B14 RBC, WBC & Bleeding Disorders

21 A 69-year-old woman complains of increasing *back pain for 1 month*. On physical examination, there is tenderness over the lower back, but no kyphosis or scoliosis. A radiograph of the spine shows a partial collapse of T11 and several 0.5- to 1.5-cm lytic lesions with a rounded "soap-bubble" appearance in the thoracic and lumbar vertebrae. A bone marrow biopsy is performed, and a smear of the aspirate shows *"punched-out" bone lesions*. Which of the following is the most likely laboratory finding in this patient? □ (A) Bence Jones proteins in the urine □ (B) t(9;22) in the karyotype of marrow □ (C) Elevated leukocyte alkaline phosphatase score □ (D) Decreased serum alkaline phosphatase level □ (E) Platelet count of 750,000/mm3 □ (F) WBC count of 394,000/mm3

(A) Bence Jones proteins in the urine The characteristic "punched-out" bone lesions of multiple myeloma seen on radiographs result from bone destruction mediated by RANKL, a cytokine produced by the myeloma cells that activates osteoclasts. Several cytokines, most notably IL-6, are important growth factors for plasma cells. They are produced by tumor cells and resident marrow stromal cells. High serum levels of IL-6 correlate with active disease and poor prognosis. The monoclonal population of plasma cells often produces a monoclonal serum "spike" seen in serum or urine protein electrophoresis. Patients can have hypercalcemia and an increased serum alkaline phosphatase level. The neoplastic cells are generally well differentiated, with features such as a perinuclear hof, similar to normal plasma cells. The t(9;22) translocation is the Philadelphia chromosome seen in chronic myelogenous leukemia (CML). CML and other myeloproliferative disorders sometimes are accompanied by a thrombocytosis, but are unlikely to produce mass lesions or bony destruction. Leukemias also can fill the marrow space, but generally do not destroy bone. BP7 429-431BP8 453-456PBD7 679-681PBD8 610

8 A 65-year-old man diagnosed with follicular non-Hodgkin's lymphoma is treated with chemotherapy. He develops fever and cough. On examination, there are bilateral pulmonary rales. A chest radiograph shows diffuse interstitial infiltrates. A shell vial assay of sputum is *positive for cytomegalovirus*. He develops scleral icterus. Laboratory studies show hemoglobin, 10.3 g/dL; hematocrit, 41.3%; MCV, 101 µm3; WBC count, 7600/mm3; and platelet count, 205,000/mm3. His serum total bilirubin is 6 mg/dL, direct bilirubin is 0.8 mg/dL, and LDH is 1020 U/L. *Coombs's test is positive*. Which of the following is the most likely mechanism for his anemia? □ (A) Binding of IgM to red blood cells □ (B) Chemotherapeutic bone marrow toxicity □ (C) Cytomegalovirus hepatitis □ (D) Dietary folate deficiency □ (E) Metastases to colon

(A) Binding of IgM to red blood cells The findings point to Coombs-positive immune hemolytic anemia. Cold agglutinin immunohemolytic anemia can be seen with lymphoid neoplasms and infections such as Mycoplasma, Epstein-Barr virus, HIV, influenza virus, and cytomegalovirus. IgM binds to RBCs at cooler peripheral body regions, then fixes complement. At warmer central regions, the antibody is eluted, but the complement marks the RBCs for extravascular destruction in the spleen, and there is minimal intravascular hemolysis. The increased RBC turnover increases the MCV and the bilirubin, which is mainly indirect. Chemotherapy can suppress bone marrow production, but more likely all cell lines, and without an immune component. This patient has CMV infection, but hepatitis would likely increase direct and indirect bilirubin, and not account for anemia. Folate deficiency could account for macrocytosis, but not a positive Coombs test. Non-Hodgkin lymphomas do not often involve colon, but this might account for gastrointestinal bleeding with features of iron deficiency and microcytosis. BP7 444-446BP8 432-433PBD7 637PBD8 653-654

46 A *14-year-old boy* complains of a feeling of discomfort in his chest that has worsened over the past 5 days. On physical examination, he has generalized lymphadenopathy. A chest radiograph shows clear lung fields, but there appears to be *widening of the mediastinum*. A chest CT scan shows a 10-cm mass in the anterior mediastinum. A biopsy specimen of the mass shows lymphoid cells with lobulated nuclei having delicate, finely stippled, nuclear chromatin. There is scant cytoplasm, and many mitoses are seen. The cells express *TdT, CD2, and CD7 antigens*. Molecular analysis reveals a *point mutation in the NOTCH1 gene*. What is the most likely diagnosis? □ (A) Acute Lymphoblastic lymphoma □ (B) Burkitt lymphoma □ (C) Hodgkin lymphoma, nodular sclerosing type □ (D) Mantle cell lymphoma □ (E) Follicular lymphoma □ (F) Small lymphocytic lymphoma

(A) Acute Lymphoblastic lymphoma The age and mediastinal location are typical of a lymphoblastic lymphoma involving the thymus. This lesion is within the spectrum of acute lymphoblastic leukemia or lymphoma (ALL). Most cases of ALL with lymphomatous presentation are of the pre-T cell type. This fact is supported by the expression of the T-cell markers CD2 and CD7. The NOTCH1 gene encodes for a transmembrane receptor required for T cell development, and more than half of pre-T cell tumors have activating point mutations. TdT is a marker of pre-T cells and pre-B cells. A Burkitt lymphoma is a B-cell lymphoma that also can be seen in adolescents, but usually is present in the jaw or abdomen. Nodular sclerosing Hodgkin lymphoma does occur in the mediastinum, but it involves mediastinal nodes, not thymus. The histologic features of Hodgkin lymphoma include the presence of Reed-Sternberg cells, and this variant has fibrous bands intersecting the lymphoid cells. Mantle cell lymphomas and follicular lymphomas are B-cell tumors usually seen in older patients, and they do not involve the thymus. Small lymphocytic lymphoma is the tissue phase of chronic lymphocytic leukemia seen in older adults.

45 A *9-year-old* boy has developed prominent bruises on his extremities over the past week. On physical examination, he has *ecchymoses and petechiae on his arms and legs*. Laboratory studies show hemoglobin, 13.8 g/dL; hematocrit, 41.9%; MCV, 93 µm3; platelet count, 22,300/mm3; and WBC count, 7720/mm3. He had *respiratory syncytial virus pneumonia 3 weeks ago. His condition improves with corticosteroid therapy*. Which of the following abnormalities is most likely to cause his hemorrhagic diathesis? □ (A) Antiplatelet antibodies □ (B) Bone marrow aplasia □ (C) Glycoprotein IIb/IIIa dysfunction □ (D) Vitamin C deficiency □ (E) Von Willebrand factor metalloproteinase deficiency

(A) Antiplatelet antibodies Acute immune thrombocytopenic purpura (ITP) and chronic ITP are caused by antiplatelet autoantibodies, but the acute form is typically seen in children after a viral disease. If the bone marrow were aplastic, all cell lines should be reduced. Glycoprotein IIb/IIIa dysfunction/deficiency can be seen with Glanzmann thrombasthenia and chronic ITP. Scurvy owing to vitamin C deficiency leads to increased capillary fragility with ecchymoses, but not to thrombocytopenia. Von Willebrand factor metalloproteinase deficiency is a feature of thrombotic thrombocytopenic purpura. BP8 471-472PBD7 652PBD8 668

17 A 34-year-old man has experienced multiple nosebleeds along with bleeding gums for the past month. On examination, his temperature is 37.3°C. He has multiple cutaneous ecchymoses. Laboratory studies show hemoglobin, *8.5 g/dL; hematocrit, 25.7%; platelet count, 13,000/mm3*; and WBC count, 52,100/mm3 with 5% segmented neutrophils, 5% bands, 2% myelocytes, 83% blasts, 3% lymphocytes, and 2% monocytes. Examination of his peripheral blood smear shows the *blasts have delicate nuclear chromatin along with fine cytoplasmic azurophilic granules*. These blasts are CD33+. Which of the following morphologic findings is most likely to be present on his peripheral blood smear? □ (A) Auer rods □ (B) Döhle bodies □ (C) Hairy projections □ (D) Heinz bodies □ (E) Sickle cells □ (F) Toxic granulations

(A) Auer rods This patient has acute myelogenous leukemia, which infiltrates the marrow and reduces normal hematopoiesis to account for anemia and marked thrombocytopenia. The initial presentation may be acute. The Auer rods are condensations of the azurophilic granules. Döhle bodies, which are patches of dilated endoplasmic reticulum, and toxic granulations, which are coarse and dark primary granules, are reactive changes in mature neutrophils most indicative of marked inflammation, such as bacterial sepsis. Hairy projections are seen on the circulating B cells of hairy-cell leukemia. Heinz bodies are seen in G6PD deficiency and are precipitates of denatured globin. Sickling of RBCs is a feature of sickle cell anemia, which is not related to leukemia. BP7 436-437BP8 461-464PBD7 692-695PBD8 622-624

57 A 9-year-old, otherwise healthy girl has complained of pain in the right armpit for the past week. Examination by the physician shows tender lymphadenopathy of the right axillary region. There are four linear and nearly healed abrasions over a 3 × 2 cm area of the distal ventral aspect of the right forearm and a single, 0.5-cm, slightly raised erythematous nodule over one of the abrasions. No other abnormalities are noted. If a lymph node biopsy were performed, the microscopic appearance of the specimen would show a pattern of stellate, necrotizing granulomas. The lymphadenopathy regresses over the next 2 months. Infection with which of the following is most likely to have produced these findings? □ (A) Bartonella henselae □ (B) Cytomegalovirus □ (C) Epstein-Barr virus □ (D) Staphylococcus aureus □ (E) Yersinia pestis

(A) Bartonella henselae This child has cat-scratch disease, a form of self-limited infectious lymphadenitis that most often is seen in children, typically "upstream" of lymphatic drainage from the site of injury, so that the axillary and cervical lymph node regions are most often involved. Cytomegalovirus infection is typically seen in immunocompromised individuals and is not a common cause of lymphadenopathy. Epstein-Barr virus (EBV) infection at this age is most often associated with infectious mononucleosis and pharyngitis, and the lymphadenopathy is nonspecific. Staphylococcus aureus can produce suppurative inflammation with sepsis. Yersinia pestis, the agent that causes bubonic plague, produces lymphadenopathy that can ulcerate and a hemorrhagic necrotizing lymphadenitis; it has a high mortality rate. BP7 419BP8 444PBD7 349, 665-666 PBD8 595-596

38 A 41-year-old man has experienced several bouts of pneumonia over the past year. He now complains of vague abdominal pain and a dragging sensation. Physical examination shows *marked splenomegaly*. CBC shows hemoglobin, 8.2 g/dL; hematocrit, 24.6%; MCV, 90 µm3; platelet count, 63,000/mm3; and WBC count, 2400/mm3. The peripheral blood smear shows many small leukocytes with *reniform nuclei and pale blue cytoplasm with threadlike extensions*. A chest x-ray shows patchy infiltrates, and a culture of sputum grows Mycobacterium kansasii. Which of the following laboratory findings is most characteristic of this disease? □ (A) CD19, CD20, and CD11c expression in leukocytes □ (B) Presence of Auer rods in leukocytes □ (C) Presence of Ph1 chromosome □ (D) Presence of toxic granulations in neutrophils □ (E) Monoclonal IgM in serum

(A) CD19, CD20, and CD11c expression in leukocytes This patient has hairy cell leukemia, an uncommon neoplastic disorder of B cells. These cells infiltrate the spleen and marrow. Pancytopenia results from poor production of hematopoietic cells in the marrow and sequestration of the mature cells in the spleen. There are two characteristic features of this disease: the presence of hairy projections from neoplastic leukocytes in the peripheral blood smear and coexpression of B cell (CD19, CD20) and monocyte (CD11c) markers. In the past, staining for tartrate-resistant acid phosphatase was used. Auer rods are seen in myeloblasts in acute myeloblastic leukemia. The Ph1 chromosome is a distinctive feature of chronic myelogenous leukemia. Toxic granulations in neutrophils are seen most often in overwhelming bacterial infections. A monoclonal IgM spike is a feature of lymphoplasmacytic lymphoma (Waldenström macroglobulinemia). BP7 435BP8 459-460PBD7 683-684PBD8 614

42 A 51-year-old man visits his physician because the skin of his face, neck, and trunk has become scaly red. He also complains of intense itching and a 3-kg weight loss over the past 2 months. On physical examination, his temperature is 37.6°C, and he has a generalized exfoliative erythroderma. Generalized nontender lymphadenopathy is present. Laboratory studies show hemoglobin, 12.9 g/dL; hematocrit, 42%; platelet count, 231,000/mm3; and WBC count, 7940/mm3 with 57% segmented neutrophils, 3% bands, 26% lymphocytes, 5% monocytes, and 9% eosinophils. A skin biopsy specimen shows the presence of *lymphoid cells in the upper dermis and epidermis. These cells have cerebriform nuclei with marked infolding of nuclear membranes*. Similar cells are seen on the peripheral blood smear. Which combination of the following phenotypic markers is most likely to be expressed on his abnormal lymphocytes? □ (A) CD3+, CD4+ □ (B) CD5+, CD56+ □ (C) CD10+, CD19+ □ (D) CD13+, CD33+ □ (E) CD19+, sIg+

(A) CD3+, CD4+ The involvement of skin and the presence of lymphocytes with complex cerebriform nuclei in the skin and the blood are features of cutaneous T-cell lymphomas. These are malignancies of CD4+ and CD3+ T cells that may produce a tumor-like infiltration of the skin (mycosis fungoides) or a leukemic picture without tumefaction in the skin (Sézary syndrome). Cutaneous T-cell lymphomas are indolent tumors, and patients have a median survival of 8 to 9 years. The other phenotypes provided here are those of CD3−, CD56+ NK cells; mature B cells with CD19+, sIg+; monocytes/granulocytes with CD33+, CD13+; and neoplastic B cells in chronic lymphocytic leukemia with CD19+, CD5+. BP7 435BP8 460PBD7 671, 685PBD8 616

51 A 65-year-old man has experienced worsening fatigue for the past 5 months. On physical examination, he is afebrile and has a pulse of 91/min, respirations of 18/min, and blood pressure of 105/60 mm Hg. There is no organomegaly. A stool sample is positive for occult blood. Laboratory findings include *hemoglobin of 5.9* g/dL, hematocrit of 17.3%, *MCV of 96* µm3, platelet count of 250,000/mm3, and WBC count of 7800/mm3. The *reticulocyte concentration is 3.9%*. No fibrin split products are detected, and direct and indirect Coombs' test results are negative. A bone marrow biopsy specimen shows *marked erythroid hyperplasia*. Which of the following conditions best explains these findings? □ (A) Chronic blood loss □ (B) Iron deficiency anemia □ (C) Aplastic anemia □ (D) Metastatic prostatic adenocarcinoma □ (E) Autoimmune hemolytic anemia

(A) Chronic blood loss The marked reticulocytosis and marrow hyperplasia indicate that the marrow is responding to a decrease in RBCs. The reticulocytes are larger RBCs that slightly increase the MCV. Iron deficiency impairs the ability of the marrow to mount a significant and sustained reticulocytosis. Iron deficiency anemia is typically microcytic and hypochromic. An aplastic marrow is very hypocellular and unable to respond to anemia; it is associated with pancytopenia. Infiltrative disorders, such as metastases in the marrow, would impair the ability to mount a reticulocytosis of this degree. The normal Coombs test results exclude an autoimmune hemolytic anemia. BP7 397-398BP8 423-424PBD7 623-625PBD8 641

58 A 63-year-old man has noticed a lump in her neck for 2 months. Examination reveals a group of *three discrete nontender right posterior cervical lymph nodes, and a mass of enlarged right axillary lymph nodes*. Chest and abdominal CT scans show *mediastinal lymphadenopathy and hepatosplenomegaly.* A cervical lymph node biopsy reveals abundant large *CD15+ and CD30+ binucleate cells with prominent acidophilic nucleoli, scattered within a sparse lymphocytic infiltrate*. What is molecular analysis of this lesion most likely to reveal? □ (A) Clonal EBV integration in the large cells □ (B) BCL6 gene rearrangements in the large cells □ (C) Deletions of 5q in all the cells □ (D) Helicobacter pylori infection in all the cells □ (E) JAK2 gene mutations in the lymphocytes

(A) Clonal EBV integration in the large cells This is the lymphocyte depletion variant of Hodgkin lymphoma with abundant Reed-Sternberg cells and paucity of lymphocytes. Most cases present with advanced disease (stage IV in this example). Epstein-Barr virus (EBV) is present in over 90% of cases. BCL6 gene rearrangements are typical of diffuse large B-cell lymphomas. Deletions of 5q are typical of myelodysplastic syndrome. Infection with Helicobacter pylori can give rise to marginal zone lymphoma. JAK2 mutations are found in polycythemia vera and other myeloproliferative diseases.

41 A *7-year-old boy* has complained of a severe headache for the past week. On physical examination, there is *tenderness on palpation of long bones, hepatosplenomegaly, and generalized lymphadenopathy*. Petechial hemorrhages are present on the skin. Laboratory studies show hemoglobin, 8.8 g/dL; hematocrit, 26.5%; platelet count, 34,700/mm3; and WBC count, 14,800/mm3. A bone marrow biopsy specimen shows 100% cellularity, with almost complete replacement by a population of large cells with scant cytoplasm lacking granules, delicate nuclear chromatin, and rare nucleoli. He receives a course of chemotherapy and has a complete remission. Which of the following combinations of phenotypic and karyotypic markers is most likely to be present in this patient? □ (A) Early pre-B (CD19+, TdT+); hyperdiploidy □ (B) Early pre-B (CD19+, TdT+); t(9;22) □ (C) Pre-B (CD5+, TdT+); normal karyotype □ (D) Pre-B (CD5+, TdT+,); t(9;22) □ (E) T cell (CD3+, CD2+); normal karyotype □ (F) T cell (CD3+, CD2+); hyperdiploidy

(A) Early pre-B (CD19+, TdT+); hyperdiploidy Three markers strongly favor a very good prognosis for acute lymphoblastic leukemia (ALL): early precursor-B cell type, hyperdiploidy, and patient age between 7 and 10 years, chromosomal trisomy, and t(12;21). Marrow infiltration by the leukemic cells leads to pancytopenia. Poor prognostic markers for acute lymphoblastic leukemia/lymphoma are T cell phenotype, patient age younger than 2 years, WBC count >100,000, presence of t(9;22), and presentation in adolescence and adulthood. In most T cell ALL cases in adolescents, a mediastinal mass arises in the thymus, and lymphoid infiltrates appear in tissues of the mononuclear phagocyte system. appear in tissues of the mononuclear phagocyte system. BP7 421-424BP8 447-449PBD7 670-673PBD8 601-603

19 A 37-year-old man known to have been *infected with HIV for the past 10 years* is admitted to the hospital with abdominal pain of 3 days' duration. Physical examination shows abdominal distention and absent bowel sounds. An abdominal CT scan shows a mass lesion involving the ileum. He undergoes surgery to remove an area of bowel obstruction in the ileum. Gross examination of the specimen shows a firm, white mass, 10 cm long and 3 cm at its greatest depth. The mass has infiltrated through the wall of the ileum. Histologic studies show a mitotically active population of *CD19+ lymphoid cells with prominent nuclei and nucleoli*. Molecular analysis is most likely to show which of the following viral genomes in the lymphoid cells? □ (A) Epstein-Barr virus □ (B) HIV □ (C) Human herpesvirus type 8 □ (D) Human T-cell leukemia/lymphoma virus type 1 □ (E) Cytomegalovirus

(A) Epstein-Barr virus This HIV-positive patient has an extranodal infiltrative mass, composed of B cells (CD19+), in the ileum. This is a diffuse large cell lymphoma of B cells. These tumors contain the Epstein-Barr virus (EBV) genome, and it is thought that immunosuppression allows unregulated proliferation and neoplastic transformation of EBV-infected B cells. HIV is not seen in normal or neoplastic B cells. Human herpesvirus type 8 (also called Kaposi sarcoma herpesvirus) is found in the spindle cells of Kaposi sarcoma and in body cavity B-cell lymphomas in patients with AIDS. Human T-cell leukemia/lymphoma virus type 1 is related to HIV-1, and it causes adult T-cell leukemia/lymphoma. Cytomegalovirus is not known to cause any tumors.

