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Objectives Lymphoid enhancer binding factor 1 (LEF1) is expressed in most cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and has shown utility in distinguishing CLL/SLL from other small B-cell lymphomas. LEF1 expression has not been systematically studied in CD5-positive marginal zone lymphomas (MZLs), lymphoplasmacytic lymphomas (LPLs), and follicular lymphomas (FLs). We evaluated whether these cases lacked LEF1, helping to distinguish them from CLL/SLL. Methods MZLs, LPLs, and FLs expressing CD5 were retrospectively studied for expression of LEF1 by immunohistochemistry. Results LEF1 was absent in 17 of 18 CD5-positive lymphomas including 13 MZLs (2 nodal, 3 splenic, and 8 mucosa-associated lymphoid tissue lymphomas), 3 LPLs, and 1 of 2 FLs. One grade 3A CD5-positive FL expressed LEF1 in a majority of tumor cells. Conclusions LEF1 is not expressed in most CD5-positive MZLs and LPLs; therefore, it is a reliable marker for distinguishing them from CLL/SLL. LEF1 may be expressed in CD5-positive FLs.

Objectives Lymphoplasmacytic lymphoma (LPL) remains a poorly defined entity, even with the discovery of MYD88L265P mutations and association with Waldenstrom macroglobulinemia (WM). Among bone marrow (BM)-based, low-grade B-cell lymphoma with plasmacytic differentiation (LGBLPD) and immunoglobulin M (IgM) paraproteins, we sought to determine whether MYD88L265P defines a distinct entity and can help refine diagnostic criteria for LPL. Methods BMs diagnosed with LGBLPD or LPL and serum IgM paraprotein were studied (2007-2013). Clinicopathologic features were reviewed and specimens were tested for MYD88L265P. Results In total, 138 (87%) of 159 cases had MYD88L265P, and 158 of 159 were clinically considered WM. MYD88L265P cases had higher disease burden than MYD88WT. Features associated with MYD88L265P include increased mast cells and lymphocyte (not plasma cell)-predominant infiltrate. Hemosiderin, Dutcher bodies, and paratrabecular growth were not associated with MYD88L265P. Conclusions Our data support a clinicopathologic approach to LPL diagnosis and recognition that it may manifest with varying morphologies, phenotypes, and molecular features.

Objectives: The differential diagnosis between bone marrow involvement by lymphoplasmacytic lymphoma (LPL) and marginal zone lymphoma (MZL) is challenging because histology and immunophenotype of both diseases overlap. We revisited the diagnostic pathology features of both diseases in the bone marrow. Methods: We studied a series of bone marrow trephine biopsy specimens from 59 patients with Waldenstrom macroglobulinemia without extramedullary involvement and bone marrow biopsy specimens from 23 patients with well-characterized MZL who also had bone marrow involvement. H&E- and immunoperoxidase-stained sections of bone marrow trephine biopsy specimens as well as flow cytometry and classic cytogenetics performed on aspirations were reviewed. The study was complemented with MYD88 L265P mutation analysis of all samples. Results: The most distinguishing features of LPL with respect to MZL were focal paratrabecular involvement ( P < .001), the presence of lymphoplasmacytoid cells ( P < .001) and Dutcher bodies ( P < .001), increased numbers of mast cells ( P < .001), and the MYD88 L265P mutation ( P < .001). Conclusions: LPL can be reliably distinguished from MZL in the bone marrow by using a combination of pathology characteristics. Our findings stress the diagnostic importance of using the combination of the following parameters for a correct LPL diagnosis: paratrabecular infiltration, the presence of lymphoplasmacytoid cells and cells with Dutcher bodies, and an increased number of mast cells in addition to the presence of MYD88 mutation.

