The correct answer is E. Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of unknown etiology. It is characterized by an increased bleeding time but a decreased platelet count,. It causes purpura, fever, renal failure, microangiopathic hemolytic anemia, and microthrombi, frequently in young women. Elevated indirect bilirubin and high LDH are characteristic, as are schistocytes in the blood smear, renal dysfunction, and neurologic and systemic symptoms. Negative findings important to rule out similar conditions include a negative Coombs test and absence of fibrin split products. TTP is thought to be initiated by endothelial injury, which releases certain procoagulant materials into the circulation, causing platelet aggregation. This condition may be precipitated by pregnancy or use of estrogens.

Autoimmune hemolytic anemia (choice A) can cause anemia and an elevated indirect bilirubin, but generally produces only mild symptoms, is not associated with thrombocytopenia, and does not cause fragmentation of red blood cells on the peripheral smear. The negative Coombs test argues against autoimmune hemolytic anemia.

Disseminated intravascular coagulation (DIC; choice B) can be differentiated from TTP because of abnormal coagulation tests. In DIC, microangiopathic hemolysis is also present, but the prothrombin time (PT) and partial thromboplastin time (PTT) are prolonged, fibrinogen levels are reduced, and fibrin split products are elevated.

Hemolytic-uremic syndrome (HUS; choice C) is not significantly different from TTP. The two conditions, in fact, are considered manifestations of the same pathogenetic spectrum. However, the vascular bed of the CNS is not involved in HUS. Thus, mental status changes are not part of the clinical picture of HUS.

Idiopathic (autoimmune) thrombocytopenic purpura (ITP; choice D) is an immune disorder caused by autoantibodies to platelet antigens. Systemic illness is not present in ITP, which is characterized by isolated thrombocytopenia without other hematologic abnormalities. Ten percent of cases will manifest in association with autoimmune hemolytic anemia (Evans syndrome).

The correct answer is A. The patient has polycythemia vera, and the clinical presentation described is fairly typical. This disease, despite its name, is actually not a pure proliferation of erythrocytes, but also includes lesser degrees of hyperplasia of granulocytic and megakaryocytic bone marrow lines. It is thought to be related to overgrowth of a clone of primitive stem cells with abnormal sensitivity to erythropoietin. Polycythemia vera, because of this multi-line proliferation, is considered to be part of the myeloproliferative disorders that also include chronic myeloid leukemia, myeloid metaplasia with myelofibrosis, and essential thrombocythemia.

Diseases related to multiple myeloma (choice B) include solitary plasmacytoma, heavy chain disease, Waldenström macroglobulinemia, and monoclonal gammopathy of undetermined significance. All of these diseases are proliferations of immunoglobulin-producing plasma cells or late stage lymphocytes.

Diseases related to sickle cell anemia (choice C) include other hemoglobinopathies (disorders of the hemoglobin structure) of which the best known are hemoglobin C and D, but which actually include many structural variants.

Vitamin B12 deficiency (choice D) causes a megaloblastic anemia; the other common cause of megaloblastic anemia is folate deficiency.

Diseases related to warm antibody autoimmune hemolytic anemia (choice E) include other autoimmune hemolytic anemias such as cold agglutinin autoimmune hemolytic anemia (IgM mediated), and cold hemolysis autoimmune hemolytic anemia (IgG mediated).

The correct answer is E. Different leukemias tend to affect populations of different ages. The disease described is chronic lymphocytic leukemia (CLL), which is a disease of older adults.

Both the one year-old (choice A) and the five year-old (choice B) would be most likely to have acute lymphocytic leukemia (ALL).

The 20 year-old (choice C) would be most likely to have acute myelocytic leukemia (AML).

The 45 year-old (choice D) would be likely to have either AML or chronic myelogenous leukemia (CML).

The correct answer is B. An increased number of eosinophils (AKA eosinophilia) occurs in association with several conditions, the most frequent of which are immune-mediated diseases (e.g., asthma, hay fever, and pemphigus vulgaris) and parasitic infestations. This is due to an absolute increase in the number of circulating eosinophils, brought about by IL-5, which stimulates differentiation of eosinophilic precursor cells in the bone marrow.

