cortical part of the metaphysis of long
bones. Nonossifying fibroma is larger and presents as an eccentric metaphyseal, radiolucent, loculated lesion rimmed by
a zone of sclerosis. Both lesions tend to involute spontaneously. On gross examination they appear yellowish to rusty
brown, depending on the amount of lipid and blood-derived
pigment (Fig. 17-50). Histologically these lesions are composed of bland fibroblasts and histiocytes, which may be
lipid-laden and vacuolated.


Fig. 17-50. Nonossifying fibroma. A, Metaphyseal brown tumor

is rimmed by a zone of sclerosis. B, Fibroblastic cells are
arranged in a storiform pattern.

Fibrous dysplasia is a relatively common benign disorder

that affects children and young adults. Considered a developmental anomaly rather than a neoplasm, it consists of fibroosseous tissue replacing the normal marrow spaces. It
may present in the more common monostotic form or a less
common polyostotic form. Approximately two thirds of
cases of fibrous dysplasia are diagnosed in persons younger
than 30 years of age. Polyostotic fibrous dysplasia may be
combined with cafe au lait skin spots, and endocrine dysfunction is a component of the syndrome. Radiologically fibrous dysplasia presents with typical " ground glass" lesions
in the medullary cavity (Fig. 17-51). Microscopically the lesions are composed of fibroblasts intermixed with bone
spicules. The trabeculae, which are composed of woven bone,
come in various shapes and have been likened to Chinese letters or alphabet soup. Fibrous dysplasia requires no treatment because most lesions stop growing after puberty.
Osteofibrous dysplasia, also known as ossifying fibroma, is
a rare lesion of children that typically is found in the tibia
and fibula. Unlike fibrous dysplasia, it arises in the cortex. On
radiograph it may be purelylytic or may have a " ground glass"
appearance and a sclerotic rim. Microscopically it is composed of fibroblasts, occasionally showing a storiform pattern, and spicules of bones lined by osteoblasts. No treatment
is required except in cases of pathologic fracture caused by
the lesion.

Giant Cell Tumor of Bone

Giant cell tumor of bone is a common benign bone lesion that
accounts for 21 percent of all bone tumors and is the only
one that affects the epiphysis and metaphysis of long bones.
With a few exceptions, giant cell tumors of bone develop after
the bones stop growing, and 80 percent of patients are in the
range 20 to 40 years old. Radiologically giant cell tumors present as radiolucent lesions of the epiphysis reaching the ar-

Fig. 17-51. Fibrous dysplasia. A, Proximal tibia contains a well-demarcated lesion that has a
typical "ground glass" appearance. B, Fibrous dysplasia. Fibroblasts are in direct contact with bone
spicules of variable shape.


ticular cartilage and often extending into the metaphysis. The

tumor may destroy the cortex, but usually there is no or only
focal sclerosis around it. Nonepiphyseal giant cell tumors are
rare. On gross examination they consist of reddish-brown
soft tissue filling a cystlike space inside the bone (Fig. 17-52).
Aneurysmal bone cyst components may replace most of the
tumor in some cases. Microscopically two components are
recognized: multinucleated giant cells and mononuclear
stromal cells. Stromal cells are spindle-shaped and contain a
moderate amount of cytoplasm. Mitotic activity is variable.
Blood vessels, foci of hemorrhage, hemosiderin, and xanthomatous macrophages are seen in varying proportions.
Immunohistochemically tumor cells display macrophagerelated markers. Giant cell tumors have a tendency to recur
after curettage and are considered by some authorities to be
a low-grade malignancy. Malignant giant cell tumors are rare.
Some malignant tumors arise after radiotherapy of benign
giant cell tumors.
Marrow Tumors
Tumors that originate from the bone marrow include
(1) Ewing sarcoma, (2) multiple myeloma and solitary plasmacytoma, (3) non-Hodgkin lymphoma, and (4) Hodgkin
lymphoma. Multiple myeloma and lymphoid neoplasms are
illustrated in Chapter 5.
Ewing sarcoma is a malignant tumor accounting for 6 percent to 14 percent of all bone tumors. It is composed of undifferentiated small cells, the nature and origin of which has
not been determined unequivocally. It is a tumor of children
and young adults, with a peak incidence in the second decade.
Males are affected twice as often as females, and it is distinctly

uncommon in African-Americans. In the past it invariably

was fatal, but with modern therapy the five-year survival rate
is 65 percent except for patients with widespread disease and
distant metastases, who have a poor prognosis. Tumors of the
same morphology occur in soft tissues.
Ewing sarcoma most often occurs in the medulla of long
bones of the extremities and in the pelvis, but it also may
occur in any other bone. Radiologically it presents as an intramedullary and extramedullary growth that imparts to the
bone a mottled or moth-eaten pattern (Fig. 17-53). Generally there also is a large soft-tissue component with illdefined margins. Another important feature of Ewing sarcoma is the presence of reactive bone within the medullary
cavity and the periosteum, which may produce an onionskin
pattern. Magnetic resonance imaging (MRI) is most useful
for evaluating the extent of bone involvement. On gross examination Ewing sarcoma appears as grayish-white, soft,
glistening tissue permeating the bone and typically breaking
through the cortex, distending the periosteum and usually
infiltrating the soft tissues. Reactive osteosclerosis may be
seen in the medullary cavity with a "sunburst" form on the
periosteum as it is lifted from the bone. Histologically Ewing
sarcoma is composed of a monotonous population of primitive small blue cells that have round to oval nuclei and scanty
cytoplasm. The nuclei have finely dispersed chromatin and
small nucleoli. The cytoplasm is clear because of its high
glycogen content. Atypical Ewing sarcoma is a variant that
shows nuclear variation, lacks glycogen, has an increased
number of mitoses, and forms neoplastic vascular structures.
All forms of Ewing sarcoma have the same chromosomal
changes, which are typical of this entity.


Fig. 17-52. Giant cell tumor of bone. A, The epimetaphysis contains a hemorrhagic meaty tumor
that destroys the cortex and expands the periosteum. B, Tumor is composed of multinucleated
giant cells and mononuclear cells.


Fig. 17-53. Ewing sarcoma. A, Radiograph shows a large lytic tumor in the shaft of long bone, with
reactive thickenings of the cortex and laminated periosteal reaction. A large soft-tissue component
is barely visible. B, The medullary cavity of the distal end of the tibia is permeated with tumor that
extends into the soft tissue even though it is still covered by periosteum. C, Tumor is composed
of uniform small blue cells. D, Electron microscopy shows aggregates of glycogen in the cytoplasm
of tumor cells.

Vascular Tumors
Vascular tumors include benign lesions such as hemangioma, skeletal angiomatosis and lymphangiomatosis,
glomus tumor, as well as malignant tumors such as hemangioendothelioma, hemangiopericytoma, and angiosarcoma.
Microscopically these tumors correspond to their soft-tissue

Miscellaneous Tumors and

Tumor-like Conditions
Adamantinoma of long bones is a rare low-grade malignant

tumor that shows both epithelial and mesenchymal differentiation and microscopically resembles adamantinoma of
the jaw. Most adamantinomas of long bones (90 percent)
have been reported in the shaft of the tibia, but they also may
occur in other bones (Fig. 17-54). Radiologically the tumors
have a typical appearance, which has been described as a
soap bubble " pattern because of numerous cysts rimmed by
sclerotic bone. On gross examination the tumor appears lobulated and is grayish-tan because of a high content of fibrous
tissue. Multiple cystlike spaces are surrounded by thick sclerotic bone, and the cortex may be scooped out or totally destroyed. Microscopically the tumor consists of epithelial
nests and stroma. The epithelial cells may resemble basal or
squamous cells of the skin and often are palisaded along the
periphery of these nests. A fibrous dysplasia component

often is seen. Management is surgical, and the prognosis is

relatively favorable. Approximately 15 percent to 30 percent
of tumors recur or metastasize.
Chordoma is a tumor of notochord that typically occurs
in the midline of the spinal column. In major cancer treatment reference centers it accounts for 4 percent of all bone
tumors. Its peak incidence is in the sixth decade. Approximately one half of the tumors are found in the sacrococcygeal
region and 37 percent are at the base of the skull in the sphenooccipital region. Radiologically it presents as a destructive
lesion of bone extending into soft tissue. On gross examination the tumor is grayish-white with myxoid areas and foci
of necrosis and hemorrhage. Histologically the tumor is
composed of round, spindle-shaped, and polygonal cells in
a loose myxomatous matrix, arranged into lobules separated
by strands of connective tissue (Fig. 17-55). Most cells show
numerous cytoplasmic vacuoles. The vacuolated cytoplasm
of physaliphorous cells, typical of chordoma, has been
likened to jellyfish. Chordoma cells are positive for keratin,
epithelial membrane antigen (EMA), and S-100 protein.
Management is surgical, but larger lesions also require radiotherapy. The prognosis depends on the size and location of
the tumor. Most tumors recur but few metastasize.
Aneurysmal bone cyst (ABC) is a relatively common bone
lesion of uncertain origin. It occurs in two forms: as a primary ABC arising de novo or as a secondary ABC that de -


Fig. 17-54. Adamantinoma of long bones. A, The shaft of tibia

shows extensive lytic lesions, giving it a "soap bubble" appearance. B, Bivalved segment of the tibia shows a medullary tumor
that is destroying the cortex and elevating the periosteum.
C, Nests of basaloid cell infiltrates are surrounded by fibrous

Fig. 17-55. Chordoma. Over a myxoid background there are

cords of large cells with vacuolated cytoplasm.

Fig. 17-56. Aneurysmal bone cyst. A, Radiograph shows an

eccentric lytic lesion in the metaphysis of the distal femur.
B, Hemorrhagic cyst has a thin bone capsule. C, Fibroblastic wall
of the cyst contains osteoclasts grouped around a space filled
with blood.


Fig. 17-57. Eosinophilic granuloma. A, Histiocytes with vesicular nuclei are surrounded by eosinophiles. B, Birbeck granules appear as rod-shaped structures in the ectoplasm of Langerhans cells.

Fig. 17-58. Villonodular synovitis. A, Brown tissue removed from the joint. B, Histologically, villi
are composed of spindle cells and scattered hemosiderin-laden macrophages.

Fig. 17-59. Synovial chondromatosis. Numerous cartilaginous

bodies were removed from the joint cavity.


velops on a preexisting bone lesion. Primary ABC accounts

for 1 percent to 6 percent of all bone lesions. Its peak incidence is in the second decade of life. The femur, tibia, and radius most commonly are involved. Radiologically the lesion
is located in the metadiaphysis and appears as a blown-out
eccentric lytic lesion with a sclerotic rim on the inner side
and destructive cortical edge (Fig. 17-56). Grossly ABC consists of multiple hemorrhagic cysts and a solid component,
which usually is not too prominent. Histologically the wall
of cysts is composed of fibroblastic stroma, macrophages,
and scattered osteoclastic giant cells. Management includes
curettage with bone packing, but up to 40 percent of lesions
recur. Malignant transformation is rare.
Eosinophilic granuloma is a form of Langerhans cell histiocytosis involving bones. Proliferation of Langerhans histiocytes is accompanied by infiltrates of eosinophiles (Fig.
17-57). These histiocytes are positive for S-100 protein and
contain Birbeck granules visible by electron microscope.

Tumors and Tumor-like Lesions of Joints

Theoretically any component of the joint may give rise to a
neoplasm, but primary tumors of the joints are quite rare.
They are classified as benign or malignant.
Pigmented villonodular synovitis (xanthofibroma) is a
tumor-like joint lesion that occurs in several forms: (1) diffuse pigmented villonodular synovitis, (2) localized nondestructive villonodular variant, and (3) nodular giant cell
tumor of the tendon sheath. The diffuse variant most often
occurs in the knee joints of young persons, but other joints
also may be involved. On gross examination the lesions appear as intraarticular villous brownish-yellow tissue (Fig.
17-58). Microscopically the synovial fronds are composed of
ovoid cells, spindle-shaped cells, multinucleated giant cells,
macrophages, and various chronic inflammatory cells, in
variable proportions. Lipid-laden macrophages and hemosiderin account for the brownish-yellow color of the tissue.
Slitlike spaces lined by flattened or ovoid cells that resemble
normal synovial surfaces also are seen, but in some lesions
solid fibrous areas predominate. Bone invasion and recurrences are encountered in the diffuse form of villonodular
Synovial chondromatosis is a rare condition that is characterized by multiple metaplastic nodules of cartilage developing in the synovium. It most often is found in the knee
joints of young persons. The altered synovial fronds detach
to become loose intraarticular bodies, which may fill the joint
(Fig. 17-59). Histologically the nodules are composed of mature cartilage surrounded by fibrous tissue.

Further Reading
Ayala AG, Raymond AK, Jaffe N: The pathologist's role in the diagnosis
and treatment of osteosarcoma in children. Hum Pathol 15:258266, 1984.
Bjornsson J, McLeod RA, Unni KK et al: Primary chondrosarcoma of
long bones and limb girdle. Cancer 83:2105-2119, 1998.
Clough JR, Price CHG: Aneurysmal bone cyst. Pathogenesis and long
term results of treatment. Clin Orthop 97:52-63, 1973.
Dahlin DC, Unni KK, Matsuno T: Malignant (fibrous) histiocytoma of
bone fact or fancy? Cancer 39:1508-1516, 1977.
deSantos LA, Murray JA, Ayala AG: The value of percutaneous needle
biopsy in the management of primary bone tumors. Cancer43:735744, 1979.
Dorfman HD, Czerniak B: Bone cancers. Cancer 75:203-210, 1995.
Dosoretz DE, Raymond AK, Murphy GF et al: Primary lymphoma of
bone. The relationship of morphologic diversity to clinical behavior. Cancer 50:1009-1014, 1982.
Greenspan A: Benign bone-forming lesions osteoma, osteoid osteoma,
and osteoblastoma. Clinical, imaging, differential considerations
(review). Skel Radio/ 22:485-500, 1993.
Jundt G, Remberger K, Roessner A et al: Adamantinoma of long bones.
A histopathological and immunohistochemical study of 23 cases.
Pathol Res Pract 191:112-120, 1995.
Kahn LB, Wood RM, Ackerman LV: Malignant chondroblastoma. Report of two cases and review of the literature. Arch Pathol 88:371376, 1969.
Loizaga JM, Calvo M, Lopez Barea K et al: Osteoblastoma and osteoid
osteoma. Clinical and morphological features of 162 cases. Pathol
Res Pract 189:33-41, 1993.
Maygarden SJ, Askin FB, Siegal GP et al: Ewing sarcomas of bone in infants and toddlers. A clinicopathologic report from the Intergroup
Ewing's Study. Cancer 71:2109-2118, 1993.
McLeod RA, Dahlin DC, Beabout JW: The spectrum of osteoblastoma.
Am J Roentgenol 126:321-335, 1976.
Okada K, Unni KK, Swee RG, Sim FH: High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer 85:1044-1054,
Reed RJ: Fibrous dysplasia of bone. A review of 25 cases. Arch Pathol
75:480-495, 1963.
Schiller AL: Diagnosis of borderline cartilage lesions of bone. Semin
Diagn Pathol 2:42-62, 1985.
Sokoloff L: Pathology and pathogenesis of osteoarthritis. In McCarty
DJ, editor: Arthritis and applied conditions, ed 9, Philadelphia, 1979,
Lea & Febiger.
Unni KK, Dahlin DC: Premalignant tumors and conditions of bone.
Am J Surg Pathol 3:47-60, 1979.
Unni KK, Ivins JC, Beabout JW, Dahlin DC: Hemangioma, hemangiopericytoma, and hemangioendothelioma (angiosarcoma) of
bone. Cancer 27:1403-1414, 1971.
Yaw KM: Pediatric bone tumors. Sem Surg Oncol 16:173-183, 1999.


Congenital myopathies are a diverse group of diseases. They
usually present early in life in the form of the so-called floppy
infant syndrome, which includes a triad of adaxial weakness,
hypotonia, and decreased spontaneous muscular motor activity. Some congenital myopathies are mild and become
symptomatic only in later childhood, whereas others are not
diagnosed until adult life. Morphologically it is possible to
identify several distinct entities, some of which are listed in
Table 18-1. Pathologic findings are constantly being amplified with molecular biology findings, and many congenital
myopathies have been linked to specific gene defects.
Central core disease, a mild proximal muscle weakness of
infants and children, is characterized by specific changes in
the muscle, which may be best demonstrated by enzyme
histochemistry or electron microscopy (EM). Enzyme histochemistry shows that the central portion of each muscle fiber
lacks oxidative enzyme activity (Fig. 18-1). By EM the central core appears as a disorganized aggregate of myofilaments.
Nemaline (rod) myopathy presents in childhood as muscle
weakness that predominantly involves the proximal parts of
the extremities and the facial muscles. Rods, which are

thought to be derived from Z-band material of the myofibrils, may be seen in muscle fibers stained with trichrome
or by EM (Fig. 18-2).
Centronuclear myopathy refers to a heterogeneous group
of diseases whose presenting symptom is muscle weakness,
which may appear in childhood or adulthood. Axial, extraocular, and facial muscles are involved. Muscle fibers contain
centrally located nuclei, occasionally with type I muscle fiber
hypotrophy (Fig. 18-3).
Sarcotubular myopathy describes a heterogeneous group
of diseases that may present early in life or even in adulthood.
The diagnosis is established by EM, which shows typical
hollow tubular structures in the cytoplasm of scattered
muscle fibers (Fig. 18-4).

