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PATHOLOGY A Color Atlas
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THE HEART,1 CONGENITAL HEART DISEASE, 2 Cardiovascular shunts and septal defects, 2 Conotruncal anomalies, 4 Cardiovascular obstructions, 6 VALVULAR LESIONS, 9 Rheumatic heart disease, 9 Infective endocarditis, 11 Other valvular lesions, 13 MYOCARDIAL DISEASES, 14 Myocarditis, 14 Cardiomyopathy, 17 CORONARY ARTERY DISEASES, 20 Coronary atherosclerosis, 20 Myocardial infarction, 22 Complications of myocardial infarction, 22 PERICARDIAL DISEASES, 25 CARDIAC TUMORS, 27
BLOOD VESSELS, 30 ARTERIOSCLEROSIS, 32 ANEURYSMS, 35 VASCULITIS, 36 Immune-mediated vasculitis, 38
UPPER RESPIRATORY TRACT, 40 INFLAMMATORY LESIONS, 42 BENIGN TUMORS AND RELATED CONDITIONS, 44 MALIGNANT TUMORS, 45
LUNGS, 48 DEVELOPMENTAL ANOMALIES, 50 PERINATAL LUNG DISEASES, 52 PULMONARY INFECTIONS, 54 PULMONARY CIRCULATORY DISORDERS, 57 Pulmonary emboli, 57 Pulmonary hypertension, 58 IMMUNE-MEDIATED LUNG DISEASES, 58 CHRONIC INFECTIONS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (CORD), 60 Bronchiectasis, 60
Chronic obstructive pulmonary disease, 60 PNEUMOCONIOSES, 62 IDIOPATHIC INTERSTITIAL LUNG DISEASES, 66 PULMONARY NEOPLASMS, 68
THE HEMATOPOIETIC AND LYMPHOID SYSTEM, 72 ANEMIAS, 74 Bone marrow changes, 74 Peripheral blood smears, 74 Tissue changes in anemia, 77 LEUKEMIAS, 78 Acute leukemias, 78 Chronic leukemias, 80 PLASMA CELL DYSCRASIAS, 82 REACTIVE LYMPHADENOPATHIES, 84 HODGKIN DISEASE, 87 Histopathologic subtypes of Hodgkin disease, 87 NON-HODGKIN LYMPHOMA, 89 OTHER HEMATOPOIETIC PROLIFERATIONS IN LYMPH NODES, 95 NEOPLASMS INVOLVING THE SPLEEN, 96 DISEASES OF THE THYMUS, 98
UPPER DIGESTIVE TRACT, loo DEVELOPMENTAL ANOMALIES, 102 INFLAMMATORY LESIONS, 103 ORGAN-SPECIFIC LESIONS, 105 Dental cysts, 105 Oral and salivary gland lesions, 108 Esophageal lesions, 110 TUMORS, 112 Oral tumors, 112 Salivary gland tumors, 112 Esophageal tumors, 118
GASTROINTESTINAL TRACT, 120 DEVELOPMENTAL DISORDERS, 122 CIRCULATORY DISTURBANCES, 124 OBSTRUCTIONS AND DILATATIONS OF INTESTINAL LUMEN, 125
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ORGAN-SPECIFIC DISEASES, 126 Gastritis and peptic ulcer, 126 Small intestinal diseases that cause malabsorption, 129 Inflammation of the appendix and the large intestine, 130 Inflammatory bowel disease (IBD), 132 TUMORS, 134 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
HEPATOBILIARY TRACT, 142 HEREDITARY METABOLIC DISEASES, 144 CIRCULATORY DISORDERS, 146 INFECTIOUS HEPATITIS, 147 Viral hepatitis, 147 Hepatitis caused by pathogens other than hepatitis viruses, 149 Biliary infections, 150 DRUG-INDUCED LIVER DISEASES, 152 ALCOHOLIC LIVER DISEASES, 153 AUTOIMMUNE LIVER DISEASES, 155 BILIARY OBSTRUCTION, 156 CIRRHOSIS, 158 TUMOR-LIKE CONDITIONS AND TUMORS, 159 Tumor-like conditions, 159 Epithelial tumors, 161 Mesenchymal tumors, 163 Metastatic tumors, 163 DISEASES OF THE GALLBLADDER, 164
PANCREAS, 166 DEVELOPMENTAL AND GENETIC DISORDERS, 168 PANCREATITIS, 169 TUMORS OF THE EXOCRINE PANCREAS, 172 Benign tumors and tumors of borderline malignancy, 172 Carcinoma of the pancreas, 174 TUMORS OFTHE ENDOCRINE PANCREAS, 176 DIABETES MELLITUS, 177
ENDOCRINE GLANDS, 180 DISEASES OF THE PITUITARY GLAND, 182 Hypopituitarism, 182 Reactive changes, 183 Tumors, 183
DISEASES OF THE THYROID GLAND, 185 Thyroid hyperplasia, 185 Thyroiditis, 186 Benign thyroid tumors, 188 Malignant thyroid tumors, 190 DISEASES OF THE PARATHYROID GLANDS, 195 DISEASES OF THE ADRENAL CORTEX, 198 Adrenocortical insufficiency, 198 Adrenocortical hyperplasia and hyperfunction, 199 Adrenocortical tumors, 201 DISEASES OFTHE ADRENAL MEDULLA, 203
KIDNEY AND URINARY TRACT, 208 DEVELOPMENTAL AND GENETIC DISORDERS, 210 Agenesis, malposition, exstrophy, and related defects, 210 Polycystic kidney disease, 212 Hereditary glomerular and tubular diseases, 213 VASCULAR DISORDERS, 216 IMMUNE-MEDIATED GLOMERULAR DISEASES, 217 Membranoproliferative glomerulonephritis, 219 Membranous glomerulonephritis, 220 IgA nephropathy and Henoch-Schonlein purpura, 222 Postinfectious glomerulonephritis, 223 Crescentic glomerulonephritis, 224 Systemic lupus erythematosus (SLE), 225 TUBULOINTERSTITIAL DISEASES, 227 LOWER URINARY TRACT INFECTIONS, 232 TUMORS, 234 Tumors of the kidney and renal pelvis, 234 Tumors of the urinary bladder, 235