Basophilic leukocytosis (choice A) is a rare event that is sometimes observed in association with chronic myelogenous leukemia. It is not seen in patients with asthma.

Lymphocytosis (choice C) may result from a vast array of conditions, but it is not typical of asthma or other allergic diseases. Lymphocytosis may develop in response to a number of infections (e.g., brucellosis, whooping cough, hepatitis, infectious mononucleosis, and tuberculosis) or manifest as part of chronic lymphocytic leukemia.

Monocytosis (choice D) refers to an increase in number of monocytes, which are circulating macrophages. Chronic infections (e.g., tuberculosis, rickettsiosis, and malaria) and chronic inflammatory conditions (e.g., collagen vascular diseases and inflammatory bowel disease) are the most common underlying causes.

Neutrophilic leukocytosis (choice E) is a typical systemic reaction to acute and chronic infections, especially those due to bacteria. The increase in neutrophil number is mediated by IL-1 and TNF, which induce a rapid release of neutrophils from the bone marrow in acute infections and stimulate proliferation of bone marrow precursors in chronic infections.

The correct answer is C. The patient is suffering from multiple myeloma, a neoplastic proliferation of plasma cells (or their precursors) found within the bone marrow. These malignant cells are responsible for the production of excessive amounts of immunoglobulin (usually IgG or IgA), producing an M- protein spike, and increasing the ESR. The decreased platelet count probably reflects infiltration of the bone marrow by myeloma cells. It is not unusual for patients with malignant myeloma to have recurring bacterial infections, particularly pneumococcal pneumonia, because the overall production of normal immunoglobulins of all isotypes is decreased. Lytic bone lesions due to infiltration by myeloma cells may lead to pathological fractures. All of the other disorders listed can be associated with an M-protein spike, but this is a nonspecific finding.

Chronic lymphocytic leukemia (CLL; choice A) is ruled out by the normal white count, since this type of leukemia is generally associated with an absolute lymphocytosis.

Patients with monoclonal gammopathy of undetermined significance (choice B) are generally asymptomatic, although they have a predisposition for subsequently developing myeloma, lymphoma, amyloidosis, or Waldenström's macroglobulinemia.

Plasmacytoma (choice D) (solitary myeloma) is a rare, isolated plasma cell neoplasm in bone or soft tissues. If the primary cancer is in bone, it is likely to disseminate; extraosseous tumors tend to remain localized. Since this patient had multiple lytic bone lesions, multiple myeloma is the correct diagnosis.

Waldenström's macroglobulinemia (choice E) is a disorder involving neoplasms of lymphocytoid plasma cells that produce monoclonal IgM. Hypergammaglobulinemia produces hyperviscosity of the blood which, along with infiltration by tumor produce the characteristic signs and symptoms. Weakness, weight loss, bone pain, hepatosplenomegaly, and lymphadenopathy occur commonly.

The correct answer is B. The history is consistent with Hodgkin disease (HD). Important clinical clues include painless lymphadenopathy, night sweats, and generalized pruritus. All forms of lymphoma lead to effacement of the nodal architecture on cut surfaces. In this case, fibrotic bands appear to divide the node into multiple nodules. This finding is suggestive of the nodular sclerosis subtype of HD, which usually affects children and young adults. Furthermore, the histologic finding of large cells with prominent nucleoli (Reed-Sternberg cells) within a polymorphic cellular background is consistent with HD. Remember that the nodular sclerosis type of HD is characterized by a subtype of Reed-Sternberg cells called lacunar cells. These are similar to classic Reed-Sternberg cells in their large, inclusion-like nucleoli, but appear surrounded by a clear halo (hence the attribute "lacunar").

Cat-scratch disease (choice A) is due to a small gram-negative bacillus (Bartonella henselae), which is transmitted to humans by a scratch or a bite by a cat. Swelling of lymph nodes develops days after the skin lesion. The history is generally sufficient for diagnosis, but occasionally a lymph node biopsy is performed for confirmation. This reveals characteristic stellate abscesses, which are also seen with tularemia and lymphogranuloma venereum.

