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The Spectrum of IgM Monoclonal Gammopathy in 430 Cases

1987; Elsevier BV; Volume: 62; Issue: 8 Linguagem: Inglês

10.1016/s0025-6196(12)65225-2

1942-5546

Robert A. Kyle, John P. Garton,

Viral-associated cancers and disorders

IgM monoclonal gammopathy consists of a broad spectrum of diseases, ranging from apparently benign to malignant conditions. In a long-term follow-up study of 430 patients in whom a monoclonal IgM serum protein had been identified, 242 (56%) had monoclonal gammopathy of undetermined significance, 71 (17%) had Waldenström's macroglobulinemia, 28 (7%) had lymphoma, 21 (5%) had chronic lymphocytic leukemia, 6 (1%) had primary amyloidosis, and 62 (14%) had other malignant lymphoproliferative diseases. More than two-thirds of the patients died, and the most common cause of death was a lymphoid malignant process. Almost a fifth of the patients with an apparently benign monoclonal gammopathy subsequently had a lymphoid malignant lesion (in one patient, more than 20 years after the detection of the serum M protein). The median duration of time from the recognition of the M protein until the development of a malignant lymphoid disease ranged from 4 to 9 years. An increased number of lymphocytes or plasma cells on bone marrow examination was not a reliable indicator of the likelihood of such an outcome. Thus, follow-up of these patients should be conducted indefinitely. IgM monoclonal gammopathy consists of a broad spectrum of diseases, ranging from apparently benign to malignant conditions. In a long-term follow-up study of 430 patients in whom a monoclonal IgM serum protein had been identified, 242 (56%) had monoclonal gammopathy of undetermined significance, 71 (17%) had Waldenström's macroglobulinemia, 28 (7%) had lymphoma, 21 (5%) had chronic lymphocytic leukemia, 6 (1%) had primary amyloidosis, and 62 (14%) had other malignant lymphoproliferative diseases. More than two-thirds of the patients died, and the most common cause of death was a lymphoid malignant process. Almost a fifth of the patients with an apparently benign monoclonal gammopathy subsequently had a lymphoid malignant lesion (in one patient, more than 20 years after the detection of the serum M protein). The median duration of time from the recognition of the M protein until the development of a malignant lymphoid disease ranged from 4 to 9 years. An increased number of lymphocytes or plasma cells on bone marrow examination was not a reliable indicator of the likelihood of such an outcome. Thus, follow-up of these patients should be conducted indefinitely. Monoclonal proteins are found in 1% of patients older than 50 years of age and in 3% of those older than 70 years of age.1Axelsson U Bachmann R Hällén J Frequency of pathological proteins (M-components) in 6,995 sera from an adult population.Acta Med Scand. 1966; 179: 235-247Crossref PubMed Scopus (365) Google Scholar, 2Kyle RA Finkelstein S Elveback LR Kurland LT Incidence of monoclonal proteins in a Minnesota community with a cluster of multiple myeloma.Blood. 1972; 40: 719-724PubMed Google Scholar During 1986, 888 patients with a newly recognized monoclonal gammopathy were examined at our institution. Of these patients, 16% had an IgM monoclonal gammopathy. More than two-thirds of all patients with a monoclonal gammopathy appeared to have a benign condition at the time of diagnosis. Only 10% had multiple myeloma. IgM monoclonal proteins have been recognized in a wide variety of lymphoproliferative diseases.3Hällén J M-components in leukaemia, in lymphosarcoma and in reticulum cell sarcoma.Acta Med Scand [Suppl]. 1966; 462: 71-79Google Scholar, 4Krauss S Sokal JE Paraproteinemia in the lymphomas.Am J Med. 1966; 40: 400-413Abstract Full Text PDF Scopus (44) Google Scholar, 5Azar HA Hill WT Osserman EF Malignant lymphoma and lymphatic leukemia associated with myeloma-type serum proteins.Am J Med. 1957; 23: 239-249Abstract Full Text PDF PubMed Scopus (51) Google Scholar, 6Moore DF Migliore PJ Shullenberger CC Alexanian R Monoclonal macroglobulinemia in malignant lymphoma.Ann Intern Med. 1970; 72: 43-47Crossref PubMed Scopus (59) Google Scholar, 7Migliore PJ Alexanian R Monoclonal gammopathy in human neoplasia.Cancer. 