Heme and Lymph Leukemia and Lymphoma

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

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

B 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. Because of the high growth fraction (40% in this case), Burkitt lymphomas respond very well to chemotherapy, including agents that disrupt the cell cycle. By contrast, slow-growing tumors with a low growth fraction are more indolent and less responsive to chemotherapy. Acute lymphoblastic lymphomas can be seen in boys this age, but the mass is in the mediastinum, and the lymphoid cells are T cells. Diffuse large-cell lymphomas are most common in adults, as are follicular lymphomas; they do not carry the t(8;14) translocation. Plasmacytomas appear in older adults and are unlikely to produce an abdominal mass.

A 12-year-old boy has had increasing abdominal distention and pain for the past 3 days. Physical examination of his abdomen shows lower abdominal tenderness with tympany and reduced bowel sounds. An abdominal CT scan shows a 7-cm mass involving the region of the ileocecal valve. Surgery is performed and the resected mass microscopically shows sheets of intermediate-sized lymphoid cells, with nuclei having coarse chromatin, several nucleoli, and many mitotic figures. 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 after a course of chemotherapy. Which of the following is the most likely diagnosis? A Acute lymphoblastic leukemia/lymphoma B Burkitt lymphoma C Diffuse large B-cell lymphoma D Follicular lymphoma E Plasmacytoma

D His age and the 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, supported by the expression of the T-cell markers CD2 and CD7. The NOTCH1 gene encodes 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 follicular lymphomas 197and mantle cell lymphomas are B-cell tumors usually seen in older patients, and they do not involve the thymus. 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. Small lymphocytic lymphoma is the tissue phase of chronic lymphocytic leukemia seen in older adults.

A 14-year-old boy complains 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 is widening of the mediastinum. A chest CT scan shows a 10-cm mass in the anterior mediastinum. A biopsy specimen of the mass is obtained and microscopically shows effacement by lymphoid cells with lobulated nuclei having delicate, finely stippled, nuclear chromatin. There is scant cytoplasm, and many mitotic figures are seen. The cells express deoxynucleotidyl transferase negative (TdT−), CD2, and CD7 antigens. Molecular analysis reveals a point mutation in the NOTCH1 gene. The oncologist tells the parents that chemotherapy can be curative in vast majority of such cases. What is the most likely diagnosis? A Burkitt lymphoma B Follicular lymphoma C Hodgkin lymphoma, nodular sclerosing type D Lymphoblastic lymphoma E Mantle cell lymphoma F Small lymphocytic lymphoma

E Splenectomy in childhood reduces humoral immunity to encapsulated bacterial organisms, because splenic IgM producing B lymphocytes and splenic macrophages aid in removal of these infectious agents. The spleen is also a recycling center for RBCs, and it 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 are slightly increased. 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) who are immunodeficient.

A 14-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

G This patient has a splenic rupture with hematoma formation in a normal-sized spleen. Note the more darkly attenuated rim of blood adjacent to the normal-sized spleen and medial to the brightly attenuated ribs at the left in the CT image. 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 20-year-old man is left at the door of the emergency department by "friends" after they spent an evening at a local pub. On examination, his vital signs are temperature, 37° C; pulse, 110/min; respirations, 26/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 underlying cause of this clinical picture? A Cirrhosis B Gaucher disease C Malaria D Myeloproliferative disorder E Nonbacterial thrombotic endocarditis F Salmonella typhi infection G Trauma

B The figure shows myeloblasts with prominent Auer rods. Along with the very high WBC count and the presence of peroxidase-positive blasts (myeloblasts) filling the marrow, these findings are characteristic of acute myelogenous leukemia (AML). 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 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. Her peripheral blood smear is shown in the figure, and these cells contain peroxidase positive granules. A bone marrow biopsy specimen shows 100% cellularity with few residual normal hematopoietic cells. 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

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. Hairy cell leukemia often is accompanied by splenomegaly, but not a mediastinal mass, and the leukemic cells are B cells. Histiocytes with Birbeck granules are characteristic of the Langerhans cell histiocytoses. 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 22-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 a biopsy of the mass microscopically shows scattered large multinucleated cells, with prominent nucleoli that mark with CD15, and lymphocytes and macrophages separated by dense collagenous bands. Which of the following cells is most likely to be seen microscopically in this biopsy specimen? A Atypical lymphocytes B Hairy cells C Langerhans cells D Lacunar cells E Lymphoblasts F Myeloblasts

A The large cells are Reed-Sternberg cells, and they elaborate cytokines that promote an accompanying reactive cellular proliferation that forms the bulk of the neoplastic mass. Reed Sternberg cells are of B-cell origin, and in many cases, Epstein-Barr virus (EBV) infection can be demonstrated in these cells. The other listed options are not part of the pathogenesis for Hodgkin lymphoma.

