Marrow and Movement BRS / Robbins

A 23-year-old man presented to his primary care physician 2 weeks ago with a nonproductive cough and malaise. He was treated with the antibiotic azithromycin for "walking pneumonia" due to Mycoplasma pneumoniae. He now returns with fatigue and pallor. Laboratory studies demonstrate a decreased red blood cell count with polychromatophilia and an increase in indirect (unconjugated) bilirubin. The laboratory findings are most likely due to (a) acute cold agglutinin disease. (B) aplastic anemia. (C) aplastic crisis. (D) paroxysmal nocturnal hemoglobinuria. (e) warm antibody autoimmune hemolytic anemia.

(A) Acute cold agglutinin disease. > Acute cold agglutinin disease is a form of hemolytic anemia due to autoantibodies to blood group antigens and is sometimes a complication of Mycoplasma pneumoniae infection. Aplastic anemia is associated with a variety of toxic exposures, including, among others, the antibiotic chloramphenicol, not azithromycin. Aplastic crises can occur as acute events in the course of hemolytic anemias, such as hereditary spherocytosis or sickle cell anemia. Paroxysmal nocturnal hemoglobinuria is an acquired defect that renders red blood cells sensitive to complement-induced lysis. Warm antibody autoimmune hemolytic anemia can be idiopathic or secondary to autoimmune disorders or lymphoid neoplasms.

A 40-year-old woman presents with a "skin rash." Questioning reveals easy bruising on minimal trauma, menorrhagia, and frequent bouts of epistaxis. She is not taking any medications, and there is no history of toxic exposures. Physical examination reveals multiple petechial hemorrhages, most prominently on the dependent portions of the lower extremities. Splenomegaly is not detected. Laboratory studies reveal marked thrombocytopenia, and a bone marrow aspiration reveals increased numbers of megakaryocytes. Which of the following is the most likely mechanism of this disorder? (a) Antibody-mediated platelet destruction (B) DIC, with consumption of platelets and coagulation factors (C) Intravascular spontaneous lysis of plate- lets due to increased osmotic fragility (D) Myeloid stem cell suppression in the bone marrow, with inability to produce platelets (e) Physical destruction of platelets while negotiating through partially blocked microvasculature

(A) Antibody-mediated platelet destruction > ITP (immune) is a chronic disease in adults, presumably caused by anti- bodies that bind to the cell surface of platelets.

An 18-year-old man is transported to the emergency department within 20 minutes of sustaining a stab wound to the chest. The patient is poorly responsive. Given that he may have lost as much as 1.5 liters of blood at the scene, which of the following is the most likely finding in this patient? (a) Decreased blood pressure (B) Decreased hematocrit (C) Decreased hemoglobin (D) Decreased red blood cell count (e) Increased MCHC

(A) Decreased blood pressure > Within the first few hours of acute blood loss, findings of hypovolemia predominate, especially with signs of hypovolemic shock, such as decreased blood pres- sure. It is likely that red cell indices (red blood cell counts, hemoglobin, and hematocrit) eventually decrease as a result of hemodilution. Increased MCHC is an unusual finding but is expected in hereditary spherocytosis.

A 62-year-old man presents with pallor, fatigue, and dyspnea on exertion. A complete blood count reveals microcytic hypochromic anemia. The most likely cause of these findings is (a) dietary deficiency of iron. (B) gastrointestinal bleeding. (C) hemodilution. (D) hemolytic anemia. (e) increased iron requirement.

(B) Gastrointestinal bleeding > Iron deficiency anemia is the most common cause of hypochromic microcytic anemia, and gastrointestinal bleeding is the most likely cause of iron deficiency in an adult male. Such a finding warrants a complete workup, including colonos- copy to detect the source of the bleeding. Dietary deficiency of iron and increased iron requirements are common causes of iron deficiency in women of child-bearing age, especially during pregnancy. Hemolytic anemia is usually accompanied by reticulocytosis. The reduced red cell parameters (hemoglobin, red blood cell count, hematocrit) that are observed with hemodilution are not truly representative of anemia, which is formally defined as a reduction in whole body red cell mass.

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) 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. Reed- Sternberg 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.

A 63-year-old man has noticed a lump in her neck for 2 months. Examination reveals a group of three discrete non- tender 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) 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.

A 56-year-old physician who has had a recent episode of unstable angina is advised by his cardiologist to take one "baby aspirin" a day because of the antithrombotic effect of aspirin. What is the mechanism by which aspirin acts as an antithrombotic agent? (a) Acetylation and activation of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) (B) Acetylation and inhibition of both COX-1 and COX-2 (C) Selective inhibition of COX-1 (D) Selective inhibition of COX-2

(B) Acetylation and inhibition of both COX-1 and COX-2 > Aspirin permanently acetylates the active site of cyclooxygenase (both COX-1 and COX-2), causing enzyme inhibition. This subsequently inhibits synthesis of the prothrombotic agent thromboxane A2. Thromboxane A2 causes activation and aggregation of platelets.

A primiparous D-negative (Rh-negative) mother has just delivered a D-positive child. Administration of which of the following substances would be indicated? (a) Anti-D IgG to child (B) Anti-D IgG to mother (C) D-positive red cells to child (D) D-positive red cells to mother

(B) Anti-D IgG to mother (B) Administration of anti-D antiserum to a D-negative mother at the time of delivery of a D-positive child prevents maternal alloimmunization by removing fetal red cells from the maternal circulation.

A 60-year-old man is referred because of splenomegaly and generalized lymphadenopathy. The total white blood cell count is markedly elevated, and the differential count reveals a preponderance of mature-appearing lymphocytes. Bone marrow examination reveals a diffuse infiltration with similar-appearing lymphocytes. Which of the following statements best characterizes this disorder? (a) A progressive increase in the number of myeloblasts and promyelocytes is indicative of acceleration of the disease process. (B) Bacterial infections are common early in the disease due to hypogammaglobulinemia. (C) Mean survival is less than 1 year after diagnosis. (D) Myelofibrosis is a common complication. (e) The neoplastic lymphoid cells are most often T cells, not B cells.

(B) Bacterial infections are common early in the disease due to hypogammaglobulinemia. > The diagnosis is CLL. Hypogammaglobulinemia may occur early in the course of the disease, leading to frequent bacterial infections. The mean survival is 3 to 7 years after diagnosis, although much longer symptom-free survivals are quite common. CLL is characterized by a proliferation of neoplastic mature lymphoid cells, which are almost always B cells.

A 55-year-old woman with chronic pancreatitis undergoes coagulation screening tests before surgery. The PT and APTT are found to be prolonged. Given the following choices, which of the following is the most likely reason for the abnormal coagulation test results? (a) Congenital inherited bleeding disorder (B) Fat malabsorption and vitamin K deficiency (C) Glutamate deficiency due to impaired digestion of dietary protein (D) Nutritional vitamin C deficiency (e) Post-pancreatitic carcinoma of thepancreas

(B) Fat malabsorption and vitamin K deficiency > Chronic pancreatitis causes fat malabsorption, because pancreatic lipase is required for fat digestion. Fat malabsorption leads to deficiency of the fat-soluble vitamins A, D, E, and K. Vitamin K is required in the synthesis of clotting factors II, VII, IX, and X as a cofactor for the conversion of glutamyl residues to γ-carboxyglutamates.

