Pathology

1 In the 25th week of pregnancy, a G1P0 woman develops increased blood pressure (160/95) and proteinuria. Physical examination demonstrates generalized edema, and serum chemistries demonstrate hyperuricemia and increased concentrations of liver enzymes. Which of the following usually provides definitive therapy for this patient's medical condition A. Anti-hypertensive medical therapy B. Delivery C. Low dose aspirin D. Oxygen supplementation E. Renal dialysis Explanation: The correct answer is B. The woman has preeclampsia, the features of which include proteinuria and increased blood pressure. A wide variety of other features of preeclampsia can also be seen, including excessive weight gain, generalized edema, ascites, hyperuricemia, hypocalciuria, increased plasma concentration of von Willebrand factor and cellular fibronectin, reduced plasma concentration of anti-thrombin III, thrombocytopenia, increased hematocrit, increased liver enzymes, intrauterine growth retardation, and intrauterine hypoxia. Modern theories suggest that the true primary lesion may involve the endothelium, and that medical control of hypertension (choice A) actually only treats a small part of the syndrome. At present, the only definitive therapy is delivery of the baby, and obstetricians often play a delicate game trying to delay delivery for a premature baby's sake as long as possible while judging the severity of the preeclampsia and its immediate risks to mother and fetus. Low dose aspirin (choice C) may have a modest effect in preventing pre-eclampsia, but this is not yet well established. Oxygen supplementation (choice D) is used in some cases of cerebral hemorrhage secondary to preeclampsia, but does not constitute definitive therapy. Renal dialysis (choice E) is usually not necessary in preeclampsia, although both renal cortical necrosis and renal tubular necrosis can occasionally occur in this disorder. A baby is born with a large red, raised discoloration of the face that persists into adulthood. This type of lesion ismost likely a component of which of the following syndromes? A. Arnold Chiari malformation

2 B. Dandy-Walker malformation C. Neurofibromatosis D. Sturge-Weber disease E. Tuberous sclerosis Explanation: The correct answer is D. The lesion is a port wine stain, which is a vascular lesion that, unlike the more common strawberry nevus, does not usually regress with age. These lesions can be a component of Sturge-Weber disease, which can also include similar vascular lesions of the meninges (leptomeningeal angiomatosis) and sometimes cutaneous angiomatosis at other sites. Arnold Chiari malformations (choice A) are a cluster of related brain and spinal cord malformations in which there is a downward displacement of the cerebellar vermis and tonsils into the foramen magnum. Dandy-Walker malformation (choice B) includes a distended fourth ventricle with a hypoplastic (or absent) cerebellum. Neurofibromatosis (choice C) includes benign and malignant peripheral nerve lesions and café au lait spots. Tuberous sclerosis (choice E) includes cortical tubers, adenoma sebaceum of the skin, pancreatic cysts, renal angiomyolipomas, and cardiac rhabdomyomas. Renal biopsy demonstrates concentric, laminated thickening of arteriolar walls due to proliferation of smooth muscle cells. This process is best described by which of the following terms? A. Atherosclerosis B. Hyaline arteriolosclerosis C. Hyperplastic arteriolosclerosis D. Mönckeberg's arteriosclerosis E. Polyarteritis nodosa Explanation: The correct answer is C. The "onion skinning" morphology of these arterioles is a feature of hyperplastic arteriolosclerosis. Affected vessels may also show necrotizing arteriolitis with acute vessel wall necrosis accompanied by fibrin deposition. This type of vessel change is a hallmark of severe (malignant) hypertension, and can damage arterioles throughout the body, notably in the kidneys, intestine, and gall bladder. Atherosclerosis (choice A) would produce luminal narrowing by plaques. Hyaline arteriolosclerosis (choice B) would produce partial replacement of arterial walls by homogeneous, pink

3 material. Mönckeberg's arteriosclerosis (choice D) is characterized by medial calcification of smaller arteries. Polyarteritis nodosa (choice E) is characterized by focal acute inflammation of smaller arteries. Two bone marrow aspirates are studied under the microscope. One is taken from an adult with Hemoglobin SS disease (sickle cell anemia) and the other is from an adult with normal Hemoglobin A. The marrow aspirate from the patient with sickle cell anemia could be identified due to its increased A. fat B. iron stores C. medullary bone D. megakaryocytes E. myeloid:erythroid ratio Explanation: The correct answer is B. Adults with sickle cell disease have undergone decades of accelerated RBC formation and destruction, leading to accelerated erythropoiesis in the bone marrow. Consequently the bone marrow becomes hyperplastic, with marked increases in the number of normoblasts (erythroblasts) at the expense of marrow fat and marrow bone (choices A and C). Although the white cell and megakaryocyte lines are undiminished (choices D and E), there is a marked increase in RBC precursors and iron stores. Iron storage increases as a consequence of both chronic transfusions and increased dietary absorption; these increased iron stores can be appreciated with a Prussian blue stain. Ultrasound examination of a developing fetus demonstrates a fluid-filled sac at the base of the fetus' spine that connects to the spinal canal and apparently contains part of the spinal cord. A dietary deficiency of which of the following is most strongly associated with this type of lesion? A. Calcium B. Folate C. Iron D. Vitamin C E. Vitamin K Explanation: The correct answer is B. The lesion is a neural tube defect, probably a meningomyelocele, in which both meninges and spinal cord herniate through a bony vertebral defect. These defects most commonly occur in the

4 lumbosacral region, typically resulting in motor and sensory deficits in the lower extremities, and bowel and bladder dysfunction. This condition is now known to be associated with low maternal folate during the first three to four weeks of pregnancy, a time when many women may be unaware of their pregnancy. It is now recommended that all women of childbearing age consume at least 400 µg of folic acid daily. Calcium deficiency (choice A) can cause osteoporosis and osteopenia. Iron deficiency (choice C) can cause iron deficiency anemia. Vitamin C deficiency (choice D) can cause scurvy. Vitamin K deficiency (choice E) can cause a bleeding diathesis. A 30-year-old patient presents to a clinician because of intermittent, severe headaches accompanied by perspiration, palpitations, and pallor. Blood pressure on the initial examination was within normal limits, but, when the patient came in later with a headache, it was 180/135 mm Hg. Urinary vanillylmandelic acid (VMA) levels were elevated. Roughly, what percentage of the tumors causing this pattern is malignant? A. 1% B. 10% C. 50% D. 90% E. 99% Explanation: The correct answer is B. The tumor is a pheochromocytoma that intermittently secretes epinephrine and other vasoactive amines, producing episodes of elevated blood pressure accompanied by headache. This is the tumor to associate with the rule of the 10's: 10% malignant, 10% bilateral, 10% extra-adrenal, 10% calcify, 10% occur in kids, and 10% are familial. It is also a favorite target on examinations, although the incidence is quite low. An 82-year-old man develops a round, fluid-filled cystic structure on the back of his knee that limits the knee's mobility. This most likely represents an enlargement of which of the following structures? A. Deep infrapatellar bursa B. Prepatellar bursa C. Semimembranous bursa D. Superficial infrapatellar bursa E. Suprapatellar bursa

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Explanation: The correct answer is C. The lesion is commonly called a Baker's cyst, and anatomically represents an enlarged semimembranous bursa. Baker's cysts are more commonly seen at the extremes of age. The deep infrapatellar bursa (choice A) is on the anterior aspect below the knee. The prepatellar bursa (choice B) is anterior to the patella. The superficial infrapatellar bursa (choice D) is on the anterior aspect of the leg below the knee. The suprapatellar bursa (choice E) is on the anterior aspect of the thigh above the knee.

