Harrisons Principles of Internal Medicine Self-Assessment and Board Review 18th Ed.

SECTION III. Oncology and Hematology

ANSWERS

III-1.   The answers are 1—C, 2—E, 3—D, 4—A, and 5—B(Chap. e17) Patients with homozygous sickle cell disease have red blood cells (RBCs) that are less pliable and more “sticky” than normal RBCs. Vaso-occlusive crisis is often precipitated by infection, fever, excessive exercise, anxiety, abrupt changes in temperature, hypoxia, or hypertonic dyes. Peripheral blood smear will show the typical elongated, crescent-shaped RBCs. There is also a nucleated RBC at the bottom of the figure, which may occur attributable to increased bone marrow production. Howell-Jolly bodies, small nuclear remnants normally removed by the intact spleen, are seen in RBCs in patients after splenectomy and with maturation or dysplastic disorders characterized by excess production. Acanthocytes are contracted dense RBCs with irregular membrane projections that vary in width and length. They are seen in patients with severe liver disease and abetalipoproteinemia and in rare patients with McLeod blood group. Iron deficiency, often caused by chronic stool blood loss in patients with colonic polyps or adenocarcinoma, causes a hypochromic microcytic anemia characterized by small, pale RBCs (a small lymphocyte is present on the smear to assess RBC size). RBCs are never hyperchromic; if more than the normal amount of hemoglobin is made, the cells get larger, not darker. Fragmented red cells, or schistocytes, are helmet-shaped cells that reflect microangiopathic hemolytic anemia (e.g., thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, hemolytic uremic syndrome, scleroderma crisis) or shear damage from a prosthetic heart valve.

III-2.   The answer is A. (Chap. 57) This patient with anemia demonstrates a low mean cell volume, low mean cell hemoglobin, and low mean cell hemoglobin concentration. The peripheral smear demonstrates microcytic and hypochromic cells, which would be expected given these laboratory findings. In addition, there is marked variation in size (anisocytosis) and shape (poikilocytosis). These findings are consistent with severe iron-deficiency anemia, and serum ferritin would be expected to be less than 10 to 15 μg/L. A low haptoglobin level would be seen in cases of hemolysis, which can be intravascular or extravascular in origin. In intravascular hemolysis, the peripheral smear would be expected to show poikilocytosis with the presence of schistocytes (fragmented red blood cells [RBCs]). In extravascular hemolysis, the peripheral smear would typically shows spherocytes. Hemoglobin electrophoresis is used to determine the presence of abnormal hemoglobin variants. Sickle cell anemia is the most common form and demonstrates sickled RBCs. Thalassemias are also common inherited hemoglobinopathies. The peripheral smear in thalassemia often shows target cells. Glucose-6-phosphate dehydrogenase deficiency leads to oxidant-induced hemolysis with presence of bite cells or blister cells. Vitamin B12 deficiency leads to macrocytosis, which is not consistent with this case.

III-3.   The answer is C. (Chap. 57) The reticulocyte index and reticulocyte production index are useful in the evaluation of anemia to determine the adequacy of bone marrow response to the anemia. A normal reticulocyte count is 1% to 2%, and in the presence of anemia, this would be expected to rise to more than two to three times the normal value (the reticulocyte index). The reticulocyte index is calculated as Reticulocyte count × (Patient’s hemoglobin/Normal hemoglobin). In this case, the reticulocyte index would be 5.4%. A second correction is further necessary in this patient given the presence of polychromatophilic macrocytes on peripheral smear. This finding indicates premature release of reticulocytes from the bone marrow (“shift cells”), and thus these cells have a longer life span. It is recommended to further divide the reticulocyte index by a factor of 2, which is known as the reticulocyte production index. In this case, the value would be 2.7%.

III-4.   The answer is C. (Chap. 57) This blood smear shows fragmented red blood cells (RBCs) of varying size and shape. In the presence of a foreign body within the circulation (prosthetic heart valve, vascular graft), RBCs can become destroyed. Such intravascular hemolysis will also cause serum lactate dehydrogenase to be elevated and hemoglobinuria. In isolated extravascular hemolysis, there is no hemoglobin or hemosiderin released into the urine. The characteristic peripheral blood smear in splenomegaly is the presence of Howell-Jolly bodies (nuclear remnants within red blood cells). Certain diseases are associated with extramedullary hematopoiesis (e.g., chronic hemolytic anemias), which can be detected by an enlarged spleen, thickened calvarium, myelofibrosis, or hepatomegaly. The peripheral blood smear may show teardrop cells or nucleated RBCs. Hypothyroidism is associated with macrocytosis, which is not demonstrated here. Chronic gastrointestinal blood loss will cause microcytosis, not schistocytes.

III-5.   The answer is A. (Chap. 81) Although cigarette smoking is the greatest modifiable risk factor for the development of cancer, the most significant risk factor for cancer in general is age. Two-thirds of all cancers are diagnosed in individuals older than 65 years, and the risk of developing cancer between the ages of 60 and 79 years is one in three in men and one in five in women. In contrast, the risk of cancer between birth and age 49 years is one in 70 for boys and men and one in 48 for girls and women. Overall, men have a slightly greater risk of developing cancer than women (44% vs. 38% lifetime risk).

III-6.   The answer is A. (Chap. 81) The cause of cancer death differs across the life span. In women who are younger than 20 years of age, the largest cause of cancer death is leukemia. Between the ages of 20 and 59 years, breast cancer becomes the leading cause of cancer death. However, lung cancer is the leading cause of cancer death after the age of 60 years and is overall the number one cause of cancer death in women.

III-7.   The answer is B. (Chap. 81) Although tumor burden is certainly a major factor in determining cancer outcomes, it is also important to consider the functional status of the patient when considering the therapeutic plan. The physiologic stresses of undergoing surgical interventions, radiation therapy, and chemotherapy can exhaust the limited reserves of a patient with multiple medical problems. It is clearly difficult to adequately measure the physiologic reserves of a patient, and most oncologists use performance status measures as a surrogate. Two of the most commonly used measures of performance status are the Eastern Cooperative Oncology Group (ECOG) and Karnofsky performance status. The ECOG scale provides a grade between 0 (fully active) and 5 (dead). Most patients are considered to have adequate reserve for undergoing treatment if the performance status is 0 to 2, with a grade 2 indicating someone who is ambulatory and capable of all self-care but unable carry out work activities. These individuals are up and about more than 50% of waking hours. A grade 3 performance score indicates someone who is capable of only limited self-care and is confined to a bed or chair more than 50% of waking hours. The Karnofsky score ranges from 0 (dead) to 100 (normal) and is graded at 10-point intervals. A Karnofsky score of less than 70 also indicates someone with poor performance status.

III-8.   The answer is D. (Chap. 81) Tumor markers are proteins produced by tumor cells that can be measured in the serum or urine. These markers are neither sensitive nor specific enough to be useful for diagnosis or screening of cancer. However, in an individual with a known malignancy, rising or falling levels may be helpful for determining disease activity and response to therapy. Common tumor markers with associated diseases are shown in Table III-8below. Of the tumor pairs listed, only human chorionic gonadotropin is correctly paired with its association with gestational trophoblastic disease.

TABLE III-8 Tumor Markers

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III-9.   The answer is C. (Chap. 83) Cancer occurs when a single cell acquires a series of genetic mutations that allow the cell to proliferate without regulation. The clonal nature of cancer is a key feature that allows a malignancy to be differentiated from hyperplasia, in which polyclonality is seen. Significant research has occurred over the past decades that allows us to understand the genetic causes of cancer in greater detail, and new research is providing a growing knowledge of cancer of any number of cell types with the hopes that future therapies can be personalized to the mutations that are present in the individual cancer. Based on laboratory research, it is thought that five to 10 mutations are needed for a cell to transform into a malignant cancer, although often many more mutations can be seen. The major genes involved in cancer are oncogenes and tumor suppressor genes. Both of these types of genes contribute to the malignant phenotype by leading to unregulated cell division or the ability to avoid programmed cell death. Oncogenes require only a single mutation to become activated and act in an autosomal dominant fashion. In contrast, tumor suppressor genes require both copies of the allele to become inactivated to lose their protective effects against unregulated cell growth. Caretaker genes are a subset of tumor suppressor genes and have no direct effect on cell growth. These genes function to help the cell protect the integrity of its genome by repairing DNA defects that occur.

III-10.  The answer is E. (Chap. 83) A small proportion of cancers occur in patients with a genetic predisposition. Roughly 100 syndromes of familial cancer have been reported. Recognition allows for genetic counseling and increased cancer surveillance. Down syndrome, or trisomy 21, is characterized clinically by a variety of features, including moderate to severe learning disability, facial and musculoskeletal deformities, duodenal atresia, congenital heart defects, and an increased risk of acute leukemia. Fanconi’s anemia is a condition that is associated with defects in DNA repair. There is a higher incidence of cancer, with leukemia and myelodysplasia being the most common cancers. von Hippel–Lindau syndrome is associated with hemangioblastomas, renal cysts, pancreatic cysts and carcinomas, and renal cell cancer. Neurofibromatosis (NF) types I and II are both associated with increased tumor formation. NF II is more associated with schwannoma. Both carry a risk of malignant peripheral nerve sheath tumors. Fragile X is a condition associated with chromosomal instability of the X chromosome. These patients have mental retardation; typical morphologic features, including macro-orchidism and prognathia; behavioral problems; and occasionally seizures. Increased cancer incidence has not been described.

III-11.  The answer is C. (Chap. 84) Cancer treatment is undergoing a revolution with an increasing number of therapies that are directed specifically against signal transduction pathways. These pathways are often activated in cancer cells and contribute to the malignant phenotype of the cell. One commonly affected signal transduction pathway is that of tyrosine kinase. Typically, tyrosine kinase is only active for a very short period. However, in malignant cells, the tyrosine kinase pathway can be constitutively activated through mutation, gene amplification, or gene translocation. Small molecule therapy that can inhibit a tyrosine kinase pathway can lead to decreased proliferation of malignant cells, decreased survival, and impeded angiogenesis. Examples of targeted small molecule therapies and their molecular targets can be found in Table III-11 on the next page. These include drugs as well as monoclonal antibodies. Among the first small molecule therapies to be used in malignancy was imatinib, which has dramatically changed therapy in chronic myeloid leukemia. This drug targets the activated tyrosine kinase pathway activated by the Bcr-Abl mutation that is present in this disease.

Bevacizumab is a monoclonal antibody targeted against pathways in vascular endothelial growth factor (VEGF) and is used in lung and colon cancer. It had previously been used for breast cancer, but the U.S. Food and Drug Administration has recommended against its use in breast cancer as of November 2011 (www.fda.gov, accessed December 1, 2011). Erlotinib and gefitinib are active against tumors carrying mutations of the epidermal growth factor receptor (EGFR), especially in lung cancer. Rituximab has been used for many years and is an anti-CD20. Its most common use is in B-cell lymphomas and leukemias, but it is undergoing trials for use in autoimmune disease as well. Sunitinib and sorafenib both have activity against a large number of kinases. Whereas sunitinib targets c-Kit, VEGFR-2, PDGFR-β, and Fit-3, sorafenib targets RAF, VEGFR-2, PDGFR-α/β, Fit-3, and c-Kit.

TABLE III-11 Some Molecularly Targeted Agents Approved by the U.S. Food and Drug Administration for the Treatment of Cancer

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III-12.  The answer is B. (Chap. 84) Epigenetics is a term that refers to changes in the chromatin structure of the cell that lead to alterations in gene expression without underlying changes in the DNA code. As such, these changes are potentially reversible and may be targets for cancer therapy. An example of an important epigenetic change is hypermethylation of promoter regions (so-called CpG islands) in tumor suppressor genes that lead to the inactivation of one allele of the gene.

III-13.  The answer is A. (Chap. 85) Generally, when metastatic disease is observed, surgical interventions do not change the outcome of a particular cancer. However, in a few instances, one should consider surgery as potentially curative. One example is metastatic osteosarcoma to the lung, which can be cured by resection of the lung lesion. There are other instances in which surgery may be effective in patients with metastatic disease. In non–small cell lung cancer, individual with a solitary brain metastasis at the time of diagnosis may also be treated with resection of the brain and lung lesions in a staged fashion. In colon cancer with liver metastases, hepatic lobectomy may produce long-term disease-free survival in as many as 25% of individuals if fewer than five lesions are observed in a single hepatic lobe. Another role for surgical resection in metastatic disease is to remove the source of hormone production that can stimulate cancer growth. This is occasionally recommended in prostate cancer, although antiandrogen therapy is most commonly used.

III-14.  The answer is D. (Chap. 85) Clinical trials in cancer drug discovery follows a stepwise process before the drug is determined to be safe and effective for treatment of a specific cancer. Before proceeding to trials in human, cancer drugs must demonstrate antitumor activity with a specific dose and interval in animal trials. After this, drugs enter phase I trials to establish safe dosage range and side effects in humans. Clinical antitumor effect is observed, but phase II trials enroll a larger group of people to more rigorously quantify antitumor effects in humans. Further side effect data is collected as well. The dose given in phase II trials is the maximal tolerated dose determined in phase I trials. Although phase I trials often given escalating doses of an agent, phase II trials use a fixed dose, and the drug is given to only a very select and homogeneous group of patients. An agent is determined to be “active” and may proceed to a phase III trial if there is a partial regression rate of at least 20% to 25% with reversible non–life-threatening side effects. Phase III trials enroll the largest numbers of patients and often compare the drug with standard therapies for the particular cancer. Phase IV trials occur after release of the drug and are called postmarketing studies. These trials provide important information about risks, benefits, and optimal use in the general population of patients with a particular cancer, which can often be quite different than those patients enrolled in a clinical trial.

