✅ DDx: Blood / Marrow / Vasculitis

Question 1

Differential Diagnosis of Thrombocytopenia: Decreased Platelet Production:

_{<strong>Disorders of primary hemostasis,</strong> such as platelet-related bleeding, tend to occur immediately after injury and often affect the mucous membranes or the skin in the form of petechiae. Disorders of secondary hemostasis, such as coagulation-related bleeding, may be delayed in onset and manifested more by deep tissue bruises (ecchymoses) and may produce hemarthroses in patients with congenital factor deficiencies.}

Answer 1

Vitamin B12 or folate deficiency

Bone marrow disorder (eg, acute leukemia, aplastic anemia, myelodysplastic syndrome)

Toxin- or drug-related bone marrow injury

Infection

Accelerated Destruction:

Immune thrombocytopenic purpura (ITP)

Heparin-induced thrombocytopenia

Chronic liver disease

Thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP-HUS)

Disseminated intravascular coagulation

HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets)

Other:

Pseudothrombocytopenia

Gestational thrombocytopenia

Question 2

Bone marrow disorder (eg, acute leukemia, aplastic anemia, myelodysplastic syndrome)

Answer 2

Associated with pancytopenia, abnormal blood smear (eg, nucleated erythrocytes, teardrop cells, immature leukocytes), and abnormal bone marrow examination.

Hx: Mucocutaneous bleeding is suggestive of a disorder of primary hemostasis.

Dx: Low hemoglobin level, leukocyte count, and platelet count (pancytopenia)

Examination of a peripheral blood smear provides an assessment of bone marrow function

Question 3

Immune thrombocytopenic purpura (ITP)

Answer 3

An acquired autoimmune condition in which autoantibodies are directed against platelet surface proteins, leading to platelet destruction.

Hx: Clinical findings may include signs or symptoms of mild to severe bleeding.

Isolated (extreme) thrombocytopenia in the absence of systemic disease, or a causative drug defines the idiopathic form of ITP.

Variants of ITP may be drug induced or part of a broader illness of abnormal immune regulation, such as systemic lupus erythematosus, HIV infection, or lymphoproliferative malignancies.

Dx: Platelets may be large because they typically have recently been released from the bone marrow. Increased megakaryocytes on bone marrow evaluation (marrow evaluation is usually not required for diagnosis in the absence of other features listed for bone marrow disorders). Diagnosis of exclusion

Tx: Therapy may be required for those with platelet counts lower than 30,000 to 40,000/µL or if bleeding is present.

Platelets, corticosteroids, IVIG, rhogam, splenectomy, rituximab.

Question 4

Heparin-induced thrombocytopenia (HIT)

Answer 4

Type 1 HIT is marked by nonimmune-mediated platelet aggregation. It results in mild thrombocytopenia (platelets rarely <100,000/mm3), usually within 2 days of heparin initiation. Type 1 HIT does not require intervention and does not cause ill effects; the thrombocytopenia resolves without cessation of heparin.

Heparin induces a conformational change to a platelet surface protein (platelet factor 4 [PF4]), which exposes a neoantigen.

In patients with type 2 HIT, the immune system responds by forming an IgG autoantibody (HIT antibody) that then coats the surface of platelets and forms complexes (heparin-PF4-HIT antibody), resulting in:

Thrombocytopenia - the reticuloendothelial system (largely the spleen) removes antibody-coated platelets, causing a mild to moderate thrombocytopenia (rarely <20,000/mm3).

Arterial and venous thrombus - HIT antibodies activate platelets, resulting in platelet aggregation and the release of procoagulant factors. The risk of thrombus is as high as 50% in untreated HIT.

Typically, type 2 HIT manifests with a >50% drop in platelets 5-10 days after the initiation of heparin, but it may occur earlier (sometimes <1 day) in patients previously exposed.

Hx: HIT occurs in approximately 5% of patients treated with unfractionated heparin for 5 or more days but develops in only about 1% of patients treated with low-molecular-weight heparin.

Dx: The criteria for diagnosing HIT include: (1) thrombocytopenia (defined as a platelet count <150,000/µL [150 × 109/L] OR a 50% decrease in the platelet count from baseline) in the presence of current heparin administration or its use over the past 3 months; (2) exclusion of other causes of thrombocytopenia; (3) reversal of thrombocytopenia on cessation of heparin.

The most serious complication of HIT is a thrombotic event, triggered by a number of mechanisms including release of procoagulant agents from platelets and endothelial activation. Venous thromboses are most common (about two thirds of events), but arterial thromboses also occur and can be life-threatening.

4T’s for the diagnosis of HIT:

Timing Thrombosis - 5-10 days (+2), >10 days (+1), <5 days (0)

Thrombosis - New, progressive or recurrent, None

Thrombocytopenia - >50%, 30-50%, <30%

alTernative, None, acceptable, Clear

Tx: Lepirudin; Once HIT is detected or even suspected, heparin must be stopped immediately and an alternative rapidly acting anticoagulant begun, even if thrombosis has not occurred.

Agatroban -> coumudin

Question 5

Chronic liver disease

Answer 5

Findings are often variable and most prominent in advanced liver disease with cirrhosis.

Portal hypertension can lead to splenic sequestration of platelets and thrombocytopenia. Liver disease may be associated with target cells. Liver disease may be occult

Question 6

(TTP-HUS): Thrombotic thrombocytopenic purpura–hemolytic uremic syndrome

Answer 6

TTP is a pathologic process characterized by abnormal activation of platelets and endothelial cells, deposition of fibrin in the microvasculature, and peripheral destruction of erythrocytes and platelets.

Shiga-like toxin is destructive against small blood vessels such as those found in the digestive tract and the kidneys; one specific target for the toxin is the vascular endothelium of the glomerulus, causing cell death, breakdown of the endothelium, hemorrhage, and activation of platelets and inflammatory pathways resulting in intravascular thrombosis and hemolysis.

Hx: TTP should be suspected in patients who have:

Hyaline clots

ADAMS-TS 13

Fever

Anemia (MAHA)

Thrombocytopenia

Renal Failure

Neurologic symptoms

Dx: A peripheral blood smear is essential to determine whether the anemia is caused by a microangiopathic hemolytic process, as indicated by the presence of schistocytes on blood smear. Also see elevated serum LDH level and decreased haptoglobin concentration.

HUS is characterized by more severe renal involvement (hematuria, elevated serum creatinine levels, and proteinuria); primarily a disease of children.

TTP by more frequent neurologic symptoms (headache, confusion, sleepiness, coma, seizures, and stroke).

Tx: Plasma exchange should be instituted emergently at diagnosis because 10% of patients die of this disease despite therapy.