Objectives The importance of distinguishing mature B-cell lymphoproliferative disorders (B-LPDs) is highlighted by the distinct treatments used for and varying prognoses seen in association with these different diseases. Immunophenotyping allows for accurate and efficient differentiation of many B-LPDs. Recently, we showed that CD200 is highly expressed in hairy cell leukemia (HCL) but not in marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), or hairy cell leukemia-variant (HCL-v). Here, we assessed the usefulness of a flow cytometric panel combining CD200 and CD1d with CD25, CD103, and CD11c to distinguish CD10-, CD5- B-LPDs. Methods We analyzed the expression of CD200 and CD1d by flow cytometric analysis in 79 cases of CD10-, CD5- mature B-LPDs. Results Distinct patterns of CD200 and CD1d expression were seen in the examined B-LPDs. HCL showed bright positivity for CD200 along with positive staining for CD1d, whereas HCL-v showed low levels of expression for both markers. LPL demonstrated positive staining for CD200 in combination with dim to negative staining for CD1d. In contrast, MZL was commonly positive for CD1d and negative for CD200. Conclusions Flow cytometric analysis of CD200 and CD1d, along with CD25, CD103, and CD11c, can aid in the diagnosis of CD10-, CD5- mature B-LPDs.

Introduction Plasma cell neoplasm (PCN) is rarely associated with Waldenstrom macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL), and its clonal relationship to WM/LPL is unclear. Methods We retrospectively analyzed five cases of PCN concomitant with WM/LPL for clinicopathologic features. Results Of five patients, three were female and two were male with a median age of 75 years at diagnosis of concurrent PCN-WM/LPL. Three cases presented with serum paraprotein of IgM type and had a diagnosis of WM/LPL before identifying concurrent PCN, with an interval of 1 to 10 years. In the remaining two cases, PCN and WM/LPL were concurrently diagnosed. All patients demonstrated biclonal M-spikes with distinct heavy chain isotypes but concordant light chain isotype (kappa or lambda) by immunofixation electrophoresis. In all four cases, two neoplastic populations were highlighted with immunohistochemistry, including expression of CD56/cyclin D1 (1), cyclin D1 (2), and IgA (1) in neoplastic plasma cells and negativity of CD56/cyclin D1 in LPL. Of three patients with clinical information available, two were treated with chemotherapy, and the other was treated with autologous stem cell transplant. At follow-up, one patient died of PCN progression at 24 months, one had recurrent WM/LPL at 144 months, and the other was alive with disease 5 months after the diagnosis of concurrent neoplasms. Conclusion Discordant heavy chain isotype restrictions between PCN and WM/LPL suggest biclonal B-cell neoplasms, which is supported by PCN’s phenotypic distinction, such as expression of cyclin D1 and/or CD56, from coexisting WM/LPL. However, our cases had WM/LPL either preceding or concurring with PCN, and all exhibited concordant light chain restrictions, raising a possibility that PCN may be evolved from WM/LPL with class switching. This issue of clonal relationship between the two B-cell neoplasm and underlying pathogenesis remains to be investigated with sequencing analysis on sorted PCN or WM/LPL and comparison of mutation profiles between them.

Objectives: To delineate the pathology of immunoglobulin M–producing multiple myeloma (IgM MM). Methods: Clinicopathologic data were reviewed for 15 cases meeting World Health Organization criteria for MM and having a serum IgM paraprotein. Immunohistochemistry was performed on diagnostic bone marrow specimens for common B-cell and plasma cell markers. Results: Of the 15 IgM MM bone marrows reviewed, 6 (40%) had lymphoplasmacytoid cytology, and 12 (80%) expressed CD19, CD20, and/or CD45. Cyclin D1 expression was common (11 cases, 73%) and usually associated with t(11;14). No cases expressed CD5 or had an associated CD5-positive B-cell population. CD117 was positive in 20% of cases. Conclusions: The frequent B-cell–associated antigen expression by IgM MM distinguishes it from other MM types, causing significant pathologic overlap with lymphoplasmacytic lymphoma (LPL). However, IgM MM is usually distinguished from LPL by aberrant cyclin D1 expression or t(11;14). Therefore, assessing for these abnormalities is recommended when evaluating bone marrow involvement by IgM-associated lymphoplasmacytoid disorders.