9 A 63-year-old woman experiences a burning sensation in her hands and feet. Two months ago, she had an episode of swelling with tenderness in the right leg, followed by dyspnea and right-sided chest pain. On physical examination, the spleen and liver now appear to be enlarged. CBC shows hemoglobin, 13.3 g/dL; hematocrit, 40.1%; MCV, 91 µm3; *platelet count, 657,000/mm3*; and WBC count, 17,400/mm3. The peripheral blood smear shows *abnormally large platelets*. Which of the following is the most likely diagnosis? □ (A) Essential thrombocythemia □ (B) Chronic myelogenous leukemia □ (C) Myelofibrosis with myeloid metaplasia □ (D) Acute myelogenous leukemia □ (E) Polycythemia vera

(A) Essential thrombocythemia Essential thrombocythemia is a myeloproliferative disorder. As with all myeloproliferative diseases, the transformation occurs in a myeloid stem cell. In this form of myeloproliferative disease, the dominant cell type affected is the megakaryocyte, and there is thrombocytosis. Other myeloproliferative disorders, such as chronic myelogenous leukemia, myelofibrosis, and polycythemia vera, also can be accompanied by an increased platelet count. The diagnosis of essential thrombocytosis can be made after other causes of reactive thrombocytosis are excluded, and if the bone marrow examination shows increased megakaryocytes with no evidence of leukemia. The throbbing, burning pain in the extremities is caused by platelet aggregates that occlude small arterioles. The major manifestation of this disease is thrombotic or hemorrhagic crises. The swelling in this patient's leg represents phlebothrombosis, followed by pulmonary embolism with infarction. The peripheral blood WBC count would be high in acute myelogenous leukemia, without thrombocytosis. BP8 464, 466PBD7 700PBD8 629-630

18 A 41-year-old woman sees her physician because of a 2-week history of multiple ecchymoses on her extremities after only minor trauma. She also reports feeling extremely weak. Over the previous 24 hours, she has developed a severe cough productive of yellowish sputum. On physical examination, her temperature is 38.4°C, and she has diffuse crackles on all lung fields. Laboratory studies show *hemoglobin, 7.2 g/dL; hematocrit, 21.4%; MCV, 88 µm3; platelet count, 35,000/mm3; and WBC count, 1400/mm3 with 20% segmented neutrophils, 1% bands, 66% lymphocytes, and 13% monocytes. The reticulocyte count is 0.1%*. Given these laboratory findings, which of the following historical findings would be most useful in determining the cause of her condition? □ (A) Exposure to drugs □ (B) Dietary history □ (C) Recent bacterial infection □ (D) Menstrual history □ (E) Family history of anemias

(A) Exposure to drugs The pancytopenia and absence of a reticulocytosis strongly suggest bone marrow failure. Aplastic anemia has no apparent cause in half of all cases. In other cases, drugs and toxins may be identified; drugs such as chemotherapeutic agents are best known for this effect. A preceding viral infection may be identified in some cases, but bacterial infections rarely cause aplastic anemias. Individuals with pancytopenia are subject to bleeding disorders because of the low platelet count and to infections because of the low WBC count. Dietary history would not be helpful because this patient's clinical and laboratory picture is not characteristic of iron deficiency or vitamin B12 deficiency. Menstrual history would be relevant if the patient had hypochromic microcytic anemia. The only known familial cause of aplastic anemia (Fanconi anemia) is rare. BP7 414BP8 439-440PBD7 647-648PBD8 663-664

15 An 18-month-old girl has developed seborrheic skin eruptions over the past 3 months. She has had *recurrent upper respiratory and middle ear infections with Streptococcus pneumoniae* for the past year. Physical examination indicates that she also has *hepatosplenomegaly and generalized lymphadenopathy. Her hearing is reduced in the right ear*. A skull radiograph shows an expansile, 2-cm lytic lesion involving the right temporal bone. Laboratory studies show no anemia, thrombocytopenia, or leukopenia. The mass is curetted. Which of the following is most likely to be seen on microscopic examination of this mass? □ (A) Histiocytes with Birbeck granules □ (B) Lymphoblasts □ (C) Plasma cells with Russell bodies □ (D) Reed-Sternberg cells □ (E) Ringed sideroblasts □ (F) Sézary cells

(A) Histiocytes with Birbeck granules The child has Letterer-Siwe disease, a form of Langerhans cell histiocytosis. The Birbeck granules are a distinctive feature, identified by electron microscopy, which are found in the cytoplasm of the Langerhans cells. Lymphoblasts that mark as T cells are seen in anterior mediastinal (thymic) masses in children with acute lymphoblastic leukemia/lymphoma. Plasma cells are seen in multiple myeloma, a disease of older adults accompanied by a monoclonal gammopathy. ReedSternberg cells are seen in Hodgkin lymphoma, which is an unlikely disease in children. Ringed sideroblasts can be seen in myelodysplastic syndromes. Sézary cells can be seen in peripheral T-cell lymphoma/leukemias, which often involve the skin. BP7 441BP8 467-468PBD7 701-702PBD8 631-632

13 A 12-year-old boy has a history of episodes of severe abdominal and back pain since early childhood. On physical examination, he is afebrile, and there is no organomegaly. Laboratory studies show hemoglobin of 11.2 g/dL, platelet count of 194,000/mm3, and WBC count of 9020/mm3. The peripheral blood smear shows occasional sickled cells, nucleated RBCs, and Howell-Jolly bodies. Hemoglobin electrophoresis shows 1% hemoglobin A2, 6% hemoglobin F, and *93% hemoglobin S*. Hydroxyurea therapy is found to be beneficial in this patient. Which of the following is the most likely basis for its therapeutic efficacy? □ (A) Increase in production of hemoglobin F □ (B) Increase in production of hemoglobin A □ (C) Decrease in overall globin synthesis □ (D) Stimulation of erythrocyte production □ (E) Increase in oxygen affinity of hemoglobin

(A) Increase in production of hemoglobin F Children and adults with sickle cell anemia may benefit from hydroxyurea therapy, which can increase the concentration of hemoglobin F in RBCs, which interferes with the polymerization of hemoglobin S. However, the therapeutic response to hydroxyurea often precedes the increase in hemoglobin F levels. Hydroxyurea also has an antiinflammatory effect, increases the mean RBC volume, and can be oxidized by heme groups to produce nitric oxide. Because hemoglobin F levels are high for the first 5 to 6 months of life, patients with sickle cell anemia do not manifest the disease during this period. Because both β-globin chains are affected, no hemoglobin A1 is produced. Globin synthesis decreases with the thalassemias. The hemolysis associated with sickling promotes erythropoiesis, but the concentration of hemoglobin S is not changed. Hydroxyurea does not shift the oxygen dissociation curve or change the oxygen affinity of the various hemoglobins. BP7 403BP8 426-428PBD7 631-632PBD8 645-648

29 A 10-year-old child has experienced multiple episodes of pneumonia and meningitis with septicemia since infancy. Causative organisms that have been cultured include Streptococcus pneumoniae and Haemophilus influenzae. On physical examination, the child has no organomegaly and no deformities. Laboratory studies show hemoglobin of 9.2 g/dL, hematocrit of 27.8%, platelet count of 372,000/mm3, and WBC count of 10,300/mm3. A hemoglobin electrophoresis shows 1% hemoglobin A2, 7% hemoglobin F, and *92% hemoglobin S*. Which of the following is the most likely cause of the repeated infections in this child? □ (A) Loss of normal splenic function from recurrent ischemic injury □ (B) Reduced synthesis of immunoglobulins □ (C) Impaired neutrophil production □ (D) Reduced synthesis of complement proteins by the liver □ (E) Reduced expression of adhesion molecules on endothelial cells

(A) Loss of normal splenic function from recurrent ischemic injury In sickle cell anemia, the cumulative damage to the spleen results in autosplenectomy, leaving behind a small fibrotic remnant of this organ. The impaired splenic function and resultant inability to clear bacteria from the bloodstream can occur early in childhood, leading to infection with encapsulated bacterial organisms. Immunodeficiency results from lack of splenic function, not from lack of immunoglobulins. There is no impairment in production or function of neutrophils. C-reactive protein is a marker of acute inflammation, and it does not help clear bacteria. Adhesion between endothelial cells and RBCs is increased in sickle cell anemia. BP7 402-403BP8 427-428PBD7 630-631PBD8 647

28 A 62-year-old man visits his physician because of prolonged fever and a 4-kg weight loss over the past 6 months. On physical examination, his temperature is 38.6°C. He has generalized nontender lymphadenopathy, and the spleen tip is palpable. Laboratory studies show hemoglobin, 10.1 g/dL; hematocrit, 30.3%; platelet count, 140,000/mm3; and WBC count, 24,500/mm3 with 10% segmented neutrophils, 1% bands, 86% lymphocytes, and 3% monocytes. A cervical lymph node biopsy specimen shows a nodular pattern of small lymphoid cells. A bone marrow specimen shows infiltrates of similar small cells having surface immunoglobulin that are *CD5+, but CD10−. Cytogenetic analysis indicates t(11;14)* in these cells. What is the most likely diagnosis? □ (A) Mantle cell lymphoma □ (B) Follicular lymphoma □ (C) Acute lymphoblastic leukemia □ (D) Burkitt lymphoma □ (E) Small lymphocytic lymphoma

(A) Mantle cell lymphoma The immunophenotype is characteristic for mantle cell lymphoma. Of the lesions listed, lymphoblastic lymphoma and Burkitt lymphoma occur in a much younger age group. Burkitt lymphoma has a t(8;14) translocation. The remaining three lesions occur in an older age group. Of these, small lymphocytic lymphoma manifests with absolute lymphocytosis and the peripheral blood picture of chronic lymphocytic leukemia. Follicular lymphoma has a distinct and characteristic translocation t(14;18) involving the BCL2 gene. In contrast, mantle cell lymphoma, seen in older men, has the t(11;14) translocation, which activates the cyclin D1 (BCL1) gene; these tumors do not respond well to chemotherapy. BP7 426-427BP8 452PBD7 671, 682-683PBD8 612-613

3 A 67-year-old man has had increasing weakness, fatigue, and weight loss over the past 5 months. He now has *decreasing vision in both eyes and has headaches and dizziness. His hands are sensitive to cold*. On physical examination, he has generalized lymphadenopathy and hepatosplenomegaly. Laboratory studies indicate hyperproteinemia with a serum protein level of 15.5 g/dL and albumin concentration of 3.2 g/dL. A bone marrow biopsy is performed, and microscopic examination of the specimen shows infiltration of small plasmacytoid lymphoid cells with *Russell bodies* in the cytoplasm. Which of the following findings is most likely to be reported for this patient? □ (A) Monoclonal IgM spike in serum □ (B) WBC count of 255,000/mm3 □ (C) Hypercalcemia □ (D) Bence Jones proteinuria □ (E) Karyotype with t(14;18) translocation

(A) Monoclonal IgM spike in serum This patient has symptoms of hyperviscosity syndrome, including visual disturbances, dizziness, and headaches. He also seems to have Raynaud phenomena. His bone marrow is infiltrated with plasmacytoid lymphocytes that have stored immunoglobulins in the cytoplasm (Russell bodies). All of these findings suggest that the patient has lymphoplasmacytic lymphoma (Waldenström macroglobulinemia). In this disorder, neoplastic B cells differentiate to IgM-producing cells; there is a monoclonal IgM spike in the serum. These IgM molecules aggregate and produce hyperviscosity, and some of them agglutinate at low temperatures and produce cold agglutinin disease. There is typically no leukemic phase to Waldenström macroglobulinemia. Myeloma, which is typically accompanied by a monoclonal gammopathy, most often does not cause liver and spleen enlargement, and morphologically, the cells resemble plasma cells. Hypercalcemia occurs with myeloma because of bone destruction, and punched-out lytic lesions are typical of multiple myeloma. Light chains in urine (Bence Jones proteins) also are a feature of multiple myeloma. A t(14;18) translocation is characteristic of a follicular lymphoma. BP7 431BP8 456PBD7 681-682PBD8 612

49 A 45-year-old woman has experienced worsening arthritis of her hands and feet for the past 15 years. On physical examination, there are marked deformities of the hands and feet, with ulnar deviation of the hands and swan-neck deformities of the fingers. Laboratory studies show an elevated level of rheumatoid factor. CBC shows hemoglobin, 11.6 g/dL; hematocrit, 34.8%; MCV, 87 µm3; platelet count, 268,000/mm3; and WBC count, 6800/mm3. There is a normal serum haptoglobin level, serum iron concentration of 20 µg/dL, total iron-binding capacity of 195 µg/dL, percent saturation of 10.2, and *serum ferritin concentration is increased*. No fibrin split products are detected. The reticulocyte concentration is 1.1%. What is the most likely mechanism underlying this patient's hematologic abnormalities? □ (A) Poor use of stored iron □ (B) Space-occupying lesions in the bone marrow □ (C) Mutation in the phosphatidylinositol glycan A (PIGA) gene □ (D) Sequestration of red blood cells in splenic sinusoids □ (E) Impaired synthesis of β-globin chains □ (F) Warm antibodies against red blood cell membranes

(A) Poor use of stored iron The iron concentration and iron-binding capacity are low; however, in contrast to the finding in anemia of iron deficiency, the serum ferritin level is increased. This increase is typical of anemia of chronic disease. Underlying chronic inflammatory or neoplastic diseases increase the secretion of cytokines such as interleukin-1, tumor necrosis factor, and interferon-γ. These cytokines promote sequestration of iron in storage compartments and depress erythropoietin production. Metastases are space-occupying lesions (myelophthisic process) that can lead to leukoerythroblastosis, with nucleated RBCs and immature WBCs appearing on the peripheral blood smear. Complement lysis is enhanced in paroxysmal nocturnal hemoglobinuria, which results from mutations in the PIGA gene. Patients with this disorder have a history of infections. Sequestration of RBCs in the spleen occur when RBC membranes are abnormal, as in hereditary spherocytosis or sickle cell anemia, or RBCs are coated by antibodies, as in autoimmune hemolytic anemias. Impaired synthesis of β-globin chains gives rise to β-thalassemias, also characterized by hemolysis. Warm auto-antibody hemolytic anemias occur in several autoimmune diseases, such as systemic lupus erythematosus, but not in patients with rheumatoid arthritis, as in this case. Normal serum haptoglobin rules out intravascular hemolysis; iron is recycled at a rapid rate. BP7 411BP8 437, 440PBD7 646-647PBD8 660-662

27 A 69-year-old man notices the presence of "lumps" in the right side of his neck that have been enlarging over the past year. Physical examination shows firm, nontender posterior cervical lymph nodes 1 to 2 cm in diameter. The overlying skin is intact and not erythematous. A lymph node is biopsied. Which of the following histologic features provides the best evidence for malignant lymphoma in this node? □ (A) Presence of lymphoid cells positive for kappa, but not lambda, light chains □ (B) Absence of a pattern of follicles with germinal centers □ (C) Proliferation of small capillaries in the medullary and paracortical regions □ (D) Presence of cells that stain with monoclonal antibody to the CD30 antigen □ (E) Absence of plasma cells and immunoblasts in sinusoidal spaces

(A) Presence of lymphoid cells positive for kappa, but not lambda, light chains All lymphoid neoplasms are derived from a single transformed cell and are monoclonal. Monoclonality in B-cell neoplasms, which comprise 80% to 85% of all lymphoid neoplasms, often can be shown by staining for light chains. Populations of normal or reactive (polyclonal) B cells contain a mixture of B cells expressing kappa and lambda light chains. Some lymphoid neoplasms have a follicular pattern. A normal pattern of follicles is sometimes absent if the node is involved, as in some inflammatory conditions or in immunosuppression. A proliferation of capillaries is typically a benign, reactive process. The CD30 antigen is a marker for activated T and B cells. Plasma cells are variably present in reactive conditions, but their absence does not indicate malignancy. BP7 420BP8 445PBD7 669-670PBD8 599

29 A 45-year-old man has experienced recurrent fevers and a 6-kg weight loss over the past 5 months. On physical examination, his temperature is 37.5°C, and he has cervical lymphadenopathy. The patient reports that the adenopathy becomes very tender after he drinks a six-pack of beer. A lymph node biopsy specimen shows effacement of the nodal architecture by a population of small lymphocytes, plasma cells, eosinophils, and macrophages. Which of the following additional cell types, which stains positively for *CD15*, is most likely to be found in this disease? □ (A) Reed-Sternberg cell □ (B) Immunoblast □ (C) Epithelioid cell □ (D) Neutrophils □ (E) Mast cell

(A) Reed-Sternberg cell The features suggest Hodgkin lymphoma (HL), mixed cellularity type, which tends to affect older men. As in all other forms of HL but lympocyte predominance, the Reed-Sternberg cells and variants stain with CD15. These cells also express CD30, an activation marker on T cells, B cells, and monocytes. Clinical symptoms are common in the mixed cellularity type of HL, and this histologic type tends to manifest in advanced stages. The pain associated with alcohol consumption is a paraneoplastic phenomenon peculiar to HL. The Reed-Sternberg cells make up a relatively small percentage of the tumor mass, with most of the cell population consisting of reactive cells such as lymphocytes, plasma cells, macrophages, and eosinophils. Immunoblasts suggest a B-cell proliferation. Epithelioid cells are seen in granulomatous inflammatory reactions. Neutrophils accumulate at sites of acute inflammation. Mast cells are not numerous in HL; they participate in type I hypersensitivity responses. BP7 432-433BP8 456-459PBD7 686-689PBD8 618-619

30 A healthy 19-year-old woman suffered blunt abdominal trauma in a motor vehicle accident. On admission to the hospital, her initial hematocrit was 33%, but over the next hour, it decreased to 28%. A paracentesis yielded serosanguineous fluid. She was taken to surgery, where a liver laceration was repaired, and 1 L of bloody fluid was removed from the peritoneal cavity. She remained stable. A CBC performed 3 days later is most likely to show which of the following morphologic findings in RBCs in the peripheral blood? □ (A) Reticulocytosis □ (B) Leukoerythroblastosis □ (C) Basophilic stippling □ (D) Hypochromia □ (E) Schistocytes

(A) Reticulocytosis The acute blood loss, in this case probably intraperitoneal hemorrhage, results in a reticulocytosis from marrow stimulation by anemia. Leukoerythroblastosis is typical of a myelophthisic process in the marrow. Basophilic stippling of RBCs suggests a marrow injury, such as with a drug or toxin. Hypochromic RBCs occur in iron deficiency and thalassemias, both associated with reduced hemoglobin synthesis. Acute blood loss does not give rise to iron deficiency. Schistocytes suggest a microangiopathic hemolytic anemia, which can accompany shock or sepsis. BP7 397-398BP8 423PBD7 623-625PBD8 641

48 A clinical study is performed in which the subjects are children 1 to 4 years old who have had multiple infections with viral, fungal, and parasitic diseases. Compared with a normal control group, these children do not have a subpopulation of cells lacking surface immunoglobulin that mark with CD1a, CD2, CD3, CD4, and CD8. Which of the following karyotypic abnormalities is most likely to be seen in the children in this study? □ (A) +21 □ (B) 22q11.2 □ (C) t(9;22) □ (D) t(15;17) □ (E) X(fra) □ (F) XXY

(B) 22q11.2 These cells mark as cortical lymphocytes in the thymus of a child. An absence of such cells can be seen in the DiGeorge anomaly with 22q11.2. Such patients also can have parathyroid hypoplasia and congenital heart disease. Patients with Down syndrome (trisomy 21) can have thymic abnormalities and the T-cell dysregulation that predisposes to acute leukemia, but the thymus is typically present. The t(9;22) gives rise to the Philadelphia chromosome, which is characteristic of chronic myelogenous leukemia. The t(15;17) is seen in patients with acute promyelocytic leukemia. Individuals with fragile X syndrome usually have some form of mental retardation. Males with Klinefelter syndrome (XXY) do not have immunological abnormalities. BP7 146, 232BP8 446, 476PBD7 706PBD8 635