Biopsy of a 4 mm rough, tan, and slightly raised skin lesion on the face of a 65-year-old man demonstrates atypical basal cells with eosinophilic cytoplasm but persistent intercellular bridges. The stratum corneum is thickened and parakeratosis is present; the remainder of the epidermis is thinned. Which of the following features would probably additionally be seen in the dermis? A. Benign nevus cells B. Blue-gray elastic fibers C. Large numbers of spindle-shaped fibroblasts D. Malignant nevus cells E. Touton giant cells Explanation: The correct answer is B. The lesion described is an actinic keratosis, which is a common premalignant lesion caused by solar damage, which also characteristically damages the elastic fibers (changing their color in stained tissue to blue-gray) of the superficial dermis. Benign nevocellular nevus cells (choice A) are found in common moles (nevocellular nevi). Large numbers of spindle-shaped fibroblasts (choice C) are found in dermatofibromas. Malignant nevus cells (choice D) are found in melanoma. Touton giant cells (choice E) are found in xanthomas.

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A 50-year-old man consults a physician because of a lesion on his nose. On examination, a fleshcolored lesion about 1 cm in diameter, with a rolled edge and central ulceration, is observed. Which of the following is the most likely diagnosis? A. Basal cell carcinoma B. Eczema C. Psoriasis D. Urticaria E. Verruca vulgaris Explanation: The correct answer is A. The description is typical for basal cell carcinoma. These skin cancers typically occur on sun-exposed areas of the head, neck, and upper trunk. Basal cell carcinoma only rarely metastasizes, but can become locally mutilating if neglected. When located on the face, it may be difficult to adequately excise without damaging facial structures. Eczema (choice B) typically involves a larger area of skin and may cause dryness, discoloration, and thickening of the involved area. Blistering, erythema, or oozing may also be observed. Psoriasis (choice C) is characterized by erythematous plaques with a silvery surface. Urticaria (choice D) causes transient, nonpitting, erythematous wheals. Verruca vulgaris (choice E), the common wart, causes well-demarcated verrucous papules, often on the hands.

A patient with respiratory symptoms undergoes bronchoalveolar lavage. Which of the following findings would be most suggestive that congestive heart failure is the cause of the symptoms? A. Ciliated bronchial epithelial cells B. Encapsulated pairs of small cocci C. Hemosiderin-laden macrophages D. Rhomboid-shaped crystals E. Single hat-shaped structures that stain with silver stains

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Explanation: The correct answer is C. Hemosiderin-laden macrophages are sometimes called "heart failure cells" because they are so often seen in congestive heart failure. The congestive heart failure causes increased pulmonary capillary pressure with tiny hemorrhages. The pulmonary alveolar macrophages phagocytize the dead erythrocytes and retain the iron from the hemoglobin in the form of hemosiderin. Ciliated bronchial epithelial cells (choice A) are a normal finding. The cocci described in choice B are pneumococcus, and can cause pneumonia. Choice D describes Charcot-Leyden crystals, found in allergic asthma. Choice E describes the Pneumocystis organism, which can infect AIDS patients.

An adult presents to a physician because of repeated episodes of fainting. EKG fails to disclose an arrhythmia. Echocardiogram shows a mass in the left atrium that is acting like a "ball valve" to produce intermittent obstruction of flow. Which of the following would most likely be seen on microscopic examination of the resected mass? A. Benign myxoid tumor B. Benign tumor with gland formation C. Benign tumor with striated muscle differentiation D. Malignant tumor with gland formation E. Malignant tumor with striated muscle differentiation Explanation: The correct answer is A. The most common primary cardiac tumor of adults is the benign atrial myxoma. 90% of these lesions involve the left atrium, where they can produce intermittent obstruction when they flop onto the mitral valve. Resection is curative. Neither benign (choice B, adenomas) nor malignant (choice D, adenocarcinomas) primary glandular tumors usually involve the heart. If adenocarcinoma is seen, suspect metastatic disease. The rhabdomyoma is the benign tumor with striated muscle differentiation (choice C) that can involve the heart.

8 This tumor is the most common cardiac tumor of children. Rhabdomyosarcomas are malignant tumors with striated muscle differentiation (choice E) and typically involve the head and neck or uterus.

A patient with long-standing, progressive congestive heart failure dies in respiratory distress. The lungs at autopsy are 3 times their normal weight. Histologically, the alveoli show a proteinaceous granular precipitate, engorged alveolar capillaries, and hemosiderin-laden macrophages. Other inflammatory cells are inapparent. Which of the following is the most likely diagnosis? A. Candida pneumonia B. Pneumococcal pneumonia C. Pneumocystis pneumonia D. Pulmonary edema E. Pulmonary infarction Explanation: The correct answer is D. These are the characteristic findings of pulmonary edema. The edema fluid is apparent as a proteinaceous granular precipitate after histologic processing of the tissue. Hemosiderin-laden macrophages in the tissue, called "heart failure cells," are the end result of ingestion of red blood cells by alveolar macrophages. Pulmonary edema develops in heart failure when the pulmonary venous pressure rises and the capacity for the tissue to reabsorb the fluid into the venous system is exceeded. In Candida pneumonia (choice A), fungal hyphae and spores would be described. In pneumococcal pneumonia (choice B), gram-positive cocci (Streptococcus pneumoniae) would be described. In Pneumocystis pneumonia (choice C), hat-shaped, silver-stained cysts would be described. In pulmonary infarction (choice E), ischemic necrosis of alveoli would be described.

A 3-year-old child is brought to the emergency room by her concerned parents. They state the girl has been complaining of a severe headache and has had two episodes of vomiting. On physical examination, there is bilateral papilledema and an impaired level of consciousness. Emergency contrast CT scan demonstrates displacement of the ventricular system by a multilocular "mass" with

9 well-defined white high-attenuation rings around black low-attenuation centers. The lesion involves the cerebellum. To which of the following conditions i this lesion most likely related? A. Bacteremia following tooth extraction B. Bacterial meningitis C. Lung abscess D. Otitis media E. Sinusitis Explanation: The correct answer is D. The child has a cerebellar abscess. Abscess of the brain can be caused by any of the choices listed, but about 60% are related to middle ear infection. Cerebellar abscess is specifically associated with middle ear infection. Bacteremia following tooth extraction (choice A) and blood borne bacteria from lung abscess (choice C) are relatively uncommon causes of intracranial abscess. Subdural empyema in infants is usually a complication of bacterial meningitis (choice B). Both middle ear infections and sinusitis (choice E) can cause frontal and temporal lobe abscesses.

