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Hematopathology / WALDENSTRM MACROGLOBULINEMIA AND CYTOGENETIC ABNORMALITIES Cytogenetic Findings in Lymphoplasmacytic Lymphoma/Waldenstrm Macroglobulinemia Chromosomal Abnormalities Are Associated With the Polymorphous Subtype and an Aggressive Clinical Course Adnan Mansoor, MD,1 L. Jeffrey Medeiros, MD,1 Donna M. Weber, MD,2 Raymond Alexanian, MD,2 Kimberly Hayes,1 Dan Jones, MD, PhD,1 Raymond Lai, MD, PhD,1 Armand Glassman, MD,1 and Carlos E. Bueso-Ramos, MD, PhD1 Key Words: Lymphoplasmacytic lymphoma; Waldenstrm macroglobulinemia; Cytogenetics; Chromosomal abnormalities Abstract We correlated bone marrow cytogenetic findings with morphologic and immunophenotypic data in 37 patients with lymphoplasmacytic lymphoma (LPL)/Waldenstrm 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. Waldenstrm 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. American Society of Clinical Pathologists Am J Clin Pathol 2001;116:543-549 543 Mansoor et al / WALDENSTRM 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. Cytogenetic Studies Conventional G-band karyotype analysis was performed on all cases. Bone marrow cells were placed in 10% Ham F10 medium with 20% fetal calf serum (Gibco BRL, Gaithersburg, MD) at a concentration of 2 to 4 106 nucleated cells per milliliter. The culture was incubated for 24 hours and 48 hours without phytohemagglutinin. Standard harvesting procedures were used. Colcemid, 0.1 mL (10 g/mL), was added to 10-mL cultures for 30 minutes. For hypotonic treatment, a 0.075-mol/L concentration of potassium chloride was used for 30 minutes at room temperature. The fixation process consisted of 3 changes of methanol: glacial acetic acid (3:1) with a 10-minute waiting period between the changes. A drying chamber (Thermatron Industries, Holland, MI) was used for slide preparation. Slides were placed in a 60C oven overnight in preparation for Gbanding. The karyotype formula was written using the International System for Human Cytogenetic Nomenclature (1994).19 Statistical Analysis Differences between groups were compared statistically using the chi square or the Fisher exact test. Results Clinical and Pathologic Features There were 20 men and 17 women with a median age of 61 years (range, 34-77 years). Physical examination revealed lymphadenopathy in 15 (41%) patients, splenomegaly in 10 (27%) patients, skin infiltration in 4 (11%) patients, and hepatomegaly in 1 (3%) patient. An elevated level of monotypic IgM in serum was detected in all patients, with a median level of 1.900 mg/dL (19.0 g/L; range, 300-6,500 mg/dL [3-65 g/L]). Light chain type was kappa in 19 and lambda in 5. Other significant laboratory abnormalities at initial examination included the following: anemia, hemoglobin less than 12.0 g/dL (<120 g/L) in 32 patients (86%) (reference range, 14.0-18.0 g/dL [140-180 g/L]); hypoalbuminemia, albumin level less than 3.0 g/dL (<30.0 g/L) in 16 (47%) of 34 patients (reference range, 3.2-4.5 g/dL [32-45 g/L]); thrombocytopenia, platelet count less than 150 103/L (<150 109/L) in 16 patients (43%) (reference range, 140-440 103/L [140-440 109/L]); and leukopenia, WBC count less than 3,000/L (<3.0 109/L) in 12 patients (32%) (reference range, 4,000-11,000/L [4.0-11.0 109/L]). Bone marrow aspiration smears and biopsy sections were available for all cases. All showed bone marrow infiltration by neoplastic lymphoid cells. The pattern of infiltration was predominantly diffuse in 16 (43%), interstitial in 13 (35%) and nodular in 8 (22%) cases. The median tumor burden on bone marrow biopsy was 50% of total