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case records of the massachusetts general hospital

Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

Case 39-2008: A 51-Year-Old Woman with Splenomegaly and Anemia

Jeremy S. Abramson, M.D., Manjil Chatterji, M.D., Aliyah Rahemtullah, M.D.

Pr e sen tat ion of C a se

Dr. Jeffrey A. Barnes (HematologyOncology): A 51-year-old woman was admitted to this hospital because of anemia and splenomegaly. The patient was in her usual state of health until approximately 2 months before admission, when fatigue developed, followed by night sweats, left-upper-quadrant fullness, early satiety, edema of the legs, and dyspnea on exertion. Furosemide was prescribed, but symptoms persisted. One month before admission, she was admitted to another hospital. On examination, the spleen extended to the pelvic brim and the legs were edematous. A direct Coombs test was negative for IgG and complement. Other laboratorytest results are shown in Tables 1, 2, and 3. Two units of red cells were transfused. Computed tomography (CT) of the chest, abdomen, and pelvis, performed after the intravenous and oral administration of contrast material, revealed an enlarged spleen (30 cm by 10 cm), ascites, and enlarged lymph nodes at multiple sites, including the left base of the neck, the splenic hilum, and the periaortic region. A test for human immunodeficiency virus was negative. On the fifth hospital day, the partial-thromboplastin time did not correct with mixing with normal plasma in a 1:1 ratio, and it remained prolonged after 2 hours. Three units of fresh-frozen plasma were given, as were 2 additional units of red cells. A bone marrow biopsy was performed, and the patient was discharged from the hospital. Pathological examination of the biopsy specimen of the bone marrow revealed lymphoid aggregates that made up approximately 10% of the marrow cellularity and increased interstitial lymphoid cells. Flow cytometry showed kappa light chain restricted B cells that expressed CD19 but not CD5, CD23, CD10, and CD103. Three weeks before admission, the patient saw a hematologist at the oncology clinic of the other hospital. Laboratory-test results are shown in Tables 1, 2, and 3. Referral to the Cancer Center of this hospital was scheduled, but the day before admission, she was readmitted to the other hospital because of increasing malaise, edema of the legs, a temperature of 38.6C, and night sweats. Laboratory-test results are shown in Tables 1, 2, and 3. Two units of packed red cells were transfused. On the second day, she was transferred to this hospital. Follicular carcinoma of the thyroid had been diagnosed many years earlier and had been treated with thyroidectomy and radioactive iodine. The patient had miFrom the Cancer Center (J.S.A.) and the Departments of Radiology (M.C.) and Pathology (A.R.), Massachusetts General Hospital; and the Departments of Medicine (J.S.A.), Radiology (M.C.), and Pathology (A.R.), Harvard Medical School. N Engl J Med 2008;359:2707-18.
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graine headaches, tremor, depression, and anxiety. She had smoked in the past and did not use alcohol or illicit drugs. Her mother had had systemic lupus erythematosus, coronary artery disease, and stroke and died at the age of 55 years. Her father was in his 80s and had a tremor; he had had a stroke, a myocardial infarction, and a cerebral aneurysm. Her three siblings were healthy. She lived with her husband and child and did not work outside the home. Medications included citalopram, ziprasidone, clonazepam, lamo trigine, furosemide, zolpidem tartrate, levothyroxine, ferrous sulfate supplements, and eletriptan as needed for headaches. She had no allergies to medications. On examination, the patient appeared anxious. The temperature was 38.3C, the blood pressure 110/68 mm Hg, the pulse 105 beats per minute, the respiration rate 18 breaths per minute, and the oxygen saturation 96% while she was breathing ambient air. There was mild scleral icterus. The abdomen was soft, without tenderness or distention. The spleen was firm and nontender and extended below the pelvic brim. There was no peripheral lymphadenopathy. The remainder of the examination was normal. The blood type was A Rh-positive; the antibody screen was negative. Levels of serum glucose, electrolytes, phosphorus, magnesium, and alkaline phosphatase and results of renal-function tests were normal; Coombs direct test and tests for cold agglutinins were negative. Urinalysis showed 1+ bilirubin. An electrocardiogram was normal. Serum protein electrophoresis revealed an IgM kappa paraprotein and a marked decrease in normal immunoglobulin. Tests for hepatitis B virus surface antibody and antigen and hepatitis C virus (HCV) antibody were negative. Levels of vitamin B12 and folate were normal. Results of other laboratory tests are shown in Tables 1, 2, and 3. CT of the chest, abdomen, and pelvis revealed unchanged splenomegaly and lymphadenopathy. Two units of red cells were transfused. Zolpidem and eletriptan were stopped, and the other medications were continued. Folic acid was begun, and vitamin K was given subcutaneously. On the third hospital day, 3 more units of red cells and 4 units of fresh-frozen plasma were transfused; no correction of the partial-thromboplastin time occurred, and a mixing study revealed that the partial-thromboplastin time did not cor-