The unsophisticated historical term dystrophy is used clinically to refer to a variety of genetic diseases that are characterized by progressive muscular weakness. Recent genetic
studies have shown that such diseases may be linked to mutations of genes encoding unique structural proteins of the
muscle fiber cytoplasm, cell membrane, or perimysial basement membrane (Diagram 18-1).

Fig. 18-I. Central core disease. A, Enzyme histochemical technique for demonstrating oxidative enzymes was used to show
reduced enzyme activity in the center of each muscle fiber.
B, By EM the central core consists of disorganized sarcomeres.

Fig. 18-2. Nemaline myopathy. A, Many small, dark bluestained

rods are seen in some muscle cells in this Gomori trichromestained slide. B, By EM the nemaline rods appear as condensed
filaments resembling Z-band material.


Congenital Myopathies

Fig. 18-3. Centronuclear myopathy. Type I muscle fibers, which

stain lighter in this slide and react for ATPase at pH 9.4, contain
a central unstained region corresponding to nuclei. Type I fibers
are abnormally small, and the darker type II fibers are enlarged.

Fig. 18-4. Sarcotubular myopathy. This EM photograph shows

cytoplasmic tubules derived from the sarcomeres.

Diagram 18-1. Dystrophin-sarcoglycan complex of striated muscle cells consists of several proteins that are essential for muscle contraction. Dystrophin, the best known of these proteins, is
linked to several other plasma membrane proteins such as dystroglycans and sarcoglycans.
Deficiency of dystrophin and related proteins has been identified as the cause of muscle diseases.
( Copyright 1997 Massachusetts Medical Society, all rights reserved. From Duggan DJ et al:
N Engl J Med 1997; 336: 618-24; with permission).


Duchenne muscular dystrophy is a severe X-linked muscle

disease that affects 1 in 3500 boys. It has been linked to abnormalities of the gene for dystrophin, a structural protein
that links the muscle cell membrane to the contractile elements. Abnormal muscle fibers become rounded up and are
recognizable in routine sections stained with hematoxylin
and eosin because of their eosinophilic cytoplasm as " hyaline fibers." Muscle fiber necrosis attracts macrophages,
which phagocytize dead muscle fibers (Fig. 18-5). Regeneration ensues but is unable to compensate for the muscle fiber
loss. Lost muscle fibers are replaced by fibrous and fat tissue,
which may even enlarge the muscles (pseudohypertrophy).
Duchenne muscular dystrophy is a lethal disease.
Becker muscular dystrophy, which is caused by milder alterations of the dystrophin gene, is a progressive muscle
disease that affects teenagers and young adults. It is a less severe form of dystrophy, and although it has a slower downward course, it also is invariably fatal. Immunohistochemical
studies with antibodies to dystrophin show a lack of immunoreactive dystrophin in the muscle of patients with
Duchenne dystrophy. The muscle from Becker dystrophy patients shows patchy staining.

Facioscapulohumeral dystrophy is a relatively mild disease

that affects the muscles of the head and neck, shoulders,
upper back, and arms. The affected muscles show numerous
atrophic and hypertrophic muscle fibers but little necrosis or
regeneration. Enzyme histochemistry techniques for demonstrating oxidative enzymes are most useful for demonstrating the abnormal muscle fibers, which appear mottled
or moth-eaten because of uneven staining of their cytoplasm
(Fig. 18-6). Scattered lymphocytes, which are found during
ingravescent stages of the disease, are unique features of this
disease that distinguish it from other dystrophies.
Limb girdle dystrophy is characterized by a declining
strength of muscles of the shoulder, pelvic girdles, and proxi mal limbs. Several distinct genetic diseases have been known
to present in this form. The muscle biopsy shows internalization of sarcolemmal nuclei, muscle fiber atrophy, and
florid compensatory hypertrophy, associated with muscle
fiber splitting (Fig. 18-7).
Myotonic muscular dystrophy is a multisystemic disease
with a prevalence of 1 in 8000. It is linked to a mutation of a
gene on chromosome 19 that shows amplification of
cytosine-thymidine-guanine triplet repeats. Symptoms
begin in early adult life and slowly progress over many years.
Myotonia is an early symptom. Muscle biopsy shows typical
atrophy of type I fibers, a multitude of internal nuclei, and
ring fiber formation (Fig. 18-8).

Fig. 18-5. Duchenne muscular dystrophy. A, In early stages of disease dead and dying fibers are
phagocytized by macrophages. B, In terminal stages of the disease muscle fibers have been
replaced by fibrous and fat tissue. C, Muscle does not react with antibodies to dystrophin.
D, Positive control was stained with antibodies to basement membrane laminin.


Fig. 18-6. Facioscapulohumeral dystrophy. In this slide stained

for demonstrating oxidative enzymes, the muscle fibers appear
moth-eaten and contain numerous small, poorly demarcated,
unreactive sarcoplasmic areas.

Fig. 18-7. Limb girdle dystrophy. The muscle contains numerous

hypertrophic fibers. Hypertrophic fiber in the center has split
into six smaller segments.

Fig. 18-8. Myotonic dystrophy. A, Many fibers show centrally located nuclei. B, Ring fibers consist of a central core in which the cross-striations run in a different direction than the crossstriations of the peripheral ring.

Inflammatory myopathies are a diverse group of diseases that
are related to infections or immune reactions and are encountered in systemic autoimmune diseases, immunemediated myositis (polymyositis or dermatomyositis), or
hypersensitivity and allergy to drugs and other exogenous
antigens (Table 18-2).
Viral myositis probably is the most common muscle infection. In systemic viral diseases it causes muscle pain, but
occasionally it may result in rhabdomyolysis. Muscle fiber injury may be accompanied by infiltrates of lymphocytes and
macrophages. In the former case the changes are indistinguishable from those of polymyositis. Similar changes may
be seen in some patients with acquired immunodeficiency
syndrome (AIDS).

Inflammatory Myopathies

SLE, Systemic lupus erythematosus.


The most common cause of parasitic myositis is trichinosis, which is caused by Trichinella spiralis. The encysted
parasites, which often are surrounded by inflammatory cells
and fibrous tissue, may be seen in the muscle (Fig. 18-9).
Polymyositis is an autoimmune disease in which the
muscle inflammation is mediated primarily by CD8 + T lymphocytes (Fig. 18-10). Muscle fibers undergo necrosis individually or in small groups and are surrounded or infiltrated
with lymphocytes and macrophages. Dermatomyositis also is
an autoimmune disease but in contrast to polymyositis, it is
an antibody-mediated disease. Immune complexes have
been localized to blood vessels, which usually are surrounded
by inflammatory cells. These infiltrates consist predominantly of CD4 + helper T lymphocytes, B lymphocytes, and
plasma cells (Fig. 18-11). Vascular changes typically are associated with perifascicular atrophy of muscle fibers (Fig.
18-12). Polyarteritis nodosa and Churg-Strauss syndrome
may affect small arteries in the muscle and also cause interstitial inflammation.
Drug-induced myositis usually represents a hypersensitivity reaction. Microscopically, it is characterized by inflammatory changes and muscle cell necrosis and inflammatory changes, usually with a prominent contribution of
eosinophils (Fig. 18-13).
Inclusion body myositis is an inflammatory myopathy of
unknown origin. It affects males more often than females and
has a peak incidence in the 50 to 70 year age group. It may
have an indolent course or a slowly progressive course that is
resistant to steroid treatment. Histologic findings are suggestive of polymyositis, but in 60 percent of patients the
muscle does not show inflammation. In all cases the muscle

fibers show vacuolar inclusions consisting of rimmed vacuoles and granules (Fig. 18-14). By EM the vacuoles contain
remnants of cytoplasmic membranes and bundles of viruslike tubulofilamentous structures. Similar virus-like particles
are found in the muscle cell nuclei.

Fig. 18-9. Trichinosis. The muscle contains encysted parasites.

Fig. 18-10. Polymyositis. A, Muscle is invaded by lymphocytes. B, Immunohistochemistry shows

that most lymphocytes are CD8+ cytotoxic or suppressor cells.


Fig. 18-I I. Dermatomyositis. A, The edge of the fascicle at the top of this picture shows atrophy,
which is referred to as perifascicular. B, Undulating tubular profiles are seen in endothelial cells.

Fig. 18-12. Dermatomyositis. The edge of the fascicle shows

perifasicular atrophy.

Fig. 18-13. Drug-induced myositis. The infiltrate contains prominent eosinophils.

Fig. 18-14. Inclusion body myositis. A, This cryostat section

stained with Gomori trichrome shows the characteristic vacuole
containing numerous small red granules. B, By EM the rimmed
vacuole contains numerous membranous profiles and bundles of
virus-like tubulofilamentous structures.


Genetic-metabolic myopathies may be grouped into three
broad categories: (1) carbohydrate storage diseases, (2) lipid
storage myopathies, and (3) mitochondrial myopathies.
Carbohydrate Storage Diseases
Carbohydrate storage diseases include disorders of glycogen
storage and degradation. These diseases traditionally have
been designated eponymically or numerically, but because
the enzymatic defect is known for all of them it is more appropriate to label them according to the underlying deficiency. Symptoms usually appear only during exercise or periods of intense energy demand. Pathologic changes vary,
depending on the extent of glycogen storage, the nature of
the metabolic defect, and the extent of glycogen storage in
the muscle. In the infantile form of acid maltase deficiency

(type II glycogenosis, or Pompe disease), the muscle fibers

show extensive vacuolation caused by massive accumulation
of glycogen beneath the sarcolemma and between the myofibrils, as may be seen by EM (Fig. 18-15). In addition, the
muscle shows deposits of basophilic material that is periodic
acidSchiff (PAS) positive but resistant to diastase digestion.
In contrast, the adult form is characterized by less prominent
vacuolation, which is seen only in some muscle fibers. The
basophilic mucopolysaccharide deposits are not seen (Fig.
18-16). Vacuolation and glycogen accumulation are seen in
debranching enzyme deficiency (type III glycogenosis, or
Forbes disease) but generally the vacuolation is more prominent (Fig. 18-17). All fibers contain subsarcolemmal vacuoles
or show extensive clearing of the central and peripheral cytoplasm. Branching enzyme deficiency (type IV glycogenosis,
or Andersen disease) is characterized by abnormal deposits

Fig. I8-15. Infantile form of acid maltase deficiency. There is

severe vacuolation of muscle fibers combined with basophilic
deposits of mucopolysaccharides in this paraffin embedded, Susa
fixativefixed tissue.

Fig. 18-16. Adult form of acid maltase deficiency. Scattered

muscle fibers are vacuolated.

Fig. 18-17. Debranching enzyme deficiency in an adult. There

are numerous large vacuoles in the muscle fibers. The tissue was
fixed in Susa fixative, embedded in paraffin, and trichrome stained.

Fig. 18-18. Branching enzyme deficiency in a young child. The

muscle fibers contain numerous bluish polyglycosan bodies.


of polysaccharides in the peripheral cytoplasm of the affected

fibers (Fig. 18-18). Carbohydrate deposits form so-called
polyglycosan bodies, which ultrastructurally appear as unbounded aggregates of branched fibrils and granular material. Polyglycosan bodies are PAS positive and diastase resistant. Myophosphorylase deficiency (type V glycogenosis, or
McArdle disease) is characterized by small subsarcolemmal
vacuoles or blebs in most muscle fibers (Fig. 18-19). Smaller
deposits may form vacuoles in the central parts of the fibers.
This material is PAS positive and at least partially digestible.
An enzyme histochemical assay for demonstrating myophosphorylase is used to confirm the diagnosis, and it typically
gives negative results (Fig. 18-20).

Lipid Storage Myopathies

Skeletal muscle cells use long-chain fatty acids as a major
source of energy during fasting and sustained exercise. The
long-chain fatty acids must be combined with carnitine to
pass through the mitochondrial membranes to the matrix
compartment, where they undergo beta-oxidation. Myopathies may result from lack of carnitine, deficiency of carnitine palmitoyltransferase, and defects of beta-oxidation.
Muscle of patients with lipid storage myopathies contains increased amounts of lipids, which may be demonstrated as cytoplasmic droplets in frozen sections stained with osmium
tetroxide (Fig. 18-21) or Sudan red 0, or by EM (Fig. 18-22).
These fat droplets are more prominent in type I fibers, which
contain more lipid even under normal circumstances. Lipid
accumulation is, however, not diagnostic of lipid storage diseases and may occur in a variety of other conditions.

Fig. 18-19. Myophosphorylase deficiency. The muscle fibers

Fig. 18-20. Myophosphorylase deficiency. The control sections

have peripheral vacuoles.

stain dark, whereas the patient's tissue is unstained and light yellow (From Schochet SS Jr: Diagnostic pathology of skeletal muscle
and peripheral nerve, Norwalk, Conn, 1986, Appleton-CenturyCrofts.)

Fig. 18-21. Lipid storage myopathy. In this frozen osmium

tetroxidestained section, lipid droplets are more prominent in
type I fibers.

Fig. 18-22. Lipid storage myopathy. In this frozen section

stained with Sudan red 0, the lipid droplets are larger in type I
fibers than in type II fibers.


Mitochondrial Myopathies
Mitochondria are organelles that are involved in generating
energy, but they also contain deoxyribonucleic acid (DNA)
and are important for the transmission of maternal cytoplasmic genetic material through the cytoplasm of the oocyte.
Numerous mitochondrial myopathies have been described.
In some of these muscle diseases the muscle shows no distinct histologic findings, whereas in others the muscle fibers
show mitochondrial abnormalities. When evident, mitochondrial abnormalities may manifest as ragged red fibers in
histologic trichrome-stained sections or enzyme histochemically by a technique for demonstrating oxidative enzymes
(Fig. 18-23 and 18-24). Mitochondrial abnormalities are
better seen by EM when they appear in the form of an increased number of normal mitochondria or as structurally
abnormal mitochondria (Figs. 18-25 and 18-26).

Fig. 18-23. Mitochondrial myopathy. Ragged red fiber has clusters of red-staining mitochondria beneath the sarcolemma in this
trichrome-stained slide.

Fig. 18-24. Mitochondrial myopathy. Clustering of mitochondria

in the peripheral cytoplasm leads to darker staining of the peripheral cytoplasm in this enzyme histochemical preparation for
demonstrating oxidative enzymes.

Fig. 18-25. Mitochondrial myopathy. By EM the muscle fibers

were found to contain increased numbers of normal

Fig. 18-26. Mitochondrial myopathy (Kearns-Sayre syndrome).

By EM the mitochondria appear abnormal.



Denervating Diseases

The welfare of muscle fibers depends on their proper innervation. Denervation results in muscle cell atrophy (Diagram
18-2). It may occur in a number of diseases involving the central nervous system or peripheral nerves (Table 18-3).

Normal motor unit

Early denervation


Late denervation

Diagram 18-2. Schema of the normal motor unit and three stages of denervation. A, Normal
motor unit. Two oversimplified motor units are shown (I and II). Each motor neuron (MN)
innervates only muscle fibers of the same type. By neurotrophic influences, the motor neuron
determines the fiber type within the motor unit. Notice that the fibers from each motor unit are
geographically dispersed and are not grouped together. B, Early denervation. Atrophic fibers in
the diseased motor unit II (dark) are angular and randomly distributed. C, Reinnervation. The
remaining motor neuron I (light) has reinnervated the type II, dark fibers by means of sprouting
collateral axons. Notice that the previous type II, dark fibers have been converted to type I, light
fibers, because the motor neuron governs the fiber type within the motor unit. This process of
reinnervation leads to type grouping. D, Grouped atrophy. In chronic denervation, groups of atrophic fibers result from the process of denervation, reinnervation, and subsequent denervation of
the reinnervated fibers.