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 microscopically shows macrophages, lymphocytes, neutrophils, eosinophils, and a few plasma cells. There are scattered CD15+ large cells with multiple nuclei or a single nucleus with multiple nuclear lobes, each with a large inclusion-like nucleolus. What is the most likely cell of origin with infectious agent for these large cells? A B lymphocyte, Epstein-Barr virus B CD4+ cell, human T lymphotropic virus C Endothelial cell, Kaposi sarcoma herpesvirus D Macrophage, human immunodeficiency virus E NK cell, cytomegalovirus

D The pale, tan-to-yellow, firm areas shown in the figure are infarcts. These lesions are either wedge-shaped and based on the capsule or are more irregularly shaped within the parenchyma. Emboli in the systemic arterial circulation most often arise in the heart, and the signs of acute infection in this case suggest emboli from vegetations on cardiac valves in a patient with infective endocarditis; these can lead to splenic infarction. Emboli exiting the aorta at the celiac axis generally take the straight route to the spleen. The kidneys and brain are other common sites for systemic emboli to lodge. Although acute myelogenous leukemia can cause enlargement of the spleen, there are typically no focal lesions—only uniform infiltration of the parenchyma—but the massive size of the spleen with chronic myelogenous leukemia predisposes to splenic infarcts. There would be scattered granulomas that are rounded and tan with granulomatous diseases of the spleen, such as histoplasmosis. In Hodgkin lymphoma, there can be focal nodules. Metastases can enlarge the spleen, but are uncommon in the spleen and are unlikely to be accompanied by signs of infection. Similarly, the congestive splenomegaly that occurs in cirrhosis and portal hypertension does not produce focal splenic lesions. In acute rheumatic fever, the verrucous vegetations are unlikely to embolize; in chronic rheumatic valvulitis, there is scarring with valve deformity, and this increases the risk of infective endocarditis.

A 27-year-old man has had a fever with chills and rigors for the past 10 days. On physical examination, his temperature is 37.9° C, pulse is 87/min, respirations are 21/min, and blood pressure is 100/55 mm Hg. A diastolic murmur is heard on auscultation of the chest. There is a tender, palpable spleen tip. Laboratory studies show hemoglobin, 12.8 g/dL; hematocrit, 38.4%; platelet count, 231,000/mm3; and WBC count, 12,980/mm3 with 69% segmented neutrophils, 8% bands, 1% metamyelocytes, 18% lymphocytes, and 4% monocytes. The representative gross appearance of the spleen is shown in the figure. What is the most likely underlying condition responsible for the changes in the spleen? A Acute myelogenous leukemia B Disseminated histoplasmosis C Hodgkin lymphoma D Infective endocarditis E Metastatic carcinoma F Micronodular cirrhosis G Rheumatic heart disease

B The binucleate cell with prominent nucleoli at the center of the figure is a Reed-Sternberg (RS) cell, characteristic for Hodgkin lymphoma. Studies have conclusively established that in most cases of Hodgkin lymphoma, RS cells are derived from B cells. Within a given tumor, all RS cells have clonal (identical) immunoglobulin gene rearrangements, typical for neoplasia. Polyclonal proliferations are typical for reactive processes. T-cell receptor gene rearrangements occur in normal or neoplastic T cells (e.g., acute lymphoblastic lymphoma). In most cases of Hodgkin lymphoma, RS cells contain the Epstein-Barr virus (EBV) genome, but not the human herpesvirus 8 (HHV-8) genome. This latter genome is 201found in cells of Kaposi sarcoma. HTLV-1 infects CD4+ T cells and gives rise to adult T-cell leukemia/lymphoma.

A 29-year-old woman has experienced fatigue, fever, night sweats, and painless lumps in the right side of her neck for the past 3 months. On physical examination, her temperature is 37.5° C. She has right cervical nontender lymphadenopathy. One of the lymph nodes is biopsied, and a histologic finding is shown at high power in the figure. A molecular analysis of large cells exemplified by the cell at the center is most likely to reveal which of the following genetic abnormalities? A Clonal rearrangement of T-cell receptor genes B Clonal rearrangement of immunoglobulin genes C Integration of the HTLV-1 genome D Integration of the human herpesvirus 8 genome E Polyclonal rearrangement of T-cell receptor genes F Polyclonal rearrangement of immunoglobulin genes

A This patient has a form of T-cell neoplasm known as anaplastic large-cell lymphoma, which most often appears in children and young adults. It is often extranodal and has a characteristic gene rearrangement on chromosome 2p23 that results in production of anaplastic lymphoma kinase (ALK) with tyrosine kinase activity. CD10 is a B-cell marker. The 200T-cell proliferations involving skin, known as mycosis fungoides/Sézary syndrome, are CD4+. The c-KIT proto-oncogene has been associated with some NK cell lymphomas. The IL-2 receptor is associated with lymphohistiocytosis with macrophage activation. The p24 antigen is part of HIV, which is most often associated with B-cell neoplasms.

