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Nuclear BCL-10 Expression Is Common in Lymphoplasmacytic Lymphoma/Waldenstro¨ M Macroglobulinemia and Does Not Correlate with P65 NF-Jb Activation

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Nuclear BCL-10 Expression Is Common in Lymphoplasmacytic Lymphoma/Waldenstro¨ M Macroglobulinemia and Does Not Correlate with P65 NF-Jb Activation Modern Pathology (2006) 19, 891–898 & 2006 USCAP, Inc All rights reserved 0893-3952/06 $30.00 www.modernpathology.org Nuclear BCL-10 expression is common in lymphoplasmacytic lymphoma/Waldenstro¨ m macroglobulinemia and does not correlate with p65 NF-jB activation Mihai Merzianu1, Liuyan Jiang2, Pei Lin1, Xuemei Wang3, Donna M Weber4, Saroj Vadhan-Raj5, Martin H Nguyen1, L Jeffrey Medeiros1 and Carlos E Bueso-Ramos1 1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Lymphoma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and 5Department of Cytokine and Supportive Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA B-cell lymphoma 10 (BCL-10) is expressed in the cytoplasm of normal germinal center and marginal zone B- cells and is involved in lymphocyte development and activation. Aberrant nuclear expression of BCL-10 occurs in a subset of extranodal marginal zone B-cell lymphomas (MALT lymphomas), primarily those with the t(1;14)(p22;q32) or t(11;18)(q21;q21). Little is known about BCL-10 expression in lymphoplasmacytic lymphoma/ Waldenstro¨ m macroglobulinemia (LPL/WM). We assessed for BCL-10 in 51 bone marrow (BM) specimens involved by LPL/WM using immunohistochemical methods. All patients had monoclonal IgM in serum. Extent of BM involvement was assessed using PAX-5/BSAP and CD20 immunostains and the pattern and percentage of B-cells positive for BCL-10 was determined. The p65 subunit of nuclear factor-kappa B (NF-jB), a molecule downstream of BCL-10, was also assessed immunohistochemically. Nuclear BCL-10 staining was present in 28/ 51 (55%) specimens. BCL-10 expression correlated with greater extent of BM involvement (P ¼ 0.001), but did not correlate with serum IgM paraprotein levels, type of immunoglobulin light chain, or clinical variables. Nuclear expression of the p65 subunit of NF-jB was detected in 17/50 (34%) specimens, suggesting that NF-jB is active in a subset of LPL/WM. p65 NF-jB activation did not correlate with nuclear BCL-10 immunostaining. Cytogenetic analysis in 29 cases showed no evidence of the t(1;14) or t(11;18). These results indicate that nuclear BCL-10 expression is common in LPL/WM and does not correlate with MALT lymphoma-associated translocations or p65 NF-jB nuclear staining. Modern Pathology (2006) 19, 891–898. doi:10.1038/modpathol.3800609; published online 21 April 2006 Keywords: BCL10; p65; NF-kB; lymphoplasmacytic lymphoma; Waldenstro¨m macroglobulinemia Waldenstro¨m macroglobulinemia (WM) has been and WM are linked in the World Health Organiza- defined as a neoplasm of B lymphocytes that tion classification.2 involves the bone marrow (BM) and is associated Lymphoplasmacytic lymphoma/Waldenstro¨m ma- with monoclonal immunoglobulin M (IgM) in croglobulinemia constitutes approximately 2% of all serum.1 Most patients with the clinical and labora- hematopoietic neoplasms.1,3–5 Patients are usually tory findings of WM have been classified as having older adults (median age, 63 years), and there is a lymphoplasmacytic lymphoma (LPL), and thus LPL slight male preponderance.5,6 The serum concentra- tion of IgM paraprotein varies widely in WM; thus presence of monoclonal IgM in serum, irrespective of level, and BM involvement are considered as two Correspondence: Dr CE Bueso-Ramos, MD, PhD, Department of of the diagnostic requirements in the definition of Hematopathology, Unit 72, The University of Texas MD Anderson WM as suggested by the Second International Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Workshop on Waldenstro¨m Macroglobulinemia E-mail: [email protected] 1 Received 23 January 2006; revised 2 March 2006; accepted 10 (Table 1). The clinical features are highly variable, March 2006; published online 21 April 2006 and many patients are asymptomatic.5 Clinically, a BCL-10 and p65 in Waldenstro¨m macroglobulinemia M Merzianu et al 892 Table 1 Diagnostic criteria for Waldenstro¨m macroglobulinemia Materials and methods recommended by the Second International Workshop on Walden- stro¨m macroglobulinemia Tissue Specimens Criteria From our archives, we retrieved BM specimens involved by LPL/WM. Approval for this study from K IgM monoclonal gammopathy of any concentration the institutional review board was obtained. LPL/ K Bone marrow infiltration by small lymphocytes showing WM was defined on the basis of a combination of plasmacytoid/plasma cell differentiation laboratory, clinical, morphologic, and immunopheno- K Intertrabecular pattern of bone marrow infiltration K Surface IgM+, CD57, CD10À, CD19+, CD20+, CD22+, CD23À, typic criteria as described by the World Health CD25+, CD27+, FMC7+, CD103À, CD138À immunophenotype. Organization2 and the International Workshop on WM guidelines (Table 1).1 The inclusion criteria for cases of LPL/WM in this study included