cellularity (range, 5% to 95%). The neoplasm was subtyped into 3 categories as outlined previously: 18 (49%) lymphoplasmacytoid, 10 (27%) lymphoplasmacytic, and 9 (24%) polymorphous Image 1, Image 2, and Image 3. In 1 case of polymorphous LPL/WM (case 7), a 544 Am J Clin Pathol 2001;116:543-549 American Society of Clinical Pathologists Hematopathology / ORIGINAL ARTICLE Image 1 (Case 8) Lymphoplasmacytoid subtype. Bone marrow aspirate smear showing numerous lymphoplasmacytoid cells with eccentric nuclei, condensed chromatin and distinct nucleoli (Wright-Giemsa, 1,000). focus composed predominantly of large cells was identified, suggestive of transformation to large cell lymphoma (Images 3A and 3B). Twenty-three (62%) of 37 patients did not receive therapy before bone marrow study; 5 (56%) of 9 patients with polymorphous subtype and 18 (64%) of 28 patients with other subtypes were untreated. All patients at some point received 2-chlorodeoxyadenosine, fludarabine, or both. The serum beta2-microglobulin results were as follows: treated group: median, 3.5 mg/L (range, 1.7-6.8 mg/L); untreated group: median, 3.0 mg/L (range, 1.9-6.7 mg/L; reference range, 0.6-2.0 mg/L). Cytogenetic Findings Cytogenetic analyses were performed in 22 cases (59%) at the time of initial diagnosis and in 15 cases (41%) during the course of disease (mean duration from time of initial diagnosis, 36 months; range, 4-120 months). In 27 patients, cytogenetic analysis was performed only once. In 10 patients, multiple cytogenetic studies were performed: for 8 patients, 2 or 3 times, and for 2 patients, more than 3 times. Follow-up karyotype showed a different pattern during the course of disease in 3 patients Table 1. Among all 37 cases, 25 (68%) had a diploid karyotype and 12 (32%) were abnormal. Eight (67%) of these 12 cases had complex cytogenetic abnormalities (Table 1). Numeric Abnormalities In 12 cases with an abnormal karyotype, 4 (33%) were pseudodiploid, 5 (42%) were hyperdiploid, and 3 (25%) were hypodiploid. Trisomy 5 and monosomy of chromosome 8 each were identified in 3 cases (25%). Trisomy 3 was seen in 2 cases (17%). Loss of chromosome Y as a single numeric abnormality was observed in 2 cases (17%). Monosomy of chromosome 4, 7, 13, 19, 21, or 22 was identified in single cases. Structural Abnormalities Deletions were more frequent than gains. Deletion of chromosome 6q, encompassing q13 to q22, was the most AB Image 2 (Case 28) Lymphoplasmacytic subtype. A, Bone marrow biopsy section showing lymphoplasmacytic infiltrate. Numerous plasma cells are present admixed with lymphoid cells (H&E, 400). B, Bone marrow aspirate smear. Marschalkotype plasma cells (with cytoplasmic vacuoles) and lymphoid cells are present (Wright-Giemsa, 1,000). American Society of Clinical Pathologists Am J Clin Pathol 2001;116:543-549 545 Mansoor et al / WALDENSTRM MACROGLOBULINEMIA AND CYTOGENETIC ABNORMALITIES AB Image 3 (Case 7) Polymorphous subtype. Bone marrow aspirate smear. A, Polymorphous lymphoid infiltrate composed of small and large cells (Wright-Giemsa, 1,000). B, A focus of large cells with vesicular chromatin, distinct nucleoli, and abundant cytoplasm (Wright-Giemsa, 1,000). common structural change, seen in 6 cases (50%) Image 4. Deletion 3q21 and 13q12 were each seen in 2 (17%) cases. Structural abnormalities of 12p occurred in 2 cases (17%), both add(12)(p11-13). One case each had del(1)(q32) and add(17)(p13). Bone Marrow Morphologic Findings Correlated With Cytogenetics Results Cytogenetic abnormalities were detected in 3 (17%) of 18 lymphoplasmacytoid, 2 (20%) of 10 lymphoplasmacytic, and 7 (78%) of 