rect with the addition of normal plasma. Levels of coagulation factors II, V, VII, and X were in the normal range. IgM antibody to hepatitis A virus was positive; total antibody to hepatitis A virus was negative. On the fourth hospital day, a procedure was performed.

DIFFER EN T I A L DI AGNOSIS
Dr. Jeremy S. Abramson: I cared for this patient and am aware of the diagnosis. The key features in her presentation are massive splenomegaly, anemia, paraproteinemia, and coagulopathy. May we review the radiographic studies? Dr. Manjil Chatterji: CT of the abdomen performed after the administration of intravenous and oral contrast material (Fig. 1) revealed massive splenomegaly and scattered, slightly enlarged lymph nodes in the para-aortic and splenic hilar regions. The spleen showed homogeneous contrast enhancement with no evidence of a focal mass or capsular disruption. Dr. Abramson: Although the differential diagnosis for splenomegaly is broad, entities that cause massive splenomegaly descending below the pelvic brim are limited (Table 4). I will first consider the diagnosis on the basis of the clinical and laboratory findings before the bone marrow biopsy, and then I will use the additional information to narrow the diagnostic possibilities.
Benign entities

The only benign blood disorder that causes such massive splenomegaly is thalassemia major, but this patients age and the absence of previous hematologic problems rule out this diagnosis. A few infections can produce this degree of splenomeg aly, including visceral leishmaniasis, hyperreactive malarial splenomegaly, and Mycobacterium avium complex, although these entities are unlikely in view of her lack of travel to areas where these organisms are endemic, absence of immune deficiency, and absence of other signs or symptoms typical for these infections. Gauchers disease1,2 presents commonly with splenomegaly and cytopenias, and although it typically presents in childhood, 20% of patients are more than 30 years of age at diagnosis; thus, it should be considered in adult patients with massive splenomegaly.2 This patient has no known family history of the dis-

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Table 1. Results of Hematologic Laboratory Tests.

Variable 36.046.0 (women) 12.016.0 (women) 450011,000 4070 2244 411 08 03 150,000350,000 80100 26.034.0 0.52.5 None None None 16 Occasional Occasional Moderate Moderate Occasional Moderate Moderate Occasional 3+ 22 24 77 78 209,000 177,000 0 1 1 2 18 9 11 2 1 8 (reference range, 03) 174,000 156,000 89 29.8 34 25 23 48 64 54 4700 4700 4500 6.1 8.9 5.7 7.2 4600 67 24 6 3 0 21.1 29.2 20.3 21.4

Reference Range, Adults*

On 1st Admission to Other Hospital, 1 Mo Earlier At Oncology Clinic, 21 Days Earlier On Admission to This Hospital

On 2nd Admission to Other Hospital, 1 Day Earlier

2nd Hospital Day 20.3 6.8 3800 63 28 7 2 0 154,000 89 29.9 9.2 3+ 1+

Hematocrit (%)

Hemoglobin (g/dl)

White-cell count (per mm3)

Differential count (%)

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils

Band forms

Platelet count (per mm3)

Mean corpuscular volume (m3)

Mean corpuscular hemoglobin (pg/cell)

Reticulocyte count (per 100 red cells)

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Anisocytosis

Polychromasia

Schistocytosis

Leukocyte alkaline phosphatase smear (U)

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* Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.