Infectious mononucleosis (choice C) can be histologically confused with HD, but the patient's condition would be characterized by a flu-like syndrome, fever, splenomegaly, and lymphadenopathy at multiple anatomic sites.

Non-Hodgkin lymphoma (choice D) is associated with effacement of lymph node architecture, and replacement by a population of atypical or frankly anaplastic lymphocytes. The presence of a polymorphic cellular background, and especially the finding of Reed-Sternberg cells, excludes non-Hodgkin lymphomas.

Reactive non-specific lymphadenitis (choice E) results in hyperplasia of germinal centers of lymphoid follicles, where maturation of B-cells takes place—follicular hyperplasia. This is probably the most common form of lymphadenopathy in otherwise healthy individuals. However, a careful search of the inciting conditions (dental abscess, skin infection, etc.) must be undertaken before reaching a conclusion of reactive lymphadenitis without histologic analysis.

The correct answer is C. The disease is Burkitt lymphoma (the major clue is the "starry sky" pattern described), which occurs as a jaw lesion in epidemic form in Africa (associated with Epstein-Barr virus) and in a sporadic form that usually involves the pelvic or abdominal organs. Burkitt lymphoma is associated with c-myc activation due to a t(8,14) translocation that places the c-myc-containing segment of chromosome 8 near an actively transcribed gene for immunoglobulin heavy chains.

t(9,22) (choice D) and abl-bcr hybrid (choice A) are associated with chronic myeloid leukemia (CML).

t(14, 18) (choice E) and bcl-2 (choice B) are associated with follicular lymphomas, not Burkitt lymphoma.

The correct answer is D. The disease is hairy cell leukemia, which, unlike most forms of leukemia, is characterized by pancytopenia rather than increased numbers of circulating cells. This disease tends to affect older men and the characteristic cells (which are not always obviously “hairy”) are positive for tartrate-resistant acid phosphatase (TRAP).

Associate Birbeck granules (choice A) with Langerhans cell histiocytosis (histiocytosis X).

Associate elevated leukocyte alkaline phosphatase (choice B) with myeloid metaplasia.

Associate Philadelphia chromosome (choice C) with chronic myeloid leukemia (and occasionally with acute lymphocytic leukemia).

Associate production of Bence-Jones proteins (choice E) with multiple myeloma.

The correct answer is C. The erythrocyte sedimentation rate (ESR) is a simple, cheap, but nonspecific test based on the rate at which red cells will settle in blood. A decreased erythrocyte sedimentation rate (cells settle out slower) can be seen in sickle cell anemia (because of the altered cell shape), polycythemia (because there are many cells), and congestive heart failure (the mechanism is not obvious).

Diseases associated with increased antibody formation tend to markedly increase the ESR by causing the erythrocytes to stick to each other better and consequently settle faster. Conditions with elevated ESR include cancer (choice A), infection (choice B), pregnancy (choice D) and connective tissue diseases such as systemic lupus erythematosus (choice E).

The correct answer is A. Autoimmune gastritis is characterized by atrophy and chronic inflammation of mucosa of the fundus and body of the stomach. This form of gastritis is due to an autoimmune response mediated by autoantibodies against intrinsic factor (IF). Most such autoantibodies block binding of vitamin B12 to IF ("blocking" antibodies), thus preventing absorption of vitamin B12. The resultant picture is megaloblastic anemia, with abnormally large (macrocytic) erythrocytes and hypersegmented neutrophils.

Chronic blood loss (choice B) and deficient iron absorption (choice C) cause iron deficiency anemia, with the former being the most common etiology in industrialized countries. Iron deficiency anemia is characterized by small (microcytic) erythrocytes (mean corpuscular volume < 80 μm³).

H. pylori infection (choice D) is an important pathogenetic factor in chronic gastritis affecting the antral mucosa in isolation, or in association with involvement of the body of the stomach. Chronic inflammation with lymphocytic infiltration of the mucosa is found on biopsy, and H. pylori can be demonstrated by appropriate silver staining. H. pylori-associated chronic gastritis is usually asymptomatic or manifests with mild and nonspecific upper abdominal discomfort. There is a strong association between H. pylori infection and peptic ulcer disease. H. pylori is also suspected to play an etiologic role in gastric lymphoma and carcinoma.

