Hematopathology / WALDENSTRÖM MACROGLOBULINEMIA AND CYTOGENETIC ABNORMALITIES Cytogenetic Findings in Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia Chromosomal Abnormalities Are Associated With the Polymorphous Subtype and an Aggressive Clinical Course

We correlated bone marrow cytogenetic findings with morphologic and immunophenotypic data in 37 patients with lymphoplasmacytic lymphoma (LPL)/Waldenström 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 +5 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. Waldenström macroglobulinemia (WM) is a lymphoproliferative disorder of B cells with variable plasmacytoid differentiation, associated with monoclonal IgM production. Most patients with the clinical and laboratory findings of WM have been classified as having lymphoplasmacytic lymphoma (LPL) in the recently proposed World Health Organization (WHO) classification scheme.1 LPL/WM accounts for approximately 2% of all hematopoietic neoplasms.2-4 Affected patients usually are elderly, with a median age of 65 years, and virtually all patients have bone marrow infiltration at the time of diagnosis. Patients may have lymphadenopathy, hepatosplenomegaly, anemia, and cytopenias.4-8 While most patients with LPL/WM have an indolent clinical course, approximately 10% to 15% of patients show more rapidly progressive disease.8 Cytogenetic reports in WM have been few and for small numbers of patients.9-16 In two of the largest studies, in which 19 and 17 cases of WM were assessed,10,11 there were inconsistent and nonrecurrent abnormalities involving chromosomes 9, 10, 11, 12, 18, and 21. Trisomy 12 has been identified in a few cases of WM and was suggested to have prognostic significance,13 but this finding was not confirmed in other reports.11 Isolated cases of WM that carried the t(8;14), t(11;18), and t(14;18) also have been described.15,17,18 However, in most studies there was little correlation with morphologic findings, and immunophenotypic data often were not available. We describe the conventional cytogenetic findings and prognostic implications for 37 cases of LPL/WM, all with compatible morphologic features and immunophenotypic data. Am J Clin Pathol 2001;116:543-549 543 © American Society of Clinical Pathologists Mansoor et al / WALDENSTRÖM MACROGLOBULINEMIA AND CYTOGENETIC ABNORMALITIES Materials and Methods We obtained 37 cases of LPL/WM for which bone marrow aspiration or biopsy material was sent for conventional cytogenetic analysis. For this study, we used a strict definition of LPL/WM, based on a combination of laboratory, clinical, morphologic, and immunophenotypic criteria as defined in the WHO classification.1 To be included in the study, the following criteria had to be fulfilled: (1) presence of monoclonal IgM paraprotein in serum; (2) presence of a neoplasm composed of small lymphocytes with some degree of plasmacytoid differentiation involving the bone marrow; and (3) immunophenotypic studies performed on all cases using flow cytometry that demonstrated a monotypic B-cell population positive for pan-B-cell antigens (CD19+ or CD20+) and negative for CD5, CD10, and CD23. Each case of LPL/WM was further classified into 1 of 3 subtypes as described by Bartl and colleagues,8 with minor modifications: lymphoplasmacytoid, lymphoplasmacytic, and polymorphous. The lymphoplasmacytoid subtype is composed of a monotonous population of small lymphocytes, a subset of which has plasmacytoid differentiation. Occasional (<5%) mature plasma cells (of the Marschalko type) were accepted in this category. In the lymphoplasmacytic subtype, a variable mixture of small lymphocytes and mature plasma cells are present, and we required 5% or more mature plasma cells (Marschalko type) to be present. In both the lymphoplasmacytoid and lymphoplasmacytic subtypes, large lymphoid cells and mitotic figures are infrequent. By contrast, the polymorphous subtype includes the presence of easily identified large lymphoid cells, including large noncleaved cells and immunoblasts, and mitotic figures are relatively frequent.8 For the present study, we used a cutoff of at least 5% large cells for designating a case of LPL/WM with polymorphous subtype. All patients were followed up by serial monitoring of physical examination, blood counts, serum IgM levels, and follow-up bone marrow aspiration and biopsy or tissue biopsy when clinically indicated. Clinical progression was defined by at least a 50% increase in serum monoclonal IgM, recurrence of adenopathy or splenomegaly, or reduction of hemoglobin by at least 1.5 g/dL (15 g/L), associated with bone marrow lymphocytosis of more than 20%. Survival was measured from diagnosis.