Military policy dictates that flight personnel in Iraq receive primaquine chemoprophylaxis for Plasmodium vivax malaria on redeploying to a non-malarious area. Several days after beginning such a regimen, a 26-year-old African-American pilot develops anemia, hemoglobinemia, and hemoglobinuria. Special studies will likely reveal an abnormality in which of the following? (a) Duffy antigen (B) G6PD (C) Intrinsic factor (D) PIG-A (e) Spectrin

(B) G6PD > Drugs that cause oxidative stress (e.g., primaquine, sulfa-containing drugs) result in intravascular hemolytic anemia in subjects (most often male) with G6PD deficiency. Current military policy exempts G6PD-deficient persons from the requirement for primaquine chemoprophylaxis or sets up screening criteria for individuals whose G6PD status is unknown. Duffy antigen is a minor red blood cell antigen, the absence of which confers some resistance to malarial infection. Intrinsic factor may be absent in pernicious anemia. PIG-A deficiency results in paroxysmal nocturnal hemoglobinuria. Spectrin is deficient in hereditary spherocytosis.

A 70-year-old man presents with severe bone pain and frequent respiratory infections. Serum protein electrophoresis demonstrates an M protein spike in the gamma region. Radiographs of the skull, long bones, and spine demonstrate multiple "punched- out" lesions, and bone marrow aspiration demonstrates large numbers of neoplastic plasma cells. Which of the following statements is true of this disorder? (a) Although this patient presents at 70 years of age, the average age of presentation is 50 years of age. (B) Renal insufficiency is a common cause of death. (C) The M spike is most often an IgM. (D) The M spike is most often polyclonal in nature. (e) This disorder is the most common T-cell neoplasm.

(B) Renal insufficiency is a common cause of death. (B) The diagnosis is multiple (plasma cell) myeloma, a neoplastic proliferation of malignant plasma cells (mature B cells, not T cells). Death is often caused by renal insufficiency caused by myeloma kidney. The average age of presentation is approximately 70 years of age. IgM myeloma is very uncommon. Both the neoplastic cells and the serum protein spike are monoclonal rather than polyclonal, and the monoclonal spike protein is most frequently an IgG or an IgA.

The peripheral blood smear of an asymptomatic 68-year-old white man exhibiting generalized lymphadenopathy and hepatosplenomegaly is shown. Blood smear shows mature lymphocytes. Which of the following is the most likely diagnosis? (a) ALL (B) AML (C) CLL (D) CML

(C) CLL Mature-appearing lymphocytes, characteristic of CLL. CLL most often affects older persons, many of whom are asymptomatic for many years. Generalized lymphadenopathy and hepatosplenomegaly are frequent findings.

A 28-year-old woman complains of fatigue, dyspnea, and malaise. She also notes that her urine has been reddish-brown, particularly with the first void of the morning. Subsequent studies confirm that she has paroxysmal nocturnal hemoglobinuria. Which of the following best describes the defect leading to this condition? (a) Anti-intrinsic factor antibodies (B) Deficiency of the intracellular structural protein spectrin (C) Impaired synthesis of the cell-surface GPI anchor (D) Ineffective erythropoiesis (E) Substitution of a valine for a glutamate residue in the β-globin gene

(C) Impaired synthesis of the cell-surface GPI anchor > Paroxysmal nocturnal hemoglobinuria results in an acquired intracor- puscular defect in the ability to synthesize GPI anchors required for appropriate place- ment of complement regulatory proteins on the surface of red blood cells. Functional deficiency of such proteins as CD55 and CD59 renders the cells sensitive to complement- mediated lysis. Anti-intrinsic factor antibodies are seen in pernicious anemia. Spectrin is deficient in hereditary spherocytosis. Ineffective erythropoiesis is seen in megaloblastic anemia due to folate or vitamin B12 deficiencies. Substitution of valine for glutamic acid in the β-globin gene underlies the defect in sickle cell anemia.

A 4-year-old boy presents with recurrent joint pain involving the knees and hips. He had always bruised easily, and recently the parents had seen blood in his urine. A pre- sumptive diagnosis of classic hemophilia (hemophilia A) is made, and coagulation blood tests are performed. Which of the following is the most likely set of findings of coagulation screening tests? (a) Normal bleeding time, platelet count, and thrombin time; prolonged PT and APTT (B) Normal bleeding time, platelet count, thrombin time, and APTT; prolonged PT (C) Normal bleeding time, platelet count, thrombin time, and PT; prolonged APTT (D) Normal platelet count and thrombin time; prolonged bleeding time, PT, and APTT (e) Prolonged bleeding time, PT, APTT, and thrombin time; decreased platelet count

(C) Normal bleeding time, platelet count, thrombin time, and PT; prolonged APTT Classic hemophilia (factor VIII deficiency) is an abnormality of the intrinsic pathway of coagulation proximal to the final common pathway, which begins at factor X → Xa activation. This defect leads to a prolonged APTT. The other laboratory tests listed remain normal, because the bleeding time is a measure of platelet plug forma- tion, the PT a measure of the extrinsic pathway of coagulation, and the thrombin time an assay of the conversion of fibrinogen to fibrin. The presumptive diagnosis is confirmed by specific factor VIII assay.

A 23-year-old African-American man with a history since early childhood of severe anemia requiring many transfusions has nonhealing leg ulcers and recurrent periods of abdominal and chest pain. The spleen of the patient would be expected to be (a) enlarged. (B) normal sized. (C) shrunken.

(C) Shrunken > Repeated episodes of splenic infarction followed by fibrotic healing lead to a fibrotic, shrunken spleen (autosplenectomy) in adult patients with sickle cell anemia. > The spleen is enlarged and congested in children with sickle cell anemia.

A 10-year-old boy presents with a large abdominal mass. Computed tomography of the abdomen reveals enlarged retroperitoneal and mesenteric lymph nodes. Biopsy of one of the involved lymph nodes shows a "starry-sky" appearance, with prominent debris-containing macrophages. A diagnosis of Burkitt lymphoma is made. Which of the following statements about this disorder is correct? (a) The sporadic (Western) form is most frequently associated with EBV. (B) The disorder is considered to be a derivative of Hodgkin lymphoma, lymphocyte depletion subtype. (C) The most common cytogenetic change is t(8;14), with increased expression of c-myc. (D) The tumor cells are derivatives of T lymphocytes. (e) The tumor most often has an indolent clinical course.

(C) The most common cytogenetic change is t(8;14), with increased expression of c-myc. > The typical cytogenetic change associated with Burkitt lymphoma is t(8;14) with increased expression of the c-myc gene. This disorder is an aggressive B-cell non-Hodgkin lymphoma most commonly affecting children. The endemic (African) form is characterized by the involvement of the maxilla or mandible, whereas the sporadic (Western) form usually involves the abdominal organs. Burkitt lymphoma is generally a rapidly growing neoplasm, and the endemic form has a frequent association with EBV.

A 60-year-old woman presents with a painless cervical lymph node mass that has been progressively enlarging over the past month. Splenomegaly is noted on abdominal examination. A cervical lymph node biopsy reveals effacement of the architecture by angulated grooved cells in a nodular pattern. Which of the following statements about this disorder is correct? (a) The findings are those of a benign neoplasm of lymphoid cells. (B) The findings are those of the least frequently occurring form of non-Hodgkin lymphoma. (C) The most likely common cytogenetic and molecular change is t(14;18) with increased expression of the oncogene bcl-2. (D) Special stains are required for the diag- nosis because the description is that of an anaplastic carcinoma. (e) This diagnosis cannot be confirmed in the absence of Reed-Sternberg cells.