III-15.  The answers are 1—D, 2—C, 3—A, 4—E, and 5—B. (Chap. 85) Cancer chemotherapy typically requires actively dividing cells to exert their actions to kill the cancer cells. The mechanism of action of the majority of chemotherapeutic agents can be broadly categorized as those affecting DNA, those affecting microtubules, and molecularly targeted agents. Within each of these broad categories, several common families of drugs operating have distinct mechanisms of action. DNA alkylating agents are cell cycle phase nonspecific agents that covalently modify DNA bases and lead to cross-linkage of DNA strands. These cells become unable to complete normal cell division. Examples of common DNA alkylating agents are cyclophosphamide, chlorambucil, dacarbazine, and the platinum agents (carboplatin, cisplatin, and oxaliplatin). Antitumor antibiotics are naturally occurring substances typically produced by bacteria that bind to DNA directly and cause free radical damage that leads to DNA breakage. Included in this group are topoisomerase poisons that are derived from plants that prevent DNA unwinding and replication. Examples of agents in this category are bleomycin, etoposide, topotecan, irinotecan, doxorubicin, daunorubicin, and mitoxantrone. Other drugs that are common anticancer agents affect DNA indirectly, especially through interference in the synthesis of purines or pyrimidines. This category of agents is known as antimetabolites and includes methotrexate, azathioprine, 5-fluorouracil, cytosine arabinoside, gemcitabine, fludarabine, asparaginase, and pemetrexed, among others.

Chemotherapeutics agents that target the microtubules interfere with cell division by inhibiting the mitotic spindle. These antimitotic agents include vincristine, vinblastine, vinorelbine, paclitaxel, and docetaxel, among others.

Molecularly targeted agents are relatively new agents for the treatment of malignancy. When compared with traditional cancer chemotherapy, these agents are directed against specific proteins within cells that are important in cell signal processing. There are many different types of molecularly targeted agents with the largest class being tyrosine kinase inhibitors. Commonly used tyrosine kinase inhibitors include imatinib, gefitinib, erlotinib, sorafenib, and sunitinib. All-trans retinoic acid is another example of a molecularly targeted agent that attaches to the promyelocytic leukemia–retinoic acid receptor fusion protein to stimulate differentiation of the promyelocytes to mature granulocytes. Other categories of targeted agents include histone deacetylase inhibitors and mTOR (mammalian target of rapamycin) inhibitors.

III-16.  The answer is E. (Chap. 85) Myelosuppression predictably occurs after administration of a variety of chemotherapeutic agents. Antimetabolites and anthracyclines (including doxorubicin) typically cause neutropenia between 6 and 14 days after administration of the agent. Febrile neutropenia is diagnosed based on a single temperature greater than 38.5°C or three temperatures greater than 38.0°C. Treatment of febrile neutropenia conventionally includes initiation of treatment with broad-spectrum antibiotics. If there is no obvious site of infection, then coverage for Pseudomonas aeruginosa is recommended. Active antibiotics include third- or fourth-generation cephalosporins (including ceftazidime), antipseudomonal penicillins, carbapenems, and aminoglycosides. Vancomycin should be considered in this patient because of her tunneled intravenous catheter despite the apparent lack of cutaneous infection and would be continued until culture demonstrated the absence of a resistant organism. There is no need for an antifungal agent because this patient has not had prolonged neutropenia, and this is the first fever recorded. Moreover, given the chemotherapy given, the expected duration of neutropenia is expected to be relatively brief. In many instances such as this, oral antibiotics such as ciprofloxacin can be given.

There is no role for granulocyte transfusions in the treatment. However, the use of colony-stimulating factors often is considered. These agents have historically been overused, and the American Society of Clinical Oncology has developed practice guidelines to assist in determining which patients should receive colony-stimulating factors. Briefly, there is no evidence for benefit in either febrile or afebrile neutropenic patients, and they should not routinely be used in acute myeloid leukemia or myelodysplastic syndromes. The only therapeutic use is in individuals who have undergone bone marrow or stem cell transplantation to speed myeloid recovery. The primary use of colony-stimulating factors is in the setting of prevention. Because this patient has now experienced an episode of febrile neutropenia, she should be given colony-stimulating factors beginning 24 to 72 hours after chemotherapy administration, and the medication should continue until the neutrophil count is 10,000/μL or greater. Colony-stimulating factors may be given after the first cycle of chemotherapy if the likelihood of febrile neutropenia is greater than 20%, if the patient has preexisting neutropenia or active infection, if the patient is older than 65 years of age and is being treated for lymphoma, or if the patient has a poor performance status or has had extensive prior chemotherapy.

III-17.  The answer is E. (Chap. 85) Nausea with or without vomiting is the most common side effect of chemotherapy. It can be anticipatory in nature, acute, or occur more than 24 hours after administration. Patients at increased risk of nausea include younger patients, women, and those with a history of motion or morning sickness. The chemotherapeutic agents used also alter the risk of nausea and vomiting. Highly emetogenic drugs include high-dose cyclophosphamide and cisplatin. Low-risk drugs include fluorouracil, taxanes, and etoposide. In patients receiving high-risk regimens, prophylactic treatment with a combination of medications acting at different sites is recommended. Typically, the regimen would include a serotonin antagonist such as dolasetron, a neurokine receptor antagonist such are aprepitant, and potent corticosteroids such as dexamethasone.

III-18.  The answer is C. (Chap. 86) Patients who have undergone allogeneic stem cell transplant remain at risk for infectious complications for an extended period despite engraftment and apparent return of normal hematopoietic capacity. Individuals with graft-versus-host disease (GVHD) often require immunosuppressive treatment that further increases their infectious risk. Prevention of infection is the goal in these individuals, and the clinician should ensure appropriate vaccinations for all patients who have undergone intensive chemotherapy, have been treated for Hodgkin’s disease, or have undergone hematopoietic stem cell transplant. No vaccines except influenza should be given before 12 months after transplant. Then the only vaccines that should be given are inactivated vaccines. Therefore, oral vaccine for poliomyelitis and the varicella zoster vaccine are contraindicated. The measles, mump, and rubella vaccine is also a live virus vaccine, but can be safely given after 24 months if the patient does not have GVHD. Other recommended vaccines include diphtheria–tetanus, inactivated poliomyelitis (by injection), Haemophilus influenzae type B, hepatitis B, and 23-valent pneumococcal polysaccharide vaccine. Meningococcal vaccination is recommended in splenectomized patients and in those living in endemic areas, including college dormitories.

III-19.  The answer is B. (Chap. 86) Specific malignancies are associated with underlying immune dysfunction and infection with specific organisms. Chronic lymphocytic leukemia and multiple myeloma may have an associated hypogammaglobulinemia. Individuals with these disorders are at risk of infections with Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. Although immunoglobulin therapy is effective, it is more cost effective to give prophylactic antibiotics in these patients. Acute myeloid or lymphocytic leukemias often have an associated neutropenia and may present with overwhelming infection from extracellular bacteria and fungi, especially if the duration of neutropenia is prolonged. Patients with lymphomatous disorders often have abnormal T-cell function despite normal numbers of T cells. Moreover, most patients also receive treatment with high doses of glucocorticoids that further impair T-cell function. These individuals have an increased risk of infection with intracellular pathogens and may contract pneumonia with Pneumocystis jiroveci.

III-20.  The answer is D. (Chap. 86) Clinicians are often faced with treatment decisions regarding catheter-related infections in patients who are immunocompromised from cancer and chemotherapy. Because many patients require several weeks of chemotherapy, tunneled catheters are often placed, and determining the need for catheter removal is an important consideration. When blood culture results are positive or there is evidence of infection along the track of the tunnel, catheter removal is recommended. When the erythema is limited to the exit site only, then it is not necessary to remove the catheter unless the erythema fails to respond to treatment. The recommended treatment for an exit site infection should be directed against coagulase-negative staphylococci. In the options presented, vancomycin alone is the best option for treatment. There is no need to add therapy for gram-negative organisms because the patient does not have neutropenia and has negative culture results.

III-21.  The answer is A. (Chap. 87) The staging criteria for melanoma include the thickness of the lesion, the presence of ulceration, and the presence and number of involved lymph nodes. Of these, the single best predictor of metastatic risk is the Breslow thickness, particularly greater than 4 mm, although the other factors also provide additional predictive value. Other factors that predict survival in melanoma are younger age, gender with female sex predicting a better survival, and anatomic site with favorable sites being the forearm and leg. The Clark level defined melanoma based on the layer of skin to which a melanoma had invaded, but this has been found to be not predictive of metastatic risk.

III-22.  The answer is E. (Chap. 87, Chapman PB et al: N Engl J Med 2011; 364: 2507-2516) Treatment of metastatic melanoma has largely shown very little improvements on mortality in this disease. The median survival after diagnosis of metastatic disease is typically 6 to 15 months. Until August 2011, the only Food and Drug Administration (FDA)–approved chemotherapy for the treatment of metastatic disease was dacarbazine, although response rates are about 20% or less. Interleukin-2 therapy has also been attempted alone or in combination with interferon-α. This therapy has lead to long-term disease-free survival in about 5% of treated patients but is associated with significant toxicity that limits its usefulness. Interleukin-2 should only be administered to patients with good performance status and at centers experienced in the treatment of IL-2 toxicity. Most recently in August 2011, the FDA approved the drug vemurafenib (PLX4032) for the treatment of metastatic melanoma. This drug targets BRAF, which is a common mutation in melanoma that results in constitutive activation of the mitogen-activated protein (MAP) kinase pathway. Vemurafenib has specifically demonstrated to have the best activity against the BRAF V600E mutation, the most common kinase mutation in metastatic melanoma. Data published in 2011 demonstrated that individuals with this specific mutation have response rates of 48% to the drug compared with only 5% for dacarbazine. Furthermore, the 6-month survival was 84% in the vemurafenib group compared with only 64% in the dacarbazine group. Ipilimumab is another promising new therapy for the treatment of metastatic melanoma. This treatment is a monoclonal antibody that blocks cytotoxic T-cell antigen 4 (CTLA-4), and a recent clinical trial demonstrated improved overall survival rates in patients treated with ipilimumab plus dacarbazine compared with dacarbazine alone (Robert C et al: N Engl J Med 2011; 364: 2517-25).

III-23.  The answer is C. (Chap. 88) Head and neck cancers account for about 3% of all malignancies in the United States and comprise a varied site of tumors, including those of the nasopharynx, oropharynx, hypopharynx, and larynx. Squamous cell history is the predominant cell type at all sites, but there are different risk factors by site. Nasopharyngeal cancers are rare in the United States but are endemic in the Mediterranean and Far East, where they are associated with Epstein-Barr virus infection. Oropharyngeal cancers are associated with tobacco use, especially smokeless tobacco, and increasing numbers of oropharyngeal cancers are found to be associated with human papilloma virus (HPV). The association with HPV virus infection, particularly serotypes 16 and 18, characterizes these oropharyngeal cancers as a form of sexually transmitted disease and is associated with oral sexual practices and an increased number of sexual partners. However, the predominant risk factors for head and neck cancers, particularly those of the hypopharynx and larynx, are alcohol and tobacco use. Cancers of the larynx often present with the subacute onset of hoarseness that does not resolve over time, but symptoms of head and neck cancer can be rather nonspecific. In more advanced cases, pain, stridor, dysphagia, odynophagia, and cranial neuropathies can occur. Diagnosis of head and neck cancer should include computed tomography of the head and neck and endoscopic examination under anesthesia to perform biopsies. Positron emission tomography scans may be used as adjunctive therapy. The staging of head and neck cancers follows a TNM staging guideline. This patient would be staged as T2N0M0 based on a tumor size without evidence of lymph node involvement or distant metastatic disease. With this designation, the patient’s overall stage would be stage II and classified as localized disease. The intent of therapy at this stage of disease is cure of cancer, and the overall 5-year survival is 60% to 90%. The choice of therapy for laryngeal cancer is radiation therapy to preserve the voice. Surgical therapy could be chosen by the patient as well but is less desirable. In locally or regionally advanced disease, patients can still be approached with curative intent, but this requires multimodality therapy with surgery followed by concomitant chemotherapy and radiation treatment.

III-24.  The answer is A. (Chap. 89) Solitary pulmonary nodules are frequent causes of referral to a pulmonologist, but most solitary pulmonary nodules are benign. In fact, more than 90% of incidentally identified nodules are of benign origin. Features that are more likely to be present in a malignant lesion are size larger than 3 cm, eccentric calcification, rapid doubling time, and lobulated and irregular contour. Ground-glass appearance on computed tomography can be either malignant or benign. Among malignant lesions, it is seen more commonly in bronchoalveolar cell carcinoma. When multiple pulmonary nodules are identified, it most commonly represents prior granulomatous disease from healed infections. If multiple nodules are malignant in origin, it usually indicates disease metastatic to the lung but can be simultaneous lung primary lesions or lesions metastatic from a primary lung cancer. Many incidentally identified nodules are too small to be diagnosed by biopsy and are nonspecific in nature. In this situation, it is prudent to follow the lesions for 2 years, especially in a patient who is high risk for lung cancer to allow for a proper doubling time to occur. If the lesion remains stable for 2 years, it is most likely benign, although some slow-growing tumors such bronchoalveolar cell carcinoma can have a slower growth rate.

III-25.  The answer is E. (Chap. 89) The evaluation and treatment of solitary pulmonary nodules is important to understand. This patient has a long smoking history with a new nodule that was not apparent by chest radiography 3 years previously. This should be assumed to be a malignant nodule, and definitive diagnosis and treatment should be attempted. The option for diagnostic and staging procedures include positron emission tomography (PET) and computed tomography (CT), bronchoscopic biopsy, percutaneous needle biopsy, and surgical biopsy with concomitant resection if positive. PET and CT would be low yield in this patient given the small size of the primary lesion (<1 cm) and the lack of enlarged mediastinal lymph nodes. Likewise, bronchoscopy would not provide a good yield because the lesion is very peripheral in origin, and a negative biopsy for malignancy would not be definitive. Appropriate approaches would be to either perform a percutaneous needle biopsy with CT guidance or perform a surgical biopsy with definitive resection if positive. Because this patient has preserved lung function, surgical biopsy and resection is a good treatment option. A repeat CT scan assessing for interval growth would only be appropriate if the patient declined further workup at this time. Referral for treatment with radiation therapy is not appropriate in the absence of tissue diagnosis of malignancy, and surgical resection is the preferred primary treatment because the patient has no contraindications to surgical intervention.