Objectives: To examine the usefulness of the MYD88 L265P somatic mutation in identifying cases of lymphoplasmacytic lymphoma (LPL) from other lymphoplasmacytic neoplasms in bone marrow biopsy specimens. Methods: We studied 64 bone marrow biopsy specimens with involvement by various small B-cell lymphomas or plasma cell myeloma. Results: The MYD88 L265P somatic mutation was present in 13/13 cases of LPL, 1/13 cases of hairy cell leukemia, and absent in the other mature B-cell neoplasms tested. A test set of diagnostically challenging bone marrow cases with lymphoplasmacytoid morphology (B-cell lymphoma, not otherwise specified) was selected for additional review and reclassified, without knowledge of the MYD88 L265P status. Of those 16 cases, 7 were positive for MYD88, including 4/4 cases that were reclassified as LPL during the review. Conclusions: Although not entirely specific, MYD88 L265P is a useful adjunct for bone marrow diagnosis in separating LPL from other small B-cell lymphomas and plasma cell myeloma.

The majority of plasma cell myelomas (PCMs) are positive for CD200, a membrane protein with immunosuppressive function. There are no flow cytometry data in the literature on plasma cell CD200 expression in other immunoproliferative disorders. Therefore we used flow cytometry to study the expression of CD200 on plasma cells in diagnostic bone marrow aspirates from 61 patients with monoclonal gammopathy of undetermined significance (MGUS) and 10 patients with lymphoplasmacytic lymphoma (LPL). For comparison, we evaluated CD200 expression in 74 PCM bone marrow biopsies. Thirty-three (54.1%) of 61 MGUS cases and 2 (20.0%) of 10 LPL cases were CD200+. Comparative clinicopathologic parameters for MGUS cases, based on CD200 expression status, showed no differences between the 2 groups. The proportion of CD200+ PCMs (73.0%) in our series was significantly higher than that of CD200+ MGUS (P = .030) and CD200+ LPL (P = .002) cases.

Objectives: Lymphoplasmacytic lymphoma (LPL) with non–immunoglobulin M (IgM) paraproteinemia remains poorly understood. The goal of this study was to investigate the clinicopathologic features of LPL in the bone marrow in patients with immunoglobulin G (IgG) or immunoglobulin A (IgA) paraproteins and evaluate MYD88 L265P mutation status to determine the relationship of these cases to Waldenstrom macroglobulinemia (WM). Methods: Bone marrows from LPL cases with IgG or IgA paraproteins diagnosed between January 1, 2007, and June 30, 2014, were retrieved from the clinical archive. Clinicopathologic features were retrospectively reviewed. MYD88 L265P mutation status was assessed by allele-specific polymerase chain reaction prospectively on all cases. Results: Of 27 cases, four were reclassified as multiple myeloma, all MYD88 mutation negative. MYD88 L265P mutations were present in 10 (43%) of 23 remaining cases. No association between MYD88 status and bone marrow morphologic or phenotypic features, including the presence of Dutcher bodies, mast cells, expression of CD19 by plasma cells, or hemosiderin, was identified, although these features were present in a subset of cases, similar to WM. Clinical features of WM such as hyperviscosity were uncommon in this group and did not correlate with MYD88 status. Conclusions: Non-IgM LPLs are a clinically and pathologically heterogeneous group and often harbor MYD88 L265P mutation, albeit at a lower rate than classic WM. MYD88 status does not correlate with any specific pathologic or clinical manifestations.

Small B-cell lymphomas with plasmacytic differentiation frequently present diagnostic challenges. Session 3 of the 2009 Society for Hematopathology/European Association for Haematopathology Workshop focused on lymphoplasmacytic lymphoma (LPL). The submitted cases illustrated classic examples of bone marrow-based and nodal LPL and cases with atypical features, including unusual phenotypes or involvement of extranodal sites. Several cases showed varying degrees of overlap with marginal zone lymphoma, and, as acknowledged in the 2008 World Health Organization classification, a definitive distinction between these 2 possibilities cannot always be established. Session 6 of the workshop focused on other non-marginal zone lymphomas that may display plasmacytic differentiation. This session highlights the wide variety of neoplasms that enter into the differential diagnosis of small B-cell lymphomas with plasmacytic differentiation and demonstrates the use of clinical features and ancillary studies in establishing an appropriate diagnosis by 2008 World Health Organization criteria.