39 6

Atrophy may involve single muscle fibers, groups of fibers,

the entire fascicle, or the entire muscle, depending on the type
and the location of nerve injury. Single atrophic denervated
fibers are smaller than normal and angular (Fig. 18-27). They
typically show increased activity of nonspecific esterase (Fig.
18-28). Chronic neurogenic atrophy shows group atrophy
(Fig. 18-29). Enzyme histochemistry for oxidative enzymes
shows that the atrophic fibers stain darkly and are surrounded by normal-sized fibers that have a targetoid appearance (Fig. 18-30). Denervation with reinnervation results in a loss of normal checkerboard distribution of type I
and type II fibers and type-specific grouping of muscle fibers
(Fig. 18-31). Spinal muscular atrophy tends to be more
prominent and is termed fascicular because it involves entire
large groups of muscles (fascicles) (Fig. 18-32).

Fig. 18-27. Denervation atrophy caused by amyotrophic lateral

sclerosis. Atrophic fibers are angular and compressed between
the normal fibers.

Fig. 18-28. Denervation atrophy. Denervated atrophic fibers show

increased esterase activity as indicated by their brown color in this
enzyme histochemical preparation for demonstrating esterase activity.

Fig. 18-29. Chronic neurogenic atrophy. Atrophic fibers are

found in groups. They stain dark in this enzyme histochemical preparation for demonstrating oxidative enzymes.

Fig. 18-30. Chronic denervation. Target fibers have pale centers in this enzyme histochemical preparation for demonstrating
oxidative enzymes.


Fig. 18-3I. Denervation with reinnervation. Type-specific

grouping has replaced the normal checkerboard pattern in this
slide stained for demonstrating ATPase at pH 9.4.

Fig. 18-32. Infantile spinal muscular atrophy. Severe atrophy involves entire fascicles.

Further Reading

Engel AG, Hohlfeld R, Banker BQ: The polymyositis and dermatomyositis syndromes. In Engel AG, Franzini-Armstrong C, editors:
Myology, ed 2, New York, 1994, McGraw-Hill.
Heffner RR: Inflammatory myopathies: a review. J Neuropathol Exp
Neurol 52:339-348. 1999.
Kuncl RW, George EB: Toxic neuropathies and myopathies. Curr Opin
Neurol 6:695-704, 1993.
Mantegazza R, Bernascone P, Confalonieri P, Cornelio F: Inflammatory myopathies and systemic disorders: a review of immunopathogenetic mechanisms and clinical features. J Neurol 244:277287, 1997.
Prayson RA: Granulomatous myositis. Clinicopathologic study of 12
cases. Am J Clin Pathol 112:63-68, 1999.
Schmalbruch H: The muscular dystrophies. In Mastaglia FL, Walton
JN, eds: Skeletal muscle pathology. London, 1992, Churchill Livingstone.
Wewer UM, Engvall E: Merosin/laminin-2 and muscular dystrophy.
NeuromuscDisord 6:409-418, 1996.

Amato AA, Gronseth GS, Jackson CE et al: Inclusion body myositis:

clinical and pathological boundaries. Ann Neu ro140:581-586, 1996.
Anderson JR: Recommendation for the biopsy procedure and assessment of skeletal muscle biopsies. Virchows Arch 431:227-233, 1997.
Arahata K, Ishihara T, Kamakura K et al: Mosaic expression of dystrophin in symptomatic carriers of Duchenne's muscular dystrophy. N Engl J Med 320:138-142, 1989.
Bell CD, Conen PE: Histopathological changes in Duchenne muscular
dystrophy. J Neurol Sci 7:529-544, 1968.
Campbell KP: Three muscular dystrophies: loss of cytoskeleton-extracellular matrix linkage. Cell 80:675-679, 1995.
Dalakas M: Inflammatory and toxic myopathies. Curr Opin Neurol
Neurosurg 5:645-654, 1992.
Dubowitz V: The muscular dystrophiesclarity or chaos? NEngl JMed
36:650-651, 1997.
Dubowitz V: Procedure of muscle biopsy: a practical approach, ed 2,
London, 1985, Bailliere Tindall.



The morphogenesis of the brain depends on the interaction
of numerous genes, which must be activated and inactivated
sequentially and in an orderly spatial manner to ensure
normal development. Because this sequence of events may
be disturbed by numerous endogenous and exogenous influences, all of which might cause developmental disturbances, it is not surprising that cerebral malformations are
quite common. Many of these abnormalities are not compatible with life and are associated with intrauterine fetal
demise and abortion. At the other end of the spectrum are
minor defects that cause no significant clinical symptoms.
Major developmental disorders are associated with distinct
clinical syndromes.

Fig. 19-I. Anencephaly. The calvaria are missing, and the base of
the skull is covered with a dark red tissue layer called the area

Neural tube defects are attributed to failure of fusion of

lateral folds of the neural plate (dysraphism) or rupture of a
previously closed tube (neuroschisis). This group of disorders
includes anencephaly, craniorrhachischisis, encephalocele,
meningocele, and spina bifida.
Anencephaly, the most severe neural tube defect, is characterized by incomplete formation of the bony cranial vault.
Calvaria is missing or is only rudimentary, and a reddish
spongy mass (area cerebrovasculosa) covered by a thin membrane occupies the gap in the skull (Fig. 19-1).
Holoprosencephaly is a severe disturbance of forebrain induction that results in incomplete separation of cerebral
hemispheres (Fig. 19-2).
Arnold-Chiari malformation and Dandy-Walker malformation result from abnormal development of the hindbrain

Fig. I9-2. Holoprosencephaly. Posterior view shows the

reflected cyst wall communicating with a unicameral ventricle.

Fig. 19-3. Arnold-Chiari malformation. A, Severe elongation of the medulla and vermis.
B, "Beaking" of the tectum (white arrow) and dilatation of the aqueduct (open arrow) caused by
compression of the fourth ventricle.


and several related posterior fossa structures (Figs. 19-3 and

19-4). Malformed and misplaced parts of the central nervous
system (CNS) cause hydrocephalus.
Agyria-pachygyria complex represents a severe defect in
neuronal migration. The brain has a smooth surface agyria
or shows a few broad convolutions with shallow sulci
( macrogyria and pachygyria) (Fig. 19-5). In polymicrogyria
the brain surface exhibits numerous small irregular gyri (Fig.


Fig. 19-4. Dandy-Walker malformation. Hypoplastic vermis and

cyst are reflected to expose a dilated fourth ventricle.

The brain is susceptible to a variety of injuries during intrauterine life and the perinatal period. The nature of these injuries is not always obvious. It is well known that premature
infants are more prone to such injuries than term infants.
Complicated or prolonged delivery and maternal ill health
predispose to brain injuries, although their pathogenesis is
conjectural. Ischemia is considered to be one of the most important causes of brain injury in this period of life. Trauma
is an important contributory factor but its role often has been
Subependymal and intraventricular hemorrhages are the
most common major intracranial complications of prematurity. Such hemorrhages are especially common in infants
born before week 34 of pregnancy or those who weigh less
than 1500 g. Hemorrhages usually develop within hours of
delivery and are associated with high mortality. These hemorrhages may begin anywhere in the periventricular germinal
matrix but most often are located near the sulcus terminalis
just posterior to the foramen of Monro (Fig. 19-7). The hemorrhages often are bilateral and vary in size from focal patchy
extravasations of blood to large hematomas that rupture into
the ventricles (Fig. 19-8). Blood from the largest hematomas
may diffusely infiltrate the brain parenchyma.

Fig. 19-5. Agyria-pachygyria complex in Miller-Dieker syndrome.

Frontal lobe is devoid of gyri (arrow), whereas the remaining
brain has broad gyri and shallow sulci.

Fig. 19-6. Polymicrogyria. The brain has a puckered, "morocco

leather" surface.

Fig. 19-7. Subependymal hemorrhage. The germinal matrix is bilaterally infiltrated with extravasated blood. The section was made
through the ganglionic eminence at foramen of Monro (arrow).


Fig. 19-8. Subependymal hemorrhage extending into the ventricles. Ventricles contain coagulated blood.

Periventricular leukomalacia presents in the form of multiple, irregular, yellowish or chalky white lesions in the white
matter adjacent to the lateral ventricles, particularly in the
rostral frontal lobes and parietooccipital regions (Fig. 19-9).
The pathogenesis of these lesions, which most often occur in
premature infants, is debatable. It is thought that they represent shock lesions associated with other CNS lesions, such
as subependymal hemorrhages, sepsis, or hypoxia. Histologically the lesions are composed of foamy macrophages, reactive astrocytes, and irregularly swollen axons that undergo
mineralization. If the infant survives the insult, periventricular leukomalacia may transform itself into unilocular or
multilocular cysts.
Infarcts of the brain occur in anatomic areas that correspond to the distribution zones of major cerebral arteries.
Ulegyria is a consequence of such ischemic lesions and is
characterized by the appearance of mushroom-shaped gyri
(Fig. 19-10). The cortex in the depth of the sulci is reduced
to a glial scar, whereas the crest remains relatively intact. Ule-

Fig. 19-9. Periventricular leukomalacia. Chalky white lesions are

indicated by arrows.

Fig. 19-10. Ulegyria. The affected gyri appear mushroom-shaped.

Fig. 19-1 I. Porencephaly. Porus, the funnel-shaped defect, is

bordered by polymicrogyria.

Fig. 19-12. Multicystic encephalopathy. The entire brain has

been transformed into numerous irregularly shaped cystic cavities.


gyria often is seen in arterial border zones, especially between

the anterior and the middle cerebral arteries, and usually is
Porencephaly and hydranencephaly represent sequelae of
major destructive brain lesions and usually occur during the
first six months of fetal life, before the immature brain is able
to mount sufficient glial reaction to injury. Porencephaly
refers to linear or funnel-shaped defects of the cerebral hemispheres (Fig. 19-11). The defect or porus communicates with
the ventricular cavity, but sometimes a thin membranous
diaphragm, usually made of arachnoid cells, seals it from the
ventricle. The porus may be surrounded by polymicrogyria,
nodular heterotopias, or radially arranged gyri that histologically exhibit abnormal cortical lamination. In hydranencephaly the cerebral hemispheres are converted to thinwalled, fluid-filled vesicles. In multicystic encephalopathy, the
cerebral hemispheres are transformed into multilocular cavities separated by gliovascular trabeculae (Fig. 19-12).

ging brain is flung back and forth against the temporarily deformed skull, resulting in major contusions on the surface of
the brain diametrically opposite the site of cranial impact;
these contusions are known as contrecoup lesions (Fig. 19-14,
Diagram 19-1, p. 404).
Laceration is a lesion that is characterized by bleeding into
tissue whose integrity has been disrupted. Lacerations occur
in the same locations as contusions, at sites of depressed fractures, and with penetrating or perforating head injuries (Fig.
19-15). Lacerations at the pontomedullary junction and tears
in medullary peduncles have been described in severe hyperextension of the neck accompanied by basal fractures of the


Trauma of the brain and the spinal cord, often related to vehicular accidents, is a major cause of morbidity and mortality in industrialized countries. In the Unites States the incidence of hospitalization for craniocerebral injuries is 2 per
1000 persons and the mortality rate for accident-related
deaths is 0.3 per 1000 persons. Brain injuries often are associated with skull fractures, but many brain contusions and
even lacerations occur in closed head injury without apparent fracture.
Contusions are bruises in which there is extravasation of
blood into tissues whose integrity is retained. A direct blow
to a resting but mobile head causes deformation and bending
of the skull bone and produces maximal contusions at the
site of cranial impact, which are known as coup contusions
(Fig. 19-13). If the head is in motion (acceleration) as in a
fall and comes to an abrupt standstill (deceleration), the lag-

Fig. 19-13. Contusion of the brain. Coup lesion with hemorrhage perpendicular to the surface was caused by a direct blow to
the head with a blunt object.

Fig. 19-14. Contusion. Contrecoup lesion in the frontal and

temporal poles are (arrows) are located opposite to a small coup
lesion over the cerebellum (small arrow).

Fig. 19-15. Laceration. Hemorrhage into brain tissue is accompanied by a loss of parenchyma.

40 4

Diagram 19-1. Comparison of impact and nonimpact injuries. A, Coup contusions at impact site.
B, Contrecoup contusions diametrically opposite impact site. C, Nonimpact contreceoup contusions caused by sudden angular acceleration of the head.

Fig. 19-16. Plaque jaune. Old contusion of orbital surface of

left frontal lobe is accompanied in this case by destruction of
olfactory bulb and nerve.

Fig. 19- 17. Edema of the brain. The gyri appear flattened and
the sulci are narrow.

Fig. 19-18. Herniation of the parahippocampal gyrus. Unilateral

herniation of the parahippocampal gyrus on the left side is accompanied by brainstem hemorrhages.


posterior fossa. Old contusions and lacerations appear as

yellow discoloration (plaque jaune), which most often is
found on the orbital surfaces of the frontal lobes and olfactory bulbs in persons who have suffered repeated brain injuries, such as alcoholics (Fig. 19-16).
Brain trauma often is accompanied by cerebral edema.
Brain edema also accompanies most space-occupying brain
lesions and infections recognizable by the flattening of gyri
and narrowing of sulci (Fig. 19-17). Because of the space
constriction provided by the rigid dura and skull, increased
intracranial pressure leads to displacement of parts of the
brain, which are known as herniations. Herniations preferentially occur down into the floor of the anterior fossa, over
the sphenoid wing, under the falx cerebri, into the tentorial notch into bony orifices, into the sella turcica, down
into the foramen magnum, or through the defect in the
fractured calvaria. Unilateral herniation of the parahippocampal gyri leads to secondary brainstem hemorrhages
(Fig. 19-18).

Circulatory disturbances of the brain present as hemorrhage
or ischemia and may be classified according to location, the
type of blood vessel affected (e.g., arterial or venous), or
pathogenesis (e.g., traumatic, hypertensive, and so forth).

Intracranial Hemorrhages
Intracranial hemorrhages may be caused by (1) trauma;
(2) hypertension; (3) spontaneous rupture of congenital

Fig. 19-19. Acute subdural hematoma. Dura was removed to

show the hematoma and intact Ieptomeninges.

aneurysms or arteriovenous malformations; (4) systemic

diseases such as hemorrhagic diathesis or fat emboli; (5) ischemic necrosis (infarcts) caused by thrombosed atherosclerotic cerebral arteries or emboli; and (6) tumors that are
either hypervascular (e.g., hemangioma) or necrotic and destructive (e.g., glioblastoma multiforme).
Traumatic hemorrhages may take place in one or more of
the potential spaces surrounding the brain (epidural, subdural, and subarachnoid spaces), brain parenchyma, or the
ventricles. Epidural hematoma usually is located in the ternporoparietal region and is related to rupture of the middle
meningeal artery caused by fracture of the temporal bone.
Subdural hematoma is caused by hemorrhage between the
dura and the outer surface of the arachnoid membrane (Diagram 19-2, p. 406). Acute subdural hematomas often are associated with severe head injuries and are bilateral in 20 percent of cases. The bleeding is from arteries or bridging veins
that drain cortical veins into the superior sagittal sinus and
often are associated with underlying cerebral contusion,
hemorrhage, or both, a condition referred to as "burst lobe."
Acute subdural hematomas are space-occupying lesions that
require emergency intervention (Fig. 19-19). Chronic subdural hematomas is encountered in the elderly in whom cerebral atrophy causes widening of the subdural space, thus exposing the bridging veins to a greater risk of rupture when
subjected to angular shearing forces. Oozing of blood usually is gradual and spreads over a large surface overlying the
brain. Granulation tissue growth into the hematoma from
the inner dura forming a "neomembrane" (Fig. 19-20).

Fig. 19-20. Chronic subdural hematoma. Reflected dura reveals

the outer membrane and the resected anterior segment of the
hematoma exposing its cavity and inner membrane.


Diagram 19-2. A, Epidural hemorrhage. Torn middle meningeal artery at skull fracture (arrow)
with accumulation of blood in epidural space causing midline shift with uncal and incipient cingulate herniations. B, Chronic subdural hematoma. Ruptured bridging vein secondary to angular acceleration with accumulation of blood in the subdural space, midline shift with uncal and incipient
cingulate herniations.


Subarachnoid hemorrhage occurs in any craniocerebral injury of substantial magnitude. Such traumatic hemorrhages
are secondary to superficial contusions or lacerations of the
brain that release blood into the subarachnoid space (Fig.
19-21). Subarachnoid hemorrhage also may result from
spontaneous rupture of aneurysms of the circle of Willis (Fig.
19-22). Such hemorrhages are located at the base of the brain
and may penetrate the brain or spread throughout the brain,
causing death within minutes or hours after rupture of the
Intracerebral hemorrhage usually occurs in older adults as
a typical complication of long-standing hypertension. Many
hypertensive hemorrhages begin in the external capsules, but
often they are so massive that the exact source cannot be determined (Fig. 19-23)..
Spinal cord hemorrhages usually are associated with
trauma, 40 percent of which is attributable to motor vehicle
accidents. Trauma may cause open injury (e.g., gunshot
wound), but more often it is a closed injury in which the

spinal cord is damaged by either hyperflexion or hyperextension, tearing of spinal ligaments, and subluxation or fracturing of vertebrae. Hemorrhage is associated with contusion, laceration, or complete transection of the spinal cord
(Fig. 19-24).