56 A 22-year-old university student reports easy fatigability of 2 months' duration. On physical examination, she has no hepatosplenomegaly or lymphadenopathy. Mucosal gingival hemorrhages are noted. CBC shows hemoglobin, 9.5 g/dL; hematocrit, 28.2%; MCV, 94 µm3; platelet count, 20,000/mm3; and WBC count, 107,000/mm3. A bone marrow biopsy specimen shows that the marrow is 100% cellular with few residual normal hematopoietic cells. Most of the cells in the marrow are large, with *nuclei having delicate chromatin and several nucleoli. The cytoplasm of these cells has azurophilic, peroxidase-positive granules*. Which of the following is the most likely diagnosis? □ (A) Acute lymphoblastic leukemia □ (B) Acute myelogenous leukemia □ (C) Chronic lymphocytic leukemia □ (D) Chronic myelogenous leukemia □ (E) Hodgkin lymphoma □ (F) Sézary syndrome

(B) Acute myelogenous leukemia The very high WBC count and the presence of peroxidase-positive blasts (myeloblasts) filling the marrow are characteristic of acute myelogenous leukemia. This type of leukemia is most often seen in individuals 15 to 39 years old. Acute lymphoblastic leukemia occurs in children and young adults. Azurophilic, peroxidase-positive granules distinguish myeloblasts from lymphoblasts. Chronic lymphocytic leukemia is characterized by the presence of small, mature lymphocytes in the peripheral blood and bone marrow of older adults. Chronic myelogenous leukemia also is seen in adults, but this is a myeloproliferative process with a range of myeloid differentiation, and most of the myeloid cells are mature, with few blasts. Hodgkin lymphoma does not have a leukemic phase. Some cutaneous T-cell lymphomas may have circulating cells, known as Sézary cells. BP7 436-437BP8 461-462PBD7 692-696PBD8 622-624

53 The figure skater Sonja Henie, who won gold medals at the 1928, 1932, and 1936 Winter Olympic Games, became progressively fatigued in her late 50s. On physical examination, she had *palpable nontender axillary and inguinal lymph nodes, and the spleen tip was palpable*. Laboratory studies showed hemoglobin, 10.1 g/dL; hematocrit, 30.5%; MCV, 90 µm3; platelet count, 89,000/mm3; and WBC count, 31,300/mm3. From the peripheral blood picture that shows *increased numbers of circulating small, round, mature lymphocytes with scant cytoplasm*, which of the following is the most likely diagnosis? □ (A) Infectious mononucleosis □ (B) Chronic lymphocytic leukemia □ (C) Iron deficiency anemia □ (D) Leukemoid reaction □ (E) Acute lymphoblastic leukemia

(B) Chronic lymphocytic leukemia Sonja Henie died from complications of chronic lymphocytic leukemia (CLL), in which there are increased numbers of circulating small, round, mature lymphocytes with scant cytoplasm seen in the peripheral blood smear. The cells express the CD5 marker and the pan B cell markers CD19 and CD20. Most patients have a disease course of 4 to 6 years before death, and symptoms appear as the leukemic cells begin to fill the marrow. In some patients, the same small lymphocytes appear in tissues; the condition is then known as small lymphocytic lymphoma. The lymphocytes seen in infectious mononucleosis are "atypical lymphocytes," which have abundant, pale blue cytoplasm that seems to be indented by the surrounding RBCs. The RBCs in iron deficiency anemia are hypochromic and microcytic, but the WBCs are not affected. Leukemoid reactions are typically of the myeloid type, and the peripheral blood contains immature myeloid cells. The WBC count can be very high, but the platelet count is normal. Acute lymphoblastic leukemia is a disease of children and young adults, characterized by proliferation of lymphoblasts. These cells are much larger than the cells in CLL and have nucleoli. BP7 424-426BP8 450-451PBD7 673-674PBD8 603-605

32 In an experiment, cell samples are collected from the bone marrow aspirates of patients who were diagnosed with lymphoproliferative disorders. Cytogenetic analyses are performed on these cells, and a subset of the cases is found to have the *BCR-ABL fusion gene from the reciprocal translocation t(9;22)(q34;11)*. The presence of this gene results in increased tyrosine kinase activity. Patients with which of the following conditions are most likely to have this gene? □ (A) Follicular lymphoma □ (B) Chronic myelogenous leukemia □ (C) Hodgkin lymphoma, lymphocyte depletion type □ (D) Acute promyelocytic leukemia □ (E) Multiple myeloma

(B) Chronic myelogenous leukemia This is the Philadelphia chromosome, or Ph1, which is characteristic of patients with chronic myelogenous leukemia (CML). This karyotypic abnormality can be found using cytogenetic techniques, including fluorescence in situ hybridization (FISH). In the few cases that appear negative by karyotyping and by FISH, molecular analysis shows BCR-ABL rearrangements, and the tyrosine kinase activated via this fusion gene is the target of current therapy for CML. This rearrangement is considered a diagnostic criterion for CML. CML is a disease of pluripotent stem cells that affects all lineages, but the granulocytic precursors expand preferentially in the chronic phase. Follicular lymphomas have a t(14;18) karyotypic abnormality involving the BCL2 gene. Hodgkin disease and myelomas usually do not have characteristic karyotypic abnormalities. Acute promyelocytic leukemias often have the t(15;17) abnormality. BP7 438-439BP8 464-465PBD7 697-698PBD8 627

20 A 70-year-old man has experienced increasing fatigue for the past 6 months. On physical examination, he has nontender axillary and cervical lymphadenopathy, but there is no hepatosplenomegaly. The hematologic work-up shows hemoglobin, 9.5 g/dL; hematocrit, 28%; MCV, 90 µm3; platelet count, 120,000/mm3; and WBC count, 42,000/mm3. *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

(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. BP7 424-426BP8 450-451PBD7 673-674PBD8 603-605

6 A 53-year-old man comes to his physician because he felt a lump near his shoulder 1 week ago. On physical examination, there is an *enlarged, nontender, supraclavicular lymph node and enlargement of the Waldeyer ring of oropharyngeal lymphoid tissue*. There is no hepatosplenomegaly. CBC is normal except for findings of mild anemia. A lymph node biopsy specimen shows replacement by a monomorphous population of large lymphoid cells with enlarged nuclei and prominent nucleoli. Immunohistochemical staining and flow cytometry of the node indicates that most lymphoid cells are CD19+, CD10+, CD3−, CD15−, and terminal deoxynucleotidyl transferase negative (TdT−). Which of the following is the most likely diagnosis? □ (A) Chronic lymphadenitis □ (B) Diffuse large B-cell lymphoma □ (C) Hodgkin lymphoma □ (D) Lymphoblastic lymphoma □ (E) Small lymphocytic lymphoma

(B) Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma occurs in older individuals and frequently manifests as localized disease with extranodal involvement, particularly of the Waldeyer ring. The staining pattern indicates a B-cell proliferation (CD19+, CD10+). T-cell (CD3) and monocytic (CD15) markers are absent. TdT can be expressed in B lineage cells at an earlier stage of maturation. Small lymphocytic lymphoma also is a B-cell neoplasm, but it manifests with widespread lymphadenopathy, liver and spleen enlargement, and lymphocytosis. Lymphoblastic lymphoma is a T-cell neoplasm that occurs typically in the mediastinum of children. Hodgkin lymphoma is characterized by Reed-Sternberg cells. In chronic lymphadenitis, the lymph node has many cell types—macrophages, lymphocytes, and plasma cells. A monomorphous infiltrate is typical of non-Hodgkin lymphomas. BP7 427-428BP8 452-453PBD7 676-677PBD8 606-607

10 A 9-year-old boy living in Uganda has had increasing pain and swelling on the right side of his face over the past 8 months. On physical examination, there is a *large, nontender mass involving the mandible*, which deforms the right side of his face. There is no lymphadenopathy and no splenomegaly, and he is afebrile. A biopsy of the mass is performed. Microscopically, the specimen is composed of intermediate-sized lymphocytes with a high mitotic rate. A chromosome analysis shows a 46,XY,*t(8;14) karyotype* in these cells. The hemoglobin concentration is 13.2 g/dL, platelet count is 272,000/mm3, and WBC count is 5820/mm3. Infection with which of the following is most likely to be causally related to the development of these findings? □ (A) Cytomegalovirus □ (B) Epstein-Barr virus □ (C) Hepatitis B virus □ (D) HIV □ (E) Human papillomavirus □ (F) Respiratory syncytial virus

(B) Epstein-Barr virus This patient has the endemic African variety of Burkitt lymphoma, a B-cell lymphoma that typically appears in the maxilla or mandible of the jaw. This particular neoplasm is related to Epstein-Barr virus infection. Cytomegalovirus infection occurs in immunocompromised patients and can be a congenital infection, but it is not a direct cause of neoplasia. Hepatitis B virus infection can be a risk factor for hepatocellular carcinoma. HIV infection can be a risk factor for the development of non-Hodgkin lymphomas, but most of these are either diffuse large B-cell lymphomas or small noncleaved Burkitt-like lymphomas. Human papillomavirus infection is related to the formation of squamous dysplasias and carcinomas, most commonly those involving the cervix. Respiratory syncytial virus infection produces pneumonia in infants and young children, but is not related to development of neoplasms. BP7 428-429BP8 453PBD7 677-678PBD8 607-608

43 A 65-year-old man sees his physician because he has experienced fatigue, a 5-kg weight loss, night sweats, and abdominal discomfort for the past year. On physical examination, he has marked splenomegaly; there is no lymphadenopathy. Laboratory studies show hemoglobin, 10.1 g/dL; hematocrit, 30.5%; MCV, 89 µm3; platelet count, 94,000/mm3; and WBC count, 14,750/mm3 with 55% segmented neutrophils, 9% bands, 20% lymphocytes, 8% monocytes, 4% metamyelocytes, 3% myelocytes, 1% eosinophils, and 2 nucleated RBCs per 100 WBCs. The peripheral blood smear also shows *teardrop cells*. The serum uric acid level is 12 mg/dL. A bone marrow biopsy specimen shows *extensive marrow fibrosis and clusters of atypical megakaryocytes*. Which of the following is most likely to account for the enlargement in this patient's spleen? □ (A) Hodgkin lymphoma □ (B) Extramedullary hematopoiesis □ (C) Portal hypertension □ (D) Granulomas with Histoplasma capsulatum □ (E) Metastatic adenocarcinoma

(B) Extramedullary hematopoiesis This patient has classic features of myelofibrosis with myeloid metaplasia. This myeloproliferative disorder also is a stem cell disorder, in which neoplastic megakaryocytes secrete fibrogenic factors leading to marrow fibrosis. The neoplastic clone then shifts to the spleen, where it shows trilineage hematopoietic proliferation (extramedullary hematopoiesis), in which megakaryocytes are prominent. The marrow fibrosis and the extramedullary hematopoiesis in the spleen fail to regulate orderly release of leukocytes into the blood. The peripheral blood has immature RBC and WBC precursors (leukoerythroblastic picture). Teardrop RBCs are misshapen RBCs that are seen when marrow undergoes fibrosis. Marrow injury also can be the result of other causes (e.g., metastatic tumors, irradiation). These causes also can give rise to a leukoerythroblastic picture, but splenic enlargement with trilineage proliferation usually is not seen. The other causes mentioned—Hodgkin lymphoma, portal hypertension, and Histoplasma capsulatum infection—can cause splenic enlargement, but not marrow fibrosis. Adenocarcinoma metastases to the spleen are uncommon. BP7 440-441BP8 466-467PBD7 696, 699-701PBD8 630-631

6 A 69-year-old, previously healthy woman has been feeling increasingly tired and weak for 4 months. On physical examination, she is afebrile. There is no hepatosplenomegaly or lymphadenopathy. Laboratory studies show hemoglobin of 9.3 g/dL, platelet count of 250,600/mm3, and WBC count of 6820/mm3. Her RBCs display hypochromia and microcytosis. Which of the following conditions should be suspected as the most likely cause of these findings? □ (A) Pernicious anemia □ (B) Gastrointestinal blood loss □ (C) Aplastic anemia □ (D) β-Thalassemia major □ (E) Warm autoimmune hemolytic anemia

(B) Gastrointestinal blood loss The RBCs display hypochromia and microcytosis, consistent with iron deficiency. The most common cause of this in elderly patients is chronic blood loss that originates from a gastrointestinal source (e.g., carcinoma, ulcer disease). At age 69, this patient is not menstruating, and vaginal bleeding is likely to be noticed as a "red flag" for a gynecologic malignancy. Pernicious anemia from vitamin B12 deficiency would result in a macrocytic anemia. The RBCs are generally normocytic in patients with aplastic anemia. Microcytosis may accompany thalassemias, but the patient would be unlikely to live to the age of 69 years with β-thalassemia major. Autoimmune hemolytic anemias usually produce a normocytic anemia, or the MCV can be slightly elevated, with a brisk reticulocytosis. BP7 398, 409-411BP8 435-437PBD7 643-646PBD8 659-662

2 A 22-year-old woman has experienced malaise and a sore throat for 2 weeks. Her fingers turn white on exposure to cold. On physical examination, she has a temperature of 37.8°C, and the pharynx is erythematous. Laboratory findings include a *positive Monospot test result. Direct and indirect Coombs test results are positive at 4°C, although not at 37°C*. Which of the following substances on the surfaces of the RBCs most likely accounts for these findings? □ (A) IgE □ (B) IgM □ (C) Histamine □ (D) IgG □ (E) Fibronectin

(B) IgM This patient has cold agglutinin disease, with antibody (usually IgM) coating RBCs. The IgM antibodies bind to the RBCs at low temperature and fix complement; however, complement is not lytic at this temperature. With an increase in temperature, the IgM is dissociated from the cell, leaving behind C3b. Most of the hemolysis occurs extravascularly in the cells of the mononuclear phagocyte system, such as Kupffer cells in the liver, because the coating of complement C3b acts as an opsonin. Raynaud phenomenon occurs in exposed, colder areas of the body, such as the fingers and toes. The patient probably has an elevated cold agglutinin titer. IgE is present in allergic conditions, and histamine is released in type I hypersensitivity reactions. IgG is typically involved in warm antibody hemolytic anemia, which is chronic and is not triggered by cold. Fibronectin is an adhesive cell surface glycoprotein that aids in tissue healing. BP7 408BP8 433PBD7 637PBD8 653-654

38 A 3-year-old boy of Italian ancestry is brought to the physician because he has a poor appetite and is underweight for his age and height. Physical examination shows hepatosplenomegaly. The hemoglobin concentration is 6 g/dL, and the peripheral blood smear shows severely hypochromic and microcytic RBCs. The total serum iron level is normal, and the reticulocyte count is 10%. *A radiograph of the skull shows maxillofacial deformities and an expanded marrow space*. Which of the following is the most likely principal cause of this child's illness? □ (A) Reduced synthesis of hemoglobin F □ (B) Imbalance in production of α-globin and β-globin chains □ (C) Sequestration of iron in reticuloendothelial cells □ (D) Increased fragility of erythrocyte membrane □ (E) Relative deficiency of vitamin B12

(B) Imbalance in production of α-globin and β-globin chains This patient, of Mediterranean descent, has β-thalassemia major. In this condition, there is a severe reduction in the synthesis of β-globin chains without impairment of α-globin synthesis. The free, unpaired α-globin chains form aggregates that precipitate within normoblasts and cause them to undergo apoptosis. The death of RBC precursors in the bone marrow is called "ineffective erythropoiesis." Not only does this cause anemia, but it also increases the absorption of dietary iron, giving rise to iron overload, which results in hemochromatosis with infiltrative cardiomyopathy, hepatic cirrhosis, and "bronze diabetes" from pancreatic islet dysfunction. The severe anemia triggers erythropoietin synthesis, which expands the erythropoietic marrow. The marrow expansion encroaches on the bones, causing maxillofacial deformities. Extramedullary hematopoiesis causes hepatosplenomegaly. In comparison, the hemolytic anemia is mild in βthalassemia minor, and there is very little ineffective erythropoiesis. Hemochromatosis is particularly detrimental to the liver and heart. Patients with chronic anemia may require RBC transfusions, which adds even more iron to body stores. The other listed options do not lead to a marked expansion of hematopoiesis. BP7 403-405BP8 428-430PBD7 632-635PBD8 649-651

47 A 60-year-old woman has had headaches and dizziness for the past 5 weeks. She has been taking cimetidine for heartburn and omeprazole for ulcers. On physical examination, she is afebrile and normotensive, and her face has a plethoric to cyanotic appearance. There is mild splenomegaly, but no other abnormal findings. Laboratory studies show *hemoglobin, 21.7 g/dL; hematocrit, 65%; platelet count, 400,000/mm3; and WBC count, 30,000/mm3 with 85% polymorphonuclear leukocytes, 10% lymphocytes, and 5% monocytes. The peripheral blood smear shows abnormally large platelets and nucleated RBCs*. The serum erythropoietin level is undetectable, but the ferritin level is normal*. Which of the following is most characteristic of the natural history of this patient's disease? □ (A) Transformation into acute B lymphoblastic leukemia □ (B) Marrow fibrosis with extramedullary hematopoiesis □ (C) Spontaneous remissions and relapses without treatment □ (D) Increase in monoclonal serum immunoglobulin □ (E) Development of a gastric non-Hodgkin lymphoma

(B) Marrow fibrosis with extramedullary hematopoiesis This patient has polycythemia vera. The symptoms result from the increased hematocrit and blood volume. Undetectable erythropoietin in the face of polycythemia is characteristic of polycythemia vera. Polycythemia vera is a myeloproliferative disorder in which the neoplastic myeloid cells differentiate preferentially along the erythroid lineage. Other lineages also are affected, however; there is leukocytosis and thrombocytosis. These patients are Ph1 chromosome negative. Untreated, these patients die of episodes of bleeding or thrombosis—both related to disordered platelet function and the hemodynamic effects on distended blood vessels. Treatment by phlebotomy reduces the hematocrit. With this treatment, the disease in 15% to 20% of patients characteristically transforms into myelofibrosis with myeloid metaplasia. Termination in acute leukemia, in contrast to in chronic myeloid leukemia, is rare. When it occurs, it is an acute myeloid leukemia, not lymphoblastic leukemia. BP7 439-440BP8 465-466PBD7 699-700PBD8 628-629

42 A 78-year-old man complains of worsening malaise and fatigue over the past 5 months. On physical examination, he is afebrile and normotensive. The spleen tip is palpable. A CBC shows hemoglobin, 10.6 g/dL; hematocrit, 29.8%; MCV, 92 µm3; platelet count, 95,000/mm3; and WBC count, 4900/mm3 with *67% segmented neutrophils, 4% bands, 2% metamyelocytes*, 22% lymphocytes, 5% monocytes, and 3 nucleated RBCs per 100 WBCs. The peripheral blood smear shows *occasional teardrop cells*. An examination of the bone marrow biopsy specimen and smear is most likely to show which of the following findings? □ (A) Marrow packed with myeloblasts □ (B) Marrow fibrosis with reduced hematopoiesis □ (C) Replacement of marrow by fat □ (D) Presence of numerous megaloblasts □ (E) Marked normoblastic erythroid hyperplasia

(B) Marrow fibrosis with reduced hematopoiesis Teardrop RBCs are indicative of a myelophthisic disorder (i.e., something filling the bone marrow, such as fibrous thrombotic thrombocytopenic purpura connective tissue). The leukoerythroblastosis, including immature RBCs and WBCs, is most indicative of myelofibrosis. Splenomegaly also is typically seen in myelofibrosis. A leukoerythroblastic picture also can be seen in patients with infections and metastases involving the marrow. Marrow packed with myeloblasts is typical of acute myeloid leukemia. In this condition, the peripheral blood also would show myeloblasts and failure of myeloid maturation. Replacement of marrow by fat occurs in aplastic anemia, which is characterized by pancytopenia. The presence of megaloblasts in the marrow indicates folate or vitamin B12 deficiency—both cause macrocytic anemia. Hyperplasia of normoblasts occurs in hemolytic anemias. Leukoerythroblastosis is not seen in hemolytic anemias. BP7 414BP8 440, 466-467PBD7 648-649PBD8 665

