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FIGURE III-43

III-44. The answer is C. (Chap. 96) Ninety percent of persons with nonseminomatous germ cell tumors produce either α-fetoprotein (AFP) or beta human chorionic gonadotropin (β-hCG); in contrast, persons with pure seminomas usually produce neither. These tumor markers are present for some time after surgery; if the presurgical levels are high, 30 days or more may be required before meaningful postsurgical levels can be obtained. The half-lives of AFP and β-hCG are 6 days and 1 day, respectively. After treatment, unequal reduction of β-hCG and AFP may occur, suggesting that the two markers are synthesized by heterogeneous clones of cells within the tumor; thus, both markers should be followed. β-hCG is similar to luteinizing hormone except for its distinctive beta subunit.

III-45. The answer is D. (Chap. 96) Testicular cancer occurs most commonly in the second and third decades of life. The treatment depends on the underlying pathology and the stage of the disease. Germ cell tumors are divided into seminomatous and nonseminomatous subtypes. Although the pathology of this patient’s tumor was seminoma, the presence of α-fetoprotein (AFP) is suggestive of occult nonseminomatous components. If there are any nonseminomatous components, the treatment follows that of a nonseminomatous germ cell tumor. This patient therefore has a clinical stage I nonseminomatous germ cell tumor. Because his AFP returned to normal after orchiectomy, there is no obvious occult disease. However, between 20% and 50% of these patients will have disease in the retroperitoneal lymph nodes. Numerous trials have indicated no overall survival difference in this cohort between observation and retroperitoneal lymph node dissection (RPLND). Because of the potential side effects of RPLND, the choice of surveillance or RPLND is based on the pathology of the primary tumor. If the primary tumor shows no evidence for lymphatic or vascular invasion and is limited to the testis, then either option is reasonable. If lymphatic or vascular invasion is present or the tumor extends into the tunica, spermatic cord, or scrotum, then surveillance should not be offered. Either approach should cure more than 95% of patients. Radiation therapy is the appropriate choice for stage I and stage II seminoma. It has no role in nonseminomatous lesions. Adjuvant chemotherapy is not indicated in early-stage testicular cancer. Hormonal therapy is effective for prostate cancer and receptor-positive breast cancer but has no role in testicular cancer. Positron emission tomography may be used to locate viable seminoma in residua which mandates surgical excision or biopsy.

III-46. The answer is A. (Chap. 97) Approximately 10% of women with ovarian cancer have a somatic mutation in one of two DNA repair genes, BRCA1 (chromosome 17q12-21) or BRCA2 (chromosome 13q12-13). Individuals inheriting a single copy of a mutant allele have a very high incidence of breast and ovarian cancer. Most of these women have a family history that is notable for multiple cases of breast or ovarian cancer (or both), although inheritance through male members of the family can camouflage this genotype through several generations. The most common malignancy in these women is breast carcinoma, although women harboring germ-line BRCA1 mutations have a marked increased risk of developing ovarian malignancies in their forties and fifties with a 30% to 50% lifetime risk of developing ovarian cancer. Women harboring a mutation in BRCA2 have a lower penetrance of ovarian cancer with perhaps a 20% to 40% chance of developing this malignancy, with onset typically in their fifties or sixties. Women with a RCA2 mutation also are at slightly increased risk of pancreatic cancer. Screening studies in this select population suggest that current screening techniques, including serial

evaluation of the CA-125 tumor marker and ultrasound, are insufficient at detecting early-stage and curable disease, so women with these germ-line mutations are advised to undergo prophylactic removal of their ovaries and fallopian tubes typically after completing childbearing and ideally before ages 35 to 40 years. Early prophylactic oophorectomy also protects these women from subsequent breast cancer with a reduction of breast cancer risk of approximately 50%.