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Reference Range, Adults 8.510.5 2.36.6 0.01.0 0.00.4 110210 932 730 6.08.3 3.35.0 2.64.1 30160 228428 10200 (women) 6141295 69309 53334 329.0 Faint IgM kappa 7.2 284 167 222 18 2.75 3.0 4.8 5.3 3.2 33 34 40 33 52 33 530 1030 0.2 0.5 1.1 0.7 1.5 2.4 0.7 1540 44 19 5.8 3.3 2.5 7.9 7.8 On 1st Admission to Other Hospital, 1 Mo Earlier At Oncology Clinic, 21 Days Earlier 8.4 On 2nd Admission to Other Hospital, 1 Day Earlier On Admission to This Hospital 2nd Hospital Day 8.2 9.6
The

Table 2. Results of Serum Chemical and Immunologic Tests.*

Variable

Calcium (mg/dl)

Uric acid (mg/dl)

Bilirubin, total (mg/dl)

2.3 0.6 1574 49 18 5.7 3.3 2.4 57 165 900 268 7 270 IgM kappa (0.12 g/dl)

Bilirubin, direct (mg/dl)

Lactate dehydrogenase (U/liter)

Aspartate aminotransferase (U/liter)

Alanine aminotransferase (U/liter)

Total protein (g/dl)

Albumin (g/dl)

Globulin (g/dl)

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Iron (g/dl)

Iron-binding capacity (g/dl)

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Ferritin (ng/ml)

IgG (mg/dl)

IgA (mg/dl)

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IgM (mg/dl)

Immunofixation

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* To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the value for uric acid to micromoles per liter, multiply by 59.48. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. To convert the values for iron to micromoles per liter, multiply by 0.1791. Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.

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Table 3. Results of Coagulation Studies.* Reference Range, Adults 015 015 22.134.0 10.313.2 64.6 14.5 1.5 13.521.5 13.024.0 150400 <5 <500 Negative 50200 75 42 38 60140 70190 16199 >14 >200 >200 <6 535 On 1st Admission to Other Hospital, 1 Mo Earlier At Oncology Clinic, 21 Days Earlier 15 <11 >100 63.0 15.5 1.6 5.2 >150.0 63.9 14.7 1.3 16.1 19.3 499 >20 2101 Positive >42 On 2nd Admission to Other Hospital, On Admission 1 Day Earlier to This Hospital

Variable Anticardiolipin IgA (APL unit) Anticardiolipin IgG (GPL unit) Anticardiolipin IgM (MPL unit) Activated partial-thromboplastin time (sec) Prothrombin time (sec) Prothrombin time (international normalized ratio) Thrombin time (sec) Reptilase time (sec) Fibrinogen (mg/dl) Fibrin-split products (g/ml)
d-Dimer

(ng/ml)

Lupus anticoagulant Factor VIII (%) Factor IX (%) Factor XI (%) Factor XII (%) Ristocetin cofactor (%) Von Willebrand factor antigen (%) Haptoglobin (mg/dl)

* APL denotes IgA phospholipid, GPL IgG phospholipid, and MPL IgM phospholipid. Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients. Testing was performed by both PTT-LA and hexagonal-phase assays. Factors VIII and XII could not be accurately quantified owing to interference from the lupus anticoagulant. A 2-hour mixing study of factor VIII was not indicative of a factor VIII inhibitor. The mean von Willebrand factor levels for the different blood groups are as follows: type O, 75%; type A, 105%; type B, 115%; and type AB, 125%.