5 A 30-year-old woman has had a constant feeling of lethargy since childhood. On physical examination, she is afebrile and has a pulse of 80/min, respirations of 15/min, and blood pressure of 110/70 mm Hg. The spleen tip is palpable, but there is no abdominal pain or tenderness. Laboratory studies show hemoglobin of 11.7 g/dL, platelet count of 159,000/mm3, and WBC count of 5390/mm3. The peripheral blood smear shows *spherocytosis*. The circulating RBCs show an increased osmotic fragility. An inherited abnormality in which of the following RBC components best accounts for these findings? □ (A) Glucose-6-phosphate dehydrogenase □ (B) Membrane cytoskeletal protein □ (C) α-Globin chain □ (D) Heme □ (E) β-Globin chain □ (F) Carbonic anhydrase

(B) Membrane cytoskeletal protein Spectrin and related proteins (e.g., protein 4.1, ankyrin) are cytoskeletal proteins that are important in maintaining the RBC shape. Hereditary spherocytosis is a condition in which a mutation affects one of several membrane cytoskeletal proteins, such as ankyrin (most common) and band 4.2, which binds spectrin to the transmembrane ion transporter, band 3, and protein 4.1, which binds the "tail" of spectrin to another transmembrane protein, glycophorin A. Cells with such mutant proteins are less deformable. The abnormal RBCs seem to lack central pallor on a peripheral blood smear, and they are sequestered and destroyed in the spleen. Glucose-6-phosphate dehydrogenase deficiency is an X-linked condition that most commonly affects black males. Thalassemias with abnormal α-globin or β-globin chains are associated with hypochromic microcytic anemias. Iron deficiency affects the heme portion of hemoglobin, leading to hypochromia and to microcytosis. Carbonic anhydrase in RBCs helps to maintain buffering capacity. BP7 399-400BP8 424-425PBD7 625-627PBD8 642-644

12 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 mg/dL, and the urea nitrogen level is 35 mg/dL. A skull radiograph shows *punched-out lytic lesions*. During his 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

(B) Numerous plasma cells 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. The Ig genes in myeloma cells always show evidence of somatic hypermutation. Bence Jones proteinuria can damage the tubules and give rise to renal failure. Multiple myeloma can be complicated by AL amyloid, which also can 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 lymphoma. Blasts suggest a leukemic process. BP7 429-431BP8 453-456PBD7 678-681PBD8 609-611

53 A 45-year-old woman has experienced episodes of *blurred vision and headaches* for the past 6 months. She has had worsening *confusion with paresthesias* over the past 3 days. On physical examination, she has a temperature of 39.6°C, pulse of 100/min, respiratory rate of 20/min, and blood pressure of 80/50 mm Hg. *Petechial hemorrhages* are noted over her trunk and extremities. Laboratory findings include hemoglobin, 10.9 g/dL; hematocrit, 34%; MCV, 96/min3; platelet count, 28,000/mm3; and WBC count, 8500/mm3. Fragmented RBCs are noted on her peripheral blood smear. Blood urea nitrogen is 40 mg/dL, and serum creatinine is 3.1 mg/dL. Which of the following is the most likely underlying cause for her findings? □ (A) Defective ADP-induced platelet aggregation □ (B) Presence of antibodies against von Willebrand's factor metalloproteinase □ (C) Formation of auto-antibodies to platelet glycoproteins IIb/IIIa and Ib-IX □ (D) Circulating toxin that injures capillary endothelium □ (E) Inappropriate release of thromboplastic substances into blood □ (F) Decreased factor VIII activity

(B) Presence of antibodies against von Willebrand's factor metalloproteinase The clinical features (neurologic abnormalities, fever, thrombocytopenia, microangiopathic hemolytic anemia, renal failure) point to thrombotic thrombocytopenic purpura (*TTP*), in which there is an inherited or acquired deficiency of the von Willebrand factor (vWF) metalloproteinase (ADAMTS-13) that normally cleaves very high molecular weight multimers of vWF. The absence of ADAMTS-13 gives rise to large multimers of vWF that promote widespread platelet aggregation, and the resulting microvascular occlusions in brain, kidney, and elsewhere produce organ dysfunction, thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and bleeding. Defective aggregation of platelets in the presence of ADP and thrombin is a feature of a rare inherited disorder of platelets called Glanzmann thrombasthenia. Circulating toxins, principally endotoxins elaborated by Enterobacteriaceae such as Escherichia coli are important in causing endothelial injury in hemolytic-uremic syndrome (HUS). HUS has similar clinical findings to TTP, but has a different pathogenesis. Release of thromboplastic substances from tumor cells or a retained dead fetus can lead to disseminated intravascular coagulation with MAHA, but this patient has no source of thromboplastins. Decreased factor VIII activity is a feature of hemophilia A, an X-linked disorder rare in women, characterized by bleeding into soft tissues, such as joints, and normal platelet number and function. BP7 448BP8 472-473PBD7 652-653PBD8 669-670

4 A 25-year-old woman has a 3-year history of arthralgias. Physical examination shows no joint deformity, but she appears pale. Laboratory studies show total RBC count of 4.7 million/mm3, hemoglobin of 12.5 g/dL, hematocrit of 37.1%, platelet count of 217,000/mm3, and WBC count of 5890/mm3. The peripheral blood smear shows *hypochromic and microcytic RBCs. Total serum iron and ferritin levels are normal*. Hemoglobin electrophoresis shows an *elevated hemoglobin A2 level of about 5.8%*. What is the most likely diagnosis? □ (A) Autoimmune hemolytic anemia □ (B) β-Thalassemia minor □ (C) Infection with Plasmodium vivax □ (D) Anemia of chronic disease □ (E) Iron deficiency anemia

(B) β-Thalassemia minor Although β-thalassemia minor and iron deficiency anemia are characterized by hypochromic and microcytic RBCs, there is no increase in hemoglobin A2 in iron deficiency states. A normal serum ferritin level also excludes iron deficiency. In contrast to β-thalassemia major, there is usually a mild anemia without major organ dysfunction. Diseases that produce hemolysis and increase erythropoiesis (e.g., autoimmune hemolytic anemia, malaria) do not alter the composition of βglobin chain production. Anemia of chronic disease may mimic iron deficiency and thalassemia minor with respect to hypochromia and microcytosis; however, anemia of chronic disease is associated with an increase in the serum concentration of ferritin. BP7 403-404BP8 428-431PBD7 632-635PBD8 649-651

16 A 50-year-old man has experienced chronic fatigue and weight loss for the past 3 months. There are no remarkable findings on physical examination. Laboratory studies show hemoglobin, 11.2 g/dL; hematocrit, 33.3%; MCV, 91 µm3; platelet count, 240,000/mm3; WBC count, 7550/mm3; serum iron 80 µg/dL; *total iron-binding capacity is reduced and serum ferritin is increased. The ANA test result is positive*. Which of the following is the most likely diagnosis? □ (A) Iron deficiency anemia □ (B) Aplastic anemia □ (C) Anemia of chronic disease □ (D) Microangiopathic hemolytic anemia □ (E) Megaloblastic anemia □ (F) Thalassemia minor

(C) Anemia of chronic disease The increased ferritin concentration and reduced total iron-binding capacity are typical of anemia of chronic disease, such as an autoimmune disease. Increased levels of cytokines such as interleukin-6 promote sequestration of storage iron, with poor use for erythropoiesis. Secretion of erythropoietin by the kidney is impaired. Various underlying diseases, including cancer, collagen vascular diseases, and chronic infections, can produce this pattern of anemia. Iron deficiency would produce a microcytic anemia, with a low serum ferritin level. Aplastic anemia is unlikely because the platelet count and WBC count are normal. Microangiopathic hemolytic anemias are caused by serious acute conditions such as disseminated intravascular coagulation; these patients have thrombocytopenia caused by widespread thrombosis. Megaloblastic anemias are macrocytic without an increase in iron stores. Thalassemia minor is uncommon and is not associated with a positive ANA test result. BP7 411BP8 437PBD7 646PBD8 662

31 A 32-year-old woman from Saigon, Vietnam, gives birth at 34 weeks' gestation to a markedly *hydropic stillborn male infant*. Autopsy findings include hepatosplenomegaly and cardiomegaly, serous effusions in all body cavities, and generalized hydrops. No congenital anomalies are noted. There is marked extramedullary hematopoiesis in visceral organs. Which of the following findings is most likely to be present on hemoglobin electrophoresis of the fetal RBCs? □ (A) Hemoglobin A1 □ (B) Hemoglobin A2 □ (C) Hemoglobin Bart's □ (D) Hemoglobin C □ (E) Hemoglobin E □ (F) Hemoglobin F □ (G) Hemoglobin H □ (H) Hemoglobin S

(C) Hemoglobin Bart's The infant had α-thalassemia major, which is most likely to be occur in individuals of Southeast Asian ancestry, each of whose parents could have two abnormal α-globin genes on chromosome 16. A complete lack of α-globin chains precludes formation of hemoglobins A1, A2, and F. Only a tetramer of γ chains (Bart's hemoglobin) can be made, leading to severe fetal anemia. Inheritance of three abnormal α-globin chains leads to hemoglobin H disease, with tetramers of β chains; survival to adulthood is possible. Individuals with hemoglobin S usually are asymptomatic in infancy because of hemoglobin F production. Hemoglobins C and E produce mild hemolytic anemias. BP7 404-406BP8 430-431PBD7 635-636PBD8 651-652

39 A 23-year-old, previously healthy man has experienced malaise and a low-grade fever and sore throat for 2 weeks. On physical examination, his temperature is 37.6°C, and he has pharyngeal erythema without exudation. There is *tender cervical, axillary, and inguinal lymphadenopathy*. Laboratory studies show hemoglobin, 12.2 g/dL; hematocrit, 36.6%; platelet count, 190,200/mm3; and WBC count, 8940/mm3. The peripheral blood smear shows *large lymphocytes with abundant cytoplasm and a large nucleus with fine chromatin*. Which of the following is the most likely risk factor for the disease that would be diagnosed in this patient? □ (A) An inherited disorder of globin chain synthesis □ (B) Transfusion of packed RBCs □ (C) Close personal contact (kissing) with his date □ (D) Sharing infected needles for intravenous drug use □ (E) Ingestion of raw oysters

(C) Close personal contact (kissing) with his date The smear shows large, "atypical" lymphocytes that are present in patients with infectious mononucleosis and other viral infections, such as those caused by cytomegalovirus. These atypical cells are large lymphocytes with abundant cytoplasm and a large nucleus with fine chromatin. Infectious mononucleosis is caused by Epstein-Barr virus (EBV) and transmitted by close personal contact. In patients with infectious mononucleosis, multiple clones of B cells are infected by EBV. The EBV genes cause proliferation and activation of B cells, and there is polyclonal B cell expansion. These B cells secrete antibodies with several specificities, including antibodies that cross-react with sheep RBCs. These heterophil antibodies produce a positive Monospot test result. The atypical lymphocytes are CD8+ T cells that are activated by EBVinfected B cells. There is no increase in basophils, eosinophils, or monocytes in infectious mononucleosis. Disorders of globin chain synthesis affect RBCs, as in the thalassemias. Infectious mononucleosis is not known as a transfusionassociated disease. Likewise, intravenous drug use is typically not a risk factor for infectious mononucleosis, but individuals sharing infected needles are at risk of bacterial infections, HIV infection, and viral hepatitis. Eating raw oysters is a risk factor for hepatitis A because oysters that filter polluted seawater concentrate the virus in their tissues.

1 For the past 6 months, a 35-year-old woman has experienced an excessively heavy menstrual flow each month. She also has noticed increasing numbers of pinpoint hemorrhages on her lower extremities in the past month. Physical examination shows no organomegaly or lymphadenopathy. CBC shows hemoglobin of 14.2 g/dL, hematocrit of 42.5%, MCV of 91 µm3, platelet count of 19,000/mm3, and WBC count of 6950/mm3. On admission to the hospital, she has melena and is given a *transfusion of platelets, but her platelet count does not increase. An emergency splenectomy is performed, and her platelet count increases*. Which of the following describes the most likely basis for her bleeding tendency? □ (A) Abnormalities in production of platelets by megakaryocytes □ (B) Suppression of pluripotent stem cells □ (C) Destruction of antibody-coated platelets by the spleen □ (D) Excessive loss of platelets in menstrual blood □ (E) Defective platelet-endothelial interactions

(C) Destruction of antibody-coated platelets by the spleen This patient's bleeding tendency is caused by a low platelet count. She most likely has idiopathic thrombocytopenic purpura (ITP), in which platelets are destroyed in the spleen after being coated with antibodies to platelet membrane glycoproteins IIb-IIIa or Ib-IX affecting both the patient's platelets and the transfused platelets. Because the spleen is the source of the antibody and the site of destruction, splenectomy can be beneficial. There is no defect in the production of platelets. Suppression of pluripotent stem cells gives rise to aplastic anemia, which is accompanied by pancytopenia. Platelet functions are normal in ITP. Chronic blood loss would not lead to thrombocytopenia when normal bone marrow function is present. Abnormal platelet-endothelial interactions are more likely to cause thrombosis.

33 A 64-year-old man has inguinal, axillary, and cervical lymphadenopathy. The nodes are firm and nontender. A biopsy specimen of a cervical node shows a histologic pattern of *nodular aggregates of small, cleaved lymphoid cells and larger cells with open nuclear chromatin, several nucleoli, and moderate amounts of cytoplasm*. A bone marrow biopsy specimen shows lymphoid aggregates of similar cells with surface immunoglobulin that are *CD10+, but CD5−*. Karyotyping of these lymphoid cells indicates the presence of *t(14;18)*. What is the most likely diagnosis? □ (A) Hodgkin lymphoma, nodular sclerosis type □ (B) Acute lymphadenitis □ (C) Follicular lymphoma □ (D) Mantle cell lymphoma □ (E) Toxoplasmosis

(C) Follicular lymphoma This patient has follicular lymphoma, the most common form of non-Hodgkin lymphoma among adults in the United States. Men and women are equally affected. The neoplastic B cells mimic a population of follicular center cells and produce a nodular or follicular pattern. Nodal involvement is often generalized, but extranodal involvement is uncommon. The t(14;18) translocation, which is characteristic, causes overexpression of the BCL2 gene; the cells are resistant to apoptosis. In keeping with this, follicular lymphomas are indolent tumors that continue to accumulate cells for 7 to 9 years. In Hodgkin lymphoma, there are few Reed-Sternberg cells, surrounded by a reactive lymphoid population. The lymphoid population in acute lymphadenitis is reactive, and there is no bone marrow involvement. Mantle cell lymphoma also is a Bcell tumor; it is more aggressive than follicular lymphoma and is typified by the t(11;14) translocation, in which the cyclin D1 gene (BCL2) is overexpressed. In toxoplasmosis, there would be a mixed population of inflammatory cells and some necrosis. BP7 426BP8 451PBD7 671, 674, 676PBD8 605-606

15 Three days after taking an *anti-inflammatory medication that includes phenacetin *, a 23-year-old African-American man passes dark reddish brown urine. He is surprised by this because he has been healthy all his life and has had no major illnesses. On physical examination, he is afebrile, and there are no remarkable findings. CBC shows a mild normocytic anemia, but the peripheral blood smear shows *precipitates of denatured globin (Heinz bodies) with supravital staining and scattered "bite cells" * in the population of RBCs. Which of the following is the most likely diagnosis? □ (A) α-Thalassemia □ (B) Sickle cell trait □ (C) Glucose-6-phosphate dehydrogenase deficiency □ (D) Autoimmune hemolytic anemia □ (E) β-Thalassemia minor □ (F) RBC membrane abnormality

(C) Glucose-6-phosphate dehydrogenase deficiency Glucose-6-phosphate dehydrogenase deficiency is an X-linked disorder that affects about 10% of African-American males. The lack of this enzyme subjects hemoglobin to damage by oxidants, including drugs such as primaquine, sulfonamides, nitrofurantoin, phenacetin, and aspirin (in large doses). Infection also can cause oxidative damage to hemoglobin. Heinz bodies damage the RBC membrane, giving rise to intravascular hemolysis. The "bite cells" result from the attempts of overeager splenic macrophages to pluck out the Heinz bodies, adding an element of extravascular hemolysis. Heterozygotes with α-thalassemia have no major problems, but in cases of α-thalassemia major, perinatal death is the rule. Likewise, β-thalassemia minor and sickle cell trait are conditions with no major problems and no relation to drug usage. Some autoimmune hemolytic anemias can be drug related, but the hemolysis is predominantly extravascular. RBC membrane abnormalities, such as hereditary spherocytosis (caused by abnormal spectrin), typically produce a mild anemia without significant hemolysis, and there is no drug sensitivity. BP7 406-407BP8 431-432PBD7 627-628PBD8 644-645

35 A 16-year-old girl has a history of easy bruising and hemorrhages. Since menarche at the age of 14 years, she has had menometrorrhagia. On physical examination, she displays joint deformity and has decreased mobility of the ankles, knees, and wrists. Laboratory studies show hemoglobin, 11.8 g/dL; hematocrit, 35.1%; platelet count, 267,000/mm3; WBC count, 5960/mm3; prothrombin time, 13 seconds; and partial thromboplastin time, 60 seconds. A 1 : 1 *dilution of the patient's plasma with normal pooled plasma corrects the partial thromboplastin time*. Which of the following is the most likely diagnosis? □ (A) Antiphospholipid syndrome □ (B) Disseminated intravascular coagulation □ (C) Hemophilia A □ (D) Idiopathic thrombocytopenic purpura □ (E) Thrombotic thrombocytopenic purpura □ (F) Vitamin K deficiency □ (G) Von Willebrand disease

(C) Hemophilia A The partial thromboplastin time (PTT) is corrected by normal pooled plasma. The patient has hemophilia A caused either by decreased factor VIII activity or by factor VIII deficiency, and inhibitors of factor VIII are absent from the patient's serum. How is this possible in a female patient? Xinactivation ("unfavorable lyonization") can explain this phenomenon and could explain why female carriers of hemophilia A or B have a tendency to bleed. ("When you have eliminated the impossible, that which remains, however improbable, must be the truth," said Sherlock Holmes in The Sign of Four.) An in vitro mixing study of patient and pooled plasma such as this usually corrects an abnormality caused by a deficiency of a procoagulant factor, but if there is a coagulation inhibitor in the patient's plasma, the clotting test would show an abnormal result. The mixing study excludes the antiphospholipid syndrome. Disseminated intravascular coagulation is an acute problem with consumption of platelets and coagulation factors, making the prothrombin time (PT) and PTT prolonged. Idiopathic thrombocytopenic purpura is characterized by the presence of antiplatelet antibodies and thrombocytopenia. Thrombotic thrombocytopenic purpura is a microangiopathic hemolytic anemia characterized by renal failure and central nervous system abnormalities. Vitamin K deficiency should prolong the PT. Von Willebrand disease is caused by decreased platelet adhesion and has features resembling thrombocytopenia. BP7 450BP8 474PBD7 654-656PBD8 164, 672

52 A 21-year-old woman known to have a protein C deficiency develops recurrent pulmonary thromboembolism and is placed on anticoagulant therapy. Two weeks after initiation of this therapy, she has a sudden change in mental status and experiences difficulty speaking and swallowing. A cerebral angiogram shows a distal left middle cerebral artery occlusion. Laboratory studies show hemoglobin of 13 g/dL, platelet count of 65,400/mm3, WBC count of 5924/mm3, prothrombin time of 12 seconds, and partial thromboplastin time of 51 seconds. The anticoagulant therapy is discontinued. Which of the following pharmacologic agents used as an anticoagulant in this patient is most likely to have caused these findings? □ (A) Acetylsalicylic acid (aspirin) □ (B) Warfarin □ (C) Heparin □ (D) Tissue plasminogen activator □ (E) Urokinase

(C) Heparin This patient has heparin-induced thrombocytopenia, which affects 3% to 5% of patients treated for 1 to 2 weeks with unfractionated heparin. These patients form IgG antibodies to heparin-platelet factor 4 complexes that bind to Fc receptors on the surface of platelets, causing platelet activation and, paradoxically, thrombosis. Aspirin has antiplatelet effects that take days to occur, and bleeding (not thrombosis) is the major risk. Warfarin (Coumadin) was avoided in this patient because of the protein C deficiency; typically, the patient is switched from heparin to warfarin. Warfarin therapy prolongs the prothrombin time by interfering with vitamin K-dependent clotting factor synthesis in the liver. Tissue plasminogen activator and urokinase are fibrinolytic agents, with the former used acutely to treat conditions such as coronary thrombosis, although the latter also may be used for venous clot lysis. BP7 447BP8 472PBD7 652PBD8 668-669

54 A clinical study is performed using patients diagnosed with peptic ulcer disease, chronic blood loss, and hypochromic microcytic anemia. Their serum ferritin levels average 5 to 7 µg/mL. The rate of duodenal iron absorption in this study group is found to be much higher than in a normal control group. After treatment with omeprazole and clarithromycin, study group patients have hematocrits of 40% to 42%, MCV of 82 to 85 µm3, and serum ferritin of less than 12 µg/mL. Measured rates of iron absorption in the study group after therapy are now decreased to the range of the normal controls. Which of the following substances derived from liver is most likely to have been increased in the study group patients before therapy, returning to normal after therapy? □ (A) Transferrin □ (B) Hemosiderin □ (C) Hepcidin □ (D) Divalent metal transporter-1 (DMT-1) □ (E) HLA-like transmembrane protein

(C) Hepcidin Iron absorption from the gut is tightly controlled. When body iron stores are adequate, absorption of dietary iron via DMT-1 in the duodenum is retarded, and release of iron from storage pools is inhibited. When body iron stores decrease, as with chronic blood loss, iron absorption increases. The liver-derived plasma peptide hepcidin has been found to be the iron absorption regulator. Hepcidin levels increase when iron stores are high. Such fine control of iron absorption may fail, as in patients with ineffective erythropoiesis (e.g., β-thalassemia) who continue to absorb iron despite excess storage iron. Hepcidin levels are inappropriately low with both hereditary and acquired hemochromatosis. Transferrin transports iron between plasma, iron stores, and developing erythroblasts. Hemosiderin is an aggregated form of ferritin that does not circulate and is found only in tissues. DMT-1 is an iron transporter that moves nonheme iron from the gut lumen to duodenal epithelium. Mutations in the HFE gene, which encodes an HLA-like transmembrane protein, lead to excessive absorption of dietary iron and hemochromatosis.