1968; 21: 1127-1131Crossref PubMed Scopus (52) Google Scholar, 8Alexanian R Monoclonal gammopathy in lymphoma.Arch Intern Med. 1975; 135: 62-66Crossref PubMed Scopus (108) Google Scholar, 9Rywlin AM Civantos F Ortega RS Dominguez CJ Bone marrow histology in monoclonal macroglobulinemia.Am J Clin Pathol. 1975; 63: 769-778PubMed Google Scholar, 10Pangalis GA Nathwani BN Rappaport H Malignant lymphoma, well differentiated lymphocytic: its relationship with chronic lymphocytic leukemia and macroglobulinemia of Waldenström.Cancer. 1977; 39: 999-1010Crossref PubMed Scopus (140) Google Scholar, 11Kim H Heller P Rappaport H Monoclonal gammopathies associated with lymphoproliferative disorders: a morphologic study.Am J Clin Pathol. 1973; 59: 282-294Crossref PubMed Scopus (43) Google Scholar, 12Ko HS Pruzanski W M components associated with lymphoma: a review of 62 cases.Am J Med Sci. 1976; 272: 175-183Crossref PubMed Scopus (15) Google Scholar, 13Hobbs JR Paraproteins, benign or malignant?.Br Med J [Clin Res]. 1967; 3: 699-704Crossref PubMed Scopus (99) Google Scholar Nonetheless, only a few series of IgM monoclonal gammopathies have been reported,14Hobbs JR Carter PM Cooke KB Foster M Oon C-J IgM paraproteins.J Clin Pathol. 1974; 1: 54-64Google Scholar, 15Stein RS Ellman L Bloch KJ The clinical correlates of IgM M-components: an analysis of thirty-four patients.Am J Med Sci. 1975; 269: 209-216Crossref PubMed Scopus (18) Google Scholar, 16Tubbs RR Hoffman GC Deodhar SD Hewlett JS IgM monoclonal gammopathy: histopathologic and clinical spectrum.Cleve Clin Q. 1976; 43: 217-235Crossref PubMed Scopus (16) Google Scholar, 17Waldenström JG Benign monoclonal gammapathy [sic].Acta Med Scand. 1984; 216: 435-447Crossref PubMed Scopus (21) Google Scholar and no large series of cases have been analyzed and subjected to long-term follow-up. Consequently, we reviewed our experience with IgM monoclonal gammopathies. We reviewed the records of all patients in whom a monoclonal IgM serum protein had been identified between Jan. 1, 1956, and Dec. 31, 1978, at our medical center. The data were abstracted on sheets suitable for keypunching. The data for multiple visits were recorded on separate sheets, and a longitudinal view was obtained. Searches for keypunching and abstracting errors were conducted by computer. Cases without a definite monoclonal IgM protein were excluded from the study. Follow-up letters were written to all patients and to their physicians if we had not seen or heard from the patients during the previous year. Letters were written to other sources of contact with the patient, such as hospitals or other medical institutions where the patient had been. Death certificates were requested, when appropriate, from the Department of Vital Statistics of the state of residence of the patient. When contacts by letter yielded no information, the patients, their relatives, or their physicians were contacted by telephone. Serum protein electrophoresis was performed with use of Whatman filter paper as a supporting medium before 1972 and cellulose acetate membranes since that time. Immunoelectrophoresis or immunofixation (or both) was performed on all specimens.18Kyle RA Classification and diagnosis of monoclonal gammopathies.in: Rose NR Friedman H Fahey JL Manual of Clinical Laboratory Immunology. Third edition. American Society for Microbiology, Washington, DC1986: 152-167Google Scholar Patients were classified into one of six diagnostic categories: (1) Waldenström's macroglobulinemia (WM)—these patients had an IgM serum spike of 3.0 g/dl or more in the serum protein electrophoretic pattern and an increase in lymphocytes or plasmacytoid lymphocytes in the bone