Waldenström macroglobulinemia (WM) is currently defined as lymphoplasmacytic lymphoma involving bone marrow (BM) associated with a serum IgM paraprotein. WM is typically composed of small lymphocytes, plasmacytoid lymphocytes, and plasma cells in variable proportions, which can change after therapy. In this study, we assessed 41 WM cases that required chemotherapy, 39 showing persistent disease in restaging BM specimens. In 10 cases, there was persistent monotypic plasmacytosis in BM in the absence of demonstrable monotypic B cells. The monotypic plasma cells represented 0.5% to 46% of the cellularity and persisted 1 to 50 months after the last course of chemotherapy. The plasma cells were best quantified by immunohistochemical analysis on paraffin sections. We conclude that WM can persist as a pure plasma cell population after therapy. This finding has implications for the immunophenotypic assessment of WM after therapy and may explain persistent IgM paraproteinemia in patients with WM with no evidence of a clonal B-lymphocyte population.

T-cell antigen expression can be observed in B-cell non-Hodgkin lymphoma (B-NHL). Although CD5 is expressed in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma, the presence of other T-cell antigens is less common. This article reports a retrospective multicenter analysis in which flow cytometry was used to evaluate aberrant CD8 expression on the pathologic B cells of 951 bone marrow samples from patients with various types of B-NHL. In a total of 18 patients, CD8 was coexpressed: 10 had B-CLL; 1, small lymphocytic lymphoma (SLL); 1, marginal zone lymphoma; 1, lymphoplasmacytic lymphoma; 2, diffuse large B-cell lymphoma; and 3, follicular lymphoma. There was a 1.89% overall frequency of CD8 coexpression in which B-CLL/SLL had a higher frequency (3.03%) than did the other B-cell neoplasms (1.18%). Most cases were characterized by a favorable outcome.

Amyloid-like pulmonary nodules have been described in patients with systemic light-chain deposition disease, but their significance in other clinical contexts is unknown. We examined biopsy specimens of amyloid-like pulmonary nodules from 3 women without systemic light-chain deposition disease. Patient 1 (aged 62 years) had multiple pulmonary nodules and underwent 2 separate lung biopsies, the first showing nodules composed of κ light-chain deposits accompanied by low-grade lymphoplasmacytic lymphoma limited to the lung and the second, obtained after chemotherapy 9 months later, showing only residual nodules without persistent lymphoma. Patients 2 (aged 65 years) and 3 (aged 69 years) had asymptomatic solitary pulmonary nodules. In all cases, electron microscopic examination showed dense granular extracellular deposits without the fibrillary characteristics of amyloid. Amyloid-like nodules should be distinguished from nodular amyloidosis and, in some patients, might represent a localized form of light-chain deposition.

We evaluated the immunohistochemical profile and specificity of CD138 reactivity in 238 specimens from hematopoietic and nonhematopoietic neoplasms. In 91 bone marrow biopsies, CD138 reactivity was observed for nonneoplastic plasma cells, neoplastic plasma cells in multiple myeloma cases (43/43), and the plasmacytic component in lymphoplasmacytic lymphoma cases (4/4). Stromal reactivity was noted in 7 multiple myeloma cases. Of 9 bone marrow specimens involved by metastatic carcinoma, tumor cells were CD138+ in 5 cases; stromal reactivity was noted in 7 cases. Studies of 76 nodal and extranodal lymphomas (B-cell, 49; T-cell, 8; Hodgkin lymphoma, 19), 1 Langerhans cell histiocytosis, and 14 nonneoplastic lymph nodes revealed CD138 reactivity only for nonneoplastic plasma cells, the neoplastic cells of 2 large B-cell lymphomas (immunoblastic type, plasmacytoid features), and the clonal plasmacytic component of 3 of 3 extranodal and 1 nodal marginal zone lymphoma. Evaluation of 56 epithelial and nonepithelial tumors revealed CD138 positivity for neoplastic cells of carcinomas of various types (30/33), frequently with associated stromal reactivity, and for neoplasms of mesenchymal, melanocytic, and other tumor types (12/23). Within the hematopoietic system, CD138 is an excellent marker of plasmacytic differentiation. Based on its broad staining profile, CD138 reactivity for neoplastic cells is not a definitive marker for plasmacytic derivation, unless a hematolymphoid origin has been established.