Question 7

Disseminated intravascular coagulation (DIC)

Answer 7

DIC results from the widespread activation of coagulation that causes formation of fibrin clots that may lead to a thrombotic disorder. However, in most patients, secondary fibrinolysis dissolves the fibrin clots, and consumption of platelets and coagulation factors causes thrombocytopenia, clotting factor deficiencies, bleeding, and vascular injury.

Hx: Coagulopathy typically occurs in the setting of sepsis, metastatic cancer, or obstetric catastrophe; patients with infections (with gram-negative organisms being the most common), cancer, and obstetrical complications.

Dx: Prolonged coagulation times: Prothrombin time (PT)[11-13s] and activated partial thromboplastin time (PTT)[25-35s], an elevated D-dimer titer, a decreased serum fibrinogen level and platelet count, and the presence of microangiopathic hemolytic anemia.

Erythrocyte consumption causes a microangiopathic hemolytic anemia with characteristic fragmented erythrocytes seen on a peripheral blood smear. (schistocytes).

Tx: Underlying disease, Plt, Cryo, FFP, pRBC

Question 8

HELLP syndrome

Answer 8

Late pregnancy complication of thrombocytopenia associated with microangiopathic hemolytic anemia, and elevated liver enzymes, and hypertension.

(Hemolysis, Elevated Liver enzymes, Low Platelets)

Question 9

Pseudothrombocytopenia

Answer 9

Pseudothrombocytopenia is a laboratory artifact in which platelets drawn into an ethylenediaminetetraacetic acid (EDTA)–anticoagulated test tube clump and fail to be counted accurately by the automated counter, resulting in a spuriously low platelet count.

Dx: Excluded by examination of a peripheral blood smear;

Tx: No therapy is needed

Question 10

Gestational thrombocytopenia

Answer 10

Mild, asymptomatic thrombocytopenia first noted late in pregnancy.

Tx: Resolves following delivery without therapy.

Question 11

Von Willebrand disease

Answer 11

Von Willebrand factor plays a critical role in platelet adhesion to injured vessels. It also functions as a carrier for factor VIII. Disorders of secondary hemostasis can occur due to low factor VIII levels in vWD

Hx: Patients have mild to moderate bleeding evidenced by nosebleeds, heavy menstrual flow, gingival bleeding, easy bruising, and bleeding associated with surgery or trauma.

Dx: The aPTT is dependent on factor VIII activity. Platelet aggregation does not detect abnormal adhesion; vWF level and ristocetin cofactor are abnormal. Ristocetin cofactor is a platelet aggregation study measuring the function of vWF. The structure of vWF can be determined by a vWF multimer assay

Diagnostic testing includes a PFA (although this may be normal in mild cases), vWF antigen level, vWF activity assay, factor VIII level (which may also be normal in mild cases), and a multimer study used to diagnose subtypes of vWD

Tx: Desmopressin releases stored vWF and factor VIII from endothelial cells and is used as first-line therapy for most subtypes of vWD. Intermediate-purity factor VIII concentrates, which contain vWF, can also be given. Cryoprecipitate is rich in vWF but carries the risk of transfusion-transmitted infection.

Question 12

Hemophilia

Answer 12

Disorder of secondary hemostasis

Hx: Hemarthrosis presents with joint pain and swelling after minimal or no trauma, and episodes typically begin during toddlerhood when the child is ambulatory. Hemorrhage into the skeletal muscle (ie, hematoma) after minor trauma is also common.

Dx: Normal prothrombin time (PT) and prolonged activated partial thromboplastin time (aPTT) that fully corrects on mixing with a 1:1 ratio of normal plasma (as opposed to the presence of an inhibitor, such as to factor VIII, which does not correct on a mixing study).

Laboratory findings in hemophilia A and B are indistinguishable.

Tx: Replacement of the deficient factor is the treatment of choice. Desmopressin for Hemophilia A.

Question 13

Ddx: Thrombophilia

_{Risk Factors for Inherited Thrombophilia:}

_{Thrombosis in ages <50 years, especially in the absence of acquired risk factors (idiopathic)}

_{History of recurrent thrombosis, especially if idiopathic}

_{First-degree relative(s) with thrombosis, especially if first VTE occurs at age <50 years}

_{Unusual site of thrombosis (mesenteric, splenic, portal, hepatic, cerebral sinus, upper extremity in the absence of central lines)}

_{Thrombotic event during pregnancy or postpartum}

_{Thrombotic event while taking oral contraceptives}

_{History of recurrent pregnancy loss}

Answer 13

Inherited:

Resistance to activated protein C most commonly due to factor V Leiden

Prothrombin gene mutation 20210A

Antithrombin deficiency

Protein C deficiency

Protein S deficiency

Hyperhomocysteinemia

Elevated factor VIII

Acquired:

Surgery – most commonly orthopedic (hip and knee replacement), cancer surgery

Malignancies – most commonly pancreas, GI, lung, ovaries, acute promyelocytic leukemia

Myeloproliferative disorders – most commonly polycythemia vera and essential thrombocythemia

Paroxysmal nocturnal hemoglobinuria

Trauma

Prolonged immobilization – (eg, air travel >6 hours, bed rest for ≥3 days)

Pregnancy/postpartum

Nephrotic syndrome

Medication related – including oral contraceptives, hormone replacement therapy, tamoxifen/raloxifene, chemotherapy, thalidomide, heparin-induced thrombocytopenia, warfarin-induced necrosis

Presence of a central venous catheter or PICC line

Antiphospholipid syndrome

Acquired states of hyperhomocysteinemia, activated protein C resistance, and antithrombin deficiency

Question 14

Factor V Leiden

Answer 14

The mutation results in protein C being unable to inactivate factor V and VIII, which then leads to unregulated prothrombin activation.

Heterozygosity of this gene increases the lifetime risk of thrombosis 7 fold, whereas homozygosity increases the risk 20 to 80 fold. This mutation is found in approximately 20% of individuals presenting with a VTE.

Dx: This mutation can be detected by gene analysis or by a coagulation assay (the activated protein C resistance assay)[(sensitivity = 98%, specificity = 99%)].

Question 15

Warfarin-induced skin necrosis (protein C deficiency)

Answer 15

Warfarin inhibits production of vitamin K–dependent clotting factors II, VII, IX, and X. It also inhibits production of the natural anticoagulants proteins C and S. This decreases protein C anticoagulant activity to 50% within the first day while levels of procoagulant factors (II, IX, and X) decline more slowly, leading to a transient hypercoagulable state. This increases the risk for venous thromboembolism and skin necrosis, especially in patients with underlying hereditary protein C deficiency.

Hx: Skin lesions typically occur on the extremities, breast, trunk, and penis and marginate over a period of hours. If left untreated, affected areas become edematous, purpuric, and ultimately necrotic.