Fig. 19-2I. Acute subarachnoid hemorrhage. The subarachnoid

space is infiltrated by blood. There are a few accentuated areas
over superficial cortical contusions.

Fig. 19-22. Subarachnoid bleeding caused by rupture of berry

aneurysm. The basal subarachnoid space is filled with blood. A
berry aneurysm at trifurcation of the middle cerebral artery is
indicated by black arrow. White arrow points to the rupture into
the temporal horn.

Fig. 19-24. Spinal hemorrhage. The localized

hemorrhage and contusion were caused by
fracture dislocation of the spine.

Fig. 19-23. Acute hypertensive hemorrhage. Massive bleeding

into the central part of the left hemisphere is associated with intraventricular extension.


Cerebral Ischemia
Cerebral ischemic lesions may be acute or chronic and localized or widespread. Ischemia usually is related to occlusion of blood vessels or hypoperfusion of the brain as a result of heart failure, systemic hypotension, or shock.
Atherosclerosis is the most common cause of cerebrovascular disease. Hypertension and diabetes are major predisposing factors that accelerate or aggravate the course of the
disease. Occlusion of an artery for a sufficient time results in
infarction, which is referred to as encephalomalacia. Infarcts
may be pale or hemorrhagic (Fig. 19-25). An infarct undergoes sequential microscopic changes reflecting its age; however, precise timing of these changes could not be reproduced
from one study to another. One of the earliest changes is loss
of affinity of myelin and neuropil for stains, which may be

seen within six to eight hours (Fig. 19-26). In the meantime,

gray matter neurons undergo eosinophilic degeneration, and
the neuropil becomes vacuolated, especially around the
blood vessels. In embolic infarcts, neutrophils and erythrocytes permeate the blood vessels during the first 24 to 48
hours and soon are replaced by macrophages. Reactive astrocytes, macrophages, and capillaries begin to appear by the
fourth day, and their numbers increase with time. Macrophages with foamy cytoplasm ( "gitter cells " ) or filled with
hemosiderin are seen in later stages. Tissue lysis accompanied by phagocytosis of the debris leads to formation of pseudocysts filled with serous fluid (Fig. 19-27).
Chronic cerebral ischemia produces a variety of changes,
including formation of lacunae, multiinfarct state, granular
atrophy of cortex, and subcortical arteriosclerotic atrophy of
cortex. Vascular changes of diabetes and hypertension lead
to formation of small cystic spaces. These changes may be
diffuse, in which case the condition is known as etat lacunaire
(Fig. 19-28). Many of these cysts represent small old infarcts,

Fig. 19-25. Cerebral infarcts in the middle cerebral artery distribution. A, Pale infarct (approximately two weeks in duration)
with "cracks" (arrows) demarcating it from intact tissue.
B, Hemorrhagic infarct consists of blood-infiltrated and necrotic
tissue (arrows)

Fig. 19-27. Old infarct. Missing tissue and cysts are found at the
site of an old infarct in the middle cerebral artery distribution.

Fig. 19-26. Acute cerebellar infarct. Pallor, in this case involving

the gray and white matter, is an early sign of ischemia.

Fig. 19-28. Multiple lacunae. On cross section the brain shows

multiple small cystic cavities (etat lacunaire), which are most prominent in the basal ganglia (arrows).


but others are related to resolved old hemorrhages, and some

may even represent dilated perivascular spaces caused by increased tortuosity and spiraling of the perforating arteries
because of hypertension. Lacunae are most prominent in the
basal ganglia, internal capsule, basis pontis, and hemispheric
white matter.
In multiinfarct state the brain contains numerous infarcts
that vary in size, shape, and distribution and usually are accompanied by dementia. Granular atrophy of cortex superficially resembles granularity of renal cortex in nephrosclerosis
(Fig. 19-29). The granularity of cortex is a result of microscopic scarring of numerous wedge-shaped or stellate intracortical infarcts. The gyri in the affected regions are thinned,
and the overlying blood vessels often are stenotic and thick.
Granular atrophy of cortex sometimes is associated with lacunae, multiple infarcts, or both.
Subcortical arteriosclerotic leukoencephalopathy (Binswanger disease) is a rare cause of vascular dementia that is
characterized by multicentric or diffuse degeneration of
white matter (Fig. 19-30). Microscopically myelin destruction and loss are associated with gliosis and scattered foamy
macrophages. The arcuate fibers typically are spared. The intraparenchymal blood vessels have thick walls and appear

Fig. 19-29. Granular atrophy of cortex. Arrows point to the

border zone distribution of the surface granularity of the cortex.

Infections of the brain, the spinal cord, and their envelopes
may be caused by a variety of pathogens, including viruses,
bacteria, and fungi. These pathogens may gain entry through
(1) hematogenous spread, as is the case in most viral infections and many bacterial and fungal infections related to
sepsis; (2) extension from local structures, such as the paranasal sinuses or middle ear; (3) direct implantation through
wounds; (4) axonal transport, which typically accounts for
CNS infections with herpesvirus and rabies virus (Diagram
19-3). Such infections may result in widespread inflamma -

Diagram 19-3. Major tumors of CNS by location and age.

Fig. 19-30. Binswanger subcortical arteriosclerotic leukoencephalopathy. The matter of centrum semiovale (arrows) appears
gray, granular, and shrunken.


tion of the entire CNS or may be localized to certain structures. They are recognized as meningitis, cerebritis, encephalitis, myelitis, or abscesses, which are designated by
their location as epidural, subdural (empyema), or intracerebral.
Bacterial infections may be localized and present as foci of
suppuration leading to abscess formation or diffuse cerebritis, meningitis, or meningoencephalitis and myelitis. Bacterial meningitis is characterized by exudation of inflammatory cells into the subarachnoid space. In acute purulent
meningitis neutrophils predominate, and on gross examination the subarachnoid space appears filled with pus (Fig.

19-31). In chronic bacterial infections lymphocytes and

macrophages predominate. In tuberculosis the subarachnoid
space at the base of the brain is obliterated by granulomas
(Fig. 19-32). Bacterial invasion of brain tissue results in cerebral abscess formation (Fig. 19-33). Over time the abscess becomes walled off by granulation tissue (Fig. 19-34). Incomplete encapsulation leads to the formation of daughter
abscesses. Some abscesses may rupture into ventricles or subarachnoid space.
Fungal infections of the brain most often are encountered
in immunosuppressed persons. Such infections may be
caused by Candida albicans, Aspergillus fumigatus, Histo-

Fig. 19-3 I. Bacterial meningitis. Streaks of purulent material

(small arrows) are obscuring the sulci (large arrow).

Fig. 19-32. Tuberculous meningitis. Dense organizing exudate is

obliterating the basilar subarachnoid space encasing the cranial
nerves (arrows).

Fig. 19-33. Brain abscess. The abscess is accompanied by daughter abscesses (arrows). (Courtesy of Dr. L. Forno.)

Fig. 19-34. Chronic brain abscess. Central area filled with pus
(white arrow) is surrounded by granulation tissue (open arrow) and
edematous brain tissue (dark arrow).


plasma capsulatum, and other fungi, which reach the brain

hematogenously and produce multiple foci of ischemic
necrosis and hemorrhage (Fig. 19-35). Histologically the
fungi are found in the wall of the blood vessels and usually
are associated with thrombosis, which causes ischemic infarction of the brain tissue. Fungi also invade the tissue
around the blood vessels, causing direct destruction of the
brain parenchyma. Mucormycosis of the brain, which typically is found in persons with diabetes, may be caused by infections that spread directly from the nasal mucosa, or it may
be related to hematogenous dissemination of fungi.
Rhinocerebral mucormycosis is characterized by large areas
of necrosis, predominantly basilar, representing foci of hemorrhagic infarction and acute cerebritis caused by intravascular growth of fungi (Fig. 19-36).

Fig. 19-35. Cerebral aspergillosis. Multiple foci of hemorrhage,

hemorrhagic and pale necrosis, and early abscess formation are
seen distributed at random.

Fig. 19-37. Toxoplasmic encephalitis. The tissue is infiltrated

with various inflammatory cells and contains free tachyzoites and
a cyst releasing tachyzoites.

Protozoal infections usually are found in immunosuppressed persons. Toxoplasma gondii infection is the most
prevalent protozoal infection of the CNS in patients with acquired immunodeficiency syndrome (AIDS). It is characterized by foci of necrotizing cerebritis that evolve into chronic
abscesses, usually in the deep gray matter. Microscopically
the irregular patches of necrosis are surrounded by zones of
vascular congestion, intense mixed inflammatory exudate,
reactive astrocytosis, and variable numbers of dormant cysts,
pseudocysts, and extracellular tachyzoites (Fig. 19-37).
Metazoal infections are rare in the United States but are
more common in Asia, Africa, and South America. Cerebral
cysticercosis is produced by larvae of the pork tapeworm,
Taenia solium, and presents with space-occupying lesions
corresponding to encysted parasites (Fig. 19-38).

Fig. 19-36. Rhinocerebral mucormycosis. Necrosis of the

medial temporal lobe simulating a contusion or herpesvirus I
infection is accompanied by necrosis of the ipsilateral optic nerve
(large arrow) and occlusion of the internal carotid artery by fungus

(small arrow).

Fig. 19-38. Cysticercosis of the brain. Multiple cysts are seen,

most often at the junction between the gray matter and the
white matter.

41 2

Viral infections of the CNS occur in a mild and transient

form during systemic viral diseases, whereas encephalitis and
meningitis caused by encephalitogenic viruses are associated
with considerable morbidity and mortality. Viruses evoke a
rather stereotypic response, such as diffuse or multifocal distribution, predominant involvement of neurons (gray
matter), glial hyperplasia in response to neuronal injury, and
perivascular cuffs of lymphocytes (Fig. 19-39). Some viruses
have a predilection for certain parts of the brain. Herpesvirus
type I commonly involves the limbic areas of the brain (orbitofrontal cortex, insula, cingulate gyrus, amygdala, and hippocampus). Infected areas show massive hemorrhage and

necrosis, and virions maybe demonstrated in neurons by immunohistochemistry or electron microscopy (EM) (Fig.
Slow viral infections characterized by chronic encephalitis include subacute sclerosing panencephalitis, progressive multifocal leukoencephalopathy, and progressive
rubella encephalitis. Subacute sclerosing panencephalitis is
attributable to the measles virus. CNS infections related to
prions cause Creutzfeldt-Jakob disease, kuru, and Gerstmann-Straussler-Scheinker syndrome. All of these diseases
are characterized by spongiform changes of the brain (Figs.
19-41 and 19-42).

Fig. 19-39. Acute viral encephalitis. The blood vessels are surrounded by cuffs of lymphocytes, whereas the brain tissue shows
reactive changes evoked by neuronal damage.

Fig. 19-40. Herpesvirus encephalitis. Infection is accompanied by

hemorrhage and necrosis. Inset shows immunoreactive infected
virus cells.

Fig. 19-41. Creutzfeldt-Jakob disease. The gray matter shows

extensive spongiform (vacuolar) degeneration of the neuropil
between nerve cell bodies.

Fig. 19-42. Creutzfeldt-Jakob disease. EM shows swelling of

neuritic processes with loss of internal organelles and formation
of lacy, abnormal membranes within the vacuolated cytoplasm.



Metabolic and Toxic Diseases of the CNS

The nervous system is directly or indirectly affected by numerous congenital and acquired metabolic diseases. Central
to understanding the pathophysiology and distribution of
various lesions is the concept of selective vulnerability, which
states that specific cell types or cell populations are more susceptible to a particular insult. An abridged classification of
metabolic and toxic diseases of the CNS is given in Table 19-1.
Wernicke disease, which most often is encounteretl in alcoholics, is caused by a deficiency of thiamine. It may occur
in an acute form, which often produces no gross findings or
only minor hemorrhages. Histologic findings include endothelial swelling and proliferation, spongiosis of the neuropil, and astrocytosis in the presence of intact neurons. These
changes are most prominent in the mamillary bodies, medial dorsal nuclei of the thalamus, and other nuclei around
the third and fourth ventricles. In chronic Wernicke disease
mamillary bodies typically show brownish discoloration and
atrophy, often associated with calcifications (Fig. 19-43). Microscopically these areas show neuronal loss and astrogliosis
and often contain foci of hemosiderin deposition and calcification (Fig. 19-44).
Central pontine myelinolysis is a disease that may present
with coma, quadriplegia, or no symptoms at all. It is an iatrogenic demyelinating disease caused by overzealous correction of chronic hyponatremia and excessive swings in
serum osmolality. It typically affects middorsal-crossing
fibers of the pons (Fig. 19-45). Microscopically the affected
areas show axonal loss, spheroids, lipophages, and astrocytes
with atypical nuclei (Fig. 19-46). Marchiafava-Bignami disease, another rare disease that is associated with alcoholism,
shares some of the demyelinating features of central pontine
myelinolysis but primarily affects the corpus callosum.
Subacute combined degeneration of the spinal cord is
caused by deficiency of vitamin B12 (cyanocobalamin). Typically associated with atrophic gastritis and pernicious
anemia, it presents with spongy changes in myelin, followed
by axonal and oligodendrocytic loss, astrocytosis, and mac -

Fig. 19-43. Wernicke encephalopathy. Periventricular hemorrhages and discoloration of mamillary bodies.

Fig. 19-44. Wernicke encephalopathy. In chronic stages there is

neuronal loss and fibrillary gliosis.

Fig. 19-45. Central pontine myelinolysis. The pons shows a

sharply demarcated area of demyelination.


rophagic response. The localization of these changes to the

posterior and posterolateral columns, particularly in the
upper thoracic cord, their asymmetry, and their transgression of tract boundaries are characteristic (Fig. 19-47). White
matter changes also are detected elsewhere.
Wilson disease (hepatolenticular degeneration) is a congenital metabolic disorder of the metabolism of copper.
Copper accumulates in the liver and brain with cytotoxic effects. CNS lesions resulting from excess copper are most
prominent in the putamen, which may show rare active
spongy change progressing to cavitary necrosis (Fig. 19-48).
Rarely, neocortical layers V and VI are involved.

Many genetic diseases affect the brain and produce changes

in the gray matter, the white matter, or both. Each disease is
characterized by a typical set of pathologic changes, which
often occur preferentially in certain parts of the CNS.
Lysosomal disorders refer to a diverse group of diseases that
are also known as lipidoses and neuronal storage diseases.
The deficiency of a catabolic enzyme in these autosomal

recessive diseases results in the accumulation or storage of

substrates and intermediate metabolites that cannot be processed further. This group of diseases includes (1) sphingolipidoses (Tay-Sachs or Niemann-Pick disease); (2) glucosaminoglycanoses (mucopolysaccharidoses; Hurler, Hunter,
and Sanfilippo syndromes); (3) sialidoses, mucolipidoses,
and glycoproteinoses (mannosidoses and fucosidosis); and
(4) glycogenoses (Pompe or Andersen disease). Tay-Sachs
disease, which is caused by a deficiency of hexosaminidase A,
is a prototype of sphingolipidoses. The brain contains ballooned neurons that have vacuolated cytoplasm (Fig. 19-49).
By EM these vacuoles correspond to lipid-rich membranous
cytoplasmic bodies (Fig. 19-50).
Leigh disease (subacute necrotizing encephalomyelopathy) produces changes similar to those seen in Wernicke
disease, which may lead to massive necrosis of the putamen,
thalamus, brainstem, and cerebral and cerebellar white
matter (Fig. 19-51).
Leukodystrophies are diseases of infancy and childhood
that typically demonstrate diffuse, confluent dysmyelination
and atrophy of cerebral and cerebellar white matter. These

Fig. 19-46. Central pontine myelinolysis. Demyelination is accompanied by the formation of spheroids (arrows), lipophages,
reactive astrocytes, and relative neuronal sparing.

Fig. 19-47. Subacute combined degeneration. Spinal cord shows

loss of myelinated axons, most prominently in the posterior

Fig. 19-48. Wilson disease. Cross section of the brain shows

cavitary necrosis of the putamen.

Fig. 19-49. Tay-Sachs disease. Neurons have finely vacuolated

cytoplasm and appear ballooned.