(C) The most likely common cytogenetic and molecular change is t(14;18) with increased expression of the oncogene bcl-2. > The findings are those of follicular lymphoma, the most frequently occurring form of non-Hodgkin lymphoma. This particular neoplasm is marked by the presence of the 14;18 translocation with increased expression of bcl-2, an inhibitor of apoptosis.

An 80-year-old woman presents with recent onset of primary hemostatic (mucocutaneous) bleeding. Questioning reveals that she has been maintaining a "tea and toast" diet for the past 4 months. Her gums are hemorrhagic and spongy in consistency, and gingival bleeding is evident. Perifollicular hyperkeratotic papules, each surrounded by a hemorrhagic halo, are scattered over the lower extremities, and each papule surrounds a twisted, corkscrew-like hair. A nutritional deficiency is suspected. Deficiency of which of the following nutrients is most likely related to the findings in this patient? (a) Vitamin A (B) Vitamin B12 (C) Vitamin C (D) Vitamin K (e) Protein

(C) Vitamin C > Vitamin C deficiency occurs in infants aged 6 to 12 months who are fed a diet deficient in citrus fruits or vegetables, or in elderly persons who maintain a "tea and toast" diet. Vitamin C cannot be synthesized by the body, and thus must be supplied by the diet. The body's reserve of vitamin C is approximately 1 to 3 months with complete dietary absence. Early signs of vitamin C deficiency include those found in this patient.

A 25-year-old man has a lifelong hemorrhagic diathesis. The PT and bleeding time are normal, but the APTT is prolonged. The most likely cause of the bleeding disorder is (a) a platelet functional disorder. (B) factor VII deficiency. (C) factor VIII deficiency. (D) factor IX deficiency. (e) von Willebrand disease.

(C) factor VIII deficiency. > The bleeding disorder is most likely factor VIII deficiency. The patient has a disorder of the intrinsic pathway of coagulation (prolonged APTT). The abnormal- ity is localized proximal to factor X → Xa activation because the PT is normal. Significant platelet-related problems, such as von Willebrand disease, are ruled out by the normal bleeding time. The two most common intrinsic pathway factor deficiencies are factor VIII and factor IX. Of these, factor VIII deficiency occurs 5 to 10 times more frequently than factor IX deficiency and, therefore, is the most likely cause of the bleeding disorder.

A 23-year-old woman with epilepsy who is desirous of becoming pregnant is found to be anemic. Examination of a peripheral blood smear reveals oval macrocytes and hypersegmented neutrophils. Neurologic examination is entirely normal. Which of the following is the most likely cause of the anemia? (a) Alloantibodies directed against fetal red cell antigens (B) Bone marrow aplasia (C) Coating of red cells by IgG "warm" autoantibodies (D) Folate deficiency (e) Neoplastic replacement of the bone marrow

(D) Folate deficiency Phenytoin is a commonly used antiseizure medication that can cause impaired folate absorption, with resultant folate deficiency and megaloblastic anemia. The drug is contraindicated for use during pregnancy, because folate is required during embryogenesis to prevent neural tube defects. Aplastic anemia results in a major failure of erythropoiesis. Myelophthisic anemia occurs in some cancer patients with metastatic disease. Warm antibody hemolytic anemia is manifested by anemia and reticulocytosis, often with spherocytosis. Hemolytic disease of the newborn most commonly occurs with Rh blood group incompatibility between mother and fetus.

A patient with severe anemia has a peripheral blood smear with oval macrocytes, hypersegmented neutrophils, and decreased platelets. The is found to be a severely malnourished alcoholic. The most likely cause of this disorder is (a) aberrant intestinal bacterial flora. (B) Crohn disease. (C) fish tapeworm infestation. (D) folate deficiency. (e) pernicious anemia.

(D) Folate deficiency. > Megaloblastic anemia associated with severe malnutrition is most often due to folate deficiency.

An 8-year-old girl is diagnosed with ALL. Which of the following cytogenetic changes would confer a good prognosis? (a) t(9;22) (B) 11q23 rearrangement (C) Hypodiploidy (D) Hyperdiploidy (e) t(1;19)

(D) Hyperdiploidy > t(12;21) and high hyperdiploidy are associated with positive outcomes in ALL, whereas t(9;22), t(1;19), 11q23 rearrangements, and hypodiploidy are all associated with poor prognosis in these leukemias. Note that the 9;22 translocation seen in ALL is cytogentically identical but molecularly distinct from the one typically seen in CML.

The peripheral blood smear of an anemic 1-year-old child is shown in the illustration of hypochromia and microcytosis. The most likely diagnosis is (a) anemia of chronic disease. (B) aplastic anemia. (C) hereditary spherocytosis. (D) iron deficiency anemia. (e) thalassemia major.

(D) Iron deficiency anemia. > Iron deficiency is the most frequent cause of hypochromic microcytic anemia. In infants and preadolescents, iron deficiency is most often nutritional in origin and is particularly common in non-breastfed babies supplemented with cow's milk, rather than iron-fortified formula, within the first 12 months of life. In young women, the cause is most often related to menstrual blood loss compounded by deficient dietary intake. In men and postmenopausal women, the usual cause is occult gastrointestinal blood loss.

A 72-year-old man who has recently had an aortic valve replacement now presents with pallor and fatigue. The red blood cell count is decreased, and schistocytes are reported on examination of a peripheral blood smear. In addition, his indirect (unconjugated) bilirubin is significantly elevated. The cause of the anemia is likely (a) cold agglutinin disease. (B) dietary deficiency. (C) hereditary spherocytosis. (D) mechanical disruption of red cells. (e) paroxysmal nocturnal hemoglobinuria.

(D) Mechanical disruption of red cells. > Turbulent blood flow over mechanical heart valves can cause shearing of red blood cells, resulting in fragmented cells termed schistocytes. The hemolysis can result in anemia and hyperbilirubinemia. Hereditary spherocytosis causes hemolytic anemia due to an intrinsic defect in the red blood cells. Dietary deficiencies do not cause fragmented red blood cells. Aplastic anemia would result in severe anemia with marked reticulocytopenia.

A 56-year-old woman with a history of breast cancer that was treated 5 years ago with lumpectomy and radiation but with no chemotherapy returns with bone pain, fatigue, and weakness. A complete blood count reveals severe anemia, as well as decreased white blood cells and platelets. Examination of a peripheral blood smear reveals small numbers of nucleated red cells, as well as an occasional "blast" cell and myelocyte. A likely cause of the hematologic abnormalities is (a) chloramphenicol. (B) Diphyllobothrium latum infestation. (C) megaloblastic anemia. (D) myelophthisic anemia. (e) sickle cell anemia.

(D) Myelophthisic anemia. > Infiltration of tumor cells from cancers, such as those of breast and prostate, displaces bone marrow elements, thereby causing myelophthisic anemia. Chloramphenicol causes aplastic anemia in some individuals. Diphyllobothrium latum infestation can result in megaloblastic anemia due to vitamin B12 deficiency. Sickle cell anemia is more common in black and Mediterranean populations.

