Diffuse large B-cell lymphoma Li, Shaoying; Young, Ken H.; Medeiros, L. Jeffrey
Pathology,
January 2018, 2018-Jan, 2018-01-00, 20180101, Volume:
50, Issue:
1
Journal Article
Peer reviewed
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide, representing approximately 30–40% of all cases in different geographic regions. Patients most often ...present with a rapidly growing tumour mass in single or multiple, nodal or extranodal sites. The most common type of DLBCL, designated as not otherwise specified, represents 80–85% of all cases and is the focus of this review. There are also rare types of lymphoma composed of large B-cells, in aggregate about 15–20% of all neoplasms that are sufficiently distinctive to recognise separately. DLBCL not otherwise specified (referred to henceforth as DLBCL) is a heterogeneous entity in terms of clinical presentation, genetic findings, response to therapy, and prognosis. A major advance was the application of gene expression profiling (GEP) to the study of DLBCL which further clarified this heterogeneity and provided a rationale for subdividing cases into groups. The most popular system divides cases of DLBCL according to cell-of-origin into germinal centre B-cell like (GCB) and activated B-cell like (ABC) subtypes, with about 10–15% of cases being unclassifiable. Patients with the GCB subtype usually have better prognosis than patients with the ABC subtype. Although cell-of-origin is useful for predicting outcome, the GCB and ABC subtypes remain heterogeneous, with better and worse prognostic subsets within each group. Next generation sequencing (NGS) analysis of DLBCL has facilitated global identification of numerous and diverse genetic abnormalities in these neoplasms and has shown that GCB and ABC tumours have different mutation profiles. Although the therapy of patients with DLBCL is an active area of research, the current 5-year overall survival rate is 60–70% using standard-of-care frontline therapy. A precision medicine approach for the design of new therapies based on molecular findings in DLBCL is likely the best path forward. As pathologists, our role has expanded beyond diagnosis. We must perform a complete work-up of DLBCL cases. In addition to our traditional role in establishing the diagnosis, we need to analyse markers that provide information regarding prognosis and potential therapeutic targets. We also must ensure that adequate tissue is triaged for molecular studies which are essential for designing therapy regimens, particularly in the setting of disease relapse.
Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation ...by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.
Sézary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of ...SS are unknown. Here we integrate whole-genome sequencing (n=6), whole-exome sequencing (n=66) and array comparative genomic hybridization-based copy-number analysis (n=80) of primary SS samples. We identify previously unknown recurrent loss-of-function aberrations targeting members of the chromatin remodelling/histone modification and trithorax families, including ARID1A in which functional loss from nonsense and frameshift mutations and/or targeted deletions is observed in 40.3% of SS genomes. We also identify recurrent gain-of-function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ∼11%). Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment. These results highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS.
8p11 myeloproliferative syndrome: a review Jackson, Courtney C., MD; Medeiros, L. Jeffrey, MD; Miranda, Roberto N., MD
Human pathology,
04/2010, Volume:
41, Issue:
4
Journal Article
Peer reviewed
Summary The 8p11 myeloproliferative syndrome is an aggressive neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 tyrosine kinase gene on chromosome ...8p11-12. By our count, 65 cases are currently reported in the literature. This neoplasm affects patients of all ages, with a slight male predominance. Patients often present with peripheral blood eosinophilia without basophilia. Bone marrow examination commonly is hypercellular, with or without eosinophilia, which usually leads to the initial diagnosis of a myeloproliferative neoplasm. Many patients also present with or develop lymphadenopathy. Lymph node biopsy in these patients has commonly shown lymphoblastic leukemia/lymphoma, most often reported as being of T-cell lineage, but bilineal myeloid/T-cell lymphomas and less often a myeloid sarcoma are also reported. The natural history of this neoplasm is to evolve into acute leukemia, usually of myeloid or mixed lineage, and less frequently of T- or B-lymphoid lineage. The prognosis is poor despite aggressive chemotherapy, with a few patients achieving long clinical remission after stem cell transplantation. At the molecular level, all cases carry a chromosomal abnormality involving the fibroblast growth factor receptor 1 ( FGFR1 ) gene at chromosome 8p11, where 10 translocations and 1 insertion have been identified. These abnormalities disrupt the FGFR1 and various partner genes, and result in the creation of novel fusion genes and chimeric proteins. The latter include the N-terminal portion of the partner genes and the C-terminal portion of FGFR1. The most common partner is ZNF198 on chromosome 13q12. In the current World Health Organization classification, the 8p11 myeloproliferative syndrome is designated as “myeloid and lymphoid neoplasms with FGFR1 abnormalities.”