Tx: Treatment involves immediate cessation of warfarin and administration of protein C concentrate.

Question 16

Protein S deficiency

Answer 16

Inherited as an autosomal dominant trait; it is a cofactor of protein C, so decreased levels of this protein also lead to less protein C activity, resulting in increased fibrin formation. Protein S deficiency is very rare.

Dx: Consider both functional level and antigenic assays

Question 17

Prothrombin gene mutation 20210A

Answer 17

A mutation in the prothrombin gene at position G20210A causes increased levels of prothrombin that leads to excess thrombin formation. This condition occurs in approximately 3% of Caucasians in the United States and confers a 3- to 4-fold risk for VTE.

Dx: Direct PCR gene test (sensitivity = 100%, specificity = 100%)

Question 18

Antithrombin deficiency

Answer 18

Antithrombin deficiency is an autosomal dominant genetic mutation associated with thrombophilia. It should be suspected in a patient whose clot does not respond to heparin therapy, since heparin requires the presence of antithrombin that is deficient in this condition.

Dx: Consider both functional level and antigenic assays

Question 19

Hyperhomocysteinemia

Answer 19

Hyperhomocysteinemia can rarely be inherited through mutations of the MTHFR gene. Levels of homocysteine increase, leading to increased clot formation. Elevated plasma factor VIII coagulant activity (VIII:C) also increases thrombotic risk independently but not as strongly as the top 5 inherited thrombophilias (factor V Leiden, prothrombin gene mutation, and deficiencies of antithrombin, protein C, and protein S). The exact genetic mutation that causes this elevated factor is not yet known.

Dx: Fasting plasma homocysteine level (risk increases when levels >1.35 mg/L (10 μmol/L)

Question 20

[APS] Antiphospholipid syndrome

Answer 20

Antiphospholipid syndrome (APS) is the most common form of acquired thrombophilia resulting from the development of antibodies directed toward plasma proteins that are bound to phospholipids.

APS is characterized by:

Venous thromboembolism or recurrent early miscarriages

Presence of an antiphospholipid antibody such as the lupus anticoagulant (LA), anticardiolipin antibody, or beta 2 glycoprotein 1 antibody

Dx: The LA occurs in 10%-30% of patients with SLE. The exact mechanism by which LA promotes coagulation in vivo is unclear. In vitro, it prolongs the partial thromboplastin time (PTT) as it binds the phospholipids used in most assays. This is a laboratory artifact and does not correlate with bleeding in vivo. The prothrombin time may also be prolonged. The PTT will not correct if mixed in a 1:1 dilution with normal plasma. Prolonged PTT is an indirect indicator for the presence of LA and highly suggestive in the correct clinical setting. Specific tests include the diluted Russell viper venom test and the kaolin clotting time.

Anticardiolipin antibodies are antiphospholipid antibodies that react with proteins associated with cardiolipin (phospholipid), and these antibodies are also responsible for false-positive tests for syphilis (such as the rapid plasma reagin test) that use cardiolipin in their assay.

Dx: ELISA testing for anticardiolipin and anti-β2-glycoprotein-I (IgG and/or IgM) antibodies

Lupus anticoagulants are antiphospholipid antibodies that, when bound to their target proteins, prolong clotting times (such as the prothrombin time and activated partial thromboplastin time); despite this clotting time prolongation, patients with lupus anticoagulants are actually thrombophilic. Because lupus anticoagulants act as inhibitors, these measures do not correct when a mixing study is performed in which the patient’s plasma is combined with plasma that contains all of the normal clotting factors.

Dx: Requires a 3-step procedure including screening tests (eg, diluted Russell viper venom and sensitive aPTT); mixing studies; and confirmatory phospholipid tests

Antiphospholipid autoantibodies APS is an acquired autoimmune disorder associated with venous or arterial thromboembolism, pregnancy loss, thrombocytopenia, kidney impairment, vasculitis, and cardiac valvular abnormalities; Antibodies are directed against the phospholipid β2-microglobulin, which is an inhibitor of coagulation and platelet aggregation.

Dx: Can be detected with enzyme immunoassays or phospholipid-dependent coagulation tests such as the (prolonged) activated partial thromboplastin time (aPTT) and the dilute Russell viper venom time.

Tx: A systematic review reported that the absolute risk of new venous thromboembolic (VTE) disease in patients with antiphospholipid antibodies is low (less than 1% per year). However, this risk may be increased to up to 10% per year in women with antiphospholipid antibodies or APS and recurrent fetal loss and more than 10% per year in patients with antiphospholipid antibodies and previous VTE who have discontinued anticoagulants within 6 months. Current recommendations are to treat these latter high-risk patients with anticoagulants indefinitely.

Question 21

Acquired hyperhomocysteinemia

Answer 21

Acquired hyperhomocysteinemia has been associated with both arterial and venous thrombosis. The increased homocysteine can stem from vitamin B6, vitamin B12, and folate deficiencies. The thrombotic risk is most closely associated with the increased fasting plasma homocysteine level, regardless of etiology, and roughly doubles the risk of venous thrombosis.

Question 22

Malignancies

Answer 22

Cancer increases the risk of VTE by 4- to 20-fold. Cancers express tissue factor on their surface and induce tissue factor expression by endothelial cells and monocytes, contributing to a prothrombotic state. Thrombotic risk varies by cancer type and stage; risk is highest with pancreatic and brain tumors, intermediate with lung cancer and lymphoma, and lower with breast and prostate cancer. Metastatic disease increases thrombotic risk twofold.

Question 23

Differential Diagnosis of MM:

Answer 23

Multiple Myeloma

Monoclonal gammopathy of undetermined significance

Polyclonal hypergammaglobulinemia

Plasma cell leukemia

POEMS syndrome

Primary systemic amyloidosis (AL amyloidosis)

Waldenström macroglobulinemia

Plasmacytoma

Question 24

Monoclonal gammopathy of undetermined significance (MGUS)

Answer 24

MGUS is defined as the presence of a serum monoclonal (M) protein level of less than 3 g/dL, bone marrow plasma cells <10%; asymptomatic, normal hemoglobin, serum calcium, serum creatinine, and bone survey (no evidence of anemia, kidney failure, bone disease, or other myeloma-related end-organ damage).

Dx: The initial evaluation of most patients with an established M protein abnormality includes a complete blood count; serum calcium, albumin, and creatinine measurement; urinalysis; serum protein and urine electrophoresis and immunofixation; quantitative immunoglobulin measurement (IgG, IgM, IgA); serum free light-chain testing; and a skeletal survey.