Ophthalmoscopic examination of a 5-year-old child demonstrates a retinal angioma. This finding should raise the possibility of which of the following syndromes? A. Neurofibromatosis type I B. Neurofibromatosis type II C. Sturge-Weber disease D. Tuberous sclerosis E. Von Hippel-Lindau disease Explanation: The correct answer is E. Retinal angioma may be a "visible" manifestation of von HippelLindau disease. This syndrome is characterized by tumors and/or cysts that can involve many structures: retinal angiomas, capillary

10 hemangioblastomas of the CNS (notably cerebellum, but also many other sites), renal carcinoma (up to 30% of cases, may occur at a young age or may be bilateral), and angiomatous or cystic lesions of many other organs (epididymis, kidneys, liver, pancreas, lung, skin). Neurofibromatosis type I (choice A) is characterized by Lisch nodules of the iris, café-au-lait macules, and peripheral nerve tumors. Neurofibromatosis type II (choice B) is characterized by acoustic neural tumors and café-au-lait macules. Sturge-Weber disease (choice C) is characterized by port-wine nevus of the head and leptomeningeal angiomatosis. Tuberous sclerosis (choice D) is characterized by adenoma sebaceum of the skin and cortical tubers.

A 45-year-old man presents to a physician with back pain and facial pain. Physical examination demonstrates coarse facial features and kyphosis. Laboratory examination is remarkable for elevated alkaline phosphatase. X-ray studies demonstrate skull thickening with narrowing of foramina, and bowing of the femur and tibia. Bone biopsy reveals a mosaic pattern of bone spicules with prominent osteoid seams. Which of the following neoplasms occurs at an increased frequency in patients with this disorder? A. Astrocytoma B. Hodgkin's lymphoma C. Meningioma D. Non-Hodgkin's lymphoma E. Osteosarcoma Explanation: The correct answer is E. The phrase "mosaic pattern" of newly formed woven bone is a specific tip-off for Paget's disease of bone, and is not seen in other bone conditions. The clinical and radiologic presentation are typical; an increased hat size may also be a clue. In its early stages, Paget's disease is characterized by osteolysis, producing patchwork areas of bone resorption with bizarre, large osteoclasts. In the middle stage of the disease, secondary osteoblastic activity compensates with new bone formation, producing the mosaic pattern. In late Paget's, the bones are dense and osteosclerotic. Paget's disease is suspected to be related to

11 prior viral infection, but the cause remains mysterious. Complications include myelophthisic anemia, high output cardiac failure, pain secondary to nerve compression, deformities secondary to skeletal changes, and in about 1% of patients, osteosarcoma or other sarcoma, typically involving the jaw, pelvis, or femur. An increased incidence of astrocytomas (choice A) is associated with tuberous sclerosis. Hodgkin's lymphoma (choice B) is usually a disease of young adults, although older patients may have the lymphocyte-depleted form. Meningiomas (choice C) are mostly benign tumors that affect adults, especially females. There may be an association with breast cancer, possibly related to high estrogen states. Non-Hodgkin's lymphoma (choice D) is more common in AIDS and other immunodeficiency states, although the incidence in the immunocompetent is increasing.

A 28-year-old man discovers a mass in his neck while buttoning his shirt collar. Physical examination reveals a 2 cm mass in one thyroid lobe, which is “cold” on scintiscan. Aspiration of the nodule demonstrates small “solid balls” of neoplastic follicular cells. Careful examination of these tissue balls reveals that they contain microscopic blood vessels and fibrous stroma in their centers. Which of the following is the most likely diagnosis? A. Follicular carcinoma B. Hashimoto's disease C. Medullary carcinoma D. Papillary carcinoma E. Thyroid adenoma Explanation: The correct answer is D. The distinctive cell balls described are broken-off papillary clusters, and are considered pathognomic for papillary carcinoma of the thyroid. This is the most common form of thyroid carcinoma. It tends to present in the 3rd to 5th decade and shows a modest female predominance. Despite its propensity for local lymphatic intrusion (which may cause multifocality of tumor in the thyroid or cervical lymph node metastases), the tumor generally has an excellent prognosis with 90% 20-year survival.

12 Follicular carcinoma (choice A) is characterized by follicular cells and colloid on aspiration, and cannot be reliably distinguished from thyroid adenoma. Distinctive features of Hashimoto's disease (choice B) on aspiration are lymphocytes, plasma cells, and macrophages. The most distinctive feature of medullary carcinoma (choice C) on aspiration is the presence of amyloid. Thyroid adenoma (choice E) shows follicular cells and colloid on aspiration, and cannot be reliably distinguished from follicular carcinoma.

A 1-year-old child with mental retardation, seizures, and facial angiofibromas develops repeated episodes of syncope. Echocardiogram reveals a mass in the left ventricle producing intermittent obstruction. Pathologic examination of the resected mass demonstrates a cardiac rhabdomyoma. Which of the following lesions would this patient most likely also have? A. Acoustic neuromas B. Berry aneurysm C. Cortical tubers D. Meningiomas E. Neurofibromas Explanation: The correct answer is C. The disease is tuberous sclerosis, in which cortical hamartomas known as tubers can be associated with facial angiofibromas, cardiac rhabdomyomas (probably actually a skeletal muscle hamartoma), seizures, mental retardation, and astrocytomas. Associate acoustic neuromas (choice A) with neurofibromatosis type II. Associate berry aneurysms (choice B) with adult polycystic kidney disease. Associate meningiomas (choice D) with breast cancer and, possibly, high estrogen states. Associate neurofibromas (choice E) with neurofibromatosis type I.

13 Endoscopy performed on a patient with persistent substernal pain despite antacid use demonstrates irregular erythematous patches several centimeters above the gastroesophageal junction. Biopsy of one of these lesions demonstrates epithelial metaplasia. Which of the following cell types was most likely observed in the involved areas? A. Ciliated columnar epithelium B. Cuboidal epithelium C. Keratinizing squamous epithelium D. Non-ciliated columnar epithelium E. Non-keratinizing squamous epithelium Explanation: The correct answer is D. The medical condition is Barrett's esophagus, in which the normally non-keratinizing squamous epithelium (choice E) of the esophagus undergoes metaplasia to gastric or intestinallike epithelium composed of non-ciliated columnar epithelial cells. Barrett's esophagus typically develops in the setting of chronic gastroesophageal reflux, and significantly increases the risk of later development of adenocarcinoma of the distal esophagus. Ciliated columnar epithelium (choice A) is found in the respiratory tract. Cuboidal epithelium (choice B) is found in the kidney, peritoneal lining, and pleural lining. Keratinizing squamous epithelium (choice C) is found in skin. Non-keratinizing squamous epithelium (choice E), in addition to being the normal epithelium of the esophagus, is found in mouth, nose, and vagina.