III-26.  The answer is E. (Chap. 89) Pancoast syndrome results from apical extension of a lung mass into the brachial plexus with frequent involvement of the eighth cervical and first and second thoracic nerves. As the tumor continues to grow, it will also involve the sympathetic ganglia of the thoracic chain. The clinical manifestations of a Pancoast tumor include shoulder and arm pain and Horner’s syndrome (ipsilateral ptosis, miosis, and anhidrosis). Often, the shoulder and arm pain presents several months before diagnosis. The most common cause of Pancoast syndrome is an apical lung tumor, usually non–small cell lung cancer. Other causes include mesothelioma and infection, among others. Although midbrain lesions can cause Horner’s syndrome, other cranial nerve abnormalities would be expected.

Enlarged mediastinal lymph nodes and masses in the middle mediastinum can occlude the superior vena cava (SVC), leading to SVC syndrome. Individuals with SVC syndrome typically present with dyspnea and have evidence of facial and upper extremity swelling. Eaton Lambert myasthenic syndrome is caused by antibodies to voltage-gated calcium channels and is characterized by generalized weakness of muscles that increases with repetitive nerve stimulation. Cervical ribs can cause thoracic outlet syndrome by compression of nerves or vasculature as they exit the chest. This typically presents with ischemic symptoms to the affected limb, but intrinsic wasting of the muscles of the hand can be seen because of neurologic compromise.

III-27.  The answer is E. (Chap. 89) At the time of diagnosis, 70% of small cell lung cancers have metastasized. In contrast to non–small cell lung cancer, small cell lung cancer is staged as limited or extensive disease based on the spread of disease in the body rather than size of the tumor burden or extent of lymph node involvement. Common sites of metastases in small cell lung cancer are thoracic lymph nodes, brain, adrenal glands, and liver. All patients diagnosed with small cell lung cancer should undergo chest and abdominal computed tomography (CT) scans as well as CT or magnetic resonance imaging (MRI) imaging of the brain. If bone pain is present, radionuclide bone scans should be performed. Bone marrow biopsies are not typically indicated as isolated bone marrow metastases are rare. If there are signs of spinal cord compression or leptomeningeal involvement, imaging of the spine by MRI or CT and lumbar puncture are indicated, respectively.

III-28.  The answer is C. (Chap. 89) Mutations of the epidermal growth factor receptor (EGFR) have recently been recognized as important mutations that affect the response of non–small cell lung cancers to treatment with EGFR tyrosine kinase inhibitors. Initial studies of erlotinib in all patients with advanced non–small cell lung cancer failed to show a treatment benefit; however, when only patients with EGFR mutations were considered, treatment with anti-EGFR therapy improved progression-free and overall survival. Patients who are more likely to have EGFR mutations are women, nonsmokers, Asians, and those with adenocarcinoma histopathology.

III-29.  The answer is B. (Chap. 89, N Engl J Med 2011; 365: 395-409) Screening for lung cancer in high-risk individuals has been investigated for many years. Screening trials require large numbers of participants that can be followed for long periods of time and are expensive to conduct. Until 2011, no screening trial had been able to demonstrate any decrease in lung cancer mortality. Previous screening modalities have been primarily chest radiographs with or without sputum cytology. In June 2011, the main results of the National Lung Cancer Screening Trial (NLST) were published in the New England Journal of Medicine. The trial enrolled more than 50,000 individuals with a greater than 30 pack-year history of cigarette smoking and randomized the individuals to yearly chest radiographs or low-dose computed tomography (CT) scans for a period of 3 years. Outcomes in the individuals continued to be followed for a total of almost 8 years, when the trial was stopped early. Individuals receiving low-dose CT scans demonstrated a 20% mortality reduction from lung cancer compared with those receiving chest radiographs alone, and more individuals receiving CT scans were diagnosed at early stages of disease. A caveat in broadly applying these results in clinical practice is that more than 90% of positive scans proved to be false positives. At this point, more research on the cost effectiveness of CT scans and the appropriate population to which to offer scans needs to be done before widespread screening is recommended.

III-30.  The answer is C. (Chap. 90) The patient has a breast cyst. This has a benign feel on examination, and aspiration of the mass showed nonbloody fluid with resolution of the mass. If there were residual mass or bloody fluid, mammography and biopsy would be the next step. In patients such as this with nonbloody fluid in whom aspiration clears the mass, reexamination in 1 month is indicated. If the mass recurs, then aspiration should be repeated. If fluid recurs, mammography and biopsy would be indicated at that point. There is no indication at this point to refer for advanced imaging or surgical evaluation. Breastfeeding is not affected by the presence of a breast cyst.

III-31.  The answer is C. (Chap. 90) Breast cancer risk is related to many factors, but age of menarche, age of first full-term pregnancy, and age at menopause together account for 70% to 80% of all breast cancer risk. The lowest risk patients have the shortest duration of total menses (i.e., later menarche and earlier menopause), as well as an early first full-term pregnancy. Specifically, the lowest risks are menarche at age 16 years old or older, first pregnancy by the age of 18 years, and menopause that begins 10 years before the median age of menopause of 52 years. Thus, patient C meets these criteria.

III-32.  The answer is D. (Chap. 90) Pathologic staging remains the most important determinant of overall prognosis. Other prognostic factors have an impact on survival and the choice of therapy. Tumors that lack estrogen or progesterone receptors are more likely to recur. The presence of estrogen receptors, particularly in postmenopausal women, is also an important factor in determining adjuvant chemotherapy. Tumors with a high growth rate are associated with early relapse. Measurement of the proportion of cells in S-phase is a measure of the growth rate. Tumors with more than the median number of cells in S-phase have a higher risk of relapse and an improved response rate to chemotherapy. Histologically, tumors with a poor nuclear grade have a higher risk of recurrence than do tumors with a good nuclear grade. At the molecular level, tumors that overexpress erbB2 (HER-2/neu) or that have a mutated p53 gene portend a poorer prognosis for patients. The overexpression of erbB2 is also useful in designing optimal treatment regimens, and a human monoclonal antibody to erbB2 (Herceptin) has been developed.

III-33.  The answer is E. (Chap. 91) Esophageal cancer is an uncommon gastrointestinal malignancy with a high mortality rate because most patients do not present until advanced disease is present. The typical presenting symptoms of esophageal cancer are dysphagia with significant weight loss. Dysphagia is typically fairly rapidly progressive over a period of weeks to months. Dysphagia initially in only to solid foods but progresses to include semisolids and liquids. For dysphagia to occur, an estimated 60% of the esophageal lumen must be occluded. Weight loss occurs because of decreased oral intake in addition to the cachexia that is common with cancer. Associated symptoms may include pain with swallowing that can radiate to the back, regurgitation or vomiting of undigested food, and aspiration pneumonia. The two major cell types of esophageal cancer in the United States are adenocarcinoma and squamous cell carcinoma, which have different risk factors. Individuals with squamous cell carcinomas typically have a history of both tobacco and alcohol abuse, but those with adenocarcinoma more often have a history of long-standing gastroesophageal reflux disease and Barrett’s esophagitis. Among those with a history of alcohol and tobacco abuse, there is an increased risk with increased intake and interestingly is more associated with whiskey drinking compared with wine or beer. Other risk factors for squamous cell carcinoma of the esophagus include ingestion of nitrites, smoked opiates, fungal toxins in pickled vegetables, and physical insults that include long-standing ingestion of very hot tea or lye.

III-34.  The answer is E. (Chap. 91) Colorectal cancer is the second most common cause of cancer death in the United States, and the mortality rate related to the disease has been decreasing in recent years. When colorectal cancer is identified, patients should be referred for surgical intervention because proper staging and prognosis cannot be determined without pathologic specimens if there is no gross evidence of metastatic disease. The preoperative workup to assess for metastatic or synchronous disease includes a complete colonoscopy if possible, chest radiography, liver function testing, carcinoembryonic antigen (CEA) testing, and computed tomography of the abdomen. Staging of colorectal cancer follows a TNM staging system. However, the T staging is not based on absolute size of the tumor rather it is based upon the extension of the tumor through the colonic wall. T1 tumors can extend into the submucosa but not beyond, T2 tumors extend into the muscularis propria, and T3 tumors involve the serosa and beyond. Nodal metastases are graded as N1 (one to three lymph nodes positive) and N2 (≥four lymph nodes positive). This patient’s stage of cancer would be T2N1M0 and would be staged as a stage III cancer. Despite the relatively advanced stage, the overall 5-year survival rate would be 50% to 70% because of improvements in overall care of the patient with colorectal cancer. Because the patient had an occluding lesion that prevents preoperative colonoscopy, the patient needs to have a complete colonoscopy performed within the first several months after surgery and every 3 years thereafter. Serial measurements of CEA every 3 months have also been advocated by some specialists. Annual CT scanning may be performed for the first 3 years after resection, although the utility of the practice is debated. Radiation therapy to the pelvis is recommended for all patients with rectal cancer because it reduces the local recurrence rate, especially in stage II and III tumors. When postoperative radiation therapy is combined with chemotherapeutic regimens containing 5-fluorouracil, the local recurrence rate is further reduced and overall survival is increased as well.

III-35.  The answer is A. (Chap. 91) Most colorectal cancers arise from adenomatous polyps. Only adenomas are premalignant, and only a minority of these lesions becomes malignant. Most polyps are asymptomatic, causing occult bleeding in fewer than 5% of patients. Sessile (flat-based) polyps are more likely to become malignant than pedunculated (stalked) polyps. Histologically, villous adenomas are more likely to become malignant than tubular adenomas. The risk of containing invasive carcinoma in the polyp increases with size with less than 2% in polyps smaller than 1.5 cm, 2% to 10% in polyps 1.5 to 2.5 cm, and 10% in polyps larger than 2. 5 cm. This patient had two polyps that were high risk based on histology (villous) and appearance (sessile) but only moderate risk by size (<1.5 cm). Polyps, particularly those larger than 2.5 cm in size, sometimes contain cancer cells but usually progress to cancer quite slowly over an approximate 5-year period. Patients with adenomatous polyps should have a follow-up colonoscopy or radiographic study in 3 years. If no polyps are found on initial study, the test (endoscopic or radiographic) should be repeated in 10 years. Computed tomography is only warranted for staging if there is a diagnosis of colon cancer, not for the presence of polyps alone.

III-36.  The answer is A. (Chap. 91) A strong family history of colon cancer should prompt consideration for hereditary nonpolyposis colon cancer (HNPCC), or Lynch syndrome, particularly if diffuse polyposis is not noted on colonoscopy. HNPCC is characterized by (1) three or more relatives with histologically proven colorectal cancer, one of whom is a first-degree relative and of the other two, at least one with the diagnosis before age 50 years, and (2) colorectal cancer in at least two generations. The disease is an autosomal dominant trait and is associated with other tumors, including in the endometrium and ovary. The proximal colon is most frequently involved, and cancer occurs with a median age of 50 years, 15 years earlier than in sporadic colon cancer. Patients with HNPCC are recommended to receive biennial colonoscopy and pelvic ultrasonography beginning at age 25 years. Innumerable polyps suggest the presence of one of the autosomal dominant polyposis syndromes, many of which carry a high malignant potential. These include familial adenomatous polyposis, Gardner’s syndrome (associated with osteomas, fibromas, epidermoid cysts), or Turcot’s syndrome (associated with brain cancer). Peutz-Jeghers syndrome is associated with mucocutaneous pigmentation and hamartomas. Tumors may develop in the ovary, breast, pancreas, and endometrium; however, malignant colon cancers are not common. Ulcerative colitis is strongly associated with development of colon cancer, but it is unusual for colon cancer to be the presenting finding in ulcerative colitis. Patients are generally symptomatic from their inflammatory bowel disease long before cancer risk develops.

III-37.  The answer is E. (Chap. 93) Pancreatic cancer is the fourth leading cause of cancer death in the United States despite representing only 3% of all newly diagnosed malignancies. Infiltrating ductal adenocarcinomas account for the vast majority of cases and arise most frequently in the head of pancreas. At the time of diagnosis, 85% to 90% of patients have inoperable or metastatic disease, which is reflected in the 5-year survival rate of only 5% for all stages combined. An improved 5-year survival of up to 20% may be achieved when the tumor is detected at an early stage and when complete surgical resection is accomplished. Over the past 30 years, 5-year survival rates have not improved substantially. Cigarette smoking may be the cause of up to 20% to 25% of all pancreatic cancers and is the most common environmental risk factor for this disease. Other risk factors are not well established because of inconsistent results from epidemiologic studies, but they include chronic pancreatitis and diabetes. Alcohol does not appear to be a risk factor unless excess consumption gives rise to chronic pancreatitis.

III-38.  The answer is B. (Chap. 93) Dual-phase, contrast-enhanced spiral computed tomography (CT) is the imaging modality of choice to visualize suspected pancreatic masses. In addition to imaging the pancreas, it also provides accurate visualization of surrounding viscera, vessels, and lymph nodes. In most cases, this study can determine surgical resectability. There is no advantage of magnetic resonance imaging (MRI) over CT in predicting tumor resectability, but selected cases may benefit from MRI to characterize the nature of small indeterminate liver lesions and to evaluate the cause of biliary dilatation when no obvious mass is seen on CT. Preoperative confirmation of malignancy is not always necessary in patients with radiologic appearances consistent with operable pancreatic cancer. Endoscopic ultrasound-guided needle biopsy is the most effective technique to evaluate the mass for malignancy. It has an accuracy of approximately 90% and has a smaller risk of intraperitoneal dissemination compared with CT-guided percutaneous biopsy. Endoscopic retrograde cholangiopancreatography (ERCP) is a useful method for obtaining ductal brushings, but the diagnostic value of pancreatic juice sampling is only 25% to 30%. CA 19-9 is elevated in approximately 70% to 80% of patients with pancreatic carcinoma, but ERCP is not recommended as a routine diagnostic or screening test because its sensitivity and specificity are inadequate for accurate diagnosis. Preoperative CA 19-9 levels correlate with tumor stage and prognosis. It is also an indicator of asymptomatic recurrence in patients with completely resected tumors. Fluorodeoxyglucose positron emission tomography (FDG-PET) should be considered before surgery for detecting distant metastases.