MALE REPRODUCTIVE SYSTEM, 238 GENETIC AND DEVELOPMENTAL DISORDERS, 240 INFECTIONS, 241 TUMORS OF THE TESTIS, 242 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 TUMORS AND TUMOR-LIKE LESIONS OF THE PROSTATE, 248 Benign prostatic hyperplasia, 248 Carcinoma of the prostate, 250
FEMALE REPRODUCTIVE SYSTEM, 256 DEVELOPMENTAL DISORDERS, 258 INFECTIONS, 260
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HORMONALLY INDUCED CHANGES, 261 TUMORS OF THE VULVA, 263 TUMORS OF THE VAGINA, 265 TUMORS OF THE CERVIX, 266 TUMORS OF THE UTERUS, 268 Endometrial adenocarcinoma, 268 Endometrial stromal tumor,s 270 Tumors of the myometrium, 271 TUMORS OF THE OVARY, 273 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 DISORDERS OF THE PLACENTA, 287 Abnormal implantation and separation of the placenta and rupture of membranes, 289 Infections, 289 Gestational trophoblastic disease, 290
BREAST, 294 FIBROCYSTIC CHANGE, 296 TUMORS, 298 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 HEREDITARY SKIN DISEASES, 312 INFECTIONS, 312 Bacterial infections, 313 Fungal infections, 314 Viral infections, 314 INFLAMMATORY DERMATOSES, 316 I mmune-mediated dermatoses, 316 Granulomatous diseases, 319 Idiopathic skin disease, 321 NEOPLASMS AND RELATED DISORDERS, 323 Pigmentary lesions, 323 Epidermal tumors, 328 Adnexal tumors, 331 Mesenchymal tumors, 333
SOFT TISSUE, 334 FIBROBLASTIC LESIONS, 336 Benign fibroblastic tumors and tumor-like lesions, 336 Fibromatoses, 337 FIBROHISTIOCYTIC TUMORS, 338 LIPOMATOUS TUMORS, 339 VASCULAR TUMORS, 341 PERIVASCULAR TUMORS, 343 SMOOTH MUSCLE CELL TUMORS, 344 TUMORS OF STRIATED MUSCLE, 345 NEURAL TUMORS, 347 Benign neural tumors, 347 Malignant neural tumors, 348 CARTILAGE AND BONE-FORMING TUMORS, 349 MISCELLANEOUS SOFT-TISSUE TUMORS, 350
BONES AND JOINTS, 354 DEVELOPMENTAL AND GENETIC DISORDERS, 356 METABOLIC AND DEGENERATIVE DISEASES, 357 Metabolic bone diseases, 357 Hyperparathyroidism, 359 Paget disease of bone, 359 Crystal-induced arthritis, 360 Osteonecrosis, 361 Degenerative joint disease, 361 I NFLAMMATORY DISEASES, 363 Infections of bones and joints, 363 Noninfectious arthropathies, 364 NEOPLASMS, 367 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
SKELETAL MUSCLES, 384 CONGENITAL MYOPATHIES, 386 MUSCULAR DYSTROPHIES, 386 I NFLAMMATORY MYOPATHIES, 389 GENETIC-METABOLIC MYOPATHIES, 392 Carbohydrate storage diseases, 392 Lipid storage myopathies, 393 Mitochondrial myopathies, 394 DENERVATION-RELATED MUSCLE DISEASES, 395
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NERVOUS SYSTEM, 398 DEVELOPMENTAL AND GENETIC DISORDERS, 400 PERINATAL BRAIN LESIONS, 401 TRAUMA OFTHE BRAIN AND THE SPINAL CORD, 403 CIRCULATORY DISTURBANCES, 405 Intracranial hemorrhages, 405 Cerebral ischemia, 408 INFECTIONS, 409 METABOLIC AND TOXIC DISEASES, 413 Inborn errors of metabolism, 414 DEMYELINATING DISEASES, 416 DEGENERATIVE DISEASES OF THE CENTRAL NERVOUS SYSTEM, 417 NEOPLASMS, 420 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 DISEASES OF PERIPHERAL NERVES, 426 Peripheral neuropathies, 426 Hereditary neuropathies, 428 Ischemic neuropathies, 430 Inflammatory neuropathies, 430 Neoplasms of peripheral nerves, 432
THE EYE AND OCULAR ADNEXA, 434 INFLAMMATION OFTHE EYE AND OCULAR ADNEXA, 436 EYE CHANGES IN SYSTEMIC DISEASES, 437 SPECIFIC OCULAR DISORDERS, 438 Glaucoma, 438 Diseases of the cornea, 440 Retinal degenerative diseases, 441 Cataracts, 442 TUMORS, 443 Melanoma, 443 Retinoblastoma, 445 Medulloepithelioma, 446
EAR, 448 INFLAMMATORY LESIONS OF THE EXTERNAL AND MIDDLE EAR, 450 PATHOLOGIC CHANGES OFTHE INNER EAR, 453 NEOPLASMS, 455 Tumors of the outer ear, 455 Tumors of the middle ear, 455 Tumors of the inner ear, 455
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PATHOLOGY A
Color Atlas
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CONGENITAL HEART DISEASE
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.
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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 (*).
A
B
C
D
Fig. 1-3. Ventricular septal defects (*). A, Membranous defect; B, Outlet defect; C, Muscular defect; D, Muscular defect that has undergone spontaneous closure (arrows).