A 29-year-old, previously healthy man has had an enlarging nodular area on his arm for the past 8 months. On physical examination, there is an ulcerated, reddish violet, 3 × 7 cm lesion on his right forearm and nontender right axillary and left inguinal lymphadenopathy. A chest radiograph shows a 4-cm nodular left pleural mass. An abdominal CT scan shows a 5-cm right retroperitoneal mass. Biopsy of an inguinal node is performed, and microscopic examination shows large cells, some of which contain horseshoe-shaped nuclei and voluminous cytoplasm. The tumor cells cluster around venules and infiltrate sinuses. The patient goes into remission after chemotherapy. Which of the following markers is most likely to be positive in the tumor cells? A ALK protein B CD10 antigen C c-KIT proto-oncogene D IL-2 receptor E p24 antigen

E 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 nodular sclerosis cases are stage I or II, and the prognosis of such early-stage cases is good. The findings do not fit with the other forms of Hodgkin lymphoma listed.

A 34-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 is performed, and microscopic examination shows a 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 of this patient's disease? A Lymphocyte depletion B Lymphocyte predominance C Lymphocyte rich D Mixed cellularity E Nodular sclerosis

B 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. Cytomegalovirus is not known to cause any tumors. HIV is not seen in normal or neoplastic B cells. Human herpesvirus 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.

A 37-year-old man 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 Cytomegalovirus B Epstein-Barr virus C HIV D Human herpesvirus 8 E Human T-cell lymphotropic virus type 1

E The peripheral blood smear is characteristic of acute promyelocytic leukemia (M3 class of acute myelogenous leukemia), with many promyelocytes containing prominent azurophilic granules and short, red, cytoplasmic, rodlike inclusions called Auer rods. Release of the granules can trigger the coagulation cascade, leading to disseminated intravascular coagulation (DIC). As in this case, many patients develop DIC. The t(15;17) translocation is characteristic of this disease; it results in the fusion of the retinoic acid receptor gene on chromosome 17 with the promyelocytic leukemia gene on chromosome 15. The fusion gene results in elaboration of an abnormal retinoic acid receptor that blocks myeloid differentiation. Therapy with retinoic acid (vitamin A) can alleviate the block and induce remission in many patients. The t(8;14) translocation can be seen in patients with Burkitt lymphoma. The t(8;21) abnormality is seen in the M2 variant of acute myelogenous leukemia. The t(9;22) translocation gives rise to the Philadelphia chromosome of chronic myelogenous leukemia. A t(14;18) karyotype suggests a follicular lymphoma.

A 38-year-old man experiences sudden onset of a severe headache. Physical examination shows no localizing neurologic signs and no organomegaly. A stool sample is positive for occult blood. Areas of purpura appear on the skin of his extremities. Laboratory studies show hemoglobin of 9.6 g/dL, hematocrit of 28.9%, platelet count of 16,400/mm3, and WBC count of 75,000/mm3. The peripheral blood smear has the appearance shown in the figure; schistocytes also are seen. The plasma D-dimer level (fibrin degradation products), prothrombin time, and partial thromboplastin time all are elevated. Cytogenetic analysis of cells from a bone marrow biopsy specimen is most likely to yield what karyotypic abnormality? A t(8;14) B t(8;21) C t(9;22) D t(14;18) E t(15;17)

D 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. Erythroleukemia is rare and is accompanied by dysplastic erythroid precursors. 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.

A 38-year-old woman has had bleeding gums for the past 3 weeks. Physical examination shows that her gingivae are thickened and friable. She has hepatosplenomegaly and generalized nontender lymphadenopathy. CBC shows hemoglobin, 11.2 g/dL; hematocrit, 33.9%; MCV, 89 μm3; platelet count, 95,000/mm3; and WBC count, 4500/mm3 with 25% segmented neutrophils, 10% bands, 2% metamyelocytes, 55% lymphocytes, 8% monocytes, and 1 nucleated RBC per 100 WBCs. A bone marrow biopsy specimen shows 100% cellularity, with many large blasts that are peroxidase negative, nonspecific esterase positive, and CD13 and CD14 positive. What is the most likely diagnosis? A Acute erythroleukemia B Acute lymphoblastic leukemia C Acute megakaryocytic leukemia D Acute monocytic leukemia E Acute promyelocytic leukemia

A 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. 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. 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.