III-47. The answer is C. (Chap. 97) Endometrial carcinoma is the most common gynecologic malignancy in the United States. Most are adenocarcinomas. Development of these tumors is a multistep process with estrogen playing an important early role in driving endometrial gland proliferation. Relative overexposure to this class of hormones is a risk factor for the subsequent development of endometrial tumors. In contrast, progestins drive glandular maturation and are protective. Hence, women with high endogenous or pharmacologic exposure to estrogens, especially if unopposed by progesterone, are at high risk for endometrial cancer. Obese women, women treated with unopposed estrogens, and women with estrogen-producing tumors (e.g., granulosa cell tumors of the ovary) are at higher risk for endometrial cancer. In addition, treatment with tamoxifen, which has anti-estrogenic effects in breast tissue but estrogenic effects in uterine epithelium, is associated with an increased risk of endometrial cancer. The majority of women with tumors of the uterine corpus present with postmenopausal vaginal bleeding caused by shedding of the malignant endometrial lining. Premenopausal women often present with atypical bleeding between typical menstrual cycles. These signs typically bring a woman to the attention of a health care professional, and hence the majority of women present with early-stage disease in which the tumor is confined to the uterine corpus. For patients with disease confined to the uterus, hysterectomy with removal of the fallopian tubes and ovaries results in approximately 90% 5-year survival.

III-48. The answer is B. (Chap. 98) Bone pain resulting from metastatic lesions may be difficult to distinguish from degenerative disease, osteoporosis, or disk disease in elderly individuals. Generally, these patients present with insidious worsening localized pain without fevers or signs of infection. In contrast to pain related to disk disease, the pain of metastatic disease is worse when the patient is lying down or at night. Neurologic symptoms related to metastatic disease constitute an emergency. Lung, breast, and prostate cancers account for approximately 80% of bone metastases. Thyroid carcinoma, renal cell carcinoma, lymphoma, and bladder carcinoma may also metastasize to bone. Metastatic lesions may be lytic or blastic. Most cancers cause a combination of both, although prostate cancer is predominantly blastic. Either lesion may cause hypercalcemia, although lytic lesions more commonly do this. Lytic lesions are best detected with plain radiography. Blastic lesions are prominent on radionuclide bone scans. Treatment and prognosis depend on the underlying malignancy. Bisphosphonates may reduce hypercalcemia, relieve pain, and limit bone resorption.

III-49. The answer is B. (Chap. 98) Metastatic tumors of bone are more common than primary bone tumors. Prostate, breast, and lung primaries account for 80% of all bone metastases. Tumors from the kidney, bladder, and thyroid and lymphomas and sarcomas also commonly metastasize to bone. Metastases usually spread hematogenously. In decreasing order, the most common sites of bone metastases include the vertebrae, proximal femur, pelvis, ribs, sternum, proximal humerus, and skull. Pain is the most common symptom. Hypercalcemia may occur with bone destruction. Lesions may be osteolytic, osteoblastic, or both. Osteoblastic lesions are associated with a higher level of alkaline phosphatase. Colon cancer typically metastasizes initially via lymphatic spread, making the liver and

lungs common sites of secondary disease.

III-50. The answer is C. (Chap. 98) The most common malignant tumors of bone are plasma cell tumors related to multiple myeloma. The bone lesions are lytic lesions caused by increased osteoclast activity without osteoblastic new bone formation. Of the nonhematopoietic tumors, the most common are osteosarcoma, chondrosarcoma, Ewing’s sarcoma, and malignant fibrous histiocytoma. Osteosarcomas account for 45% of bone sarcomas and produce osteoid (unmineralized bone) or bone. They typically occur in children, adolescents, and adults up to the third decade of life. The “sunburst” appearance of the lesion and Codman’s triangle in this young man are indicative of an osteosarcoma. Whereas osteosarcomas have a predilection for long bones, chondrosarcomas are more often found in flat bones, especially the shoulder and pelvic girdles. Osteosarcomas are radioresistant. Long-term survival with combined chemotherapy and surgery is 60% to 80%. Chondrosarcomas account for 20% to 25% of bone sarcomas and are most common in adults in the fourth to sixth decades of life. They typically present indolently with pain and swelling. They are often difficult to distinguish from benign bone lesions. Most chondrosarcomas are chemoresistant, and the mainstay of therapy is resection of the primary as well as metastatic sites.