An elderly man comes to medical attention because of anemia and multiple infections. Physical examination is remarkable for hepatosplenomegaly. An automated blood count demonstrates pancytopenia. Review of the peripheral smear by a hematologist demonstrates rare, distinctive, neoplastic white cells covered by fine, hairlike projections. Which of the following characteristics would likely be associated with these cells? A. Birbeck granules B. Elevated leukocyte alkaline phosphatase

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C. Philadelphia chromosome D. Positive tartrate-resistant acid phosphatase E. Production of Bence-Jones proteins Explanation: The correct answer is D. The disease is hairy cell leukemia, which, unlike most forms of leukemia, is characterized by pancytopenia rather than increased numbers of circulating cells. This disease tends to affect older men and the characteristic cells (which are not always obviously “hairy”) are positive for tartrate-resistant acid phosphatase (TRAP). Associate Birbeck granules (choice A) with Langerhans cell histiocytosis (histiocytosis X). Associate elevated leukocyte alkaline phosphatase (choice B) with myeloid metaplasia. Associate Philadelphia chromosome (choice C) with chronic myeloid leukemia (and occasionally with acute lymphocytic leukemia). Associate production of Bence-Jones proteins (choice E) with multiple myeloma.

A pathologist reports the presence of koilocytotic atypia in a cervical biopsy from a 25-year-old woman. On the basis of this histopathologic finding, which of the following conditions does this patient most likely have? A. Chlamydia infection B. Gonococcal infection C. Herpes simplex virus infection D. Human papillomavirus infection E. Severe squamous dysplasia F. Squamous cell carcinoma in situ G. Trichomonas infection Explanation: The correct answer is D. Human papillomavirus (HPV) is the cause of condyloma, which may occur on any

15 mucocutaneous surface of the male or female external genitalia. Squamous epithelial cells infected by HPV show characteristic nuclear and cytoplasmic changes, referred to as koilocytosis or koilocytotic atypia, on tissue sections or Pap smears. These changes allow the diagnosis of HPV infection to be made. The nuclei are condensed and have irregular contours, acquiring a "raisin-like" appearance; cytoplasm vacuolization creates a perinuclear halo. HPV is a crucial etiopathogenetic factor in the development of squamous cell carcinoma of the cervix. Not all types of HPV, however, are associated with cervical carcinoma. High-risk types are 16 and 18, whereas the most frequent low-risk types are 6 and 11. HPV types 16 and 18 express proteins (E6 and E7) that inactivate p53 and Rb tumor suppressor genes, leading to neoplastic transformation. Although HPV infection is a risk factor for the development of squamous dysplasia and carcinoma, koilocytosis is not equivalent to severe squamous dysplasia (choice E) or carcinoma in situ (choice F). In the current Bethesda system for diagnosing and reporting Pap smears, koilocytosis is likened to a low-grade squamous intraepithelial lesion, ie, mild atypia. Remember that koilocytosis (koilocytotic atypia) = HPV infection, not severe dysplasia/carcinoma. Chlamydia infection (choice A) of the genital tract is due to Chlamydia trachomatis. Approximately half a million cases of Chlamydia urethritis (nongonococcal urethritis) are reported each year in the U.S. The infection is often symptomatic in men and clinically silent in women. In addition to urethritis and lymphogranuloma venereum, C. trachomatis causes trachoma, an eye infection endemic in some developing countries. Gonococcal infection (choice B), or gonorrhea, is due to Neisseria gonorrhoeae, a gram-negative diplococcus. There are about 700,000 cases of gonorrhea each year in the U.S. Infection by herpes simplex virus (choice C) is the most common sexually transmitted disease in the U.S. It is generally due to herpes simplex type 2 virus and manifests with painless blisters, which subsequently break down, forming painful erosions. Trichomonas infection (choice G) is also sexually transmitted. It is caused by Trichomonas vaginalis, an anaerobic flagellated protozoon, and manifests with itching and a frothy white discharge in women. The infection is usually asymptomatic in men. There are approximately 3 million cases of T. vaginalis infection each year in the U.S.

A 52-year-old woman has long-standing rheumatoid arthritis (RA) and is being treated with corticosteroids and

16 nonsteroidal anti-inflammatory drugs (NSAIDs). Which of the following cardiac complications may arise in this clinical setting? A. Constrictive pericarditis B. Dilated cardiomyopathy C. Hypersensitivity myocarditis D. Hypertrophic cardiomyopathy E. Restrictive cardiomyopathy Explanation: The correct answer is E. What links rheumatoid arthritis (RA) to restrictive cardiomyopathy? Amyloid! Long-standing inflammatory conditions such as RA are associated with deposition of a form of amyloid known as AA (amyloid-associated protein), which may involve kidneys, heart, liver, skeletal muscle, and skin, for example. Amyloid deposition in the myocardium results in decreased compliance and impaired diastolic filling, i.e., restrictive cardiomyopathy. The myocardium has a rigid and waxy texture. This form of amyloid, as well as any other biochemical form, can be visualized on tissue section by staining with Congo red, which acquires a characteristic apple-green birefringence under polarized light. Constrictive pericarditis (choice A) is due to any pathologic process that results in fibrous thickening of the pericardium, with resultant impaired compliance. Clinically, therefore, this condition manifests with a picture similar to restrictive cardiomyopathy because of impaired diastolic filling. Constrictive pericarditis is usually caused by previous episodes of acute pericarditis, especially hemorrhagic, suppurative, and caseous pericarditis. Dilated cardiomyopathy (choice B) is characterized by massive ventricular dilatation and may be caused by genetic alterations, myocarditis, toxic insults (alcohol), metabolic disorders (hemochromatosis), etc. Most cases are idiopathic. The main pathophysiologic alteration is impaired contractility. You may be tempted to think that this patient is prone to developing hypersensitivity myocarditis (choice C), but this form of myocardial disease has been reported after treatment with some antihypertensive agents, antibiotics, and diuretics -- not with corticosteroids or NSAIDs. Furthermore, myocarditis manifests acutely with arrhythmias and heart failure, and chronically with dilated cardiomyopathy and congestive heart failure.

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Most cases of hypertrophic cardiomyopathy (choice D) are familial and due to mutations in one of the genes encoding proteins of the sarcomeres, most frequently β-myosin heavy chain. This form of cardiomyopathy leads to asymmetric hypertrophy of the left ventricle, with predominant thickening of the interventricular septum. In this case, too, impairment of ventricular compliance is the basic mechanism leading to reduced diastolic filling and heart failure.