A 4-year-old boy has appeared listless during the past week. He exhibits irritability when his arms or legs are touched. In the past 2 days, large ecchymoses have appeared on the right thigh and left shoulder. CBC shows hemoglobin, 9.3 g/dL; hematocrit, 28.7%; 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 deoxynucleotidyl transferase negative (TdT−). Flow cytometry shows the phenotype of blasts to be CD19+, CD3−, and sIg−. 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 Idiopathic thrombocytopenic purpura

B The figure shows mononuclear cells with reniform nuclei and pale blue cytoplasm with threadlike extensions. This patient has hairy cell leukemia, an uncommon neoplastic disorder of B cells. These CD19+, CD20+, and CD11c+ cells infiltrate the spleen and marrow. Pancytopenia results from poor production of hematopoietic cells in the marrow and sequestration of the mature cells in the spleen. There are two characteristic features of this disease: the presence of hairy projections from neoplastic leukocytes in the peripheral blood smear and coexpression of B-cell (CD19, CD20) and monocyte (CD11c) markers. In the past, staining for tartrate-resistant acid phosphatase (TRAP) was used to identify these abnormal cells as shown in the right panel of the figure. Auer rods are seen in myeloblasts in acute myeloblastic leukemia. A monoclonal IgM spike is a feature of lymphoplasmacytic lymphoma (Waldenström macroglobulinemia). The Ph1 chromosome is a distinctive feature of chronic myelogenous leukemia. Toxic granulations in neutrophils are seen most often in overwhelming bacterial infections.

A 41-year-old man has experienced several bouts of pneumonia over the past year. He now complains of vague abdominal pain and a dragging sensation. Physical examination shows marked splenomegaly. CBC shows hemoglobin, 8.2 g/dL; hematocrit, 24.6%; MCV, 90 μm3; platelet count, 63,000/mm3; and WBC count, 2400/mm3. The peripheral blood smear shows many small leukocytes with the features shown in the figure. A chest radiograph shows patchy infiltrates, and a culture of sputum grows Mycobacterium kansasii. Which of the following laboratory findings is most characteristic of this disorder? A Cytoplasmic Auer rods in myeloid cells B CD20 and CD11c positive lymphocytes C Monoclonal IgM in serum D t(9:22) translocation in stem cells E Cytoplasmic toxic granulations in neutrophils

B This classic history for chronic myelogenous leukemia (CML) is 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 but 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 original 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+. A myelodysplastic syndrome, not present here, can precede the development of acute myelogenous leukemia. Hairy cell leukemia is an indolent disease without blasts. The Sézary syndrome has a leukemic component of CD4+ cells in addition to the skin involvement (mycosis fungoides).

A 45-year-old man has experienced a gradual weight loss and weakness, anorexia, and easy fatigability for 9 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 the figure. Karyotypic analysis shows the Ph1 chromosome. The patient undergoes chemotherapy with imatinib mesylate (tyrosine kinase inhibitor). He remains in remission for 3 years and then begins to experience fatigue and an 8-kg weight loss. CBC shows hemoglobin, 10.5 g/dL; hematocrit, 30%; platelet count, 60,000/μL; and WBC count, 40,000/μL. Karyotypic analysis shows two Ph1 chromosomes and aneuploidy. Flow cytometric analysis of the peripheral blood shows CD19+, CD10+, sIg−, and CD3− cells. Which of the following complications of the initial disease did this patient develop after therapy? A Acute myeloblastic leukemia B B-cell lymphoblastic leukemia C Hairy cell leukemia D Myelodysplastic syndrome E Sézary syndrome

B 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, as shown by the small (2.8 g) spike of γ-globulin, which is determined by immunoelectrophoresis to be IgG kappa. MGUS can progress to multiple myeloma in about 20% of patients over 10 to 15 years. Heavy-chain disease is a rare condition. 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 plasmacytoma is a mass lesion that would appear on a bone scan, but they may also be extraosseous. Waldenström macroglobulinemia would be accompanied by an IgM spike, hepatosplenomegaly, and lymphadenopathy; the protein would be very high with hyperviscosity.

A 48-year-old man has a routine health maintenance examination. He has no concerns 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. The results of the serum protein electrophoresis are shown in the figure. A bone marrow biopsy specimen shows normal cellularity with maturation of all cell lines. Plasma cells constitute about 4% of the marrow. The results of a bone scan are normal, and there are no areas of increased uptake. What is the most likely diagnosis? A Heavy chain disease with lymphoplasmacytic lymphoma B Monoclonal gammopathy of undetermined significance C Multiple myeloma with IgD immunophenotype D Reactive systemic amyloidosis E Solitary plasmacytoma of the lung F Waldenström macroglobulinemia with hyperviscosity