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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.
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B
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).
A
B
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).
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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 ventricle).
A
B
Fig. 1-7. Complete transposition of great arteries. A, Anterior view. B, Long axis view showing ventriculoarterial discordance.
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Diagram 1-3. Valvular and arterial stenosis. Upper panel shows aortic stenosis. Lower panel shows pulmonary stenosis and aortic coarctation. A
B
C
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.
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B
C
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 positions).
A
B
C
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 view).
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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.
VALVULAR LESIONS 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 era. 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 (*).
A
B
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).
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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.
B
C
A
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 value.
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A
B
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.
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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 Endocarditis
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 Osteomyelitis Mycotic aneurysm Lung abscess Sepsis Infectious Arteritis with Thrombotic Occlusion Infarcts—brain, 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.
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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. 1-24).
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 valve.
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 translucent.
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B
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 calcification.
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B
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
MYOCARDIAL DISEASES The most important myocardial diseases are myocarditis and cardiomyopathies.
Myocarditis 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
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A
B
C
D
E
F
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.
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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: la—focal mild; lb— diffuse mild; 2—focal moderate; 3a—multifocal moderate; 3b—diffuse moderate or severe; or 4—severe (Figs. 1-32 and 1-33). 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).
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Fig. 1-33. Cardiac transplant rejection. Multifocal, moderate (grade 3a).
Fig. 1-34. Eosinophilic myocarditis. The interstitium contains infiltrates of lymphocyte and eosinophils.
Cardiomyopathy 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.
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Diagram 1-4. Specific and less specific causes of dilated, hypertrophic, and restrictive cardiomyopathy.
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.
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Fig. 1-38. Congenital hypertrophic cardiomyopathy. Histologically the cardiac myocytes are hypertrophied and show branching and disarray. There also is considerable interstitial fibrosis.
Fig. 1-39. Amyloidosis of the heart. The ventricular myocardium appears thickened but pale.
A
B
Fig. 1-40. Amyloidosis. A, The cardiac myocytes are surrounded by hyalinized material. B, Electron microscopy shows pericellular amyloid fibers.
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CORONARY ARTERY DISEASES 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.
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Fig. 1-44. Coronary thrombus. In this picro-Mallory trichome—stained 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.
