Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.

Plasmablastic lymphoma was initially described as a variant of diffuse large B-cell lymphoma (DLBCL) involving the oral cavity of HIV+ patients and characterized by immunoblastic morphology and a plasma cell phenotype. However, other lymphomas may exhibit similar morphologic and immunophenotypic features. To determine the significance of plasmablastic differentiation in DLBCL and examine the heterogeneity of lymphomas with these characteristics, we examined 50 DLBCLs with low/absent CD20/CD79a and an immunophenotype indicative of terminal B-cell differentiation (MUM1/CD38/CD138/EMA-positive). We were able to define several distinct subgroups. Twenty-three tumors were classified as plasmablastic lymphoma of the oral mucosa type and showed a monomorphic population of immunoblasts with no or minimal plasmacytic differentiation. Most patients were HIV+ and EBV was positive in 74%. Eleven (48%) cases presented in the oral mucosa, but the remaining presented in other extranodal (39%) or nodal (13%) sites. Sixteen cases were classified as plasmablastic lymphoma with plasmacytic differentiation. These were composed predominantly of immunoblasts and plasmablasts, but in addition exhibited more differentiation to mature plasma cells. Only 33% were HIV+, EBV was detected in 62%, and 44% had nodal presentation. Nine cases, morphologically indistinguishable from the previous group, were secondary extramedullary plasmablastic tumors occurring in patients with prior or synchronous plasma cell neoplasms, classified as multiple myeloma in 7 of the 9. Two additional neoplasms were an HHV-8+ extracavitary variant of primary effusion lymphoma and an ALK+ DLBCL. HHV-8 was examined in 39 additional cases, and was negative in all. In conclusion, DLBCLs with plasmablastic differentiation are a heterogeneous group of neoplasms with different clinicopathological characteristics that may correspond to different entities.

Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.next-generation sequencing | cancer genetics | cancer heterogeneity M antle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1 (1). CCND1 is a weak oncogene that requires the cooperation of other oncogenic events to transform lymphoid cells (2). Molecular studies have identified alterations in components of the cell-cycle regulation, DNA damage response, and cell survival pathways (3, 4), but the profile of mutated genes contributing to the pathogenesis of MCL and cooperating with CCND1 is not well defined (1). Most MCL cases have a rapid evolution and an aggressive behavior with an unfavorable outcome with current therapies (5). Paradoxically, a subset of patients follows an indolent clinical evolution with stable disease even in the absence of chemotherapy (6, 7). This favorable behavior has been associated with IGHV-mutated (8, 9) and lack of expression of SOX11 (10, 11), a transcription factor highly specific of MCL that contributes to the aggressive behavior of this tumor (12). However, the molecular mechanisms responsible for this clinical heterogeneity are not well understood.To gain insight into the molecular pathogenesis of MCL we performed whole-genome sequencing (WGS) and whole-exome sequencing (WES) of 29 MCL and further investigated mutated genes in an expanded series of patients. We also analyzed the subclonal heterogeneity of the tumors and their modulation during the evolution of the disease. Results Landscape of Mutations in MCL.We performed WGS and WES of 4 and 29 MCL, respectively. These patients were re...

To analyze the relationship between immunophenotyping profile and main clinicopathological features and outcome in diffuse large B-cell lymphoma (DLBCL), we studied 128 patients (59 men, 69 women; median age 65 years) consecutively diagnosed with de novo DLBCL in a single institution. Cells from each patient were immunostained with CD20, CD79a, CD5, CD10, bcl-6, MUM1, CD138, bcl-2, p53, p27, and Ki-67 antibodies. Four immunophenotyping profiles were distinguished according to the pattern of differentiation: germinal center-CD10 ؉ (GC-, and plasmablastic (CD10 ؊ /bcl-6 ؊ / MUM1 ؉ /CD138 ؉ ). Rearrangement of bcl-2 was studied by polymerase chain reaction (PCR) in 57 patients. Single-antigen expression was as follows: CD5, 2%; CD10, 21%; bcl-6, 72%; MUM1, 54%; CD138, 2%; bcl-2, 59%; p53, 28%; p27, 40%. Distribution according to differentiation profiles was as follows: GC-CD10 ؉ , 24 patients, GC-CD10-, 30 patients; pGC, 60 patients; plasmablastic, 2 patients; other patterns, 12 patients. The pGC profile was associated with primary nodal presentation and immunoblastic morphology, whereas GC-CD10 ؉ tumors showed disseminated disease, centroblastic morphology, bcl-2 rearrangement, and lower Ki-67 proliferative index.