Immune-mediated hemolysis (choice E) results in hemolytic anemia, which is characterized by brisk reticulocytosis (increased number of circulating young erythrocytes), unconjugated hyperbilirubinemia, and splenomegaly. Demonstration of antibodies attached to the surface of red blood cells relies on the Coombs antiglobulin test. The temperature-dependence of this test helps to divide antibodies into warm agglutinins and cold agglutinins. Drugs (penicillin, quinidine), infections (Mycoplasma pneumoniae), and lymphoproliferative disorders (lymphomas) are the most frequent underlying conditions associated with immunohemolytic anemias.

The correct answer is A. The French-American-British classification of acute leukemias is in widespread use, and you should become familiar with its structure. This patient has an acute lymphoblastic leukemia (indicated by B cell markers) rather than an acute myelogenous leukemia, so the appropriate letter designation is L rather than M. The lymphoblasts have uniform nuclei and scant cytoplasm, typical of the L1 subtype. Acute lymphoblastic leukemia is more common in childhood than adulthood. The presentation illustrated is typical. At the time of diagnosis, anemia and thrombocytopenia are common. The white cell count may be low, normal, or high and its absolute value should not be used to either include or exclude the diagnosis.

Type L2 (choice B) is characterized by lymphoblasts with more variability in appearance, often irregularity of nuclei, and more cytoplasm than type L1.

Type M1 (choice C) is undifferentiated myeloblastic leukemia and the leukemic cells do not show cytoplasmic granulation.

Type M2 (choice D) is differentiated myeloblastic leukemia and has at least a few cells showing sparse granulation.

Type M3 (choice E) is promyelocytic leukemia and shows cells resembling promyelocytes with often abundant granulation.

The correct answer is B. First, what type of anemia is it? It must be a hemolytic form, since it is associated with unconjugated hyperbilirubinemia (hence the yellow sclerae), resulting from increased destruction of red blood cells. Increased erythrocyte destruction is the cause (not the effect) of splenomegaly. Furthermore, a positive Coombs test implies that hemolysis is mediated by antibodies attached to red blood cells. Thus, the correct choice must be either IgG or IgM. Since the Coombs test is positive at warm temperature (37 C), the antibody is a warm agglutinin. Warm agglutinins are virtually always of IgG type and may be triggered by a variety of disorders, including lymphomas, drugs, and autoimmune diseases such as SLE. IgG-coated red cells are then sequestered by the spleen, where hemolysis occurs, thus explaining splenomegaly. By contrast, cold agglutinins are IgM (choice C) and can be demonstrated by Coombs test at cold temperature (0-4 C). Cold agglutinins are usually triggered by Mycoplasma pneumoniae infection or lymphomas.

Bone marrow aplasia (choice A) is due to failure or suppression of myeloid stem cells, with decreased production of red blood cells, platelets, and leukocytes (pancytopenia). Most commonly, this condition is caused by chemical agents (especially drugs such as chloramphenicol, phenylbutazone, alkylating agents, and antimetabolites) or total body irradiation.

Renal failure (choice D) causes normochromic, normocytic anemia because of decreased synthesis of erythropoietin. Erythropoietin administration is currently the standard treatment for this form of anemia. Although renal failure is a frequent consequence of SLE, there is no evidence that it plays a role in this patient's anemia.

Spleen sequestration (choice E) may cause anemia in case of massive splenomegaly because of an exaggeration of the normal role of the spleen as repository of blood cells.

The correct answer is A. The French-American-British classification of acute leukemias is in widespread use, and you should become familiar with its structure. This patient has an acute lymphoblastic leukemia (indicated by B cell markers) rather than an acute myelogenous leukemia, so the appropriate letter designation is L rather than M. The lymphoblasts have uniform nuclei and scant cytoplasm, typical of the L1 subtype. Acute lymphoblastic leukemia is more common in childhood than adulthood. The presentation illustrated is typical. At the time of diagnosis, anemia and thrombocytopenia are common. The white cell count may be low, normal, or high and its absolute value should not be used to either include or exclude the diagnosis.