9 polymorphous cases. Table 1 Clinical Data, Histologic Subtype, and Karyotype in 12 Patients With Lymphoplasmacytic Lymphoma/Waldenstrm Macroglobulinemia Case No./Sex/ Age (y) Previous Chemotherapy Survival (mo)* Karyotype Polymorphous 1/M/63 2/F A/61 + B/62 3/M/67 4/F/69 5/F A/56 B/57 6/M/73 7/F/52 Lymphoplasmacytoid 8/F/72 + + + + + + 9/M/63 10/F A/43 B/53 C/54 Lymphoplasmacytic 11/F/54 12/M/65 + + + + A (24+) D (110) D (70) D (43) A (72+) D (6) D (46) D (48) A (40+) D (57) D (33) A (127+) 44-46,XY,del(6)(q21),add(8)(q24.3)[cp2]/46,XY[11] 43-46,X,add(X)(q28),del(1)(p22),2, del(3)(p11), del(3)(q21),del(4)(q28),del(6)(q16),8, add(9)(p23),del(10)(p12),add(11)(q25),add(12)(p13),19,21,22,+4-7mar [cp5] 46,XY[20] 45,X,Y[4]/46,XY[16] 46-47,XX,+5[cp2]/46,XX[8] 46,XX[20] 46,XX,del(13)(q12)[5]/46-47,XX,+5[cp2] 46,XX[15] 47,XY,del(3)(q21),4,del(6)(q21),8,add(12)(p11),+3mar[3]/46,XY[17] 49-50,XX,del(1)(q32),+3,+5,del(6)(q22),+7,8,+3-4 mar [cp7]/46,XX[2] 46,XX,der(5;8)(q10;q10),+16,add(17)(p13),add(19)(q13.4)[2]/46,XX,X,+1-2 mar [cp2]/46,XX[15] 44-46,XY,del(6)(q21),add(8)(q24.3)[cp2]/46,XY[11] 46,XX,del(13)(q12)[2]/48,XX,+3,+4,13,+18[1]/46,XX[21] 46,XX[19] 46,XX[12] 45,X,X,del(6)(q21)[3]/46,XX[27] 45,X,Y[19] * As of January 31, 2001. A, alive; D, dead. 546 Am J Clin Pathol 2001;116:543-549 American Society of Clinical Pathologists Hematopathology / ORIGINAL ARTICLE lymphoplasmacytoid or lymphoplasmacytic LPL/WM (6/20 [30%]) (P < .01). 21 Image 4 (Case 11) Giemsa-banded chromosome 6 showing del(6)(q21) (right) and normal chromosome 6 (left). When the lymphoplasmacytoid and lymphoplasmacytic groups were combined for statistical analysis, polymorphous tumors were significantly more likely to be aneuploid (7/9 [78%]) than were lymphoplasmacytoid and lymphoplasmacytic tumors (5/28 [18%]) (P < .005). Bone Marrow Morphologic Findings Correlated With Clinical Course Clinical follow-up was available for 28 (76%) of 37 patients, with a median follow-up of 36 months (range, 3180 months). Sixteen patients had an indolent clinical course, clinical evidence of disease progression developed in 7 patients, and large cell lymphoma developed in 5 patients. Thirteen patients had lymphoplasmacytoid tumors, 7 had lymphoplasmacytic tumors, and 8 had polymorphous tumors. Cytogenetics data for these cases showed diploid in 19 and aneuploid in 9. Four patients (31%) with lymphoplasmacytoid tumors (2 aneuploid, 2 diploid) had a poor clinical course: 3 had progressive disease, and large cell lymphoma developed in 1. Two (29%) of 7 patients with lymphoplasmacytic tumors had progressive disease. Both patients with progressive disease had aneuploid tumors. None of these patients developed large cell lymphoma. By contrast, 6 patients (75%) with polymorphous LPL/WM had a poor clinical course: 2 had progressive disease, and large cell lymphoma developed in 4. Five of 6 patients with a poor prognosis had aneuploid tumors. Combining the lymphoplasmacytoid and lymphoplasmacytic groups for statistical analysis showed that patients with polymorphous LPL/WM (6/8 [75%]) were significantly more likely to have a poorer prognosis than patients with Discussion We report the results of conventional cytogenetics analysis in 37 cases of LPL/WM, each case with compatible immunophenotypic findings and subclassified morphologically using the Kiel criteria as described by Bartl and colleagues.8 Twelve cases (32%) had an abnormal karyotype, as shown in Table 1. There was no correlation between the cytogenetic results and either previous therapy or serum beta2-microglobulin levels. The presence of chromosomal abnormalities correlated