ease, is not a member of an ethnic group that has a high prevalence of the disease, does not have hepatomegaly or bone disease, and has profound anemia and systemic symptoms, which are not characteristic of Gauchers disease.
Myeloproliferative Diseases

resulting in characteristic findings on the peripheral-blood smear, including nucleated red cells, teardrop erythrocytes, and white-cell precursors, none of which were reported in this case.
B-Cell Lymphomas

Myeloproliferative diseases are clonal stem-cell disorders characterized clinically by an increase in one or more blood-cell lines. They often result in splenomegaly. Among these diseases, chronic idiopathic myelofibrosis may present with cytopenias and splenomegaly. However, this disorder is characterized by prominent bone marrow fibrosis,

Many lymphomas may involve the spleen and pre sent with splenomegaly. Diffuse large-B-cell lymphoma is the most common lymphoma in adults in the United States, but it does not commonly present with splenomegaly in the absence of prominent nodal or extranodal disease and typically produces mass lesions within the spleen, rather than

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30 cm

Figure 1. Computed Tomography of the Abdomen. Coronal (Panel A) and axial (Panel B) images show splenomegaly (30 cm in greatest length, Panel A) and RETAKE 1st AUTHOR Abramson ICM scattered, slightly enlarged lymph nodes in the paraREG F FIGURE 1a&b aortic and splenic hilar regions (arrows, Panel B). 2nd
CASE EMail

TITLE 4-C Line H/T H/T Follicular and Combo

3rd

Revised

SIZE Enon ARTIST: mst diffuse enlargement. mantle-cell 16p6 FILL lymphoma often present with splenomegaly and AUTHOR, PLEASE NOTE: may have diffuse involvement, but both usually Figure has been redrawn and type has been reset. also check carefully. have prominent,Please generalized lymphadenopathy. None of these entities commonly produce an IgM JOB: 35925 ISSUE: 12-18-08 paraprotein. Chronic lymphocytic leukemia or small lymphocytic lymphoma is a common indolent B-cell neoplasm in patients older than 50 years that frequently involves the spleen as well as peripheral blood and lymph nodes.3 Hypogammaglobuline-

mia and a monoclonal paraprotein may be observed, as in this patient, but her degree of splenomegaly in the absence of a circulating lymphocytosis or peripheral lymphadenopathy would be unusual. Lymphoplasmacytic lymphoma typically infiltrates the bone marrow, lymph nodes, spleen, and other organs and often produces an IgM paraprotein, a syndrome known as Waldenstrms macroglobulinemia.3 The IgM paraprotein is often associated with hyperviscosity and autoimmune phenomena including cytopenias, and it may also directly bind clotting factors, resulting in coagulopathy, a notable feature in this patient. The IgM level in Waldenstrms macroglobulinemia is usually above 3 g per deciliter, and although the diagnostic criteria for this disease do not define a minimum serum level,4 the relatively low serum IgM level in this patient despite the massive tumor bulk in the spleen argues against this diagnosis. Hairy-cell leukemia also typically presents with splenomegaly and pancytopenia,3 characteristically with monocytopenia. The bone marrow is virtually always involved, and circulating malignant cells with circumferential cytoplasmic projections may be identified; these were not seen in this case. This patients massive splenomegaly without prominent lymphadenopathy makes this a compelling possibility, although her lack of pancytopenia and monocytopenia argue against it, as does the paraprotein, which is not characteristic of hairy-cell leukemia. The infiltrate of hairy-cell leukemia is very distinctive on bone marrow specimens obtained by trephine biopsies, and the findings on bone marrow biopsy will help to distinguish this from other entities in the differential diagnosis. Splenic marginal-zone lymphoma, a rare indolent B-cell lymphoma that most commonly involves the spleen and bone marrow, deserves consideration. Patients typically present with splenomegaly (which may be massive), minimal lymphadenopathy, and anemia; circulating villous lymphocytes and IgM paraproteins may be seen, but hyperviscosity is rare.3,5-9 Autoimmune phenomena are common,10 particularly autoimmune hemolytic anemia, but immune thrombocytopenic purpura, IgM anticardiolipin antibodies, and lupus anticoagulants have been reported.10-14 An association with HCV infection is reported in some parts of the world.15 This patients clinical and laboratory findings fit the diagnosis of splenic marginal-zone lymphoma.