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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.
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. 1-49. 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.
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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.
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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 infarct.
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.
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PERICARDIAL DISEASES 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 TYPE
CAUSE
Infectious Viral Pyogenic Tuberculous Fungal
Coxsackievirus B Staphylococcus aureus Mycobacterium tuberculosis Histoplasma capsulatum
I mmune-mediated Rheumatic fever Sarcoidosis Systemic lupus erythematosus Dressler syndrome
— — — Myocardial infarction
Idiopathic Irradiation Surgery
Radiotherapy Open heart surgery
Metabolic Uremic
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.
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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 tissue.
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.
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CARDIAC TUMORS 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. 1-68).
A
B
C
D
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.
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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.
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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, 1987. Burke AP, Cowan D, Virmani R: Primary sarcomas of the heart. Cancer 69:387-395,1992. 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.
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ARTERIOSCLEROSIS 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 spleen. 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.
A A
B
B
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.
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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.
A
B
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.
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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 tissue.
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.
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ANEURYSMS
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).
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Fig. 2-17. Syphilitic aneurysm. A, The aortic arch is dilated. B, Intima has a "tree-bark" appearance.
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VASCULITIS 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.
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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 Unknown 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 vessels.
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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
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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.
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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, 1997. 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.
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I NFLAMMATORY LESIONS 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).
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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.
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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. 3-4. Chronic laryngitis. As seen through the laryngoscope, the lesion appears as thickening of vocal cords. (Courtesy of Dr. V. Kambic, Ljubljana, Slovenia.)
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.
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BENIGN TUMORS AND RELATED CONDITIONS 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 common. 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.)
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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.
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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.
MALIGNANT TUMORS
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 keratin. 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.
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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.
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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 lymphocytes.
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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.
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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, 1976. 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.
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DEVELOPMENTAL ANOMALIES 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 dysphagia.
Fig. 4-2. Bronchogenic cyst. This resected cyst has a rugged internal surface.
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Diagram 4-I. Tracheoesophageal fistulas. Type C malformations account for 85 percent of all cases.
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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 background.
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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.
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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.
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PERINATAL LUNG DISEASES 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. 4-12).
Fig. 4-7. Neonatal atelectasis. The atelectatic parenchyma appears dark red in contrast to the paler areas of normally aerated lung (right upper corner).
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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.
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Fig. 4-9. Bronchopulmonary dysplasia. Lungs are in part consolidated and in part cystic.
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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.
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PULMONARY INFECTIONS 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. 4-13. 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. 4-15. 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.
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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.
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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).
A
B
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.
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PULMONARY CIRCULATORY DISORDERS 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. 4-25). 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 hemorrhagic.
Fig. 4-28. Pulmonary infarct. The septa are necrotic and the alveoli contain blood.
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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).
I MMUNE-MEDIATED LUNG DISEASES 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
A
B
C
D
E
F
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, Elastica–van Gieson stain.)
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B
C
A
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 tissue.
Fig. 4-34. Eosinophilic pneumonia. The alveoli and thickened septa are infiltrated by eosinophils and lymphocytes.
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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 INFECTIONS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) 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 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).
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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 candy—like texture.
Fig. 4-41. Subpleural bullae.
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PNEUMOCONIOSES 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.
A
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 present. 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).
B
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.
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Fig. 4-44. Coal workers' pneumoconiosis. The lungs show increased black pigmentation.
A
B
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.
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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 cells.
Fig. 4-50. Sarcoidosis. Noncaseating granulomas are found in the peribronchiolar parencyma.
Diagram 4-2. Commercial and noncommercial asbestos.
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A
B
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.
A
B
Fig. 4-54. Malignant mesothelioma. A, This epithelial variant shows a glandulopapillary growth pattern. B, Fibrosarcomatous mesothelioma is composed of spindle shaped cells.
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I DIOPATHIC INTERSTITIAL LUNG DISEASES 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 pneumonia. 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).
A
B
C
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.
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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)
Duration Weeks Weeks to months Years Years Months
Histologic appearance Uniform Uniform Heterogeneous Uniform Uniform
Distribution Diffuse Patchy Patchy Diffuse Patchy
BOOP, bronchiolitis obliterans—organizing 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.
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PULMONARY NEOPLASMS 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 metaplasia.
A
B
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.
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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.
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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.
A
B
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.
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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, 1992. 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.
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ANEMIAS 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 5-1).
Morphologic Classification of Anemias Microcytic hypochromic anemias Iron deficiency Chronic disease Thalassemia 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.
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Fig. 5-4. Parvovirus BI9—induced 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 metamyelocytes.
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 transfusion.