III-39.  The answer is D. (Chap. 94) Bladder cancer is the fourth most common cancer in men and the thirteenth most common cancer in women. Cigarette smoking has a strong association with bladder cancer, particularly in men. The increased risk persists for at least 10 years after quitting. Bladder cancer is a small cause of cancer deaths because most detected cases are superficial with an excellent prognosis. Most cases of bladder cancer come to medical attention by the presence of gross hematuria emanating from exophytic lesions. Microscopic hematuria is more likely caused by prostate cancer than bladder cancer. Cystoscopy under anesthesia is indicated to evaluate for bladder cancer. In cases of superficial disease, bacille Calmette-Guérin (BCG) is an effective adjuvant to decrease recurrence or treat unresectable superficial disease. In the United States, cystectomy is generally recommended for invasive disease. Even invasive cancer with nodal involvement has a greater than 40% 10-year survival after surgery and adjuvant therapy.

III-40 and III-41. The answers are C and E, respectively. (Chap. 94) The incidence of renal cell carcinoma continues to rise and is now nearly 58,000 cases annually in the United States, resulting in 13,000 deaths. The male-to-female ratio is 2 to 1. Incidence peaks between the ages of 50 and 70 years, although this malignancy may be diagnosed at any age. Many environmental factors have been investigated as possible contributing causes; the strongest association is with cigarette smoking. Risk is also increased for patients who have acquired cystic disease of the kidney associated with end-stage renal disease and for those with tuberous sclerosis. Most renal cell carcinomas are clear cell tumors (60%) with papillary and chromophobic tumors less common. Clear cell tumors account for more than 80% of patients who develop metastases. The classic triad of hematuria, flank pain, and a palpable mass is only present in 10% to 20% of patients initially. Most cases currently are found as incidental findings on computed tomography or ultrasonography done for different reasons. The increasing number of incidentally discovered low-stage tumors has contributed to an improved 5-year survival. The paraneoplastic phenomenon of erythrocytosis caused by increased production of erythropoietin is only found in 3% of cases; anemia caused by advanced disease is far more common. Stage 1 and 2 tumors are confined to the kidney and have a greater than 80% survival after radical nephrectomy. Stage 4 tumors with distant metastases have a 50year survival of 10%. Renal cell carcinoma is notably resistant to traditional chemotherapeutic agents. Cytokine therapy with interleukin-2 or interferon-gamma produces regression in 10% to 20% of patients with metastatic disease. Recently, the advent of antiangiogenic medications has changed the treatment of advance renal cell carcinoma. Sunitinib was demonstrated to be superior to interferon-gamma, and it (or sorafenib) is now first-line therapy for patients with advanced metastatic disease.

III-42.  The answer is A. (Chap. 95) The results from several large double-blind, randomized chemoprevention trials have established 5 alpha-reductase inhibitors as the predominant therapy to reduce the future risk of a prostate cancer diagnosis. Randomized placebo-controlled trials have shown that finasteride and dutasteride reduce the period prevalence of prostate cancer. Trials of selenium, vitamin C, and vitamin E have shown no benefit versus placebo.

III-43.  The answer is E. (Chap. 95) As shown in Figure III-43, transrectal ultrasound-guided biopsy is recommended for men with either an abnormal digital rectal examination (DRE) or abnormal serum prostate-specific antigen (PSA) results. Twenty-five percent of men with a PSA above 4 ng/mL and abnormal DRE results have cancer, as do 17% of men with a PSA of 2.5 to 4 ng/mL and normal DRE results.

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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.

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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

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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.

III-64.  The answer is C. (Chap. 105) The peripheral blood smear shows hypochromasia, macrocytosis, and a hypersegmented (>five lobes) neutrophil. These findings are typical for a megaloblastic anemia as seen in cobalamin or folate deficiency. The mean corpuscular volume is typically greater than 100 fL, and there is significant anisocytosis and poikilocytosis. There may also be leukopenia and thrombocytopenia that correlate with the degree of deficiency. Other less common causes of megaloblastic anemia include therapy with drugs that interfere with folate metabolism (methotrexate) or DNA synthesis (hydroxyurea, AZT, cytosine arabinoside, 6-mercaptopurine) and some cases of acute myeloblastic leukemia or myelodysplasia. Autoantibodies to ADAMTS-13 are associated with thrombotic thrombocytopenic purpura, which causes a microangiopathic hemolytic anemia. Epstein-Barr virus infection is associated with large atypical lymphocytes, not hypersegmented neutrophils. Iron-deficiency anemia causes a microcytic hypochromic anemia.

III-65.  The answer is B. (Chap. 106) Red blood cells (RBCs) use glutathione produced by the hexose monophosphate shunt to compensate for increased production of reactive oxygen species (oxidant stress), usually induced by drugs or toxins. Defects in glucose-6-phosphate dehydrogenase (G6PD) are the most common congenital hexose monophosphate shunt defect. If the RBC is unable to maintain an adequate level of glutathione during oxidant stress, hemoglobin precipitates in the RBC, producing Heinz bodies. Because the G6PD gene is on the X chromosome, almost all affected patients are males. G6PD deficiency is widely distributed throughout regions that are currently or were once highly malarial endemic. It is common in males of African, African American, Sardinian, and Sephardic descent. In most persons with G6PD deficiency, there is no evidence of symptomatic disease. However, infection, ingestion of fava beans, or exposure to an oxidative agent (drug or toxin) can trigger an acute hemolytic event. Bite cells, Heinz bodies, and bizarre poikilocytes may be evident on smear. The drugs that most commonly precipitate a G6PD crisis include dapsone, sulfamethoxazole, primaquine, and nitrofurantoin. The anemia is often severe with rapid onset after drug ingestion, and renal failure can occur.

III-66.  The answer is B. (Chaps. 106 and 319) This patient’s lupus and her rapid development of truly life-threatening hemolytic anemia are both very suggestive of autoimmune hemolytic anemia. Diagnosis is made by a positive Coombs test documenting antibodies to the red cell membrane, but smear will often show microspherocytes, indicative of the damage incurred to the red cells in the spleen. Schistocytes are typical for microangiopathic hemolytic anemias such as hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura. The lack of thrombocytopenia makes these diagnoses considerably less plausible. Macrocytosis and polymorphonuclear leukocytes with hypersegmented nuclei are very suggestive of vitamin B12 deficiency, which causes more chronic, non–life-threatening anemia. Target cells are seen in liver disease and thalassemias. Sickle cell anemia is associated with aplastic crises, but this patient has no known diagnosis of sickle cell disease and is showing evidence of erythropoietin response based on the presence of elevated reticulocyte count.

III-67.  The answer is C. (Chap. 106) The peripheral blood smear shows microspherocytes, small densely staining red blood cells (RBCs) that have lost their central pallor characteristic of hereditary spherocytosis. Spherocytosis is almost the only condition with an increased mean corpuscular hemoglobin concentration. Hereditary spherocytosis is a heterogeneous RBC membranopathy that can be either congenital (usually autosomal dominant) or acquired; it is characterized by predominantly extravascular hemolysis in the spleen caused by defects in membrane structural proteins. This spleen-mediated hemolysis leads to the conversion of classic biconcave RBCs on smear to spherocytes. Splenomegaly is common. This disorder can be severe, depending on the site of mutation, but is often overlooked until some stressor such as pregnancy leads to a multifactorial anemia, or an infection such as parvovirus B19 transiently eliminates RBC production altogether. Acute treatment is with transfusion. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a cause of hemolysis that is usually triggered by the presence of an offending oxidative agent. The peripheral blood smear may show Heinz bodies. Parvovirus infection may cause a pure RBC aplasia. The presence of active reticulocytosis and laboratory findings consistent with hemolysis are not compatible with that diagnosis. Chronic gastrointestinal blood loss, such as caused by a colonic polyp, would cause a microcytic, hypochromic anemia without evidence of hemolysis (indirect bilirubin, haptoglobin abnormalities).

III-68.  The answer is D. (Chap. 106) Each of the listed diagnoses has a rather characteristic set of laboratory findings that are virtually diagnostic for the disease once the disease has progressed to a severe stage. The combination of portal vein thrombosis, hemolysis, and pancytopenia is typical for paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare disorder characterized by hemolytic anemia (particularly at night), venous thrombosis, and deficient hematopoiesis. It is a stem cell–derived intracorpuscular defect. Anemia is usually moderate in severity, and there is often concomitant granulocytopenia and thrombocytopenia. Venous thrombosis occurs much more commonly than in the population at large. The intraabdominal veins are often involved, and patients may present with Budd-Chiari syndrome. Cerebral sinus thrombosis is a common cause of death in patients with PNH. The presence of pancytopenia and hemolysis should raise suspicion for this diagnosis even before the development of a venous thrombosis. In the past, PNH was diagnosed by abnormalities on the Ham or sucrose lysis test; however, currently flow cytometry analysis of glycosylphosphatidylinositol (GPI) linked proteins (e.g., CD55 and CD59) on red blood cells and granulocytes is recommended. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) both cause hemolysis and thrombocytopenia, as well as fevers. Cerebrovascular events and mental status change occur more commonly in TTP, and renal failure is more common in HUS. Severe leptospirosis, or Weil’s disease, is notable for fevers, hyperbilirubinemia, and renal failure. Conjunctival suffusion is another helpful clue. Acute promyelocytic leukemia is notable for anemia, thrombocytopenia, and either elevated or a decreased white blood cell count, all in the presence of disseminated intravascular coagulation.

III-69.  The answer is A. (Chap. 106) Haptoglobin is an α-globulin normally present in serum. It binds specifically to the globin portion of hemoglobin, and the complex is cleared by the mononuclear cell phagocytosis. Haptoglobin is reduced in all hemolytic anemias because it binds free hemoglobin. It can also be reduced in cirrhosis and so is not diagnostic of hemolysis outside of the correct clinical context. Assuming normal bone marrow and iron stores, the reticulocyte count will be elevated as well to try to compensate for the increased red blood cell (RBC) destruction of hemolysis. Release of intracellular contents from the RBC (including hemoglobin and lactate dehydrogenase) induces heme metabolism, producing unconjugated bilirubinemia. If the haptoglobin system is overwhelmed, the kidney will filter free hemoglobin and reabsorb it in the proximal tubule for storage of iron by ferritin and hemosiderin. Hemosiderin in the urine is a marker of filtered hemoglobin by the kidneys. In massive hemolysis, free hemoglobin may be excreted in urine.

III-70.  The answer is E. (Chap. 106) Hemolytic anemias may be classified as intracorpuscular or extracorpuscular. In intracorpuscular disorders, the patient’s red blood cells (RBCs) have an abnormally short life span because of an intrinsic RBC factor. In extracorpuscular disorders, the RBC has a short life span because of a nonintrinsic RBC factor. Thrombotic thrombocytopenic purpura (TTP) is an acquired disorder in which red blood cell and platelet destruction occur not because of defects of these cell lines but rather as a result of microangiopathy leading to destructive shear forces on the cells. Other clinical signs and symptoms include fever; mental status change; and, less commonly, renal impairment. Most acquired adult cases of TTP are associated with autoantibodies to ADAMTS-13 (or von Willebrand factor–cleaving protease). All cases of hemolysis in conjunction with thrombocytopenia should be rapidly ruled out for TTP by evaluation of a peripheral smear for schistocytes because plasmapheresis is lifesaving. Other causes of extravascular hemolytic anemia include hypersplenism, autoimmune hemolytic anemia, disseminated intravascular coagulation, and other microangiopathic hemolytic anemias. The other four disorders listed in the question all refer to some defect of the RBC itself that leads to hemolysis. Elliptocytosis is a membranopathy that leads to varying degrees of destruction of the RBC in the reticuloendothelial system. Sickle cell anemia is a congenital hemoglobinopathy classified by recurrent pain crises and numerous long-term sequelae that is caused by a well-defined β-globin mutation. Pyruvate kinase deficiency is a rare disorder of the glycolytic pathway that causes hemolytic anemia. Paroxysmal nocturnal hemoglobinuria (PNH) is a form of acquired hemolysis caused by an intrinsic abnormality of the RBCs. It also often causes thrombosis and cytopenias. Bone marrow failure is a feared association with PNH.

III-71.  The answer is C. (Chap. 107) Pure red blood cell aplasia (PRCA) is a condition characterized by the absence of reticulocytes and erythroid precursors. A variety of conditions may cause PRCA. It may be idiopathic. It may be associated with certain medications, such as trimethoprim–sulfamethoxazole (TMP-SMX) and phenytoin. It can be associated with a variety of neoplasms, either as a precursor to a hematologic malignancy such as leukemia or myelodysplasia or as part of an autoimmune phenomenon, as in the case of thymoma. Infections also may cause PRCA. Parvovirus B19 is a single-strand DNA virus that is associated with erythema infectiosum, or fifth disease in children. It is also associated with arthropathy and a flulike illness in adults. It is thought to attack the P antigen on proerythroblasts directly. Patients with a chronic hemolytic anemia, such as sickle cell disease, or with an immunodeficiency are less able to tolerate a transient drop in reticulocytes because their red blood cells do not survive in the peripheral blood for an adequate period. In this patient, her daughter had an illness before the appearance of her symptoms. It is reasonable to check her parvovirus immunoglobulin M (IgM) titers. If the results are positive, a dose of intravenous Ig is indicated. Because her laboratory test results and smear are not suggestive of dramatic sickling, an exchange transfusion is not indicated. Immunosuppression with prednisone, cyclosporine, or both may be indicated if another etiology of the PRCA is identified. However, that would not be the next step. Similarly, a bone marrow transplant might be a consideration in a young patient with myelodysplasia or leukemia, but there is no evidence of that at this time. Antibiotics have no role in light of her normal white blood cell count and the lack of evidence for a bacterial infection.