Inborn Errors of Metabolism


changes are accompanied by significant axonal loss and relative sparing of arcuate (subcortical U) fibers (Fig. 19-52).
In addition to common features that include loss of myelin
and oligodendroglia, accumulation of myelin breakdown
products, and reactive astrogliosis, each specific disease
shows additional characteristic light and electron microscopic features. Globoid cell leukodystrophy (Krabbe disease)
is characterized by accumulation of large uninuclear or multinuclear globoid cells that are periodic acidSchiff-positive
(Fig. 19-53).
Myelinolytic diseases are characterized by widespread demyelination of axons. Spongy degeneration of the CNS in infancy (Canavan-Van Bogaert-Bertrand disease) is a prototype of congenital myelinolytic disorders that primarily
affect the white matter . of the CNS, which undergoes grossly
visible gelatinous to aqueous transformation (Fig. 19-54).
Histologically there is spongy vacuolar myelinopathy, with a
paucity of myelin breakdown products and macrophages.

Fig. 19-51. Leigh disease (subacute necrotizing encephalomyelopathy). Cross section of the brain shows necrotic lesions in
the caudae and putamen.

Fig. 19-53. Globoid cell leukodystrophy (Krabbe disease). Brain

contains numerous multinucleated globoid cells.

Fig. 19-50. Tay-Sachs disease. Whorls of membranes forming

round cytoplasmic bodies are typical of sphingolipidoses, especially gangliosidoses.

Fig. 19-52. Leukodystrophy (globoid cell). Cross section of the

brain shows confluent demyelination with relative sparing of
arcuate fibers (arrows).

Fig. 19-54. Spongy degeneration of the CNS in infancy (CanavanVan Bogaert-Bertrand disease). The white matter shows gelatinous transformation, which is most noticeable at arcuate fibers.


Demyelinating disease are sporadic inflammatory diseases
that are characterized by immune or infectious destruction
of biochemically normal myelin or its supporting cells, with
relative sparing of axons. This group of diseases includes
multiple sclerosis, acute disseminated encephalomyelitis,
and infectious diseases such as progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis.
Multiple sclerosis is a relatively common neurologic disease of young adults (20 to 40 years). It has both a genetic
and an environmental component, as evidenced by the predominance of disease among persons of certain human
leukocyte antigen (HLA) types and its geographic distribution. Clinical and laboratory data suggest that the disease has
an autoimmune pathogenesis. The pathologic hallmark of
the disease, the demyelinative plaque, is a sharply demarcated
lesion, which usually is focal, asymmetric if bilateral, and disrespectful of anatomic boundaries such as tracts or gray
matterwhite matter junctions (Figs. 19-55 and 19-56). Sites
of predilection for the plaques are the pial surface of the optic

nerves and optic chiasms, basis pontis, spinal cord, and

periventricular white matter, that is, white matter close to
cerebrospinal fluid spaces and deep cerebral veins. Acute lesions contain CD4 + and CD8 + lymphocytes, macrophages,
and scattered plasma cells (Fig. 19-57). Demyelination of
oligodendroglial cells and relative sparing of axons are typical of chronic lesions (Fig. 19-58).
Subacute sclerosing panencephalitis (SSPE) is a demyelinating disease attributable to infection caused by measles
virus that lacks a membrane (M) protein. It typically occurs
several to many years after infection and has a fatal course.
The brain shows destruction and loss of white matter and
also loss of neurons from the gray matter. The white matter
typically is infiltrated with lymphocytes and plasma cells and
shows gliosis. Demyelination and axonal loss are associated
with typical intranuclear inclusions in oligodendroglial cells
(Fig. 19-59).

Fig. 19-55. Multiple sclerosis. Most prominent preventricular

demyelinative plaques are accompanied by others at the corticomedullary junction (arrow).

Fig. 19-56. Multiple sclerosis. In unfixed state the medulla oblongata appears grayish-pink. The lesions do not respect anatomic boundaries.

Fig. 19-57. Multiple sclerosis, acute stage. Lesions are infiltrated

with lymphocytes and macrophages.

Fig. 19-58. Multiple sclerosis. Chronic lesions show extensive



Fig. 19-59. Subacute sclerosing panencephalitis. Demyelination

of white matter is accompanied by chronic inflammation, reactive astrocytosis, and intranuclear inclusions in the oligodendroglial cells. Intranuclear inclusions have a halo separating them
from the nuclear membrane.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that is seen in immunocompromised

persons and is believed to be caused by JC polyomavirus.
Multifocal destructive lesions of the white matter consist microscopically of lipophages, bizarre hypertrophic astrocytes,
demyelinating axons, and enlarged oligodendroglial nuclei
that contain amphophilic inclusions (Fig. 19-60).

Fig. 19-60. Progressive multifocal leukoencephalopathy. Oligodendroglial cells, which show typical intranuclear inclusions, are
surrounded by atypical astrocytes and lipophages.

Neurodegenerative Diseases



Degenerative diseases constitute a heterogeneous group of

idiopathic diseases that are primarily germane to the CNS.
They share a gradual symmetric loss of specific neurons,
groups of neurons, and nerve fiber tracts that often are functionally related (multisystem degeneration). These diseases
may be classified according to whether they primarily affect
the cortical or subcortical parts of the cerebrum, cerebellum,
brainstem and spinal cord, or motor neurons (Table 19-2).
Alzheimer disease (senile dementia of Alzheimer type) is
characterized by atrophy of gyri and widening of sulci, most
prominently in the frontal and temporal lobe and notably
the hippocampi (Fig. 19-61). The disease is characterized by
a loss of neurons and the typical appearance of senile plaques
and neurofibrillary tangles (Fig. 19-62). Senile plaques, also
known as neuritic, dendritic, and amyloid plaques, are argyrophilic and are best seen in silver-impregnated slides. They
appear as spherical bodies often are located near capillaries.
Mature plaques have an amyloid core surrounded by a ring
of radiating bulbous irregular neurites and processes of microglial and astrocytes. Neurofibrillary tangles are cytoplasmic bodies composed of coarse linear fibrils. Their appearance varies, depending on their stage and the shape of the cell
in which they are located. They are faintly basophilic in routine hematoxylin-eosin (H&E) sections and are best demonstrated by silver impregnation techniques.

Diseases shown in boldface type are the best characterized.


Fig. 19-61. Alzheimer disease. Compared with an age-matched

control (lower specimen), the affected brain is smaller and shows
narrow gyri and widened sulci.

Fig. 19-62. Alzheimer disease. Senile plaques appear as spherical

bodies in silver-impregnated slides. Neurofibrillary tangles are
formed of coarse fibrils that react with silver (inset).

Fig. 19-63. Pick disease. Atrophy of gyri is most prominent in

the frontal lobe ("knife edge gyri") (arrow).

Pick disease is an uncommon cause of sporadic dementia.

It typically presents with severe brain atrophy (lobar sclerosis), classically involving the orbitofrontal and anterior
temporal regions (Fig. 19-63). The corresponding white
matter is greatly attenuated and firm, resulting in hydrocephalus ex vacuo. Atrophy of the caudate nucleus may simulate Huntington disease. Microscopically the affected gyri
show considerable neuronal loss, prominent astrogliosis, ballooned neurons (Pick cells), and intracytoplasmic globular
agyrophilic masses (Pick bodies) (Fig. 19-64).
Huntington disease is an autosomal dominant neurodegenerative disease that becomes symptomatic in the fourth
decade. It is characterized by dementia, emotional disturbances, and chorea. The most prominent change in the brain
is atrophy of the caudate nucleus, which results in enlarge-

ment of the anterior horns of the lateral ventricles (Fig.

19-65). The putamen also is affected, but involvement of
other nuclei and cortex is not constant. Microscopically the
disease is characterized by astrocytosis and a loss of small and
medium-sized neurons.
Multisystem atrophy is a term that refers to three clinicopathologic entities: striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. The disease
becomes symptomatic between the fourth and sixth decades
and is characterized by parkinsonism, cerebellar atrophy, and
autonomic dysfunction. Loss of neurons and myelinated
fibers results in atrophy of the cerebellum and pons (Fig.
19-66). Argyrophilic cytoplasmic inclusions in oligodendroglial cells and Pick-like inclusions in neurons are a typical microscopic findings.


Fig. 19-64. Pick disease. Pick cell has a ballooned cytoplasm and
an eccentric nucleus (left). Pick body appears as a basophilic
globule in the perikaryon (right).

Fig. 19-65. Huntington disease. The ventricles are dilated because of atrophy of the caudate nuclei on their lateral sides.

Fig. 19-66. Olivopontocerebellar atrophy. Cerebellar hemispheres appear disproportionately small and the pontine bulge is

Parkinson disease (idiopathic parkinsonism) is a common

neurodegenerative disease that has its highest prevalence in
the eighth decade. It usually is sporadic and idiopathic, but
it also may be secondary to infectious disease, exposure to
toxins, or drugs. Major pathologic changes are found in the
substantia nigra and the locus coeruleus, which appear pale
because of the destruction of neuromelanin-containing neurons (Fig. 19-67). Some of the surviving neurons are slightly
enlarged and pale, whereas others display the diagnostic cytoplasmic inclusions. These inclusions, which are known as
Lewy bodies, appear as spherical eosinophilic cytoplasmic
bodies (Fig. 19-68). Diffuse Lewy body disease, in which such
cytoplasmic inclusions are seen in cortical neurons, may be
associated with dementia.

Fig. 19-67. Parkinson disease. Substantia nigra is depigmented,

as evidenced in the atrophic specimen (left) compared with an
age-matched control (right).

Fig. 19-68. Parkinson disease. Lewy bodies appear as round cytoplasmic masses in the pigmented neurons.


Fig. 19-69. Friedreich ataxia. Attenuation and fattening of dorsal

spinal cord caused by nerve fiber loss in ascending tracts (c, cuneate; g, gracile; psc, posterior spinocerebellar) and descending
pyramidal (py) tracts.

Friedreich ataxia is the best characterized of the hereditary degenerative spinocerebellar syndromes. It is an autosomal recessive disease that becomes clinically apparent in
the second decade. It has a rapid downhill course, and most
patients die within five years after onset of symptoms. Mixed
cerebellar and sensory ataxia caused by peripheral neuropathy dominate the clinical picture. The spinal cord is thin because of loss of ascending and descending myelinated fiber
tracts and their replacement with astrocytes (Fig. 19-69).
Amyotrophic lateral sclerosis and motor neuron disease are
two terms that are used interchangeably to describe the
same disease of unknown etiology and pathogenesis. It affects persons over the age of 55 years and occurs at a rate of
1.5 per 1,000,000. Most cases are sporadic, but 10 percent
have a family history and are inherited in an autosomal
dominant manner. Both upper and lower motor neurons
are involved, causing progressive loss of muscle strength.
The anterior spinal roots are atrophic and gray (Fig. 19-70).
The spinal cord shows loss of myelinated fibers, most
prominently in the lateral corticospinal tracts (Fig. 19-71).
Spinal cord changes are secondary to loss of motor neurons,
best appreciated in the hypoglossal nuclei and anterior
horns of the cervical and lumbosacral enlargements of the
spinal cord.


Fig. 19-70. Amyotrophic lateral sclerosis. Atrophic and gray

posterior roots of cauda equina (black arrow) in contrast to normal posterior roots (white arrow).

Primary neoplasms of the CNS account for 9 percent of primary cancers. These neoplasms occur at a rate of 10 to 20 per
100,000. They occur in all age groups and are an especially
significant cause of morbidity and mortality in children and
young adults. In the first decade of life brain tumors account
for 15 to 18 percent of all malignant tumors (Diagram 19-4).
Neoplasms of the CNS may be grouped into several major
categories: (1) astrocytic, oligodendroglial, ependymal, and
choroid plexus tumors; glial neoplasms; (2) neuronal, mixed
neuronal-glial and neuroendocrine tumors including medulloepithelioma, medulloblastoma, neuroblastoma, and
primitive neuroectodermal tumor (PNET); (3) meningeal
tumors; (4) nerve sheath tumors; (5) vascular neoplasms;
(6) hematopoietic and lymphoid cell tumors; (7) germ cell
tumors; and (8) pineal tumors.

Fig. 19-71. Amyotrophic lateral sclerosis. Cross section of the spinal

cord shows pale crossed (long arrow) and uncrossed (short arrow)
pyramidal tracts.


Diagram 19-4. Major tumor of CNS by location and age.


Astrocytic Tumors
Astrocytic tumors include astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme. Less common variants
include astroblastoma and pleomorphic xanthoastrocytoma. Astrocytic tumors represent 70 percent of all primary
CNS tumors. Astrocytomas infiltrate the normal structures
of the brain, causing them to enlarge or expand (Fig. 19-72).
Cerebellar astrocytomas of childhood typically are cystic
(Fig. 19-73). Microscopically astrocytomas are composed of
fibrillar or protoplasmic astrocytes that have slightly atypical
nuclei. In anaplastic astrocytomas, which usually are more
cellular, the nuclei are more anaplastic (Fig. 19-74). Glioblastoma multiforme is a highly malignant invasive neoplasm,
which may extend from one hemisphere to the other (Fig.
19-75). On cross section the tumor has a variegated appearance because of large areas of necrosis and hemorrhage. Microscopically it may exhibit uniform or diverse cytologic fea-

tures and is composed of small, large, or bizarre cells (Figs.

19-76 and 19-77). The blood vessels usually are prominent
and typically show endothelial cell hyperplasia, which may
assume glomeruloid features.

Oligodendrogliomas are tumors composed of oligodendrocytes. They represent 10 percent of all primary brain tumors
and usually occur in middle-aged adults. On gross examination they appear relatively well demarcated from the surrounding brain tissue, with occasional cystic areas and calcifications. Microscopically oligodendrogliomas are
composed of sheets of uniform cells that resemble
oligodendroglial cells. These cells have closely apposed, welldefined cell borders and round nuclei (Fig. 19-78). The cytoplasm of these cells is clear, and if the tissue is not promptly
fixed, a perinuclear halo forms, which gives them a " fried egg"
appearance. Anaplastic oligodendroglioma is a rare variant
that exhibits more pronounced nuclear atypia.


Fig. 19-72. Astrocytoma of pons. Diffusely infiltrating glioma has

caused irregular enlargement of the pons and middle cerebellar

Fig. 19-73. Cystic astrocytoma of cerebellum in a child. The

tumor appears cystic. It involves the cerebellar hemisphere and
partly fills the fourth ventricle.

Ependymomas are composed of neoplastic ependymal cells.

These tumors account for 5 percent of all primary CNS neoplasms and 10 percent of CNS tumors in children and adolescents. Ependymomas may occur anywhere in the CNS, but
60 percent to 70 percent are infratentorial. A favorite site is
the fourth ventricle, where it usually arises from the floor as
a globular to lobulated exophytic mass. It may protrude from
the roof foramina and partially encircle the brainstem.
Supratentorial ependymomas, however, tend to expand
within the adjacent brain rather than grow into the ventricles (Fig. 19-79). Less common sites are the cerebellopontine
angle, posterior third ventricle, and aqueduct. Ependymomas are the most common intraspinal tumor. Microscopically there are several variants. So-called cellular type is
the most common variant, in which cells form sheets or align
themselves around blood vessels, forming " perivascular
pseudorosettes" (Fig.19-80). Nuclei of typical ependymomas
display little pleomorphism. However, in anaplastic ependy-

Fig. 19-74. Anaplastic astrocytoma. Tumor cells show moderate

anaplasia. Endothelial cells are prominent.


Fig. I9-76. Glioblastoma multiforme. The tumor is composed

of small cells showing primitive palisading. Endothelial cells are
prominent and there are areas of necrosis.
Fig. 19-75. Glioblastoma multiforme. The tumor involves the
splenium of corpus callosum spreading into adjacent hemisphere.

Fig. 19-77. Glioblastoma multiforme. Tumor cells show marked


Fig. 19-78. Oligodendroglioma. Tumor cells have round nuclei

surrounded by clear cytoplasm in the form of a halo. Capillaries
are delicate.

Fig. 19-79. Ependymoma. The tumor distorts the pons and compresses the cerebellum.