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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.
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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 conditions.
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B
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 red–brilliant 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.
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Fig. 5-12. Thalassemia. The peripheral blood smear contains numerous target cells. A, Thalassemia minor. B, Thalassemia major.
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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.
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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 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 acid–Schiff (PAS) negative (Fig. 5-24).
11
Pro
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.
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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. 5-21. 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.
Fig. 5-24. Acute lymphoblastic leukemia. The cytoplasm of L3 lymphoblasts in a marrow aspirate contains sharply outlined cytoplasmic vacuoles.
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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
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Chronic Lymphoproliferative Disorders B-cell lymphoproliferative disorders Chronic lymphocytic leukemia Typical 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.
A
B
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.
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PLASMA CELL DYSCRASIAS 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 Disorders 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. 5-35). 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.
A
B
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.
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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 restricted.
A
B
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 green.
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.
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REACTIVE LYMPHADENOPATHIES 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 5-7). 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 neutrophiles.
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 Syphilis Angiofollicular hyperplasia (Castleman disease) HIV-related 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 cells.
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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.
A
B
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 monocytes.
A
B
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.
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A
B
C
D
E
F
Fig. 5-43. Diagnostic Reed-Sternberg cells and variants. A, Diagnostic Reed-Sternberg cell: a large multinucleated or multilobated cell with inclusion body–like 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.
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HODGKIN DISEASE
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 find. Nodular sclerosis type HD is characterized by a thickened lymph node capsule. Bands of collagen extend inward from
5-45).
The Pathologic Classification of Hodgkin Disease Jackson & Parker Paragranuloma
Granuloma
Lukes & Butler I. Lymphocytic and histiocytic a. Nodular b. Diffuse 2. Nodular sclerosis
Rye Conference Lymphocytic predominance
Frequency (%)* 5
Nodular sclerosis
70
3. Mixed cellularity 4. Diffuse fibrosis 5. Radicular
Mixed cellularity
22
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.
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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.
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NON-HODGKIN LYMPHOMA 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 5-9). 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
Frequency (%) 4
Plasmacytoid B. Follicular, predominantly small cleaved cell
B-cell Neoplasms
REAL Classification T-cell Neoplasms
B-cell CLUSLUPLL Marginal zone/MALT Mantle cell
T-cell CLUPLL LGL
Lymphoplasmacytoid 26
Follicle center, follicular, grade I Mantle zone Marginal zone
C. Follicular, mixed small cleaved and large cell
9
Follicle center, follicular, grade II Marginal zone/MALT
D. Follicular, large cell
4
Follicle center, follicular, grade III
E. Diffuse, small cleaved cell
8
Mantle cell Follicle center, diffuse small cell Marginal zone/MALT
T-cell CLUPLL LGL Peripheral T-cell, unspecified ATUL Angioimmunoblastic Angiocentric
F. Diffuse, mixed small and large cell
7
Large B-cell lymphoma (rich in T-cells) Follicle center, diffuse small cell Lymphoplasmacytoid Marginal zone/MALT Mantle cell
Peripheral T-cell, unspecified ATUL Angioimmunoblastic Angiocentric
22
Diffuse large B-cell lymphoma ATUL Angioimmunoblastic Angiocentric
Peripheral T-cell, unspecified
H. Large cell Immunoblastic
9
Diffuse large B-cell lymphoma
Peripheral T-cell, unspecified ATUL Angioimmunoblastic Angiocentric Anaplastic large-cell
I.
Lymphoblastic
5
Precursor B-lymphoblastic
Precursor T-lymphoblastic
Small noncleaved cell Burkitt Non-Burkitt
6 Burkitt High-grade B-cell, Burkitt-like
Peripheral T-cell, unspecified
G. Diffuse, large cell
J
.
From Skarin AT, Dorfman DM: Non-Hodgkin's lymphoma: current classification and management, CA Cancer /. permission.
Clin
47:351-372, 1997. Reproduced with
*Categories A–C = low-grade (survival 5 to 10 or more years untreated); D–G = intermediate grade (survival 2 to 5 years untreated); H –J = high grade (survival 0.5 to 2.0 years untreated). Categories D–H 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.
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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 ring—like 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.
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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 outlines.
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).
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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 features.
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
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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.
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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 nuclei.
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
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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 magnification.
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).
OTHER HEMATOPOIETIC PROLIFERATIONS IN LYMPH NODES
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.
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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 bean—like 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.
NEOPLASMS INVOLVING THE SPLEEN 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 Neoplasia 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 Sarcoidosis Infections Infectious mononucleosis, brucellosis, etc. Malaria, toxoplasmosis, etc. Sepsis Congestion Cirrhosis of the liver Budd-Chiari syndrome Chronic congestive heart disease Storage diseases Gaucher disease, Niemann-Pick disease Amyloidosis
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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.