III-72.  The answer is D. (Chap. 107) Aplastic anemia is defined as pancytopenia with bone marrow hypocellularity. Aplastic anemia may be acquired, iatrogenic (chemotherapy), or genetic (e.g., Fanconi’s anemia). Acquired aplastic anemia may be caused by drugs or chemicals (expected toxicity or idiosyncratic effects), viral infections, immune diseases, paroxysmal nocturnal hemoglobinuria, pregnancy, or idiopathic causes. Aplastic anemia from idiosyncratic drug reactions (including those listed as well others, including as quinacrine, phenytoin, sulfonamides, or cimetidine) are uncommon but may be encountered given the wide usage of some of these agents. In these cases, there is usually not a dose-dependent response; the reaction is idiosyncratic. Seronegative hepatitis is a cause of aplastic anemia, particularly in young men who recovered from an episode of liver inflammation 1 to 2 months earlier. Parvovirus B19 infection most commonly causes pure red blood cell (RBC) aplasia, particularly in patients with chronic hemolytic states and high RBC turnover (e.g., sickle cell anemia).

III-73.  The answer is D. (Chap. 107) This patient has aplastic anemia. In the absence of drugs or toxins that cause bone marrow suppression, it is most likely that he has an immune-mediated injury. Growth factors are not effective in the setting of hypoplastic bone marrow. Transfusion should be avoided unless emergently needed to prevent the development of alloantibodies. Glucocorticoids have no efficacy in aplastic anemia. Immunosuppression with antithymocyte globulin and cyclosporine is a therapy with proven efficacy for this autoimmune disease with a response rate of up to 70%. Relapses are common, and myelodysplastic syndrome or leukemia may occur in approximately 15% of treated patients. Immunosuppression is the treatment of choice for patients without suitable bone marrow transplant donors. Bone marrow transplantation is the best current therapy for young patients with matched sibling donors. Allogeneic bone marrow transplants from matched siblings result in long-term survival in more than 80% of patients, with better results in children than adults. The effectiveness of androgens has not been verified in controlled trials, but occasional patients will respond or even demonstrate blood count dependence on continued therapy. Sex hormones upregulate telomerase gene activity in vitro, possibly also their mechanism of action in improving marrow function. For patients with moderate disease or those with severe pancytopenia in whom immunosuppression has failed, a 3 to 4-month trial is appropriate.

III-74.  The answer is B. (Chap. 107) Myelodysplasia, or the MDSs, are a heterogeneous group of hematologic disorders broadly characterized by cytopenias associated with a dysmorphic (or abnormal appearing) and usually cellular bone marrow and by consequent ineffective blood cell production. The mean onset of age is after 70 years. MDS is associated with environmental exposures such as radiation and benzene; other risk factors have been reported inconsistently. Secondary MDS occurs as a late toxicity of cancer treatment, usually with a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5–7 years) or the DNA topoisomerase inhibitors (2 years). Both acquired aplastic anemia after immunosuppressive treatment and Fanconi’s anemia can evolve into MDS. MDS is a clonal hematopoietic stem cell disorder leading to impaired cell proliferation and differentiation. Cytogenetic abnormalities are found in approximately half of patients, and some of the same specific lesions are also seen in frank leukemia. Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic, and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important historic fact. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process. About 20% of patients have splenomegaly. Bone marrow is typically hypercellular. Median survival varies from months to years, depending on the number of blasts in marrow and the specific cytogenetic abnormality. Isolated 5q- is associated with a median survival in years. Most patients die as a result of complications of pancytopenia and not because of leukemic transformation; perhaps one-third will succumb to other diseases unrelated to their MDS. Precipitous worsening of pancytopenia, acquisition of new chromosomal abnormalities on serial cytogenetic determination, increase in the number of blasts, and marrow fibrosis are all poor prognostic indicators. The outlook in therapy-related MDS, regardless of type, is extremely poor, and most patients progress within a few months to refractory acute myeloid leukemia. Historically, the therapy of MDS has been unsatisfactory. Only stem cell transplantation offers cure. Survival rates of 50% at 3 years have been reported, but older patients are particularly prone to develop treatment-related mortality and morbidity. Results of transplant using matched unrelated donors are comparable, although most series contain younger and more highly selected cases. However, multiple new drugs have been approved for use in MDS. Several regimens appear to not only improve blood counts but also to delay onset of leukemia and to improve survival.

Lenalidomide, a thalidomide derivative with a more favorable toxicity profile, is particularly effective in reversing anemia in MDS patients with 5q- syndrome; a high proportion of these patients become transfusion independent.

III-75.  The answer is E. (Chap. 108) The World Health Organization’s classification of the chronic myeloproliferative diseases (MPDs) includes eight disorders, some of which are rare or poorly characterized but all of which share an origin in a multipotent hematopoietic progenitor cell, overproduction of one or more of the formed elements of the blood without significant dysplasia, a predilection to extramedullary hematopoiesis or myelofibrosis, and transformation at varying rates to acute leukemia. Within this broad classification, however, significant phenotypic heterogeneity exists. Some diseases such as chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), and chronic eosinophilic leukemia (CEL) express primarily a myeloid phenotype, but in others, such as polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocytosis (ET), erythroid or megakaryocytic hyperplasia predominates. The latter three disorders, in contrast to the former three, also appear capable of transforming into each other. Such phenotypic heterogeneity has a genetic basis. CML is the consequence of the balanced translocation between chromosomes 9 and 22 [t(9;22)(q34;11)], CNL has been associated with a t(15;19) translocation, and CEL occurs with a deletion or balanced translocations involving the PDGFR-alpha gene. By contrast, to a greater or lesser extent, PV, PMF, and ET are characterized by expression of a JAK2 mutation, V617F, that causes constitutive activation of this tyrosine kinase that is essential for the function of the erythropoietin and thrombopoietin receptors but not the granulocyte colony-stimulating factor receptor. This essential distinction is also reflected in the natural history of CML, CNL, and CEL, which is usually measured in years, and their high rate of transformation into acute leukemia. By contrast, the natural history of PV, PMF, and ET is usually measured in decades, and transformation to acute leukemia is uncommon in the absence of exposure to mutagenic agents. Primary effusion lymphoma is not a myeloproliferative disease. It is one of the diseases (Kaposi’s sarcoma, multicentric Castleman’s disease) associated with infection with human herpes virus-8, particularly in immunocompromised hosts.

III-76.  The answer is A. (Chap. 108) Polycythemia vera (PV) is a clonal disorder that involves a multipotent hematopoietic progenitor cell. Clinically, it is characterized by a proliferation of red blood cells (RBCs), granulocytes, and platelets. The precise etiology is unknown. Unlike chronic myelogenous leukemia, no consistent cytogenetic abnormality has been associated with the disorder. However, a mutation in the autoinhibitory, pseudokinase domain of the tyrosine kinase JAK2—that replaces valine with phenylalanine (V617F), causing constitutive activation of the kinase—appears to have a central role in the pathogenesis of PV. Erythropoiesis is regulated by the hormone erythropoietin. Hypoxia is the physiologic stimulus that increases the number of cells that produce erythropoietin. Erythropoietin may be elevated in patients with hormone-secreting tumors. Levels are usually “normal” in patients with hypoxic erythrocytosis. In PV, however, because erythrocytosis occurs independently of erythropoietin, levels of the hormone are usually low. Therefore, an elevated level is not consistent with the diagnosis. PV is a chronic, indolent disease with a low rate of transformation to acute leukemia, especially in the absence of treatment with radiation or hydroxyurea. Thrombotic complications are the main risk for PV and correlate with the erythrocytosis. Thrombocytosis, although sometimes prominent, does not correlate with the risk of thrombotic complications. Salicylates are useful in treating erythromelalgia but are not indicated in asymptomatic patients. There is no evidence that thrombotic risk is significantly lowered with their use in patients whose hematocrits are appropriately controlled with phlebotomy. Phlebotomy is the mainstay of treatment. Induction of a state of iron deficiency is critical to prevent a reexpansion of the RBC mass. Chemotherapeutics and other agents are useful in cases of symptomatic splenomegaly. Their use is limited by side effects, and there is a risk of leukemogenesis with hydroxyurea.

III-77.  The answer is A. (Chap. 108) Chronic primary myelofibrosis (PMF) is the least common myeloproliferative disorder and is considered a diagnosis of exclusion after other causes of myelofibrosis have been ruled out. The typical patient with PMF presents in the sixth decade of life, and the disorder is asymptomatic in many patients. Fevers, fatigue, night sweats, and weight loss may occur in PMF, but these symptoms are rare in other myeloproliferative disorders. However, no signs or symptoms are specific for the diagnosis of PMF. Often marked splenomegaly is present and may extend across the midline and to the pelvic brim. A peripheral blood smear demonstrates the typical findings of myelofibrosis, including teardrop-shaped red blood cells (RBCs), nucleated RBCs, myelocytes, and metamyelocytes that are indicative of extramedullary hematopoiesis. Anemia is usually mild, and platelet and leukocyte counts are often normal. About 50% of patients with PMF have the JAK2 V617F mutation. Bone marrow aspirate is frequently unsuccessful because the extent of marrow fibrosis makes aspiration impossible. When a bone marrow biopsy is performed, it demonstrates hypercellular marrow with trilineage hyperplasia and increased number of megakaryocytes with large dysplastic nuclei. Interestingly, individuals with PMF often have associated autoantibodies, including rheumatoid factor, antinuclear antibodies, or a positive Coombs test results. To diagnose someone as having PMF, it must be shown that he or she does not have another myeloproliferative disorder or hematologic malignancy that is the cause of myelofibrosis. The most common disorders that present in a similar fashion to PMF are polycythemia vera and chronic myelogenous leukemia. Other nonmalignant disorders that can cause myelofibrosis include HIV infection, hyperparathyroidism, renal osteodystrophy, systemic lupus erythematosus, tuberculosis, and bone marrow replacement in other cancers such as prostate and breast cancer. In the patient described here, there is no other identifiable cause of myelofibrosis; thus, chronic PMF can be diagnosed.

III-78.  The answer is E. (Chap. 108) Thrombocytosis may be “primary” or “secondary.” Essential thrombocytosis is a myeloproliferative disorder that involves a multipotent hematopoietic progenitor cell. Unfortunately, no clonal marker can reliably distinguish it from more common nonclonal, reactive forms of thrombocytosis. Only 50% of patients with essential (primary) thrombocytosis have the JAK2 V617F mutation. Therefore, the diagnosis is one of exclusion. Common causes of secondary thrombocytosis include infection, inflammatory conditions, malignancy, iron deficiency, hemorrhage, and postsurgical states. Other myeloproliferative disorders, such as CML and myelofibrosis, may result in thrombocytosis. Similarly, myelodysplastic syndromes, particularly the 5q-syndrome, may cause thrombocytosis. Pernicious anemia caused by vitamin B12 deficiency does not typically cause thrombocytosis. However, correction of B12 deficiency or folate deficiency may cause a “rebound” thrombocytosis. Similarly, cessation of chronic ethanol use may also cause rebound thrombocytosis.

III-79.  The answer is E. (Chap. 108) In a patient presenting with an elevated hemoglobin and hematocrit, the initial step in the evaluation is to determine whether erythrocytosis represents a true elevation in red blood cell (RBC) mass or whether spurious erythrocytosis is present because of plasma volume contraction. (See Figure III-79.) This step may be not necessary, however, in individuals with hemoglobin greater than 20 g/dL. After absolute erythrocytosis has been determined by measurement of RBC mass and plasma volume, the cause of erythrocytosis must be determined. If there is not an obvious cause of the erythrocytosis, an erythropoietin level should be checked. An elevated erythropoietin level suggests hypoxia or autonomous production of erythropoietin as the cause of erythrocytosis. However, a normal erythropoietin level does not exclude hypoxia as a cause. A low erythropoietin level should be seen in the myeloproliferative disorder polycythemia vera (PV), the most likely cause of erythrocytosis in this patient. PV is often discovered incidentally when elevated hemoglobin is found during testing for other reasons. When symptoms are present, the most common complaints are related to hyper-viscosity of the blood and include vertigo, headache, tinnitus, and transient ischemic attacks. Patients may also complain of pruritus after showering. Erythromelalgia is the term give to the symptoms complex of burning, pain, and erythema in the extremities and is associated with thrombocytosis in PV. Isolated systolic hypertension and splenomegaly may be found. In addition to elevated red RBC mass and low erythropoietin levels, other laboratory findings in PV include thrombocytosis and leukocytosis with abnormal leukocytes present. Uric acid levels and leukocyte alkaline phosphatase may be elevated but are not diagnostic for PV. Approximately 30% of individuals with PV are homozygous for the JAK2 V617F mutation, and more than 90% are heterozygous for this mutation. This mutation located on the short arm of chromosome 9 causes constitutive activation of the Janus kinase (JAK) protein, a tyrosine kinase that renders erythrocytes resistant to apoptosis and allows them to continue production independently from erythropoietin. However, not every patient with PV expresses this mutation, and approximately 50% of patients with chronic myelofibrosis and essential thrombocytosis express this mutation. Thus, it is not recommended as an initial diagnostic test for PV but may be used for confirmatory purposes. Bone marrow biopsy provides no specific information in PV and is not recommended.

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FIGURE III-79

III-80.  The answer is C. (Chap. 109) This patient presents with typical findings of chronic myelogenous leukemia (CML), which has an incidence of 1.5 per 100,000 people yearly. The typical age of onset is in the mid-forties, and there is a slight male predominance. Half of individuals are asymptomatic at the time of diagnosis. If symptoms are present, they are typically nonspecific and include fatigue and weight loss. Occasionally, patients have symptoms related to splenic enlargement such as early satiety and left upper quadrant pain. Laboratory findings are suggestive of CML. A high leukocyte count of 100,000/μL is typical, with a predominant granulocytic differential, including neutrophils, myelocytes, metamyelocytes, and band forms. The circulating blast count should be less than 5%. Anemia and thrombocytosis are also common. The bone marrow demonstrates non-specific increase in cellularity with an increase in the myeloid-to-erythroid ratio. The diagnosis of CML is established by identifying a clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22. This translocation results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22q11 with the ABL1 (named after the Abelson murine leukemia virus) gene located on chromosome 9q34. The bcr-abl fusion protein results in constitutive activation of abl tyrosine kinase enzyme that prevents apoptosis and leads to increased survival of the cells containing the mutation. Ultimately, untreated CML develops into an accelerated phase with increasing numbers of mutations and leads to acute blast crisis. The deletion of the long arm of chromosome 5 is present in some individuals with acute myeloid leukemias and is associated with older age at diagnosis. The inversion of chromosome 16 is typically present in acute myelomonocytic leukemia (M4 subtype). The translocation of the long arms of chromosomes 15 and 17 is the mutation associated with acute promyelocytic anemia that results in arrest of cellular differentiation that can be treated with pharmacologic doses of ATRA (all-trans retinoic acid). Finally, trisomy 12 is one of several mutations that may result in the development of chronic lymphocytic leukemia.