Type L2 (choice B) is characterized by lymphoblasts with more variability in appearance, often irregularity of nuclei, and more cytoplasm than type L1.

Type M1 (choice C) is undifferentiated myeloblastic leukemia and the leukemic cells do not show cytoplasmic granulation.

Type M2 (choice D) is differentiated myeloblastic leukemia and has at least a few cells showing sparse granulation.

Type M3 (choice E) is promyelocytic leukemia and shows cells resembling promyelocytes with often abundant granulation.

The correct answer is C. The child is presenting with lead poisoning. In this disorder, there is initially constipation, colicky abdominal pain, headache and irritability. As the blood levels increase, moderate to severe neuropathy can be noted. Once blood levels reach 50 - 70 µg/dL, laboratory examination will often reveal a microcytic anemia with basophilic stippling and elevated free erythrocyte protoporphyrin. Edetate calcium disodium (EDTA) is used parenterally for the chelation of lead.

Allopurinol (choice A) is used primarily for the treatment of hyperuricemic disorders, such as gout. Gout is associated with pain in the distal joints and high uric acid blood levels.

Dimercaprol (BAL, choice B) is most commonly used in the treatment of mercury intoxication, which is associated with the development of severe abdominal pain, vomiting, bloody diarrhea, shock, and potential renal failure. It is also used as an arsenic chelator, and in severe lead poisoning, in conjunction with EDTA.

Naloxone (choice D) is used in the treatment of opioid intoxication. Opioid overdose is associated with respiratory depression, sedation and possible coma, pinpoint pupils, and decreased bowel sounds.

Physostigmine (choice E) is used to treat a variety of conditions caused by the excessive use of agents with anticholinergic properties.

The correct answer is B. Nodular lymphomas of all types are derived from the B-cell line. The translocation t(14, 18), with bcl-2 activation, is associated with these lymphomas.

An abl-bcr hybrid (bcr-c-abl; choice A) and t(9, 22) translocation (choice E) are associated with chronic myeloid leukemia (CML).

c-myc activation (choice C) and t(8, 14) (choice D) are associated with Burkitt's lymphoma.

The correct answer is A. The spleen shows the changes of chronic congestive splenomegaly, typically associated with hepatic cirrhosis. The described small scars are called Gamna-Gandy nodules, and are thought to be the result of organization of old hemorrhages.

Hodgkin's disease (choice B) produces large splenic nodules in which Reed-Sternberg cells can be found surrounded by mature lymphocytes, eosinophils, and neutrophils.

Rheumatoid arthritis (choice C) and many other chronic inflammatory disorders induce reactive hyperplasia of the spleen with formation of many large germinal centers in the splenic follicles.

Sickle cell anemia (choice D) produces many small (often triangularly shaped) infarctions in the spleen.

Trauma (choice E) can cause splenic rupture.

The correct answer is E. Hairy cell leukemia is characterized by pancytopenia and splenomegaly. Lymphadenopathy is unusual. The proliferating cells express the pan B-cell markers (CD19 and CD20), the monocyte marker (CD11c), the interleukin-2 receptor (CD25), and plasma cell-associated antigen-1 (PCA-1). Histologically, the cells display fine, hairlike projections when viewed with phase-contrast microscopy. A "fried-egg" appearance on stained bone marrow biopsy arises because of fixation artifacts that occur as a result of the hairlike projections on many of the cells. Tartrate-resistant acid phosphatase is virtually diagnostic of hairy cell leukemia.

CD4 (choice A) is a cluster designation antigen that is displayed on the surfaces of T cells and maturing thymocytes.

GpIIb/IIIa (choice B) is a platelet membrane receptor for fibrinogen, fibronectin, and von Willebrand's factor.

Myeloperoxidase (choice C) is a marker for late myeloblasts and mature granulocytes. Monocytes also stain to some extent.

Diffuse nonspecific esterase (choice D) staining is used to identify cells in the monocytic lineage. Punctate nonspecific esterase staining is observed in T cells.

The correct answer is B. The Philadelphia chromosome is a hallmark of chronic myeloid leukemia (CML). CML typically presents with markedly increased numbers of circulating neutrophils and metamyelocytes, with lesser numbers of eosinophils and basophils and a small number of blasts. The disease follows an indolent course, and usually progresses to an accelerated phase with increased numbers of circulating blasts only after several years.

