Tandem triplication of the BCL2 gene in CD5-positive intravascular large B cell lymphoma with bone marrow involvement

Abstract

Dear Editor, Intravascular large B cell lymphoma (IVLBCL) is a rare subtype of diffuse large B cell lymphoma (DLBCL) characterized by the selective growth of lymphoma cells within the lumina of vessels [1]. Cytogenetically, the majority of IVLBCL cases demonstrated complex karyotypes with multiple numerical and structural changes, and the most frequent duplicated regions were shown to be the 11q13→qter region and all of chromosome 18 [2, 3]. On the other hand, triplications of chromosome segments other than 1q have been rarely found in hematological malignancies [4–8]. Here, we describe an unusual case of IVLBCL with a tandem triplication of the BCL2 gene at 18q21. An 82 year-old female was admitted because of fever. Computed tomography scans revealed hepatosplenomegaly without lymphadenopathy. Peripheral blood (PB) examination showed hemoglobin 105 g/L, platelets 52×10/L, and leukocytes 10.1× 10/Lwith 15% abnormal lymphocytes. Serum levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor were 6,382 IU/L (normal range, 115~217) and 8,429 U/mL (124~ 466), respectively. Bone marrow (BM) was normocellular with 42.4 % abnormal lymphocytes positive for CD5, CD19, CD20, and HLA-DR (Fig. 1a). Pathological examination of the BM revealed a focal and sinusoidal growth pattern of large lymphoid cells, indicating a diagnosis of IVLBCL (Fig. 1b). Immunohistochemistry demonstrated that they were positive for CD5, CD20, BCL2, and MUM1, but negative for CD10 and BCL6 (Fig. 1c, d). The patient received R-CHOP therapy and achieved hematological complete remission. However, 12 months later, she relapsed and died of progressive disease. G banding and spectral karyotyping of BM cells showed 47,XX,del (2)(q?),+del(3)(p?),der(10)t(10;20)(q24;?), dup(17)(q21q23),dup(18)(q11.2q23) [20] (Fig. 1e). Unexpectedly, fluorescence in situ hybridization (FISH) detected three BCL2 signals on the dup(18)(q11.2q23), indicating a tandem triplication of BCL2 (Fig. 1f). Namely, the short 18q fragment containing BCL2 attached to the dup(18). FISH on interphase nuclei confirmed four BCL2 signals. According to the Mitelman Database, nine cases of hematological malignancies with duplication/triplication of 18q (duplication, eight; triplication, one) in the stem-lines have been described [4, 9, 10]. All cases were diagnosed with B lymphoid malignancies. The duplicated regions in two cases of acute lymphoblastic leukemia did not contain 18q21, whereas those in seven cases of B cell lymphomas (DLBCL, four; IVLBCL, one; Burkitt lymphoma, one; mantle cell lymphoma, one) retained 18q21. Thus, duplication/triplication of 18q including 18q21 seems to be specifically associated with B cell lymphomas and suggests the significance of BCL2 in their pathogenesis. Among these, one case with trp(18)(?q21q23) exhibited a tandem triplication of BCL2 [2]. This 62-year-old male was diagnosed as having IVLBCL with BM/PB involvement, thrombocytopenia (34×10/L), and high LDH (2,266 U/L). Lymphoma cells were positive for K. Yamamoto (*) :A. Okamura :K. Yakushijin :H. Matsuoka : H. Minami Division of Medical Oncology/Hematology, Department of Medicine, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan e-mail: kyamamo@med.kobe-u.ac.jp