Following an upper respiratory infection, a 7-year-old child develops multiple petechial hemorrhages over her entire body. Her mother takes her to the physician, who does a complete blood count, revealing marked thrombocytopenia. Which of the following diagnoses is most appropriate for this individual? A. Bernard-Soulier syndrome B. Idiopathic thrombocytopenic purpura C. Thrombasthenia D. Thrombotic thrombocytopenic purpura E. Von Willebrand's disease Explanation: The correct answer is B. The process described is commonly called acute idiopathic thrombocytopenic purpura (ITP), even though the autoimmune basis has been clearly established (some authors use "immune thrombocytopenic purpura,” so that the initials still work). The thrombocytopenia in this disorder appears to be secondary to splenic destruction of opsonized platelets, and usually follows a viral upper respiratory tract infection or exanthem. The acute form of ITP is usually explosive, but self-limited; a chronic form in adults may respond to steroid therapy or splenectomy. In Bernard-Soulier syndrome (choice A), platelets are unable to adhere to collagen. Thrombasthenia (choice C), is associated with a functional defect in platelets (they do not aggregate). In thrombotic thrombocytopenic purpura (choice D), platelets are consumed in intravascular platelet microthrombi. In von Willebrand's disease (choice E), deficient von Willebrand factor produces platelet dysfunction, but

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A 20-year-old man has a testicular mass, which on orchiectomy shows a malignant tumor with yolk sac differentiation. Which of the following tumor markers would probably be most useful in monitoring the patient for recurrent or metastatic disease? A. Alpha-fetoprotein B. Bombesin C. Carcinoembryonic antigen (CEA) D. Prostate-specific antigen (PSA) E. S-100 Explanation: The correct answer is A. Of the markers listed, alpha-fetoprotein is the best marker for nonseminomatous germ cell tumors of the testes, such as this patient's yolk sac tumor. Alpha-fetoprotein is also a good marker for hepatocellular carcinomas. Bombesin (choice B) is a marker for neuroblastoma, small cell carcinomas, gastric carcinomas, and pancreatic carcinomas. CEA (choice C, carcinoembryonic antigen) is a nonspecific marker, but has the advantage that it is produced by about 70% of colorectal and pancreatic cancers. It is also produced by some gastric and breast cancers. PSA (choice D, prostatic specific antigen) is a marker for prostatic carcinoma. S-100 (choice E) is a marker for melanoma, neural tumors, and astrocytomas.

A 61-year-old woman with leukemia abruptly develops an intensely itchy rash. Physical examination demonstrates multiple erythematous patches of the distal arms and legs, some of which involve the palms and soles. Some of the patches show central clearing with surrounding erythematous rings. Which of the following is the most likely diagnosis? A. Erythema migrans chronicum B. Erythema multiforme

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C. Kaposi's sarcoma D. Psoriasis E. Urticaria Explanation: The correct answer is B. The most specific clue in the description is the presence of erythematous patches with central clearing, known clinically as "target lesions," which are associated with erythema multiforme. Both erythema multiforme and its severe, life-threatening version, known as Stevens-Johnson syndrome, are produced by immune complex deposition in dermal blood vessels. In approximately 50% of patients, no specific precipitating cause is identified. In the remainder of patients, however, a variety of causes have been implicated, including certain infections (herpes simplex, enteroviruses, Mycoplasma pneumoniae, Chlamydia, histoplasmosis), drugs (penicillin, sulfonamides, phenytoin, aspirin, corticosteroids, cimetidine, allopurinol, oral contraceptives), neoplasia (leukemia, lymphoma, multiple myeloma, internal malignancy), sarcoidosis, and foods (notably emulsifiers in margarine). Erythema migrans chronicum (choice A) also produces an annular erythematous rash with central clearing, but usually affects the thigh, groin, and axilla; it is associated with Lyme disease. Kaposi's sarcoma (choice C) causes purple lesions with no target lesions. Psoriasis (choice D) causes erythematous plaques with silvery scale but does not produce target lesions. Urticaria (choice E) causes wheals that are intensely pruritic, but does not produce target lesions.

A jaundiced, 43-year-old alcoholic male presents to the emergency room complaining of bright red blood in his last two stools. He denies pain on defecation or changes in his bowel habits. Which of the following would be the most likely finding on sigmoidoscopic examination? A. Colorectal carcinoma B. Diverticulitis C. Hemorrhoids D. Hyperplastic polyps

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E. Ulcerative colitis Explanation: The correct answer is C. The patient's jaundice indicates that he has significant alcoholic liver disease. Hepatic fibrosis or cirrhosis both produce vascular injury and portal hypertension, which leads to the development of portosystemic shunts-most typically causing esophageal varices, caput medusae, and hemorrhoids. Bright red blood in stools is a classic presentation of hemorrhoids. Colorectal carcinoma (choice A) generally develops in an older population, and produces occult blood loss rather than frankly bloody stools. Although diverticulosis (choice B) may be an asymptomatic condition, diverticulitis is associated with significant abdominal distress, which may be accompanied by blood loss and diarrhea and/or constipation. Hyperplastic polyps (choice D) are asymptomatic, non-neoplastic, polypoid growths, generally less than 5mm in diameter. They do not produce bleeding or any increased risk of carcinoma. Ulcerative colitis (choice E) is an inflammatory bowel disease that produces mucoid diarrhea accompanied by lower abdominal pain and cramps. Painless bleeding is unlikely to be ulcerative colitis.

SPACE FOR PHOTO The cells and related structures indicated by the arrow are reduced in number in which of the following disorders?

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A. Hirschsprung's disease B. Kwashiorkor C. Polio D. Schwannoma E. Scurvy Explanation: The correct answer is A. These are autonomic motor ganglion cells and nerve fibers surrounded by smooth muscle of the muscularis externus. The close proximity of the smooth muscle and the orientation of the fibers are keys to deciding that this is a myenteric plexus. Ganglion cells usually have a spherical cell body, although they are considered multipolar, with a round nucleus and a prominent "owl's eye" nucleolus. The nerve fibers typically appear wavy in light microscopic views. The reduction in number of these cells and associated fibers leads to the lack of peristaltic control in the small and large bowel. The aganglionic bowel segment is narrowed because the lack of peristalsis keeps stool from moving into that segment. The distal rectum is always involved, and the lesion can extend proximally anywhere from a few centimeters past the rectum all the way up to the small intestine. The bowel proximal to the lesion is usually dilated.

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In kwashiorkor (choice B), a condition of extreme malnutrition, protein-secreting cells atrophy. The cells in this figure do not contain protein granules. In such cells, the rough endoplasmic reticulum would also be abundant, and this is not evident here. In polio (choice C), motor neurons are lost from the anterior horn of the spinal cord. Schwann cells produce schwannomas (choice D). Schwann cells are present among the nerve fibers, but they are not abundant, and they are not specifically affected in Hirschsprung's disease. Vitamin C deficiency leads to scurvy (choice E), characterized by abnormal collagen hydroxylation. The wavy fibers do not have the typical bundle arrangement of collagen, but rather, have an appearance that is characteristic of nerve.