with morphologic findings. Fewer than one quarter of the lymphoplasmacytoid and lymphoplasmacytic LPL/WM cases had an aneuploid karyotype. By contrast, most cases of polymorphous LPL/WM had abnormal cytogenetic findings (P < .005), and in many of these cases, the karyotype was complex. In a recent case report, Jankovic and colleagues16 also described complex karyotypic findings in a case of polymorphous LPL/WM. However, in most other studies reported in the literature, no correlation between morphologic findings and karyotype has been observed. In addition, every case of polymorphous LPL/WM with a complex karyotype in the present study also had a variable number of diploid metaphases. These findings suggest that the polymorphous type of LPL/WM represents a more advanced phase of clonal evolution among differentiated cells that produce clonal IgM. In a recent study, Ciric and colleagues20 also described a case of LPL/WM that demonstrated intraclonal heterogeneity, supporting our interpretation. One can further hypothesize that clonal evolution results in progression to a clinically more aggressive form of disease. Others have reported that polymorphous LPL/WM is clinically more aggressive than other subtypes of LPL/WM.8 The most frequent structural abnormality identified in this study, in 6 (50%) of 12 cases with an abnormal karyotype, was del(6q), encompassing the q13 to q22 region. Deletion of 6q has been associated with various types of Bcell non-Hodgkin lymphoma21,22 and may be more common in high-grade lymphomas that have transformed from lowgrade follicular lymphoma.9 Thus, it seems reasonable to suggest that the presence of 6q is a marker of transformation in LPL/WM and that the polymorphous subtype is the initial manifestation of transformation to large cell lymphoma. We report 2 recurrent trisomies in 5 cases of LPL/WM that have not been published previously. Three cases were trisomic for chromosome 5, and 2 cases had trisomy 3. One case had trisomy of both chromosomes 3 and 5. Trisomy 3 American Society of Clinical Pathologists Am J Clin Pathol 2001;116:543-549 547 Mansoor et al / WALDENSTRM MACROGLOBULINEMIA AND CYTOGENETIC ABNORMALITIES has been identified as a recurrent chromosomal abnormality in nodal and extranodal marginal zone B-cell lymphomas.23-25 The role of trisomy 3 in the pathogenesis of LPL/WM is unknown. Comparative genomic hybridization analysis has shown that the minimal overrepresented region involves 3q21-23 to 3q25-29. The bcl-6 proto-oncogene, located on 3q27, may be involved. All 3 cases with trisomy 5 were the polymorphous subtype of LPL/WM, and large Bcell lymphoma subsequently developed in 1 patient (data not shown). Trisomy 5 has been reported to be an adverse prognostic finding in patients with centroblastic lymphoma.26 Thus, trisomy 5 also may be an adverse prognostic marker in cases of LPL/WM. The t(9;14)(p13;q32) originally was identified in a retrospective analysis of 474 nodal and extranodal malignant lymphomas by Offit et al27 and was correlated with plasmacytoid differentiation. In the t(9;14), the pax-5 gene at 9p13 is fused to the immunoglobulin heavy chain gene at 14q32.28 The pax-5 is transcribed throughout B-cell ontogeny but undergoes down-regulation during plasma cell differentiation. The t(9;14) has been reported in lymphoplasmacytoid lymphoma and splenic marginal zone B-cell lymphoma by others28,29; however, we were unable to identify the t(9;14) in any of the cases in the present study. Similar results using fluorescence in situ hybridization techniques have been reported by others.30 These results suggest that