D Thymomas are rare neoplasms that can be benign or malignant. In one third to one half of cases, thymomas are associated with 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 for them. Hodgkin lymphoma involves lymph nodes in the middle or posterior mediastinum, with a component of Reed-Sternberg cells. Lymphoblastic lymphoma of the T-cell variety is seen in the mediastinal region, including thymus, in children, but 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 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 cause of this mass lesion? A Extrapulmonary tuberculosis B Hodgkin lymphoma C Lymphoblastic lymphoma D Malignant thymoma E Metastatic breast carcinoma F Organizing abscess

E This patient has polycythemia vera (PCV), 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, PCV 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 PCV. 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 (often with the BCR-ABL fusion gene) develop chronic myelogenous leukemia. Myelodysplastic syndromes and the other myeloproliferative disorders, such as essential thrombocytosis (with JAK2 mutations), are not accompanied by such a marked 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 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 165/95 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. What is the most likely diagnosis? A Chronic myelogenous leukemia B Erythroleukemia C Essential thrombocytosis D Myelodysplastic syndrome E Polycythemia vera

C Myelodysplasia is 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 these abnormal hematopoietic cells fail to mature normally, they are not released into the peripheral blood, leading to pancytopenia and susceptibility to infections. Myelodysplasias are clonal stem cell disorders that develop either de novo or after chemotherapy with alkylating agents, as in this case. The presence of chromosomal deletions, such as 5q, is a marker of posttherapy myelodysplasia. These morphologic abnormalities in the marrow are not seen in any of the other listed conditions.

A 50-year-old man with a diffuse large B-cell lymphoma 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. This clinical picture is most consistent with which of the following conditions? A De novo acute myeloblastic leukemia B Myeloid metaplasia with myelofibrosis C Myelodysplasia related to therapy D Relapse of his previous lymphoma E Transformation into myeloid leukemia

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

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

F Marginal zone 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 54-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 extensive 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

C Diffuse large B-cell lymphoma occurs in older individuals and frequently manifests as localized disease with extranodal involvement, particularly of the Waldeyer ring. A third of cases have BCL6 rearrangements or mutations. 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. Lymphoblastic lymphoma is a T-cell neoplasm that occurs typically in the mediastinum of children. In chronic lymphadenitis, the lymph node has many cell types—macrophages, lymphocytes, and plasma cells. A monomorphous infiltrate is typical of non-Hodgkin lymphomas. Reed-Sternberg cells characterize Hodgkin lymphoma. Small lymphocytic lymphoma also is a B-cell neoplasm, but it manifests with widespread lymphadenopathy, liver and spleen enlargement, and lymphocytosis.

A 55-year-old man 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 lymphoid cells that are twice the size of normal lymphocytes, 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−). A BCL6 gene mutation is present. Which of the following is the most likely diagnosis? A Acute lymphoblastic lymphoma B Chronic lymphadenitis C Diffuse large B-cell lymphoma D Hodgkin lymphoma E Small lymphocytic lymphoma

F 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. Cat-scratch disease from Bartonella henselae infection results in lymphadenopathy with microscopic stellate necrosis. 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. Helicobacter pylori can be associated with MALT lesions. HIV is best known to be associated with non-Hodgkin lymphomas and with Kaposi sarcoma, but not leukemias

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. Which of the following infectious agents most likely caused his illness? A Bartonella henselae B Cytomegalovirus (CMV) C Epstein-Barr virus (EBV) D Helicobacter pylori E HIV F HTLV-1

C The cytopenias along with the splenomegaly suggest hypersplenism as a cause for this patient's anemia, leukopenia, and thrombocytopenia. The circulating blood cells are sequestered within the large spleen. One of the most common causes is congestive splenomegaly from portal hypertension resulting from hepatic cirrhosis. The elevation of AST more than ALT suggests alcoholic liver disease. The WBC count should be quite high with acute leukemias. Although infectious mononucleosis can lead to splenomegaly and can be marked by lymphocytosis, the course is typically not 9 months, and it is more common in younger individuals. Niemann-Pick disease is a storage disease from an inborn error of metabolism involving sphingomyelinase, and typically appears in childhood and leads to profound neurologic problems. The spleen is an uncommon location for metastases. Systemic lupus erythematosus can lead to cytopenias from reduced bone marrow function, but the spleen is not usually enlarged.

