T- and NK-cell lymphomas are neoplasms derived from immature T cells (lymphoblastic lymphomas), or more commonly, from mature T and NK cells (peripheral T-cell lymphomas, PTCLs). PTCLs are rare but ...show marked biologic and clinical diversity. They are usually aggressive and may present in lymph nodes, blood, bone marrow or other organs. More than 30 T/NK-cell derived neoplastic entities are recognized in the International Consensus Classification and the classification of the World Health Organization (5th edition), both published in 2022, which integrate most recent knowledge in hematology, immunology, pathology and genetics. In both proposals, disease definition aims to integrate clinical features, etiology, implied cell of origin, morphology, phenotype and genetic features into biologically and clinically relevant clinico-pathologic entities. Cell derivation from innate immune cells, or specific functional subsets of CD4+ T cells like follicular helper T cells, are major determinants delineating entities. Accurate diagnosis of T/NK-cell lymphoma is essential for clinical management and mostly relies on tissue biopsies. Because the histologic presentation may be heterogeneous and overlaps with that of many benign lymphoid proliferations and B-cell lymphomas, the diagnosis is often challenging. Disease location, morphology and immunophenotyping remain the main features guiding the diagnosis, often complemented by genetic analysis including clonality and high-throughput sequencing mutational studies. This review provides a comprehensive overview of the classification and diagnosis of T-cell lymphoma in the context of current concepts and scientific knowledge.
Adult hematopoietic Stem and Progenitor Cells (HSPCs) reside in the bone marrow hematopoietic niche, which regulates HSPC quiescence, self-renewal, and commitment in a demand-adapted manner. While ...the complex bone marrow niche is responsible for adult hematopoiesis, evidence exists for simpler, albeit functional and more accessible, extramedullary hematopoietic niches. Inspired by the anecdotal description of retroperitoneal hematopoietic masses occurring at higher frequency upon hormonal dysregulation within the adrenal gland, we hypothesized that the adult adrenal gland could be induced into a hematopoietic supportive environment in a systematic manner, thus revealing mechanisms underlying de novo niche formation in the adult. Here we show that upon splenectomy and hormonal stimulation, the adult adrenal gland of mice can be induced to recruit and host functional HSPCs, capable of serial transplantation, and that this phenomenon is associated with de novo formation of platelet-derived growth factor receptor α (PDGFRα) expressing stromal nodules. We further show in CXCL12-GFP reporter mice that adrenal glands contain a stromal population reminiscent of the CXCL12-Abundant Reticular (CAR) cells which compose the bone marrow HSPC niche. Mechanistically, HSPC homing to hormonally-induced adrenal glands was found dependent on the CXCR4/CXCL12 axis. Mirroring our findings in mice, we found reticular CXCL12+ cells co-expressing master niche-regulator FOXC1 in primary samples from human adrenal myelolipomas, a benign tumor composed of adipose and hematopoietic tissue. Our findings reignite long-standing questions regarding hormonal regulation of hematopoiesis and provide a novel model to facilitate the study of adult-specific inducible hematopoietic niches which may pave the way to therapeutic applications.
The impact of Human Immunodeficiency Virus (HIV) infection on the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL), one of the most common co-morbidities following HIV infection, is not ...well understood. Here, we have employed multiplexed immunofluorescence (mIF) and spatial transcriptomic analysis to dissect the impact of viral infections (EBV, HIV/EBV) on cHL TME. Compared to HIV-EBV-, HIV-EBV+ cHL TME was characterized by higher cell densities of CD8high T cells co-expressing inhibitory receptors (PD-1, TIGIT), macrophage subsets and an in situ inflammatory molecular profile associated with increased expression of TCR and BCR cell signaling pathways. Compared to HIV-EBV+, HIV+EBV+ cHL TME was characterized by significantly less CD8high T cells co-expressing PD-1 and TIGIT, a profile concomitant with significantly increased cell densities of CD155high neoplastic cells. Significant downregulation of in situ TCR-signaling and upregulation of extracellular matrix reorganization pathways were found in HIV+EBV+ cHL TME, in line with an altered topological organization of CXCL13 and heparan sulfate, an extracellular matrix glycosaminoglycan. Our data reveal the complexity of the cellular and molecular composition of cHL TME in the presence of viral infections, with possible implications for combinatorial immunotherapies. Furthermore, the data suggest specific molecular targets and pathways for further investigation that could improve our understanding of possible mechanistic links between HIV and lymphomagenesis.The impact of Human Immunodeficiency Virus (HIV) infection on the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL), one of the most common co-morbidities following HIV infection, is not well understood. Here, we have employed multiplexed immunofluorescence (mIF) and spatial transcriptomic analysis to dissect the impact of viral infections (EBV, HIV/EBV) on cHL TME. Compared to HIV-EBV-, HIV-EBV+ cHL TME was characterized by higher cell densities of CD8high T cells co-expressing inhibitory receptors (PD-1, TIGIT), macrophage subsets and an in situ inflammatory molecular profile associated with increased expression of TCR and BCR cell signaling pathways. Compared to HIV-EBV+, HIV+EBV+ cHL TME was characterized by significantly less CD8high T cells co-expressing PD-1 and TIGIT, a profile concomitant with significantly increased cell densities of CD155high neoplastic cells. Significant downregulation of in situ TCR-signaling and upregulation of extracellular matrix reorganization pathways were found in HIV+EBV+ cHL TME, in line with an altered topological organization of CXCL13 and heparan sulfate, an extracellular matrix glycosaminoglycan. Our data reveal the complexity of the cellular and molecular composition of cHL TME in the presence of viral infections, with possible implications for combinatorial immunotherapies. Furthermore, the data suggest specific molecular targets and pathways for further investigation that could improve our understanding of possible mechanistic links between HIV and lymphomagenesis.