III-51. The answer is B. (Chap. 99) Patients with cancer from an unknown primary site present a common diagnostic dilemma. Initial evaluation should include history, physical examination, appropriate imaging, and blood studies based on gender (e.g., prostate-specific antigen in men, mammography in women). Immunohistochemical staining of biopsy samples using antibodies to specific cell components may help elucidate the site of the primary tumor. Although many immunohistochemical stains are available, a logical approach is represented in Figure III-51. Additional tests may be helpful based on the appearance under light microscopy or the results of the cytokeratin stains. In cases of cancer of unknown primary, cytokeratin staining is usually the first branch point from which the tumor lineage is determined. Cytokeratin is positive in carcinoma because all epithelial tumors contain this protein. Subsets of cytokeratin, such as CK7 and CK20, may be useful to determine the likely etiology of the primary tumor. Leukocyte common antigen, thyroglobulin, and thyroid transcription factor 1 are characteristic of lymphoma, thyroid cancer, and lung or thyroid cancer, respectively. α-Fetoprotein staining is typically positive in germ cell, stomach, and liver carcinoma.

FIGURE III-51

III-52. The answer is C. (Chap. 99) The patient presents with symptoms suggestive of ovarian cancer. Although her peritoneal fluid is positive for adenocarcinoma, further speciation cannot be done. Surprisingly, the physical examination and imaging do not show a primary source. Although the differential diagnosis of this patient’s disorder includes gastric cancer or another gastrointestinal malignancy and breast cancer, peritoneal carcinomatosis is most commonly caused by ovarian cancer in women even when the ovaries are normal at surgery. Elevated CA-125 levels or the presence of psammoma bodies is further suggestive of an ovarian origin, and such patients should receive surgical debulking and carboplatin or cisplatin plus paclitaxel. Patients with this presentation have a similar stage-specific survival compared with other patients with known ovarian cancer. Ten percent of patients with this disorder, also known as primary peritoneal papillary serous carcinoma, will remain disease free 2 years after treatment.

III-53. The answer is B. (Chap. 99) The patient is a young man with asymmetric hilar adenopathy. The

differential diagnosis would include lymphoma; testicular cancer; and, less likely, tuberculosis or histoplasmosis. Because of his young age, testicular examination and ultrasonography would be indicated, as would measurement of α-fetoprotein (AFP) or beta human chorionic gonadotropin (β-hCG), which are generally markedly elevated. In men with carcinoma of unknown primary source, AFP and β-hCG should be checked because the presence of testicular cancer portends an improved prognosis compared with possible primary sources. Biopsy would show lymphoma. The ACE level may be elevated but is not diagnostic of sarcoidosis. Sarcoidosis should not be considered likely in the presence of asymmetric hilar adenopathy. Thyroid disorders are not likely to present with unilateral hilar adenopathy. Finally, prostate-specific antigen is not indicated in this age category, and C-reactive protein would not differentiate any of the disorders mentioned above. Biopsy is clearly the most important diagnostic procedure.

III-54. The answer is E. (Chap. 100) Hypercalcemia is a common oncologic complication of metastatic cancer. Symptoms include confusion, lethargy, change in mental status, fatigue, polyuria, and constipation. Regardless of the underlying disease, the treatment is similar. These patients are often dehydrated because hypercalcemia may cause nephrogenic diabetes insipidus and are often unable to take fluids orally. Therefore, the primary management entails reestablishment of euvolemia. Often hypercalcemia resolves with hydration alone. Patients should be monitored for hypophosphatemia. Bisphosphonates are now the mainstay of therapy because they stabilize osteoclast resorption of calcium from the bone. However, their effects may take 1 to 2 days to manifest. Care must be taken in cases of renal insufficiency because rapid administration of pamidronate may exacerbate renal failure. When euvolemia is achieved, furosemide may be given to increase calciuresis. Nasal or subcutaneous calcitonin further aids the shift of calcium out of the intravascular space. Since the advent of bisphosphonates, calcitonin is only used in severe cases of hypercalcemia because of its rapid effect. Glucocorticoids may be useful in patients with lymphoid malignancies because the mechanism of hypercalcemia in these conditions is often related to excess hydroxylation of vitamin D. However, in this patient with prostate cancer, dexamethasone will have little effect on the calcium level and may exacerbate the altered mental status.