Tx: May evolve to MM, but no therapy reduces the likelihood of malignant transformation

Question 25

Polyclonal hypergammaglobulinemia

Answer 25

A nonclonal increase in serum immunoglobulins. No increased risk of evolving into MM. Associated with liver disease, connective tissue disease, chronic infections (eg, HIV), lymphoproliferative disorders, and nonhematologic malignancies

Question 26

Plasma cell leukemia

Answer 26

Circulating plasma cells seen on peripheral blood smear. Worse prognosis than typical MM

Question 27

POEMS syndrome

Answer 27

Rare variant of MM consisting of Peripheral neuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell proliferative disorder, Skin changes, sclerotic bone lesions, papilledema, fingernail clubbing, edema, effusions, and, possibly, Castleman disease.a Not all features required for diagnosis; minimum of peripheral neuropathy, plasma cell dyscrasia, and either sclerotic bone lesion or Castleman disease. Better overall prognosis than MM

Question 28

Primary systemic amyloidosis (AL amyloidosis)

Answer 28

A clonal plasma cell proliferative disorder in which fibrils of monoclonal light chains are deposited in the kidney and other tissues (liver, heart, peripheral nervous system),

Hx: Nephrotic syndrome, cardiomyopathy, orthostatic hypotension, cholestatic liver disease, symmetric distal sensorimotor neuropathy, macroglossia, and carpal tunnel syndrome.

Px: Periorbital purpura and macroglossia are characteristic of AL amyloidosis.

Dx: Most patients have small serum M proteins and approximately 5% bone marrow plasma cells; 6% to 15% of patients with AL amyloidosis have coexisting MM

Characteristic findings on tissue biopsy, the presence of a monoclonal plasma cell disorder, and evidence that the amyloid deposits are composed of clonal light chains.

An abdominal fat pad aspirate revealing amorphous eosinophilic material that demonstrates apple-green birefringence when stained with Congo red and viewed under polarized light

Question 29

Waldenström macroglobulinemia

Answer 29

WM is a B-cell malignancy characterized by the excessive production of monoclonal IgM antibody.

IgM is a large immunoglobulin, and high levels can clog the microvasculature, resulting in hyperviscosity syndrome.

Hx: Symptoms typically include vision changes, headaches, vertigo, dizziness, and/or ataxia; rarely, stroke or coma may occur. Other IgM-mediated conditions commonly seen in patients with WM include peripheral neuropathy, cryoglobulinemia, and renal insufficiency.

Px: Physical examination typically shows “sausage-link” (dilated, segmented, tortuous) retinal veins, and laboratory studies usually reveal anemia, a gamma gap (difference between total protein and albumin), and elevated erythrocyte sedimentation rate (ESR).

Dx: Peripheral blood smear may show rouleaux formation (or erythrocyte agglutination) due to elevated serum protein.

Serum protein electrophoresis (SPEP) is an important screening study; patients with WM have a monoclonal spike (M-spike) of IgM. Diagnosis is then confirmed by bone marrow biopsy showing >10% clonal B cells with specific cytogenetic features.

Tx: More responsive to purine nucleoside analogues and anti-CD20 immunotherapy

Question 30

Plasmacytoma

Answer 30

A localized collection of plasmacytes that may occur as a single lytic lesion in bone or extramedullary (upper respiratory tract, especially sinuses, nasopharynx, or larynx) sites. Patients may or may not have M protein in the serum or urine. No increase in bone marrow plasma cells, anemia, hypercalcemia, or renal insufficiency. Treated with local therapy (excision, radiation). Patients have increased risk for developing MM

Question 31

Multiple Myeloma

Answer 31

Plasma cell neoplasm that often presents with constitutional symptoms (weight loss, fatigue) or bone pain.

Dx: MM should be suspected in elderly patients with laboratory findings of hypercalcemia, normocytic anemia, renal insufficiency, and a protein gap (difference between total protein and albumin >4 g/dL). Multiple myeloma is a malignancy of plasma cells.

Hx: Bone pain, pancytopenia, kidney disease, and hypercalcemia.

Dx: Monoclonal IgG, IgA, or light chains.

CBC, Blood smear

• Rouleaux formation, leukopenia and thrombocytopenia.
• May cause acute kidney injury (AKI), anemia, hypercalcemia, and a decreased anion gap.
  
  • The anion gap, normally approximately 12 plus or minus 2 mEq/L (12 ± 2 mmol/L), may be decreased in patients with multiple myeloma because of the presence of an unmeasured cationic light chain that causes an increase in negative ions to maintain electroneutrality, thereby decreasing the calculated gap between measured positive and negative serum ions.

Serum/Urine Protein electrophoresis (SPEP)

Most myelomas produce a monoclonal (M) protein consisting of an intact immunoglobulin composed of a heavy chain (IgG, IgA, or IgD) and a κ or λ light chain, but they may secrete free light chains alone (16% of cases), or rarely no immunoglobulin.

Urine Immunofixation:

Immunofixation confirms the presence of an M protein and determines its type. The absence of an M protein in the serum and the finding of hypogammaglobulinemia suggest that the M protein is a light chain, which is filtered by the glomerulus and is readily found by urine immunofixation but not found in the serum.

Serum Immunofixation:

Bone marrow Biopsy:

Asymptomatic (smoldering) multiple myeloma is characterized by a serum M protein level of 3 g/dL or more, regardless of isotype, or 10% or more of clonal plasma cells on bone marrow examination and the absence of myeloma-related end-organ damage. The risk of asymptomatic multiple myeloma progressing to symptomatic multiple myeloma or AL amyloidosis is 73% at 15 years, with a median time to progression of 4.8 years.

Symptomatic myeloma is diagnosed by the presence of 10% or more clonal plasma cells on bone marrow biopsy, the presence of an M protein, and evidence of myeloma-related end-organ damage.

Tx: Glucocorticoid therapy is the initial treatment in most cases of malignant spinal cord compression as they decrease inflammation and reduce the mass effect of many tumors. Glucocorticoid therapy has the added benefit of directly treating the hypercalcemia and plasma cell myeloma. Glucocorticoid treatment is then followed with more definitive therapy, usually radiation; neurosurgical intervention may be indicated in extreme situations.

Question 32

Ddx: Transfusion Reactions

Answer 32

Acute Hemolytic Transfusion Reaction

Delayed Hemolytic Transfusion Reaction

Transfusion-Associated Circulatory Overload

Transfusion-Related Acute Lung Injury

Febrile Nonhemolytic Transfusion Reaction

Allergic Reactions and Anaphylaxis

Transfusion Graft-Versus-Host Disease

Infectious Complications

Question 33

Acute Hemolytic Transfusion Reaction (AHTR)

Answer 33

The acute hemolytic transfusion reaction (AHTR) is a rapid intravascular hemolysis that is the most feared complication of transfusion. It is almost always caused by ABO incompatibility between donor and recipient and, in most cases, results from a clerical or procedural error such as the mislabeling of a pretransfusion specimen.