marrow; (2) lymphoma (LY)—on initial examination, these patients had lymphadenopathy or an extranodal lymphoid tumor, and biopsy findings were consistent with a lymphoma; (3) chronic lymphocytic leukemia (CLL)—these patients had more than 9,000 lymphocytes/mm3 in a peripheral blood specimen; (4) primary amyloidosis (AL)—histologic proof of amyloid was found in a biopsy specimen of appropriate tissue; (5) monoclonal gammopathy of undetermined significance (MGUS)—these patients had an IgM protein of less than 3.0 g/dl, no constitutional symptoms, no hepatosplenomegaly or lymphadenopathy, no anemia, and no chemotherapy; and (6) malignant lymphoproliferative disease (LP)—these patients could not be classified in the foregoing categories; they had an IgM protein of less than 3.0 g/dl and usually had bone marrow infiltration with lymphocytes or plasmacytoid lymphocytes and required therapy because of anemia or constitutional symptoms. A monoclonal IgM serum protein was identified in 430 patients. The gammopathies were classified as shown in Table 1. Many of the patients who were categorized as having LP had hepatosplenomegaly or lymphadenopathy, constitutional symptoms, anemia, and an increased number of lymphocytes or plasmacytoid lymphocytes in the bone marrow and would have been classified as having WM except that their M protein was less than 3 g/dl. Patients with Sjögren's syndrome and a lymphoproliferative process (three cases), hairy cell leukemia (two cases), angioimmunoblastic lymphadenopathy (one case), and Sézary syndrome (one case) were included in the LP group.Table 1Classification of IgM Monoclonal Gammopathies Among 430 PatientsPatientsClassificationNo.%Monoclonal gammopathy of undetermined significance (MGUS)24256Waldenström's macroglobulinemia (WM)7117Lymphoma (LY)287Chronic lymphocytic leukemia (CLL)215Primary amyloidosis (AL)61Lymphoproliferative disease (LP)6214 Total430100 Open table in a new tab IgM monoclonal proteins were identified in 75 patients during the first 13 years of the study (1956 through 1968) and in 208 patients during the last 4 years (1975 through 1978). The percentage of patients with MGUS was greater during the last 4 years (66% versus 28%), whereas the number of patients with a neoplastic lymphoproliferative process (WM, LY, CLL, or LP) was greater during the first 13 years (23% versus 9%). The median age of the total group was 65 years, similar to that found in patients with AL or multiple myeloma. Only 2% were younger than 40 years of age. Men were more commonly involved than women (Table 2). Only in the LP group were female patients preponderant.Table 2Age and Sex Distribution of 430 Patients With Various Types of IgM Monoclonal Gammopathies*AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia.MGUSWMLYCLLALLPTotalAge (yr) Median67636563696365 Range37–9330–8923–8242–8161–9334–9423–94No. of patients <40 yr2110037Sex distribution (%) Male65625476504561 Female35384624505539* AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia. Open table in a new tab A family history of a malignant lesion was recorded in 30% of the first-degree relatives. Among the first-degree relatives, multiple myeloma had been diagnosed in three and WM in two. Relatives who were said to have cancer of the bone or bone marrow were excluded from this tally unless definite evidence of multiple myeloma was available, because metastatic carcinoma could not be excluded. A history of leukemia was noted in six first-degree relatives, Hodgkin's disease in three, non-Hodgkin's lymphoma in three, and MGUS in one. Cancer (excluding skin and hematologic malignant lesions) was diagnosed before the identification of the M protein in 42 patients, at the same time in 13, and after the recognition of the M protein in 5. Carcinoma involved the colon or rectum in 12 patients, the breast in 9, the prostate in 7, and the lung in 4. The frequency of hepatosplenomegaly and lymphadenopathy is shown in Table 3. Only four of the patients