A 60-year-old man with a history of chronic alcohol abuse has had increasing abdominal discomfort and fatigue for the past 9 months. He has noted easy bruising of his skin with minor trauma for the past month. On examination, he is afebrile, but his spleen is enlarged and tender. Laboratory studies show hemoglobin, 7.7 g/dL; hematocrit, 23%; platelet count, 30,000/mm3; and WBC count, 2300/mm3 with 45% polymorphonuclear leukocytes, 50% lymphocytes, and 5% monocytes. What is the most likely diagnosis? A Acute myelogenous leukemia B Infectious mononucleosis C Micronodular cirrhosis D Niemann-Pick disease E Metastatic adenocarcinoma F Systemic lupus erythematosus

C The symptoms of polycythemia vera (PCV) result from an increased RBC mass with increased hematocrit and blood volume. Undetectable erythropoietin in the face of polycythemia is characteristic of PCV, a myeloproliferative disorder in which the neoplastic myeloid cells differentiate preferentially along the erythroid lineage. Other lineages also are affected, with leukocytosis and thrombocytosis in this case. 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 60-year-old woman has had headaches and dizziness for the past 5 weeks. She has been taking 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. Which of the following is most characteristic of the natural history of this patient's disease? A Development of a gastric non-Hodgkin lymphoma B Increase in monoclonal serum immunoglobulin C Marrow fibrosis with extramedullary hematopoiesis D Spontaneous remissions and relapses without treatment E Transformation into acute B-lymphoblastic leukemia

C Multiple myeloma produces mass lesions of plasma cells that lead to bone 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 renal 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. Blasts suggest a leukemic process. 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. Granulomatous disease (which is not produced by pneumococcus) can involve the marrow, but usually it does not produce such sharply demarcated lytic lesions.

A 61-year-old man reports 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 growing 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. a bone marrow biopsy specimen from this man is most likely to show increased numbers of which of the following? A Myeloblasts B Small mature lymphocytes C plasma cells D Reed-Sternberg cells E Non-necrotizing granulomas

A Diffuse large-cell lymphoma of B cells often involve extranodal sites, show large anaplastic lymphoid cells that involve the tissues diffusely, and contain BCL6 gene rearrangements. Their clinical course is aggressive, and they become rapidly fatal if untreated. With intensive chemotherapy, however, 60% to 80% of patients achieve complete remission, and up to 50% can be cured. More aggressive lymphomas tend to be localized, whereas the indolent lymphomas tend to involve multiple nodal sites or multiple organs such as liver, spleen, and marrow.

A 62-year-old man has experienced vague abdominal discomfort accompanied by bloating and diarrhea for the past 6 months. On physical examination, there is a midabdominal firm mass. The stool is positive for occult blood. An abdominal CT scan shows an 11 × 4 cm mass involving the wall of the distal ileum and adjacent mesentery. A laparotomy is performed, and the mass is removed. Microscopically, the mass is composed of sheets of large lymphoid cells with large nuclei, prominent nucleoli, and frequent mitotic figures. The neoplastic cells mark with CD19+ and CD20+ and have the BCL6 gene rearrangement. Which of the following prognostic features is most applicable to this case? A Aggressive, can be cured by chemotherapy B Aggressive, often spreads to liver, spleen, and marrow C Aggressive, often transforms to acute leukemia D Indolent, can be cured by chemotherapy E Indolent, often undergoes spontaneous remission F Indolent, survival of 7 to 9 years without treatment

D 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, particularly when it involves the peripheral blood.

A 62-year-old man has had 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 microscopically shows a nodular pattern of small lymphoid cells. A bone marrow biopsy specimen shows infiltrates of similar small cells having surface immunoglobulins that are CD5+, but CD10−. Cytogenetic analysis indicates t(11;14) in these cells. What is the most likely diagnosis? A Acute lymphoblastic lymphoma B Burkitt lymphoma C Follicular lymphoma D Mantle cell lymphoma E Small lymphocytic lymphoma

A The lymphocyte depletion variant of Hodgkin lymphoma has an abundance of Reed-Sternberg cells and a 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 63-year-old man has noticed a lump in his neck for 2 months. Examination reveals a group of three discrete nontender right posterior cervical lymph nodes, and a mass of enlarged right axillary lymph nodes. Chest and abdominal CT scans show mediastinal lymphadenopathy and hepatosplenomegaly. Microscopic examination of 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

E The features suggest Hodgkin lymphoma (HL), mixed cellularity type, which tends to affect older men. As in all other forms of HL except the lymphocyte predominance type, 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 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. Epithelioid cells are seen in granulomatous inflammatory reactions. Immunoblasts suggest a B-cell proliferation. Mast cells are not numerous in HL; they participate in type I hypersensitivity responses. Myeloblasts are numerous with acute myelogenous leukemia.

A 74-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 splenomegaly. An abdominal CT scan shows mesenteric lymphadenopathy. 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 and CD30, is most likely to be found in this disease? A Epithelioid cell B Immunoblast C Mast cell D Myeloblast E Reed-Sternberg cell

C Essential thrombocytosis 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 202accompanied 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 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 Acute myelogenous leukemia B Chronic myelogenous leukemia C Essential thrombocytosis D Myelofibrosis with myeloid metaplasia E Polycythemia vera

A Myelofibrosis with myeloid metaplasia is a myeloproliferative disorder that is also 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). Hematopoietic cell proliferation and turnover increases purine metabolism and uric acid production. 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. Metastases to the spleen are uncommon.