IgM paraprotein in serum, presence of lymphoma in the BM composed of small lymphocytes of which a subset of patients has evidence of lymphadenopa- subset had plasmacytoid differentiation, and results 3,7–10 thy, hepatosplenomegaly, anemia, cytopenias, of immunophenotypic studies (flow cytometry 5 and hyperviscosity syndrome. The latter, however, and/or immunohistochemistry) that demonstrated is uncommon in patients with LPL/WM in our a monoclonal B-cell population positive for pan-B- 11 experience. Patients with LPL/WM usually have cell antigens (CD19 or CD20) and negative for CD5 clinically indolent disease, with a median survival and CD10. We also excluded neoplasms that were of 5 years, and up to 40% of patients survive associated with IgA or IgG serum paraprotein, as 6,12 more than 10 years or die from unrelated causes. well as patients with IgM lymphoproliferative Some patients, however, can develop transformation disorders associated with nodal or bulky splenic 13 to diffuse large B-cell lymphoma. LPL/WM is disease. generally incurable with available therapy. We also assessed a control group of formalin- BCL-10 is a proapoptic gene in vitro with a fixed, paraffin-embedded BM specimens including role in lymphocyte maturation, differentiation, 10 normal BM and 64 lymphomas of various types: 14 and activation. BCL-10 cytoplasmic protein in 14 MALT lymphoma (four with t(11;18)), two humans is relatively restricted to lymphocytes, nodal marginal zone B-cell lymphoma, one splenic being expressed in B-cells with the strongest marginal zone B-cell lymphoma, 11 follicular lym- intensity in the germinal center, and less intensely phoma, 20 chronic lymphocytic leukemia/small 14 in the marginal zone. Strong BCL-10 nuclear ex- lymphocytic lymphoma, 11 mantle cell lymphoma, pression was first described in extranodal marginal and five diffuse large B-cell lymphoma. zone B-cell lymphomas (MALT lymphoma) with the t(1;14)(p22;q32) and the BCL-10 gene was subse- quently cloned and breakpoints identified.15,16 Mod- Immunohistochemistry erate nuclear expression of BCL-10 also has been reported in MALT lymphomas with the t(11;18) and We performed immunostaining using 5-mm-thick, strong cytoplasmic expression occurs in MALT formalin-fixed, paraffin-embedded tissue sections, lymphomas with the t(14;18) involving the MALT1 heat-induced epitope retrieval, and the Envision þ gene.17–20 system (Dakocytomation, Carpinteria, CA, USA) NF-kB is a transcription factor composed of five according to the manufacturer’s recommendations. proteins (p50, p52, p65, c-Rel, and RelB) with a role The staining was carried out using Autostainer Plus in apoptosis regulation, cell proliferation, survival, (Dakocytomation). The washing buffer used was and metastasis.21,22 NF-kB, when inactive, is located 0.05-M Tris-buffered saline supplemented with in the cytoplasm and is bound to an inhibitory 0.05% Tween. molecule, I kappa B (IkB). Upon phosphorylation, ubiquitination, and degradation of IkB, NF-kBis Single antibody staining released into the cytosol, translocates into the The following monoclonal antibodies were used: nucleus, and transactivates several genes. Constitu- CD20 (Dako; 1:300), BCL-10 (Zymed, San Francisco, tive activation of NF-kB is implicated in onco- CA, USA; 1:40), NF-kB antibody p65, rabbit (poly- genesis of many neoplasms.23–26 The presence of clonal GTX27970, GeneTex Inc., San Antonio, TX, NF-kB proteins in the nucleus of the neoplastic cells USA; 1:100), and PAX-5/BSAP (BD Transduction is a harbinger of activation of the NF-kB complex. Laboratories, San Diego, CA, USA; 1:20). In this study, we evaluated for nuclear expression Sections were first deparaffinized in xylene of BCL-10 by immunohistochemistry in cases of and rehydrated through graded concentrations of LPL/WM. Furthermore, nuclear expression of p65 alcohol. Sections were heated in a steamer (Black was used as a surrogate of NF-kB complex activa- & Decker HS2776 Type 1, Miami Lakes, FL, USA) for tion. Correlation between BCL-10, p65, available 20 min in target retrieval solution (Dakocytomation) cytogenetic data, and various clinical and patho- for antigen retrieval. The activity of endogenous logic parameters was also performed. peroxidase was blocked with peroxidase-blocking Modern Pathology (2006) 19, 891–898 BCL-10 and p65 in Waldenstro¨m macroglobulinemia M Merzianu et al 893 reagent (Dakocytomation) for 5 min. After washing been followed-up with routine monitoring of serum the sections with buffer, we incubated them with IgM levels, BM aspiration and biopsy, or tissue primary antibodies for 30 min at 231C. Sections were biopsy when clinically indicated. The patients’ then washed again with buffer. demographic data, time from original diagnosis, The Envision þ HRP system (Dakocytomation) concentration of serum monoclonal IgM at time of was used to visualize antigen expression. Diamino- biopsy (determined by nephelometry), and presence benzidine tetrahydrochloride was used as the or absence of therapy were retrieved, statistically chromogen, and all sections were counterstained analyzed, and tabulated.
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