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Burkitt lymphoma arising from lymphoplasmacytic lymphoma following acquisition of MYC translocation and loss of the ETV6 tumor suppressor gene.

Lymphoplasmacytic lymphoma is defined as a neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells that primarily involves the bone marrow and less commonly the lymph nodes and spleen. Frequently, lymphoplasmacytic lymphoma is associated with a monoclonal immunoglobulin M (IgM) paraproteinemia, a condition named Waldenstrom macroglobulinemia. (1) Lymphoplasmacytic lymphoma is a low-grade lymphoma with an indolent clinical course and a median survival of 5 to 10 years. Uncommonly, transformation of lymphoplasmacytic lymphoma to a more aggressive disease, including diffuse large B-cell lymphoma, may occur. (2-5)

Burkitt lymphoma is a high grade B-cell neoplasm with an extremely fast doubling time and rapid clinical course. (6) Burkitt lymphoma is characterized by translocation involving MYC at 8q24 with one of several partners, including the immunoglobulin heavy chain gene at 14q32, the [kappa] light chain gene at 2p12, or the [lambda] light chain gene at 22q11. Transformation of a variety of lower-grade or small B-cell lymphomas, such as follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, or small cell lymphoma/chronic lymphocytic leukemia to Burkitt lymphoma has been reported, frequently associated with MYC gene rearrangement. (7-9)

We report a patient with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia with monoclonal IgM k paraproteinemia who, 9 years after initial diagnosis, developed Burkitt lymphoma with acquisition of a MYC translocation. To our knowledge, this is the first reported case with convincing molecular evidence that the transformed lymphoma evolved from the same clone as the original lymphoplasmacytic lymphoma.


Clinicopathologic Findings

The following case was evaluated and reported in compliance with the University of South Florida's (Tampa) Institutional Review Board Policy No. 311. A 70-year-old woman was initially found to have a monoclonal IgM [kappa] paraproteinemia during a workup for a nonproductive cough and peripheral neuropathy in 1999. She had elevated serum IgM (8000 mg/dL) with a free [kappa] light chain and a small IgM band detected in the urine. There were no other significant findings, such as lytic bone lesions, peripheral lymphocytosis, or lymphadenopathy.

A bone marrow biopsy (biopsy 1) was performed in 2000 that displayed a diffuse, interstitial involvement by small plasmacytoid lymphocytes (Figure, A) admixed with a few mature plasma cells (Figure, A, inset). The corresponding flow cytometry demonstrated a monoclonal B-cell population, expressing CD19 and bright CD20 with k light chain restriction. The neoplastic B cells did not show coexpression of CD5, CD10, or CD23 (triple negativity). A diagnosis of lymphoplasmacytic lymphoma was rendered based on the clinical, histopathologic, and phenotypic findings. The patient initially responded to treatment with chlorambucil and prednisone (1 cycle), but relapsed in 2002. She received 2-chlorodeoxyadenosine combined with cytoxan and Rituxan with a second complete remission achieved. She relapsed again in 2006, after which she received 5 cycles of fludarabine and rituximab with a good response. She developed transient pancytopenia during her disease course, which was attributed to chemotherapy.

In 2007, she presented with a swelling in the right mandibular area, which showed a 2- to 3-cm mass on physical examination. A tissue biopsy (biopsy 2) showed diffuse involvement by small monotonous lymphocytes with plasmacytic features without evidence of lymphoepithelial lesions or increased large cell components (Figure, B). A battery of immunohistochemical stains was performed. The neoplastic cells stained positive for CD20, CD79a, and CD43 and negative for CD5, BCL-1, CD10, and CD23, supporting a diagnosis of low-grade B-cell lymphoma, recurrent lymphoplasmacytic lymphoma (Figure, B, inset). She was put on observation without any therapy.