A 38-year-old female presents to the physician with complaints of excessive thirst and urination for the past 4 weeks. Her appetite has been normal and she has not had diarrhea. Blood chemistry shows mildly elevated glucose and glucagon. Physical examination reveals tenderness in the left upper quadrant and an erythematous necrotizing skin eruption on her legs. Radiographic studies show a tumor in the pancreas. Which of the following cells is responsible for this lesion? A. Acinar cell B. Alpha cell C. Beta cell D. Delta cell E. G cell Explanation: The correct answer is B. The symptoms described are typical for a patient with glucagon excess. Glucagon is secreted by alpha cells of the pancreatic islets of Langerhans. Increased levels are rare, usually due to carcinoma (70%) or adenoma (30%) of the islets. Two-thirds of patients with carcinoma have liver metastasis at the time of diagnosis. Increased glucagon causes a syndrome similar to diabetes mellitus, due to antagonism of insulin effects. Patients also have migratory skin rashes, alopecia, hyperpigmentation of the skin, and glossitis. Diagnosis is made by measuring glucagon.

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The acinar cell (choice A), the main exocrine cell of the pancreas, contains digestive enzymes. Increases in the release of these enzymes (especially amylase and lipase) occur with pancreatitis. Acute pancreatitis is considered an emergent medical condition. Chronic pancreatitis is associated with fibrosis and atrophy of the acinar structures. Beta cells (choice C) are responsible for insulin release. An adenoma of beta cells (insulinoma) would cause hyperinsulinism. 70% are solitary and 10% are multiple. Insulinomas cause hypoglycemia, dizziness, confusion, and excessive sweating. Glucose needs to be given promptly to avoid coma and death. Diagnosis is made by finding increased insulin and hypoglycemia. Delta cells (choice D) are islet cells that secrete somatostatin. Tumors producing increased somatostatin are usually malignant. Clinically, a diabetes mellitus-like syndrome occurs along with diarrhea. Diagnosis is made from elevated serum somatostatin levels, but can be difficult because of the hormone's short half-life. The G cell (choice E) is the islet cell that secretes gastrin. Gastrin excess is usually associated with gastrinomas, 70% of which are malignant. Zollinger-Ellison syndrome ensues, causing low gastric and duodenal pH, mucosal ulceration, and diarrhea. Diagnosis is made from high serum gastrin levels.

The patient shown in the pedigree above did poorly in school, then became increasingly forgetful and irrational. Over a period of years, he developed ataxia and began posturing. Eventually, he was demented and unable to care for himself. At autopsy, extensive cortical demyelination is observed. Microscopic examination of the areas of demyelination reveals numerous macrophages containing crystals that stain a light brown color with toluidine blue. This presentation is probably due to a deficiency of A. arylsulfatase A B. galactocerebroside β-galactosidase C. glucocerebrosidase D. hexosaminidase A E. sphingomyelinase

24 Explanation: The correct answer is A. The presentation and autopsy findings are consistent with metachromatic leukodystrophy. The crystals in the macrophages that stained brown with toluidine blue are sulfatides, which accumulate in this disorder. The color shift seen in the toluidine blue stain is termed metachromasia (hence the term metachromatic leukodystrophy). The cause of metachromatic leukodystrophy is deficiency of arylsulfatase A. Galactocerebroside β-galactosidase (choice B) deficiency produces Krabbe's disease. In this disorder, multinucleated cells derived from macrophages (globoid cells) are seen around blood vessels. Electron microscopy of the macrophages reveals the presence of linear inclusions. Glucocerebrosidase (choice C) deficiency results in Gaucher's disease, characterized by accumulation of glucocerebrosides. Gaucher's cells are cells distended with material that resembles crumpled tissue paper. Hexosaminidase A (choice D) deficiency is associated with Tay Sachs disease, characterized by accumulation of GM2 ganglioside in the central and autonomic nervous systems. Sphingomyelinase deficiency (choice E) produces Niemann-Pick disease, in which sphingomyelin accumulates, especially in cells of the mononuclear phagocytic system.

An IV drug abuser develops an aggressive form of nephrotic syndrome that does not respond to steroids. A renal biopsy is performed. Which of the following histological diagnoses will most likely be made from the biopsy tissue? A. Focal segmental glomerulosclerosis B. IgA nephropathy C. Lipoid nephrosis D. Membranoproliferative glomerulonephritis E. Membranous glomerulonephritis Explanation: The correct answer is A. You should be aware of a specific association between focal segmental glomerulosclerosis and both IV drug abuse and HIV nephropathy. This disorder usually presents as an

25 aggressive form of nephrotic syndrome; the prognosis is generally poor, with rare cases responding to steroid therapy. Histologically, there is focal (affecting only some glomeruli) and segmental (affecting only a portion of each glomerular capillary tuft) sclerosis and hyalinization with focal deposits of IgM and C3. In IgA nephropathy (choice B), there are mesangial deposits of IgA and mesangial proliferation. Lipoid nephrosis (choice C), or minimal change disease, is the most frequent cause of nephrotic syndrome in children. Light microscopic changes are generally minimal or absent. Membranoproliferative glomerulonephritis (choice D) is characterized by proliferation of glomerular cells and thickening of capillary loops. It is not particularly associated with drug abuse. Membranous glomerulonephritis (choice E) is an important cause of nephrotic syndrome in adults, characterized by diffuse thickening of the walls of glomerular capillaries.

A 54-year-old man comes to the emergency room four hours after the onset of severe chest pain radiating to the left arm. Examination of the levels of which of the following serum markers would best aid in the evaluation of this individual's chest pain? A. Aspartate aminotransferase (AST) B. Creatine kinase-MB isozyme (CK-MB) C. Lactate dehydrogenase-1 isozyme (LDH1) D. Total creatine kinase E. Troponin Explanation: The correct answer is E. Cardiac-specific forms of troponin-T and troponin-I are not normally detectable in the blood, but may increase 20-fold following a myocardial infarction. Slight amino acid differences between cardiac and skeletal muscle forms of troponin allow specific association of the troponin with heart muscle damage, rather than skeletal muscle damage. Troponin is the best serum marker for myocardial infarction for the first eight hours, and because levels of the cardiac troponins remain elevated for 7-10 days, it may be useful for evaluation of small, CK-negative infarctions for several days after the event. AST (choice A) is a nonspecific marker for cardiac, liver, and skeletal muscle. Due to its lack of specificity, it is

26 much less useful as a marker of myocardial infarction than CK-MB or troponin . Both total creatine kinase (choice D) and its more cardiac specific form CK-MB (choice B) are most useful from 8 to 24 hours after infarction, typically with peaks at 12-18 hours. LDH1(choice C), the cardiac specific form of lactic dehydrogenase, is the test of choice 2 to 7 days after a suspected myocardial infarction.

