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Virchows Archiv : An International... Jan 2023Non-cutaneous extranodal NK/T cell lymphoproliferations constitute a heterogenous group of rare neoplasms, occurring primarily in the gastro-intestinal tract, nasal... (Review)
Review
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.
Topics: Humans; Killer Cells, Natural; Lymphoma, Large-Cell, Anaplastic; Lymphoma, Extranodal NK-T-Cell; Lymphoproliferative Disorders; Gastrointestinal Tract
PubMed: 36336765
DOI: 10.1007/s00428-022-03434-0 -
Journal of Hematology & Oncology Jun 2022Natural killer (NK)/T-cell lymphomas are aggressive malignancies with a predilection for Asian and South American populations. Epstein-Barr virus (EBV) infection in... (Review)
Review
Natural killer (NK)/T-cell lymphomas are aggressive malignancies with a predilection for Asian and South American populations. Epstein-Barr virus (EBV) infection in lymphoma cells is universal. Predominantly extranodal, NK/T-cell lymphomas are divided clinically into nasal (involving the nose and upper aerodigestive tract), non-nasal (involving the skin, gastrointestinal tract, testes, and other organs), and aggressive leukaemia/lymphoma (involving the marrow and multiple organs) subtypes. Initial assessment should include imaging with positron emission tomography computed tomography (PET/CT), quantification of plasma EBV DNA as a surrogate marker of lymphoma load, and bone marrow examination with in situ hybridization for EBV-encoded small RNA. Prognostication can be based on presentation parameters (age, stage, lymph node involvement, clinical subtypes, and EBV DNA), which represent patient factors and lymphoma load; and dynamic parameters during treatment (serial plasma EBV DNA and interim/end-of-treatment PET/CT), which reflect response to therapy. Therapeutic goals are to achieve undetectable plasma EBV DNA and normal PET/CT (Deauville score ≤ 3). NK/T-cell lymphomas express the multidrug resistance phenotype, rendering anthracycline-containing regimens ineffective. Stage I/II nasal cases are treated with non-anthracycline asparaginase-based regimens plus sequential/concurrent radiotherapy. Stage III/IV nasal, and non-nasal and aggressive leukaemia/lymphoma cases are treated with asparaginase-containing regimens and consolidated by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable patients. Autologous HSCT does not improve outcome. In relapsed/refractory cases, novel approaches comprise immune checkpoint blockade of PD1/PD-L1, EBV-specific cytotoxic T-cells, monoclonal antibodies, and histone deacetylase inhibitors. Future strategies may include inhibition of signalling pathways and driver mutations, and immunotherapy targeting the lymphoma and its microenvironment.
Topics: Anthracyclines; Asparaginase; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Leukemia; Lymphoma, Extranodal NK-T-Cell; Positron Emission Tomography Computed Tomography; Tumor Microenvironment
PubMed: 35659326
DOI: 10.1186/s13045-022-01293-5 -
Leukemia Sep 2021Natural killer/T-cell lymphoma (NKTL) is a sub-type of Epstein-Barr virus (EBV)-related non-Hodgkin lymphomas common in Asia and Latin America but rare elsewhere. Its... (Review)
Review
Natural killer/T-cell lymphoma (NKTL) is a sub-type of Epstein-Barr virus (EBV)-related non-Hodgkin lymphomas common in Asia and Latin America but rare elsewhere. Its pathogenesis is complex and incompletely understood. Lymphoma cells are transformed from NK- or T-cells, sometimes both. EBV-infection and subsequent genetic alterations in infected cells are central to NKTL development. Hemophagocytic syndrome is a common complication. Accurate staging is important to predict outcomes but there is controversy which system is best. More than two-thirds of NKTL lympohmas are localized at diagnosis, are frequently treated with radiation therapy only and have 5-year survival of about 70 percent. Persons with advanced NKTLs receive radiation therapy synchronously or metachronously with diverse multi-drug chemotherapy typically including L-asparginase with 5-year survival of about 40 percent. Some persons with widespread NKTL receive chemotherapy only. There are few data on safety and efficacy of high-dose therapy and a haematopoietic cell autotransplant. Immune therapies, histone deacetylase (HDAC)-inhibitors and other drugs are in early clinical trials. There are few randomized controlled clinical trials in NKTLs and no therapy strategy is clearly best; more effective therapy(ies) are needed. Some consensus recommendations are not convincingly evidence-based. Mechanisms of multi-drug resistance are considered. We discuss these issues including recent advances in our understanding of and therapy of NKTLs.