Eventually, in January of 2008, she presented with a rapidly growing mass in her left anterior neck, for which she underwent a fine-needle aspiration. The cytologic examination showed a monotonous population of intermediate-sized lymphoid cells with round to oval nuclei, one or more small nucleoli, and a scant to moderate amount of dark blue cytoplasm containing characteristic peripheral lipid vacuoles, representative of typical Burkitt lymphoma (Figure, C). Flow cytometric analysis exhibited [lambda] monoclonal B cells with coexpression of CD10 and FMC-7, which were negative for CD5, CD23, CD11c, CD25, CD103, and [kappa] light chain. Also detected by flow cytometry were admixed polyclonal B cells and reactive T cells.

A simultaneous staging bone marrow biopsy (biopsy 3) demonstrated diffuse infiltration by a monomorphic population of predominantly medium-sized atypical lymphoid cells associated with a "starry sky" pattern (Figure, C, right inset). Flow cytometric analysis on the bone marrow aspirate showed an identical immunophenotype to that noted in the fine-needle aspiration from the left neck mass. In addition, immunohistochemical staining revealed no BCL-2 reactivity in the neoplastic B-cells, and Ki-67 proliferation index approached 100% by immunohistochemistry (Figure, C, left inset). No low-grade lymphoma was identified in either specimen. The flow cytometry did not detect any immature lymphoid or myeloid precursor with expression of TdT, CD34, CD13, or CD33 in the bone marrow specimen, excluding B-lymphoblastic leukemia/lymphoma. Based on the cytologic and flow cytometric findings, a diagnosis of Burkitt lymphoma was rendered. Conventional karyotyping demonstrated complex cytogenetic abnormalities with t(8; 14)(q24; q32) (Figure, E), confirming a Burkitt lymphoma. The patient received 2 cycles of cyclophosphamide, Adriamycin (hydroxydoxorubicin), Oncovin (vincristine), and prednisone-rituximab (R-CHOP) with no response. In a short period, the patient developed multiple complications including severe sepsis during the hospital course. She died in March 2008, after 2 months of hospitalization.

Molecular Study Findings

Polymerase chain reaction, performed on the left neck fine-needle aspiration sample, was positive for B-cell immunoglobulin and k light chain gene rearrangements, confirming the clonality.

In order to prove that the Burkitt lymphoma was derived from the same clone as the previous lymphoplasmacytic lymphoma, additional polymerase chain reaction gene rearrangement analyses were performed on available paraffin-embedded tissue blocks from (1) the patient's original bone marrow biopsy from 2000 showing lymphoplasmacytic lymphoma, (2) the biopsy from the right mandibular region in 2007 showing low-grade B-cell lymphoma with plasmacytic differentiation, and (3) the bone marrow biopsy with Burkitt lymphoma performed in 2008. The polymerase chain reaction demonstrated identical immunoglobulin gene rearrangement peaks in the last 2 specimens (biopsies 2 and 3), confirming that they were from the same clone. Specifically, both specimens showed identical monoclonal peaks of 332 and 346 base pairs in the IgH FR1 region. Additionally, they shared a monoclonal peak of 151 base pairs in the k light chain region (Figure, D). The polymerase chain reaction products from biopsy 1 were limited and the monoclonal peaks were low, likely attributable to prolonged storage and degeneration of DNA quality on a decalcified specimen (data not shown in Figure, D).

Cytogenetics and Fluorescence In Situ Hybridization Findings

Cytogenetic study performed on the patient's initial bone marrow (biopsy 1) and right mandibular mass (biopsy 2) revealed a normal female karyotype, 46,XX. The left neck fine-needle aspiration sample from 2008 was also submitted for fluorescence in situ hybridization analysis but failed to yield an interpretable result because of insufficient material. Conventional karyotyping performed on the bone marrow biopsy from 2008 (biopsy 3) revealed a complex female karyotype, reported as 48,XX,add(2)(p23),+7,t(8; 14)(q24; q32),idic(12)(p11.2),der(12)t(12; 17) (p13; q21),-17,+21,+mar[cp20] (Figure, E).