Fig. 19-80. Ependymoma. This cellular type of ependymoma is

composed of uniform cells that form perivascular pseudorosettes.


moma the cells show marked pleomorphism and nuclear

Choroid plexus papillomas are rare tumors that account
for 1 percent of all primary brain neoplasms. They have a
predilection for the lateral ventricles in children and the
fourth ventricle in adults. The tumors have a cauliflower-like
granular surface expanding the cavity in which they arise.
Microscopically they recapitulate the features of the choroid
plexus, except that the cells lining fronds are more crowded
and mildly pleomorphic (Fig. 19-81). Choroid plexus carcinomas have all the features of malignant epithelial tumors,
and it may be difficult to distinguish them from metastatic

Neuronal, Mixed Neuronal-Glial, and

Neuroendocrine Neoplasms
Medulloepithelioma, medulloblastoma, and neuroblastoma
are designated in the World Health Organization classification as embryonal and cytologically pluripotential neoplasms. Medulloblastoma is the most common, accounting
for 7 percent to 8 percent of all primary brain neoplasms. It
has two peaks of incidence, one at 10 and the other at 22 years
of age. After cerebellar astrocytoma it is the most common
CNS neoplasm of children.
Medulloblastomas typically arise in the vermis of cerebellum and usually appear as a well-demarcated grayish mass
with variable zones of necrosis and hemorrhage (Fig. 19-82).
They protrude into the fourth ventricle, infiltrate its floor,
and extend into the cerebellar peduncles. Microscopically
medulloblastomas exhibit highly variable histologic features,
mostly appearing as infiltrative, highly cellular, undifferentiated neoplasms composed of small cells (Fig. 19-83). The
cells have carrot-shaped ovoid nuclei with coarse dark chromatin and scant or no visible cytoplasm. Mitoses and
necrosis may be found, and some cells form Homer Wright
rosettes. Medulloblastomas are highly malignant neoplasms.
Nevertheless, with modern surgical ablation and radiotherapy, up to 75 percent of patients may survive 5 to 10 years.

Fig. 19-81. Choroid plexus papilloma. The tumor is composed

of papillae lined by cuboidal cells.

Fig. 19-82. Medulloblastoma. This cerebellar tumor appears

partially necrotic, filling in part the fourth ventricle.

Pineal Tumors
Most pineal tumors originate from misplaced germ cells and
are similar to the more common germ cell tumors of the testis
or ovary. Tumors composed of neoplastic pineal cells are
called pineoblastomas or pineocytomas. Pineoblastomas are
tumors of children and young adults (Fig. 19-84). Such tumors are composed of poorly differentiated cells that have
the cytologic and histologic features of a medulloblastoma.
Tumor cells may form Homer Wright or Flexner-Wintersteiner rosettes and even "fleurettes" indicative of photoreceptor differentiation. Although they are radiosensitive, they
have a poor prognosis because they tend to recur after resection and disseminate into the subarachnoid space. Pineocytomas tend to be more localized and slower growing than pineoblastomas. Pineocytomas are formed of relatively mature
uniform cells, which are arranged into sheets or lobules and
intervening paucicellular fibrillated zones forming rosettes

Fig. 19-83. Medulloblastoma. The tumor is composed of primitive cells that have elongated nuclei and scant cytoplasm.


Fig. 19-85. Pineocytoma. Pineocytes surrounded by fibrillar

material form vague rosettes.
Fig. 19-84. Pineoblastoma. Sagittal section reveals a large necrotic mass extending from the pineal region into the diencephalon.

(Fig. 19-85). The prognosis is variable but is considered more

favorable than that of pineoblastoma.

Meningiomas are tumors that are composed of meningothelial cells. They arise from leptomeningeal arachnoid cells,
which are most concentrated in the parasagittal arachnoid
granulations and dural sleeves of the spinal canal. Tumors
typically are attached to the dura, are firm, and compress the
adjacent brain or spinal cord (Fig. 19-86). Several histologic
types are recognized, including syncytial, fibroblastic, psammomatous, angioblastic, and so forth. Tumor cells typically
have ovoid pale nuclei, which are larger than those of astrocytes, with vacuoles of cytoplasmic invaginations (often exaggerated in frozen sections) and well-developed cytoplasm
that shows no distinct borders. The cells often form whorls,
which may contain centrally located psammoma bodies (Fig.
19-87). They are indolent in their growth but commonly invade dura, bone, or dural sinuses. Although such invasion
does not herald malignancy, it is responsible for most recurrences, the rate of which is estimated to be in the range of 15
percent over the five-year period after removal. Several degenerative, reactive, or metaplastic changes may complicate
the recognition of its meningeal origin: myxomatous, xanthomatous, lipoblastic, osteoblastic, chondroid, chordoid,
microcystic, secretory, and inflammatory changes. Malignant meningiomas rarely occur, but the criteria for their histologic recognition are imprecise. Meninges also may give
rise to sarcomas and malignant melanomas.

Fig. 19-86. Meningioma. This midline well-circumscribed tumor

originated from the falx (not shown). It occupies a cavity that
has formed by the tumor pushing itself into the cerebral hemisphere.

Vascular Neoplasms
Hemangiopericytoma and hemangioblastoma are the most
common vascular tumors in the cranial cavity. Hemangiopericytomas represent an invasive malignant tumor that has
a 50 percent recurrence rate. Hemangioblastomas present as
intraaxial lesions of the cerebellum or brainstem, representing 10 percent of posterior fossa tumors. They occur less

Fig. 19-87. Meningioma. Tumor cells have oval nuclei and inconspicuous cytoplasmic borders. Cell form nests, which show
some whorling.


Fig. 19-88. Hemangioblastoma. The tumor is composed of thinwalled vessels surrounded by vacuolated clear stromal cells.

Fig. 19-89. Colloid cyst. Cyst is located in the third ventricle.

often in the spinal cord. They may be multiple in patients

with Lindau or von HippelLindau disease, which is known
to be related to a tumor suppressor gene defect. Hemangioblastomas are well demarcated, cystic, or solid; many consist
of a solid yellow to red mural nodule in a cyst filled with
yellow or brown fluid. Microscopically the tumors consist of
small to dilated vascular channels lined by hypercellular endothelium and surrounded by pericytes and vacuolated
stromal cells (Fig. 19-88). Hemangioblastomas infiltrate
parenchyma to some degree and tend to recur if they are incompletely excised.

embedding it in plastic for thin sectioning and EM and by

submitting it for tease preparation.
Disease may begin in any of these anatomic structures.
The initial lesion usually is followed by secondary changes in
other compartments. Pathogenetically, peripheral neuropathies are thus classified as (1) axonal injury (axonopathy or
primary axonal degeneration); (2) myelin sheath injury (primary demyelination or demyelinating diseases); (3) vascular
diseases involving nerves such as ischemic neuropathy or
neuropathy caused by vasculitis; and (4) diseases caused by
deposition of extraneous substances in the connective tissue,
such as amyloidosis.
Acute axonopathy may be recognized in routine
H&Estained slides as myelin ovoids, which appear as vacuolated spaces and eosinophilic material arranged in the form
of a linear chain. These changes are better appreciated in
plastic-embedded thick sections (Fig. 19-90). The necrotic
debris is derived from the axon and the corresponding myelin
sheath enclosed within the parameter of the original nerve
fiber, but later it is taken up by macrophages. In teased-fiber
preparations, linear chains of myelin ovoids are readily visualized as round or fusiform bodies in the confines of individual nerve fibers. Because the interval from injury to total
axonal fragmentation is generally less than two weeks, acute
axonopathy is characterized by abundant degenerating
Chronic axonopathy is characterized by a loss of axons.
The number of axons per cross-sectional diameter is diminished, and the endorieural space is filled with collagen replacing the lost axons (Fig. 19-91). Axonal degeneration is
accompanied by axonal regeneration, which appears as
sprouting of axons. In plastic-embedded thin sections, regenerating axons may be recognized as thinly myelinated
axons clustered closely together (Fig. 19-92). By EM they are
surrounded by a band of Biangner. In teased-fiber preparations, the internodal length of regenerated axons appears
uniformly shorter than normal.
Demyelination refers to pathologic processes that selectively interfere with the ability of Schwann cells to maintain

Malformative and Nonneoplastic Mass Lesions

This heterogeneous group includes tumors such as craniopharyngioma, dermoid cysts, arachnoid cysts, and colloid
cysts. Colloid cysts usually are located in the anterior roof of
the third ventricle (Fig. 19-89). They are congenital lesions
that are derived from misplaced endoderm. The cysts are
lined by columnar pseudostratified epithelium containing
ciliated or mucus-producing cells, resting on a collagenous
capsule. The lumen of the cyst is filled with colloid.


Peripheral Neuropathies
Peripheral neuropathies may be classified as acute or chronic;
limited to one nerve (mononeuropathy) or involving several
nerves at the same time (polyneuropathy or mononeuropathy multiplex); and etiologically as inflammatory, metabolic/toxic, nutritional, ischemic, or cryptogenic. Clinically
they present in the form of several syndromes such as acute
ascending paralysis, subacute sensorimotor neuropathy,
chronic progressive sensorimotor neuropathy, chronic relapsing-remitting neuropathy, mononeuropathy, or mononeuropathy multiplex.
Peripheral nerves are composed of axons, myelin sheaths,
connective tissue forming the endoneurium and perineurium, and blood vessels. These components of the nerve
are best evaluated in nerve biopsy specimen prepared not
only for paraffin embedded routine sectioning but also by


Fig. 19-90. Acute axonopathy. A, Degenerating axons with myelin debris completely replacing
the axonal profile in cross section of the nerve embedded in plastic and sectioned at I micron
thickness (arrow). B, Myelin ovoids (teased fiber preparation). C, Most axons are in acute stages
of axonal degeneration.

Fig. 19-91. Chronic axonopathy. The nerve contains only a few

myelinated axons, whereas most others have been lost and have
been replaced by collagen.

myelin sheaths. Because each Schwann cell myelinates the

segment of the axon between two nodes of Ranvier, injury to
individual Schwann cells leads to internodal loss of myelin
surrounding segments of the axon. Disintegration of myelin
is accompanied by preservation of the axon, which appears
segmentally denuded in teased-fiber preparations (Fig.
19-93). Segmental demyelination cannot be assessed in
routinely processed paraffin-embedded tissue. In plasticembedded sections, the nerve contains normal axons and
axons whose myelin sheath is too thin for their caliber (Fig.
19-94). This variability in myelin thickness in plasticembedded cross-sectioned nerves is a hallmark of a demyelinating neuropathy.
Remyelinated axons appear in teased-fiber preparations
thin er and have shorter internode segments. Therefore,
after emyelination, the internodes are of variable length and
kness varies along the length of a single fiber (Fig.
19-93). Repetitive episodes of demyelination and remyelina -

Fig. 19-92. Axonal regeneration. Axonal sprouts appear as clusters of small myelinated axons (arrows).

Fig. 19-93. Segmental demyelination. In teased-fiber preparation the demyelinated segment (between arrows) had a thin myelin sheath and is shorter than adjacent internodes.


tion are accompanied by formation of additio 1 periaxonal

layers by Schwann cell processes ( " onion
formation" ),
which are reminiscent of changes seen in hypertrophic axonal neuropathies.

Hereditary Neuropathies

Fig. 19-94. Segmental demyelination. Axons of the same caliber

have myelin sheaths that vary in thickness. This variation typically is seen in nerves that have undergone segmental demyelination.

Hereditary Peripheral Neuropathies

Hereditary neuropathies occur in several clinically distinct

forms, with an estimated prevalence of 1 in 2500. Two major
groups are recognized: hereditary motor and sensory neuropathies (HMSN) and hereditary sensory and autonomic
neuropathies (HSAN) (Table 19-3).
Charcot-Marie-Tooth disease ( MCT) is the most common
hereditary neuropathy. It is inherited as an autosomal dominant trait and occurs in two forms. Type I is more common


and presents as a demyelinating neuropathy, whereas type II

presents as axonal neuropathy. Type I MCT is characterized
by a moderate loss of large caliber axons and prominent
onion bulb formation (Fig. 19-95). Type II MCT is characterized by axonal loss and onion bulbs are not prominent.
Dejerine-Sottas disease is a hereditary neuropathy of childhood that is inherited as an autosomal recessive trait. Microscopically the nerves show prominent onion bulb formation,
which is readily apparent in routine H&Estained -sections
(Fig. 19-96).
Giant axonal neuropathy is an uncommon peripheral neuropathy of childhood that is inherited as an autosomal recessive trait. Microscopically it is recognized by the presence
of greatly enlarged axons that appear in routine sections as
homogeneous eosinophilic spheroids (Fig. 19-97). Immunohistochemistry shows that these spheroids are filled with
Tomaculous neuropathy is an autosomal dominant hereditary neuropathy that is characterized by a tendency to develop compression neuropathy. In plastic sections a few fibers

Fig. I9-96. Dejerine-Sottas disease. Cross section of peripheral

nerve shows numerous onion bulbs.



Fig. 19-95. Charcot-Marie-Tooth disease, type I. A, Onion bulbs

may be difficult to identify in routine histologic sections. They
appear as ill-defined layers of Schwann cell processes and are
accentuated by the appearance of two Schwann cell nuclei adjacent to a single fiber. B, In plastic-embedded tissue sectioned at
I micron thickness, onion bulbs are composed of concentric
layers of Schwann cell cytoplasm with only occasional Schwann
cell nuclei identifiable.

Fig. 19-97. Giant axonal neuropathy. A, Prominent eosinophilic

enlarged axons are distributed at random and are occasionally
surrounded by rings of Schwann cells (Schwann cell hyperplasia).
B, Immunohistochemistry shows that axonal spheroids contain


have excessively thick myelin sheaths, which in teased-fiber

preparations have been likened to sausages (Latin: tomaculum) (Fig. 19-98).
Hereditary amyloid neuropathy is characterized by endoneurial deposition of amyloid, most often derived from
transthyretin. Although they have been described in several
parts of the world, many appear to be based on mutations of
the same segment of the transthyretin gene. Microscopically
amyloid is found in the endoneurium and in the wall of blood
vessels (Fig. 19-99).

Ischemic Neuropathies
Microangiopathy caused by diabetes, hypertension, and
atherosclerosis accounts for most ischemic neuropathies.
Nerve biopsies show chronic axonal loss that involves both
large caliber and small caliber myelinated axons, which are
replaced by collagenous tissue (Fig. 19-100).
Polyarteritis nodosa and Churg-Strauss syndrome may
cause acute and chronic neuronal ischemia, which typically
is segmental. The diagnosis is made by identifying foci of
polyarteritis in the nerve biopsy (Fig. 19-101).

Inflammatory Neuropathies
Guillain-Barre syndrome is an acute or subacute demyelinating peripheral neuropathy with an incidence of 1 to 2 per
100,000. It usually occurs after a self-limited viral disease,
after immunization, in patients with AIDS, following
surgery, and with infection by Campylobacter jejuni. It is considered to be an immune-mediated disorder. Nerve changes,
which are most prominent in the spinal roots, include acute
demyelination and foci of inflammation composed of lymphocytes and macrophages (Fig. 19-102).

Fig. 19-98. Tomaculous neuropathy. A, Cross section of the

nerve shows scattered "hypermyelinated" axons with thickened
myelin sheaths. B, In teased-fiber preparation the nerve fibers
show fusiform thickening.

Fig. 19-99. Familial amyloid neuropathy. Amyloid deposits in the

form of homogeneously eosinophilic material are present in the
wall of blood vessels and the endoneurium.

Fig. 19-100. Ischemic neuropathy. Cross section of the nerve

shows loss of axons from broad areas.


Chronic inflammatory demyelinating polyneuropathy is

similar to Guillain-Barre syndrome in its immune-mediated
pathogenesis and targeted demyelination. However, it is distinguished by an insidious onset, progressive course, and
variable response to therapy. Microscopically the affected
nerves show chronic demyelination, with variable amounts
of inflammation, which often is perivascular or not present
at all (Fig. 19-103).
Systemic inflammatory diseases such as sarcoid6sis may
involve nerves, which typically contain granulomas (Fig.
Sensory perineuritis is a disease of unknown etiology. It
is characterized by chronic granulomatous inflammation
that is restricted to the perineural layers (Fig. 19-105). Infections of nerves with viruses such as herpes simplex or bacteria such as Mycobacterium leprae produce distinct morphologic changes and variable destruction of nerve tissue.

Fig. 19-102. Guillain-Barre syndrome. Scattered axons show

acute demyelination (arrow). Variation in the thickness of myelin
sheaths of axons of the same caliber also is evident.

Fig. 19-104. Sarcoidosis. The epineurium contains noncaseating


Fig. 19-101. Polyarteritis nodosa. The blood vessel is infiltrated

by inflammatory cells.

Fig. 19-103. Chronic inflammatory demyelinating polyradiculoneuropathy. In cross section the nerve shows marked variation
in the thickness of myelin sheaths and focal axonal loss.

Fig. 19-105. Perineuritis. The perineurial layers contain chronic

inflammatory cells forming granulomas.