A 23-year-old man of northern European lineage presents with anemia. His father and paternal aunt had a similar illness that was treated successfully by splenectomy. His peripheral blood smear shows spherocytes. Which of the following additional abnormalities is expected? (a) Bilirubinuria (B) Decreased mean corpuscular volume (C) Increased direct (conjugated) serum bilirubin (D) Polychromatophilic erythrocytes on peripheral blood smear (e) Positive DAT (Coombs) test

(D) Polychromatophilic erythrocytes on peripheral blood smear > Spherocytes are present on the peripheral blood smear and, along with the history, strongly suggest a diagnosis of hereditary spherocytosis. Similar cells are also observed in warm antibody autoimmune hemolytic anemia; therefore, these two conditions must be distinguished by means of the direct Coombs test, which is negative in hereditary spherocytosis and positive in warm antibody autoimmune hemolytic anemia. An expected finding would be an increase in indirect (unconjugated) serum bilirubin, not direct (conjugated). The jaundice is acholuric (no bilirubin in the urine, so bilirubinuria would not be expected). The MCHC is often increased. Because hereditary spherocytosis is a normocytic anemia, the mean corpuscular volume is not decreased. Polychromatophilic erythrocytes are an expected finding, as in any hemolytic anemia.

A 23-year-old African-American man with a history since early childhood of severe anemia requiring many transfusions has nonhealing leg ulcers and recurrent periods of abdominal and chest pain. These signs and symptoms are most likely to be associated with which of the following laboratory abnormalities? (a) Decreased erythropoietin (B) Increased erythrocyte osmotic fragility (C) Schistocytes (D) Sickle cells on peripheral blood smear (e) Teardrop-shaped cells

(D) Sickle cells on peripheral blood smear > Sickle cell anemia is the most common hereditary anemia in persons of African lineage. Leg ulcers and recurring painful crises are characteristic. In sickle cell anemia, in contrast to sickle cell trait, sickle cells are often seen on the peripheral blood smear.

A 35-year-old woman presents with fever, fatigue, mucocutaneous bleeding, and changing neurologic signs. Laboratory examination reveals thrombocytopenia, anemia, and reticulocytosis, as well as increased concentrations of creatinine and urea nitrogen. Examination of a peripheral blood smear reveals many fragmented circulating red cells (helmet cells and schistocytes). The most likely diagnosis is (a) Bernard-Soulier disease. (B) DIC. (C) ITP. (D) TTP. (e) von Willebrand disease.

(D) TTP. > The classic pentad of TTP includes fever, microangiopathic hemolytic anemia, thrombocytopenia, renal insufficiency, and neurologic abnormalities. Hyaline microaggregates of platelets in small vessels can be observed on histologic examination. The disorder is caused by deficiency of the enzyme vWF metalloprotease (ADAMTS 13). The enzyme promotes degradation of very-high-molecular-weight multi- mers of vWF, and the enzyme deficiency results in multimer accumulation in the plasma and consequent platelet microaggregate formation. The enzyme deficiency can be caused by a mutation in the gene that codes for the enzyme, or it can be caused by an antibody inhibiting the enzyme. Treatment is by plasma exchange, and the disorder can be fatal if diagnosis and therapy are delayed.

A 55-year-old man presents with abdominal discomfort and fullness. Physical examination is remarkable for a massively enlarged spleen. Attempts at bone marrow aspiration are unsuccessful. A bone marrow core biopsy reveals numerous cells that have a single round nucleus surrounded by a cytoplasm with fine fibrillary projections. A stain for TRAP confirms the likely diagnosis. Which of the following statements about this disorder is correct? (a) The cell surface marker CD3 is almost always demonstrable. (B) The neoplastic cells stain positive for nonspecific esterase, a marker of monocytic maturation. (C) The typical patient with this disorder presents with a markedly elevated total leukocyte count. (D) This is an example of a well-known B-cell disorder. (e) There is currently no effective therapy for this condition.

(D) This is an example of a well-known B-cell disorder. The diagnosis is hairy cell leukemia, as evidenced by the presentation with splenomegaly, typical cellular morphology, and a positive stain for TRAP. Hairy cell leukemia is a B-cell disease, and the neoplastic cells are positive for the B cell markers CD19, CD20, and CD22. The most common presentation is in middle-aged men who present with anemia, leukopenia, and thrombocytopenia. The most common physical finding is massive splenomegaly. Hairy cell leukemia is of special interest because of the striking therapeutic efficacy of agents such as α-interferon, 2-chlorodeoxyadenosine, and deoxycoformycin.

A 7-year-old boy presents with palpable purpura on the buttocks and legs, fever, abdominal pain and vomiting, arthritis in his knees and ankles, melena, and hematuria. His mother states that he had an upper respiratory illness approximately 1 week ago, but has otherwise been well. Blood tests reveal mild renal insufficiency. The most likely cause of the bleeding into the skin observed in this patient is (a) coagulation factor deficiency. (B) qualitative platelet dysfunction. (C) quantitative platelet dysfunction. (D) vasculitis. (e) vitamin deficiency.

(D) vasculitis. > The clinical description is that of Henoch-Schönlein purpura, a form of leukocytoclastic angiitis (hypersensitivity vasculitis) resulting from an immune reaction that damages the vascular endothelium. Henoch-Schönlein purpura is closely related to IgA nephropathy, a glomerulopathy resulting in nephritic syndrome, and may represent a systemic version of this disease.

A 23-year-old woman presents with cervical and mediastinal lymphadenopathy. Biopsy of a cervical lymph node reveals a nodular appearance with fibrous bands, effacement of the lymph node architecture, and numerous lacunar cells. Which of the following is characteristic of this disorder? (a) Benign neoplasm (B) Frequent association with EBV infection (C) Most often a complication of human immunodeficiency virus infection (D) Peak incidence in early childhood (e) Relatively favorable clinical course

(E) Relatively favorable clinical course > The diagnosis is Hodgkin lymphoma, NS subtype. This form of Hodgkin lymphoma differs from other forms of classical Hodgkin lymphoma in being the most common in young women, having a relatively favorable clinical course, and having little association with EBV infection. Lacunar cells are considered a Reed-Sternberg cell variant, and the diagnosis of NS can be based on the finding of fibrous bands and lacunar cells.

A patient with severe anemia has a peripheral blood smear with oval macrocytes, hypersegmented neutrophils, and decreased platelets. The most likely cause of the anemia is (a) a red cell membrane protein defect. (B) an amino acid substitution in the β-globin chain. (C) iron deficiency. (D) marrow hypoplasia. (e) vitamin B12 or folate deficiency.

(E) Vitamin B12 or folate deficiency. > Megaloblastic anemia due to deficiency of vitamin B12 or folate is characterized by oval macrocytes, hypersegmented neutrophils, and decreased platelets.

A 45-year-old woman presents with marked splenomegaly. Her leukocyte count is increased to 300,000/μL. The differential count reveals the presence of small numbers of myeloblasts and promyelocytes, with a predominance of myelocytes, metamyelocytes, bands, and segmented neutrophils. Basophils are also increased in number, as are platelets. The patient is not anemic. Leukocyte alkaline phosphatase is decreased. Which of the following describes a major characteristic of this disorder? (a) 9;22 translocation (B) Expansion of mature B lymphocytes within multiple lymph nodes (C) Hypogammaglobulinemia (D) Neoplastic cells exhibiting hair-like filamentous projections (e) Peak incidence at 65 years of age

(a) 9;22 translocation > CML is almost invariably marked by the finding of the Philadelphia chromosome, a small residual chromosome 22 with the addition of a small segment of chromosome 9, resulting from a 9;22 translocation.

