Hematology/Oncology Review

1. Hematology/Oncology Review November 23, 2009

2. Topics to Review • Leukemias • Lymphomas • Plasma Cell Dyscrasias • Myeloproliferative Disorders • Myelodysplastic Disorders • Platelet disorders • Topics in medical oncology

3. Question 1 • A 37 year old woman visits her physician because of a cough and fever of 1 week’s duration. On physical examination, her temperature is 38.3°C. She has diffuse crackles in all lung fields. A chest radiograph shows bilateral extensive infiltrates. CBC shows hemoglogin of 13.9 g/dL, hematocrit 42%, MCV 89, platelet count 210,000, and WBC count 56,000 with 63% seg. Neutrophils, 15% bands, 6% metamyelocytes, 3% myelocytes, and 1% blasts, 8% lymphocytes, 2% monocytes, and 2% eosinophils. The peripheral blood leukocyte alkaline phosphatase score is increased. Which of the following is the most likely diagnosis? • A) Chronic myelogenous leukemia • B) Hairy cell leukemia • C) Hodgkin disease, lymphocyte depletion type • D) Leukemoid reaction • E) Acute Lymphoblastic Leukemia

4. Answer 1 • The answer is D, leukemoid reaction. Marked leukocytosis and immature myeloid cells in the peripheral blood can represent an exaggerated response to infection (leukemoid reaction), or they can be a manifestation of chronic myelogenous leukemia (CML). The leukocyte alkaline phosphatase score is high in the more differentiated cell population seen in reactive leukocytosis, whereas in CML, the leukocyte alkaline phosphatase score is low. The Philadelphia Chromosome (universally present in CML) is lacking in patients with leukemoid reactions. Hairy cell leukemia is accompanied by peripheral blood leukocytes that mark with tartrate-resistant acid phosphatase. Hodgkin disease is not characterized by an increased WBC count. Acute lymphoblastic leukemia is a disease of children and young adults, and the lymphoid cells do not have leukocyte alkaline phosphatase.

5. Question 2 • A 50 year old man has had headache and dizziness for the past 3 months. He has also experienced generalized and severe pruritis, particularly when showering. He notes that his stools are dark. On physical examination, he is afebrile, and his blood pressure is 165/90 mmHg. There is no hepatosplenomegaly or lymphadenopathy. A stool sample is positive for occult blood. CBC shows hemoglobin of 22.3 g/dL, hematocrit 67.1%, MCV 94, platelet count 453,000, and WBC count 7800. Which of the following is the most likely diagnosis? • A) Myelodysplastic syndrome • B) Essential thrombocytosis • C) Chronic Myelogenous Leukemia • D) Erythroleukemia • E) Polycythemia Vera

6. Answer 2 • This patient has polycythemia vera, a myeloproliferative disorder characterized by an increased RBC mass, with hematocrit concentrations typically exceeding 60%. Although the increased RBC mass is responsible for most of the symptoms and signs, these patients also have thrombocytosis and granulocytosis. This occurs because, like other myeloproliferative disorders, polycythemia vera results from transformation of a multipotent stem cell. The high hematocrit concentration causes an increase in blood volume and distention of blood vessels. When combined with abnormal platelet function, this condition presdisposes the patient to bleeding. The abnormal platelet function can also presdispose to thrombosis. The pruritis and peptic ulceration most likely are the result of the histamine release from basophils. In some patients, the disease “burns out” to myelofibrosis. A few patients “blast out” to AML. Myelodysplastic syndromes and other myeloproliferative disorders, such as essential thrombocytosis, are not accompanied by such an increase in RBC mass. Erythroleukemia is not typically accompanied by such a high hematocrit concentration, because leukemic erythroid progenitors do not differentiate into mature RBC’s