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DISEASES OF THE THYMUS 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 neoplasia. 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.
A
B
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.
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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 lymphocytes.
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-cell—rich 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, 1993.
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DEVELOPMENTAL ANOMALIES 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 gingiva. 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.
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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.
I NFLAMMATORY LESIONS 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 acanthosis. 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.
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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 Herpangina 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.
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B
Fig. 6-12. Esophagitis. A, Herpes simplex—infected cells have multinucleated "ground glass" nuclei. B, Viral particles can be demonstrated by immunohistochemistry.
ORGAN-SPECIFIC LESIONS 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-
A
B
C
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.
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WHO Classification of Cysts of the Jaws NonodontogeniC
Developmental Odontogenic 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 Inflammatory 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.
A
B
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.) A
B
C
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 parakeratosis.
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A
B 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 orthokeratin.
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B
C
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.
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Fig. 6-19. Mucocele. Mucus is infiltrated with inflammatory cells.
Fig. 6-20. Mucous retention cyst. The cyst is lined by squamous epithelium.
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 arrangement.
Fig. 6-22. Necrotizing sialometaplasia. The epithelial nests represent ducts that have undergone squamous metaplasia. The nests are surrounded by loose connective tissue.
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B
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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 hernia.
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. 6-24). 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.
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B
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.
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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.
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TUMORS 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. 6-31). 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.
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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 Benign ;" ' Epithelial Ameloblastoma Odontogenic adenomatoid tumor Calcifying epithelial odontogenic tumor Mesenchymal Myxoma Odontogenic fibroma Cemental tumors Mixed epithelial and mesenchymal origin Ameloblastic fibroma Ameloblastic fibroodontoma Complex and compound odontomas
Malignant Epithelial Malignant ameloblastoma Ameloblastic carcinoma Mesenchymal Ameloblastic fibrosarcoma
Classification of Epithelial Salivary Gland Tumors Benign Pleomorphic adenoma (mixed tumor) Papillary cystadenoma lymphomatosum (Warthin tumor) Monomorphic adenoma • Basal cell • Ductal • Oncocytic Myoepithelioma Ductal papilloma • Intraductal • Sialadenoma papilliferum • Inverted Cystadenoma Sebaceous adenoma Sebaceous lymphadenoma Malignant Arising from Preexisting Benign Tumor Carcinoma • Ex pleomorphic adenoma • Ex monomorphic adenon cell a oma.
NNW
Ex Warthin tumor Ex myoepithelioma Malignant Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Epimyoepithelial (clear cell) carcinoma Salivary duct carcinoma Papillary and nonpapillary adenocarcinoma Mucinous adenocarcinoma Cystadenocarcinoma Adenocarcinoma, NOS Epidermoid (squamous cell) carcinoma Sebaceous carcinoma Basal cell adenocarcinoma Undifferentiated carcinoma • Large cell lymphoepithelial • Small cell lymphoepithelial Carcinosarcoma
NOS, Not otherwise specified.
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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. 6-38). 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 stroma.
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B
Fig. 6-36. Adenocarcinoma arising in pleomorphic adenoma. A, The tumor has an invasive growth pattern. B, Histologically it is an adenocarcinoma.
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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.
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B
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.
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A
B
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).
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B
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Fig. 6-42. Adenoid cystic carcinoma. A, Cribriform pattern. B, Solid pattern. C, Tubular pattern.
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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 cytoplasm.
Fig. 6-46. Salivary duct carcinoma. Tumor nests are composed of cells arranged in a cribriform pattern that resembles breast carcinoma.
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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 ulcerated.
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.
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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.
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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 tumors—a 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.
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DEVELOPMENTAL DISORDERS 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.
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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.)
A
B
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.)
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CIRCULATORY DISTURBANCES 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.
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Fig.7 - 1I . Intestinal hemangiomas.
Fig. 7-12. Dieulafoy ulcer. The ulcer contains ruptured superficial tortuous arteries.
OBSTRUCTIONS AND DILATATIONS OF INTESTINAL LUMEN 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.
7-17).
A
B
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 mucus.
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Fig. 7-15. Volvulus. Intestinal loops twisted around mesocolon have undergone hemorrhagic necrosis.
Fig. 7-16. Intussusception. Loops of bowel invaginating one into another.
A
B
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).
ORGAN-SPECIFIC DISEASES 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 (Table-7-1). 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
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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 plaques.
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.
A
B
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.