24 A 42-year-old woman has had nosebleeds, easy bruising, and increased bleeding with her menstrual periods for the past 4 months. On physical examination, her temperature is 37°C, pulse is 88/min, respirations are 18/min, and blood pressure is 90/60 mm Hg. She has scattered petechiae over the distal extremities. There is no organomegaly. Laboratory studies show hemoglobin of 12.3 g/dL, hematocrit of 37%, *platelet count of 21,500/mm3*, and WBC count of 7370/mm3. A bone marrow biopsy specimen shows a marked *increase in megakaryocytes*. The prothrombin and partial thromboplastin times are within the reference range. What is the most likely diagnosis? □ (A) Disseminated intravascular coagulation □ (B) Hemophilia B □ (C) Idiopathic thrombocytopenic purpura □ (D) Metastatic breast carcinoma □ (E) Thrombotic thrombocytopenic purpura □ (F) Vitamin K deficiency □ (G) Von Willebrand disease

(C) Idiopathic thrombocytopenic purpura Reduced numbers of platelets can result from decreased production or increased destruction. Marrow examination in this case shows numerous megakaryocytes, which excludes decreased production. Accelerated destruction can be caused by hypersplenism, but there is no splenomegaly in this case. Peripheral platelet destruction is often immunologically mediated and can result from well-known autoimmune diseases such as systemic lupus erythematosus, or it can be idiopathic. When all known causes of thrombocytopenia are excluded, a diagnosis of idiopathic (immune) thrombocytopenic purpura (ITP) can be made. This patient seems to have no other symptoms or signs and has no history of drug intake or infections that can cause thrombocytopenia. ITP is most likely. *Thrombotic thrombocytopenic purpura (TTP) is another entity to be considered, but TTP produces a microangiopathic hemolytic anemia (MAHA) that typically is associated with fever, neurologic symptoms, and renal failure*. Disseminated intravascular coagulation is another form of MAHA. Hemophilia B, similar to hemophilia A, leads to soft-tissue bleeding, and the partial thromboplastin time is prolonged, but the platelet count is normal. Metastases can act as a space-occupying lesion in the marrow to reduce hematopoiesis, but this is unlikely to be selective with megakaryocytes, and in this case, there is a megakaryocytic hyperplasia. Vitamin K deficiency prolongs the prothrombin time initially and the partial thromboplastin time if severe, but does not affect platelets. In von Willebrand disease, bleeding is due to abnormal platelet adhesion, but platelet numbers are normal. BP7 447BP8 471-472PBD7 650-651PBD8 667-668

25 A 12-year-old boy experienced sudden onset of severe abdominal pain and cramping accompanied by chest pain, nonproductive cough, and fever. On physical examination, his temperature is 39°C, pulse is 110/min, respirations are 22/min, and blood pressure is 80/50 mm Hg. He has diffuse abdominal tenderness, but no masses or organomegaly. Laboratory studies show a hematocrit of 18%. The peripheral blood smear shows *crescent-shaped RBCs*. A chest x-ray shows bilateral pulmonary infiltrates. Which of the following is the most likely mechanism for initiation of his pulmonary problems? □ (A) Intravascular hemolysis □ (B) Chronic hypoxia of the pulmonary parenchyma □ (C) Increased RBC adhesion to endothelium □ (D) Defects in the alternative pathway of complement activation □ (E) Formation of autoantibodies to alveolar basement membrane

(C) Increased RBC adhesion to endothelium The crescent-shaped RBCs (sickled RBCs) are characteristic of hemoglobin SS. This disease is most common in individuals of African and eastern Arabian descent. The sickled RBCs are susceptible to hemolysis (mainly vascular, in the spleen), but they also can cause microvascular occlusions anywhere in the body, most commonly bone, lungs, liver, and brain, leading to ischemia and severe pain. Vascular occlusions in the lungs are often accompanied by infection and lead to the "acute chest syndrome." The cell membranes of reversibly sickled cells are abnormally "sticky," and they adhere to capillary endothelium, especially in lungs. Vasoconstriction is caused by depletion of NO by free hemoglobin. Adhesion of RBCs to endothelium retards blood flow, creates hypoxia, and precipitates local sickling and vascular occlusion. Chronic tissue hypoxia does occur in sickle cell anemia, but it produces insidious impairment of function in organs such as heart, kidneys, and lungs. Defects in the alternative pathway of complement activation predispose to infection with encapsulated bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae. BP7 400-403BP8 426-428PBD7 628-632PBD8 645-646

13 A 26-year-old man has noted lumps in his neck that have been enlarging for the past 6 months. On physical examination, he has a group of enlarged, nontender right cervical lymph nodes. A biopsy of one of the lymph nodes shows scattered Reed-Sternberg cells, macrophages, lymphocytes, neutrophils, eosinophils, and a few plasma cells. Which of the following factors elaborated by the Reed-Sternberg cells has led to the appearance of the eosinophils within this lesion? □ (A) Platelet-derived growth factor □ (B) Cyclin D1 □ (C) Interleukin-5 □ (D) Trans-retinoic acid □ (E) Erythropoietin

(C) Interleukin-5 Interleukin-5 acts as an eosinophilic chemotactic factor to form an eosinophilic cellular component of the mixed cellularity and nodular sclerosis types of Hodgkin lymphoma. In contrast, transforming growth factor-β secreted by eosinophils promotes the fibrosis that is part of nodular sclerosing Hodgkin lymphoma. Platelet-derived growth factor does not play a major role in Hodgkin lymphoma, although it may be elaborated by cells in some carcinomas and gliomas. Cyclin D1 is involved in the cell cycle and proliferation. Trans-retinoic acid is used in treating acute promyelocytic leukemia, in which the abnormal gene fusion product of the t(15;17) blocks myeloid maturation at the promyelocyte stage. Erythropoietin drives erythroid cell line proliferation. BP8 459PBD7 690PBD8 620

50 An infant is born at 34 weeks' gestation to a 28-year-old woman, G3, P2. At birth, the infant is observed to be markedly *hydropic and icteric*. A cord blood sample is taken, and *Direct Coombs' test result is positive* for the infant's RBCs. Which of the following is the most likely diagnosis? □ (A) Mechanical fragmentation of RBCs □ (B) Nuclear maturation defects resulting from impaired DNA synthesis □ (C) Impaired globin synthesis □ (D) Hemolysis of antibody-coated cells □ (E) Stem cell defect □ (F) Oxidative injury to hemoglobin □ (G) Reduced deformability of the RBC membrane

(D) Hemolysis of antibody-coated cells The infant most likely has erythroblastosis fetalis because of the maternal antibodies coating the fetal cells. A fetalmaternal hemorrhage in utero or at the time of delivery in a previous pregnancy (or with previous transfusion of incompatible blood) can sensitize the mother, resulting in production of IgG antibodies. In subsequent pregnancies, these antibodies (in contrast to the naturally occurring IgM antibodies) can cross the placenta to attach to fetal cells, leading to hemolysis. In the past, most cases were caused by Rh incompatibility (e.g., Rh-negative mother, Rh-positive infant), but the use of RhoGAM administered at birth to Rh-negative mothers has eliminated almost all such cases. Other, less common blood group antigens can be involved in this process, however. The other conditions listed are not antibody mediated. Mechanical fragmentation of RBCs is typical of microangiopathic hemolytic anemias, such as disseminated intravascular coagulation, which is more typical of pregnant women with obstetric complications. Impaired RBC nuclear maturation occurs as a result of vitamin B12 or folate deficiency. Impaired globin synthesis occurs in thalassemias. A stem cell defect results in aplastic anemia and immunodeficiency. Oxidative injury to hemoglobin is typical of glucose-6phosphate dehydrogenase deficiency. Reduced RBC membrane deformability is seen in patients with abnormalities in cytoskeletal proteins, such as spectrin; the latter causes hereditary spherocytosis. BP7 407-408BP8 261-262, 424PBD7 485-486, 623PBD8 460-461, 641

28 A 45-year-old man has a 3-day history of flank pain and fever. On physical examination, his temperature is 37.9°C. There is *right costovertebral angle tenderness*. Laboratory studies include a urine culture that is positive for *Escherichia coli*. The WBC count is 13,310/mm3. Two days later, he becomes hypotensive, and a blood culture is positive for E. coli. He requires increasing pressor support to maintain blood pressure. He develops a *guaiac-positive stool and ecchymoses of the skin*. CBC shows hemoglobin of 9.2 g/dL, hematocrit of 28.1%, and platelet count of 70,000/mm3. *Increased amounts of fibrin split products are identified in the blood (elevated D dimer)*. Which of the following conditions is most likely responsible for the low hematocrit? □ (A) Warm autoimmune hemolytic anemia □ (B) Paroxysmal nocturnal hemoglobinuria □ (C) Microangiopathic hemolytic anemia □ (D) β-Thalassemia major □ (E) Aplastic anemia

(C) Microangiopathic hemolytic anemia This patient has disseminated intravascular coagulation, which can result from gram-negative septicemia. This is a form of microangiopathic hemolytic anemia, in which there is deposition of fibrin strands in small vessels. The RBCs are damaged during passage between these strands. Coagulation factors and platelets are consumed, which does not occur with other forms of hemolytic anemia. Paroxysmal nocturnal hemoglobinuria and the hemolytic anemias do not typically cause a consumptive coagulopathy. Thalassemias produce chronic anemia with ineffective erythropoiesis; there also is an extravascular hemolytic component without the complication of bleeding. Aplastic anemia refers to the loss of marrow stem cell activity and is associated with anemia, leukopenia, and thrombocytopenia. Aplastic anemia can follow infections, most often viral, but rarely bacterial. BP7 444-446BP8 469-471PBD7 358, 656-658PBD8 673-674

54 A 48-year old man visits his physician for a routine health maintenance examination. He has no complaints other than worrying about getting older and having cancer. Physical examination shows that he is afebrile and normotensive. There is no hepatosplenomegaly or lymphadenopathy. Laboratory studies show a total serum protein level of 7.4 g/dL and albumin level of 3.9 g/dL. Serum calcium and phosphorus levels are normal. Urinalysis shows *no Bence Jones proteinuria*. Hemoglobin is 13.6 g/dL, platelet count is 301,500/mm3, and WBC count is 6630/mm3. A serum protein electrophoresis shows a small (2.8-g) *spike of γ-globulin, which is determined by immunoelectrophoresis to be IgG kappa*. A bone marrow biopsy specimen shows normal cellularity with maturation of all cell lines. *Plasma cells constitute about 4% of the marrow. A bone scan is normal, and there are no areas of increased uptake*. What is the most likely diagnosis? □ (A) Solitary plasmacytoma □ (B) Waldenström macroglobulinemia □ (C) Monoclonal gammopathy of undetermined significance □ (D) Heavy-chain disease □ (E) Multiple myeloma □ (F) Reactive systemic amyloidosis

(C) Monoclonal gammopathy of undetermined significance Monoclonal gammopathy of uncertain significance (MGUS) is characterized by the presence of an M protein "spike" in the absence of any associated disease of B cells. The diagnosis of MGUS is made when the monoclonal spike is small (<3 g), and the patient has no Bence Jones proteinuria. MGUS can progress to multiple myeloma in about 20% of patients over 10 to 15 years. A plasmacytoma would appear on a bone scan. Waldenström macroglobulinemia would be accompanied by an IgM spike, hepatosplenomegaly, and lymphadenopathy. Heavy-chain disease is a rare condition that can be seen in chronic lymphocytic leukemia. In multiple myeloma, the spike is greater than 3 g, and usually the patient has bone lesions. In reactive systemic amyloidosis, serum amyloid-associated (SAA) protein derived from chronic inflammatory conditions is deposited as AA amyloid in visceral organs, but there is no monoclonal gammopathy. BP7 430BP8 454PBD7 679, 681PBD8 611

22 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 ReedSternberg 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

(C) Nodular sclerosis, stage I The bands of fibrosis are typical of the nodular sclerosis type of Hodgkin lymphoma, which is most commonly seen in young adults, particularly women. 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. BP7 432-433BP8 456-459PBD7 686-689PBD8 618

37 A 62-year-old man goes to the emergency department in an obvious state of inebriation. He is well known there because this scenario has been repeated many times over the years. On physical examination, he is afebrile. The spleen tip is palpable, and the liver edge is firm. Laboratory studies show hemoglobin of 8.2 g/dL, hematocrit of 25.1%, MCV of 107 µm3, platelet count of 135,000/mm3, and WBC count of 3920/mm3. The peripheral blood smear shows prominent anisocytosis and macrocytosis. Polychromatophilic RBCs are difficult to find. *A few of the neutrophils show six to seven nuclear lobes*. Which of the following is the most likely explanation of these findings? □ (A) Mechanical fragmentation of RBCs □ (B) Increased susceptibility to lysis by complement □ (C) Nuclear maturation defects resulting from impaired DNA synthesis □ (D) Hemolysis of antibody-coated cells □ (E) Reduced deformability of the RBC membrane □ (F) Production of abnormal hemoglobin □ (G) Imbalance in synthesis of α-globin and β-globin chains

(C) Nuclear maturation defects resulting from impaired DNA synthesis This patient has chronic alcoholism and folate deficiency, giving rise to megaloblastic anemia. Folic acid and vitamin B12 act as coenzymes in the DNA synthetic pathway. A deficiency of either impairs the normal process of nuclear maturation. The nuclei remain large and primitive looking, giving rise to megaloblasts. The mature RBCs also are larger than normal (macrocytes). The nuclear maturation defect affects all rapidly dividing cells in the body, including other hematopoietic lineages. Patients can have thrombocytopenia and leukopenia, often because of secondary hypersplenism (alcoholic cirrhosis, leading to splenomegaly). Neutrophils often show defective segmentation, manifested by extra nuclear lobes. Polychromatophilic RBCs represent reticulocytes, and their number is reduced because of the failure of marrow to produce adequate numbers of RBCs despite anemia. Mechanical fragmentation of RBCs is typical of microangiopathic hemolytic anemias, such as disseminated intravascular coagulation. Complement lysis is enhanced in paroxysmal nocturnal hemoglobinuria, which results from mutations in the PIGA gene. Hemolytic anemias, in which antibody coats RBCs, can occur in autoimmune diseases, prior transfusion, and erythroblastosis fetalis. Reduced RBC membrane deformability is seen in patients with abnormalities of cytoskeletal proteins, such as spectrin; the latter causes hereditary spherocytosis. Hemoglobinopathies can produce a mild macrocytosis because more reticulocytes are released. An imbalance in α-globin and β-globin chain synthesis, seen in thalassemias, leads to microcytosis of RBCs. BP7 412-413BP8 438PBD7 642-643PBD8 658-659

32 A 17-year-old boy reports passage of dark urine to his physician. He has a history of multiple bacterial infections and venous thromboses for the past 10 years, including portal vein thrombosis in the previous year. On physical examination, his right leg is swollen and tender. CBC shows hemoglobin, 9.8 g/dL; hematocrit, 29.9%; MCV, 92 µm3; platelet count, 150,000/mm3; and WBC count, 3800/mm3 with 24% segmented neutrophils, 1% bands, 64% lymphocytes, 10% monocytes, and 1% eosinophils. He has a reticulocytosis, and his serum haptoglobin level is very low. A mutation affecting which of the following gene products is most likely to give rise to this clinical condition? □ (A) Spectrin □ (B) Glucose-6-phosphate dehydrogenase □ (C) Phosphatidylinositol glycan A (PIGA) □ (D) β-Globin chain □ (E) Factor V □ (F) Prothrombin G20210A

(C) Phosphatidylinositol glycan A (PIGA) This patient has paroxysmal nocturnal hemoglobinuria, a disorder that results from an acquired myeloid stem cell membrane defect produced by a mutation in the PIGA gene. A mutation in this gene prevents the membrane expression of certain proteins that require a glycolipid anchor. These include proteins that protect cells from lysis by spontaneously activated complement. As a result, RBCs, granulocytes, and platelets are exquisitely sensitive to the lytic activity of complement. The RBC lysis is intravascular; patients can have hemoglobinuria (dark urine). Defects in platelet function are believed to be responsible for venous thrombosis. Recurrent infections can be caused by impaired leukocyte functions. Patients with paroxysmal nocturnal hemoglobinuria also may have acute leukemia or aplastic anemia as complications. Spectrin mutations give rise to hereditary spherocytosis. Patients with glucose-6-phosphate dehydrogenase deficiency have an episodic course from exposure to agents such as drugs that induce hemolysis. Mutations in the βglobin chain can give rise to hemoglobinopathies such as sickle cell anemia. Patients with factor V (Leiden) and prothrombin G20210A mutations can present with thromboses, but there is no anemia or leukopenia. BP7 407BP8 432PBD7 636PBD8 652-653

44 A 26-year-old woman has experienced chronic fatigue since early childhood. She also has had episodes of severe pain in the abdomen, back, and legs. On physical examination, there is no organomegaly. Laboratory studies show hemoglobin, 8.9 g/dL; hematocrit, 26.9%; platelet count, 300,100/mm3; and WBC count, 5560/mm3. Hemoglobin electrophoresis shows 1% hemoglobin A2, 6% hemoglobin F, and *93% hemoglobin S*. Which of the following is this patient most likely to develop as a complication of the underlying disease? □ (A) Micronodular cirrhosis □ (B) Chronic atrophic gastritis □ (C) Pigment gallstones □ (D) High rate of stillbirths □ (E) Esophageal web