A 66-year-old man has experienced fatigue, a 5-kg weight loss, night sweats, and abdominal discomfort for 10 months. 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 Extramedullary hematopoiesis B Granulomas with Histoplasma capsulatum C Hodgkin lymphoma D Metastatic adenocarcinoma E Portal hypertension

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

A 66-year-old man has noted an increasing number and size of lumps over his body in the past 5 months. On examination, there is firm, nontender inguinal, axillary, and cervical lymphadenopathy. A biopsy specimen of a cervical node shows a histologic pattern of nodular aggregates of small, cleaved lymphoid cells and larger cells with open nuclear chromatin, several nucleoli, and moderate amounts of cytoplasm. A bone marrow biopsy specimen shows lymphoid aggregates of similar cells with surface immunoglobulins that are CD10+, but CD5−. Karyotyping of these lymphoid cells indicates the presence of t(14;18). What is the most likely diagnosis? A Acute lymphadenitis B Hodgkin lymphoma, nodular sclerosis type C Follicular lymphoma D Mantle cell lymphoma E Toxoplasmosis

D Hyperviscosity syndrome includes visual disturbances, dizziness, headache, and Raynaud phenomena. His bone marrow is infiltrated with plasmacytoid lymphocytes that have stored immunoglobulins in their cytoplasm (Russell bodies). All of these findings are consistent with 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. 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. Light chains in urine (Bence Jones proteins) also are a feature of multiple myeloma. Hypercalcemia occurs with myeloma because myeloma cells produce MIP1-α that up-regulates RANKL production and increased osteoclastic activity, so punched-out lytic bone lesions are typical of multiple myeloma. A t(14;18) translocation is characteristic of a follicular lymphoma. There is typically no leukemic phase to Waldenström macroglobulinemia.

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 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 by numerous small plasmacytoid lymphoid cells with Russell bodies in the cytoplasm. Which of the following additional laboratory findings is most likely to be reported for this patient? A Bence Jones proteinuria B Hypercalcemia C Karyotype with t(14;18) translocation D Monoclonal IgM spike in serum E WBC count of 255,000/mm3

D The figure shows a follicular non-Hodgkin lymphoma. All lymphoid neoplasms are derived from a single transformed cell and are monoclonal. B-cell neoplasms comprise 80% to 85% of all lymphoid neoplasms, and their monoclonality can often be shown by immunostaining that reveals one light chain in the neoplastic cells. Populations of normal or reactive (polyclonal) B cells contain a mixture of B cells expressing both 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. 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 proliferation of capillaries is typically a benign, reactive process.

A 69-year-old man notices the presence of lumps in the right side of his neck that have been enlarging for 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 and the microscopic appearance is shown in the figure. Molecular analysis of the DNA extracted from the cells reveals B cell receptor gene rearrangements. Which of the following features provides the best evidence for malignant lymphoma in this node? A Absence of a pattern of lymphoid follicles with germinal centers B Diminished sinusoidal plasma cells and immunoblasts C Presence of CD30+ large, multinucleated cells D Uniform expression of kappa, but not lambda, light chains in the lymphoid cells E Proliferation of small capillaries in the medullary and paracortical regions

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 by 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. Myeloma is unlikely to be accompanied by leukocytosis. Patients with bone destruction and remodeling 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), with a low leukocyte alkaline phosphatase score. Leukemias, including CML, and myeloproliferative disorders can fill the marrow spaces, sometimes are accompanied by a thrombocytosis, but are unlikely to produce mass lesions or bony destruction.

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 T10 and multiple 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 laboratory findings is most likely to be seen in this patient? A Bence Jones proteins in the urine B Decreased serum alkaline phosphatase level C Hypogammaglobulinemia D Platelet count of 750,000/mm3 E t(9;22) in the karyotype of marrow cells F WBC count of 394,000/mm3

A These markers strongly favor a very good prognosis for acute lymphoblastic leukemia (ALL), the most common malignancy in children: early precursor-B-cell type, hyperdiploidy, and patient age between 2 and 10 years, chromosomal trisomy, and t(12;21). Marrow infiltration by the leukemic cells leads to pancytopenia. Poor prognostic markers for acute lymphoblastic leukemia/lymphoma are T-cell phenotype, patient age younger than 2 years, WBC count >100,000, presence of t(9;22) MLL gene mutations, and presentation in adolescence and adulthood. In most T-cell ALL cases in adolescents, a mediastinal mass arises in the thymus, and lymphoid infiltrates appear in tissues of the mononuclear phagocyte system. The success of a treatment plan is also aided by a caring and supportive family.