Radiographic examination of a 65-year- old man with back pain caused by a compression fracture of T12 reveals multiple "punched-out" lytic bone lesions. Which of the following additional abnormalities is likely? (a) A serum IgG kappa M protein (B) Hypocalcemia (C) Increased serum alkaline phosphatase (D) Marked splenomegaly (e) Polyclonal urinary light chains

(a) A serum IgG kappa M protein > Widespread "punched-out" lytic bone lesions in a patient in the older age group are highly suggestive of multiple (plasma cell) myeloma. IgG or IgA M proteins are almost always found in multiple myeloma. Frequent additional laboratory abnormalities include hypercalcemia and urinary excretion of Bence Jones protein (free kappa or lambda monoclonal light chains), red cell Rouleaux formation resulting from hyperglobulinemia, and indicators of renal insufficiency.

A 60-year-old chronic alcoholic with known alcoholic cirrhosis presents with upper gastrointestinal hemorrhage. Despite prolonged tamponade, bleeding is persistent. A coagulation defect related to the liver disease is suspected. Which of the following abnormalities is most consistent with this possibility? (a) Deficiency of all clotting factors except for vWF (B) Deficiency of factors II, VII, IX, and X (C) Deficiency of factors II, V, VII, and X (D) Deficiency of factors IX, X, XI, and XII (e) Deficiency of vWF

(a) Deficiency of all clotting factors except for vWF > The liver is the site of production of all coagulation factors except vWF, and severe hepatic dysfunction can thus be associated with multiple factor deficiencies, excluding vWF.

A 60-year-old man is referred for evaluation of marked erythrocytosis and splenomegaly. Laboratory studies confirm an elevated red blood cell count and additionally demonstrate a moderate increase in circulating granulocytes and platelets. Oxygen saturation studies are normal, and isotopic studies reveal an increase in total red cell mass. Which of the following is characteristic of this disorder? (a) Frequent association with thrombosis or hemorrhagic phenomena (B) Increased erythropoietin concentration (C) Manifestation of Cushing syndrome (D) Most often secondary to hypoxia (e) Usual termination in CML

(a) Frequent association with thrombosis or hemorrhagic phenomena > The diagnosis is polycythemia vera (primary polycythemia), one of the myeloproliferative syndromes. The disorder is characterized by prominent erythrocytosis, moderate granulocytosis, and thrombocytosis. Because of hyperviscosity and sludging of blood, there is a frequent association with thrombosis or hemorrhagic phenomena. Marked splenomegaly and decreased erythropoietin are other classic characteristics. Cushing syndrome and hypoxic states are associated with secondary polycythemia, not polycythemia vera. About 3% of patients terminate in acute leukemia, not CML.

A 3-year-old boy presents with epistaxis and fever. Multiple cutaneous petechiae are evident, and there is generalized enlargement of lymph nodes, as well as palpable splenomegaly. The hemoglobin and platelet count are markedly decreased, and the white blood cell count is elevated to 40,000 cells/μL, with a preponderance of lymphoblasts. Which of the following statements best characterizes this disorder? (a) It is the form of acute leukemia that is most responsive to therapy. (B) It occurs most often in adults but can occur in children. (C) Lymphoblastic cells cause damage to normal blood cells, resulting in low cell counts. (D) The presence of the CD10 marker is indicative of a poorer prognosis.

(a) It is the form of acute leukemia that is most responsive to therapy. > ALL is the most common malignancy in children and is the form of acute leukemia that is most responsive to therapy. ALL is characterized by a predominance of lymphoblasts in the circulating blood and in the bone marrow. Other progenitor cells do not mature normally, resulting in neutropenia and thrombocytopenia. CD10- positive ALL is the most frequently occurring form of ALL and is the most amenable to therapy. Thus CD10 is a favorable prognostic marker of this disease.

A 50-year-old man presents because of a pruritic rash of several years' duration. The rash is characterized by erythematous, eczematoid patches, and raised plaques and is distributed asymmetrically over the chest and abdomen. Biopsy of the plaques reveals atypical CD4+ T cells with cerebriform nuclei. Further marker studies lead to a diagnosis of mycosis fungoides. Which of the following is true of this disease? (a) The disease eventually disseminates to lymph nodes and internal organs. (B) The neoplastic cells most commonly display cell markers of CD19 and CD20. (C) The skin rash most commonly disappears over time. (D) This disease is caused by a chronic fungal infection in the skin. (e) This is a benign condition and no further workup is necessary.

(a) The disease eventually disseminates to lymph nodes and internal organs. > Mycosis fungoides is a T-cell lymphoma characterized by a rash that may be sited at any cutaneous location. Atypical CD4+ T cells with cerebriform nuclei are found on biopsy. The disorder may remain localized to the skin for many years, but the neoplastic cells eventually disseminate to lymph nodes and other organs. Sézary syndrome, the leukemic form of this cutaneous T-cell lymphoma, is characterized by the combination of skin lesions and circulating neoplastic cells.

A 14-year-old girl presents with prolonged bleeding from wounds and minor trauma and severe menorrhagia. Family history reveals that her father also has prolonged bleeding from wounds and minor trauma, as does her brother. Which of the following is the most likely mechanism of this patient's disorder? (a) Absence of platelet glycoprotein IIb-IIIa (B) Antiplatelet antibodies reacting with platelet surface glycoproteins (C) Deficiency of factor VIII (D) Deficiency of factor IX (e) Deficiency of vWF

(e) Deficiency of vWF > von Willebrand disease, a disorder transmitted by autosomal modes of inheritance (both dominant and recessive) is the most common hereditary bleeding dis- order. There are many variants, all marked by either qualitative or quantitative deficiencies of vWF.

A lymph node from a 10-year-old boy reveals large pleomorphic lymphocytes with CD30 positivity, frequent mitoses, and scattered cells bearing kidney-shaped nuclei. Which of the following statements is true? (a) t(2;5) translocation imparts a worsened prognosis. (B) ALK protein immunostaining is seen in a minority of cases. (C) This tumor occurs exclusively in children. (D) Lacunar cells are a feature. (e) Hallmark cells are a feature.

(e) Hallmark cells are a feature. > This patient has anaplastic large cell lymphoma (aLCL) which is characterized by pleomorphic large lymphocytes with abundant cytoplasm and frequent mitoses. Morphologically it may mimic metastatic carcinoma. The constituent cells are positive for CD30. Scattered cells showing kidney or donut-shaped nuclei with an eosinophilic region adjacent to the nucleus are known as "Hallmark cells." They do not show lacunar cells, which are a feature of NS classical Hodgkin lymphoma. The majority of cases in children shows a t(2;5) translocation which correlates with ALK positivity and improved survival. Although it is more common in children, it shows a bimodal incidence with a second peak in older individuals.

Examination of a lymph node from the neck of a 26-year-old man reveals total effacement of architecture, and at higher power, the characteristic cell shown below. You see Reed-Sternberg cells. Which additional studies are needed to confirm the diagnosis? (a) Angiotensin-converting factor (B) Gene rearrangement studies (C) Osteoclastic factor assay (D) Urine for Bence Jones protein (e) No additional studies

(e) No additional studies The illustration shows Hodgkin lymphoma. A prominent Reed-Sternberg cell can be seen. The diagnosis is based entirely on the biopsy findings, and there are no confirmatory laboratory tests. In particular, flow cytometry is not currently useful because present techniques fail to reliably detect the neoplastic cell population.