7. Question 3 • A 46 year old man notices that his friends have been commenting about his increasingly ruddy complexion over the past 4 months. He has also been experiencing increasing fatigue. On physical examination, he is afebrile, and his spleen tip is palpable. Laboratory studies show hemoglobin of 21.3 g/dL, hematocrit 63.9%, platelet count 376,000, and WBC 9210. The serum erythropoietin level is very low. Which of the following is most likely to produce these findings? • A) Dehydration • B) Renal cell carcinoma • C) Polycythemia Vera • D) Cyanotic Heart Disease • E) Living at high altitude

8. Answer 3 • Polycythemia Vera, one of the myeloproliferative disorders, is a neoplastic disorder of myeloid stem cells, which tend to differentiate predominantly along the erythroid lineage, giving rise to polycythemia. The neoplastic erythroid progenitor cells require extremely small amounts of erythropoietin for survival and proliferation; hence, the levels of erythropoietin are virtually undetectable in polycythemia vera. In patients with chronic hypoxemia, erythropoietin levels are elevated, producing excess RBC’s. Erythropoietin secretion is triggered by anoxia in high altitude dwellers and in patients with chronic lung disease or cyanotic heart disease. Renal cell carcinomas can produce erythropoietin and trigger a paraneoplastic erythrocytosis. In dehydration, hemoconcentration can cause transient polycythemia, but this does not affect normal erythropoietin secretion.

9. Question 4 • A 50 year old man was diagnosed with a diffuse large B cell lymphoma. He underwent intensive chemotherapy, and a complete remission was achieved for seven years. He now reports fatigue and recurrent pulmonary and urinary tract infections over the past 4 months. Physical examination shows no masses, lymphadenopathy, or hepatosplenomegaly. CBC shows hemoglobin of 8.7, hematocrit 25.2%, MCV 88, platelets 67,000, and WBC 2300 with 15% seg neutrophils, 5% bands, 2% metamyelocytes, 2% myelocytes, 6% myeloblasts, 33% lymphocytes, 35% monocytes, and 2% eosinophils. A bone marrow biopsy specimen shows 90% cellularity with many immature cells, including ringed sideroblasts, megaloblasts, hypolobated megakaryocytes, and myeloblasts. Karyotypic analysis shows 5q deletions in many cells. Which of the following is most likely to have now occurred in this patient? • A) Relapse of his previous lymphoma • B) Transformation of the lymphoma into myeloid leukemia • C) Myelodysplasia related to therapy for the previous tumor • D) De novo acute myeloblastic leukemia • E) Myeloid metaplasia with myelofibrosis

10. Answer 4 • The answer is C. This patient has developed a myelodysplasia, characterized by a cellular marrow in which there are maturation defects in multiple lineages. This diagnosis is supported by the presence of ringed sideroblasts, megaloblasts, abnormal megakaryocytes, and myeloblasts in the marrow. Because the hematopoietic cells fail to mature normally, they are not released into the peripheral blood. The patient has pancytopenia and is susceptible to infections. Myelodysplasias are clonal stem cell disorders that develop de novo or after chemotherapy with alkylating agents, as in this case. The presence of chromosomal deletions such as 5q is a marker of post-therapy myelodysplasia. The morphologic abnormalities in the marrow are not seen in any of the other listed conditions.

11. Question 5 • A 61 year old man reports a history of back pain for 5 months. He has recently developed a cough that is productive of yellow sputum. On physical examination, he is febrile, and diffuse rales are heard on auscultation of the lungs. He has no lymphadenopathy or splenomegaly. Laboratory studies include a sputum culture that grew Streptococcus Pneumoniae. The serum creatinine level is 3.7. and the urea nitrogen level is 35 mg/dL. A skull radiograph is shown. During the course of hospitalization, a bone marrow biopsy is performed. Which of the following is the biopsy specimen most likely to show? • A) Scattered small granulomas • B) Numerous Plasma Cells • C) Nodules of small, mature lymphocytes • D) Occasional Reed Sternberg cells • E) Hypercellularity with many blasts