A 7-year-old boy has complained of a severe headache for the past week. On physical examination, there is tenderness on palpation of long bones, hepatosplenomegaly, and generalized lymphadenopathy. Petechial hemorrhages are present on the skin. Laboratory studies show hemoglobin, 8.8 g/dL; hematocrit, 26.5%; platelet count, 34,700/mm3; and WBC count, 14,800/mm3. A bone marrow biopsy specimen shows 100% cellularity, with almost complete replacement by a population of large cells with scant cytoplasm lacking granules, delicate nuclear chromatin, and rare nucleoli. His oncologist is confident that chemotherapy will induce a complete remission. Which of the following combinations of phenotypic and karyotypic markers is most likely to be present in marrow cells from this boy? A Early pre-B CD19+ hyperdiploidy B Early pre-B CD20+ t(9;22) C Pre-B CD5+ normal karyotype D Pre-B CD23+ 11q deletion E T cell CD2+ numerous blasts F T cell CD3+ MLL gene translocation

A The clinical history, the peripheral blood smear, and the phenotypic markers are characteristic of chronic lymphocytic leukemia (CLL), a clonal B-cell neoplasm in which immunoglobulin genes are rearranged, and T-cell receptor genes are in germline configuration. There is typically a tissue component of small lymphocytic lymphoma (SLL). The t(8;14) translocation is typical of Burkitt lymphoma; this lymphoma occurs in children at extranodal sites. The t(9;22) is a feature of chronic myeloid leukemia. 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 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 CBC shows hemoglobin, 9.5 g/dL; hematocrit, 28%; MCV, 90 μm3; platelet count, 120,000/mm3; and WBC count, 42,000/mm3. His peripheral blood smear shows a monotonous population of small, round, mature-looking lymphocytes. Flow cytometry shows these cells to be CD19+, CD5+, and deoxynucleotidyl transferase negative (TdT−). Cytogenetic and molecular analysis of the abnormal cells in his blood are most likely to reveal which of the following alterations? A Clonal rearrangement of immunoglobulin genes B Clonal rearrangement of T-cell receptor genes C t(8;14) leading to c-MYC overexpression D t(9;22) leading to BCR-ABL rearrangement E t(14;18) leading to BCL2 overexpression

D Shown here are 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. Tuberculosis can produce granulomatous disease with bony destruction, but the macrophages present in the granulomas are epithelioid macrophages that do not have Birbeck granules. Hodgkin lymphoma is seen in young adults and does not produce skin lesions or bone lesions. Myeloma is a disease of adults that can produce lytic bone lesions, but not skin lesions.

A 9-year-old boy has developed a fever over the past 15 days. He has been diagnosed and treated for otitis media multiple times in the past year. On physical examination, he has mild lymphadenopathy, hepatomegaly, and splenomegaly. There are extensive crusted papules on his skin. A CT scan of his head shows a 4-cm osteolytic mass in the mastoid bone. A biopsy of the mass is performed, with the electron micrograph shown in the figure. What is the most likely diagnosis? A Acute lymphoblastic leukemia B Disseminated tuberculosis C Hodgkin lymphoma, mixed cellularity type D Langerhans cell histiocytosis E Multiple myeloma

B The endemic African variety of Burkitt lymphoma is 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 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 or splenomegaly, and he is afebrile. A biopsy of the mass is performed and microscopic examination shows 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 viruses is most likely to be causally related to the development of these findings? A Cytomegalovirus B Epstein-Barr virus C Hepatitis B virus D HIV E Human papillomavirus F Respiratory syncytial virus

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

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

A Letterer-Siwe disease is a form of Langerhans cell histiocytosis, with Birbeck granules as a distinctive feature identified by electron microscopy, which are found in the cytoplasm of the Langerhans cells. Lymphoblasts that mark as T cells (CD3 positive) 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.

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 marking with CD3 C Plasma cells with Russell bodies D Reed-Sternberg cells and variants E Ring sideroblasts with perinuclear granules F Sézary cells with cerebriform nuclei

B Sonja Henie died from complications of chronic lymphocytic leukemia (CLL). The figure shows increased numbers of circulating small, round, mature lymphocytes with scant cytoplasm in the peripheral blood smear. The CLL 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. 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. The lymphocytes seen in infectious mononucleosis are atypical lymphocytes, which have abundant, pale 198blue 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.

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 smear shown in the figure, which of the following is the most likely diagnosis? A Acute lymphoblastic leukemia B Chronic lymphocytic leukemia C Infectious mononucleosis D Iron deficiency anemia E Leukemoid reaction