Abstract Background Accumulating evidence suggests that DNA methylation markers could serve as sensitive and specific cancer biomarkers. Objective To determine whether a panel of methylated genes ...would have the potential to identify primary bladder cancer (BCa) in voided urine samples. Design, setting, and participants A pharmacologic unmasking reexpression analysis in BCa cell lines was initially undertaken to unveil candidate methylated genes, which were then evaluated in methylation-specific polymerase chain reaction (MSP) assays performed on DNA extracted from noncancerous and cancerous bladder tissues. The most frequently methylated genes in cancerous tissues, with 100% specificity, were retained for subsequent MSP analysis in DNA extracted from urine samples to build and validate a panel of potential methylated gene markers. Urine samples were prospectively collected at three urologic centres from patients with histologically proven BCa and processed for use in real-time MSP and cytologic analysis. Patients with nonmalignant urologic disorders were included as controls. Measurements A urine sample was classified as valid when ≥10 copies of the gene encoding ß-actin were measured in the urine sediment genomic DNA. Sensitivity, specificity, and predictive values of the MSP and cytology tests were assessed and compared. Results and limitations MSP assays performed on 466 of the 496 (94%) valid urine samples identified two genes, TWIST1 and NID2, that were frequently methylated in urine samples collected from BCa patients, including those with early-stage and low-grade disease. The sensitivity of this two-gene panel (90%) was significantly better than that of cytology (48%), with comparable specificity (93% and 96%, respectively). The positive predictive value and negative predictive value of the two-gene panel was 86% and 95%, respectively. Conclusions Detection of the methylated TWIST1 and NID2 genes in urine sediments using MSP provides a highly (≥90%) sensitive and specific, noninvasive approach for detecting primary BCa. Trial registration BlCa-001 study – EudraCt 2006-003303-40.
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a Hodgkin lymphoma expressing functional B-cell receptors (BCRs). Recently, we described a dual stimulation model of IgD+ ...lymphocyte-predominant (LP) cells by Moraxella catarrhalis antigen RpoC and its superantigen MID/hag, associated with extralong CDR3s and HLA-DRB1*04 or HLA-DRB1*07 haplotype. Aim of the present study was to extend the antigen screening to further bacteria and viruses. Fabs of 7 new and 15 previously reported cases were analyzed. The reactivity of non-Moraxella spp.-reactive Fabs against lysates of Rothia mucilaginosa was observed in 5/22 (22.7%) cases. Galactofuranosyl transferase (Gltf) and 2,3-butanediol dehydrogenase (Bdh) of R. mucilaginosa were identified by comparative silver-and immunostaining in two-dimensional gels, with subsequent mass spectrometry and validation by Western blots and ELISA. Both R. mucilaginosa Gltf and Bdh induced BCR pathway activation and proliferation in vitro. Apoptosis was induced by recombinant Gltf/ETA'- immunotoxin conjugates in DEV cells expressing recombinant R. mucilaginosa-reactive BCRs. Reactivity against M. catarrhalis RpoC was confirmed in 3/7 newly expressed BCRs (total 10/22 reactive to Moraxella spp.), resulting in 15/22 (68.2%) cases with BCR reactivity against defined bacterial antigens. These findings strengthen the hypothesis of bacterial trigger contributing to subsets of NLPHL.