LPL/WM in bone marrow is not related to nodal lymphomas with plasmacytoid differentiation that carry the t(9;14). The p53 gene, located at 17p13, may be deleted or mutated in low-grade B-cell lymphomas, particularly in cases that have undergone histologic transformation to higher grade lymphoma.31 In the present study, deletions of 17p13 were not detected in any cases of LPL/WM. Thus, inactivation of the p53 gene does not seem to be involved in the pathogenesis of LPL/WM, in agreement with the findings of others.31-33 Similarly, deletions of 13q, 13q14, and trisomy 12, while common in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma were not noted in the present series, confirming the findings of other reports.10,11,32,33 We have reported a large series of cases of LPL/WM and have shown conventional cytogenetic abnormalities in approximately one third of these cases. These cytogenetic abnormalities, which usually are complex, occur more commonly in the polymorphous subtype of LPL/WM than in the lymphoplasmacytoid and lymphoplasmacytic subtypes and are associated with a poor prognosis. The presence of some of these genetic changes, such as deletion of 6q, supports clinical and histologic evidence that the polymorphous subtype of LPL/WM represents an early stage of morphologic transformation to large B-cell lymphoma. From the Departments of 1Hematopathology and 2Lymphoma/Myeloma, the University of Texas M.D. Anderson Cancer Center, Houston. Address reprint requests to Dr Bueso-Ramos: Division of Pathology and Laboratory Medicine, Box 72, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. References 1. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues: report of the Clinical Advisory Committee meeting: Airlie House, Virginia, November 1997. J Clin Oncol. 1999;17:3835-3849. 2. Kyle RA, Garton JP. The spectrum of IgM monoclonal gammopathy in 430 cases. Mayo Clin Proc. 1987;62:719-731. 3. Herrinton LJ, Weiss NS. Incidence of Waldenstrm's macroglobulinemia. Blood. 1993;82:3148-3150. 4. Dimopoulos MA, Alexanian R. Waldenstrm's macroglobulinemia. Blood. 1994;83:1452-1459. 5. Morel P, Monconduit M, Jacomy D, et al. Prognostic factors in Waldenstrm macroglobulinemia: a report on 232 patients with the description of a new scoring system and its validation on 253 other patients. Blood. 2000;96:852-858. 6. Owen RG, Parapia LA, Higginson J, et al. Clinicopathologic correlates of IgM paraproteinemias. Clin Lymphoma. 2000; 1:39-43. 7. Owen RG, Johnson SA, Morgan GJ. Waldenstrm's macroglobulinemia: laboratory diagnosis and treatment. Hematol Oncol. 2000;18:41-49. 8. Bartl R, Frisch B, Mahl G, et al. Bone marrow histology in Waldenstrm's macroglobulinaemia. Scand J Haematol. 1983;31:359-375. 9. Dewald GW, Jenkins RB. Cytogenetic studies on patients with monoclonal gammopathies. In: Wiernik PH, Canellos GP, Dutcher JP, et al, eds. Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone; 1996:515-523. 10. Palka G, Spadano A, Geraci L, et al. Chromosome changes in 19 patients with Waldenstrm's macroglobulinemia. Cancer Genet Cytogenet. 1987;29:261-269. 11. Carbone P, Caradonna F, Granata G, et al. Chromosomal abnormalities in Waldenstrm's macroglobulinemia. Cancer Genet Cytogenet. 1992;61:147-151. 12. Ueshima Y, Fukuhara S, Nagai K, et al. Cytogenetic studies and clinical aspects of patients with plasma cell leukemia and Waldenstrm macroglobulinemia. Cancer Res. 1983;43:905912. 13. Han T, Sadamori N, Takeuchi J, et al. Clonal chromosome abnormalities in patients with Waldenstrm's and CLLassociated macroglobulinemia: significance of trisomy 12. Blood. 1983;62:525-531. 