III-55. The answer is E. (Chap. 100) A variety of hormones are produced ectopically by tumors that may cause symptomatic disease. Eutopic production of parathyroid hormone (PTH) by the parathyroid gland is the most common cause of hypercalcemia. Hypercalcemia may rarely be produced by ectopic hyperparathyroid production but is most often caused by parathyroid hormone related protein (PTH-rp) production by squamous cell (head and neck, lung, skin), breast, genitourinary, and gastrointestinal tumors. This protein can be measured as a serum assay. Antidiuretic hormone (ADH), causing hyponatremia, is commonly produced by lung (squamous, small cell), gastrointestinal, genitourinary, and ovary tumors. Adrenocorticotropic hormone (ACTH), causing Cushing’s syndrome, is commonly produced by tumors in the lung (small cell, bronchial carcinoid, adenocarcinoma, squamous), thymus, pancreatic islet, and medullary thyroid carcinoma. Insulin-like growth factor secreted by mesenchymal tumors, sarcomas, and adrenal, hepatic, gastrointestinal, kidney, or prostate tumors may cause symptomatic hypoglycemia.

III-56. The answer is C. (Chap. 101) One of the better characterized paraneoplastic neurologic syndromes is cerebellar ataxia caused by Purkinje cell drop-out in the cerebellum; it is manifested by dysarthria, limb and gait ataxia, and nystagmus. Radiologic imaging reveals cerebellar atrophy. Many

antibodies have been associated with this syndrome, including anti-Yo, anti-Tr, and antibodies to the glutamate receptor. Although lung cancer, particularly small cell cancer, accounts for a large number of patients with neoplasm-associated cerebellar ataxia, those with the syndrome who display anti-Yo antibodies in the serum typically have breast or ovarian cancer. Cerebellar ataxia may also be seen in Hodgkin’s lymphoma in association with anti-Tr antibodies.

III-57. The answer is A. (Chap. e20) About 40% of patients with thymoma have another systemic autoimmune illness related to the thymoma. About 30% of patients with thymoma have myasthenia gravis, 5% to 8% have pure red blood cell (RBC) aplasia, and about 5% have hypogammaglobulinemia. Thymectomy results in the resolution of pure RBC aplasia in about 30% of patients but rarely benefits patients with hypogammaglobulinemia. Among patients with myasthenia gravis, about 10% to 15% have a thymoma. Thymectomy produces at least some symptomatic improvement in about 65% of patients with myasthenia gravis. In one large series, thymoma patients with myasthenia gravis had a better long-term survival from thymoma resection than did those without myasthenia gravis. Thymoma more rarely may be associated with polymyositis, systemic lupus erythematosus, thyroiditis, Sjögren’s syndrome, ulcerative colitis, pernicious anemia, Addison’s disease, scleroderma, and panhypopituitarism. In one series, 70% of patients with thymoma were found to have another systemic illness. Erythrocytosis caused by ectopic production of erythropoietin is often seen in conjunction with renal cell and hepatocellular carcinomas.