12. Multiple Myeloma

13. Answer 5 • The answer is B. Multiple Myeloma produces mass lesions of plasma cells in bone that lead to lysis and pain. The skull radiograph shows typical punched-out lytic lesions, produced by expanding masses of plasma cells. Bence Jones proteinuria can damage the tubules and give rise to renal failure. Multiple myeloma can be complicated by AL amyloid, which can also lead to renal failure. Patients with myeloma often have infections with encapsulated bacteria because of decreased production of IgG, required for opsonization. Granulomatous disease (which is not produced by pneumococcus) can involve the marrow, but usually it does not produce such sharply demarcated lytic lesions. Nodules of small lymphocytes suggest a small cell lymphocytic leukemia/lymphoma, which is not likely to produce lytic lesions. Reed-Sternberg cells suggest Hodgkin disease. Blasts suggest a leukemic process.

14. Question 6 • A 53 year old woman has experienced nausea with vomiting and early satiety for the past 7 months. On physical exam, she is afebrile and has no lymphadenopathy or hepatosplenomegaly. CBC shows hemoglobin of 12.9, hematocrite 41.9%, platelet count 263,000, and WBC count 8430. An upper GI endoscopy shows loss of the rugal folds of the stomach over a 4x8 cm area of the fundus. Gastric biopsy specimens reveal the presence of Helicobacter pylori organisms in the mucus overlying superficial epithelial cells. There are mucosal and submucosal monomorphous infiltrates of small lymphocytes, which are CD19+ and CD20+ but CD3-. After treatment of the H. Pylori infection, her condition improves. Which of the following is the most likely diagnosis? • A) Acute lymphoblastic leukemia • B) Chronic lymphocytic leukemia • C) Diffuse Large B cell lymphoma • D) Follicular Lymphoma • E) Hodgkin disease, mixed cellularity subtype • F) MALT (marginal zone) lymphoma • G) Waldenstrom macroglobulinemia

15. Answer 6 • The answer is F, MALT (marginal zone) lymphoma. These lympomas arise in middle aged adults at sites of autoimmune or infectious stimulation. If the lesion is associated with lymphoid tissue, it is sometimes called a mucosa-associated lymphoid tissue tumor. The most common sites are the thyroid (Hashimoto throiditis), the salivary glands (in Sjogren syndrome), or the stomach (in H. Pylori associated chronic gastritis. Although monoclonal (like a neoplasm), these MALT lesions can regress with antibiotic therapy for H. Pylori. A MALT lesion can transform to diffuse large B cell lymphoma. The cells correspond to the marginal B cells found at the periphery of stimulated lymphoid follicles. The other lesions are neoplastic conditions that are not related to H. Pylori and require chemotherapy to control.

16. Question 7 • A 50 year old woman sees her physician because of a 3 month history of fatigue and dizziness. She has recently experienced syncopal episodes. On physical examination, she is afebrile, with a pulse of 88, respirations 19, and blood pressure 115/75. She exhibits marked pallor but no hepatosplenomegaly or lymphadenopathy. Laboratory findings show hemoglobin of 6.6, hematocrit 19.9%, platelet count 199,800, WBC 4780, and reticulocyte count 0.1%. The MCV, MCHC, and serum ferritin level are normal. A bone marrow biopsy specimen of aspirate shows normal cellularity, but the cells of the erythroid series, such as pronormoblasts, normoblasts, and later stages, are greatly reduced. Other elements are normal in number and differentiation. Which of the following is the most likely diagnosis? • A) Breast carcinoma • B) Hairy cell leukemia • C) Hodgkin disease, mixed cellularity subtype • D) Multiple myeloma • E) Mycosis fungoides • F) Thymoma • G) Waldenstrom macroglobulinemia

17. Answer 7 • The answer is F, thymoma. The patient has a rare disorder called pure red cell aplasia, which is characterized by selective suppression of the erythroid lineage in the bone marrow. This curious entity is sometimes associated with a thymic tumor. In about one half of such cases, removal of the thymic tumor relieves the RBC aplasia, suggesting some autoimmune mechanism as the cause of the aplasia. Carcinomas can infiltrate the marrow space, a myelophthisic process, and reduce hematopoiesis, but not the erythroid line selectively. Hodgkin disease, multiple myeloma, and Waldenstrom macroglobulinemia can do the same. Patients with leukemias tend to have an elevated peripheral blood WBC count, and when the leukemic cells fill the marrow, all other cell lines are reduced. Mycosis fungoides is a T cell neoplasm involving the skin.