Neoplasms of Peripheral Nerves

Peripheral nerve tumors are common but usually are small
and benign and thus of limited clinical significance. Malignant tumors are uncommon.
Schwannoma (neurilemoma) is the most common peripheral nerve tumor. Most schwannomas present in the
form of firm, encapsulated tumors that may ostensibly be attached to a peripheral nerve (Fig. 19-106). Microscopically
the tumors are composed of uniform Schwann cells that have
elongated nuclei with tapering ends. In parallel alignment,
they form interwoven fascicles. Densely cellular areas are
termed Antoni A areas, and those that are myxomatous are
called Antoni B areas (Fig. 19-107). Palisading tumor cells
forming rows that alternate with acellular areas are called
Verocay bodies.
Neurofibroma is a benign tumor composed of nerve
sheathderived cells, some of which resemble Schwann cells,
perineurial cells, or endoneurial fibroblasts. It may present
as a solitary intradermal lesion or perineurial masses; or it

may cause ropelike, fusiform expansion of the involved nerve

segment (plexiform neurofibroma). In neurofibromatosis
type I (von Recklinghausen disease), neurofibromas may be
multiple. On gross examination they appear soft and malleable with a mucoid translucent cut surface (Fig. 19-108).
Microscopically they consist of elongated cells and moderately abundant matrix (Fig. 19-109). Neurofibromas tend to
infiltrate nerves and ganglions and may contain entrapped
neural elements. Some tumor cells stain with antibody to
S-100 protein, like Schwann cells; others stain with antibodies to epithelial membrane antigen (EMA), like perineurial cells; and still others do not express any markers and are
considered to be fibroblasts.
Other benign tumors and tumor-like conditions of peripheral nerves that have distinct features are granular cell
tumor, perineuroma, ganglioneuroma, and Morton neuroma.
Perineurioma is a localized mass that occupies a single
nerve and expands each of its fascicles. Each individual fas-

Fig. 19-106. Schwannoma. The tumor is grayish-yellow, encapsulated, and lobulated. Blood vessels are seen on its surface.

Fig. 19-107. Schwannoma. The tumor is composed of spindleshaped cells that show typical palisading.

Fig. 19-108. Neurofibroma. Tumor lobules follow the course of

the nerve.

Fig. 19-109. Neurofibroma. Neurofibroma has infiltrated a ganglion, as evidenced by the presence of scattered ganglion cells
between elongated tumor cells.


Fig. I9-1 10. Perineurioma. Concentrically oriented cells create

a hypercellular endoneurium.

Fig. 19-I 1 I . Morton neuroma. Fibrosis of the perineurial layer

is accompanied by a central loss of axons.

cicle is enlarged and is hypercellular with a single cell species.

The tumor cells lie concentric to the perineurial sheath or
concentrically around individual nerve fibers (Fig. 19-110).
The latter pattern is reminiscent of onion bulbs in the hereditary hypertrophic neuropathies and has led to the synonymous term localized hypertrophic neuropathy. Like neurofibromas, perineuriomas may occur as intraneural plexiform
tumors or as solitary extraneural tumors (intramuscular
Morton neuroma (perineurial fibrosis) is a painful enlargement of an interdigital plantar nerve, usually between
the third and fourth metatarsal bones. Females are affected
more often than males. The focal segment of the affected
nerve is thickened because of fibrosis of the perineurium
compressing the nerve trunk showing a loss of axons (Fig.

DeArmond SJ, Prusiner SB: Etiology and pathogenesis of prion disease.

Am J Pathol 146:785-811, 1995.
Dyck PJ, Giannini C: Pathologic alterations in the diabetic neuropathies
of humans. J Neuropathol Exp Neurol 55:1181-1193, 1996.
Forno LS: Neuropathology of Parkinson's disease. J Neuropathol Exp
Neurol 55:259-272, 1996.
Golden JA: Holoprosencephaly: a defect in brain pattering. J Neuropathol Exp Neurol 57:991-999, 1998.
Inagawa T, Hirano A: Ruptured intracranial aneurysms. An autopsy
study of 133 patients. Surg Neurol 33:117-123, 1990.
Jellinger K: Vascular malformations of the central nervous system. A
morphological overview. Neurosurg Rev 9:177-216, 1986.
Kepes JJ, Moral LA, Wilkenson SB et al: Rhabdoid transformation of
tumor cells in meningiomas: a histologic indication of increased
proliferative activity. Report of four cases. Am J Surg Pathol 22:231238, 1998.
Kepes JJ, Scheithauer B: Pathology of selected neoplasms of central nervous system. Mod Pathol 9:579-597, 1996.
Koppen AH: The hereditary ataxias. J Neuropathol Exp Neurol 57:531543, 1998.
Lie JT: Primary (granulomatous) angiitis of the central nervous system.
A clinicopathologic analysis of 15 new cases and review of the literature. Hum Pathol 23:164-171, 1992.
Ludwig C, Smith M, Godfrey A, Armbrustmacher V: A clinicopathologic study of 323 patients with oligodendrogliomas. Ann Neurol
19:15-21, 1986.
Mirra SS, Hart MN, Terry RD: Making the diagnosis of Alzheimer's disease. Arch Pathol Lab Med 117:132-144, 1993.
Said G, Goulon-Goeau C, Lacroix C, Moulonguet A: Nerve biopsy findings in different patterns of proximal diabetic neuropathy. Ann
Neurol 35:559-569, 1994.
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Further Reading
Anthony DC, Crain BJ: Peripheral nerve biopsies. Arch Pathol Lab Med
120:26-34, 1996.
Asbury AK, Amason BG, Adams RD: The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis. Medicine 48:173-215,
Bigner SH, Schold SC. The diagnosis of metastases to the central nervous system. Pathol Annu 19(pt 2):89-119, 1984.
Bjornsson J, Scheithauer BW, Okazaki H, Leech RW: Intracranial germ
cell tumors. Pathobiological and immunohistochemical aspects of
70 cases. J Neuropathol Exp Neurol 44:32-46, 1985.
Burger PC, Scheithauer BW: Tumors of the central nervous system. Atlas
of tumor pathology, series 3, fascicle 10, Washington, DC, 1994,
Armed Forces Institute of Pathology.
Chuaqui R, Tapia J. Histologic assessment of the age of recent brain infarcts in man. J Neuropathol Exp Neurol 52:481-489, 1993.
Coffin CM, Wick MR, Braun JT, Dehner LP: Choroid plexus neoplasms. Clinicopathologic and immunohistochemical studies. Am
J Surg Pathol 10:394-404, 1986.



Inflammation of the eye is common. It may be related to infections, allergies, systemic diseases, irritants, drugs and
chemicals, mechanical devices, and tumors.
Inflammation may be limited to the conjunctiva (conjunctivitis), cornea (keratitis), cornea and conjunctiva (keratoconjunctivitis), corneal stroma (interstitial keratitis),
episclera (episcleritis), sclera (scleritis), orbital connective
tissue (orbital cellulitis), uvea (uveitis), iris (iritis), ciliary
body (cyclitis), choroid (choroiditis), iris and ciliary body
(iridocyclitis), retina (retinitis), optic nerve (optic neuritis),
eyelid (blepharitis), choroid and retina (chorioretinitis), vitreous (vitritis), pars plana of ciliary body (pars planitis),
lacrimal gland (dacryoadenitis), the intraocular contents

with sparing of the sclera and orbit (endophthalmitis), or the

ocular contents and cornea or sclera (panophthalmitis).
Conjunctivitis is classified according to the nature of the
inflammatory reaction (acute conjunctivitis, chronic conjunctivitis, granulomatous conjunctivitis, inclusion conjunctivitis, ligneous conjunctivitis, membranous conjunctivitis, pseudomembranous conjunctivitis, chronic follicular
conjunctivitis, giant papillary conjunctivitis, vernal conjunctivitis), or it is classified according to the etiologic agent (bacterial conjunctivitis, viral conjunctivitis, allergic conjunctivitis, trachoma) (Fig. 20-1).
Chalazion is an inflammation associated with obstruction
of sebaceous glands (meibomian or Zeis glands). Histologically it presents as a chronic lipogranulomatous reaction
(Fig. 20-2).

Fig. 20-I. Chronic follicular conjunctivitis. This follicle contains

a germinal center. The conjunctiva's normal resident population
of lymphocytes has been stimulated to proliferate.

Fig. 20-2. Chalazion. A mass of chronic inflammatory cells is

seen anterior to the tarsal plate of the eyelid. Empty lipid vacuoles are necessary for the diagnosis of li pogranulomatous

Fig. 20-3. Fungal endophthalmitis. Multiple vitreous microabscesses developed due to Fusarium infection acquired during
cataract surgery. Multiple vitreous microabscesses are a characteristic finding in fungal endophthalmitis.

Fig. 20-4. Sympathetic uveitis, choroid. The choroid is massively thickened by a diffuse chronic inflammatory infiltrate composed of epithelioid histiocytes and lymphocytes. The choriocapillaris is visible ("spared"). A Dalen-Fuchs nodule of epithelioid histiocytes elevates the retinal pigment epithelium (RPE)
from Bruch membrane at right. The retina is detached.


Endophthalmitis and panophthalmitis may be classified as

an endogenous or exogenous intraocular infection that results in abscesses and chronic destructive inflammatory lesions (Fig. 20-3).
Sympathetic uveitis is a rare but very important bilateral
granulomatous reaction that follows unilateral ocular injury
or surgery, usually complicated by incarceration of uveal
tissue in the wound. The condition is. thought to represent
an autoimmune response to sensitization to ocular isoantigens and is characterized by chronic lymphocytic inflammation (Fig. 20-4).
Keratitis caused by bacteria, viruses, or fungi is characterized by destruction of the corneal epithelium and the
Bowman layer, and by prominent inflammatory infiltrates
(Fig. 20-5). Histologic examination of the eye rarely provides
an insight into the cause of the disease. Pathogens such as
cytomegalovirus (CMV), herpesvirus, or parasites occasionally may be identified (Fig. 20-6).


The eye is involved in numerous systemic diseases, some of
which are listed in Table 20-1. The most important among
these systemic diseases are hypertension, atherosclerosis, and
diabetes mellitus. These diseases produce a variety of changes
in the retina, iris, and vitroretinal part of the eye, all of which
are related either to ischemia or to microvascular injury.
Pathologic changes correspond to those seen on ophthalmoscopy as cotton wool spots, microaneurysms, or neovascularization of the eye background (Figs. 20-7 to 20-10).
Extraocular muscles are involved in Graves disease. These
thickened muscles are fibrotic and histologically show lymphocytic myositis (Fig. 20-11).

Examples of Systemic Diseases That

Affect the Eyes

CMV, cytomegalovirus
Fig. 20-5. Acute keratitis and scleritis caused by Pseudomonas
aeruginosa. Pseudomonas infections of the cornea often extend
posteriorly as an acute infectious scleritis.

Fig. 20-6. Ocular toxocariasis. Eosinophilic abscess contains

fragment of nematode larva.

Fig. 20-7. Cotton wool spot and hard exudates of retina. Blockage of axoplasmic flow thickens nerve fiber layer at left. Several
cytoid bodies in cotton wool spot contain darkly-staining nucleoids of dammed organelles. Hard exudates are seen as pools of
proteinaceous fluid centered on outer plexiform layer at right.


Fig. 20-8. Retinal arterial macroaneurysm with hard exudates.

Fibrin surrounds dilated vessel in inner retina, which is thought
to represent an arterial macroaneurysm. Hard exudates and
hemorrhage are seen in outer plexiform layer.

Fig. 20-10. Diabetic microaneurysms of the retina. Whole

mount of retina shows saccular dilatations (Courtesy of Dr. J.M.B.
Bloodworth, Madison, Wisconsin.)

Fig. 20-9. Proliferative diabetic retinopathy. Neovascularization

occurs on anterior surface of retina and extends onto the posterior face of the detached vitreous. Hemorrhage is present in
the vitreous and the subhyaloid space. The vitreoretinal membrane is beginning to cause a tractional retinal detachment.

Fig. 20-11. Graves disease. Postmortem exenteration specimen

showing massive enlargement of extraocular muscles. (Case
reported by Hufnagel TJ et al, Ophthalmology 91:141 I, 1984).

Hereditary tumor syndromes that involve more than one

organ system also may involve the eye. Eye involvement is a
typical feature of neurofibromatosis type I and von HippelLindau disease (Fig. 20-12).


Glaucoma is a term that denotes a group of disorders char-

Fig. 20-12. Retinal capillary hemangioma, von Hippel-Lindau

disease. Although they often are called retinal capillary hemangiomas, histopathologically the retinal tumors are identical to
cerebellar hemangioblastomas. Lipidized stromal cells are found
between the capillary vessels.

acterized by optic neuropathy associated with a characteristic excavation of the optic disk and a progressive loss of visual field sensitivity. In most cases the intraocular pressure is
elevated. The condition may develop without an apparent
antecedent underlying ocular disease (primary glaucoma), or
it may follow or occur concomitantly with a known ocular
disorder (secondary glaucoma). Primary and secondary glaucomas are subdivided into open-angle and closed-angle types,
depending on whether the iridocorneal angle appears open


Fig. 20-13. End-stage glaucomatous cupping of optic nerve head.

This massively excavated nerve head has a bean pot configuration. The lamina cribrosa is bowed posteriorly.

Fig. 20-14. Glaucomatous retinal atrophy. Atrophy is limited to

the ganglion cell and nerve fiber layers of the retina. A few glial
cells are seen in the nerve fiber layer.

Fig. 20-15. Narrow angle, anterior chamber. The peripheral

stroma of the iris is in close proximity to the trabecular meshwork. Patients with the narrow angle configuration are at risk
for developing an acute attack of angle closure glaucoma.

Fig. 20-16. Peripheral anterior synechiae. The anterior surface

of the peripheral iris is adherent to the trabecular meshwork.
Uveal melanoma was the indication for enucleation.

or closed. Glaucoma also may be subdivided into congenital

(developmental) or acquired types, depending on the time
of onset. Primary open-angle glaucoma, the most common
form, affects 1 percent to 3 percent of all persons over 40 years
of age. Congenital glaucoma is the least common form.
Pathologic studies on eyes with glaucoma disclose abnormalities relevant to the effects of elevated intraocular pressure, such as a loss of ganglion cells and axons in the retinal
nerve fiber layer, posterior bowing of the lamina cribrosa, excavation of the optic nerve head ( "glaucomatous cupping"),
and optic atrophy (Figs. 20-13 to 20-18). With long-standing
glaucoma the corneal endothelium may be deficient and the
cornea may have features of a bullous keratopathy. Most enucleated blind glaucomatous eyes have secondary closed-angle
glaucoma. Pathologic alterations relevant to the cause of the
glaucoma may also be apparent. These abnormalities include
the presence of epithelium on the surface of the iris and even

Fig. 20-17. Postcontusion angle recession (recessed angle), eye

with pseudoexfoliation syndrome. The iris root and first ciliary
process are displaced posteriorly. The ciliary muscle has a fusiform shape caused by ischemic atrophy of its inner part after
tear into face of ciliary body during contusion injury.


in the vitreous ( "epithelial downgrowth"). Neovascularization of the iris is found in cases of neovascular glaucoma, the
most common and clinically significant form of secondary
closed-angle glaucoma.

Diseases of the Cornea

Fig. 20-18. Congenital glaucoma, gross photo showing enlarged

cornea with healed ruptures of Descemet membrane. Corneal
enlargement occurs when the intraocular pressure is elevated in
childhood. Stretching may produce spontaneous tears in
Descemet membrane called Haab striae. The healed ruptures
are seen as radiating lucent ridges on the posterior corneal surface in the photo.

Fig. 20-19. Pseudophakic bullous keratopathy. Descemet membrane is normal. The endothelial cells are absent, and the stroma
is edematous. Endothelial damage caused by cataract surgery and
prosthetic intraocular lens implantation is the most common
indication for corneal transplantation.

Fig. 20-21. Fuchs corneal dystrophy. Guttate excrescences of

abnormal basement membrane material stud posterior surface
of thickened Descemet membrane. Some residual endothelial
cells contain granules of melanin pigment from iris. Stroma has
edematous "cotton candy" appearance.

Diseases of the cornea often show unique features, although

their nature is not fully understood. Bullous keratopathy is a
common disease in which the corneal stroma and epithelium
become edematous and bullae form between the epithelium
and the Bowman layer. The changes are classified according
to the cause of epithelial loss: cataract extraction (aphakic
bullous keratopathy), cataract extraction combined with implantation of a prosthetic intraocular lens (pseudophakic
bullous keratopathy), and Fuchs corneal dystrophy (Figs.
20-19 to 20-23). Corneal graft rejection may cause similar
Fuchs corneal dystrophy, which accounts for many corneal
specimens submitted for pathologic examination in the

Fig. 20-20. Granular corneal dystrophy. Stroma contains aggregates of intensely eosinophilic crystalloids with "rock candy"
appearance. Material stains intensely with Luxol fast blue and
shows acid fuchsinophilia (red staining) with Masson trichrome.