Hx: Patients often present with fever, chills, flank pain, and hemoglobinuria within an hour of transfusion. This can progress to renal failure and disseminated intravascular coagulation (DIC).

Tx: When AHTR is suspected, the transfusion must be stopped immediately and a specimen sent to the blood bank to evaluate for incompatibility. Treatment is supportive.

Question 34

Delayed Hemolytic Transfusion Reaction (DHTR)

Answer 34

A delayed hemolytic transfusion reaction (DHTR) occurs 3 to 10 days after erythrocyte transfusion. In contrast to AHTR, the DHTR is a gradual extravascular hemolysis caused by an amnestic minor, non-ABO erythrocyte antibody. Following a transfusion, there is a 1.0% to 1.6% chance of developing these minor non-ABO alloantibodies, and DHTR occurs when the patient is re-exposed to the same antigen with a subsequent transfusion.

Hx: Clinical symptoms include an unexpected drop in hemoglobin, jaundice, and fever, although many patients will be asymptomatic. Life-threatening complications are rare, but patients with sickle cell disease may present with a worsening pain crisis.

Tx: Treatment is supportive.

Dx: A repeat type and screen will identify the presence of a new alloantibody, and subsequent transfusions should be minimized, but not withheld, when indicated. All subsequent transfusions should be tested to ensure they do not have the identified antigen.

Question 35

Transfusion-Associated Circulatory Overload

Answer 35

Transfusion-associated circulatory overload (TACO) is a frequent and serious transfusion complication, which most commonly affects those with limited cardiopulmonary reserve, including the very young and the elderly.

Hx: Presenting symptoms occur during or within 1 to 2 hours of a transfusion and include dyspnea, cough, tachycardia, cyanosis, edema, and chest tightness.

Px: Physical examination will typically reveal signs of fluid overload, and unlike TRALI, there will be an elevated N-terminal pro-B-type natriuretic peptide.

Tx: Treatment consists of supplemental oxygenation and intravenous diuretics. The risk of TACO can be reduced by avoiding overly rapid transfusion rates.

Question 36

Transfusion-Related Acute Lung Injury (TRALI)

Answer 36

Transfusion-related acute lung injury (TRALI) occurs in 1 of 5000 transfusions and is the most common cause of transfusion-related death, with a mortality rate of 5%. Transfusions containing higher concentrations of plasma, such as platelets and whole blood, pose the greatest risk. The pathogenesis of TRALI is not completely understood, but is thought to be due to the “priming” of neutrophils in the lung vasculature (by insults such as surgery, infection, or trauma) that make them vulnerable to activation, which occurs with exposure to an antineutrophil or HLA antibody contained in the transfusion. Upon activation, leukocyte sequestration occurs in the lung, and capillary leak ensues.

Dx: The diagnostic criteria for TRALI includes the acute onset of dyspnea, hypoxia, and bilateral infiltrates on chest radiograph occurring within 6 hours of transfusion with no other cause for acute lung injury. The clinical and radiographic differential diagnosis includes TACO, acute respiratory distress syndrome, and heart failure.

Tx: Unlike patients with acute respiratory distress syndrome, patients with TRALI typically improve within days. As such, treatment of TRALI is primarily supportive and prevention entails exclusion of the implicated donor from future transfusions.

Question 37

Febrile Nonhemolytic Transfusion Reaction

Answer 37

The febrile nonhemolytic transfusion reaction (FNHTR) is the most common transfusion reaction and is benign. It presents with fever and chills 1 to 6 hours after erythrocyte or platelet transfusion. However, it cannot be clinically differentiated from the more severe and life-threatening AHTR. Recipient-derived leukoreactive antibodies and donor-derived cytokines are thought to represent the most common causes. When fever develops, the transfusion should be stopped immediately until AHTR can be excluded and causes of fever unrelated to the transfusion considered. After AHTR has been excluded, the transfusion can continue with close monitoring. Pretransfusion antipyretics such as acetaminophen, or leukoreduction of cellular blood products, may prevent recurrence.

Question 38

Allergic Reactions and Anaphylaxis

Answer 38

Anaphylaxistypically occurs seconds to minutes after transfusion.

Mild allergic reactions consisting of urticaria commonly occur, especially in multiply transfused patients. Most reactions are caused by donor plasma proteins reacting with preexisting IgE antibodies in the recipient and may not recur with subsequent transfusions. After stopping the transfusion, if the urticaria resolves without signs of anaphylaxis, the transfusion can resume. Rarely is urticaria the first sign of a more serious reaction. Pretreatment with antihistamines or washing of cellular blood products to remove plasma proteins is often effective in preventing recurrence.

Severe anaphylactic reactions are rare and typically occur in patients who are IgA deficient and have anti-IgA antibodies. These antibodies react to IgA contained in the transfused blood.

Hx: Patients present with rapid onset of hypotension, gastrointestinal symptoms, angioedema, stridor, and respiratory distress.

Tx: When transfusing IgA-deficient patients, plasma products must be obtained from IgA-deficient donors and all subsequent cellular products should be washed thoroughly to remove plasma proteins.

Tx: Requires prompt and rapid cessation of the transfusion, epinephrine, airway maintenance, and fluid resuscitation.

Question 39

Transfusion Graft-Versus-Host Disease

Answer 39

Transfusion-associated GVHD (T-GVHD) is a rare, but often fatal, transfusion complication. It usually occurs in immunocompromised patients who receive a transfusion product that is contaminated with lymphocytes. Immunocompetent patients are not usually affected because their immune system destroys the lymphocytes in the donor transfusion. Patients at risk for T-GVHD include hematopoietic stem cell or solid organ transplant recipients, recipients of transfusions from first-degree relatives, and patients with immunosuppression associated with hematologic malignancies such as Hodgkin lymphoma.T

he basic pathophysiologic mechanism involved is recognition of host major and minor HLA-antigens by donor T-cells and consequent cell-mediated immune response.

Hx: The target organs for GVHD are the skin (maculopapular rash involving palms, soles, and face that may generalize is typical), intestine (blood-positive diarrhea), and liver (abnormal liver function tests and jaundice).

No treatment has proved effective; therefore, prevention is key. Gamma irradiation of cellular products virtually eliminates the risk for T-GVHD and should be performed before transfusion for all at-risk patients.