A 37-year-old man presents with an unexplained 30 lb. weight loss and poorly-defined ill health over the past six months. The physician suspects cancer, but does not know which type of primary tumor is involved. A panel of tumor markers is ordered, demonstrating markedly elevated alpha-fetoprotein. Which of the following tumors would most likely produce an elevation of this substance? A. Colorectal and pancreatic cancers B. Liver and yolk sac tumors C. Melanoma, neural tumors, and astrocytomas D. Neuroblastoma, small cell carcinomas, gastric carcinomas, and pancreatic carcinomas E. Prostatic carcinoma Explanation: The correct answer is B. Alpha-fetoprotein (AFP) is a normal fetal protein that can be produced in the adult by hepatocellular carcinomas and nonseminomatous germ cell tumors of the testes. The germ cell tumors most likely to be associated with elevated AFP are yolk sac tumors and mixed germ cell tumors with a yolk sac component. CEA is associated with both colorectal and pancreatic cancers (choice A). S100 is the tumor marker associated with melanoma, neural tumors, and astrocytomas (choice C). Bombesin is a tumor marker associated with neuroblastoma, small cell carcinomas, gastric carcinomas, and pancreatic carcinomas (choice D). Prostate specific antigen is often markedly elevated in cases of prostatic carcinoma (choice E).

27 A 75-year-old female with a long history of cigarette smoking is found to have a small tumor at the periphery of her right upper lobe. Initially, the tumor was believed to be a Stage I carcinoma (T1 NO MO), but after surgery it is found to be Stage II (T1 N1 MO). What is found at surgery that changed the staging? A. Involvement of the chest wall B. Positive bronchial lymph nodes C. Small cell histology D. Tumor at the carina E. Tumor size greater than 3 cm Explanation: The correct answer is B. Although it is nearly impossible to memorize the staging rules for all the different kinds of tumors, there are several basic principles common to all. The TNM stage of a tumor is determined by the tumor size and extent (T for tumor), lymph node involvement (N for nodes), and metastasis (M for metastasis). N0 always means no lymph nodes are involved. An NI lesion has positive nodes, and only choice B, positive bronchial lymph nodes, changes the patient's nodal status. Involvement of the chest wall is a feature of tumor size and extent-thus, it is a component of the T in TNM-staging. T2 lesions involve the chest wall (choice A). Histological features of the tumor, such as small cell morphology (choice C), are not considered in tumor stage, but rather in tumor grade. Small cell tumors are considered high-grade carcinomas. Tumor extending to the carina reflects the tumor size and extent-thus, it is a component of the T in TNM-staging: T3 lesions involve the carina (choice D). Tumor size is a consideration in the T of TNM-staging. Tumors greater than 3 cm (choice E) are at least T2 lesions.

A 30-year-old pregnant woman of Jewish descent presents to a physician with painful oral ulcers. Physical examination demonstrates widespread erosions of her mucous membranes. Close examination reveals a friable mucosa, but no well-defined aphthous ulcers. Biopsy of perilesional mucosa demonstrates acantholysis; direct immunofluorescence demonstrates an intraepidermal band of IgG and C3. Which of the following is the most

28 likely diagnosis? A. Bullous pemphigoid B. Dermatitis herpetiformis C. Herpes simplex I D. Herpes simplex II E. Pemphigus vulgaris Explanation: The correct answer is E. This is pemphigus vulgaris, in which autoantibody directed against transmembrane cadherin adhesion molecules induces acantholysis (breakdown of epithelial cell-cell connections) with resulting intraepidermal blister formation. It may develop spontaneously or following triggers such as drugs (thiols, penicillamine), physical injury (burns), cancer, pregnancy, other skin diseases, and emotional stress. Pemphigus vulgaris is a relatively rare blistering disease; it is seen more commonly in patients with Jewish or Mediterranean heritage. In addition to the usually prominent oral ulcers, uncomfortable skin erosions can also occur when the blisters rupture rapidly and are not observed. The epidermis at the edge of these erosions is often easily disrupted by sliding pressure (Nikolsky sign). Bullous pemphigoid (choice A) is characterized by deeper blisters, occurring at the dermalepidermal junction. Dermatitis herpetiformis (choice B) is characterized by severe, intense pruritus and groups of papules and vesicles. Herpes simplex I (choice C) or II (choice D) can show multinucleated giant cells on scrapings of the ulcer base.

A 35-year-old woman with a ten-year history of vague arthralgias and fevers has antibody studies performed that demonstrate autoantibody directed against double-stranded DNA. Later, she develops a photosensitive rash over her nose and cheeks. Biopsy of the rash would most likely demonstrate which of the following? A. Fibroblastic-like cells in a storiform pattern B. Granular complement and IgG at the dermal-epidermal junction C. Multiple horn cysts

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D. Pautrier microabscesses E. Sawtooth dermal/epidermal junction Explanation: The correct answer is B. The disease is systemic lupus erythematosus; the most useful specific clue to the diagnosis is the presence of autoantibodies to double-stranded DNA (one type of antinuclear antibody or ANA). The characteristic "butterfly" facial rash of lupus is due to deposition of antibodies and complement at the dermal/epidermal junction. Cells similar to fibroblasts growing in a storiform ("pinwheel") pattern (choice A) are characteristic of dermatofibrosarcoma protuberans, a slow-growing type of fibrosarcoma. Horn cysts (choice C) are lamellated collections of keratin that occur in seborrheic keratoses, a type of benign epithelial tumor of the skin. Pautrier microabscesses (choice D) are a feature of mycosis fungoides, a cutaneous T-cell lymphoma. A sawtooth dermal/epidermal junction (choice E) is a feature of lichen planus, an inflammatory skin condition.

A demented elderly man is transferred from a nursing home to the emergency department because of generalized edema. The patient is afebrile, and his blood pressure is within normal limits. Blood samples are sent to the laboratory for analysis, yielding a serum creatinine of 2.0 mg/dL and serum urea nitrogen of 65 mg/dL. Which of the following is the most likely diagnosis? A. Acute tubular necrosis B. Congestive heart failure C. Low protein intake D. Prostatic hyperplasia E. Severe liver disease Explanation: The correct answer is D. This elderly patient with oliguria and edema has high serum creatinine (normal 0.6-1.2

30 mg/dL) and high serum urea nitrogen (normal 7-18 mg/dL). The serum urea nitrogen/serum creatinine ratio is 32, greater than the normal 12 to 20 for individuals on a normal diet. High ratios with elevated creatinine levels can occur in postrenal obstruction (probably benign prostatic hyperplasia in this elderly man) and in prerenal azotemia that is superimposed on renal disease (but not pure prerenal azotemia, as would occur in simple congestive heart failure). The reason for the high ratio is that urine flow obstruction causes back pressure on the renal tubules, favoring back diffusion of urea into the blood from the tubules. Acute tubular necrosis (choice A) is typically characterized by a low urea nitrogen/creatinine ratio. Congestive heart failure (choice B) generally causes prerenal azotemia. This is associated with a high urea nitrogen/creatinine ratio, mainly because of an increased plasma urea nitrogen, with the creatinine level usually near normal. Low protein intake (choice C) and severe liver disease (choice E) can cause a low urea nitrogen/creatinine ratio.