A 50-year-old man has been in the medical intensive care unit for septic shock for the past few days. He has now developed rectal bleeding, epistaxis, and gingival bleed- ing. DIC is suspected. Which of the following sets of results for a panel of screening tests is most consistent with this diagnosis? (a) Normal bleeding time, PT, APTT, thrombin time, and platelet count (B) Prolonged bleeding time, PT, APTT, and thrombin time; reduced platelet count (C) Prolonged PT and APTT; normal bleeding time, platelet count, and thrombin time (D) Prolonged PT and APTT; reduced platelet count; normal bleeding time and thrombin time (e) Prolonged bleeding time, PT, and APTT; normal platelet count and thrombin time

B) Prolonged bleeding time, PT, APTT, and thrombin time; reduced platelet count (B) DIC is characterized by widespread clotting with resultant consumption of platelets, coagulation factors, and fibrinogen, and secondary activation of the fibrinolytic system. Laboratory studies reveal thrombocytopenia; prolonged bleeding time, PT, APTT, and thrombin time (reflecting decreased fibrinogen); and increased fibrin and fibrinogen split products. In addition, DIC is often marked by microangiopathic hemolytic anemia with circulating fragmented red cells.

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

The correct answer is A. (A) 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.

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

The correct answer is A. (A) 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 anti- inflammatory 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.

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

The correct answer is A. (A) 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.

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) Lymphoblastic lymphoma □ (B) Burkitt lymphoma □ (C) Hodgkin lymphoma, nodular sclerosing type □ (D) Mantle cell lymphoma □ (E) Follicular lymphoma □ (F) Small lymphocytic lymphoma

The correct answer is A. (A) 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.

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 is shown in the figure. 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

The correct answer is A. (A) 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.

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

The correct answer is A. (A) 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.

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

The correct answer is A. (A) 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.

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

The correct answer is A. (A) 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.

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

The correct answer is A. (A) 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.

A 73-year-old man has been healthy all his life. He takes no medications and has had no major illnesses or surgeries. For the past year, he has become increasingly tired and listless, and he appears pale. Physical examination shows no hepatosplenomegaly and no deformities. CBC shows hemoglobin, 9.7 g/dL; hematocrit, 29.9%; MCV, 69.7 mm3; RBC count, 4.28 million/mm3; platelet count, 331,000/mm3; and WBC count, 5500/mm3. Which of the following is the most likely underlying condition causing this patient's findings? □ (A) Occult malignancy □ (B) Autoimmune hemolytic anemia □ (C) β-Thalassemia major □ (D) Chronic alcoholism □ (E) Vitamin B12 deficiency □ (F) Hemophilia A

The correct answer is A. (A) This patient has a microcytic anemia, which is typical of iron deficiency. Iron deficiency is the most common form of anemia worldwide. The lack of iron impairs heme synthesis. The marrow response is to "downsize" the RBCs, resulting in a microcytic and hypochromic anemia. At this patient's age, bleeding from an occult malignancy should be strongly suspected as the cause of iron deficiency. An autoimmune hemolytic anemia would appear as a normocytic anemia or as a slightly increased MCV with pronounced reticulocytosis. Thalassemias may result in a microcytosis, but β-thalassemia major causes severe anemia soon after birth, and survival to age 73 years is unlikely. Macrocytosis would accompany a history of chronic alcoholism, probably because of poor diet and folate deficiency. Vitamin B12 deficiency also results in a macrocytic anemia. By this patient's age, hemophilia A would result in joint problems; because the bleeding is mainly into soft tissues without blood loss, the iron is recycled. > Occult means Hidden/unknown

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

The correct answer is A. (A) 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.

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

The correct answer is A. 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.

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. The figure shows a skull radiograph. During his hospitalization, a bone marrow biopsy is performed (Lytic lesions). 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

The correct answer is B. (B) Multiple myeloma produces mass lesions of plasma cells in bone that lead to lysis and pain. The skull radiograph shows typical punched-out lytic lesions, produced by expanding masses of plasma cells. 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.

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

The correct answer is B. (B) 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.

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. The appearance of the peripheral blood smear is shown in the figure. It his 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

The correct answer is B. (B) 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.

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

The correct answer is B. (B) 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.

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 A 2 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

The correct answer is B. (B) 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 β- globin 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.

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 shown in the figure "Smudge cells", which of the following is the most likely diagnosis? □ (A) Infectious mononucleosis □ (B) Chronic lymphocytic leukemia □ (C) Iron deficiency anemia □ (D) Leukemia reaction □ (E) Acute lymphoblastic leukemia

The correct answer is B. (B) 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.

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

The correct answer is B. (B) 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.

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

The correct answer is B. (B) 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.

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

The correct answer is B. (B) 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.

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) Complement C3b □ (C) Histamine □ (D) IgG □ (E) Fibronectin

The correct answer is B. (B) 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.

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

The correct answer is B. (B) 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.

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

The correct answer is B. 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.

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

The correct answer is C. (C) 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.

A 41-year-old man has had fevers with chills and rigors for the past 2 weeks. On physical examination, his temperature is 39.2°C. CBC shows hemoglobin, 13.9 g/dL; hematocrit, 40.5%; MCV, 93 μm3; platelet count, 210,000/mm3; and WBC count, 13,750/mm3 with 75% segmented neutrophils, 10% bands, 10% lymphocytes, and 5% monocytes. A bone marrow biopsy specimen shows hypercellularity with a marked increase in myeloid precursors at all stages of maturation and in band neutrophils. These findings are most likely caused by which of the following conditions? □ (A) Acute viral hepatitis □ (B) Glucocorticoid therapy □ (C) Lung abscess □ (D) Vigorous exercise □ (E) Acute myelogenous leukemia

The correct answer is C. (C) Chronic infections and chronic inflammatory conditions, such as lung abscesses, can lead to an expansion of the myeloid precursor pool in the bone marrow; this manifests as neutrophilic leukocytosis. Acute viral hepatitis, in contrast to acute bacterial infections, does not cause neutrophilic leukocytosis. Glucocorticoids can increase the release of marrow storage pool cells and diminish extravasation of neutrophils into tissues. Vigorous exercise can produce neutrophilia transiently from demargination of neutrophils. In acute myelogenous leukemia, the marrow is filled with blasts, not maturing myeloid elements.

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

The correct answer is C. (C) 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.

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

The correct answer is C. (C) 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.

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 is shown in the figure, "Atypical lymphocytes". 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

The correct answer is C. (C) 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 EBV- infected 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 transfusion- associated 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.

A 50-year-old man was diagnosed with a diffuse large B-cell lymphoma. He underwent intensive chemotherapy, and a complete remission was achieved for 7 years. He now reports fatigue and recurrent pulmonary and urinary tract infections over the past 4 months. Physical examination shows no masses, lymphadenopathy, or hepatosplenomegaly. CBC shows hemoglobin, 8.7 g/dL; hematocrit, 25.2%; MCV, 88 μm3; platelet count, 67,000/mm3; and WBC count, 2300/mm3 with 15% segmented neutrophils, 5% bands, 2% metamyelocytes, 2% myelocytes, 6% myeloblasts, 33% lymphocytes, 35% monocytes, and 2% eosinophils. A bone marrow biopsy specimen shows 90% cellularity with many immature cells, including ringed sideroblasts, megaloblasts, hypolobated megakaryocytes, and myeloblasts. Karyotypic analysis shows 5q deletions in many cells. Which of the following is most likely now to have occurred in this patient? □ (A) Relapse of his previous lymphoma □ (B) Transformation of lymphoma into myeloid leukemia □ (C) Myelodysplasia related to therapy for the previous tumor □ (D) De novo acute myeloblastic leukemia □ (E) Myeloid metaplasia with myelofibrosis