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T-Cell Lymphomas

T-cell lymphomas are much less common than B-cell lymphomas, accounting for only 12% of nonHodgkins lymphomas.3 A few are characterized by predominant splenomegaly and should be considered in this case. T-cell prolymphocytic leukemia typically presents with massive splenomegaly; however, patients usually have marked lymphocytosis with highly elevated white-cell counts, unlike our patient. T-cell large granular lymphocytic leukemia presents with splenomegaly,3 without lymphadenopathy, and with modest lymphocytosis that is characterized by large granular lymphocytes and neutropenia. Autoimmune phenomena, including autoimmune hemolytic anemia, occur frequently,16 but splenomegaly is rarely as massive as was found in our patient, and this fact and the absence of neutropenia make this diagnosis unlikely. Hepatosplenic T-cell lymphoma3 presents with hepato splenomegaly and cytopenias, most often thrombo cytopenia and anemia, without peripheral-blood involvement or lymphadenopathy, similar to the findings in our patient. This disease typically affects men in their 20s or 30s, many of whom have immunosuppression after solid-organ trans plan tation17,18; however, older patients and women may be affected. This patients sex, age, lack of hepatomegaly, and preserved platelet count make this diagnosis unlikely.
Anemia

Table 4. Causes of Splenomegaly. Causes of Splenomegaly Red-cell membrane defects Hemoglobinopathies Autoimmune hemolytic anemias Rheumatologic Rheumatoid arthritis Systemic lupus erythematosus Sarcoidosis Infectious Viral Bacterial Mycobacterial Fungal Parasitic Hepatic cirrhosis Venous thromboses (hepatic, portal, splenic) Congestive heart failure Infiltrative Lymphomas Myeloproliferative neoplasms Metastatic cancer Amyloidosis Gauchers disease NiemannPick disease Glycogen storage diseases Hemophagocytic syndrome Langerhans-cell histiocytosis Lymphomas Myeloproliferative neoplasms Gauchers disease Visceral leishmaniasis Hyperreactive malarial splenomegaly syndrome Mycobacterium avium complex Congestive Causes of Massive Splenomegaly Hematologic Thalassemia major

This patient also has anemia and an abnormal partial-thromboplastin time could understanding the causes of these aid in making the diagnosis? The increased reticulocyte count suggests increased red-cell destruction or bleeding, and the combination of an increased lactate dehydrogenase level, undetectable haptoglobin, and an increased indirect bilirubin level is highly specific for a hemolytic anemia.19 Intrinsic red-cell defects are all unlikely in this case. Extrinsic forces that act on red cells can be classified as either immune or nonimmune. This patient does not have clinical evidence of syndromes associated with mechanical hemolysis or the presence of characteristic schistocytes on the peripheral-blood smear. Nonimmune mechanical destruction via splenic sequestration is likely in this patient with massive splenomegaly but by itself would not be expected to produce the progressively increasing transfusion requirement. The

lactate dehydrogenase level seems disproportionately elevated; although lymphomas can themselves produce elevations in the lactate dehydrogenase level, this is unusual in cases of indolent lymphomas. Although this patient has a negative Coombs direct test, 3 to 7% of warm-type autoimmune hemolytic anemias may produce negative tests.20 Routine Coombs tests evaluate binding of IgG and complement to red cells. A negative test may result from the presence of warm-reacting IgA or IgM autoantibodies. This patients IgM paraprotein may be functioning as a warm antibody, causing

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autoimmune hemolytic anemia, along with other nostic procedure was to obtain the bone marrow epiphenomena, including the IgM anticardiolipin slides for review. In addition, because of the masantibody and false positive antihepatitis A IgM. sive and symptomatic splenomegaly, we performed splenectomy, both for therapy and for diagnosis.
Coagulopathy