Knowledge of programmed death ligand 1 (PD-L1) expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might ...identify biomarkers that predict the efficacy of immunotherapy with anti–programmed death-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression. We found that PD-L1 expression, particularly in nongerminal center B cell–derived diffuse large B-cell lymphoma (DLBCL), is controlled and regulated by several interactive signaling pathways, including the B-cell receptor (BCR) and JAK2/STAT3 signaling pathways. We found that that BCR-mediated NFATc1 activation upregulates IL-10 chemokine expression in PD-L1+ B-cell lymphoma cells. Released IL-10 activates the JAK2/STAT3 pathway, leading to STAT3-induced PD-L1 expression. IL-10 antagonist antibody abrogates IL-10/STAT3 signaling and PD-L1 protein expression. We also found that BCR pathway inhibition by BTK inhibitors (ibrutinib, acalabrutinib, and BGB-3111) blocks NFATc1 and STAT3 activation, thereby inhibiting IL-10 and PD-L1 expression. Finally, we validated the PD-L1 signaling network in 2 primary DLBCL cohorts consisting of 428 and 350 cases and showed significant correlations among IL-10, STAT3, and PD-L1. Thus, our findings reveal a complex signaling network regulating PD-L1 expression in B-cell lymphoma cells and suggest that PD-L1 expression can be modulated by small molecule inhibitors to potentiate immunotherapies.
•BCR-mediated NFATc1 activation stimulates the immunosuppressive IL-10/STAT3/PD-L1 signaling pathway in DLBCL cells.•Small molecule inhibitors of BTK block BCR-mediated NFATc1 activation and, thereby, downregulate IL-10/STAT3/PD-L1 signaling in DLBCL cells.
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In this review, we focus on the current understanding of the diagnosis of human herpesvirus 8 (HHV8)-associated lymphoproliferative disorders-a group of entities that range from hyperplastic ...proliferations to frank lymphomas. These diseases tend to occur in immunodeficient patients, but may occur in immunocompetent individuals as well. In recent years, we have learned of occasional cases with overlapping features among HHV8 entities, such as lesions intermediate between primary effusion lymphoma and HHV8-positive diffuse large B-cell lymphoma, not otherwise specified or cases sharing features of multicentric Castleman disease and germinotropic lymphoproliferative disorder. There is also a significant clinical overlap between these entities. It is important to have a better understanding of the biology of these lesions and to refine diagnostic criteria of these lesions, as the use of immunosuppressive agents to treat a variety of diseases, the expanded use of transplant as a therapeutic modality for a variety of cancers and organ failure patients, and the extended longevity of HIV-positive patients will likely result in an increased incidence of these lymphoproliferative processes in the future.
Mutations of the TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including lymphomas. Tumor suppression by p53 occurs via both ...transcription-dependent activities in the nucleus by which p53 regulates transcription of genes involved in cell cycle, DNA repair, apoptosis, signaling, transcription, and metabolism; and transcription-independent activities that induces apoptosis and autophagy in the cytoplasm. In lymphoid malignancies, the frequency of TP53 deletions and mutations is lower than in other types of cancer. Nonetheless, the status of TP53 is an independent prognostic factor in most lymphoma types. Dysfunction of TP53 with wild-type coding sequence can result from deregulated gene expression, stability, and activity of p53. To overcome TP53 pathway inactivation, therapeutic delivery of wild-type p53, activation of mutant p53, inhibition of MDM2-mediated degradation of p53, and activation of p53-dependent and -independent apoptotic pathways have been explored experimentally and in clinical trials. We review the mechanisms of TP53 dysfunction, recent advances implicated in lymphomagenesis, and therapeutic approaches to overcoming p53 inactivation.
Clonal cytogenetic evolution with additional chromosomal abnormalities (ACAs) in chronic myelogenous leukemia (CML) is generally associated with decreased response to tyrosine kinase inhibitor (TKI) ...therapy and adverse survival. Although ACAs are considered as a sign of disease progression and have been used as one of the criteria for accelerated phase, the differential prognostic impact of individual ACAs in CML is unknown, and a classification system to reflect such prognostic impact is lacking. In this study, we aimed to address these questions using a large cohort of CML patients treated in the era of TKIs. We focused on cases with single chromosomal changes at the time of ACA emergence and stratified the 6 most common ACAs into 2 groups: group 1 with a relatively good prognosis including trisomy 8, −Y, and an extra copy of Philadelphia chromosome; and group 2 with a relatively poor prognosis including i(17)(q10), −7/del7q, and 3q26.2 rearrangements. Patients in group 1 showed much better treatment response and survival than patients in group 2. When compared with cases with no ACAs, ACAs in group 2 conferred a worse survival irrelevant to the emergence phase and time. In contrast, ACAs in group 1 had no adverse impact on survival when they emerged from chronic phase or at the time of CML diagnosis. The concurrent presence of 2 or more ACAs conferred an inferior survival and can be categorized into the poor prognostic group.
•Based on their impact on treatment and survival, ACAs in CML were stratified into good and poor prognostic groups.•ACAs in the good prognostic group showed no adverse impact on survival when they emerged from chronic phase or at the initial CML diagnosis.
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on ...the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.
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