III-81.  The answer is D. (Chap. 109) The acute myeloid leukemias (AMLs) are a group of hemato-logic malignancies derived from hematologic stem cells that have acquired chromosomal mutations that prevent differentiation into mature myeloid cells. The specific chromosomal abnormalities predict in which stage of differentiation the cell is arrested and are associated with the several subtypes of AML that have been identified. In the United States, more than 16,000 new cases of AML are diagnosed yearly, and the numbers of new cases of AML has increased in the past 10 years. Men are diagnosed with AML more frequently than women (4.6 cases per 100,000 population vs. 3.0 cases per 100,000, respectively). In addition, older age is associated with increased incidence of AML, with an incidence of 18.6 cases per 100,000 population in those older than 65 years of age. AML is uncommon in adolescents. Other known risk factors for the development of AML include hereditary genetic abnormalities, radiation and chemical exposures, and drugs. The most common hereditary abnormality linked to AML is trisomy 21 (Down syndrome). Other hereditary syndromes associated with an increase of AML include diseases associated with defective DNA repair such as Fanconi’s anemia and ataxia telangiectasia. Survivors of the atomic bomb explosions in Japan were found to have a high incidence of AML as have survivors of other high-dose radiation exposures. However, therapeutic radiation is not associated with an increased risk of AML unless the patient was also treated concomitantly with alkylating agents. Anticancer drugs are the most common causes of drug-associated AML. Of the chemotherapeutic agents, alkylating agents and topoisomerase II inhibitors are the drugs most likely to be associated with AML.

III-82.  The answer is C. (Chap. 109) The goal of therapy in chronic myelogenous leukemia (CML) is to achieve prolonged, durable, nonneoplastic, nonclonal hematopoiesis, which entails the eradication of any residual cells containing the BCR-ABL1 transcript. Hence, the goal is complete molecular remission and cure. Therapy of CML has changed in recent years because of the presence of a proven curative treatment (allogeneic transplantation) that has significant toxicity and a targeted treatment (imatinib) with outstanding outcome based on 8-year follow-up data. New tyrosine kinase inhibitors are becoming available, making this a dynamic topic. Many experts currently recommend initiating therapy with a tyro-sine kinase inhibitor and reserving allogeneic transplantation for those who develop drug resistance. Imatinib mesylate is a tyrosine kinase inhibitor that acts to decrease the activity of the bcr-abl fusion protein that results from the reciprocal translocation of chromosomes 9 and 22 (Philadelphia chromosome). It acts as a competitive inhibitor of the abl kinase at its ATP binding site and thus leads to inhibition of tyrosine phosphorylation of proteins in bcr-abl signal transduction. In newly diagnosed CML, imatinib results in a complete hematologic remission in 95% of patients initially and 76% at 18 months. Low-risk patients have a higher durable remission rate. All imatinib-treated patients who achieved major molecular remission (26%), defined as3 log or greater reduction in BCR-ABL1 transcript level at 18 months compared with pretreatment level, were progression free at 5 years. There is a consensus that molecular responses can be used as a treatment goal in CML. Imatinib, taken orally, has limited side effects that include nausea, fluid retention, diarrhea, and skin rash and is usually well tolerated. Interferon-α was previously the first-line chemotherapy if bone marrow transplant was not an option, but it has been replaced by imatinib mesylate. Autologous stem cell transplant is not currently used for treatment of CML because there is no reliable way to select residual normal hematopoietic progenitor cells. Leukopheresis is used for control of leukocyte counts when the patient is experiencing complications such as respiratory failure or cerebral ischemia related to the high white blood cell count.

III-83 and III-84. The answers are D and E, respectively. (Chap. 109) Treatment of acute promyelocytic leukemia (PML) is an interesting example of how understanding the function of the protein produced by the genetic abnormality can be used to develop a treatment for the disease. The translocation of the long arms of chromosomes 15 and 17, t(15;17), results in the production of a chimeric protein called promyelocytic leukemia (Pml)/retinoic acid receptor α (Rar-α). The Pml-Rar-α fusion protein suppresses gene transcription and arrests differentiation of the cells in an immature state, leading to promyelocytic leukemia. Pharmacologic doses of the ligand of the Rar-α receptor, tretinoin, stimulate the cells to resume differentiation. With use of tretinoin, the leukemic cells differentiate to mature neutrophils and undergo subsequent apoptosis. Tretinoin plus concurrent anthracycline-based chemotherapy appears to be among the most effective treatments for APL, leading to complete remission (CR) rates of 90% to 95%. The primary side effect of tretinoin is the development of retinoic acid syndrome. The onset of retinoic acid syndrome from ATRA (all-trans retinoic acid) is usually within the first 3 weeks of treatment. Typical symptoms are chest pain, fever, and dyspnea. Hypoxia is common, and chest radiography usually shows diffuse alveolar infiltrates with pleural effusions. Pericardial effusions may also occur. The cause of retinoic acid syndrome is possibly related to the adhesion of the differentiated leukemia cells to the pulmonary endothelium or the release of cytokines by these cells to cause vascular leak. The mortality rate for patients with retinoic acid syndrome is 10%. High-dose glucocorticoid therapy is usually effective in the treatment of retinoic acid syndrome. Arsenic trioxide has antileukemic activity and may be used in tretinoin refractory cases. It is also under investigation for combination chemotherapy. Cyclophosphamide, daunorubicin, vinblastine, and prednisone are the constituents of the combination chemotherapy commonly known as CHOP, which is indicated for the treatment of B-cell lymphomas. Rituximab is most commonly used as a treatment of B-cell non-Hodgkin’s lymphoma and a variety of autoimmune disorders. Rituximab is a monoclonal antibody directed against the CD20 cell-surface molecule of B lymphocytes. It has no current role in the treatment of acute myeloid leukemias. Whole-body irradiation is used primarily before bone marrow transplant to ensure complete eradication of cancerous leukemic cells in the bone marrow.

III-85.  The answer is C. (Chap. 109) Patients with acute leukemia frequently present with nonspecific symptoms of fatigue and weight loss. In addition, weight loss and anorexia are also common. About half have had symptoms for more than 3 months at the time of presentation. Fever is present in only about 10% of patients at presentation, and 5% have evidence of abnormal hemostasis. On physical examination, hepatomegaly, splenomegaly, sternal tenderness, and evidence of infection or hemorrhage are common presenting signs. Laboratory studies are confirmatory with evidence of anemia, thrombocytopenia, and leukocytosis often present. The median presenting leukocyte count at presentation is 15,000/μL. About 20% to 40% have presenting leukocyte counts less than 5000/μL, and another 20% have counts greater than 100,000/μL. Review of the peripheral smear confirms leukemia in most cases. If Auer rods are seen, the diagnosis of acute myeloid leukemia (AML) is virtually certain. Thrombocytopenia (platelet count <100,000/μL) is seen in more than 75% of individuals with AML. After the diagnosis of AML has been confirmed, rapid evaluation and treatment should be undertaken. The general health of the cardiovascular, pulmonary, hepatic, and renal systems should be evaluated because chemotherapy has adverse effects that may cause organ dysfunction in any of these systems. Overall, chromosome findings at diagnosis are currently the most important independent prognostic factor. Patients with t(15;17) have a very good prognosis (~85% cured), and those with t(8;21) and inv(16) have a good prognosis (~55% cured), but those with no cytogenetic abnormality have a moderately favorable outcome (~40% cured). Patients with a complex karyotype, t(6;9), inv(3), or –7, have a very poor prognosis. Among the prognostic factors that predict poor outcomes in AML, age at diagnosis is one of the most important because individuals of advanced age tolerate induction chemotherapy poorly. In addition, advanced age is more likely to be associated with multiple chromosomal abnormalities that predict poorer response to chemotherapy, although some chromosomal markers predict a better response to chemotherapy. Poor performance status independent of age also decreases survival in AML. Responsiveness to chemotherapy and survival are also worse if the leukocyte count is greater than 100,000/μL or the antecedent course of symptoms is prolonged. Anemia, leukopenia, or thrombocytopenia present for more than 3 months is a poor prognostic indicator. However, there is no absolute degree of anemia or thrombocytopenia that predicts worse outcomes.

III-86.  The answer is E. (Chap. 110) Viscosity testing is typically reserved for cases of multiple myeloma in which paraproteins (particularly immunoglobulin M) can lead to vascular sludging and subsequent tissue ischemia. Acute lymphoid leukemia (ALL) can lead to end-organ abnormalities in kidney and liver; therefore, routine chemistry tests are indicated. A lumbar puncture must be performed in cases of newly diagnosed ALL to rule out spread of disease to the central nervous system. Bone marrow biopsy reveals the degree of marrow infiltration and is often necessary for classification of the tumor. Immunologic cell-surface marker testing often identifies the cell lineage involved and the type of tumor, information that is often impossible to discern from morphologic interpretation alone. Cytogenetic testing provides prognostic information on the disease natural history. In ALL, prognosis depends on the genetic characteristics of the tumor, the patient’s age, the white cell count, and the patient’s overall clinical status and major organ function.

III-87.  The answer is B. (Chap. 110) Hepatitis B and C are both common causes of cirrhosis and are strongly associated with the development of hepatocellular carcinoma. Hepatitis C, but not hepatitis B, can also lead to a lymphoplasmacytic lymphoma, often in the spleen, that resolves with cure of hepatitis C. Epstein-Barr virus has been associated with a large number of lymphoid malignancies, including posttransplant lymphoproliferative disease (PTLD), Hodgkin’s disease, central nervous system lymphoma, and Burkitt’s lymphoma. Helicobacter pylori infection is necessary and sufficient for gastric mucosa-associated lymphoid tissue (MALT) lymphoma development, and cure can be achieved with eradication of the organism in some cases. HHV8 is a known cause of body cavity lymphoma, including primary pleural lymphoma. In addition to those listed, HTLV-1 is associated with adult T-cell lymphoma or leukemia. Other disorders associated with lymphoma include celiac sprue, autoimmune disease, and biologic therapies for autoimmune disease. Celiac sprue has been associated with gastrointestinal tract lymphoma. Many collagen vascular diseases (e.g., Sjogren’s) and anti–tumor necrosis factor therapies have been associated with the development of lymphoma.

III-88.  The answer is B. (Chap. 110) Autoimmune hemolytic anemia and thrombocytopenia are common, and a peripheral blood smear and a Coombs test help evaluate their presence. Hypersplenism is also seen in chronic lymphoid leukemia (CLL) as the spleen sequesters large numbers of circulating blood cells and enlarges. Hence, a careful left upper quadrant examination looking for a palpable splenic tip is the standard of care in this situation. This patient is at risk of hepatic decompensation as well, given his hepatitis C that can also cause anemia and thrombocytopenia. Bone marrow infiltration of tumor cells can lead to cytopenias in CLL. However, this is in effect a diagnosis of exclusion. After these three possibilities have been ruled out, a bone marrow biopsy is a reasonable next step. This initial evaluation before presuming spread of CLL is critical for therapy because each possibility requires different therapy (glucocorticoids or rituximab for hemolysis, hepatology referral for liver failure, and splenectomy for symptomatic hypersplenism).

III-89.  The answer is C. (Chap. 110) The peripheral smear shows increased numbers of small, well-differentiated, normal-appearing lymphocytes characteristic of chronic lymphocytic leukemia, the most common leukemia or lymphoma in adults. Common presenting complaints typically include fatigue, frequent infections, new lymphadenopathy, and abdominal complaints relating to splenomegaly. Hairy cell leukemia is a rare disease that presents predominantly in older men. Typical presentation involves pancytopenia, although occasional patients will have a leukemic presentation. Splenomegaly is usual. The malignant cells appear to have “hairy” projections on light and electron microscopy. Patients with this disorder are prone to unusual infections, including infection by Mycobacterium avium intracellulare, and to vasculitic syndromes. Hairy cell leukemia is responsive to chemotherapy with cladribine with clinical complete remissions in the majority of patients and frequent long-term disease-free survival.

III-90.  The answer is E. (Chap. 110) Classical Hodgkin’s disease carries a better prognosis than all types of non-Hodgkin’s lymphoma. Patients with good prognostic factors can achieve cure with extended field radiation alone, but those with a higher risk disease often achieve cure with high-dose chemotherapy and sometimes radiation. The chance of cure is so high (>90%) that many protocols are now considering long-term sequelae of current therapy such as carcinomas, hypothyroidism, premature coronary disease, and constrictive pericarditis in those receiving radiation therapy. A variety of chemotherapy regimens are effective with long-term disease-free survival in patients with advanced disease achieved in more than 75% of patients who lack systemic symptoms and in 60% to 70% of patients with systemic symptoms.

III-91.  The answer is D. (Chap. 110) The large cell with a bilobed nucleus and prominent nucleoli giving an “owl’s eyes” appearance near the center of the field is a Reed-Sternberg cell, confirming the diagnosis of Hodgkin’s disease. Hodgkin’s disease occurs in 8000 patients in the United States each year, and the disease does not appear to be increasing in frequency. Most patients present with palpable lymphadenopathy that is nontender; in most patients, these lymph nodes are in the neck, supraclavicular area, and axilla. More than half the patients have mediastinal adenopathy at diagnosis, and this is sometimes the initial manifestation. Subdiaphragmatic presentation of Hodgkin’s disease is unusual and more common in older men. One-third of patients present with fevers, night sweats, or weight loss, which are B symptoms in the Ann Arbor staging classification. Occasionally, Hodgkin’s disease can present as a fever of unknown origin. This is more common in older patients who are found to have mixed cellularity Hodgkin’s disease in an abdominal site. Rarely, the fevers persist for days to weeks followed by afebrile intervals and then recurrence of the fever (Pel-Ebstein fever). The differential diagnosis of a lymph node biopsy suspicious for Hodgkin’s disease includes inflammatory processes, mononucleosis, non-Hodgkin’s lymphoma, phenytoin-induced adenopathy, and nonlymphomatous malignancies.