Topics: Animals; Combined Modality Therapy; Humans; Lymphoma, Extranodal NK-T-Cell; Lymphoma, T-Cell, Peripheral; Prognosis
PubMed: 34117356
DOI: 10.1038/s41375-021-01313-2 -
Molecular Biomedicine Sep 2023Approximately 30% of lymphomas occur outside the lymph nodes, spleen, or bone marrow, and the incidence of extranodal lymphoma has been rising in the past decade. While... (Review)
Review
Approximately 30% of lymphomas occur outside the lymph nodes, spleen, or bone marrow, and the incidence of extranodal lymphoma has been rising in the past decade. While traditional chemotherapy and radiation therapy can improve survival outcomes for certain patients, the prognosis for extranodal lymphoma patients remains unsatisfactory. Extranodal lymphomas in different anatomical sites often have distinct cellular origins, pathogenic mechanisms, and clinical manifestations, significantly influencing their diagnosis and treatment. Therefore, it is necessary to provide a comprehensive summary of the pathogenesis, diagnosis, and treatment progress of extranodal lymphoma overall and specifically for different anatomical sites. This review summarizes the current progress in the common key signaling pathways in the development of extranodal lymphomas and intervention therapy. Furthermore, it provides insights into the pathogenesis, diagnosis, and treatment strategies of common extranodal lymphomas, including gastric mucosa-associated lymphoid tissue (MALT) lymphoma, mycosis fungoides (MF), natural killer/T-cell lymphoma (nasal type, NKTCL-NT), and primary central nervous system lymphoma (PCNSL). Additionally, as PCNSL is one of the extranodal lymphomas with the worst prognosis, this review specifically summarizes prognostic indicators and discusses the challenges and opportunities related to its clinical applications. The aim of this review is to assist clinical physicians and researchers in understanding the current status of extranodal lymphomas, enabling them to make informed clinical decisions that contribute to improving patient prognosis.
PubMed: 37718386
DOI: 10.1186/s43556-023-00141-3 -
Leukemia & Lymphoma Dec 2020A modification of the SMILE regimen with dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) followed by Intensity-Modulated Radiotherapy (IMRT)...
A modification of the SMILE regimen with dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) followed by Intensity-Modulated Radiotherapy (IMRT) at lower than usual dose, has been adopted as standard of care for extranodal NK-/T-cell lymphoma (ENKL) at our institution. mSMILE is a short course, intensive regimen incorporating pegylated asparaginase. Here, we describe clinical details, outcome and safety of patients receiving mSMILE. Among 28 patients with ENKL treated, response post-mSMILE was 93% (CR 68%), response post IMRT was 95% (CR 87.5%). Among early-stage patients/low PINK-E ( = 13), overall survival (OS) was 100% at the median follow-up of 31 months; progression-free survival (PFS) was 92%. Advanced-stage and intermediate/high PINK-E patients fared similarly (OS 43%, PFS 33.3% at the median follow-up). Thirty-two percent of the patients experienced G3-4 non-hematologic toxicity, all experienced hematologic toxicity. Most localized-stage patients achieved long-term disease control. Despite high response rates, most of the advanced stage patients relapsed quickly.
Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Dexamethasone; Humans; Ifosfamide; Lymphoma, Extranodal NK-T-Cell; Radiotherapy, Intensity-Modulated; Treatment Outcome
PubMed: 32844695
DOI: 10.1080/10428194.2020.1811864 -
Haematologica Dec 2023The extranodal mature T-cell and NK-cell lymphomas and lymphoproliferative disorders represent a unique group of rare neoplasms with both overlapping and distinct... (Review)
Review
The extranodal mature T-cell and NK-cell lymphomas and lymphoproliferative disorders represent a unique group of rare neoplasms with both overlapping and distinct clinicopathological, biological, and genomic features. Their predilection for specific sites, such as the gastrointestinal tract, aerodigestive tract, liver, spleen, and skin/soft tissues, underlies their classification. Recent genomic advances have furthered our understanding of the biology and pathogenesis of these diseases, which is critical for accurate diagnosis, prognostic assessment, and therapeutic decision-making. Here we review clinical, pathological, genomic, and biological features of the following extranodal mature T-cell and NK-cell lymphomas and lymphoproliferative disorders: primary intestinal T-cell and NK-cell neoplasms, hepatosplenic T-cell lymphoma, extranodal NK/T-cell lymphoma, nasal type, and subcutaneous panniculitis-like T-cell lymphoma.