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Fig. 7-23. Peptic ulcer. Two ulcers appear as sharp, deep hemorrhagic defects of gastric mucosa.
Comparison of Type A and Type B Gastritis ?~'? Location Distribution Cause Autoantibodies Gastric acidity Cancer risk Prevalence
ype A (atrophic) Fundus Diffuses Autoimmune + —
Type B (nonatrophic) Antrum Focal Helicobacter pylori
— +
+/—
+
Uncommon
Common
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).
B
A
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.
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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 Findings 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 disease) Fungi (e.g., Cryptococcus neoformans) Protozoa (e.g., Giardia lamblia) Metazoa (e.g., Strongyloides stercoralis) Diagnostic tissue changes Abetalipoproteinemia Amyloidosis Lymphangiectasia 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.
A
B
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-Neelsen–stained slide.
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B
A
C
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. 7-31). 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).
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A
B
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.
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A
B
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 -
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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 Feature Macroscopic Location Pattern Wall Mucosa in chronic stages Complications
Ulcerative colitis
Crohn disease
Colon Diffuse Thin Flat or pseudopolyposis
Ileum and colon Patchy with skip areas Thick Cobblestone-like
Megacolon
Adhesions Fistulas
Mucosal Deep
Transmural Superficial
Microscopic Inflammation Ulcerations Pseudopolyps Granulomas Fibrosis Peritonitis
+(50%) + +
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 surface.
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Fig. 7-40. Crohn disease. The ulcerated thickened inflamed mucosa has a "cobblestone" appearance.
TUMORS 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.
B A
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.
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TYPE I A
TYPE Ila TYPE Ilb TYPE Ilc B
TYPE III 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 ring—like.
Fig. 7-45. Spindle cell leiomyoma. The tumor cells have elongated nuclei with round tips and eosinophilic cytoplasm.
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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.)
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B
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 IBD,
.>
.
Lymphoid hyperplasia Mucosal prolapse Solitary rectal ulcer syndrome Diverticular disease Pneumatosis intestinalis
Adenoma Tubular Villous Tubulovillous Carcinoma _ cinoid
Stromal tumor Leiomyoma Lipoma GIST Lymphoma
Inflammatory bowel disease; GIST, gastrointestinal stromal tumor.
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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.
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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.
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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.
A
B
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 cells.
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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, 1998. Willenbucher RF: Inflammatory bowel disease. Semin Gastrointest Dis 7:94-104, 1996.
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HEREDITARY METABOLIC DISEASES 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.
A
B
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.
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Histopathology of Viral Hepatitides Disease Crigler-Najjar, type I Crigler-Najjar, type II Gilbert Rotor Dubin Johnson
Principal Defect in Bilirubin Metabolism Conjugation Conjugation Conjugation and/or uptake Unknown but may include uptake, conjugation, or excretion 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 None or excess lipofuscin in zone 3 and 2 hepatocytes None 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 eosinophilic.
A B
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.
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CIRCULATORY DISORDERS 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.
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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).
I NFECTIOUS HEPATITIS 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 viruses—hepatitis 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.
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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.
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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 infection.
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.
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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. 8-26).
A
B
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 pus.
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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).
A B
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.
A
B
Fig. 8-28. Echinococcus granulosus cyst. A, Cyst has a hyaline fibrotic wall. B, Cyst contains cross-sectioned scolices of the parasite.
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Fig. 8-29. Schistosomiasis. The parasite in tissue is surrounded by chronic inflammation and fibrosis.
DRUG-INDUCED LIVER DISEASES 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 Ps„,-
Drug Examples Isoniazid = `ds-like Spotty necrosis Methyldopa Submassive Halothane, acetaminophen necrosis, zone 3 • Submassive Paraaminosalicylic acid, necrosis, zone I halothane • Massive necrosis Isoniazid, halothane, chlorinated naphthalenes Granulomas Methyldopa, sulfonamides phenylbutazone Cholestasis Chlorpromazine, oral contraceptives Fatty change Tetracycline, salicylates
• Microvesicular • Macrovesicular Vascular changes • Venoocclusive disease
Amiodarone Methotrexate
▪ Peliosis hepatis Hyperplastic changes
Anabolic steroids, tamoxifen Oral contraceptives
Cytotoxic drugs
Toxins
Mushrooms, copper sulfate Phosphorus, ferrous sulfate CCI4
Fig. 8-31. Drug-induced hepatitis. This patient developed a hepatitis-like disease after treatment for tuberculosis with isoniazid.
CCII , mushrooms, phosphorus
Senecio or Crotalaria alkaloids
Fig. 8-32. Massive hepatic necrosis induced by acetaminophen.