An increased lymphocyte count (choice A) would be seen in chronic lymphocytic leukemia (CLL), another indolent leukemia.

Increased numbers of blasts (choices C and D) are seen in the late stages of CML and CLL, or in the acute leukemias. The Philadelphia chromosome is occasionally associated with acute lymphoblastic leukemia and acute myeloblastic leukemia, but these are diseases of children and young adults.

Pancytopenia (choice E) is most typical of the myelodysplastic syndromes (MDS), in which ineffective hematopoiesis of a pluripotent stem cell produces abnormal development of all cell types. No specific chromosomal abnormality is associated with MDS.

The correct answer is B. Aplastic anemia is characterized by pancytopenia. The bone marrow biopsy typically reveals a normal architecture with a decrease in cellularity to levels less than 25% of normal. The corrected reticulocyte count (i.e., reticulocyte count × patient's hematocrit/45) is often 1%. Platelet counts range from 20 to 60 × 10⁹/L, and the absolute neutrophil counts are often less than 0.5 × 10⁹/L. Aplastic anemia may be either hereditary (e.g., Fanconi's anemia) or acquired. Certain pharmacologic agents, such as busulfan and vincristine, often produce severe marrow hypoplasia or aplasia. Chloramphenicol, some anticonvulsant drugs, phenylbutazone, and a variety of other agents may produce aplastic anemia in an idiosyncratic manner. Aplastic anemias have also been linked to exposure to environmental toxins, such as benzene and insecticides, and are often found to be preceded by viral infections from cytomegalovirus, parvovirus, and hepatitis. The fever and sore throat in the patient described in the question are consistent with cytomegalovirus infection.

Anemia of chronic disease (choice A) produces an isolated deficit of red cell production and may resemble iron deficiency.

The myelodysplastic syndromes (e.g., myelodysplasia with myelofibrosis, choice C) are characterized by replacement of the bone marrow with abnormal (dysplastic) stem cells and ineffective hematopoiesis.

Myelophthisic anemia (choice D) is caused by infiltration of the bone marrow by expansile lesions (e.g., metastatic carcinoma) that distort the marrow architecture and generally depress the production of all three types of formed blood elements.

Pure red cell aplasia (choice E) would produce a selective deficit of the erythrocytic lineage, not all three lineages.

The correct answer is B. Disseminated intravascular coagulation can develop during treatment of acute myelogenous leukemias as a consequence of release of granules (in the form of Auer rods) from cells in the promyelocytic line. Anti-neoplastic agents may trigger this release of granules. This phenomenon is most striking in type M3 acute myelogenous leukemia, also known as promyelocytic leukemia. This form has the largest number of Auer rods in the cytoplasm of the leukemic cells. DIC is also occasionally seen (usually with less severe cases) in types M4 and M5. Patients with type M3 acute myelogenous leukemia require very careful management during the administration of chemotherapy, but have a very good long term prognosis if the DIC and hemorrhage are adequately controlled and treated.

M1 (choice A) is acute myelogenous leukemia without maturation, and is not usually associated with DIC.

M5 (choice C) is acute monoblastic leukemia and has some tendency to cause DIC, but less so than M3.

M6 (choice D) is acute erythroleukemia, and is not usually associated with DIC.

M7 (choice E) is acute megakaryoblastic leukemia, and is not usually associated with DIC.

The correct answer is C. Lacunar cells specifically suggest the nodular sclerosing variant of Hodgkin's disease. Broad collagen bands should also be seen in the biopsy. The actual tumor cell in this lesion is the lacunar cell, and classic Reed-Sternberg cells are difficult to find.

In Burkitt's lymphoma (choice A), sheets of small lymphocytes are interspersed with larger histiocytes, producing a "starry sky" pattern.

In mixed cellularity Hodgkin's disease (choice B), classic Reed-Sternberg cells are plentiful.

Lacunar cells would not be seen in a normal lymph node (choice D) or in predominately small cleaved cell lymphoma (choice E), a non-Hodgkin's lymphoma.