Mucosa-associated lymphoid tissue (MALT) lymphoma is specifically associated with t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21). t(11;18)(q21;q21) fuses the N-terminus of the API2 gene to the C-terminus of the MALT1 gene and generates a functional API2-MALT1 product. t(1;14)(p22;q32) and t(14;18)(q32;q21) bring the BCL10 and MALT1 genes respectively to the IGH locus and deregulate their expression. The oncogenic activity of the three chromosomal translocations is linked by the physiological role of BCL10 and MALT1 in antigen receptor-mediated NFkappaB activation. In this study, MALT1 and BCL10 expression was examined in normal lymphoid tissues and 423 cases of MALT lymphoma from eight sites, and their expression was correlated with the above translocations, which were detected by molecular and molecular cytogenetic methods. In normal B-cell follicles, both MALT1 and BCL10 were expressed predominantly in the cytoplasm, high in centroblasts, moderate in centrocytes and weak/negative in mantle zone B-cells. In MALT lymphoma, MALT1 and BCL10 expression varied among cases with different chromosomal translocations. In 9/9 MALT lymphomas with t(14;18)(q32;q21), tumour cells showed strong homogeneous cytoplasmic expression of both MALT1 and BCL10. In 12/12 cases with evidence of t(1;14)(p22;q32) or variants, tumour cells expressed MALT1 weakly in the cytoplasm but BCL10 strongly in the nuclei. In all 67 MALT lymphomas with t(11;18)(q21;q21), tumour cells expressed weak cytoplasmic MALT1 and moderate nuclear BCL10. In MALT lymphomas without the above translocations, both MALT1 and BCL10, in general, were expressed weakly in the cytoplasm. Real-time quantitative RT-PCR showed a good correlation between MALT1 and BCL10 mRNA expression and underlining genetic changes, with t(14;18)(q32;q21)- and t(1;14)(p22;q32)-positive cases displaying the highest MALT1 and BCL10 mRNA expression respectively. These results show that MALT1 expression pattern is identical to that of BCL10 in normal lymphoid tissues but varies in MALT lymphomas, with high cytoplasmic expression of both MALT1 and BCL10 characterizing those with t(14;18)(q32;q21).
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK LBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma with characteristic ALK rearrangements. Diagnosis of ALK LBCL can be challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. The purpose of this study is to further explore the clinicopathologic features of ALK LBCL to ensure the awareness and accurate diagnosis of this entity. We retrospectively reviewed the data from 26 cases in our institutions and additional 108 cases from the literature. ALK LBCL typically occurred in the lymph nodes of young and middle-aged, immunocompetent patients. The medium age was 35 years with a male to female ratio of 3.5:1. Vast majority of cases showed immunoblastic and/or plasmablastic morphology. All cases expressed ALK protein with a cytoplasmic granular pattern in most of them. Common B-cell markers (CD20, CD79a, and PAX5) were typically negative, but the tumor cells mostly expressed 2 B-cell transcriptional factors, BOB1 and OCT2. The 5-year overall survival (OS) was 34%, and the median survival was 1.83 years. In patients with stage III/IV disease, the 5-year OS was only 8%. Moreover, patients below 35 years of age had a significantly better OS than those aged 35 years or above.
Angioimmunoblastic T cell lymphoma (AITL) originates from follicular helper T-cells and is characterised by a polymorphic infiltrate with the neoplastic T-cells forming small clusters around the follicle and high endothelial venules. Despite the recent advances in its phenotypic characterisation, the genetics and molecular mechanisms underlying AITL are not fully understood. In the present study, we performed whole exome sequencing in 9 cases of AITL from Taiwan (n = 6) and U.K. (n = 3). We confirmed frequent mutations in TET2 (9/9), DNMT3A (3/9), IDH2 (3/9), RHOA (3/9) and PLCG1 (2/9) as recently reported by others. More importantly, we identified mutations in TNFRSF21 (1/9), CCND3 (1/9) and SAMSN1 (1/9), which are not yet seen or strongly implicated in the pathogenesis of AITL. Among the pathogenic mutations identified in AITL, mutations in DNA methylation regulators TET2 and DNMT3A occur early in hematopoietic stem cells as shown by previous studies, and these genetic events enhance the self-renewal of hematopoietic stem cells, but are unlikely to have any major impact on T-cell differentiation. Mutations in RHOA, PLCG1 and TNFRSF21 (DR6), which encode proteins critical for T-cell biology, most likely promote T-cell differentiation and malignant transformation, consequently generating the malignant phenotype. Our findings extend the molecular insights into the multistage development of AITL.
Angioimmunoblastic T‐cell lymphoma (AITL) is a neoplastic proliferation of T follicular helper cells with clinical and histological presentations suggesting a role of antigenic drive in its development. Genetically, it is characterized by a stepwise acquisition of somatic mutations, with early mutations involving epigenetic regulators (TET2, DNMT3A) and occurring in haematopoietic stem cells, with subsequent changes involving signaling molecules (RHOA, VAV1, PLCG1, CD28) critical for T‐cell biology. To search for evidence of potential oncogenic cooperation between genetic changes and intrinsic T cell receptor (TCR) signaling, we investigated somatic mutations and T‐cell receptor β (TRB) rearrangement in 119 AITL, 11 peripheral T‐cell lymphomas with T follicular helper phenotype (PTCL‐TFH), and 25 PTCL‐NOS using Fluidigm polymerase chain reaction (PCR) and Illumina MiSeq sequencing. We confirmed frequent TET2, DNMT3A, and RHOA mutations in AITL (72%, 34%, 61%) and PTCL‐TFH (73%, 36%, 45%) and showed multiple TET2 mutations (2 or 3) in 57% of the involved AITL and PTCL‐TFH. Clonal TRB rearrangement was seen in 76 cases with multiple functional rearrangements (2–4) in 18 cases (24%). In selected cases, we confirmed bi‐clonal T‐cell populations and further demonstrated that these independent T‐cell populations harboured identical TET2 mutations by using BaseScope in situ hybridization, suggesting their derivation from a common TET2 mutant progenitor cell population. Furthermore, both T‐cell populations expressed CD4. Finally, in comparison with tonsillar TFH cells, both AITL and PTCL‐TFH showed a significant overrepresentation of several TRB variable family members, particularly TRBV19*01. Our findings suggest the presence of parallel neoplastic evolutions from a common TET2 mutant haematopoietic progenitor pool in AITL and PTCL‐TFH, albeit to be confirmed in a large series of cases. The biased TRBV usage in these lymphomas suggests that antigenic stimulation may play an important role in predilection of T cells to clonal expansion and malignant transformation. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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