The differential diagnosis of coagulopathy is guided by the pattern of prolongation of the prothrombin time, partial-thromboplastin time, and thrombin time (Table 1 and Fig. 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). This patients coagulopathy was initially characterized by a prolonged prothrombin time and partial-thromboplastin time with a normal thrombin time. The prothrombin time was corrected after treatment with vitamin K and fresh-frozen plasma, suggesting a mild nutritional deficiency, leaving an isolated prolonged partial-thromboplastin time. Acquired von Willebrand disease as well as acquired inhibitors to factors VIII, IX, and X have been reported in patients with lymphoproliferative diseases,21-26 but this patients partial-thromboplastin time was not corrected in vitro or in vivo by normal plasma, findings that argue against a factor deficiency. A screening von Willebrand panel was normal and testing for factor inhibitors was negative, but a lupus anticoagulant was found, which was the cause of her prolonged partial-thromboplastin time.
Summary and conclusions

Dr . Jer em y S . A br a msons Di agnosis

Splenic marginal-zone lymphoma, with anemia due to Coombs-negative autoimmune hemolytic anemia and splenic sequestration, and prolonged partial-thromboplastin time due to a lupus anticoagulant.

PATHOL O GIC A L DISCUSSION

Dr. Aliyah Rahemtullah: Pathological examination of the specimen from the bone marrow biopsy performed at the other hospital confirmed the presence of nodular aggregates of small B cells, some of which were present within marrow sinuses (Fig. 2A and top inset). This pattern of infiltration excludes a diagnosis of hairy-cell leukemia, which produces a diffuse interstitial, rather than nodular, infiltrate. The presence of sinusoidal infiltration is characteristic of but not specific for splenic marginal-zone lymphoma. The cells did not show prominent plasmacytic differentiation. Examination of a peripheral-blood smear showed occasional mildly enlarged lymphocytes with moderately abundant cytoplasm containing noncircumferential villous cytoplasmic projections (Fig. 2A, bottom inset). Flow cytometry of the peripheral blood confirmed the presence of a B-cell population expressing kappa light chain but lacking markers specific for any particular small-B-cell lymphoma subtype (Fig. 2 of the Supplementary Appendix). The combination of morphologic and immunophenotypic findings is characteristic of splenic marginal-zone lymphoma.27,28 The spleen weighed 2.42 kg. Gross examination showed prominence of the white pulp, without mass lesions (Fig. 2B). Histologic examination showed that the white pulp was replaced by an infiltrate of small, monomorphous cells that had irregular nuclei and moderately abundant pale cytoplasm and resembled those in the bone marrow (Fig. 2C and inset). Small clusters of similarappearing cells were present in the red pulp. A similar infiltrate was present in an accessory spleen and a splenic hilar lymph node. Flow cytometric

In this 51-year-old woman with massive splenomegaly, minimal lymphadenopathy, isolated anemia, and mild IgM paraproteinemia, the diagnosis of splenic marginal zone lymphoma was most likely. The hemolytic anemia and coagulopathy are both characteristic features of this disease and further support the diagnosis. The next steps in confirming the diagnosis were bone marrow aspiration and biopsy, as well as testing of the bone marrow and peripheral blood by means of flow cytometry. A clonal B-cell population was positive for CD19 and negative for CD5, CD10, and CD23, a finding that was consistent with this diagnosis; however, that immunophenotype is not specific for marginal-zone lymphoma and may be seen in lymphoplasmacytic lymphoma, hairy-cell leukemia, or rarely, follicular lymphoma or mantle-cell lymphoma. The characteristics of the infiltrate in the bone marrow specimen obtained by trephine biopsy and in the spleen are useful in distinguishing between these entities. Thus, the first diag-