Question 40

Infectious Complications

Answer 40

Given improved donor screening and pretransfusion testing, blood is currently safer than ever before. For example, the risk of HIV is less than 1 in 1,900,000 units; hepatitis C is less than 1 in 1,000,000 units; and hepatitis B is less than 1 in 205,000 units. However, infectious risk, including the transmission of West Nile virus, dengue virus, prions causing Creutzfeldt-Jakob disease, Chagas disease, and babesiosis, still remain, and new bloodborne pathogens will continue to emerge.

The risk for bacterial infection is higher than viral infection and can come from donor blood, donor skin, phlebotomists’ skin, and environmental contamination. Because platelets are stored at room temperature, bacterial contamination occurs more commonly with platelet transfusions, with an estimated frequency of 1 in 3000 platelet units. There are other bacteria such as Yersinia enterocolitica that may survive refrigeration of erythrocyte units and can lead to fatal sepsis.

Question 41

Tumor lysis syndrome (TLS)

Answer 41

Can develop in patients with aggressive hematologic malignancies who begin cytotoxic chemotherapy. Large-scale cell death increases vascular concentrations of intracellular products, resulting in potentially life-threatening electrolyte and metabolic abnormalities. The following are often observed:

Hyperuricemia – Nucleic acids are released and metabolized into uric acid.

Hyperkalemia and hyperphosphatemia – Intracellular ions are liberated.

Hypocalcemia – Phosphate binds and precipitates calcium, reducing intravascular levels.

Symptoms of TLS are primarily due to electrolyte abnormalities and include nausea, vomiting, diarrhea, muscle cramps, seizures, and tetany. Cardiac arrhythmias (hyperkalemia, hypocalcemia) and acute kidney injury (renal tubule deposition of uric acid and/or calcium phosphate) are common complications. The use of intravenous fluids to flush the kidneys and uric acid metabolism inhibitors (allopurinol, rasburicase) helps moderate the risk of uric acid-mediated renal damage; however, calcium phosphate-induced renal injury may still occur.

Question 42

Ddx: Hematopoietic Stem cell disorders

Answer 42

Chronic myeloid leukemia (CML)

Acute myeloid leukemia (AML)

Myelodysplastic Syndrome (MDS)

Leukemoid Reaction

Aplastic Anemia

Chronic lymphocytic leukemia (CLL)

Acute lymphoblastic leukemia (ALL)

Chronic lymphocytic leukemia (CLL)

Hodgkin lymphoma (HL)

B-cell NHL:

Follicular lymphoma

Marginal zone lymphoma

Small lymphocytic lymphoma

Mantle cell lymphoma

Diffuse large B-cell lymphoma

Burkitt lymphoma

Infectious Mononucleosis

Question 43

Aplastic Anemia

Answer 43

Aplastic anemia is an acquired deficiency or absence of pluripotent stem cells. It is associated with exposures (eg, drugs, toxins, radiation), viral infections (eg, parvovirus B19, HIV, Epstein-Barr virus), and autoimmune conditions (eg, lupus, eosinophilic fasciitis). Direct damage to and autoimmune targeting of stem cells are 2 potential mechanisms that result in aplasia. Bone marrow fails to produce blood cells, resulting in a hypocellular bone marrow and pancytopenia. Epstein-Barr virus and cytomegalovirus infection, can cause aplastic anemia.

Patients manifest the following sequelae of pancytopenia:

Anemia (eg, severe fatigue, pallor)

Leukopenia (eg, infections such as pneumonia)

Thrombocytopenia (eg, mucocutaneous bleeding)

Dx: The complete blood count and peripheral smear are notable for pancytopenia and inadequate erythropoiesis demonstrated by a low reticulocyte count; however, the cells are all morphologically normal and the anemia is usually normocytic. A definitive diagnosis is made by bone marrow biopsy demonstrating hypocellular marrow with a few normal hematopoietic cells, no myeloid infiltration or fibrosis, and predominantly stroma and adipocytes.

Question 44

Acute lymphoblastic leukemia (ALL)

Answer 44

A disorder of committed progenitor cells characterized by a proliferation of immature lymphoblasts. ALL constitutes less than 20% of acute leukemias in adult patients, with the highest incidence occurring in the seventh decade of life.

Hx: Patients present with lymphocytosis, neutropenia, anemia, and thrombocytopenia, as well as lymphadenopathy and hepatosplenomegaly.

Rapidly increasing blast cells in the blood and bone marrow, bulky lymphadenopathy (especially in the mediastinum), and cytopenia secondary to bone marrow involvement are the usual presenting clinical features.

Question 45

Acute myeloid leukemia (AML)

Answer 45

Malignancy of myeloid progenitor cells characterized by a median age at diagnosis of 67 years.

Hx: While AML most commonly occurs in patients with no antecedent risk factors, its incidence is increased in patients who are Exposed to radiation or benzene or following therapy with chemotherapy, especially alkylating agents.

Clinical manifestations of marrow failure develop over days to months and include fatigue, dyspnea, and easy bleeding. Fever is commonly caused by infection.

Dx: The bone marrow biopsy in patients with AML would show an abundance of myeloid blasts.

Auer rods, which are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts are sometimes seen on the peripheral smear.

Tx: Given the risk for central nervous system involvement in ALL, intrathecal chemoprophylaxis is routinely administered with or without cranial irradiation.

Acute promyelocytic leukemia (APL) is a subtype of AML that occurs in 10% of patients with AML. Dx: Patients with APL may have circulating blasts, but the predominant cell is a large immature granulocyte with multiple granules overlying the cytoplasm and nucleus. Tx: The disorder is exquisitely sensitive to anthracycline cytotoxic therapy. The addition of all-trans-retinoic acid and arsenic trioxide to the therapy has resulted in high cure and salvage rates in patients with APL.

Question 46

Burkitt lymphoma

Answer 46

Dx: On histology, the “starry sky” pattern is classic and all cases have a translocation of the c-myc oncogene. Often associated with tumor lysis at the time of, or even before, treatment.

Tx: Chemoimmunotherapy. Prophylactic intrathecal chemotherapy is given to reduce the likelihood of relapse within the CNS.

Curable.

5-year overall survival rate in adults is 50% to 70%.

Question 47

Chronic lymphocytic leukemia (CLL)

Answer 47

Chronic lymphocytic leukemia (CLL) (sometimes referred to as small lymphocytic lymphoma) is the most common type of leukemia in the United States. It is almost always seen in the elderly (median age at diagnosis is 70).

Hx: Patients are often asymptomatic but can present with extreme fatigue, B symptoms (eg, night sweats, fevers), infection, or weight loss.

Px: Painless lymphadenopathy (cervical, supraclavicular, axillary), hepatosplenomegaly, and anemia or thrombocytopenia.