18. Question 8 • A 70 year old man has experienced increasing fatigue for the past 6 months. On physical exam, he has nontender axillary and cervical lymphadenopathy, but there is no hepatosplenomegaly. The hematologic workup shows hemoglobin of 9.5, hematocrit 28%, MCV 90, platelet count 120,000, and WBC 42,000. The peripheral blood smear shows a monotonous population of small, round, mature looking lymphocytes. Flow cytometry shows these cells to be CD19+, CD5+, and TdT-. Which of the following is most likely to be seen with cytogenetic and molecular analysis of the cells in the patient’s blood? • A) t(9;22) leading to BCR-ABL rearrangement • B) Clonal rearrangement of immunoglobulin genes • C) Clonal rearrangement of T-cell receptor genes • D) t(8;14) leading to c-myc overexpression • E) t(14;18) leading to BCL2 overexpression

19. CLL/SLL

20. Answer 8 • The answer is B, clonal rearrangement of immunoglobulin genes. The clinical history, the peripheral blood smear, and the phenotypic markers are characteristic of chronic lymphocytic leukemia, a clonal B-cell neoplasm in which immunoglobulin genes are rearranged and T-cell receptor genes are in germline configuration. The t(9;22) is a feature of chronic myeloid leukemia. The t(8;14) translocation is typical of Burkitt lymphoma; this lymphoma occurs in children at extranodal sites. The t(14;18) translocation is a feature of follicular lymphomas, which are distinctive B cell tumors that involve the nodes and produce a follicular pattern. The lymphoma cells can be present in blood, but they do not look like mature lymphocytes.

21. Question 9 • A 33 year old woman reports having generalized fatigue and night sweats for 3 months. Physical examination shows nontender right cervical lymphadenopathy. Biopsy of one lymph node shows a microscopic pattern of thick bands of fibrous connective tissue with intervening lymphocytes, plasma cells, eosinophils, macrophages, and occasional Reed-Sternberg cells. An abdominal CT scan and bone marrow biopsy specimen show no abnormalities. Which of the following is the most likely subtype and stage of this patient’s disease? • A) Lymphocyte predominance, stage I • B) Lymphocyte predominance, stage II • C) Nodular sclerosis, stage I • D) Mixed cellularity, stage II • E) Lymphocyte depletion, stage III

22. Hodgkin disease- Reed Sternberg cell

23. Answer 9 • The answer is C, nodular sclerosis stage I. The bands of fibrosis are typical of the nodular sclerosis type, which is most commonly seen in young adults, particularly female patients. Involvement of one group of lymph nodes places this in stage I. Mediastinal involvement is common. Most of such cases are stage I or II, and the prognosis of such early stage cases is good.

24. Question 10 • A 4 year old child has appeared listless for about 1 week. He now complains of pain when he is picked up by his mother, and he demonstrates irritability when his arms or legs are touched. In the past 2 days, several large ecchymoses have appeared on the right thigh and left shoulder. CBC shows hemoglobin of 10.2, hematocrit 30.5%, MCV 96, platelet count 45,000, and WBC 13,990. Examination of the peripheral blood smear shows blasts that lack peroxidase positive granules but contain PAS-positive aggregates and stain positively for TdT. Flow cytometry shows the phenotype of blasts to be CD19+, CD3-, and sIg-. Which of the following is the most likely diagnosis? • A) Chronic myelogenous leukemia • B) Idiopathic thrombocytopenic purpura • C) Acute myelogenous leukemia • D) Chronic lymphocytic leukemia • E) Acute lymphoblastic leukemia