14. Wong KF, Kwong YL, Wong TK. Concomitant partial tetrasomy 3q and trisomy 18 in Waldenstrm's macroglobulinemia. Cancer Genet Cytogenet. 1995;81:92-93. 15. Hirase N, Yufu Y, Abe Y, et al. Primary macroglobulinemia with t(11;18)(q21;q21). Cancer Genet Cytogenet. 2000; 117:13-17. 16. Jankovic GM, Colovic MD, Wiernik PH, et al. Multiple karyotypic aberrations in a polymorphous variant of Waldenstrm's macroglobulinemia. Cancer Genet Cytogenet. 1999;111:77-80. 548 Am J Clin Pathol 2001;116:543-549 American Society of Clinical Pathologists Hematopathology / ORIGINAL ARTICLE 17. Chong Y Y-Y, Lau L-C, Lui W-O, et al. A case of t(8;14) with total and partial trisomy 3 in Waldenstrm's macroglobulinemia. Cancer Genet Cytogenet. 1998;103:65-67. 18. San Roman C, Ferro T, Guzman M, et al. Clonal abnormalities in patients with Waldenstrm's macroglobulinemia with special reference to a Burkitt-type t(8;14). Cancer Genet Cytogenet. 1985;18:155-158. 19. Mitelman F, ed. ISCN (1995): An International System for Human Cytogenetic Nomenclature. Basel, Switzerland: S Karger; 1995. 20. Ciric B, Van Keulen V, Rodriguez M, et al. Clonal evolution in Waldenstrm macroglobulinemia highlights functional role of B-cell receptor. Blood. 2001;97:321-323. 21. Zhang Y, Weber-Matthiesen K, Siebert R, et al. Frequent deletions of 6q23-24 in B-cell non-Hodgkin's lymphomas detected by fluorescence in situ hybridization. Genes Chromosomes Cancer. 1997;18:310-313. 22. Offit K, Jhanwar SC, Landanyi M. Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: correlations between recurrent aberrations, histology, and exposure to cytotoxic treatment. Genes Chromosomes Cancer. 1991;3:189-202. 23. Wotherspoon AC, Finn T, Isaacson PG. Trisomy 3 in lowgrade B-cell lymphomas of mucosa-associated lymphoid tissue. Blood. 1995;85:2000-2004. 24. Brynes RK, Almaguer PD, Leathery KE, et al. Numerical cytogenetic abnormalities of chromosomes 3, 7, and 12 in marginal zone B-cell lymphomas. Mod Pathol. 1996;9:9951000. 25. Dierlamm J, Wlodarska I, Michaux L, et al. Genetic abnormalities in marginal zone B-cell lymphoma. Hematol Oncol. 2000;18:1-13. 26. Schlegelberger B, Zwingers T, Harder L, et al, for the KielWien-Lymphoma Study Group. Clinicopathogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma. Blood. 1999;94:31143120. 27. Offit K, Parsa NZ, Fillipa D, et al. Translocation (9;14)(p13;q32) denotes a subset of low-grade non-Hodgkin's lymphoma with plasmacytoid differentiation. Blood. 1992;80:2594-2599. 28. Iida S, Rao PH, Nallasivam P, et al. The t(9;14)(p13;q32) chromosomal translocation associated with lymphoplasmacytoid lymphoma involves the PAX-5 gene. Blood. 1996;88:4110-4117. 29. Morrison AM, Jager U, Chott A, et al. Deregulated PAX-5 transcription from a translocated IgH promoter in marginal zone lymphoma. Blood. 1998;92:3865-3878. 30. Schop RFJ, Jalal SM, Van Weir SA, et al. Absence of t(9;14)(p13;q32) translocation in clinically defined Waldenstrm's macroglobulinemia [abstract]. Blood. 2000;96(suppl 2):162b. 31. Preudhomme C, Fenaux P. The clinical significance of mutations of the p53 tumour suppressor gene in haematological malignancies. Br J Haematol. 1997;98:502511. 32. Jabbar SAB, Ganeshaguru K, Wickremasingle RG, et al. Deletion of chromosome 13 (band q14) but not trisomy 12 is a clonal event in B-chronic lymphocytic leukemia (CLL). Br J Haematol. 1995;90:476-478. 33. Schop RFJ, Jalal SM, Van Weir SA, et al. Deletions of 17p13.1 and 13q14 are rare in Waldenstrm's macroglobulinemia clonal cells [abstract]. Blood. 2000;96(suppl 1):372a. American Society of Clinical Pathologists Am J Clin Pathol 2001;116:543-549 549