III-92.  The answer is E. (Chap. e20) A “dry tap” is defined as the inability to aspirate bone marrow and is reported in approximately 5% of attempts. It is rare in the case of normal bone marrow. The differential diagnosis includes metastatic carcinoma infiltration (17%); chronic myeloid leukemia (15%); myelofibrosis (14%); hairy cell leukemia (10%); acute leukemia (10%); and lymphomas, including Hodgkin’s disease (9%).

III-93.  The answer is B. (Chap. e20) The diagnostic criteria for chronic eosinophilic leukemia and the hypereosinophilic syndrome first requires the presence of persistent eosinophilia greater than 1500/μL in blood, increased marrow eosinophils, and less than 20% myelob-lasts in blood or marrow. Additional disorders that must be excluded include all causes of reactive eosinophilia, primary neoplasms associated with eosinophilia (e.g., T-cell lymphoma, Hodgkin’s disease, acute lymphoid leukemia, mastocytosis, chronic myelogenous leukemia, acute myeloid leukemia [AML], myelodysplasia, and myeloproliferative syndromes), and T-cell reaction with increased interleukin-5 or cytokine production. If these entities have been excluded and the myeloid cells show a clonal chromosome abnormality and blast cells (>2%) are present in peripheral blood or are increased in marrow (but <20%), then the diagnosis is chronic eosinophilic leukemia. Patients with hypereosinophilic syndrome and chronic eosinophilic leukemia may be asymptomatic (discovered on routine testing) or present with systemic findings such as fever, shortness of breath, new neurologic findings, or rheumatologic findings. The heart, lungs, and central nervous system are most often affected by eosinophil-mediated tissue damage.

III-94.  The answer is D. (Chap. e21) Mastocytosis is a proliferation and accumulation of mast cells in one or more organ systems. Only the skin is involved in approximately 80% of cases with the other 20% being defined as systemic mastocytosis caused by the involvement of another organ system. The most common manifestation of mastocytosis is cutaneous urticaria pigmentosa, a maculopapular pigmented rash involving the papillary dermis. Other cutaneous forms include diffuse cutaneous mastocytosis (almost entirely in children) and mastocytoma. Clinical manifestations of systemic mastocytosis are related to either cellular infiltration of organs or release of histamine, proteases, eicosanoids, or heparin from mast cells. Therefore, signs and symptoms may include constitutional symptoms, skin manifestations (pruritus, dermatographia, rash), mediator-related symptoms (abdominal pain, flushing, syncope, hypertension, diarrhea), and bone related symptoms (fracture, pain, arthralgia). In a recent series, 40% of patients with systemic mastocytosis had an associated myeloid neoplasm, most commonly myeloproliferative syndrome, chronic myelogenous leukemia, and myelodysplastic syndrome. Eosinophilia was present in approximately one-third of patients. Elevated serum tryptase, bone marrow involvement, splenomegaly, skeletal involvement, cytopenia, and malabsorption predict more aggressive disease and a worse prognosis. Many patients with systemic mastocytosis have an activating mutation of c-Kit, a kinase inhibited by imatinib; however, the mutation appears relatively resistant to this agent.

III-95.  The answer is A. (Chap. 111) The patient presents with pneumococcal pneumonia and evidence of hypercalcemia, renal failure, and a wide protein gap suggestive of an M protein. These findings are classic for multiple myeloma. Although the patient appears to be making large quantities of immunoglobulins, they are in fact generally monoclonal, and patients actually have functional hypogammaglobulinemia related to both decreased production and increased destruction of normal antibodies. This hypogammaglobulinemia predisposes patients to infections, most commonly pneumonia with pneumococcus or Staphylococcus aureus or gram-negative pyelonephritis. Bone marrow biopsy would confirm the presence of clonal plasma cells and define the quantity, which will help define treatment options. A serum protein electrophoresis would also be indicated to prove the presence of the M protein suspected by the wide protein gap. Although HIV may be associated with kidney injury, both acute and chronic, hypercalcemia would be an unusual feature. There is no clinical history of aspiration, and the location of infiltrate, upper lobe, is unusual for aspiration. Sweat chloride testing is not indicated because there is no suspicion for cystic fibrosis. Because solid organ malignancy is not suspected, computed tomography of the body is unlikely to be helpful.

III-96.  The answer is A. (Chap. 112) This patient presents with a multisystem illness involving the heart, kidneys, and peripheral nervous system. The physical examination is suggestive of amyloidosis with classic waxy papules in the folds of his body. The laboratory test results are remarkable for renal failure of unclear etiology with significant proteinuria but no cellular casts. A possible etiology of the renal failure is suggested by the elevated gamma globulin fraction and low hematocrit, bringing to mind a monoclonal gammopathy perhaps leading to renal failure through amyloid AL deposition. This could also account for the enlarged heart seen on the echocardiography and the peripheral neuropathy. The fat pad biopsy is generally reported to be 60% to 80% sensitive for amyloid; however, it would not allow a diagnosis of this patient’s likely myeloma. A right heart catheterization probably would prove that the patient has restrictive cardiomyopathy secondary to amyloid deposition; however, it too would not diagnose the underlying plasma cell dyscrasia. Renal ultrasonography, although warranted to rule out obstructive uropathy, would not be diagnostic. Similarly, the electromyographic and nerve conduction studies would not be diagnostic. The bone marrow biopsy is about 50% to 60% sensitive for amyloid, but it would allow evaluation of the percent of plasma cells in the bone marrow and allow the diagnosis of multiple myeloma to be made. Multiple myeloma is associated with amyloid AL in approximately 20% of cases. Light chains most commonly deposit systemically in the heart, kidneys, liver, and nervous system, causing organ dysfunction. In these organs, biopsy would show the classic eosinophilic material that, when exposed to Congo red stain, has a characteristic apple-green birefringence.

III-97.  The answer is C. (Chap. 115) Heparin-induced thrombocytopenia (HIT) is a clinical diagnosis that must not be missed because life-threatening thrombosis can occur if not treated appropriately. The cause of HIT is the formation of antibodies to the complex of heparin and platelet factor 4 (PF4). This complex is able to activate platelets, monocytes, and endothelial cells. Many patients exposed to heparin will develop antibodies to the heparin–PF4 complex, but only a few of these will progress to develop thrombocytopenia or thrombocytopenia with thrombosis (HITT). The typical patient will develop evidence of HIT 5 to 14 days after exposure to heparin, although it can occur within 5 days in individuals exposed to heparin within about the previous 100 days as would be expected in this patient given his recent hospitalization. The nadir platelet count is typically greater than 20,000/μL. When HIT is suspected, one should not delay treatment for laboratory testing because no currently available test has adequate sensitivity or specificity for the diagnosis. The antiheparin/PF4 antibody test result is positive in many individuals who have been exposed to heparin regardless of whether HIT is present. The platelet activation assay is more specific but less sensitive for HIT. As soon as HIT is suspected, heparin should be discontinued and replaced with an alternative form of anticoagulation to protect against development of new thromboses. Low-molecular-weight heparins (LMWHs) such as enoxaparin are not appropriate treatment options in individuals with HIT. Although heparin is 10 times more likely to cause HIT, LMWHs also cause the illness and should not be used. The primary agents used for HIT in the United States are the direct thrombin inhibitors argatroban and lepirudin. Argatroban is the preferred agent for this patient because of his renal failure. The drug is not excreted by the kidneys, and no dosage adjustment is required. In contrast, lepirudin is markedly increased in renal failure, and a significant dosage adjustment is required. Danaparoid has previously been used frequently for HIT and HITT, but this medication is no longer available in the United States. Other anticoagulants that are used for treatment of HITT include bivalirudin and fondaparinux, but these also are not currently approved for use in the United States.

III-98.  The answer is E. (Chap. 115) This patient presents with symptoms of thrombocytopenia, including bleeding gums and easy bruising. The only finding on physical examination may be petechiae at points of increased venous pressure, especially in the feet and ankles. The laboratory findings confirm thrombocytopenia but show no abnormalities in other cell lines. When evaluating isolated thrombocytopenia, one must initially consider whether an underlying infection or medication is causing the platelet count to fall. There is a long list of medications that are implicated in thrombocytopenia, including aspirin, acetaminophen, penicillins, H2 blockers, heparin, and many others. This patient discontinued all medications over 6 weeks previously, and the platelet count would be expected to recover if a medication reaction were the cause. She gives no signs of any acute infection. Thus, the most likely diagnosis is immune thrombocytopenia purpura (ITP). This disorder is also known as idiopathic thrombocytopenia purpura and refers to an immune-mediated destruction of platelets and possible inhibition of platelet release from megakaryocytes. ITP can truly be idiopathic, or it can be secondary to an underlying disorder, including systemic lupus erythematosus (SLE), HIV, or chronic hepatitis C virus (HCV) infection. The platelet count can be quite low (<5000/μL) in patients with ITP and usually presents with mucocutaneous bleeding. Laboratory testing for ITP should include a peripheral smear that typically demonstrates large platelets with otherwise normal morphology. Initial testing should evaluate for secondary causes of ITP, including HIV antibodies, HCV antibodies, serologic testing for SLE, serum protein electrophoresis, and immunoglobulins. If anemia is also present, a direct Coombs test is indicated to assess whether there is a combined autoimmune hemolytic anemia with ITP (Evans syndrome). Antiplatelet antibody testing is not recommended because these tests have low sensitivity and specificity for ITP. In addition, bone marrow biopsy is typically not performed unless there are other abnormalities that are not explained by ITP or the patient has failed to respond to usual therapy.

III-99 and III-100. The answers are A and E, respectively. (Chap. 115) This patient presents with the classic pentad of thrombotic thrombocytopenic purpura (TTP), which is fever, neurologic symptoms, acute renal failure, thrombocytopenia, and microscopic angiopathic hemolytic anemia (MAHA). Although this is the classic presentation, it is not necessary to have all five characteristics for an individual to be diagnosed with TTP. In recent years, the pathogenesis of inherited and idiopathic TTP has been discovered to be attributable to a deficiency of or antibodies directed against the ADAMTS-13 protein. The ADAMTS-13 protein is a metalloproteinase that cleaves von Willebrand factor (VWF). In the absence of ADAMTS-13, ultra-large VWF multimers circulate in the blood and can cause pathogenic platelet adhesion and activation, resulting in microvascular ischemia and microangiopathic hemolytic anemia. However, it appears as if there is a necessary inciting event because not all individuals with an inherited deficiency of ADAMTS-13 develop TTP. Some drugs have been implicated as causative agents in TTP. Ticlopidine and possibly clopidogrel cause TTP by inducing antibody formation. Other drugs, including mitomycin C, cyclosporine, and quinine, can cause TTP by causing direct endothelial toxicity.

A dziagnosis of TTP can be made based on clinical factors. It should be differentiated from disseminated intravascular coagulation, which causes MAHA but has a predominant coagulopathy. Hemolytic uremic syndrome also causes MAHA and appears very similar to TTP in clinical presentation, although neurologic symptoms are less prominent. Often a preceding diarrheal illness alerts one to hemolytic syndrome as the cause of MAHA. It is important to make a prompt and correct diagnosis because the mortality rate for patients with TTP without treatment is 85% to 100%, decreasing to 10% to 30% with treatment. The primary treatment for TTP remains plasma exchange. Plasma exchange should be continued until the platelet count returns to the normal range and there is no further evidence of hemolysis for at least 2 days. Glucocorticoids can be used as adjunctive treatment in TTP but are not effective as the sole therapy. Recent research suggests that rituximab may be useful in primary treatment of TTP. However, relapse is common with rituximab.

III-101. The answer is D. (Chap. 116) The hemophilias are X-linked inherited disorders that cause deficiency of factor VIII (hemophilia A) or factor 9 (hemophilia B). The hemophilias affect about one in 10,000 males worldwide with hemophilia A responsible for 80% of cases. Clinically, there is no difference between hemophilia A and B. The disease presentation largely depends on the residual activity of factor VIII or factor IX. Severe disease is typically seen when factor activity is less than 1%, and moderate disease appears when the levels range between 1% and 5%. The clinical manifestation of moderate and severe disease is commonly bleeding into the joints, soft tissues, and muscles that occurs after minimal trauma or even spontaneously. When factor activity is greater than 25%, bleeding would occur only after major trauma or surgery, and the diagnosis may not be made unless a prolonged activated partial thromboplastin time is seen on routine laboratory examination. To make a definitive diagnosis, one would need to measure specific levels of factor VIII and IX. Without treatment, life expectancy is limited, but given the changes in therapy since the 1980s, life span is about 65 years. Early treatment of hemophilia required the use of pooled plasma that was used to make factor concentrates. Given the large number of donors required to generate the factor concentrates and the frequent need for transfusion in some individuals, bloodborne pathogens such as HIV and hepatitis C are among the leading cause of death in patients with hemophilia. In the 1990s, recombinant factor VIII and IX were developed. Primary prophylaxis is given to individuals with baseline factor activity levels of less than 1% to prevent spontaneous bleeding, especially hemarthroses. Although this strategy is highly recommended, only about 50% of eligible patients receive prophylactic therapy because of the high costs and need for regular intravenous infusions. When an individual is suspected of having a bleed, the treatment should begin as soon as possible and not delayed until factor activity levels return. Factor concentrates should be given to raise the activity level to 50% for large hematomas or deep muscle bleeds, and an individual may require treatment for a period of 7 days or more. For milder bleeds, including uncomplicated hemarthrosis, the goal factor activity level is 30% to 50% with maintenance of levels between 15% and 25% for 2 to 3 days after the initial transfusions. In addition to treatment with factor concentrates, care should be taken to avoid medications that inhibit platelet function. DDAVP, a desmopressin analogue, can be given as adjunctive therapy for acute bleeding episodes in hemophilia A because this may cause a transient rise in factor VIII levels and von Willebrand factor because of release from endothelial cells. This medication is typically only useful in mild to moderate disease. Antifibrinolytic drugs such as tranexamic acid or ε-amino caproic acid are helpful in promoting hemostasis for mucosal bleeding.