25. Answer 10 • These findings are characteristic of a childhood acute lymphoblastic leukemia of the pre-B cell type. The rapid expansion of the marrow caused by proliferation of blasts can lead to bone pain and tenderness. Features supporting an acute leukemia are anemia, thrombocytopenia, and the presence of blasts in the peripheral blood and bone marrow. Anemia and thrombocytopenia result from suppression of normal hematopoiesis by the leukemic clone in the marrow. The phenotype of CD19+, CD3-, and sIg- is typical of pre-B cells. TdT is a marker of early T and B cell type lymphoid cells. Chronic myelogenous leukemia is a disease of adults, and the WBC is quite high; the peripheral blood contains some myeloblasts, but other stages of myeloid differentiation are also detected. In ITP, only the platelet count is reduced, because of antibody mediated destruction of platelets. An AML is a disease of young to middle aged adults, and there would be peroxidase positive myeloblasts and phenotypic features of myeloid cells. CLL is a disease of older adults; patients have many small circulating mature B lymphocytes.

26. Question 11 • A 39 year old man experiences sudden onset of a severe headache. Physical examination shows no localizing neurologic signs and no organomegaly. A stool sample is positive for occult blood. Areas of purpura appear on the skin of his extremities. Laboratory studies show hemoglobin of 9.6, hematocrit 28.9%, platelet count 26,400, and WBC 75,000. The peripheral blood smear has the appearance shown, and shistocytes are also seen. The plasma D dimer level (fibrin degradation products), prothrombin time, and partial thromboplastin time are all elevated. Cytogenetic analysis of cells from a bone marrow biopsy specimen is most likely to yield which of the following karyotypic abnormalities? • A) t(8;21) • B) t(9;22) • C) t(14;18) • D) t(15;17) • E) t(8;14)

27. Auer rods- acute promyelocytic leukemia

28. Answer 11 • The answer is D, t(15;17). This peripheral blood smear is characteristic of acute promyelocytic leukemia (M3 class of AML), with many promyelocytes containing prominent azurophilic granules and short, red, cytoplasmic, rodlike inclusion called Auer rods. Release of the granules can trigger the coagulation cascade, leading to disseminated intravascular coagulation (DIC). As in this case, many patients develop DIC. The t(15;17) translocation is characteristic of this disease; it results in the fusion of the retinoic acid receptor gene on chromosome 17 with the promyelocytic leukemia gene on chromosome 15. The fusion gene results in elaboration of an abnormal retinoic acid receptor that blocks myeloid differentiation. Therapy with retinoic acid (Vitamin A) can alleviate the block and induce remission in many patients. The t(8;21) abnormality is seen in the M2 variant of acute myelogenous leukemia.

29. Question 12 A 20 y/o female presents with anemia secondary to a history of heavy menstrual periods since menarche. On further questioning, her mother also has a history of heavy periods and “some kind of clotting disorder.” Given the mostly likely diagnosis, evaluation of platelets, bleeding time and coagulation would likely show which of the following? • Increased bleeding time, decreased platelets • Increased PT, PTT, bleeding time, dec platelets • Increased bleeding time and PTT, normal platelets • No abnormality • Increased PTT only

30. Answer 12 • The correct answer is C. The patient likely has von Willebrand Disease. See chart

31. Question 13 • A 44 year-old female reports a waxing and waning cough, dyspnea and vague chest discomfort for the past five years. She also has intermittent fevers over the same time period with a six pound weight loss. On exam, red, tender subcutaneous swelling is found on both lower limbs, and decreased breath sounds and rales are found bilaterally. A biopsy of one of the skin lesions shows noncaseating granulomas. A chest X-ray shows mediastinal lymphadenopathy. Which of the following electrolyte abnormalities is most likely evident in this patient's plasma?A. HypercalcemiaB. HyperkalemiaC. HypernatremiaD. HypocholermiaE. Hyponatremia

32. Answer 13 • A is the correct answerThe likely diagnosis is pulmonary sarcoidosis. The noncaseating granulomas are evident in the skin lesions of erythema nodosum and the chest X-ray shows hilar adenopathy. An increase in serum vitamin D levels are a result of hypersecretion by pulmonary macrophages, resulting in the body retaining calcium. Hypercalcemia and hypercalciuria are apparent on laboratory examination.