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

A 26-year-old man has had a fever with nonproductive cough for the past 10 weeks. On examination, his temperature is 37.4°C. A chest radiograph shows a 4-cm left upper lobe nodule. CBC shows hemoglobin, 13.3 g/dL; hematocrit, 40.5%; platelet count, 281,000/mm3; and WBC count, 13,760/mm3 with 38% segmented neutrophils, 2% bands, 45% lymphocytes, and 15% monocytes. What is the most likely diagnosis? □ (A) Acute lymphoblastic leukemia/lymphoma □ (B) Hodgkin lymphoma, lymphocyte rich type □ (C) Mycobacterium tuberculosis granuloma □ (D) Myelodysplastic syndrome □ (E) Staphylococcus aureus abscess

The correct answer is C. (C) This patient has granulomatous infection leading to leukocytosis with lymphocytosis and monocytosis. The most consistent form of leukocytosis from infection is neutrophilia with acute bacterial infections, such as S. aureus infection. Viral, mycobacterial, and fungal infections produce less consistent peripheral blood findings. An acute lymphoblastic leukemia is likely to be accompanied by a higher WBC count with circulating lymphoblasts. Hodgkin lymphomas have no consistent peripheral blood findings and are not likely to produce solitary lung nodules. Myelodysplastic syndromes are marked by the presence of immature myeloid cells and cytopenias in the peripheral blood

A 45-year-old woman has experienced malaise with nausea and vomiting for 3 months. On physical examination, she has scleral icterus and a yellowish hue to her skin. She has difficulty remembering three objects after 3 minutes. There are no neurologic deficits. Laboratory studies show a positive serologic test result for hepatitis C, a serum ALT of 310 U/L, AST of 275 U/L, total bilirubin of 7.6 mg/dL, direct bilirubin of 5.8 mg/dL, alkaline phosphatase of 75 U/L, and ammonia of 55 μmol/L. An abnormal result of which of the following laboratory studies of hemostatic function is most likely to be reported? □ (A) Immunoassay for plasma von Willebrand factor □ (B) Platelet count □ (C) Prothrombin time □ (D) Fibrin split products □ (E) Platelet aggregation

The correct answer is C. (C) This patient has hepatitis C with severe hepatocyte damage. Many of the clotting factors that are instrumental in the in vitro measurement of the extrinsic pathway of coagulation, as measured by the prothrombin time, are synthesized in the liver. Von Willebrand factor is produced by endothelial cells, not hepatocytes. The platelet count is not affected directly by liver disease. Increased fibrin split products suggest a consumptive coagulopathy, such as disseminated intravascular coagulation. Platelet aggregation is a measure of platelet function, which is not significantly affected by liver disease.

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

The correct answer is C. (C) 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.

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

The correct answer is D. (D) 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.

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. The peripheral blood smear is depicted in part A of the figure. 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 Ph 1 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

The correct answer is D. (D) 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.

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

The correct answer is D. 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.

A 23-year-old woman has had a history of bleeding problems all of her life, primarily heavy menstruation and bleeding gums. A sister and an uncle also have bleeding problems. Physical examination shows several bruises ranging in color from red to blue to purple on her arms and legs. There is no organomegaly, and no deformities are noted. Laboratory studies show hemoglobin, 9.5 g/dL; hematocrit, 28.2%; platelet count, 229,300/mm3; WBC count, 7185/mm3; prothrombin time, 12 seconds; and partial thromboplastin time, 38 seconds. A 1 : 1 dilution of the patient's plasma with normal pooled plasma corrects the partial thromboplastin time. Ristocetin-dependent platelet aggregation in patient plasma is markedly reduced. Factor VIII activity is 30% (reference range 50% to 150%). Which of the following responses should the physician use when advising the patient of potential consequences of this disease? □ (A) You might need allogeneic bone marrow transplantation □ (B) Expect increasing difficulty with joint mobility □ (C) Anticoagulation is needed to prevent deep venous thrombosis □ (D) You could experience excessive bleeding after oral surgery □ (E) A splenectomy might be necessary to control the disease

The correct answer is D. (D) An inherited bleeding disorder with normal platelet count and prolonged bleeding time suggests von Willebrand disease, confirmed by the ristocetin-dependent bioassay for von Willebrand factor (vWF). Von Willebrand disease is a common bleeding disorder, with an estimated frequency of 1%. In most cases, it is inherited as an autosomal dominant trait. In these cases, a reduction in the quantity of vWF impairs platelet adhesion to damaged vessel walls, and hemostasis is compromised. Because vWF acts as a carrier for factor VIII, the level of this procoagulant protein (needed for the intrinsic pathway) is diminished, as in this case. The levels of factor VIII rarely are reduced enough, however, to be clinically significant. Prolonged partial thromboplastin time corrected by normal plasma is a reflection of factor VIII deficiency. Because the disease is not a disorder of stem cells, transplantation is not helpful. Joint hemorrhages are a feature of hemophilia A and B, not von Willebrand disease. Patients with von Willebrand disease are not prone to thrombosis, as are individuals with factor V (Leiden) mutation or other inherited disorders of anticoagulation. Splenectomy is useful in cases of idiopathic thrombocytopenic purpura, but the platelets are not consumed in von Willebrand disease.

A 76-year-old woman notices that small, pinpoint-to-blotchy areas of superficial hemorrhage have appeared on her gums and on the skin of her arms and legs over the past 3 weeks. On physical examination, she is afebrile and has no organomegaly. Laboratory studies show a normal prothrombin time and partial thromboplastin time. CBC shows hemoglobin of 12.7 g/dL, hematocrit of 37.2%, MCV of 80 μm3, platelet count of 276,000/mm3, and WBC count of 5600/mm3. Platelet function studies and fibrinogen level are normal, and no fibrin split products are detectable. Which of the following conditions best explains these findings? □ (A) Macronodular cirrhosis □ (B) Chronic renal failure □ (C) Meningococcemia □ (D) Vitamin C deficiency □ (E) Metastatic carcinoma

The correct answer is D. (D) Platelet number and function in this case are normal, and there is no detectable abnormality in the extrinsic or intrinsic pathways of coagulation as measured by the prothrombin time or partial thromboplastin time. Petechiae and ecchymoses can result from increased vascular fragility, a consequence of nutritional deficiency (e.g., vitamin C), infection (e.g., meningococcemia), and vasculitic diseases. Liver disease would affect the prothrombin time. Chronic renal failure may depress platelet function. Meningococcemia is an acute illness. Metastatic disease does not directly affect hemostasis, although extensive marrow metastases could diminish platelet production.

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

The correct answer is D. (D) 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.

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 hepatosplenomegaly. 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

The correct answer is D. (D) 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 fromR. henselae infection results in lymphadenopathy with microscopic stellate necrosis. Plague from Y. pestis can produce acute lymphadenopathy with microscopic hemorrhagic necrosis.

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

The correct answer is D. (D) 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.