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Figure 2. Bone Marrow, Peripheral Blood, and Spleen. The bone marrow biopsy specimen (Panel A) contains multiple ill-circumscribed and nonparatrabecular lymphoid aggregates (arrow) and increased interstitial lymphocytes; lymphocytes make up approximately 10% of the marrow RETAKE cellularity. The lymphoid aggregates and interstitial lymphocytes are mainly CD20+1st B cells (Panel A, top inset); AUTHOR Abramson ICM 2nd CD20 stain reveals a linear distribution some of the B cells (arrow), suggesting localization within bone marrow REG F of FIGURE 2a-d 3rd CASE sinusoids. A peripheral-blood smear (Panel A, bottom inset) shows occasional mildly enlarged lymphocytes with TITLE Revised EMail and moderately abundant slightly open chromatin, small nucleoli, pale Line 4-C basophilic cytoplasm with noncircumferenSIZE tial villous cytoplasmic projectionsEnon (arrow). On gross of the cut surface of the spleen (Panel B), there is ARTIST: mstexamination H/T H/T FILL with nodules that range Comboin size from 33p9 a relative prominence of the white pulp, 0.1 to 0.3 cm in diameter. On microscopical examination, the white-pulp nodules are expanded and NOTE: replaced by an infiltrate of monomorphous, small AUTHOR, PLEASE has been redrawn and type has been reset.(Panel C and inset). Clusters of simlymphocytes with irregular nuclei and Figure scant-to-moderately-abundant cytoplasm Please check carefully. ilar cells were also present in the red pulp. Immunohistochemical stains show that the atypical cells are CD20+ B cells (Panel D). They strongly coexpressed IgM heavy chain, but not IgD, with immunoglobulin kappa light chain JOB: 35925 ISSUE: 12-18-08 restriction by in situ hybridization (not shown).

analysis of splenic tissue confirmed the presence of a B-cell population with the same immuno phenotype as seen in the peripheral blood. Immunohistochemical stains revealed CD20+ B cells (Fig. 2D) that strongly expressed IgM heavy chain, with immunoglobulin kappa light chain restriction by in situ hybridization, and lacked IgD. Cyto genetic analysis of splenic tissue revealed a normal female karyotype without deletion of 7q2132 by fluorescence in situ hybridization. The morphologic and immunophenotypic findings are diagnostic of splenic marginal-zone lymphoma.

Splenic marginal-zone lymphoma derives its name from the fact that in many cases, the neoplastic cells expand the marginal zones at the periphery of the white-pulp follicles; however, they also involve the rest of the follicle, and in many cases, such as this one, the marginal-zone accentuation is not seen. Although originally thought to correspond to a post-germinal center, marginalzone B cell, the normal counterpart is really not known. The immunophenotype and genetic features of splenic marginal-zone lymphoma are heterogeneous and may predict prognosis.29-31

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Cases that lack somatic hypermutation in the immunoglobulin variable-region genes, have allelic loss of 7q2132, and express IgD tend to have a more aggressive clinical course than those lacking these features. Mutational analysis of the immunoglobulin heavy-chain variable region is not routinely performed, but in this case, the absence of IgD and the normal cytogenetic features suggest the presence of somatic hypermutation and predict a favorable prognosis. The lupus anticoagulant and anticardiolipin antibody detected in this patient are acquired autoantibodies directed against phospholipidprotein complexes, which are associated with an increased risk of both venous and arterial thrombosis.32 Although it promotes hypercoagulability, the lupus anticoagulant prolongs in vitro clotting times because it binds to phospholipid and interferes with its ability to serve as a cofactor for coagulation.33 For this reason, factors VIII and XII could not be accurately quantified in this patient with the use of standard assays based on partial-thromboplastin time. The apparently low levels of factors IX and XI reported at another laboratory, before the presence of the lupus anticoagulant was known, are probably false underestimates due to interference from the lupus anticoagulant. The autoantibodies found in this patient and others with splenic marginal-zone lymphoma11-14,34 may represent a direct autoimmune effect of the IgM produced by the lymphoma, which in this disease, as in some other lymphomas, frequently has variable regions that are typical of auto antibodies.14,30,31 In other cases, the autoantibodies may result indirectly from stimulation by T-cellindependent antigens that promote clonal expansion of B cells.14,31