Lymphoplasmacytic lymphoma is a rare subtype of non-Hodgkin lymphoma, accounting for only 1% to 2% of these lymphomas, (3) and is often associated with paraproteinemia, usually of the IgM type. (1) Although it usually has an indolent clinical course, transformation to a highergrade lymphoma, frequently diffuse large B-cell lymphoma, may occur. (2-5) According to a large series of 92 patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia treated at MD Anderson Cancer Center (Houston, Texas), the frequency of transformation to diffuse large B-cell lymphoma from lymphoplasmacytic lymphoma is 13%, occurring between 12 and 128 months (median, 44 months) after the diagnosis of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. Of the reported 12 cases, none had been diagnosed with Burkitt lymphoma. (3) Thus, the development of Burkitt lymphoma from lymphoplasmacytic lymphoma is extremely rare. A literature search revealed only one case, reported by Prochorec-Sobieszek et al (9); however, there was no demonstration of molecular evidence of origination from the same clone in that case.

The current patient's initial lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia was diagnosed based on the typical clinical picture and laboratory results, including IgM monoclonal gammopathy, macroglobulinemia, and hyperviscosity syndrome (ie, neurologic symptoms including peripheral neuropathy), as well as the characteristic pattern of bone marrow involvement. Although most cases involve the bone marrow, (1) extramedullary involvement by lymphoplasmacytic lymphoma has also been reported. (10) Our patient presented with a mass in the mandibular region that was diagnosed as recurrent lymphoplasmacytic lymphoma based on histomorphology and phenotyping.

Our patient had multiple episodes of relapse of her lymphoplasmacytic lymphoma, despite her initial response to several courses of chemotherapy. She eventually developed Burkitt lymphoma after approximately 9 years of clinical course. Available cytogenetic studies performed on her bone marrow and tissue biopsies prior to development of Burkitt lymphoma demonstrated a normal female karyotype. The last karyotyping, performed on her bone marrow biopsy with aggressive lymphoma, showed complex cytogenetic aberrations including t(8; 14)(q24; q32). The break point indicated translocation of the MYC gene at 8q24 to the immunoglobulin heavy chain locus at 14q32 resulting in deregulation of the MYC proto-oncogene. (11) The MYC/IgH gene rearrangement, along with complex cytogenetic abnormalities, though infrequent, has also been reported in Burkitt lymphoma. (12) The isodicentricity of chromosome 12 resulted in loss of 12p13, the locus of the ETV6 gene (also known as TEL1). ETV6 gene fusions have been reported in other hematologic malignancies such as lymphoblastic lymphoma. (13) In the current case, loss of the ETV6 gene might have functioned as either a tumor suppressor or an oncogenic fusion partner to enhance aggressive tumor behavior.

The findings support the notion that in our patient, Burkitt lymphoma arose from the same clone as her low-grade lymphoplasmacytic lymphoma after acquisition of the MYC proto-oncogene, loss of the ETV6 tumor suppressor gene at 12p13, and loss of p53 through monosomy 17. Most importantly, we were able to prove a clonal relationship between the patient's original lymphoplasmacytic lymphoma and her Burkitt lymphoma by comparing their B-cell gene rearrangement peaks (Figure, D).

Of note, the initial biopsy (biopsy 1) showed a k light chain restriction, whereas biopsy 3 with the diagnosis of Burkitt lymphoma demonstrated [lambda] light chain restriction. The light chain switch has been reported in various transformed lymphomas. (14) The mechanism of alteration in our case is uncertain because of lack of materials to conduct further molecular experiments.

Most reported cases of Burkitt lymphoma that transformed from or arose in the setting of a lower grade B-cell lymphoma have occurred within a few years of the initial diagnosis. (7-9) In our case, the interval between the 2 diagnoses was unusually long (9 years). Transformation of lymphoplasmacytic lymphoma to high-grade lymphoma usually portends an adverse prognosis, and there is no established treatment regimen. Benefits of aggressive therapy in such patients have been reported, (15) which may apply especially to those with MYC translocation.


In summary, this is an unusual case of long-standing low-grade lymphoplasmacytic lymphoma transforming to Burkitt lymphoma with the demonstration of origination from the same clone following acquisition of a MYC translocation and deletion of the ETV6 gene. MYC translocation acquisition is very uncommon in lymphoplasmacytic lymphoma, the mechanism of which remains worthy of further investigation.