Dx: Dramatic lymphocytosis (>5000/µL) is the classic hallmark of CLL. Immunophenotyping (🎤flow cytometry) demonstrates clonality of the circulating B-lymphocytes. Immunophenotyping will show a monoclonal proliferation of mature B lymphocytes expressing CD19, CD20, and CD5. Peripheral smear reveals mature lymphocytes with the presence of smudge cells (a pathognomonic characteristic of CLL).

Question 48

Chronic myeloid leukemia (CML)

Answer 48

CML is a clonal hematopoietic progenitor cell disorder characterized by myeloid proliferation. CML consists of a chronic, accelerated, and blast phase.

Hx: Fatigue, night sweats, weight loss, abdominal discomfort, early satiety (splenomegaly), and bleeding.

Dx: In chronic-phase CML, the leukocyte count is high, the hemoglobin level is low or normal, and the platelet count is normal or high.

🧫 Peripheral blood smear in CML reveals dramatic leukocytosis (often >100,000/mm3) with absolute basophilia and a shift toward very early neutrophil precursors (promyelocytes, myelocytes). [Leukocytosis with circulating myeloid precursors in all stages of development.] The peripheral blood smear shows neutrophilia and left-shifted granulopoiesis.

Detection of the (9;22) translocation by routine cytogenetic studies or fluorescence in situ hybridization assay or of the BCR-ABL fusion transcript by reverse transcriptase-polymerase chain reaction is diagnostic of CML

Px: Splenomegaly

Tx: First-line treatment for most CML patients involves tyrosine kinase inhibitors such as imatinib. Although these drugs are not curative, they often can induce long-term remission.

Question 49

Diffuse large B-cell lymphoma

Answer 49

Dx: Aggressive. Most common type of NHL. May occur outside the lymph nodes in up to 40% of patients, including within the CNS, the gastrointestinal tract, genitourinary tract, or bones.

5-year overall survival rate ranges from 30% to 50% for all stages. Early-stage, low-risk patients may have overall survival rates up to 90%.

Tx: Treatment for all patients with large B-cell NHL includes chemotherapy (usually cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab [R-CHOP]) and immunotherapy with rituximab.

Radiation therapy is used after chemoimmunotherapy for patients with localized or bulky disease.

Curable.

Question 50

Follicular lymphoma

Answer 50

Dx: Indolent. Second most common type of NHL. Average age at diagnosis is 60, and 80% have advanced disease at presentation.

Tx:

Observation in asymptomatic patients. When symptoms occur, options include chemotherapy, immunotherapy, or chemoimmunotherapy. Some patients may receive radiation therapy.

Incurable.

Average survival may exceed 8 to 10 years.

Question 51

Hodgkin lymphoma (HL)

Answer 51

Classical HL is a B cell–derived malignancy, and the malignant cell of origin is the Reed-Sternberg cell. The cellular makeup of HL is unique in that the tumor tissue is composed of a minority of the malignant Reed-Sternberg cells are surrounded by many inflammatory cells.

Hx: Weight loss, fever, and night sweats are often referred to as “B” symptoms based on the Ann Arbor classification system for lymphomas that adds the suffix B to a stage if systemic symptoms are present. B symptoms are frequently seen in patients with HL. Cough and dyspnea on exertion are generally caused by an anterior mediastinal mass, a common finding in classical HL.

Cx: The most common secondary solid tumor malignancies are lung (especially in smokers), breast, thyroid, bone, and gastrointestinal (eg, colorectal, esophageal, gastric tumors).

Question 52

Infectious Mononucleosis

Answer 52

Caused by the Epstein-Barr virus and is characterized by fever, pharyngitis, and lymphadenopathy. Most symptoms resolve within 1 month, although fatigue may persist for longer. Lymphadenopathy is usually tender, and the complete blood count is often notable for atypical lymphocytosis.

Question 53

Leukemoid Reaction (LR)

Answer 53

Severe infections can cause LR due to the mobilization of mature and immature leukocytes from the bone marrow.

Dx: Usually defined as a non-leukemic leukocytosis exceeding 50,000/µL and is characterized by an increase in early neutrophil precursors in the peripheral blood.

Leukocyte count is dramatically elevated, with a predominance of late neutrophil precursors (metamyelocytes, bands) rather than early precursors (promyelocytes, myelocytes). This, combined with a high leukocyte alkaline phosphatase (LAP) score, suggests leukemoid reaction (LR).

LR must be differentiated from chronic myelogenous leukemia (CML), a myeloproliferative disorder that also presents with neutrophilia and dramatic leukocytosis.

Unlike LR, CML is characterized by a low LAP score (due to cytochemically abnormal neutrophils) and a peripheral smear that features absolute basophilia and early neutrophil precursor cells.

Given the severity of the infection, it may take >24 hours for clinical improvement with antibiotics.

Question 54

Mantle cell lymphoma

Answer 54

Dx: May be indolent or aggressive. Associated with the cyclin D1 protein overexpression. Most patients have widely advanced disease at presentation.

Tx:

Chemoimmunotherapy.

Incurable.

Average survival is 3 to 5 years.

Question 55

Marginal zone lymphoma

Answer 55

Dx:

Indolent. Derives from the marginal zone of lymph nodes or spleen. Average age is 60. Includes splenic marginal zone lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, and nodal marginal zone lymphoma.

Tx:

Same as for follicular lymphoma.

Question 56

Myelodysplastic Syndrome (MDS)

Answer 56

The myelodysplastic syndromes are progenitor cell clonal disorders characterized by ineffective hematopoiesis and various peripheral cytopenias.

Clonal hematopoietic progenitor cell disorders characterized by ineffective hematopoiesis and a variable rate of transformation to acute myeloid leukemia. The incidence of MDS increases with age.

Many chromosomal abnormalities are associated with myelodysplastic syndromes, including abnormal numbers of chromosomes, translocations, and structural abnormalities.

Hx: Fatigue and easy bleeding.

Patients have signs and symptoms referable to a specific cytopenia (most often, megaloblastic anemia) and bone marrow findings showing a hypercellular marrow with dyserythropoiesis. Many chromosomal abnormalities are associated with myelodysplastic syndromes, including abnormal numbers of chromosomes, translocations, and structural abnormalities.

Dx: Normocytic or macrocytic anemia. Dysplastic changes on the peripheral blood smear may include nucleated erythrocytes and hypolobated, hypogranular neutrophils. Bone marrow findings showing a hypercellular marrow with dyserythropoiesis.

Tx: Patients with myelodysplastic syndrome treated with azacitidine have significantly delayed transformation to leukemia and improved quality of life.

Question 57

Small lymphocytic lymphoma

Answer 57

Dx:

Indolent. Characterized by an excess of small, mature-appearing lymphocytes in the blood, bone marrow, or lymph nodes. When a peripheral blood lymphocytosis is seen, it is also called chronic lymphocytic leukemia (CLL).