DISCUSSION OF M A NAGEMEN T
Dr. Abramson: Although virtually all patients with splenic marginal-zone lymphoma present as this patient did, with stage IV disease, the prognosis is generally favorable with a median overall surviv al of approximately 10 years from diagnosis.7,9,10 Poor prognostic factors include anemia, hypoalbuminemia, and an elevated lactate dehydrogenase level, which have been incorporated into a risk model predicting 5-year overall survival, ranging from 56% in the poorest-risk cohort to 83% in the most-favorable-risk cohort.5 Other adverse prog-

nostic features include lymphocytosis, presence of paraprotein, an elevated 2-microglobulin level, and involvement of nonhematopoietic sites.7,9,10 On the basis of these factors, this patient was in the poorest-risk cohort. Since her disease cannot be cured, our goals were to prolong survival, treat symptoms, and prevent complications. If she were asymptomatic, she could be safely observed without therapy5,35; however, treatment was indicated because of symptomatic splenomegaly, cytopenias, systemic symptoms, and autoimmune complications. Our options included splenectomy, splenic radiation, chemotherapy, and monoclonal-antibody therapy with rituximab.36-38 If she had HCV infection, treatment with interferon and ribavirin would be expected to produce a response.39,40 There are no randomized clinical trials assessing the relative efficacy of different treatments for HCV-negative patients such as this patient. Since systemic chemotherapy with alkylating agents and purine analogues, which is effective in other indolent B-cell lymphomas, has been disappointing in this disease, the most common strategy is splenectomy alone. This may produce sustained re sponses,6,10,35,41 including resolution of cytopenias, B symptoms (fever, unintentional weight loss, and night sweats), and paraproteinemia,10,41 and partial or complete resolution of autoimmune complications such as hemolytic anemia.13 Lowmolecular-weight heparin was given for perioperative prophylaxis against thrombosis and then was discontinued. After splenectomy, this patients hematocrit and hemoglobin returned to normal levels within 6 weeks, but the lactate dehydrogenase level remained high and the haptoglobin low, suggesting the presence of ongoing hemolysis. The partial-thromboplastin time returned to normal, but the level of anticardiolipin IgM remained elevated, and the paraprotein level decreased but did not disappear. A small population of clonal B cells persisted in the peripheral blood, detected by flow cytometry. She was initially followed without further therapy for the lymphoma. Unfortunately, 15 months after splenectomy, fatigue recurred, and the patient was found to be anemic, with recurrent elevation in the level of IgM paraprotein, an elevated level of IgM anticardiolipin antibody, a weakly positive Coombs test for complement but not for IgG (a finding consistent with warm IgM autoantibody activity of her para-

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case records of the massachusetts gener al hospital

protein), and retroperitoneal lymphadenopathy. A deep-vein thrombosis was found, and therapy with low-molecular-weight heparin was begun. CT-guided needle biopsy of a retroperitoneal lymph node was performed because of concern for possible transformation to diffuse large-B-cell lymphoma, which disclosed recurrent marginal-zone lymphoma. We began treatment with rituximab, cyclophosphamide, vincristine, and prednisone; the anemia rapidly resolved, the lymphadenopathy regressed, and the levels of paraprotein and anticardiolipin antibody fell. She is currently in
References
1. Beutler E. Lipid storage diseases. In:

the seventh of eight planned cycles of treatment and is responding with a reduction in lymphadenopathy and a decrease in the paraprotein level.

A nat omic a l Di agnosis

Splenic marginal-zone lymphoma, with an IgM paraprotein, antiphospholipid antibodies (lupus anticoagulant and IgM anticardiolipin antibody), and autoimmune hemolytic anemia.
No potential conflict of interest relevant to this article was reported.

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