(1.) Swerdlow SH, Campo E, Harris NL, et al. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008. World Health Organization Classification of Tumors; vol. 3.

(2.) Appenzeller P, Leith CP, Foucar K, Scott AA, Bigler CF, Thompson CT. Cutaneous Waldenstrom macroglobulinemia in transformation. Am J Dermatopathol. 1999; 21(2):151-155.

(3.) Lin P, Mansoor A, Bueso-Ramos C, Hao S, Lai R, Medeiros LJ. Diffuse large B-cell lymphoma occurring in patients with lymphoplasmacytic lymphoma/ Waldenstrom macroglobulinemia: clinicopathologic features of 12 cases. Am J Clin Pathol. 2003; 120(2):246-253.

(4.) Rosique P, Majado MJ, Bas A. Unusual evolution to immunoblastic lymphoma of a case of Waldenstrom macroglobulinemia presenting with thrombocytopenia. Haematologica. 1997; 82(4):509-510.

(5.) Leonhard SA, Muhleman AF, Hurtubise PE, Martelo OJ. Emergence of immunoblastic sarcoma in Waldenstrom's macroglobulinemia. Cancer. 1980; 45(12):3102-3107.

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(7.) Felten CL, Stephenson CF, Ortiz RO, Hertzberg L. Burkitt transformation of mantle cell lymphoma. Leuk Lymphoma. 2004; 45(10):2143-2147.

(8.) Parker SM, Olteanu H, Vantuinen P, et al. Follicular lymphoma transformation to dual translocated Burkitt-like lymphoma: improved disease control associated with radiation therapy. Int J Hematol. 2009; 90(5):616-622.

(9.) Prochorec-Sobieszek M, Majewski M, Sikorska A, et al. Transformation in lymphomas--morphological, immunophenotypic and molecular features. Pol J Pathol. 2006; 57(2):63-70.

(10.) Lin P, Bueso-Ramos C, Wilson CS, Mansoor A, Medeiros LJ. Waldenstrom macroglobulinemia involving extramedullary sites: morphologic and immunophenotypic findings in 44 patients. Am J Surg Pathol. 2003; 27(8):1104-1113.

(11.) Sanchez-Beato M, Sanchez-Aguilera A, Piris MA. Cell cycle deregulation in B-cell lymphomas. Blood. 2003; 101(4):1220-1235.

(12.) Hummel M, Bentink S, Berger H, et al. A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006; 354(23):2419-2430.

(13.) Cazzaniga G, Daniotti M, Tosi S, et al. The paired box domain gene PAX5 is fused to ETV6sol; TEL in an acute lymphoblastic leukemia case. Cancer Res. 2001; 61(12):4666-4670.

(14.) Kobrin C, Cha SC, Qin H, et al. Molecular analysis of light-chain switch and acute lymphoblstic leukemia transformation in two follicular lymphomas: implications for lymphomagenesis. Leuk Lymphoma. 2006; 47(8):1523-1534.

(15.) Yamamoto R, Takaori-Kondo A, Kanda J, et al. Durable remission of large B-cell lymphoma transformed from lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia successfully treated with sequential immunochemotherapy followed by reduced-intensity allogeneic stem cell transplantation. Bone Marrow Transplant. 2008; 41(6):591-593.

Deniz Peker, MD; Brian Quigley, MD; Dahui Qin, MD, PhD; Peter Papenhausen, PhD; Ling Zhang, MD

Accepted for publication January 20, 2012.

From the Department of Hematopathology & Laboratory Medicine, Moffitt Cancer Center, Tampa, Florida (Drs Peker, Qin, and Zhang); the Department of Anatomic Pathology, University of South Florida, Tampa (Dr Quigley); and the Genetics Department, LabCorp Diagnostics, Research Triangle Park, North Carolina (Dr Papenhausen).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Ling Zhang, MD, Department of Hematopathology & Laboratory Medicine, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 (e-mail:


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Author:Peker, Deniz; Quigley, Brian; Qin, Dahui; Papenhausen, Peter; Zhang, Ling
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Case study
Date:Jan 1, 2013
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