(C) Pigment gallstones The hemolysis that accompanies sickle cell anemia results in an increased indirect hyperbilirubinemia, which favors the development of gallstones containing bilirubin pigment. Cirrhosis can occur because of hemochromatosis in βthalassemia major. Chronic atrophic gastritis leads to loss of parietal cells, and the resulting vitamin B12 malabsorption causes pernicious anemia. Stillbirths suggest thalassemia major. Esophageal webs occur rarely in the setting of chronic iron deficiency anemia. BP7 402-403BP8 424PBD7 624, 630PBD8 642

44 A 60-year-old man has experienced vague abdominal discomfort accompanied by bloating and diarrhea for the past 6 months. On physical examination, there is a mid-abdominal firm mass. The stool is positive for occult blood. An abdominal CT scan shows a 5 × 12 cm mass involving the wall of the distal ileum and adjacent mesentery. A laparotomy is performed, and the mass is removed. Microscopically, the mass is composed of sheets of large lymphoid cells with large nuclei, prominent nucleoli, and frequent mitoses. *The neoplastic cells mark with CD19+ and CD20+ and have the BCL6 gene rearrangement*. Which of the following prognostic features is most applicable to this case? □ (A) Indolent, survival of 7 to 9 years without treatment □ (B) Indolent, can be cured by chemotherapy □ (C) Indolent, often undergoes spontaneous remission □ (D) Aggressive, can be cured by chemotherapy □ (E) Aggressive, often transforms to acute leukemia □ (F) Aggressive, often spreads to liver, spleen, and marrow

(D) Aggressive, can be cured by chemotherapy This patient has the clinical and morphologic features of diffuse large-cell lymphoma of B cells. These tumors often involve extranodal sites, show large anaplastic lymphoid cells that involve the tissues diffusely, and contain BCL6 gene rearrangements. Their clinical course is aggressive, and they become rapidly fatal if untreated. With intensive chemotherapy, however, 60% to 80% of patients achieve complete remission, and about 50% can be cured. More aggressive lymphomas tend to be localized, whereas the indolent lymphomas tend to involve multiple nodal sites or multiple organs such as liver, spleen, and marrow. BP7 427-428BP8 452-453PBD7 671, 676-677PBD8 606-607

45 A 45-year-old man has experienced a gradual weight loss and weakness, anorexia, and easy fatigability for 7 months. Physical examination shows marked splenomegaly. CBC shows hemoglobin, 12.9 g/dL; hematocrit, 38.1%; MCV, 92 µm3; platelet count, 410,000/mm3; and WBC count, 168,000/mm3. Karyotypic analysis shows the *Ph1 chromosome*. The patient undergoes chemotherapy with imatinib mesylate (tyrosine kinase inhibitor), which reduces the spleen size and brings the total leukocyte count within normal range. He remains in remission for 3 years and then begins to experience fatigue and a 10-kg weight loss. Physical examination now shows petechial hemorrhages. CBC shows hemoglobin, 10.5 g/dL; hematocrit, 30%; platelet count, 60,000/µL; and WBC count, 40,000/µL. A peripheral blood smear is depicted in part B of the figure. Karyotypic analysis shows two Ph1 chromosomes and aneuploidy. Flow cytometric analysis of the peripheral blood shows *CD19+, CD10+, sIg−, and CD3− cells*. Which of the following complications of the initial disease did this patient develop after therapy? □ (A) Sézary syndrome □ (B) Myelodysplastic syndrome □ (C) Hairy cell leukemia □ (D) B lymphoblastic leukemia □ (E) Acute myeloblastic leukemia

(D) B lymphoblastic leukemia This patient came to his physician with a classic history of chronic myelogenous leukemia (CML), confirmed by the presence of different stages of myeloid differentiation in the blood and by the presence of the Philadelphia chromosome. He went into a remission and then entered a blast crisis involving B cells (CD19+). The fact that the B cells carry the original Ph1 chromosome and some additional abnormalities indicates that the B cells and the myeloid cells belong to the same clone. The best explanation for this is that the initial transforming event affected a pluripotent stem cell, which differentiated along the myeloid lineage to produce a picture of CML. Analysis, even at this stage, indicates that the molecular counterpart of the Ph1 chromosome—the BCR-ABL rearrangement—affects all lineages, including B cells, T cells, and myeloid cells. With the evolution of the disease, additional mutations accumulate in the stem cells, which differentiate mainly along B lineages, giving rise to B lymphoblastic leukemia; blast crisis also can affect myeloid cells, but they are not CD19+. The Sézary syndrome has a leukemic component of CD4+ cells in addition to the skin involvement (mycosis fungoides). Myelodysplastic syndromes can precede the development of acute myelogenous leukemia. Hairy cell leukemia is an indolent disease without blasts. BP7 438-439BP8 464-466PBD7 697-698PBD8 627-628

26 A clinical study of patients who inherit mutations that *reduce the level of spectrin* in the RBC membrane cytoskeleton shows an increased prevalence of chronic anemia with splenomegaly. For many patients, it is observed that *splenectomy reduces the severity of anemia*. This beneficial effect of splenectomy is most likely related to which of the following processes? □ (A) Increase in synthesis of spectrin in RBCs □ (B) Increase in deformability of RBCs □ (C) Decrease in opsonization of RBCs □ (D) Decrease in trapping of RBCs in the spleen □ (E) Decrease in production of reactive oxygen species

(D) Decrease in trapping of RBCs in the spleen In patients with hereditary spherocytosis, spheroidal cells are trapped and destroyed in the spleen because the abnormal RBCs have reduced deformability. Splenectomy is beneficial because the spherocytes are no longer detained by the spleen. Splenectomy has no effect on the synthesis of spectrin or RBC deformability as a result; the RBCs in spherocytosis are not killed by opsonization. In warm antibody hemolytic anemias, opsonized RBCs are removed by the spleen. Reactive oxygen species do not play a role in anemias. BP7 399-400BP8 424-425PBD7 625-627PBD8 642-644

31 A 58-year-old man from *Nagasaki, Japan*, has noted an *increasing number of skin lesions* for the past 8 months. On examination, there are scaling red-brown patches on all skin surfaces. He also has generalized lymphadenopathy and hepatosplenomegal. Laboratory studies show hemoglobin, 9.7 g/dL; hematocrit, 31%; MCV, 89 µm3; platelet count, 177,000/mm3; and WBC count, 18,940/mm3 with differential count of 35 segmented neutrophils, 2 band neutrophils, 58 lymphocytes, and 5 monocytes. His serum calcium is 11.5 mg/dL. Examination of his peripheral blood smear shows multilobated "cloverleaf" cells. Despite aggressive chemotherapy, his condition worsens with development of paresthesias along with erythematous plaques and red-brown nodules on his skin. Which of the following infectious agents most likely caused his illness? □ (A) Cytomegalovirus □ (B) Epstein-Barr virus (EBV) □ (C) HIV □ (D) HTLV-1 □ (E) Rochalimaea henselae □ (F) Yersinia pestis

(D) HTLV-1 The patient lives in an area endemic for HTLV-1, which can cause leukemia/lymphoma and demyelinating disease. The neoplastic lymphoid cells can infiltrate many organs. Skin lesions resemble those of mycosis fungoides. CMV is not associated with development of neoplasms, but it can complicate the course of patients with neoplasms who become immunocompromised. EBV can be associated with African Burkitt lymphoma. HIV is best known to be associated with lymphomas and with Kaposi sarcoma, but not leukemias. Cat-scratch disease from R. henselae infection results in lymphadenopathy with microscopic stellate necrosis. Plague from Y. pestis can produce acute lymphadenopathy with microscopic hemorrhagic necrosis. BP7 199-200BP8 460PBD7 685PBD8 615-616

21 A 23-year-old woman in her *25th week of pregnancy* has felt no fetal movement for the past 3 days. Three weeks later, she still has not given birth and suddenly develops dyspnea with cyanosis. On physical examination, her temperature is 36.9°C, pulse is 102/min, respirations are 21/min, and blood pressure is 80/40 mm Hg. She has *large ecchymoses over the skin of her entire body*. A stool sample is positive for occult blood. Laboratory studies show an *elevated prothrombin time and partial thromboplastin time. The platelet count is decreased, plasma fibrinogen is markedly decreased, and fibrin split products are detected*. A blood culture is negative. Which of the following is the most likely cause of the bleeding diathesis? □ (A) Increased vascular fragility □ (B) Toxic injury to the endothelium □ (C) Reduced production of platelets □ (D) Increased consumption of clotting factors and platelets □ (E) Defects in platelet adhesion and aggregation

(D) Increased consumption of clotting factors and platelets The presence of thrombocytopenia, increased prothrombin and partial thromboplastin times, and fibrin split products, and the low fibrinogen concentration all suggest disseminated intravascular coagulation (DIC), which was most likely caused by a retained dead fetus, an obstetric complication that can lead to DIC through release of thromboplastins from the fetus. This release causes widespread microvascular thrombosis and consumes clotting factors and platelets. There is no damage to the vascular endothelium or vascular wall. Platelet production is normal, but platelets are consumed by widespread thrombosis of small vessels. There is no defect in platelet function. BP7 444-446BP8 468-471PBD7 656-658PBD8 673-674

49 A 38-year-old woman has experienced increasing dyspnea for the past 2 months. On physical examination, she is afebrile and normotensive. Inspiratory wheezes are noted on auscultation of the chest. A chest CT scan shows an 8 × 10 cm posterior mediastinal mass that impinges on the trachea and esophagus. A mediastinoscopy is performed, and the mass is biopsied. Histologically, there are *scattered large multinucleated cells, with prominent nucleoli that mark with CD15, and lymphocytes and macrophages separated by dense collagenous bands*. Which of the following is most likely to be seen microscopically in this biopsy specimen? □ (A) Atypical lymphocytes □ (B) Histiocytes with Birbeck granules □ (C) Hairy cells □ (D) Lacunar cells □ (E) Lymphoblasts □ (F) Myeloblasts

(D) Lacunar cells The lacunar cells and the CD15+ Reed-Sternberg cells indicate Hodgkin lymphoma, and the fibrous bands suggest the nodular sclerosis type. Lacunar cells have multilobed nuclei containing many small nucleoli. These cells have artifactual retraction of the cytoplasm around the nucleus, giving the cells their distinctive appearance. The nodular sclerosis type of Hodgkin lymphoma is more common in women. Atypical lymphocytes are characteristic in the peripheral blood of individuals with infectious mononucleosis. Histiocytes with Birbeck granules are characteristic of the Langerhans cell histiocytoses. Hairy cell leukemia often is accompanied by splenomegaly, but not a mediastinal mass, and the leukemic cells are B cells. Lymphoblasts that mark as T cells are seen in anterior mediastinal (thymic) masses in children with acute lymphoblastic leukemia/lymphoma. Myeloblasts are characteristic of acute myelogenous leukemia, which is occasionally accompanied by soft-tissue masses. BP7 431-434BP8 456-469PBD7 696-697PBD8 617-618

2 A 9-year-old boy is taken to his pediatrician because of a generalized seborrheic skin eruption and fever. He has been diagnosed and treated for otitis media several times in the past year. On physical examination, he has mild lymphadenopathy, hepatomegaly, and splenomegaly. The electron micrograph shows rodlike tubular Birbeck granules from a mass lesion involving the mastoid bone. What is the most likely diagnosis? □ (A) Acute lymphoblastic leukemia □ (B) Multiple myeloma □ (C) Hodgkin lymphoma, mixed cellularity type □ (D) Langerhans cell histiocytosis □ (E) Disseminated tuberculosis

(D) Langerhans cell histiocytosis Shown here are the famous rodlike tubular Birbeck granules, with the characteristic periodicity seen in Langerhans cell proliferations. In this case, the skin eruptions, organomegaly, and lesion in the mastoid suggest infiltrates in multiple organs. The diagnosis is multifocal Langerhans cell histiocytosis, a disease most often seen in children. In half of these cases, exophthalmos occurs, and involvement of the hypothalamus and pituitary stalk leads to diabetes insipidus; these findings are called Hand-Schüller-Christian disease. Acute lymphoblastic leukemia in children can involve the marrow, but does not produce skin or bone lesions. Myeloma is a disease of adults that can produce lytic bone lesions, but not skin lesions. Hodgkin lymphoma is seen in young adults and does not produce skin lesions or bone lesions. Tuberculosis can produce granulomatous disease with bony destruction, but the macrophages present in the granulomas are epithelioid macrophages that do not have Birbeck granules. BP7 441BP8 467-468PBD7 701-702PBD8 631

4 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 hemoglobin, 13.9 g/dL; hematocrit, 42%; MCV, 89 µm3; platelet count, 210,000/mm3; and WBC count, 56,000/mm3 with 63% segmented neutrophils, 15% bands, 6% metamyelocytes, 3% myelocytes, 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 lymphoma, lymphocyte depletion type □ (D) Leukemoid reaction □ (E) Acute lymphoblastic leukemia

(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 lymphoma 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. BP7 59, 416BP8 442PBD7 665PBD8 593-595

17 In an epidemiologic study of anemias, the findings show that there is an increased prevalence of anemia in individuals of West African ancestry. By hemoglobin electrophoresis, a subset of individuals of this ancestry are found to have increased hemoglobin S levels. The distribution of infectious illnesses is correlated with the prevalence of hemoglobin S in this population. Which of the following infectious agents is most likely to account for these observations? □ (A) Cryptococcus neoformans □ (B) Borrelia burgdorferi □ (C) Treponema pallidum □ (D) Plasmodium falciparum □ (E) Clostridium perfringens □ (F) Trypanosoma gambiense □ (G) Schistosoma haematobium

(D) Plasmodium falciparum Throughout human history, malaria has been the driving force for increasing the gene frequency of hemoglobin S. Individuals who are heterozygous for hemoglobin S have the sickle cell trait. They are resistant to malaria because the parasites grow poorly or die at low oxygen concentrations, perhaps because of low potassium levels caused by potassium efflux from RBCs on hemoglobin sickling. The malarial parasite cannot complete its life cycle. Clostridium neoformans can cause granulomatous disease in immunocompromised individuals. Borrelia burgdorferi is the spirochete that causes Lyme disease. Treponema pallidum is the infectious agent causing syphilis. Clostridium perfringens may produce gas gangrene after soft-tissue injuries. Trypanosoma gambiense infection causes sleeping sickness. Schistosoma haematobium infection leads to hematuria and iron deficiency anemia. BP7 400BP8 426-428, 433-434PBD7 402, 628-629PBD8 645

9 A 29-year-old woman has had malaise and a low-grade fever for the past week. On physical examination, she appears very pale. She has a history of chronic anemia, and spherocytes are observed on a peripheral blood smear. Her hematocrit, which normally ranges from 35% to 38%, is now 28%, and the *reticulocyte count is very low*. The serum bilirubin level is 0.9 mg/dL. Which of the following events is most likely to have occurred in this patient? □ (A) Development of anti-RBC antibodies □ (B) Disseminated intravascular coagulation □ (C) Accelerated extravascular hemolysis in the spleen □ (D) Reduced erythropoiesis from parvovirus infection □ (E) Superimposed iron deficiency

(D) Reduced erythropoiesis from parvovirus infection This patient has aplastic crisis, precipitated by a parvovirus infection. In adults who do not have a defect in normal RBC production, such as hereditary spherocytosis or sickle cell anemia, or who are not immunosuppressed, parvovirus infection is self-limited and often goes unnoticed. When RBC production is shut down by parvovirus, there is no reticulocytosis. Disseminated intravascular coagulation gives rise to thrombocytopenia, bleeding, and the appearance of fragmented RBCs in the blood smear. Reticulocytosis would be prominent with RBC antibodies. Iron deficiency does not occur in hemolytic anemias because the iron that is released from hemolyzed cells is reused. BP8 425, 428PBD7 627PBD8 665

10 A 60-year-old man has developed widespread ecchymoses over the skin in the past month. His medical history includes a diagnosis of *mucinous adenocarcinoma* of the rectum. On physical examination, he appears cachectic and pale. An abdominal CT scan shows multiple hepatic masses. Laboratory studies show prothrombin time of 30 seconds, partial thromboplastin time of 55 seconds, platelet count of 15,200/mm3, and fibrinogen level of 75 mg/dL, and *fibrin split product levels (D dimer) that are very elevated*. Which of the following morphologic findings is most likely to be present on examination of his peripheral blood smear? □ (A) Howell-Jolly bodies □ (B) Teardrop cells □ (C) Macro-ovalocytes □ (D) Schistocytes □ (E) Target cells

(D) Schistocytes This is an example of disseminated intravascular coagulation (DIC) with associated microangiopathic hemolytic anemia. The DIC developed in the setting of a mucin-secreting adenocarcinoma. Howell-Jolly bodies are small, round inclusions in RBCs that appear when the spleen is absent. Teardrop cells are most characteristic of myelofibrosis and other infiltrative disorders of the marrow. Macro-ovalocytes are seen in megaloblastic anemias, such as vitamin B12 deficiency. Target cells appear in hemoglobin C disease or severe liver disease. BP7 444-446BP8 469-471PBD7 656-658PBD8 673-674

27 A 39-year-old woman sees her physician because she has experienced abdominal pain and intermittent low-volume diarrhea for the past 3 months. On physical examination, she is afebrile. A stool sample is positive for occult blood. A colonoscopy is performed, and biopsy specimens from the terminal ileum and colon show microscopic findings consistent with Crohn's disease. Because she has failed to respond to medical therapy, surgery is warranted, and *part of the colon and terminal ileum are removed*. She is transfused with 2 U of packed RBCs during surgery. Several weeks later, she appears healthy, but complains of easy fatigability. On investigation, CBC findings show hemoglobin of 10.6 g/dL, hematocrit of 31.6%, RBC count of 2.69 million/µL, *MCV of 118 µm3*, platelet count of 378,000/mm3, and WBC count of 9800/mm3. The reticulocyte count is 0.3%. Which of the following is most likely to produce these findings? □ (A) Hemolytic anemia □ (B) Aplastic anemia □ (C) Chronic blood loss □ (D) Vitamin B12 deficiency □ (E) Anemia of chronic disease □ (F) Bone marrow metastases

(D) Vitamin B12 deficiency The high MCV indicates a marked macrocytosis, greater than would be accounted for by a reticulocytosis alone. The two best-known causes for such an anemia (also known as megaloblastic anemia when characteristic megaloblastic precursors are seen in the bone marrow) are vitamin B12 and folate deficiency. Because vitamin B12 is absorbed in the terminal ileum, its removal can cause vitamin B12 deficiency. Hemolytic anemia is unlikely several weeks after blood transfusion. Chronic blood loss and iron deficiency produce a microcytic pattern of anemia, as does dietary iron deficiency. Anemia of chronic disease is generally a normocytic anemia. Inflammatory bowel diseases (e.g., Crohn disease) increase the risk of malignancy, but myelophthisic anemias (from space-occupying lesions of the marrow) are usually normocytic to mildly macrocytic (from reticulocytosis). BP7 411-413BP8 438-439PBD7 638-642PBD8 655-658

33 A 32-year-old man has reported easy fatigability since childhood. On physical examination, he is normally developed and is afebrile. Laboratory studies show hemoglobin of 8.8 g/dL, hematocrit of 26.3%, platelet count of 199,000/mm3, and WBC count of 5350/mm3. α-Globin inclusions are present in erythroblasts and erythrocytes, leading to increased phagocytosis by cells of the mononuclear phagocyte system. Hemoglobin electrophoresis shows *hemoglobin A2 of 6% *, hemoglobin F of 1%, and hemoglobin A1 of 93%. The serum ferritin level is 3090 ng/mL. Which of the following is the most likely diagnosis? □ (A) Autoimmune hemolytic anemia □ (B) Glucose-6-phosphate dehydrogenase deficiency □ (C) Megaloblastic anemia □ (D) β-Thalassemia □ (E) Sickle cell anemia □ (F) Paroxysmal nocturnal hemoglobinuria