with MGUS had a liver palpable more than 5 cm below the right costal margin. The hepatomegaly was readily explained by the presence of metastatic carcinoma in two patients, hemochromatosis in one, and alcoholic cirrhosis in one. Nine patients with MGUS had a spleen palpable more than 1 cm below the left costal margin. This finding was due to polycythemia vera in two patients and to agnogenic myeloid metaplasia, chronic granulocytic leukemia, cold agglutinin disease, and carcinoma of the pancreas in one patient each. The cause was not apparent in three patients. Lymphadenopathy (more than 1 cm) attributable to metastatic carcinoma of the prostate occurred in one patient with MGUS. No patient had macroglossia.Table 3Physical Findings Among 430 Patients With Various Types of IgM Monoclonal Gammopathies*AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia.MGUSWMLYCLLALLPTotalPalpable liver (%)11253248332919Palpable spleen (%)6202962173417Lymphadenopathy (%)317436703916* AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia. Open table in a new tab A sensorimotor peripheral neuropathy was found in 20 patients, and 12 of these patients had MGUS. The ingestion of ethanol played a role in the peripheral neuropathy in only one patient. One patient had a facial diplegia in addition to the peripheral neuropathy. A carpal tunnel syndrome was recognized in eight patients, three of whom had AL; three others did not undergo surgical decompression, and in the remaining two, tissue was not obtained for evaluation. The median hemoglobin values and ranges are shown in Table 4. An autoimmune hemolytic anemia was diagnosed in 5 of the 430 patients. An anemia (hemoglobin concentration of less than 11 g/dl) was found in 17 patients with MGUS—due to metastatic carcinoma in 4, gastrointestinal bleeding in 3, myelodysplastic syndrome in 2, and agnogenic myeloid metaplasia, chronic diarrhea, renal insufficiency, rheumatoid arthritis, and polymyalgia rheumatica in 1 each. In three patients, no cause for the anemia was found. Two of these three patients had hemoglobin values of 10.5 and 10.7 g/dl initially that increased to 11.5 and 13.7 g/dl, respectively. No serious disease developed during 6 1/2 and 11 years of follow-up. The third patient had an initial hemoglobin concentration of 7.9 g/dl and an unexplained febrile episode; the hemoglobin value increased to 12.3 g/dl, and no serious disease developed during an 8-year period.Table 4Initial Hematologic Data in 430 Patients With Various Types of IgM Monoclonal Gammopathies*AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia.MGUSWMLYCLLALLPHemoglobin (g/dl) Median13.610.012.710.913.010.9 Range6.7–18.04.8–14.25.1–17.07.8–14.911.0–15.04.7–15.4Leukocytes (103/mm3) Median7.06.06.928.27.86.3 Range2.7–66.00.7–26.51.5–13.08.2–99.95.0–11.81.5–22.7Lymphocytes (103/mm3) Median1.71.71.520.91.51.4 Range0.18–6.20.06–18.80.3–8.81.5–90.9†Four patients with <9,000 lymphocytes/mm3 received chemotherapy before discovery of the M protein.0.55–2.40.3–15.7Platelets (103/mm3) Median274181228155259225 Range79–9685–54338–89418–303115–76126–785Serum M protein (g/dl) Median1.54.31.31.21.42.0 Range0.3–2.93.0–7.90.4–2.40.1–3.10.5–2.10.7–2.9* AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia.† Four patients with <9,000 lymphocytes/mm3 received chemotherapy before discovery of the M protein. Open table in a new tab Six of the eight patients with CLL and a leukocyte count of less than 20,000/mm3 had been treated for the CLL before the identification of the M protein. The two remaining patients had an absolute lymphocyte count of more than 9,000/mm3 and infiltration of the bone marrow with lymphocytes, consistent with the diagnosis of CLL. A leukocyte count in excess of 20,000/mm3 was found in five patients without CLL. The leukocytosis was due to chronic granulocytic leukemia, agnogenic myeloid metaplasia, and Sezary syndrome in one patient each. Another patient had neutrophilia of undetermined cause, and the fifth