III-58. The answer is D. (Chap. e20) Thymoma is the most common cause of an anterior mediastinal mass in adults, accounting for about 40% of all mediastinal masses. The other major causes of anterior mediastinal masses are lymphomas, germ cell tumors, and substernal thyroid tumors. Carcinoid tumors, lipomas, and thymic cysts also may produce radiographic masses. After combination chemotherapy for another malignancy, teenagers and young adults may develop a rebound thymic hyperplasia in the first few months after treatment. Granulomatous inflammatory diseases (tuberculosis, sarcoidosis) can produce thymic enlargement. Thymomas are most common in the fifth and sixth decades of life, are uncommon in children, and are distributed evenly between men and women. About 40% to 50% of patients are asymptomatic; masses are detected incidentally on routine chest radiographs. When symptomatic, patients may have cough, chest pain, dyspnea, fever, wheezing, fatigue, weight loss, night sweats, or anorexia. Occasionally, thymomas may obstruct the superior vena cava. After a mediastinal mass has been detected, a surgical procedure is required for definitive diagnosis. An initial mediastinoscopy or limited thoracotomy can be undertaken to get sufficient tissue to make an accurate diagnosis. Fine-needle aspiration is poor at distinguishing between lymphomas and thymomas but is more reliable in diagnosing germ cell tumors and metastatic carcinoma. Thymomas and lymphomas require sufficient tissue to examine the tumor architecture to ensure an accurate diagnosis and obtain prognostic information. Thymomas are epithelial tumors, and all of them have malignant potential. It is not worthwhile to try to divide them into benign and malignant forms. Staging systems are based on degree of invasiveness and correlate with prognosis. About 65% of thymomas are encapsulated and noninvasive, and about 35% are invasive. Tumors that are encapsulated and non-invasive (stage 1) have a 96% 5-year survival after complete resection surgery.

III-59. The answer is D. (Chap. 103) Iron-deficiency anemia is a condition consisting of anemia and clear evidence of iron deficiency. It is one of the most prevalent forms of malnutrition. Globally, 50% of anemia is attributable to iron deficiency and accounts for approximately 841,000 deaths annually

worldwide. Africa and parts of Asia bear 71% of the global mortality burden; North America represents only 1.4% of the total morbidity and mortality associated with iron deficiency. Initially, a state of negative iron balance occurs during which iron stores become slowly depleted. Serum ferritin may decrease, and the presence of stainable iron on bone marrow preparation decreases. When iron stores are depleted, serum iron begins to fall. Total iron-binding capacity (TIBC) starts to increase, reflecting the presence of circulating unbound transferrin. When the transferrin saturation falls to 15% to 20%, hemoglobin synthesis is impaired. The peripheral blood smear reveals the presence of microcytic and hypochromic red blood cells. Reticulocytes may also become hypochromic. Reticulocyte numbers are reduced relative to the level of anemia, reflecting a hypoproduction anemia secondary to iron deficiency. Clinically, these patients exhibit the usual signs of anemia, which are fatigue, pallor, and reduced exercise capacity. Cheilosis and koilonychia are signs of advanced tissue iron deficiency. Some patients may experience pica, a desire to ingest certain materials, such as ice (pagophagia) and clay (geophagia).

III-60. The answer is C. (Chap. 103) (See Table III-60 on the following page.) The differential diagnosis of microcytic anemia includes iron deficiency, hemoglobinopathy (e.g., thalassemia), myelodysplastic syndromes (including sideroblastic anemia), and chronic inflammation. Inflammation can be distinguished from iron deficiency because iron deficiency typically includes a very low ferritin level (<50 μg/L) and iron binding saturation, but in inflammation, they are normal or increased. Any chronic inflammatory state may cause a hypoproliferative anemia caused by inadequate marrow utilization of iron related to hyperproduction of a number of cytokines, including tumor necrosis factor, interferon-gamma, and inter-leukin-1. The anemia of chronic disease may be normocytic/normochromic or microcytic. Serum iron and iron binding are normal to high in thalassemia and sideroblastic anemia. Folate deficiency causes macrocytic anemia.