A 30-year-old male presents to the dermatologist with silvery, scaling plaques on his elbows and knees. His mother has been afflicted with the same condition in the past. The most likely diagnosis is A. acne rosacea B. acne vulgaris C. pemphigus vulgaris D. pityriasis rosea E. psoriasis vulgaris Explanation: The correct answer is E. Psoriasis vulgaris usually appears on the nails, knees, elbows, and scalp. It does not generally affect the mucous membranes. Lesions are well-demarcated coral-colored plaques with a white or silvery scale (classic clue). Histologically, epidermal hyperplasia causing thickening and lengthening of the rete ridges is apparent, as is thinning of the epidermis over the dermal papillae. There is a recognized genetic component to this condition. Peak incidence is at age 30.

31 Here's a point-saving strategy: It is easy to get confused on this question because of the similar looking answer choices, especially under time pressure. Be extra careful in such cases to mark the proper choice on your answer grid. Acne rosacea (choice A) affects the central face. Erythema, telangiectasias, acneform lesions (papules, cysts, pustules), and rhinophyma (telangiectasias and hyperplasia of nasal soft tissue) are found in various combinations. It is common from ages 30-50. Women are affected three times more frequently than men, but the syndrome is more severe in the latter. Acne vulgaris (choice B) causes comedones, papules, and cysts. It may be related to hormones, drugs, diet, irritants, and genetic factors. Allergy to Propionibacterium acnes has been found to contribute to this condition. Pemphigus vulgaris (choice C) starts with small vesicles, usually on the oral or nasal mucosa, then spreads to other parts of the body. Bullae are delicate and flaccid. The condition is due to autoantibodies to intercellular junctions between keratinocytes. Nikolsky's sign (production of blistering by light stroking or rubbing of the skin) is positive. Pemphigus is most common from ages 40-60. Pityriasis rosea (choice D) presents first with a red, scaling, "herald patch" approximately 4 cm in diameter. It is followed within days by eruption in a "short-sleeve turtleneck" distribution. The classic clue to the diagnosis is the appearance of crops of small, pink, oval patches in a "fir tree configuration" on the flexural lines.

A 38-year-old man presents to the emergency room with multiple arm and leg fractures following a minor fall. Physical examination reveals a slight weakness of facial muscles on the left. A complete blood count shows a mild anemia. X-ray studies reveal a generalized bony widening with partial obliteration of marrow spaces. The patient's disorder is most likely due to abnormal function of which of the following cell types? A. Granulocytic stem cells B. Megakaryocytes C. Plasma cells D. Osteoblasts E. Osteoclasts

32 Explanation: The correct answer is E. The disease is osteopetrosis (Albers-Schonberg disease), which is a group of hereditary diseases in which impaired osteoclast function leads to reduced bone resorption. The abnormal osteoclasts frequently are enlarged, with bizarre shapes. The bones become thick and brittle; other features include anemia secondary to marrow loss and cranial nerve deficits secondary to narrowing of bony ostea. An autosomal recessive, severe form of the disease produces death in childhood. A relatively benign, autosomal dominant form presents in adulthood. Abnormal proliferation of granulocytic stem cells (choice A) can produce myelocytic leukemias. Megakaryocyte abnormalities (choice B) can produce platelet disorders, but not deficient bone resorption. In multiple myeloma, neoplastic plasma cells (choice C) can cause lytic bone lesions characterized by excessive resorption of bone. Abnormally low osteoclast, rather than osteoblast (choice D), function is apparently the problem in osteopetrosis.

A four-year-old child develops steroid-sensitive nephrotic syndrome. Renal biopsy studies demonstrate normal appearing glomeruli by light microscopy and fusion of foot processes by electron microscopy. Which of the following proteins would be present in the urine in the highest concentration? A. Albumin B. Ceruloplasmin C. IgA D. Kappa light chain E. Lambda light chain Explanation: The correct answer is A. Severe, persistent, proteinuria is required to produce nephrotic syndrome. The renal histology described is that of minimal change disease, which produces a proteinuria that is relatively selective for albumin.

33 Ceruloplasmin (choice B) is a copper-binding normal serum protein that could be spilled into the urine in many types of glomerulonephritis that cause nonselective proteinuria. IgA (choice C) can also be spilled into urine in non-selective proteinurias. Both kappa and lambda light chains (choices D and E) are freely filtered at the glomerulus, but are usually present in only trivial amounts in patients who do not have multiple myeloma or related diseases.

A 24-year-old man has progressive, painless enlargement of neck lymph nodes. Routine chest film followed by CT scan demonstrates marked enlargement of mediastinal nodes. No nodules are seen in the liver or lungs. When evaluating the biopsy of one of the involved nodes, the pathologist should specifically look for which of the following? A. Abnormal plasma cells B. Giant platelets C. Immature neutrophil precursors D. Melanin pigment E. Reed-Sternberg cells Explanation: The correct answer is E. This is a classic presentation of Hodgkin's disease, which is a form of lymphoma characterized by neoplastic proliferation of Reed-Sternberg cells admixed with variable numbers of reactive lymphocytes, neutrophils, and eosinophils. The cell of origin of the Reed-Sternberg cells is still disputed. These cells have a distinctive appearance with a large double nucleus that contains paired, large, nucleoli which are often red, producing an "owl's eye" effect. Abnormal plasma cells (choice A) would be a feature of multiple myeloma or some B-cell leukemias and lymphomas, which are not as likely in this patient. Giant platelets (choice B) are a feature seen in several myeloproliferative disorders (notably essential thrombocytopenia), which do not cause lymphadenopathy. Immature neutrophil precursors (choice C) would most likely be a feature of a myeloid leukemia, which would not cause a lymphadenopathy.

34 Melanin pigment (choice D) would be a feature of malignant melanoma, which would probably have caused lung or liver metastases if it were at such an advanced stage as to have caused massive lymphadenopathy.

A surgeon operates on a patient with a pheochromocytoma involving the adrenal gland. He requests examination of intraoperative frozen sections by the pathology laboratory. Which of the following criteria can be used to determine if the lesion is benign or malignant? A. Blood vessel invasion B. Cannot be determined by microscopic examination C. Hemorrhage and necrosis D. Nuclear pleomorphism E. Number of mitoses Explanation: The correct answer is B. Pheochromocytomas, and their related counterparts in extra-adrenal sites called paragangliomas, are notorious because the only reliable indicator of metastatic potential is the presence of distant metastases. Very malignant-appearing tumors may not metastasize and benignappearing tumors may produce metastases. In practice, there is no way for the pathologist to make the decision on frozen (or permanent) section analysis unless metastasis has already occurred and can be documented. These tumors should all be considered "potentially malignant."