LAUSR

Dear Editor, Mantle cell lymphoma can be distinguished from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) by the status of its cyclin D1 expression and CCND1‐IGH fusion in the vast majority of the cases. Nevertheless, rare cases of mantle cell lymphoma have no CCND1‐IGH fusion or cyclin D1 expression, resulting in diagnostic confusion with CLL/SLL because of its morphologic and phenotypic similarity. Recently, CCND2 and CCND3 genes have been identified as rearranged with immunoglobulin gene in cyclin D1‐negative mantle cell lymphoma. This finding updates the pathogenesis of mantle cell lymphoma, and raises the possibility of these genetic alterations as markers for the diagnosis of cyclin D1‐negative mantle cell lymphoma; however, occurrence of CCND2 and CCND3 rearrangements in other B‐cell lymphoma remains to be investigated to ensure the specificity of these genetic markers. Herein, we report a case of CLL with t(6;14) (p21;q32) CCND3‐IGH, arguing against CCND3 rearrangement as a genomic hallmark to confirm the diagnosis of cyclin D1‐negative mantle cell lymphoma. A 74‐year‐old male patient was found to have marked leukocytosis with absolute lymphocytosis during a routine clinic visit. His full blood cell count showed leukocytes 50.9 � 10 L (lymphocytes 39.7 � 10 L−1; 78%), hemoglobin 12.0 gL−1, and platelets 130 � 10 L. A blood film review exhibited a monotonous population of small lymphocytes with clumped chromatin in a background of many smudge cells (Figure 1A). Subsequent bone marrow examination demonstrated a diffuse infiltrate of small mature lymphocytes that essentially replaced the hematopoietic elements. Of note, aggregates of larger lymphoid cells with prominent nucleoli were scattered throughout the lymphoid infiltrate with features suggestive of proliferation centers (Figure 1B). The vast majority of lymphocytes, including those in the proliferation centers, were positive for CD20 (Figure 1C) and LEF1 (Figure 1C, inset), and they were negative for CD3 (Figure 1C), cyclin D1, and SOX11 by immunohistochemistry. These scattered proliferation centers were highlighted by Ki67 stain (data not shown). Flow cytometry of blood and bone marrow samples demonstrated 62% and 76% monoclonal B‐cells, respectively, with discrete CD5 (Figure 1D), CD23 (Figure 1E) and restricted dim kappa light chain expression (Figure 1F). The morphologic features and immunophenotypic profile of the monoclonal B‐cells are consistent with the diagnosis of CLL. While FISH detected changes suggestive of IGH rearrangement in 63.5% and trisomy 12 in 73.5% of interphase nuclei, no CCND1‐IGH fusion was identified. Chromosome analysis revealed a clonal karyotypic abnormality: 47,XY,t(6;14) (p21;q32),+12[15]/46,XY[5]. The banding features of t(6;14) (p21;q32) (Figure 2A) was consistent with CCND3‐ IGH fusion. An interphase FISH analysis for CCND3 rearrangement was retrospectively performed on paraffin embedded section, using a break apart probe, which demonstrated rearrangement of CCND3 gene (Figure 2B). Given the evidence of rearranged IGH gene, CCND3‐IGH fusion is essentially confirmed in our case. Staging positron emission tomography/computed tomography scan demonstrated no significant lymphadenopathy or hepatosplenomegaly except a few slightly enlarged lymph nodes without avid F‐ fluorodeoxyglucose (FDG) uptake in pelvis. Given the low stage of the disease without symptoms, the patient was followed without specific treatment for his CLL. A pathognomonic hallmark of mantle cell lymphoma is the t (11;14) (q13;q32) translocation resulting in CCND1‐IGH fusion and overexpression of the CCND1 gene product cyclin D1 in lymphoma cells. Rare cases with morphologic features, immunophenotype, and clinical presentation indistinguishable from conventional mantle cell lymphoma but with no CCND1‐IGH or cyclin D1 expression are designated as cyclin D1‐negative mantle cell lymphoma. Studies have demonstrated significantly overlapped gene expression signatures and global genomic mutation profiles between conventional mantle cell lymphoma and its cyclin D1‐negative variant, suggesting they are biological kindred. A definitive diagnosis of cyclin D1‐ negative mantle cell lymphoma is challenging, especially for the case of leukemic non‐nodal variant, which is often indistinguishable from CLL in clinical presentation, morphology, immunophenotype, and cytogenetics. Diagnostic markers specific for cyclin D1‐negative mantle cell lymphoma are needed in order to make an accurate diagnosis. In their study, Vegliante et al. demonstrated that upregulation of SOX11 plays a pivotal role in the development of mantle cell lymphoma, particularly the conventional type. A separate investigation showed that SOX11 was expressed in 93% of conventional mantle cell lymphoma and 100% of cyclin D1‐negative mantle cell lymphoma. However, its expression was also detected in a significant fraction of other lymphoid neoplasms, including lymphoblastic lymphoma, T‐cell prolymphocytic leukemia, and Burkitt lymphoma.