TABLE III-60 Diagnosis of Microcytic Anemia

III-61. The answer is C. (Chap. 103) Progressive chronic kidney disease (CKD) is usually associated with a moderate to severe hypoproliferative anemia. The level of the anemia correlates with the stage of CKD. Red blood cells (RBCs) are typically normocytic and normochromic, and reticulocytes are decreased. The anemia is primarily caused by a failure of erythropoietin (EPO) production by the diseased kidney and a reduction in RBC survival. Polycystic kidney disease shows a smaller degree of EPO deficiency for a given level of renal failure. By contrast, patients with diabetes or myeloma have more severe EPO deficiency for a given level of renal failure. Assessment of iron status provides information to distinguish the anemia of CKD from other forms of hypoproliferative anemia and to guide management. Patients with the anemia of CKD usually present with normal serum iron, total iron-binding capacity, and ferritin levels. However, those maintained on chronic hemodialysis may develop iron deficiency from blood loss through the dialysis procedure. EPO therapy is effective in correcting the anemia of CKD. Iron must be replenished in patients with concomitant iron deficiency to ensure an adequate response to EPO therapy.

III-62. The answer is B. (Chap. 104, N Engl J Med 2009; 361:2309-2317) The most significant recent advance in the therapy of sickle cell anemia has been the introduction of hydroxyurea as a mainstay of therapy for patients with severe symptoms. Hydroxyurea increases fetal hemoglobin and may exert

beneficial effects on red blood cell (RBC) hydration, vascular wall adherence, and suppression of the granulocyte and reticulocyte counts. Hemoglobin F levels increase in most patients within a few months. Hydroxyurea should be considered in patients experiencing repeated episodes of acute chest syndrome or with more than three crises per year requiring hospitalization. The utility of this agent for reducing the incidence of other complications (priapism, retinopathy) is under evaluation, as are the long-term side effects. Hydroxyurea offers broad benefits to most patients whose disease is severe enough to impair their functional status, and it may improve survival. The main adverse effect is a reduction in white blood cell (WBC) count; dosage should be titrated to maintain a WBC count at 5000 to 8000/μL. WBCs and reticulocytes may play a major role in the pathogenesis of sickle cell crisis, and their suppression may be an important benefit of hydroxyurea therapy. A recent study demonstrated that non-myeloablative bone marrow transplantation in patients with sickle cell disease could produce a stable chimera that corrected RBC counts and reversed the sickle cell phenotype.

III-63. The answer is B. (Chap. 105) Serum cobalamin is measured by an enzyme-linked immunosorbent assay test and is the most cost-effective test to rule out deficiency. Normal serum levels are typically above 200 ng/L. In patients with megaloblastic anemia caused by cobalamin deficiency, the level is usually less than 100 ng/L. In general, the more severe the deficiency, the lower the serum cobalamin level. In patients with spinal cord damage caused by the deficiency, levels are very low even in the absence of anemia. Borderline low levels may occur in pregnancy in patients with megaloblastic anemia caused by folate deficiency. In patients with cobalamin deficiency sufficient to cause anemia or neuropathy, the serum methylmalonate (MMA) level is increased. Serum MMA and homocysteine levels have been proposed for the early diagnosis of cobalamin deficiency even in the absence of hematologic abnormalities or subnormal levels of serum cobalamin. Serum MMA levels fluctuate, however, in patients with renal failure. Mildly elevated serum MMA or homocysteine levels occur in up to 30% of apparently healthy volunteers and 15% of elderly subjects. These findings bring into question the exact cutoff points for normal MMA and homocysteine levels. It is also unclear at present whether these mildly increased metabolite levels have clinical consequences. Serum homocysteine is increased in both early cobalamin and folate deficiency but may also be increased in other conditions (e.g., chronic renal disease; alcoholism; smoking; pyridoxine deficiency; hypothyroidism; and therapy with steroids, cyclosporine, and other drugs). The red blood cell folate assay is a test of body folate stores. It is less affected than the serum assay by recent diet and traces of hemolysis. Subnormal levels occur in patients with megaloblastic anemia caused by folate deficiency but also in nearly two-thirds of patients with severe cobalamin deficiency. False-normal results may occur if a folate-deficient patient has received a recent blood transfusion or if a patient has an increased reticulocyte count. Serum pepsinogen may be low in patients with pernicious anemia.