Tx:

Same as for follicular lymphoma.

Question 58

Acute Infection

Answer 58

Acute bacterial infections cause a neutrophilic leukocytosis; eosinophils are usually undetectable owing to the stress effect of catecholamines and cortisol.

Question 59

Ddx: Polycythemia

Answer 59

Primary (↓ EPO)

• Polycythemia vera (JAK2 mutation)
• EPO receptor mutations

Secondary (normal/↑ EPO)

• Hypoxemia
  
  • Cardiopulmonary disease
  • Obstructive sleep apnea
  • High altitude
• EPO-producing tumors (renal, hepatic)
• Congenital (high-affinity hemoglobin)
• Following renal transplantation
• Androgen supplementation

Polycythemia is generally classified as follows:

• Primary polycythemia is largely caused by malignant transformation of erythrocyte progenitor cells, which results in unregulated erythrocyte production (eg, polycythemia vera). Erythropoietin (EPO), the hormone that stimulates red blood cell production, will be low or absent because elevated red blood cell mass exerts a negative feedback effect on EPO-producing cells in the renal cortex.
• Secondary polycythemia is typically due to elevated circulating EPO levels. Most cases are caused by conditions associated with chronic hypoxia (eg, cardiopulmonary disease, obstructive sleep apnea), which stimulates EPO secretion, or by EPO-producing tumors (eg, renal cell carcinoma).

Question 60

polycythemia vera (PV)

Answer 60

PV is a neoplastic disorder that originates from pluripotent hematopoietic progenitor cells. The symptoms of PV are the same as those of erythrocytosis from any cause and include confusion, transient ischemic attack–like symptoms, tinnitus, blurred vision, and headache, the last of which occurs in 50% of patients. Symptoms that are more specific for PV and other myeloproliferative disorders include generalized pruritus that often worsens after bathing, erythromelalgia (a burning sensation in the palms and soles possibly caused by platelet activation), and hypermetabolic symptoms such as fever, weight loss, and sweating. On physical examination, patients may have plethora and hepatosplenomegaly. Findings of a hemoglobin level greater than 18.5 g/dL in men or greater than 16.5 g/dL in women invariably indicate an elevated red blood cell mass. Concomitant leukocytosis (often with basophilia) and thrombocytosis (suggesting trilineage myeloproliferation) as well as hepatosplenomegaly further support the diagnosis. In addition, more than 97% of patients with PV have an activating mutation in the signaling protein JAK2 (JAK2 V617F mutation). Serum erythropoietin levels are usually suppressed; measurement of the red blood cell mass, previously a diagnostic study for PV, is no longer done. 🧯Low-dose aspirin has been shown to decrease the risk of thrombosis and should be given to all patients in the absence of contraindications. Phlebotomy results in the highest overall survival rates and should be performed once or twice weekly until a target hematocrit value of less than 45% is achieved, followed by intermittent phlebotomy to maintain the hematocrit value between 40% and 45%.

Question 61

Ddx: Lymphadenopathy

_{Location, size, consistency (eg, soft, rubbery, fluctuant, firm, hard), and mobility of any involved nodes; if multiple nodes are involved, also determine whether the nodes are discrete or matted. Features concerning for malignancy include size <strong>>2 cm</strong>, hard consistency, and fixed and/or matted nodes.}

_{<strong>Supraclavicular lymphadenopathy</strong> is usually a sign of a serious underlying condition, whereas inguinal lymphadenopathy is very common and often benign.}

_{<strong>A single supraclavicular node</strong> suggests metastatic cancer, whereas <strong>generalized lymphadenopathy</strong> suggests a systemic inflammatory or infectious disease, such as syphilis or HIV infection.}

_{<strong>“ALL STAGES”</strong> PNEUMONIC}

Age: >40 y

Location: Supraclavicular, mediastinal, abdominal

Length of time present: >4 wk

Size: >2 cm

Texture: Hard, matted

Associated signs: Nontender (unless massive), fixed

Generalized vs localized: Not helpful predictor but may be useful in identifying cause

Extranodal associations: Splenomegaly, weight loss, arthritis, persistent fever

Setting: Risk factors for malignancy

Answer 61

Cancer

Hypersensitivity

Infection

Connective tissue disease

Atypical lymphoproliferative disorder

Granulomatous disease

Other unusual cause

Question 62

Cancer

Answer 62

Lymphoma, leukemia, metastatic cancer (numerous primary sites)

subacute onset

“B” symptoms (eg, fever, night sweats, weight loss) are sometimes present.

Chest radiographs are obtained when lymphoma, lung cancer, or granulomatous disease is in the differential diagnosis. Computed tomography and magnetic resonance imaging may be useful when assessing for the presence of intrathoracic or intra-abdominal lymphadenopathy.

Question 63

Hypersensitivity

Answer 63

Drug reaction, vaccine reaction, serum sickness

Question 64

Infection

Answer 64

Viral (EBV, CMV, or HIV infection), bacterial (eg, cat scratch fever, staphylococcal or streptococcal infection, syphilis, chlamydia), mycobacterial (eg, tuberculosis, nontuberculous mycobacterial infection), parasitic (toxoplasmosis), fungal (histoplasmosis, coccidioidomycosis), rickettsial (typhus).

Benign immunologic reactions resolve in 2 to 4 weeks

A complete blood count with differential is a useful initial test, as it can provide clues regarding a possible infection (eg, atypical monocytosis in the case of Epstein-Barr virus infection).

Question 65

Connective tissue disease

Answer 65

Systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome

Question 66

Atypical lymphoproliferative disorder

Answer 66

Castleman disease (giant lymph node hyperplasia)

Question 67

Granulomatous disease

Answer 67

Sarcoidosis, silicosis, berylliosis

Question 68

Other unusual cause

Answer 68

Kikuchi disease (histiocytic necrotizing lymphadenitis)

Question 70

Migratory superficial thrombophlebitis (Trousseau syndrome)

Answer 70

Trousseau syndrome is a hypercoagulable disorder that usually presents with unexplained superficial venous thrombosis at unusual sites (eg, arm, chest area). The syndrome is usually diagnosed prior to (sometimes months to years before) or at the same time as an occult visceral malignancy.

Trousseau syndrome is usually associated with cancer involving the pancreas (most common), lung, prostate, stomach, and colon, and acute leukemias. Factors associated with higher risk of pancreatic cancer include increasing age and smoking. The tumor likely releases mucins that react with platelets to form platelet-rich microthrombi.

Patients should be referred for CT scan of the abdomen to evaluate for an occult tumor (eg, pancreatic carcinoma).