patient had macroglobulinemia. Neutropenia (less than 2,000 neutrophils/mm3) occurred in five patients with MGUS. Although two of these patients had acute nonlymphocytic leukemia, no apparent cause was found in the others. Neutrophilia (more than 10,000 neutrophils/mm3) was found in five patients with MGUS and was due to chronic granulocytic leukemia, agnogenic myeloid metaplasia, pneumonia, acute asthma, and acute urinary retention in one patient each. Thrombocytopenia (less than 130,000 platelets/mm3) was seen initially in eight patients with MGUS. The causes included myelodysplastic syndrome in two patients and cold agglutinin disease, alcoholism, and carcinoma of the endometrium in one patient each. The cause was not apparent in the remaining three cases. Five patients with MGUS had thrombocytosis (more than 500,000 platelets/mm3). The associated diagnoses included sideroblastic anemia, bronchogenic carcinoma, fever, and carcinoma of the rectum. Hypercalcemia (11 mg/dl or more), which occurred in seven patients, seemed to be related to the lymphoid malignant lesion in five patients and to hyperparathyroidism in one; no apparent cause was identified in the seventh patient. The serum creatinine concentration was more than 2.0 mg/dl in 13 patients. The increase was due to a lymphoproliferative malignant lesion in four patients, chronic renal disease (suspected glomerulonephritis) in two, and vasculitis, polyarteritis nodosa, acute urinary retention, metastatic carcinoma, and hypertension in one each; the cause was unknown in two. These two patients were older than 70 years of age and each had a creatinine level of 2.2 mg/dl. The serum alkaline phosphatase was more than 250 U/liter (normal, 76 to 250 U/liter) in 10 patients. This finding was due to carcinoma of the pancreas in two patients and to carcinoma of the cystic duct, polycythemia vera, alcoholism, metastatic carcinoma, and congestive heart failure in one patient each. The cause was unexplained in three patients. Patients with WM or LP had the lowest median levels of serum cholesterol (139 and 148 mg/dl, respectively) and triglycerides (71 and 74 mg/dl, respectively); the corresponding measurements in patients with MGUS were 210 and 103 mg/dl, respectively. On electrophoresis, 84% of the M proteins migrated with gamma mobility. In all but one of the patients with WM, migration with gamma mobility was noted (Table 5). The sizes of the serum M protein are shown in Table 4. The median size of the M spike was 4.3 g/dl in patients with WM and 2.0 g/dl in those with LP, but the rest of the patients had a median M spike of 1.5 g/dl or less. The M protein disappeared in two patients with MGUS. CLL was diagnosed before the identification of the M protein in 12 patients and concurrently with the recognition of the M protein in the other 9 patients. AL was diagnosed before the recognition of the M protein in two patients and concomitantly in the remaining four patients. Of the 430 patients, 76% had a kappa light chain and the rest had a lambda light chain (Table 6). Eighteen patients (4%) had a biclonal gammopathy (Table 7). One of the components consisted of an IgM protein in all patients, and both components were IgM in six patients. Both components were kappa in 11 patients, and both were lambda in 1; the light chain was mixed in the remaining 6 patients. Two patients had triclonal gammopathies (IgM kappa, IgA kappa, and IgG kappa; IgM kappa, IgM lambda, and IgG kappa). No diagnostic group had an excess of patients with biclonal gammopathies.Table 5Results of Serum Protein Electrophoresis in 430 Patients With Various Types of IgM Monoclonal Gammopathies*AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia.TotalMobilityMGUSWMLYCLLALLPNo.%Alpha (%)0005001 4.0 cP0150002‡M spikes of 3.7 and 5.0 g/dl developed during course of disease. >1.8 cP164632118Viscosity (cP) Median1.72.81.81.92.02.0 Range1.0–2.91.2–14.81.3–2.81.8–2.82.01.2–6.5* Normal = ≤1.8 cP.† AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia.‡ M spikes of 3.7 and 5.0 g/dl developed during course of disease. Open table in a new tab A predominance of globulin spikes of gamma mobility was found in the urine. Three patients had a urinary globulin spike of more than 2 g/24 h. Two of these patients had WM with destructive skeletal lesions, and the third patient had AL and 15% plasma cells in a bone marrow specimen. Five patients had urinary albumin excretion of more than 3 g/24 h. In two of these five patients, a renal biopsy specimen showed membranous glomerulonephritis but no evidence of amyloid; a third patient had a hypernephroma, and the other two patients did not undergo renal biopsy or autopsy evaluation. Consequently, amyloidosis cannot be excluded in these two patients. Eight other patients had mainly albumin and a small globulin peak consisting of more than 2 g of protein in 24 hours. A monoclonal kappa protein was found in five, lambda in two, and no M protein in the eighth patient. Two of these patients had AL, one had vasculitis, and three had no apparent cause. In two patients, the urinary protein level decreased from 5.1 to 0.05 g/24 h and from 2.4 to 0.3 g/24 h without apparent reason. The urinary globulin measurements are shown in Table 10. The median values for urinary albumin were 0.5 g/24 h or less in all diagnostic groups.Table 10Initial Urinary Protein Data in Patients With Various Types of IgM Monoclonal Gammopathies*AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia.MGUSWMLYCLLALLPNo. of patients tested117571010538Urinary globulin spike No. of patients21254317 Measurement (g/24 h) Median0.41.01.21.711.71.0 Range0.1–1.50.2–4.40.6–2.21.3–1.811.70.2–2.0Urinary albumin No. of patients681124217 Measurement (g/24 h) Median0.30.40.40.50.40.3 Range0.1–8.70.1–16.20.1–0.60.2–1.00.3–0.40.1–11.6* AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia. Open table in a new tab Of the total group, 52% had a monoclonal light chain in the urine, and kappa light chains predominated. Of those patients with WM, 80% had a urinary monoclonal light chain (Table 11).Table 11Urinary Light Chain Types in 430 Patients With Various Types of IgM Monoclonal Gammopathies*AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia.Type of light chainMGUSWMLYCLLALLPTotalKappa (%)36566738253842Lambda (%)52403725310None (%)59203325505948* AL = primary amyloidosis; CLL = chronic lymphocytic leukemia; LP = malignant lymphoproliferative disease; LY = lymphoma; MGUS = monoclonal gammopathy of undetermined significance; WM = Waldenström's macroglobulinemia. Open table in a new tab Multiple lytic skeletal lesions were found in six patients. These lesions were attributable to macroglobulinemia in three patients (all had plasma cells but some had lymphoid features) and to an unrelated metastatic carcinoma in the other three (with MGUS). Two of the three patients with macroglobulinemia were given chlorambucil but did not respond. Melphalan was prescribed, and both patients lived for more than 2 years. One patient did not have an objective response, and the data were inadequate to ascertain the response in the other. The third patient was given melphalan and had an excellent response but subsequently became resistant to the agent and died 3 1/2 years after diagnosis. The bone marrow aspirate had an increased number of lymphocytes or plasma cells in 85% of patients with WM. The marrow biopsy was positive in all 11 patients with WM who had a negative aspirate. Two-thirds of the patients with LP had a positive bone marrow aspirate. The bone marrow biopsy was positive in 12 of the 20 patients with LP who had a negative aspirate. A lymph node biopsy or histologic examination of extranodal tissue confirmed the diagnosis in all but one of the rest of the patients with LP. This patient had bilateral pleural effusion and a clinical course consistent with a malignant LP. The bone marrow aspirate was positive in approximately half the patients with lymphom