Peripheral T-cell lymphoma, not otherwise specified is a heterogeneous group of aggressive neoplasms with indistinct borders. By gene expression profiling we previously reported unsupervised clusters ...of peripheral T-cell lymphomas, not otherwise specified correlating with CD30 expression. In this work we extended the analysis of peripheral T-cell lymphoma molecular profiles to prototypical CD30(+) peripheral T-cell lymphomas (anaplastic large cell lymphomas), and validated mRNA expression profiles at the protein level. Existing transcriptomic datasets from peripheral T-cell lymphomas, not otherwise specified and anaplastic large cell lymphomas were reanalyzed. Twenty-one markers were selected for immunohistochemical validation on 80 peripheral T-cell lymphoma samples (not otherwise specified, CD30(+) and CD30(-); anaplastic large cell lymphomas, ALK(+) and ALK(-)), and differences between subgroups were assessed. Clinical follow-up was recorded. Compared to CD30(-) tumors, CD30(+) peripheral T-cell lymphomas, not otherwise specified were significantly enriched in ALK(-) anaplastic large cell lymphoma-related genes. By immunohistochemistry, CD30(+) peripheral T-cell lymphomas, not otherwise specified differed significantly from CD30(-) samples down-regulated expression of T-cell receptor-associated proximal tyrosine kinases (Lck, Fyn, Itk) and of proteins involved in T-cell differentiation/activation (CD69, ICOS, CD52, NFATc2); upregulation of JunB and MUM1, while overlapping with anaplastic large cell lymphomas. CD30(-) peripheral T-cell lymphomas, not otherwise specified tended to have an inferior clinical outcome compared to the CD30(+) subgroups. In conclusion, we show molecular and phenotypic features common to CD30(+) peripheral T-cell lymphomas, and significant differences between CD30(-) and CD30(+) peripheral T-cell lymphomas, not otherwise specified, suggesting that CD30 expression might delineate two biologically distinct subgroups.
The genetics and pathogenesis of splenic marginal zone lymphoma are poorly understood. The lymphoma lacks chromosome translocation, and approximately 30% of cases are featured by 7q deletion, but the ...gene targeted by the deletion is unknown. A recent study showed inactivation of A20, a "global" NF-κB negative regulator, in 1 of 12 splenic marginal zone lymphomas. To investigate further whether deregulation of the NF-κB pathway plays a role in the pathogenesis of splenic marginal zone lymphoma, we screened several NF-κB regulators for genetic changes by PCR and sequencing. Somatic mutations were found in A20 (6/46=13%), MYD88 (6/46=13%), CARD11 (3/34=8.8%), but not in CD79A, CD79B and ABIN1. Interestingly, these genetic changes are largely mutually exclusive from each other and MYD88 mutation was also mutually exclusive from 7q deletion. These results strongly suggest that deregulation of the TLR (toll like receptor) and BCR (B-cell receptor) signaling pathway may play an important role in the pathogenesis of splenic marginal zone lymphoma.
Extranodal T- and NK-cell lymphomas de Leval, Laurence; Feldman, Andrew L.; Pileri, Stefano ...
Virchows Archiv,
01/2023, Letnik:
482, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Non-cutaneous extranodal NK/T cell lymphoproliferations constitute a heterogenous group of rare neoplasms, occurring primarily in the gastro-intestinal tract, nasal area, spleen, and liver. Their ...nomenclature refers to their usual clinical presentation and predilection for specific anatomic sites—i.e. extranodal NK/T-cell lymphoma, nasal-type, hepatosplenic T-cell lymphoma, primary intestinal T-cell lymphomas, indolent lymphoproliferative disorders of the gastrointestinal tract, and breast implant-associated anaplastic large cell lymphoma. Extranodal tissues may also be involved by T-cell leukemias, or other entities usually presenting as nodal diseases. Primary extranodal entities range from indolent to highly aggressive diseases. Here, we will review the clinicopathologic features of the pertinent entities including the recent advances in their molecular and genetic characterization, with an emphasis on the changes introduced in the 2022 International Consensus Classification of lymphoid neoplasms, and highlight the diagnostic criteria helpful to sort out the distinction with potential mimickers.
Since the publication of the Revised European-American Classification of mature lymphoid neoplasms in 1994, subsequent updates of the classification of mature lymphoid neoplasms have been generated ...through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress in the characterization of malignancies of the immune system in the last years, with many new insights provided by genomic studies, have led to the current proposal. We have followed the same process that was successfully used for the 3rd and 4th editions of the WHO classification of hematological neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional are now upgraded to definite entities. Terminology of some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification (ICC) of mature lymphoid, histiocytic, and dendritic cell tumors.
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