A 49-year-old woman has experienced increasing weakness and chest pain over the past 6 months. On physical examination, she is afebrile and normotensive. Motor strength is 5/5 in all extremities, but diminishes to 4/5 with repetitive movement. There is no muscle pain or tenderness. Laboratory studies show hemoglobin, 14 g/dL; hematocrit, 42%; platelet count, 246,000/mm3; and WBC count, 6480/mm3. A chest CT scan shows an irregular 10 × 12 cm anterior mediastinal mass. The surgeon has difficulty removing the mass because it infiltrates surrounding structures. Microscopically, the mass is composed of large, spindled, atypical epithelial cells mixed with lymphoid cells. Which of the following is the most likely diagnosis of this lesion? □ (A) Granulomatous inflammation □ (B) Hodgkin lymphoma □ (C) Lymphoblastic lymphoma □ (D) Malignant thymoma □ (E) Metastatic breast carcinoma □ (F) Organizing abscess

The correct answer is D. (D) Thymomas are rare neoplasms that can be benign or malignant. In one third to one half of cases, thymomas produce myasthenia gravis as an initial presentation (as in this case). Benign thymomas have a mixed population of lymphocytes and epithelial cells and are circumscribed, whereas malignant thymomas are invasive and have atypical cells. Thymic carcinomas resemble squamous cell carcinomas. Granulomas can have epithelioid macrophages and lymphocytes, but the thymus is an unusual location. Hodgkin lymphoma involves lymph nodes in the middle or posterior mediastinum. Lymphoblastic lymphoma of the T cell variety is seen in the thymus in children, and it has no epithelial component. Metastases to the thymus are quite unusual. An organizing abscess could have granulation tissue at its edge, with a mixture of inflammatory cell types, but not atypical cells.

A 9-year-old boy is taken to his pediatrician because of a generalized seborrheic skin eruption and fever. Histology shows "tennis-like" shaped cells. 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 shown in the figure was taken 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

The correct answer is D. 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 Robbins & Cotran Review of Pathology Pg. 261 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.

A 15-year-old boy visits his physician because of high fever of 10 days' duration. Physical examination shows a temperature of 38°C. He has scattered petechial hemorrhages on the trunk and extremities. There is no enlargement of liver, spleen, or lymph nodes. The CBC shows hemoglobin, 13.2 g/dL; hematocrit, 38.9%; MCV, 93 μm3; platelet count, 175,000/mm3; and WBC count, 1850/mm3 with 1% segmented neutrophils, 98% lymphocytes, and 1% monocytes. Bone marrow biopsy examination does not show any abnormal cells. Which of the following is the most likely diagnosis? □ (A) Acute lymphoblastic leukemia □ (B) Acute myelogenous leukemia □ (C) Aplastic anemia □ (D) Idiopathic thrombocytopenic purpura □ (E) Overwhelming bacterial infection

The correct answer is E. The major finding in this patient is marked granulocytopenia. All that remains on the peripheral smear are mononuclear cells (remember to multiply the percentages in the differential by the total WBC count to get the absolute values; rather than one cell line being overrepresented, another may be nearly missing). Accelerated removal or destruction of neutrophils could account for the selective absence of granulocytes in this case. Overwhelming infections cause increased peripheral use of neutrophils at sites of inflammation. Petechial hemorrhages also can occur in overwhelming bacterial infections, such as those caused by Neisseria meningitidis. Bleeding is unlikely to be caused by thrombocytopenia because the platelet count is normal. Normal bone marrow findings exclude acute lymphoid or myeloid leukemia. In aplastic anemia, the marrow is poorly cellular, and there is a reduction in RBCs, WBCs, and platelet production.

A 7-year-old boy has complained of worsening pain in the right side of his groin region for the past week. Physical examination shows painful, swollen lymph nodes in the right inguinal region. An inguinal lymph node biopsy is performed. Histologically, the node has large, variably sized, germinal centers containing tingible-body macrophages and numerous mitotic figures. There are numerous parafollicular and sinusoidal neutrophils. What is the most likely cause of these histologic changes? □ (A) Acute lymphoblastic leukemia □ (B) Sarcoidosis □ (C) Follicular lymphoma □ (D) Cat-scratch disease □ (E) Acute lymphadenitis □ (F) Toxoplasmosis

The correct answer is E. (E) Painful and acute enlarged nodes suggest a reactive condition and not a neoplastic process, such as a lymphoma or a leukemia. In children, enlarged tender nodes and acute lymphadenitis are common. Many infectious processes can give rise to these findings, particularly bacterial infections. Children are quite active and acquire plenty of cuts and scrapes on extremities, which can become infected. Sarcoidosis is a chronic granulomatous process typically seen in adults and characterized by the formation of noncaseating granulomas. Follicular lymphomas are B-cell neoplasms that efface the normal architecture of the lymph nodes; these tumors do not occur in children. Cat-scratch disease can produce sarcoid- like granulomas with stellate abscesses. Toxoplasmosis can be a congenital infection or can be seen in immunocompromised individuals; it produces a pattern of follicular hyperplasia.

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

The correct answer is E. (E) 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).

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 thrombocytopenia purpura □ (C) Acute myelogenous leukemia □ (D) Chronic lymphocytic leukemia □ (E) Acute lymphoblastic leukemia

The correct answer is E. (E) 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.

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

The correct answer is E. (E) 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.

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 μm 3; 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

The correct answer is E. (E) 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.

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

The correct answer is E. (E) 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.

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

The correct answer is E. 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.

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

The correct answer is F. (F) 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 B- cell 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.

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

The correct answer is F. (F) 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.

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

The correct answer is F. (F) 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.

A 20-year-old man is left at the door of the emergency department by his "friends" after they spent an evening at a local pub. On examination, his vital signs are temperature, 37°C; pulse, 110/min; respirations, 20/min; and blood pressure, 75/40 mm Hg. He has left upper quadrant tenderness on palpation. An abdominal CT scan was obtained and is shown in the figure. What is the most likely etiology for this man's findings? □ (A) Amyloidosis □ (B) Cirrhosis □ (C) Gaucher disease □ (D) Myeloproliferative disorder □ (E) Nonbacterial thrombotic endocarditis □ (F) Salmonella typhi infection □ (G) Trauma

The correct answer is G. (G) This patient has a splenic rupture with hematoma formation in a normal-sized spleen. The likelihood of acute alcohol ingestion favors trauma from falls, fights, and vehicular accidents. A "spontaneous" rupture of the spleen in the absence of trauma may occur when there is splenic enlargement from infections and neoplasms. Other causes of splenic enlargement include amyloid deposition, congestive splenomegaly from portal hypertension with cirrhosis, storage diseases such as Gaucher disease, and myeloproliferative disorders. Embolic events from endocarditis are most likely to occur with infective endocarditis and nonbacterial thrombotic endocarditis.

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

The correct is answer is A. (A) 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.

An 80-year-old woman with no bleeding history despite a number of prior surgeries is receiving antibiotics through a peripherally inserted central catheter (PICC). She is on no medications otherwise. She is noted to have a normal PT and a prolonged PTT. Additional labs demonstrate a prolonged thrombin time (TT) and a normal reptilase time. Which of the following is the most likely the etiology of her laboratory findings? a) Heparin b) Factor I (fibrinogen) deficiency c) Factor VII deficiency d) Factor VIII deficiency e) Factor XII deficiency

a) Heparin The patient has had no prior bleeding complications with surgeries. The prolonged PTT with a normal PT indicates either one of several possibilities... 1. factor deficiency of XII, XI, IX, or VIII 2. acquired inhibitor to one of the same factors 3. a lupus anticoagulant being present 4. heparin effect (since heparin preferencially effects the PTT) We are also told the thrombin time is prolonged. This is interesting as it only really tests the conversion of fibrinogen to fibrin. Things that prolong the TT include the following: 1. Hypofibrinogenemia 2. Dysfibrinogenemia 3. Heparin Of the above, hypofibrinogenemia would be expected to lead to a prolonged PT. Dysfibrinogenemia only variably effects the PT. However, the fact that the reptilase tiem is normal confirms the presence of heparin effect.