(D) β-Thalassemia The reduced β-globin synthesis results in a relative excess of α-globin chains that precipitate in RBCs and their precursors. These precipitates make the cells more susceptible to damage and removal. This intramedullary loss of RBC precursors is termed ineffective erythropoiesis. It acts as a trigger for greater dietary absorption of iron by unknown mechanisms. Hemolysis of RBCs in the periphery (e.g., spleen, liver) releases iron that can be reused for hemoglobin synthesis. Hemolysis can occur in glucose-6-phosphate dehydrogenase deficiency with oxidative injury to RBCs, particularly in ingestion of certain drugs. In megaloblastic anemias, there is enough iron but not enough vitamin B12 or folate. In sickle cell anemia, the β-globin chains are abnormal, leading to sickling of RBCs, which are destroyed in the spleen; however, there is no ineffective erythropoiesis. Complement lysis is enhanced in paroxysmal nocturnal hemoglobinuria, which results from mutations in the PIGA gene. Patients with this disorder have a history of infections. BP7 403-405BP8 428-430PBD7 632-635PBD8 649-650

25 A *4-year-old boy* has appeared listless for about 1 week. He now complains of pain when he is picked up by his mother, and he exhibits 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, 10.2 g/dL; hematocrit, 30.5%; MCV, 96 µm3; platelet count, 45,000/mm3; and WBC count, 13,990/mm3. 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

(E) Acute lymphoblastic leukemia These findings are characteristic of a childhood acute lymphoblastic leukemia of the precursor-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 cell-type and B cell-type lymphoid cells. Chronic myelogenous leukemia is a disease of adults, and the WBC count is quite high; the peripheral blood contains some myeloblasts, but other stages of myeloid differentiation also are detected. In idiopathic thrombocytopenic purpura, only the platelet count is reduced because of antibody-mediated destruction of platelets. An acute myelogenous leukemia is a disease of young to middle-aged adults, and there would be peroxidase-positive myeloblasts and phenotypic features of myeloid cells. Chronic lymphocytic leukemia is a disease of older adults; patients have many small circulating mature B lymphocytes. BP7 421-422BP8 446-447PBD7 670-673PBD8 602-603

40 A 38-year-old woman visits her physician because she has had bleeding gums for the past 3 weeks. Physical examination shows that her gingivae are thickened and friable. She has hepatosplenomegaly and generalized nontender lymphadenopathy. CBC shows hemoglobin, 11.2 g/dL; hematocrit, 33.9%; MCV, 89 µm3; platelet count, 95,000/mm3; and WBC count, 4500/mm3 with 25% segmented neutrophils, 10% bands, 2% metamyelocytes, 55% lymphocytes, 8% monocytes, and 1 nucleated RBC per 100 WBCs. A bone marrow biopsy specimen shows 100% cellularity, with many large blasts that are peroxidase negative and nonspecific esterase positive. What is the most likely diagnosis? □ (A) Acute lymphoblastic leukemia □ (B) Acute megakaryocytic leukemia □ (C) Acute promyelocytic leukemia □ (D) Acute erythroleukemia □ (E) Acute monocytic leukemia

(E) Acute monocytic leukemia This patient has an "aleukemic" leukemia, in which the peripheral blood count of leukocytes is not high, but the leukemic blasts fill the marrow. These blasts show features of monoblasts because they are peroxidase negative and nonspecific esterase positive. This patient has an M5 leukemia, characterized by a high incidence of tissue infiltration and organomegaly. Acute lymphoblastic leukemia is typically seen in children and young adults. Acute megakaryocytic leukemia is rare, it is typically accompanied by myelofibrosis, and the blasts react with platelet-specific antibodies. The M3 variant of acute myelogenous leukemia (promyelocytic leukemia) has many promyelocytes filled with azurophilic granules, making them strongly peroxidase positive. Erythroleukemia is rare and is accompanied by dysplastic erythroid precursors. BP7 436-437BP8 447PBD7 692-694PBD8 622-623

5 A 12-year-old boy is taken to the physician because he has had increasing abdominal distention and pain for the past 3 days. Physical examination shows lower abdominal tenderness, and the abdomen is tympanitic with reduced bowel sounds. An abdominal CT scan shows a 7-cm mass involving the region of the ileocecal valve. Surgery is performed to remove the mass. Histologic examination of the mass shows sheets of intermediate-sized lymphoid cells, with nuclei having coarse chromatin, several nucleoli, and many mitoses. A bone marrow biopsy sample is negative for this cell population. Cytogenetic analysis of the cells from the mass shows a *t(8;14) karyotype*. Flow cytometric analysis reveals 40% of the cells are in S phase. The tumor shrinks dramatically in size after a course of chemotherapy. Which of the following is the most likely diagnosis? □ (A) Diffuse large B-cell lymphoma □ (B) Follicular lymphoma □ (C) Acute lymphoblastic leukemia □ (D) Plasmacytoma □ (E) Burkitt lymphoma

(E) Burkitt lymphoma Burkitt and Burkitt-like lymphomas can be seen sporadically (in young individuals), in an endemic form in Africa (in children), and in association with HIV infection. All forms are highly associated with translocations of the MYC gene on chromosome 8. In the African form and in HIV-infected patients, the cells are latently infected with Epstein-Barr virus (EBV), but sporadic cases are negative for EBV. This form of lymphoma is typically extranodal. Diffuse large cell lymphomas are most common in adults, as are follicular lymphomas; they do not carry the t(8;14) translocation. Acute lymphoblastic lymphomas can be seen in boys this age, but the mass is in the mediastinum, and the lymphoid cells are T cells. Plasmacytomas appear in older adults and are unlikely to produce an abdominal mass. Because of the high growth fraction (40% in this case), Burkitt lymphomas respond very well to chemotherapy that includes cycle acting agents. By contrast, slow-growing tumors with a low growth fraction are more indolent and less responsive to chemotherapy. BP7 428-429BP8 453PBD7 677-678PBD8 607-608

48 During the past 6 months, a 60-year-old man has noticed a malar skin rash that is made worse by sun exposure. He also has had arthralgias and myalgias. On physical examination, he is afebrile and has a pulse of 100/min, respirations of 20/min, and blood pressure of 100/60 mm Hg. There is erythema of skin over the bridge of the nose. No organomegaly is noted. Laboratory findings include positive serologic test results for ANA and double-stranded DNA, hemoglobin of 8.1 g/dL, hematocrit of 24.4%, platelet count of 87,000/mm3, and WBC count of 3950/mm3. The peripheral blood smear shows nucleated RBCs. A dipstick urinalysis is positive for blood, but there are no WBCs, RBCs, or casts seen on microscopic examination of the urine. Which of the following serum laboratory findings is most likely to be present? □ (A) Elevated D dimer □ (B) Negative Coombs antiglobulin test □ (C) Decreased iron □ (D) Elevated prostate-specific antigen □ (E) Diminished haptoglobin

(E) Diminished haptoglobin Haptoglobin is a serum protein that binds to free hemoglobin. Ordinarily, circulating hemoglobin is contained within RBCs, but hemolysis can release free hemoglobin. The haptoglobin is used up as the amount of free hemoglobin increases. An elevated D dimer level suggests a microangiopathic hemolytic anemia. Systemic lupus erythematosus is an autoimmune disease that can result in hemolysis by means of autoantibodies directed at RBCs, and the Coombs test result is often positive. Decreased iron can cause a hypochromic, microcytic anemia, but with hemolysis, the RBCs are recycled, and the iron is not lost. Prostatic adenocarcinoma could produce leukoerythroblastosis if widely metastatic to bone, but not hemolysis. BP7 398BP8 424, 440PBD7 624-625PBD8 642

19 A clinical study of patients with hemoglobinopathies reveals that some of these patients developed episodes of acute chest, back, and abdominal pain; recurrent infections with Streptococcus pneumoniae; and chronic anemia as children and adults. They experienced none of these problems as infants, however. The presence of which of the following types of hemoglobin during infancy most likely provided protection from complications of their hemoglobinopathy? □ (A) A1 □ (B) A2 □ (C) C □ (D) E □ (E) F

(E) F These patients have sickle cell disease with hemoglobin S. During infancy, the amount of fetal hemoglobin being produced is sufficient to prevent most complications of the disease, such as vaso-occlusive crises and infections. After infancy, the amount of hemoglobin F declines, but drugs such as hydroxyurea can induce increased production of hemoglobin F. Hemoglobin A1 is the normal adult hemoglobin that is absent with homozygous sickle cell anemia. Hemoglobin A2 is not produced in sufficient quantities to ameliorate the effects of hemoglobinopathies. Hemoglobins C and E when homozygous produce anemia much milder than hemoglobin S disease, and when heterozygous help ameliorate hemoglobin S, but there is no differential production of hemoglobin C or E in infancy. BP7 402-403BP8 427-428PBD7 630-631PBD8 645-648

20 A 5-year-old boy has had a history of *easy bruising and blood in his urine since infancy*. Physical examination shows no organomegaly. He has several ecchymoses of the skin on the lower extremities. Laboratory studies show hemoglobin, 13.1 g/dL; hematocrit, 39.3%; platelet count, 287,600/mm3; WBC count, 6830/mm3; prothrombin time, 13 seconds; partial thromboplastin time, 54 seconds; and *less than 1% factor VIII activity measured in plasma*. If he does not receive transfusions of recombinant factor VIII concentrate, which of the following manifestations of this illness is most likely to ensue? □ (A) Splenomegaly □ (B) Conjunctival petechiae □ (C) Hemolysis □ (D) Hemochromatosis □ (E) Hemarthroses

(E) Hemarthroses The severity of hemophilia A depends on the amount of factor VIII activity. With less than 1% activity, there is severe disease, and joint hemorrhages are common, leading to severe joint deformity and ankylosis. Mild (1% to 5%) and moderate (5% to 75%) activity is often asymptomatic except in severe trauma. The bleeding tendency is not associated with splenomegaly. Petechiae, seen in patients with thrombocytopenia, are not a feature of hemophilia. Factor VIII deficiency does not affect the life span of RBCs. Because individuals with factor VIII deficiency do not depend on RBC transfusions, iron overload is not a usual consequence.

46 A 77-year-old man has experienced increasing malaise and a 6-kg weight loss over the past year. He has noted more severe and *constant back pain for the past 3 months*. On physical examination, his temperature is 38.7°C. *His prostate is firm and irregular when palpated on digital rectal examination*. There is no organomegaly. A stool sample is negative for occult blood. Laboratory studies include a urine culture positive for Escherichia coli, serum glucose of 70 mg/dL, creatinine of 1.1 mg/dL, total bilirubin of 1 mg/dL, alkaline phosphatase of 293 U/L, calcium of 10.3 mg/dL, phosphorus of 2.6 mg/dL, and PSA of 25 ng/mL. CBC shows hemoglobin, 9.1 g/dL; hematocrit, 27.3%; MCV, 94 µm3; platelet count, 55,600/mm3; and WBC count, 3570/mm3 with 18% segmented neutrophils, 7% bands, 2% metamyelocytes, 1% myelocytes, 61% lymphocytes, 11% monocytes, and 3 nucleated RBCs per 100 WBCs. What is the most likely diagnosis? □ (A) Anemia of chronic disease □ (B) Aplastic anemia □ (C) Hemolytic anemia □ (D) Megaloblastic anemia □ (E) Myelophthisic anemia □ (F) Thalassemia

(E) Myelophthisic anemia This patient has findings most suggestive of prostatic adenocarcinoma that has metastasized to the bone. High alkaline phosphatase, hypercalcemia, and a leukoerythroblastic pattern in the peripheral blood (immature WBCs and RBCs) are a consequence of the tumor acting as a space-occupying lesion. Myelophthisic anemias also may be caused by infections. The anemia of chronic disease is mild. Aplastic anemias are unlikely to include leukoerythroblastosis. Hemolytic anemia should be accompanied by an increase in bilirubin and no abnormalities in calcium metabolism. The MCV in this case is not in the megaloblastic range. Thalassemias can lead to ineffective erythropoiesis, but not to pancytopenia. BP7 414BP8 44, 466PBD7 648-649PBD8 665

43 A clinical study is performed to assess outcomes in patients who have macrocytic anemias. A comparison of laboratory testing strategies shows that the best strategy includes testing for vitamin B12 (cobalamin) and folate. What is the most important reason for ordering these tests simultaneously? □ (A) Both nutrients are absorbed similarly □ (B) Therapy for one deficiency also treats the other □ (C) The peripheral blood smear appears the same for both deficiencies □ (D) Aplastic anemia can result from lack of either nutrient □ (E) Neurologic injury must be avoided

(E) Neurologic injury must be avoided Although folate and vitamin B12 deficiency give rise to a macrocytic anemia, a deficiency of vitamin B12 also can result in demyelination of the posterior and lateral columns of the spinal cord. The anemia caused by vitamin B12 deficiency can be ameliorated by increased administration of folate; this masks the potential neurologic injury by improving the anemia. Treating vitamin B12 deficiency does not improve the anemia caused by folate deficiency, however. Folate has no cofactor for absorption, but vitamin B12 must be complexed to intrinsic factor and secreted by gastric parietal cells, and then the complex must be absorbed in the terminal ileum, so diseases such as atrophic gastritis and Crohn's disease can affect vitamin B12 absorption more than folate. The peripheral smear could appear the same and offers no means for distinguishing these deficiencies. An aplastic anemia is unlikely to result from a nutritional deficiency. BP7 411-413BP8 438PBD7 639-642PBD8 658

7 A 50-year-old man has had headache, dizziness, and fatigue for the past 3 months. His friends have been commenting about his increasingly ruddy complexion. He also has experienced generalized and severe pruritus, particularly when showering. He notes that his stools are dark. On physical examination, he is afebrile, and his blood pressure is 165/90 mm Hg. There is no hepatosplenomegaly or lymphadenopathy. A stool sample is positive for occult blood. CBC shows hemoglobin, 22.3 g/dL; *hematocrit, 67.1%; MCV, 94 µm3*; platelet count, 453,000/mm3; and WBC count, 7800/mm3. The serum *erythropoietin level is very low*. What is the most likely diagnosis? □ (A) Myelodysplastic syndrome □ (B) Essential thrombocytosis □ (C) Chronic myelogenous leukemia □ (D) Erythroleukemia □ (E) Polycythemia vera

(E) Polycythemia vera 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, similar to 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. The neoplastic erythroid progenitor cells require extremely small amounts of erythropoietin for survival and proliferation; the levels of erythropoietin are virtually undetectable in polycythemia vera. When combined with abnormal platelet function, this condition predisposes the patient to bleeding. Abnormal platelet function also can predispose to thrombosis. The pruritus 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" into acute myelogenous leukemia, and other patients develop chronic myelogenous leukemia. Myelodysplastic syndromes and myeloproliferative disorders, such as essential thrombocytosis, are not accompanied by such an increase in RBC mass. Erythroleukemia typically is not accompanied by such a high hematocrit concentration because leukemic erythroid progenitors do not differentiate into mature RBCs. BP7 439-440BP8 465-466PBD7 699-700PBD8 628-629

A 30-year-old woman has had mild fatigue for many years. Physical examination reveals a palpable spleen tip. Laboratory studies show Hgb 11.1 g/dL, Hct 28.8%, *MCV 77 fL*, platelet count 229,000/microliter, and WBC count 7340/microliter. Her reticulocyte count is 3.9%. Examination of her peripheral blood smear shows *small RBCs that lack central pallor*. Which of the following patterns of inheritance is most likely present with her disease? A Autosomal dominant, European ancestry B Autosomal recessive, Asian ancestry C X-linked recessive, Middle Eastern ancestry D Autosomal recessive, West African ancestry E Sporadic occurrence

A Autosomal dominant, European ancestry Hereditary spherocytosis is the most common inherited hemolytic anemia in persons of northern European descent. It has a frequency in this population of 1 in 5000. An abnormality in the structural membrane proteins ankyrin or spectrin accounts for the abnormality. Question 4

24 A 15-year-old boy has developed a cough and a high fever over the past 4 days. On physical examination, he has a temperature of 39.2°C. Diffuse rales are heard over all lung fields. Laboratory studies show hemoglobin, 14.8 g/dL; hematocrit, 44.4%; platelet count, 496,000/mm3; and WBC count, 15,600/mm3. Examination of the peripheral blood smear shows *RBCs with marked anisocytosis and Howell-Jolly bodies*. A sputum culture grows Haemophilus influenzae. Which of the following is the most likely diagnosis? □ (A) DiGeorge syndrome □ (B) Galactosemia □ (C) Gaucher disease □ (D) Myeloproliferative disorder □ (E) Prior splenectomy □ (F) Trisomy 21

(E) Prior splenectomy Splenectomy in childhood reduces immunity to encapsulated bacterial organisms. The spleen recycles old RBCs and removes inclusions such as Howell-Jolly bodies (similar to getting the cherry pits out without damaging the cherry). About one third of all circulating platelets are pooled in the spleen, and granulocytes are marginated in splenic sinusoids, so that when the spleen is absent, the WBC and platelet counts increase. DiGeorge syndrome leads to cell-mediated immunodeficiency and increased viral, fungal, and parasitic diseases. Galactosemia results from an inborn error of metabolism, leading to liver disease and fibrosis that can cause splenomegaly. Gaucher disease leads to splenomegaly without significant immunodeficiency. Myeloproliferative disorders increase the size of the spleen. The thymus, but not the spleen, is sometimes involved in patients with Down syndrome (trisomy 21). BP8 426PBD7 702-703PBD8 189, 634

40 A 55-year-old, otherwise healthy man has experienced minor fatigue on exertion for the past 9 months. He has no significant previous medical or surgical history. On physical examination, there are no remarkable findings. Laboratory studies show hemoglobin of 11.7 g/dL, hematocrit of 34.8%, MCV of 73 µm3, platelet count of 315,000/mm3, and WBC count of 8035/mm3. Which of the following is the most sensitive and cost-effective test that the physician should order to help to determine the cause of these findings? □ (A) Serum iron □ (B) Serum transferrin □ (C) Serum haptoglobin □ (D) Bone marrow biopsy □ (E) Serum ferritin □ (F) Hemoglobin electrophoresis

(E) Serum ferritin This patient has a microcytic anemia, so iron deficiency anemia must be considered. The ferritin concentration is a measure of storage iron because it is derived from the total body storage pool in the liver, spleen, and marrow. About 80% of functional body iron is contained in hemoglobin; the remainder is in muscle myoglobin. Transferrin, a serum transport protein for iron, usually has about 33% iron saturation. Individuals with severe liver disease can have an elevated serum ferritin level because of its release from liver stores. The serum iron concentration or transferrin level by itself gives no indication of iron stores because in anemia of chronic disease, the patient's iron level can be normal to low, and the transferrin levels also can be normal to low, but iron stores are increased. The serum haptoglobin level is decreased with intravascular hemolysis, but the anemia is normocytic because the iron can be recycled. A bone marrow biopsy specimen provides a good indication of iron stores because the iron stain of the marrow shows hemosiderin in macrophages, but such a biopsy is an expensive procedure. Some patients with hemoglobinopathies, such as β-thalassemias, also can have a microcytic anemia, but this is far less common than iron deficiency. BP7 409BP8 435-437PBD7 643-644PBD8 660-661

11 A 30-year-old woman reports becoming increasingly tired for the past 5 months. On physical examination, she is afebrile and has mild splenomegaly. Laboratory studies show a hemoglobin concentration of 11.8 g/dL and hematocrit of 35.1%. The peripheral blood smear shows spherocytes and rare nucleated RBCs. *Direct and indirect Coombs test results are positive at 37°C, although not at 4°C*. Which of the following underlying diseases is most likely to be diagnosed in this patient? □ (A) Infectious mononucleosis □ (B) Mycoplasma pneumoniae infection □ (C) Hereditary spherocytosis □ (D) Escherichia coli septicemia □ (E) Systemic lupus erythematosus