III-102. The answer is D. (Chap. 116) Disseminated intravascular coagulation (DIC) is a consumptive coagulopathy that is characterized by diffuse intravascular fibrin formation that overcomes the body’s natural anticoagulant mechanisms. DIC is most commonly associated with sepsis, trauma, or malignancy or in obstetric complications. The pathogenesis of DIC is not completely elucidated, but it involves intravascular exposure to phospholipids from damaged tissue, hemolysis, and endothelial damage. This leads to stimulation of procoagulant pathways with uncontrolled thrombin generation and microvascular ischemia. A secondary hyperfibrinolysis subsequently occurs. The primary clinical manifestations of DIC are bleeding at venipuncture sites, petechiae, and ecchymoses. Severe gastrointestinal and pulmonary hemorrhage can occur. The clinical diagnosis of DIC is based on laboratory findings in the appropriate clinical setting, such as severe sepsis. Although there is no single test for DIC, the common constellation of findings is thrombocytopenia (<100,000/μL), elevated prothrombin time and activated partial thromboplastin time, evidence of micro-angiopathic hemolytic anemia, and elevated fibrin degradation productions and D-dimer. The fibrinogen level may be less than 100 mg/dL but often does not decrease acutely unless the DIC is very severe. The primary treatment of DIC is to treat the underlying cause, which in this case would be antibiotic therapy directed against Neisseria meningitidis. For patients such as this one who are experiencing bleeding related to the DIC, attempts to correct the coagulopathy should be undertaken. Platelet transfusions and fresh-frozen plasma (FFP) should be given. In addition, cryoprecipitate is indicated as the fibrinogen level is less than 100 mg/dL. In general, 10 U of cryoprecipitate are required for every 2 to 3 units of FFP. In acute DIC, heparin is not been demonstrated to be helpful and may increase bleeding. Low-dose heparin therapy (5–10 U/kg) is used for chronic low-grade DIC such as that seen in acute promyelocytic leukemia or removal of a dead fetus.

III-103. The answer is E. (Chap. 116) Vitamin K is a fat-soluble vitamin that plays an essential role in hemostasis. It is absorbed in the small intestine and stored in the liver. It serves as a cofactor in the enzymatic carboxylation of glutamic acid residues on prothrombin-complex proteins. The three major causes of vitamin K deficiency are poor dietary intake, intestinal malabsorption, and liver disease. The prothrombin complex proteins (factors II, VII, IX, and X and protein C and protein S) all decrease with vitamin K deficiency. Factor VII and protein C have the shortest half-lives of these factors and therefore decrease first. Therefore, vitamin K deficiency manifests with prolongation of the prothrombin time first. With severe deficiency, the activated partial thromboplastin time will be prolonged as well. Factor VIII is not influenced by vitamin K.

III-104. The answer is E. (Chap. 116) Hemophilia A results from a deficiency of factor VIII. Replacement of factor VIII is the centerpiece of treatment. Cessation of aspirin or nonsteroidal anti-inflammatory drugs is highly recommended. Fresh-frozen plasma (FFP) contains pooled plasma from human sources. Cryoprecipitate refers to FFP that is cooled, resulting in the precipitation of material at the bottom of the plasma. This product contains about half the factor VIII activity of FFP in a tenth of the volume. Both agents are therefore reasonable treatment options. DDAVP (desmopressin) causes the release of a number of factors and von Willebrand factor from the liver and endothelial cells. This may be useful for patients with mild hemophilia. Recombinant or purified factor VIII (i.e., Humate P) is indicated in patients with more severe bleeding. Therapy may be required for weeks, with levels of factor VIII kept at 50%, for postsurgical or severe bleeding. Plasmapheresis has no role in the treatment of patients with hemophilia A.

III-105. The answer is C. (Chap. 116) Lupus anticoagulants (Las) cause prolongation of coagulation tests by binding to phospholipids. Although most often encountered in patients with systemic lupus erythematosus, they may also develop in normal individuals. The diagnosis is first suggested by prolongation of coagulation tests. Failure to correct with incubation with normal plasma confirms the presence of a circulating inhibitor. Contrary to the name, patients with LA activity have normal hemostasis and are not predisposed to bleeding. Instead, they are at risk for venous and arterial thromboembolisms. Patients with a history of recurrent unplanned abortions or thrombosis should undergo lifelong anticoagulation. The presence of LAs or anticardiolipin antibodies without a history of thrombosis may be observed because many of these patients will not go on to develop a thrombotic event.

III-106. The answer is D. (Chap. 116) The activated partial thromboplastin time (aPTT) involves the factors of the intrinsic pathway of coagulation. Prolongation of the aPTT reflects either a deficiency of one of these factors (factor VIII, IX, XI, XII, and so on) or inhibition of the activity of one of the factors or components of the aPTT assay (i.e., phospholipids). This may be further characterized by the “mixing study” in which the patient’s plasma is mixed with pooled plasma. Correction of the aPTT reflects a deficiency of factors that are replaced by the pooled sample. Failure to correct the aPTT reflects the presence of a factor inhibitor or phospholipid inhibitor. Common causes of a failure to correct include the presence of heparin in the sample, factor inhibitors (factor VIII inhibitor being the most common), and the presence of antiphospholipid antibodies. Factor VII is involved in the extrinsic pathway of coagulation. Inhibitors to factor VII would result in prolongation of the prothrombin time.

III-107. The answer is D. (Chap. 116) This patient presents with a significant upper gastrointestinal (GI) bleed with a prolonged prothrombin time (PT). Hemophilia should not cause a prolonged PT. This and the presence of ascites raise the possibility of liver disease and cirrhosis. The contamination of blood products in the 1970s and 1980s resulted in widespread transmission of HIV and hepatitis C virus (HCV) within the hemophilia population receiving factor infusions. It is estimated in 2006, that more than 80% of hemophilia patients older than 20 years old are infected with HCV. Viral inactivation steps were introduced in the 1980s, and recombinant factor VIII and IX were first produced in the 1990s. HCV is the major cause of morbidity and the second leading cause of death in patients exposed to older factor concentrates. Patients develop cirrhosis and complications that include ascites and variceal bleeding. End-stage liver disease requiring a liver transplant is curative for the cirrhosis and the hemophilia (the liver produces factor VIII). Hepatitis B was not transmitted in significant numbers to patients with hemophilia. Diverticular disease or peptic ulcer disease would not explain the prolonged PT. Patients with inadequately repleted factor VIII levels are more likely to develop hemarthroses than GI bleeds, and the slightly prolonged activated partial thromboplastin time makes this unlikely.

III-108. The answer is E. (Chap. 116) The differentiation between disseminated intravascular coagulation (DIC) and severe liver disease is challenging. Both entities may manifest with similar laboratory findings, which are elevated fibrinogen degradation products, prolonged activated partial thromboplastin time and prothrombin time, anemia, and thrombocytopenia. When suspecting DIC, these tests should be repeated over a period of 6 to 8 hours because abnormalities may change dramatically in patients with severe DIC. In contrast, these test results should not fluctuate as much in patients with severe liver disease. Bacterial sepsis with positive blood cultures is a common cause of DIC but is not diagnostic.

III-109. The answer is B. (Chap. 117) Venous thrombosis occurs through activation of the coagulation cascade primarily through the exposure to tissue factor, and the genetic factors that contribute to a predisposition to venous thrombosis typically are polymorphisms affecting procoagulant or fibrinolytic pathways. In contrast, arterial thrombosis occurs in the setting a platelet activation, and the genetic predisposition for arterial thrombosis includes mutations that affect platelet receptors or redox enzymes. The most common inherited risk factors for venous thrombosis are the factor V Leiden mutation and prothrombin 20210 mutation. Other mutations predisposing an individual to venous thrombosis include inherited deficiency of protein C or S and mutations of fibrinogen, tissue plasminogen activator, thrombomodulin, or plasminogen activator inhibitor. The glycoprotein 1b platelet receptor mutation would increase the risk of arterial, but not venous, thrombosis.

III-110. The answer is A. (Chap. 117)D-Dimer is a degradation product of cross-linked fibrin and is elevated in conditions of ongoing thrombosis. Low concentrations of D-dimer are considered to indicate the absence of thrombosis. Patients older than the age of 70 years frequently have elevated D-dimers in the absence of thrombosis, making this test less predictive of acute disease. Clinical symptoms are often not present in patients with deep venous thrombosis (DVT) and do not affect interpretation of a D-dimer. Tobacco use, although frequently considered a risk factor for DVT, and previous DVT should not affect the predictive value of D-dimer. Homan’s sign, calf pain elicited by dorsiflexion of the foot, is not predictive of DVT and is unrelated to D-dimer.

III-111. The answer is E. (Chaps. 117 and 262) The clinical probability of pulmonary embolism (PE) can be delineated into low to high likelihood using the clinical decision rule shown in Table III-111below. In those with a score of 3 or less, PE is low or moderately likely, and a D-dimer test should be performed. A normal D-dimer result combined with a low to moderate clinical probability of PE identifies patients who do not need further testing or anticoagulation therapy. Those with either a likely clinical probability (score >3) or an abnormal D-dimer (with unlikely clinical probability) require an imaging test to rule out PE. Currently, the most attractive imaging method to detect PE is the multislice computed tomography (CT). It is accurate and, if the result is normal, safely rules out PE. This patient has a clinical probability score of 4.5 because of her resting tachycardia and the lack of an alternative diagnosis at least as likely as PE. Therefore, there is no indication for measuring D-dimer, and she should proceed directly to multislice CT of the chest. If this cannot be performed expeditiously, she should receive one dose of low-molecular-weight heparin while awaiting the test.

TABLE III-111 Clinical Decision Rules

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III-112. The answer is C. (Chap. 118) In recent years, a variety of new anticoagulant and antiplatelet drugs have been developed for clinical use. Platelets play an important role in arterial thrombosis, particularly in coronary artery and cerebrovascular disease. Aspirin is the most widely used antiplatelet drug worldwide. Aspirin exerts its effects through inhibition of cyclooxygenase-1. Other commonly used oral antiplatelet agents are clopidogrel and dipyridamole. Clopidogrel is in a class of agents called thienopyridines along with ticlopidine. Thienopyridines act to block a specific adenosine diphosphate receptor (P2Y12) and inhibit platelet aggregation. Dipyridamole inhibits phosphodiesterase to decrease the breakdown of cyclic adenosine monophosphate (cAMP) to decrease platelet aggregation. Intravenous antiplatelet agents have also become increasingly important in the treatment of acute coronary syndromes. All of the intravenous agents act to inhibit platelet aggregation by blocking the glycoprotein (GP) IIb/IIIa receptor. The three agents in clinical use as GP IIb/IIIa inhibitors are abciximab, eptifibatide, and tirofiban.

Anticoagulant agents are primarily used for the prevention and treatment of venous thrombosis. Many anticoagulants are available and act by a variety of mechanisms. Heparin has been used for many years but requires frequent monitoring to be used safely. More recently, low-molecular-weight heparins (LMWHs) have been introduced. These agents are given subcutaneously and generally preferred in many instances over heparin given a more predictable anticoagulant effect. Both heparin and the LMWHs are indirect thrombin inhibitors that act primarily through activation of antithrombin. When activated, antithrombin inhibits clotting enzymes, especially thrombin and factor Xa. Fondaparinux is a newer anticoagulant that inhibits only factor Xa, although it is a synthetic analogue of the pentasaccharide sequence in heparin that binds antithrombin. However, it is too short to bridge antithrombin to thrombin. The direct thrombin inhibitors bind directly to thrombin (rather than antithrombin) to exert their activity. The direct thrombin inhibitors include lepirudin, argatroban, and bivalirudin. The most commonly used oral anticoagulant is warfarin, which inhibits the production of vitamin K–dependent clotting factors. Given the need for frequent monitoring and extensive drug interactions, developing other oral anticoagulants that are safe and effective has been desired for many years. No oral drug has yet been introduced into the market. However, several are in the final stages of development. These include two factor Xa inhibitors (rivaroxaban and apixaban) and one factor IIa inhibitor (dabigatran etexilate).

III-113. The answer is B. (Chap. 118) After implantation of a bare metal coronary artery stent, aspirin and clopidogrel are recommended for at least 4 weeks to decrease the risk of instent restenosis. This patient, however, developed the complication despite adherence to her therapy. This generally suggests resistance to clopidogrel with a decreased ability of clopidogrel to inhibit platelet aggregation. There is a known genetic component to clopidogrel resistance related to specific genetic polymorphisms of the CYP isoenzymes. Up to 25% of whites, 30% of African Americans, and 50% of Asians may carry an allele that renders them resistant to clopidogrel. These polymorphisms are less important in the activation of prasugrel. Thus, in individuals who have evidence of clopidogrel resistance, switching to prasugrel should be considered.

Aspirin resistance is a more controversial subject. It is defined simply in clinical terms as failure of aspirin to prevent ischemic vascular events. Biochemically, aspirin resistance can be defined by failure of usual doses of the drug to produce inhibitory effects on platelet function. However, resistance to aspirin is not reversed by higher doses of aspirin or adding another antiplatelet agent. Because the primary mechanism of arterial thrombosis is platelet aggregation, the anticoagulant agents warfarin and low-molecular-weight heparin are not indicated.

III-114. The answer is B. (Chap. 118) Low-molecular-weight heparins (LMWHs) have largely replaced heparin for most indications if a patient does not have any contraindications to therapy. LMWHs have better bioavailability and longer half-lives after subcutaneous injection. Thus, they can be given at routine intervals for both prophylaxis and treatment. In addition, dosing of LMWHs is simplified because these drugs have a dose-independent clearance, and predictable anticoagulant effects means that monitoring of anticoagulant effect is not required in most patients. Finally, LMWHs have a lower risk of heparin-induced thrombocytopenia, which is important in both short- and long-term administration.