Fig. 20-22. Lattice corneal dystrophy. Smudgy oval deposit of

stromal amyloid stained positively with Congo red and showed
apple-green birefringence and dichroism on polarization microscopy.


United States, is characterized by multiple, centrally located,

wartlike excrescences ("corneal guttae " ) on a thickened
Descemet membrane in addition to features of bullous keratopathy (Fig. 20-21). The inherited lattice corneal dystrophies are characterized by irregular linear opacities caused by
stromal amyloid deposits in corneas with an unremarkable
Descemet membrane and endothelium (Fig. 20-22). Macular
dystrophies are characterized by accumulation of keratan sulfaterelated glycosaminoglycan within the fibroblasts, in the
endothelium of the cornea, among the collagen lamellae, and
in the Descemet membrane (Fig. 20-23). Hale colloidal iron
technique and the Alcian blue stain are particularly useful in
coloring the abnormal accumulations.
Keratoconus is a common progressive disease that is characterized by thinning of the central corneal stroma, which
causes conical distortion of the cornea, without evidence of
inflammation or vascularization. This poorly understood
disorder may be familial and occasionally is associated with
other hereditary disorders such as Marfan syndrome. Excessive eye rubbing is common in patients with keratoconus and
may precede the formation of a conical cornea. Histologically the epithelium of the cornea is ectatic and the Bowman
layer contains typical dehiscences. The epithelium often contains a ring of stainable iron surrounding the cone (Fleischer
ring) (Fig. 20-24).

Fig. 20-23. Macular corneal dystrophy. Deposits of lucent,

finely granular storage material (abnormal nonsulfated keratan
sulfate) are seen in anterior interlamellar spaces.

Retinal Degenerative Diseases

Retinal degenerative changes may occur at any age but are
more common in older people. Most important among these
disorders are macular degeneration and retinal detachment
(Fig. 20-25). Pigmentary retinopathy, which is better known
by the generic misnomer retinitis pigmentosa, a term that encompasses a large group of progressive degenerative diseases
of the retina, is characterized by a loss of retinal photoreceptors and by perivascular accumulation of pigment within
the retina (Fig. 20-26).

Fig. 20-25. Age-related macular degeneration. The retina is shallowly detached by serous fluid. Detached hemorrhagic-retinal
pigmentary epithelium is undergoing organization into a collagenous disciform scar.

Fig. 20-24. Keratoconus. A, The central corneal stroma is

markedly ectatic. In this area the corneal epithelium has undergone compensatory hyperplasia. Dehiscences are seen in the
Bowman membrane. B, Fleischer iron ring in corneal epithelium.

Fig. 20-26. Retinitis pigmentosa. Retinal atrophy is confined to

the photoreceptors. A single row of residual cone nuclei comprises the outer nuclear layer in the posterior retina. The
remaining inner segments are atrophic. The retinal pigmentary
epithelium and the inner retinal layers are intact.


A cataract is an opacity in the lens that usually is severe
enough to impair visual acuity. Cataracts may have numerous causes and are classified as genetic, metabolic, druginduced, and so forth. Most cataracts are associated with
aging. Four basic types of cataract are recognized histopathologically: (1) cortical, (2) nuclear, (3) anterior subcapsular,
and (4) posterior subcapsular (Figs. 20-27 to 20-30).
In the nuclear sclerotic cataract the hardened central lens
nucleus appears yellowish or brown, reflecting the accumulation of the photooxidation pigment urochrome. The colored lens absorbs blue light, which distorts color vision. An
increase in the index of refraction of the lens causes lenticular myopia. Nuclear sclerosis is characterized microscopically by increased eosinophilia and homogeneity of the lens
nucleus, which lacks the artifactitious clefts that are observed
in a normal lens cortex (Fig. 20-27). Nuclear cataracts occasionally contain oval birefringent crystals of calcium oxalate.
Cortical (soft) cataracts result from degeneration of the
lens cells or fibers and are characterized by fractures, degen-

eration, and liquefaction of the fiber cells of the lens cortex

(Fig. 20-28). There initially is formation of vacuoles or clefts
in the lens cortex, but subsequently interrupted and folded
lens fibers and cortical clefts are filled with morgagnian globules. The sclerotic nucleus usually resists liquefaction. The
osmotic effect of the degenerated cortex causes the lens to
imbibe aqueous and swell. Total cortical liquefaction eventually may ensue, leading to the formation of a so-called morgagnian cataract.
Anterior subcapsular cataract is characterized by inflammation and adhesions between the iris and the lens (posterior synechiae). Other factors besides inflammation occasionally stimulate the anterior subcapsular monolayer of
cuboidal lens epithelium to proliferate, undergo metaplasia,
or migrate posteriorly. The proliferating lens epithelial cells
synthesize a thick plaque of collagen beneath a sinuously
folded anterior lens capsule (Fig. 20-29). Within the plaque
the cells are surrounded by basement membrane material
that is periodic acidSchiff positive, bearing testimony to the
lens epithelial lineage of the cells. Proliferation and fibrous
transformation of residual lens epithelial cells is a major
cause of posterior capsular fibrosis after extracapsular cataract extraction.

Fig. 20-27. Nuclear sclerotic cataract. Artifactitious cleft separates dense sclerotic nucleus from degenerated cortex. Nucleus
shows intense homogeneous staining and lacks artifactitiously
intercellular clefts seen in cortex.

Fig. 20-28. Cortical cataract. Morgagnian globules of degenerated lens protein fill cleft in lens cortex.

Fig. 20-29. Anterior subcapsular cataract. Collagenous plaque

made by distressed lens epithelial cells is seen beneath folded
anterior lens capsule. Basement membrane capsules surround
residual lens epithelial cells within plaque. A fibrous papillary
membrane rests on the anterior surface of this cataract.

Fig. 20-30. Posterior subcapsular cataract with Wed! cells. An

aggregate of Wedl or bladder cells formed by posterior migration of the lens epithelium is seen next to thin posterior lens
capsule. Wed! cells represent abortive attempts by lens epithelial
cells to form new lens fibers.


Posterior subcapsular cataract results from the migration

of lens epithelial cells posterior to the normal termination of

the epithelium at the lens equator. Situated abnormally, the
cells retain their nuclei and form large aberrant globular lens
fibers called bladder or Wedl cells (Fig. 20-30). Globular
transparent aggregates of lens cortical material called
Elschnig pearls, which occasionally develop after extracapsular cataract surgery, reflect an identical proliferation of
residual lens epithelial cells.

Benign and malignant tumors of the eye and ocular adnexa
may be classified as extraocular or intraocular. Extraocular
tumors originate from the conjunctiva, cornea, palpebral
skin, adnexal glands, and various mesenchymal cells of the
orbit. These tumors are histologically similar to equivalent
tumors in other sites (Fig. 20-32). Occasionally, some pigmented lesions, such as primary acquired melanosis, may pose
problems. In traocular tumors are more unique, but even these
neoplasms rarely exhibit features that are not seen in other

Melanoma is the most common primary intraocular tumor
of adults, although it is regarded as rare. Only approximately
1500 new intraocular melanomas are diagnosed in the
United States yearly. Persons of fair skin are at greater risk of
developing melanoma than are those who have a dark complexion.
Intraocular malignant melanomas arise from melanocytes in the iris, ciliary body, and choroid. They usually are
solitary and unilateral. These tumors range from totally amelanotic white lesions to jet-black masses, and parts of individual tumors often vary greatly in pigment content.
Melanomas of the choroid or ciliary body initially are ovoid,
but choroidal tumors often rupture through Bruch membrane and proliferate in the subretinal space, so a characteristic mushroom or "collar button" configuration is assumed
(Figs. 20-33 and 20-34). A flat, diffuse, or multinodular
growth pattern occasionally occurs but is more typical of

Fig. 20-32. Primary acquired melanosis with atypia in conjunctiva. Conjunctival epithelium is massively thickened by atypical
melanocytes, including epithelioid cells. Substantia propria contains lymphocytes and plasma cells. Invasive malignant melanoma
was found nearby.
Fig. 20-3I. Basal cell carcinoma. Tumor is composed of basaloid cells showing peripheral palisading.

Fig. 20-33. Choroidal malignant melanoma. Bruch membrane is

intact overlying an almond-shaped tumor, which remains confined to the choroid. The tumor is variably pigmented.

Fig. 20-34. Choroidal malignant melanoma. This melanoma has

a characteristic mushroom or collar button configuration, which
results when the tumor perforates Bruch membrane and grows
in the subretinal space. The overlying retina is detached by the
mushrooming head of the tumor and adjacent serous fluid. The
mushroom configuration is typical of uveal melanoma.


metastatic than primary tumors. Histologically, uveal

melanomas are composed of spindle-shaped or epithelioid
cells. Spindle-shaped melanoma cells grow in a cohesive
manner, forming a syncytium. Some spindle cells have
slender nuclei (occasionally with a prominent longitudinal
fold in the nuclear membrane) without nucleoli (spindle A
cells) (Fig. 20-35). Other spindle-shaped cells have plumper
nuclei with small distinct nucleoli (spindle B cells) (Fig.
20-36). Less differentiated epithelioid cells are larger, polygonal, and poorly cohesive, with distinct cytoplasmic margins. Epithelioid cell nuclei are round or oval, have one or
more prominent nucleoli, and their chromatin clumps along
the nuclear membrane.

Most primary uveal melanomas contain variable numbers

of spindle A and B cells and epithelioid cells (mixed cell
melanomas) (Figs. 20-37 and 20-38). Poorly differentiated
melanomas sometimes contain abundant cytoplasmic lipid
( " balloon cell degeneration" ) or bizarre giant cells. Necrosis
is common in all melanomas. Complications include hemorrhage, cataract, glaucoma, retinal detachment, and inflammation. The five-year survival rate is in the range of 55
percent to 85 percent, depending primarily on the size of the
tumor. Other prognostic factors include the location, histologic type, and pigmentation of the tumor.

Fig. 20-35. Malignant melanoma, spindle A cell type. Spindle A

cells have slender cigar-shaped nuclei, finely dispersed chromatin, indistinct nucleoli, and a chromatin stripe caused by a longitudinal fold in the nuclear membrane.

Fig. 20-36. Malignant melanoma, spindle B cell type. Spindle B

cells have plumper oval-shaped nuclei with a distinct nucleolus.

Fig. 20-37. Choroidal malignant melanoma, epithelioid cell type.

Nuclei are large and round and have prominent nucleoli. The
chromatin is often clumped along the inside of the nuclear membrane (peripheral margination of chromatin). These cells are
poorly cohesive.

Fig. 20-38. Malignant choroidal melanoma, mixed spindle and

epithelioid cell type. This field contains a prominent clone of
amelanotic epithelioid cells. In some mixed tumors epithelioid
cells are admixed diffusely among the spindle cells.


Retinoblastoma is the most common primary malignant eye

tumor of children. Most tumors are diagnosed before the age

of two years. Approximately 90 percent of tumors are sporadic and 10 percent are familial. Bilateral tumors are found
in approximately 10 percent of cases. Tumors are related to
deletion or inactivation of the retinoblastoma (Rb) gene.
Retinoblastoma originates from the retinal cells or their
precursors. Tumors may show an exophytic, endophytic, or
mixed endophytic and exophytic growth pattern. Clinically
they produce leukokoria, which often is associated with strabismus (Fig. 20-39). Small tumors cause retinal detachment,
whereas larger tumors fill the eye (Fig. 20-40). Tumors are

composed of primitive cells that correspond to fetal

retinoblasts and their neuroblastic precursors. The degree of
differentiation varies from one tumor to another. Some tumors are composed of densely packed, poorly differentiated
neuroblastic cells with round, hyperchromatic nuclei, scant
cytoplasm, and prominent mitoses; others contain typical
Flexner-Wintersteiner rosettes consisting of a central round
lumen surrounded by more differentiated cells that have a
well-developed apical cytoplasm corresponding to the subretinal space (Fig. 20-41). The cells forming the rosettes are
joined by a series of zonulae adherens analogous to the outer
li miting membrane of the normal retina. The nuclei are

Fig. 20-39. Retinoblastoma. Leukokoria, a white papillary reflex,

is a classic sign of retinoblastoma.

Fig. 20-40. Retinoblastoma. This exophytic growth arising from

outer layers of the retina has caused total retinal detachment.
The retina adheres to the posterior surface of lens, which is displaced anteriorly. This eye had secondary closed-angle glaucoma.

Fig. 20-41. Retinoblastoma. Flexner-Wintersteiner rosettes

have a true lumen, which is analogous to the subretinal space.
The apices of the cells comprising the rosette are joined by zonulae adherens like the external limiting membrane of the retina.

Fig. 20-42. Retinoblastoma. The center of a Homer VYright

rosette contains a tangle of neural processes. A lumen is not present. Relatively nonspecific Homer Wright rosettes are found in
other tumors such as neuroblastoma.


Fig. 20-43. Retinoblastoma. The tumor shows photoreceptor

differentiation and forms fleurettes and bouquets composed of
neoplastic photoreceptor inner segments.

Fig. 20-44. Medulloepithelioma of the ciliary body. The tumor

is located on the inner surface of ciliary process. The tumor consists of bands of thicker cells corresponding to primitive medullary epithelium and flat cells lining cystic spaces filled with
vitreous-like fluid

placed abluminally, indicating that these cells are showing

photoreceptor-like differentiation. The most differentiated
tumors contain bouquet-like aggregates of relatively bland
neoplastic photoreceptors called fleurettes, which are composed of bulbous eosinophilic cell processes that correspond
to photoreceptor inner segments (Fig. 20-42). Less frequently
the neuroblastic cells form Homer Wright rosettes that lack
a central lumen and resemble those in neuroblastomas (Fig.
20-43). Extensive areas of necrosis often leave only a few
perivascular cells intact, and viable tumor cells cuffing blood
vessels may impart the appearance of pseudorosettes. Deoxyribonucleic acid released from the necrotic tumor cells may
precipitate and impregnate intraocular blood vessels, the iris,
the trabecular meshwork, the lens capsule, and other intraocular basement membranes. Neovascularization of the iris
is common and may cause peripheral anterior synechiae and
neovascular glaucoma.
Long-term survival may be achieved with appropriate
therapy, and in most developed countries the rate is in the

range of 90 percent. Favorable histologic findings include the

presence of numerous fleurettes or Flexner-Wintersteiner rosettes. Ominous prognostic signs are optic nerve, choroidal,
and orbital invasion.
Patients with germline deletions of the Rb gene occasionally develop a benign counterpart of retinoblastoma called
retinocytoma or retinoma. These tumors are almost completely composed of fleurette-forming cells, and although
they may evolve into retinoblastoma, they have a favorable

Medulloepithelioma is a rare pediatric tumor composed of
cords or sheets of polarized neuroepithelial cells that form
elongated tubules and line cystic spaces in a loose mesenchymal stroma that is rich in hyaluronic acid, similar to primitive vitreous (Fig. 20-44). Parts of medulloepithelioma may
resemble retinoblastoma, and such tumors may invade the
cranium through the optic nerve. .


Further Reading
Albert D: The ocular melanoma story. Am J Ophthalmol 123:729-741,
Akhtar S, Meek K, Ridgeway AEA et al: Deposits and proteoglycan
changes in primary and recurrent granular dystrophy of the cornea.
Arch Ophthalmol 117:310-321, 1999.
Cunnigham ET, Seiff SR, Berger TG et al: Intraocular coccidiooidomycosis diagnosed by skin biopsy. Arch Ophthalmol 116:674677, 1998.
Dunlop AAS, Cree IA, Hague S et al: Muitifocal chorioiditis. Clinicopathologic correlation. Arch Ophthalmol 116:801-803, 1998.
Folberg R, Verdick R, Weingeist T, Montague P: Gross examination of
eyes removed for ciliary body or choroidal melanoma. Ophthalmology 93:1643-1647, 1986.
Font RL, Smith SL, Bryan RG: Malignant epithelial tumors of the
lacrimal gland. A clinicopathologic study of 21 cases. Arch Ophthalmol 116:613-616, 1998.
Kresloff MS, Castellarin AA, Zarbin MA: Endophthalmitis. Sur) Ophthalmol 43:193-224, 1998.

Margo CE, Mulla ZD: Malignant tumors of the eyelid. A populationbased study of non-basal cell and non-squamous cell malignant
neoplasms. Arch Ophthalmol 116:195-198, 1998.
Margo CE, Waltz K: Basal cell carcinoma of the eyelid and periocular
skin. Sun' Ophthalmol 38:169-192, 1993.
Moorthy RS, Mermoud A, Baerveldt G et al: Glaucoma associated with
uveitis. Sun, Ophthalmol 41:361-394, 1997.
Mooy CD, De Jong PTVM: Prognostic paramete