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Fig. 8-33. Drug-induced chronic hepatitis. Liver changes in this patient treated with methyldopa resemble those of chronic hepatitis.
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.
ALCOHOLIC LIVER DISEASES
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
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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 macronodular.
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 trichrome—stained slide zone 3 shows periventricular fibrosis extending between hepatocytes.
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 content.
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AUTOIMMUNE LIVER DISEASES 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 antibody—positive; (2) liver-kidney microsomal antibody—positive; and (3) liver-pancreas antibody—positive (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.
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A
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.
BILIARY OBSTRUCTION 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.
Congenital • Atresia • Agenesis Gallstones Inflammation/Fibrosis • Primary sclerosing cholangitis • Bacterial cholangitis • Surgical stricture
Tumors • Carcinoma of head of pancreas • Carcinoma of ampulla of Vater • Carcinoma of common bile ducts • Lymphoma of hilar lymph nodes
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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 obstruction.
Fig. 8-54. Bile infarct. Dissolution of liver cells is a late consequence of chronic biliary obstruction.
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CIRRHOSIS 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 Hemochromatosis Wilson disease a,-antitrypsin deficiency Galactosemia 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.
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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 carcinoma.
TUMOR-LIKE CONDITIONS AND TUMORS 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).
A
B
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.)
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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 cell—thick 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 -
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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 cell–thick 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 cell–thick 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 cell—thick 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.
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(acinar), and scirrhous (Figs. 8-71 and 8-72). Irrespective of its growth pattern, hepatocellular carcinoma has a poor prognosis. 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.
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B
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.
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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 stones.
DISEASES OF THE GALLBLADDER 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 disease. 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 cholecystitis.
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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, 1994. 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. Definition—classification—histopathology—immunopathogenesis. 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.
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DEVELOPMENTAL AND GENETIC DISORDERS 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.
A
B
Fig. 9-2. Cyst of the pancreas. A, These cysts, which may be multiple, usually are asymptomatic. B, Cyst is lined by cuboidal epithelium.
Fig. 9-4. Diffuse nesidioblastosis. The irregularly shaped islet is attached to a small duct, forming a ductuloinsular complex.
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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.
PANCREATITIS 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 cells.
Fig. 9-7. Interstitial pancreatitis. The interstitial spaces, which appear dilated because of edema, contain a few inflammatory cells.
Fig. 9-9. Acute hemorrhagic pancreatitis. The pancreas has been completely obliterated by blood.
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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 section.
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.
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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.
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TUMORS OF THE EXOCRINE PANCREAS 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 mucin—rich 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
A B
Fig. 9-19. Serous cystadenoma. A, The tumor is well circumscribed. B, On cross section it appears microcystic.
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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.
A
B
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.
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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.
A
Fig. 9-26. Carcinoma of the tail of the pancreas. The tumor invades the spleen.
B
C
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 ring—like cells in small clusters. There is a moderate desmoplastic reaction.
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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.
A
B
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.
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A
B
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.
TUMORS OF THE ENDOCRINE PANCREAS 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 pancreas.
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 polypeptide—secreting tumor); (5) gastrinoma; (6) VIPoma (vasoactive intestinal polypeptide-secreting tumor); (7) nonfunctioning tumors; and (8) ectopic hormone—secreting 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.
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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.
DIABETES MELLITUS 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 -
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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.
A
Fig. 9-41. Type I diabetes (IDDM). The islet cells stain with fluorescein-labeled anti-islet autoantibodies typically found in patients with IDDM.
B
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.
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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 clusters.
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, 1994. 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.
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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.
DISEASES OF THE PITUITARY GLAND Hypopituitarism 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.
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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 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 acini.
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 cell—PRL 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 Oncocytoma Unclassified adeno
Percentage 7.2 6.4 0.4 26.5 3.7 I.3 1.7 9.9 1.5 2.1 1.4 1.0 9.3 12.7 13.1 1.8
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.
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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-eosin—stained 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. A
Fig. 10-8. Pituitary adenoma. On cross section the tumor nodule is sharply demarcated from the normal pituitary. B
C
Fig. 10-9. Pituitary adenomas A, Acidophilic. B, Basophilic. C, Chromophobic. A
B
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").
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A
B
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.
DISEASES OF THE THYROID GLAND 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.
A
B
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.
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B A
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.
Thyroiditis
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
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A
B
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) Hashimoto
Riedel
Clinical Features Common finding at autopsy; asymptomatic 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)
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A
B
C
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. 10-19).
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
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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 (arrow).
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 hemorrhage.
Fig. 10-21. Follicular adenoma, microfollicular pattern. Tumor cells form small