Of 92 patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) treated at our institution, diffuse large B-cell lymphoma (DLBCL) also developed in 12 (13%). In 10 patients, DLBCL developed 12 to 128 months (median, 44 months) after the diagnosis of LPL/WM. Two patients had LPL/WM and DLBCL simultaneously. Clinicopathologic features at diagnosis of LPL/WM did not predict the risk of DLBCL. Onset of DLBCL was characterized by worsening constitutional symptoms, profound cytopenias, extramedullary disease, and organomegaly. Immunoglobulin light chain expression was identical in both LPL/WM and DLBCL. In situ hybridization for Epstein-Barr virus (EBV) in 8 cases of DLBCL was negative. Of 11 patients with clinical follow-up information available, 8 (73%) died within 10 months of diagnosis of DLBCL. DLBCL, most likely as a result of histologic transformation, occurs in a subset of patients with LPL/WM and is associated with aggressive clinical course and poor outcome. EBV is unlikely to be involved in transformation.

Expression of the CD5 antigen by neoplastic cells often is considered a diagnostic criterion for B-cell chronic lymphocytic leukemia (B-CLL). However, published series frequently include a number of CD5 - cases. We studied the spectrum of CD5 - B-cell lymphoproliferative disorders presenting with leukemic involvement and reassessed the prevalence of CD5 - B-CLL. We immunophenotyped 192 cases of clonal, small lymphocytic B-cell disorders involving peripheral blood or bone marrow. Of these, 41 CD5 - cases were further analyzed, correlating the immunophenotypic findings with pathologic material and clinical data. Only 3 CD5 - cases were classified as CD5 - B-CLL. These 3 cases had features unusual for B-CLL, including bright surface immunoglobulin expression, bright CD20 expression, and absence of CD23 expression (2 cases) or Richter syndrome (I case). The remainder of the CD5 - cases consisted of hairy cell leukemia, hairy cell variant, prolymphocytic leukemia, follicular center cell lymphoma, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma with marrow fibrosis, and lymphoma, not further classified. Eight cases remained unclassified, but some displayed features of SMZL. CD5 - lymphoproliferative disorders of peripheral blood or bone marrow are unlikely to be CLL and often are classified more appropriately as non-Hodgkin lymphoma in the leukemic phase.

Objectives: To evaluate CD200 expression in B-cell proliferative disorders. Methods: We analyzed 180 recent specimens of B-cell neoplasms for CD200 expression by flow cytometric immunophenotypic analysis, which is better able to assess relative intensity of staining than immunohistochemical staining. Results: We found that hairy cell leukemia exhibits a high level of staining for CD200 in comparison to other B-cell lymphoproliferative disorders, including hairy cell leukemia-variant (HCL-V), marginal zone lymphoma, and lymphoplasmacytic lymphoma. We confirmed this observation by semiquantitative immunohistochemical staining. Conclusions: Assessment of the CD200 expression level is helpful to distinguish HCL from HCL-V and other B-cell lymphoproliferative disorders and in the differential diagnosis of B-cell neoplasms in general.

Waldenstrom macroglobulinemia (WM) is characterized by monoclonal gammopathy, usually IgM, in association with lymphoplasmacytic lymphoma (LPL). Little is known of the expression of nuclear proteins involved in B-cell development in LPL/WM. In this study, the expression patterns of PAX5/BSAP, MUM1/IRF4, and PRDM1/BLIMP1 were analyzed in plasma cells and lymphocytes in 29 cases of newly diagnosed LPL/WM by double immunohistochemical staining with CD138 and CD22. These patterns were compared with the expression profiles seen in normal bone marrow samples, reactive tonsils, and cases of plasma cell myeloma and marginal zone lymphoma. The median percentage of plasma cells coexpressing CD138 and PAX5 was significantly higher in LPL/WM compared with benign tissues (P = .001), marginal zone lymphoma (P = .002), and plasma cell myeloma (P < .0001), whereas the median percentage of plasma cells coexpressing CD138 and MUM1 was lower in LPL/WM than plasma cells in benign tissues (P = .02), marginal zone lymphoma (P = .001), and plasma cell myeloma (P = .0002). These findings show that a subset of plasma cells in LPL/WM demonstrates a nuclear protein expression pattern characteristic of the B-cell developmental program. Thus, the results better define the immunophenotypic profile of the neoplastic cells in LPL/WM.