33. Question 14 • A patient comes to you for counseling about his risk for colon cancer. Which of the following risk factors in this patient is thought to be associated with colon cancer? • A. Hx of colon CA in a 2nd cousin • B. Obesity • C. Irritable Bowel Syndrome • D. Diet rich in fruit and vegetables • E. Smoking

34. Answer 14 • The answer is B, obesity • Colon cancer is thought to be associated with obesity, history of cancer in a 1st degree relative, inflammatory bowel disease, and diets rich in red meat. • Diets rich in fruits, veggies and fiber can be colon protective. Regular exercise may also be of benefit

35. Question 15 • A firm, irregular prostatic nodule is discovered during annual physical examination of a 66y/o patient. Biopsy reveals the presence of prostate cancer. Which of the following factors has the greatest prognostic impact? • A. Degree of cellular atypia • B. Histological grading • C. Initial PSA level • D. Pathological staging • E. Presence of mitotic figures

36. Answer 15 • The answer is D, Pathological Staging Stage is determined by extent of tumor infiltration and metastasis. TNM is a common method. Survival has been more closely correlated with staging vs grading of tumor. PSA is not a reliable prognostic indicator but can be useful in monitoring disease recurrence.

37. Breast Cancer facts • Fibrocystic changes- Most common cause of “breast lump” (lumpy/bumpy breast)—irregular and not a discrete mass, ductal proliferation/dilation and fibrosis, cyclic changes • Fibroadenoma- discrete, firm breast mass in young woman (20’s/30’s), fibrous proliferation with compressed ductules, enlarge during pregnancy or with menstrual cycle • Intraductal papilloma- small mass lesion in lactiferous sinuses, most common reason for bloody nipple discharge • Fat necrosis- can present as a discrete painless breast mass with irregular borders (mimicking cancer), often associated with trauma, microscopically see macrophages and neutrophils around necrotic adipocytes • Mastitis- Red, hot, tender breast lesions, often found in lactating women, most common cause= Staphylococcus Aureus

38. Breast Cancer Facts • Fibrocystic change may be assossiated with proliferative changes that increase chance for breast cancer (epithelial hyperplasia, atypical hyperplasia) • DCIS- At least half of mammographically detectable breast cancers (trt. = surgical excision and radiotherapy), cribriform lesions, calcification due to necrosis of neoplastic cells, necrotic cells exuding into ducts= comedocarcinoma • Paget disease of nipple- extension of malignant cells of DCIS to nipple and areola, causing a skin lesion resembling seborrheic dermatitis • Colloid carcinoma- mucin, medullary carcinoma- large, lymphocytes • LCIS- lesion most likely to be bilateral, invasive lobular- “indian filing” • Invasive cancer- Painless, firm, enlarging lesion with irregular borders, possible axillary lymphadenopathy, can infiltrate lymphatics and cause “inflammatory carcinoma”- peau d’orange skin • ER/PR + = good marker (trt. with tamoxifen), HER 2 neu + trt. With trastuzumab

39. Sources • Questions: • Klatt, Edward C, M.D. and Kumar, Vinay, M.D. Robbins and Kotran Review of Pathology: Second Edition. 2005 • www.wikitestprep.org • Deja ReviewUSMLE Step 1 Essentials • USMLE Step 1: Lange Q&A • Images: • www.path.sunysb.edu/labs/test%20web/stains.html • http://www.bindingsite.com/news-5.asp?id=226&view=archive • http://www.wadsworth.org/chemheme/heme/glass/slide_002_smudge_cells.htm • http://www.lmp.ualberta.ca/resources/pathoimages/PC-R.htm • http://wjso.com/content/figures/1477-7819-6-34-5-l.jpg