(E) Systemic lupus erythematosus This patient has a warm autoimmune hemolytic anemia secondary to systemic lupus erythematosus (SLE). A positive Coombs test result indicates the presence of anti-RBC antibodies in the serum and on the RBC surface. Most cases of warm autoimmune hemolytic anemia are idiopathic, but one fourth occur in individuals with an identifiable autoimmune disease, such as SLE. Some are caused by drugs such as α-methyldopa. The immunoglobulin coating the RBCs acts as an opsonin to promote splenic phagocytosis. Nucleated RBCs can be seen in active hemolysis because the marrow compensates by releasing immature RBCs. Infections such as mononucleosis and Mycoplasma are associated with cold autoimmune hemolytic anemia (with an elevated cold agglutinin titer). The increased RBC destruction in hereditary spherocytosis is extravascular and not immune mediated. Septicemia is more likely to lead to a microangiopathic hemolytic anemia. BP7 407-408BP8 432-433PBD7 636-637PBD8 653-654

22 A 54-year-old woman sees her physician because of sudden onset of headaches and photophobia. This condition has been worsening for the past 2 days. On physical examination, she has a temperature of 38°C and is disoriented. CBC shows hemoglobin of 11.2 g/dL, hematocrit of 33.7%, MCV of 94 µm3, platelet count of 32,000/mm3, and WBC count of 9900/mm3. The peripheral blood smear shows schistocytes. The serum urea nitrogen level is 38 mg/dL, and the creatinine level is 3.9 mg/dL. Which of the following is the most likely diagnosis? □ (A) β-Thalassemia major □ (B) Disseminated intravascular coagulation □ (C) Hereditary spherocytosis □ (D) Idiopathic thrombocytopenic purpura □ (E) Paroxysmal nocturnal hemoglobinuria □ (F) Thrombotic thrombocytopenic purpura □ (G) Warm autoimmune hemolytic anemia

(F) Thrombotic thrombocytopenic purpura The diagnosis of thrombotic thrombocytopenic purpura (TTP) is based on finding a classic pentad: transient neurologic problems, fever, thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The diagnosis is confirmed by demonstration of von Willebrand factor monomers in the serum. These abnormalities are produced by small platelet-fibrin thrombi in small vessels in multiple organs. The heart, brain, and kidney often are severely affected. Of the other choices, only disseminated intravascular coagulation is a microangiopathic hemolytic anemia, but the pentad of TTP is missing. BP7 448BP8 472-473PBD7 652-653PBD8 669-670

14 A 53-year-old woman has experienced nausea with vomiting and early satiety for the past 7 months. On physical examination, she is afebrile and has no lymphadenopathy or hepatosplenomegaly. CBC shows hemoglobin, 12.9 g/dL; hematocrit, 41.9%; platelet count, 263,000/mm3; and WBC count, 8430/mm3. An upper gastrointestinal endoscopy shows loss of the rugal folds of the stomach over a 4 × 8 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. What is the most likely diagnosis? □ (A) Acute lymphoblastic leukemia □ (B) Chronic lymphocytic leukemia □ (C) Diffuse large B-cell lymphoma □ (D) Follicular lymphoma □ (E) Hodgkin lymphoma, mixed cellularity type □ (F) MALT (marginal zone) lymphoma □ (G) Waldenström macroglobulinemia

(F) MALT (marginal zone) lymphoma These lymphomas 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 (MALT lymphoma, or MALToma). The most common sites are the thyroid (in Hashimoto thyroiditis), the salivary glands (in Sjögren syndrome), or the stomach (in Helicobacter pylori infection). Although monoclonal (similar to 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 conditions listed are neoplastic conditions that are not related to H. pylori, and that require chemotherapy to control. BP7 435BP8 459PBD7 683PBD8 613-614

23 A 30-year-old, previously healthy man passes dark brown urine several days after starting the prophylactic antimalarial drug *primaquine*. On physical examination, he appears pale and is afebrile. There is no organomegaly. Laboratory studies show that his serum *haptoglobin level is decreased*. Which of the following is the most likely explanation of these findings? □ (A) Mechanical fragmentation of RBCs □ (B) Increased susceptibility to lysis by complement □ (C) Nuclear maturation defects resulting from impaired DNA synthesis □ (D) Impaired globin synthesis □ (E) Hemolysis of antibody-coated cells □ (F) Oxidative injury to hemoglobin □ (G) Reduced deformability of the RBC membrane

(F) Oxidative injury to hemoglobin This patient has glucose-6-phosphate dehydrogenase deficiency. A drug that leads to oxidative injury to the RBCs, such as primaquine, can induce hemolysis. Oxidant injury to hemoglobin produces inclusion of denatured hemoglobin within RBCs. The inclusions damage the cell membrane directly, giving rise to intravascular hemolysis. These cells have reduced membrane deformability, and they are removed from the circulation by the spleen. The remaining mechanisms listed are not directly drug dependent. Mechanical fragmentation of RBCs is typical of microangiopathic hemolytic anemias, such as disseminated intravascular coagulation. Complement lysis is enhanced in paroxysmal nocturnal hemoglobinuria, which results from mutations in the PIGA gene. Impaired RBC nuclear maturation occurs as a result of vitamin B12 or folate deficiency. Impaired globin synthesis occurs in thalassemias. Hemolytic anemias with antibody coating RBCs can occur with autoimmune diseases, prior transfusion, and erythroblastosis fetalis. Reduced RBC membrane deformability is seen in patients with abnormalities in cytoskeletal proteins, such as spectrin; the latter causes hereditary spherocytosis. BP7 406-407BP8 431-432PBD7 627-628PBD8 644-645

37 A 39-year-old woman felt a lump in her breast 1 week ago. She visits the physician, who palpates a firm, fixed, irregular 3-cm mass in the upper outer quadrant of the right breast and a firm, nontender lymph node in the right axilla. A lumpectomy and axillary node dissection are performed, and microscopic examination shows an infiltrating ductal carcinoma present in the breast. Flow cytometric analysis of the node shows a polyclonal population of *CD3+, CD19+, CD20+, and CD68+ cells with no aneuploidy or increase in S phase*. Which of the following is most likely to be present on microscopic examination of this axillary node? □ (A) Acute lymphadenitis □ (B) Diffuse large B-cell lymphoma □ (C) Metastatic infiltrating ductal carcinoma □ (D) Necrotizing granulomas □ (E) Plasmacytosis □ (F) Sinus histiocytosis

(F) Sinus histiocytosis Lymph nodes draining from a cancer often show a reactive pattern, with dilated sinusoids that have endothelial hypertrophy and are filled with histiocytes (i.e., macrophages). Sinus histiocytosis represents an immunological response to cancer antigens. Not all enlarged nodes are caused by metastatic disease in cancer patients. CD3 is a T cell marker, CD19 and CD20 are B cell markers, and CD68 is a macrophage (histiocyte) marker. Polyclonal proliferations are typically benign reactive processes, whereas a monoclonal proliferation suggests a neoplasm. Aneuploidy and high S phase are characteristics of malignant neoplasms; a high S phase mostly occurs in rapidly growing tumors, such as diffuse large Bcell lymphomas, and in a few carcinomas, such as small-cell anaplastic carcinoma. Inflammation would produce pain and tenderness, and the patient may be febrile. Generalized inflammatory diseases or chronic infections can increase the numbers of plasma cells in lymph nodes. BP7 418-419BP8 443-444PBD7 665-666PBD8 595-596

39 A 28-year-old, previously healthy man has noted increasing fatigue for the past 6 months and formation of bruises after minimal trauma. Over the past 2 days, he has developed a cough. On physical examination, his temperature is 38.9°C, and he has diffuse rales in both lungs. He has no hepatosplenomegaly and no lymphadenopathy. Laboratory findings include a sputum culture positive for *Streptococcus pneumoniae*, *hemoglobin of 7.2 g/dL, hematocrit of 21.7%, platelet count of 23,400/mm3, WBC count of 1310/mm3*, prothrombin time of 13 seconds, partial thromboplastin time of 28 seconds, and total bilirubin of 1 mg/dL. The ANA test result is negative. What is the most likely explanation of these findings? □ (A) Hemolysis of antibody-coated cells □ (B) Hypersplenism □ (C) Increased susceptibility to lysis by complement □ (D) Metastatic adenocarcinoma □ (E) Nuclear maturation defects resulting from impaired DNA synthesis □ (F) Stem cell defect □ (G) Varicella-zoster virus infection

(F) Stem cell defect This patient has aplastic anemia with marked pancytopenia. Many cases are idiopathic, although some can follow toxic exposures to chemotherapy drugs or to chemicals, such as benzene. Some cases may follow viral hepatitis infections. An intrinsic defect in stem cells, or T lymphocyte suppression of stem cells, can play a role in the development of aplastic anemia. Hemolysis is unlikely because the bilirubin is normal, and there is no history of an autoimmune disease. Sequestration of peripheral blood cells in an enlarged spleen could account for mild pancytopenia, but in this case the spleen is not enlarged. An increased susceptibility to complement lysis occurs in paroxysmal nocturnal hemoglobinuria as a result of mutations in the PIGA gene. It is unlikely that the patient has metastatic disease at this age, with no prior illness; metastases are more likely to produce a leukoerythroblastic peripheral blood appearance. Nuclear maturation defects are typical of megaloblastic anemias. Chickenpox (varicella-zoster virus infection) is unlikely to produce aplastic anemia; the virus becomes latent in neuronal ganglia.

11 A 23-year-old man undergoing *chemotherapy for acute lymphoblastic leukemia* has developed a fever and abdominal pain within the past week. He now has a severe cough. On physical examination, his temperature is 38.4°C. On auscultation, crackles are heard over all lung fields. Laboratory studies show hemoglobin, 12.8 g/dL; hematocrit, 39%; MCV, 90 µm3; platelet count, 221,000/mm3; and WBC count, 16,475/mm3 with 51% segmented neutrophils, 5% bands, 18% lymphocytes, 8% monocytes, and *18% eosinophils*. Infection with which of the following organisms is most likely to be complicating the course of this patient's disease? □ (A) Cryptococcus neoformans □ (B) Cytomegalovirus □ (C) Helicobacter pylori □ (D) Hepatitis C virus □ (E) Pseudomonas aeruginosa □ (F) Strongyloides stercoralis □ (G) Toxoplasma gondii □ (H) Varicella-zoster virus

(F) Strongyloides stercoralis The eosinophilia suggests a parasitic infestation. Immunocompromised individuals can have superinfection and dissemination with strongyloidiasis. The other organisms listed are not known to be associated with eosinophilia. BP7 416BP8 442PBD7 664PBD8 594

41 A clinical study is performed involving adult patients diagnosed with microangiopathic hemolytic anemia. The patients did not have diarrhea. The patients had schistocytes present on peripheral blood smears. Some of these patients were found to have a deficiency of a metalloproteinase known as ADAMTS-13. *Which of the following conditions were these ADAMTS-13-deficient patients most likely to have*? □ (A) Disseminated intravascular coagulopathy (DIC) □ (B) Hemolytic-uremic syndrome (HUS) □ (C) Heparin-induced thrombocytopenia (HIT) □ (D) Idiopathic thrombocytopenic purpura (ITP) □ (E) Systemic lupus erythematosus (SLE) □ (F) Thrombotic thrombocytopenic purpura (TTP)

(F) Thrombotic thrombocytopenic purpura (TTP) A deficiency of ADAMTS-13, from an acquired antibody to this metalloproteinase or a genetic mutation in the encoding gene, can lead to accumulation of large von Willebrand multimers that promote platelet microaggregate formation, resulting in TTP marked by microangiopathic hemolytic anemia, fever, neurologic changes, thrombocytopenia, and renal failure. DIC results from conditions that promote consumption of coagulation factors, not a metalloproteinase deficiency. HUS is very similar to TTP, but is more likely related to a preceding infectious gastroenteritis with diarrhea. HIT occurs in about 5% of individuals receiving heparin, and the most serious complication is widespread arterial and venous thrombosis. ITP is mainly complicated by bleeding from thrombocytopenia. SLE can be associated with autoimmune mediated cytopenias. BP7 448BP8 472PBD7 652-653PBD8 669

A 69-year-old man has noted the presence of several lumps on the right side of his neck for the past 5 months. On physical examination he has firm, non-tender, movable lymph nodes palpable in right posterior cervical region. He does not have splenomegaly or hepatomegaly. Laboratory studies show Hgb 11.3 g/dL, Hct 40%, MCV 87 fL, platelet count 256,000/microliter, and WBC count 7230/microliter. A cervical lymph node biopsy is performed and on microscopic examination shows numerous crowded nodules of small, monomorphic lymphocytes. Which of the following is the most likely diagnosis? A Chronic lymphocytic leukemia B Follicular lymphoma C Infectious mononucleosis D Hodgkin lymphoma, lymphocyte predominance type E Reactive hyperplasia

B Follicular lymphoma Lymphadenopathy with malignant lymphoma is typically nontender, as contrasted with the lymphadenopathy of infections. Follicular lymphomas occur in adults. Question 9

A 17-year-old adolescent has had malaise for the past 3 weeks. He has a mild pharyngitis on physical examination, as well as tender axillary and inguinal lymphadenopathy. The spleen is palpable. A CBC shows Hgb 14.0 g/dL, Hct 42.2%, MCV 90 fL, platelet count 301,300/microliter, and WBC count 8120/microliter with 'atypical lymphocytes' on the peripheral blood smear. His illness is most likely to be acquired via which of the following mechanisms? A congenital genetic abnormality B From close contact on a date C As a result of an insect bite D Through an environmental exposure at work E Without any known etiology

B From close contact on a date Infectious mononucleosis with Epstein-Barr virus (EBV) infection is typically acquired with close personal contact. This self-limited viral infection resolves in weeks. Question 3

A 30-year-old man has had a progressively worsening productive cough for one month. On physical examination, a few small non-tender lymph nodes are palpable in the axillae, and the tip of the spleen is palpable. Laboratory studies show Hgb 10.2 g/dL, Hct 31.1%, MCV 90 fL, *WBC count 67,000/microliter*, and platelet count 36,000/microliter. Microscopic examination of his peripheral blood smear shows many *blasts with Auer rods*. Which of the following is the most likely diagnosis? A Leukemoid reaction B Acute myelogenous leukemia C Chronic lymphocytic leukemia D Lymphoblastic leukemia E Leukoerythroblastosis

B Acute myelogenous leukemia The high WBC count with the blasts and Auer rods are very characteristic for an acute myelogenous leukemia (AML) that can occur in young adults. Question 7

A 68-year-old man has had malaise for the past year. On physical examination, there are no abnormal findings. His Hgb is 10.5 g/dL, Hct 31.5%, MCV 88 fL, platelet count 211,000/microliter, and WBC count 6980/microliter. *His total serum iron is 130 microgm/dL total iron binding capacity (TIBC) 230 microgm/dL, and soluble serum transferrin receptor is normal*. A bone marrow biopsy is performed and microscopic examination shows that maturation is occurring in all cell lines and there are no abnormal cells seen. *Stainable iron in the bone marrow is increased*. Which of the following underlying diseases is he most likely to have? A Diverticulosis B Hepatitis C infection C Systemic lupus erythematosus D Atrophic gastritis E Fanconi anemia

B Hepatitis C infection He has findings of anemia of chronic disease, with a high (or normal) % iron saturation, increased iron stores, and normal soluble serum transferrin receptor. In iron deficiency, iron stores are diminished, % saturation decreased, and soluble serum transferrin receptor increased. Hepatitis C viral infection is a chronic disease. Question 8

A 33-year-old woman has experienced low grade fevers, night sweats, and generalized malaise for the past 2 months. On physical examination she has non-tender cervical and supraclavicular lymphadenopathy. A cervical lymph node biopsy is performed. On microscopic examination at high magnification there are *occasional CD15+ and CD30+ Reed-Sternberg cells along with large and small lymphocytes and bands of fibrosis*. Which of the following is the most likely diagnosis? A Burkitt lymphoma B Hodgkin lymphoma C Cat scratch disease D Mycosis fungoides E Multiple myeloma

B Hodgkin lymphoma CORRECT. Reed-Sternberg cells are multinucleated with large nucleoli. Variants of them called lacunar cells are also seen with some forms of Hodgkin lymphoma. Her 2 lymph node groups on one side of the diaphragm put this at stage II, but the prognosis is still good. Question 2

A 40-year-old woman has had a week long course of *fever and mental confusion*. Physical examination shows T 38.2°C, P 100/minute, RR 22/minute, and BP 100/60 mm Hg. She has widespread *petechiae of skin and mucosal surfaces*. Laboratory studies show her serum urea nitrogen is 52 mg/dL with *creatinine 5.3 mg/dL*. She has a hemoglobin of 12.2 g/dL, hematocrit 36.8%, MCV 93 fL, platelet count 19,000/microliter, and WBC count 8180/microliter. *Schistocytes* are seen on her peripheral blood smear. Her prothrombin time, partial thromboplastin time, and D-dimer are not elevated. Which of the following is the most likely diagnosis? A Disseminated intravascular coagulopathy B Idiopathic thrombocytopenic purpura C Thrombotic thrombocytopenic purpura D Trousseau syndrome E Warm autoimmune hemolytic anemia

C Thrombotic thrombocytopenic purpura The pentad of fever, mental changes, renal failure, thrombocytopenia, and microangiopathic hemolytic anemia is characteristic of TTP. Platelets are activated directly, and not the coagulation system as a whole, so that the prothrombin time, partial thromboplastin time, and D-dimer are either not elevated or minimally elevated. The platelet activation leads to formation of hyaline thrombi in small arteries that promotes tissue ischemia in organs such as brain, with consequent neurologic impairment. Platelet transfusion is contraindicated. Question 12

A 62-year-old man has had dull, constant back pain for 3 months. He recently developed a cough productive of yellowish sputum. On physical examination there are crackles at the right lung base. A plain film radiograph of the spine reveals several 1 to 2 cm lytic lesions of the vertebral bodies. Laboratory studies show glucose 78 mg/dL, urea nitrogen 49 mg/dL, creatinine 5 mg/dL, total protein 8.3 g/dL, albumin 3.7 g/dL, alkaline phosphatase 176 U/L, AST 45 U/L, ALT 22 U/L, and total bilirubin 1.2 mg/dL. A sputum culture grows Streptococcus pneumoniae. Which of the following pathologic findings is most likely to be seen in a bone marrow biopsy from this man? A Scattered small granulomas B Nodules of small mature lymphocytes C Occasional Reed-Sternberg cells D Numerous plasma cells E Hypercellularity with many blasts

D Numerous plasma cells (D) CORRECT. The findings suggest multiple myeloma. He has a markedly increased level of serum globulins. The renal failure from light chains deposited in the kidneys, and the increased risk for encapsulated bacterial infections is typical. The lytic bone lesions are collections of plasma cells. Question 1

For the past 4 months, a *62-year-old* previously healthy man has noted increasing fatigue and shortness of breath with minimal exercise. He has felt some *abdominal discomfort* over the past month. On physical examination he has *non-tender cervical lymphadenopathy*. The liver span is 15 cm in the right mid-clavicular line; the edge is smooth and palpable just below right costal margin. The spleen is palpated 3 cm below left costal margin on inspiration. A CBC shows WBC count 23,100/microliter with 16 segs, 2 bands, *78 lymphs*, and 4 monos, Hgb 11.9 g/dL, Hct 36%, MCV 90, and platelet count 277,300/microliter. The direct Coombs test is positive. Which of the following is the most likely diagnosis? A Leukemoid reaction B Chronic myelogenous leukemia C Acute myelogenous leukemia D Acute lymphocytic leukemia E Chronic lymphocytic leukemia F Systemic lupus erythematosus

E Chronic lymphocytic leukemia Most of the circulating cells are small, mature lymphocytes with CLL. Most persons with CLL are older adults. CLL can have a tissue component called small lymphocytic lymphoma (SLL) with the same small lymphocytes infiltrating organs such as liver and spleen. Question 13