Detection of the integrin subunit CD103 is a useful diagnostic tool in the diagnosis of hairy cell leukemia (HCL). Currently, flow cytometric analysis (FC) and frozen section immunohistochemistry (IHC) represent the only available methods of detection. This study is the first to describe the successful use of a CD103 antibody to identify HCL and HCL-variant in paraffin sections of formalin- or Bouin solution– fixed specimens (n = 68) using an immunoperoxidase technique. In other B-cell lymphoproliferative disorders that morphologically may resemble HCL, including chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 32), mantle cell lymphoma (n = 23), lymphoplasmacytic lymphoma (n = 27), follicular lymphoma (n = 7), and marginal zone lymphoma (n = 13), lymphoid cells are nonreactive for CD103. In HCL, the CD103 staining pattern is predominantly membranous with delineation of delicate cytoplasmic projections. This CD103 antibody is an extremely valuable addition to the IHC panel for the diagnosis of HCL, especially in cases lacking FC analysis.

Immunophenotyping is indispensable in the differential diagnosis of B-cell chronic lymphoproliferative disorders (B-CLPDs). However, B-CLPDs often show overlapping immunophenotypic profiles and may be diagnostically challenging. CD1d is an HLA class I-like molecule that presents glycolipids to invariant natural killer T cells. Normal mature B cells constitutively express CD1d, but with the exception of some conflicting data, its expression in B-CLPDs is unknown. We demonstrate that in 222 B-CLPD cases, CD1d expression of less than 45% is strongly predictive of CLL (likelihood ratio, 32.3; specificity, 97.4%; sensitivity, 84.1%). In addition, CD1d showed significantly higher staining intensity in splenic marginal zone lymphoma compared with atypical hairy cell leukemia, lymphoplasmacytic lymphoma, and mantle cell lymphoma, thus allowing the discrimination of the former from the latter immunophenotypically overlapping B-CLPDs. It is important to note that in a given patient, CD1d expression on malignant B cells was similar between tissues and remained unaffected by disease stage and treatment status. Our findings strongly argue for the incorporation of CD1d into routine lymphoma panels.

Marginal zone lymphomas of all types (nodal, splenic, and extranodal mucosa-associated lymphoid tissue [MALT]) may show plasmacytic differentiation. Distinguishing marginal zone lymphomas from other small B-cell lymphomas with plasmacytic differentiation, especially lymphoplasmacytic lymphoma, or from plasma cell neoplasms may be challenging. Marginal zone lymphomas with plasmacytic differentiation were discussed in 2 sessions of the 2009 Society for Hematopathology/European Association for Haematopathology Workshop. Session 4 focused on nodal marginal zone lymphomas, including cases exhibiting classic features and cases displaying atypical phenotypes. The difficulties of classification of cases with increased numbers of large cells were also discussed. Session 5 examined nonnodal marginal zone lymphomas and related entities, including splenic marginal zone lymphoma, MALT lymphoma, γ heavy chain disease, and cryoglobulin-associated lymphoproliferative disorders. These cases illustrate the importance of clinical data and, in some cases, phenotypic and cytogenetic findings in appropriately applying the 2008 World Health Organization criteria.

We identified 382 consecutive patients with lymphoid neoplasms associated with serum monoclonal IgM paraprotein and classified each neoplasm according to World Health Organization criteria. Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) was most common, 225 cases (median serum IgM level, 2.2 g/dL; range, 0.2-10.9 g/dL). For 157 cases, classification and median (and range in g/dL) IgM levels were as follows: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 77), 0.9 (0.1-2.1); marginal zone lymphoma (n = 27), 0.5 (0.1-2.4); follicular lymphoma (n = 18), 0.4 (0.1-1.6); mantle cell lymphoma (n = 11), 0.4 (0.2-1.3); diffuse large B-cell lymphoma (DLBCL; n = 7), 0.5 (0.2-1.0); DLBCL associated with low-grade lymphoma (n = 5), 0.9 (0.4-3.0); angioimmunoblastic T-cell lymphoma (n = 4), 0.8 (0.8); and CD5+CD23- low-grade B-cell lymphoma, unclassified (n = 8), 0.5 (0.3-2.9). The results show IgM paraproteinemia was associated most commonly with LPL/WM (58.9%), followed by CLL/SLL (20.2%). Although serum IgM levels greater than 3 g/dL were restricted to patients with LPL/WM, most patients with LPL/WM had paraprotein levels less than 3 g/dL. Thus, serum IgM paraprotein level is not a reliable discriminator in differential diagnosis.

We correlated bone marrow cytogenetic findings with morphologic and immunophenotypic data in 37 patients with lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM). Each LPL/WM case was classified as lymphoplasmacytoid (n = 18), lymphoplasmacytic (n = 10), or polymorphous (n = 9) using the Kiel criteria. Of 12 cases with chromosomal abnormalities, a single numeric abnormality was present in 4 and a complex karyotype in 8. The most common numeric abnormalities were and -8 in 3 cases each; the most common structural abnormality was del(6q) in 6 cases. Cytogenetic abnormalities were significantly less common in the lymphoplasmacytic and lymphoplasmacytoid groups (5/28 [18%]) compared with the polymorphous group (7/9 [78%]). Clinical follow-up was available for 28 patients for a median of 36 months. Six (67%) of 9 patients with aneuploid tumors, including 4 with polymorphous subtype, subsequently had clinical progression or developed high-grade lymphoma. In contrast, 4 (21%) of 19 patients with diploid tumors, including 1 of polymorphous type, developed clinical progression or high-grade lymphoma. We conclude that abnormal cytogenetic findings in LPL/WM correlate with the polymorphous subtype and poor prognosis.

Although the clinical course of lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) is usually indolent, high-grade non-Hodgkin lymphoma may develop in a small subset of patients. We have not found any patients with LPL/WM associated with Hodgkin disease (HD) described in the literature, prompting us to report 2 cases. In case 1, the patient had LPL/WM involving bone marrow diagnosed 1 week before left supraclavicular lymph node biopsy revealed LPL/WM and classical HD. In case 2, the patient had a 15-year history of LPL/WM before classical HD developed involving bone marrow, liver, and lymph node. Both cases were positive for IgM, monotypic immunoglobulin light chain, and B-cell antigens and were CD3–. The neoplastic Hodgkin cells were CD15+, CD20+ (case 1), CD30+, CD3–, and CD45– and were negative for Epstein-Barr virus RNA. Both patients were treated with chemotherapy for HD. In case 1, clinical response was excellent with no histologic evidence of HD in subsequent biopsy specimens. In case 2, HD was progressive at last follow-up, despite therapy. Patients with LPL/WM, similar to patients with other types of low-grade B-cell lymphoma, can develop HD that may respond to chemotherapy. Waldenstrom macroglobulinemia (WM) is a clinicopathologic entity in which patients have bone marrow involvement by low-grade B-cell lymphoma, most commonly lymphoplasmacytic lymphoma (LPL), associated with IgM gammopathy. 1-4 Other anatomic sites also may be involved by LPL/WM, including liver, spleen, lymph node, and peripheral blood. 5,6 Most patients with LPL/WM are elderly, with a median age of 65 years, and have an indolent clinical course. 2,4-6 Clinical complications of LPL/WM are related to the presence of elevated IgM in serum and to tissue infiltration by LPL and include serum hyperviscosity, cryoglobulinemia, bleeding diathesis, amyloidosis, and pancytopenia. 5,6 In a subset of patients with LPL/WM, higher grade nonHodgkin lymphoma may subsequently develop, as reported by others. 7-16 In 1983, Garcia and colleagues 10 collected from the literature 16 well-document ed cases of large cell lymphoma arising in patients with LPL/WM. Occasional cases have been reported subsequently. 11-16 Of these, in 1 large study, 3 of 167 patients with WM developed large cell lymphoma, for an incidence of 1.8%. 16 However, we are not aware of previous reports of patients with both LPL/WM and Hodgkin disease (HD). Thus, we describe 2 patients with LPL/WM in whom classical HD also developed.

Within the group of small lymphocytic proliferations, three clinicopathologic disease entities are generally recognized: small lymphocytic (well-differentiated) non-Hodgkin's lymphoma (SLL), lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia, LPL), and chronic lymphocytic leukemia (CLL) 1 . This classification is based on certain hematologic and serum immunoglobulin findings, as indicated in Table 1. Small lymphocytic disorders are neoplasias of B cells, at several stages of differentiation, and therefore express immunologic features of the B-cell lineage 2,3