Topics: Humans; T-Lymphocytes; Killer Cells, Natural; Lymphoproliferative Disorders; Lymphoma, Extranodal NK-T-Cell; Biology
PubMed: 38037802
DOI: 10.3324/haematol.2023.282718 -
Modern Pathology : An Official Journal... Jan 2013Although almost any non-Hodgkin lymphoma can involve the spleen or an extranodal site as part of more widely disseminated disease, there is a group of small B-cell... (Review)
Review
Although almost any non-Hodgkin lymphoma can involve the spleen or an extranodal site as part of more widely disseminated disease, there is a group of small B-cell lymphomas that specifically arise in these locations. These are important to recognise as some appear to have a behaviour and prognosis that is distinct from their nodal counterparts. In addition, there are entities that are specific to extranodal locations (such as extranodal marginal zone lymphoma) and to the red or white pulp of the spleen. In this review, the characteristics of these entities will be presented as well as clues to help distinguish lymphoma from reactive infiltrates in extranodal sites and measure to distinguish between small B-cell lymphomas encountered in the spleen and at extranodal locations.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymph Nodes; Lymphoma, B-Cell, Marginal Zone; Prognosis; Spleen; Splenic Neoplasms
PubMed: 23281435
DOI: 10.1038/modpathol.2012.183 -
Journal of Hematology & Oncology Apr 2019Extranodal NK/T cell lymphoma, nasal type (ENKTL) is an aggressive malignancy with a dismal prognosis. Although L-asparaginase-based chemotherapy has resulted in... (Review)
Review
Extranodal NK/T cell lymphoma, nasal type (ENKTL) is an aggressive malignancy with a dismal prognosis. Although L-asparaginase-based chemotherapy has resulted in improved response rates, relapse occurs in up to 50% of patients with disseminated disease. There is hence an urgent need for effective targeted therapy, especially for patients with relapsed or refractory disease. Novel insights gleaned from high-throughput molecular and genomic profiling studies in recent years have contributed significantly to the understanding of the molecular biology of ENKTL, which exemplifies many of the hallmarks of cancer. Deregulated pro-proliferative signaling pathways, such as the Janus-associated kinase/signal transducer and activator of transcription (JAK/STAT), platelet-derived growth factor (PDGF), Aurora kinase, MYC, and NF-κB, have been identified as potential therapeutic targets. The discovery of the non-canonical function of EZH2 as a pro-proliferative transcriptional co-activator has shed further light on the pathogenesis of ENKTL. Loss of key tumor suppressor genes located on chromosome 6q21 also plays an important role. The best-studied examples include PR domain zinc finger protein 1(PRDM1), protein tyrosine phosphatase kappa (PTPRK), and FOXO3. Promoter hypermethylation has been shown to result in the downregulation of other tumor suppressor genes in ENKTL, which may be potentially targeted through hypomethylating agents. Deregulation of apoptosis through p53 mutations and upregulation of the anti-apoptotic protein, survivin, may provide a further growth advantage to this tumor. A deranged DNA damage response as a result of the aberration of ataxia telangiectasia-related (ATR) kinases can lead to significant genomic instability and may contribute to chemoresistance of ENKTL. Recently, immune evasion has emerged as a critical pathway for survival in ENKTL and may be a consequence of HLA dysregulation or STAT3-driven upregulation of programmed cell death ligand 1 (PD-L1). Immunotherapy via inhibition of programmed cell death 1 (PD-1)/PD-L1 checkpoint signaling holds great promise as a novel therapeutic option. In this review, we present an overview of the key molecular and pathogenic pathways in ENKTL, organized using the framework of the "hallmarks of cancer" as described by Hanahan and Weinberg, with a focus on those with the greatest translational potential.
Topics: Female; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Prognosis
PubMed: 30935402
DOI: 10.1186/s13045-019-0716-7 -
Oncoimmunology 2023Natural killer/T-cell lymphoma (NKTCL) is an incurable aggressive T-cell lymphoma closely correlated with Epstein‒Barr virus (EBV) infection. Chronic and consistent...
Natural killer/T-cell lymphoma (NKTCL) is an incurable aggressive T-cell lymphoma closely correlated with Epstein‒Barr virus (EBV) infection. Chronic and consistent viral infection induces T-cell exhaustion. Herein, we describe T-cell dysfunction in NKTCL patients for the first time. Peripheral blood mononuclear cells (PBMCs) from age-matched healthy donors (HDs) and NKTCL patients were collected, and lymphocyte distributions, multiple surface inhibitory receptors (IRs), effector cytokine production and cell proliferation were determined by flow cytometry. PBMCs from HDs were cocultured with NKTCL cell lines to verify the clinical findings. IR expression was further assessed in NKTCL tumor biopsies using multiplex immunohistochemistry (mIHC). NKTCL patients have higher frequencies than HDs of inhibitory T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). T-cell distribution also varies between NKTCL patients and HDs. T cells from NKTCL patients demonstrated higher expression levels of multiple IRs than HDs. Meanwhile, T-cell proliferation and interferon-γ production was significantly reduced in NKTCL patients. More importantly, the number of EBV-specific cytotoxic cells was lower in NTKCL patients, and these cells demonstrated upregulation of multiple IRs and secreted fewer effector cytokines. Interestingly, NKTCL cells caused normal PBMCs to acquire T-cell exhaustion phenotypes and induced generation of Tregs and MDSCs. In line with ex vivo finding, mIHC results showed that CD8+ T cells from NKTCL tumor biopsies expressed much higher level of IRs compared with reactive lymphoid hyperplasia individuals. The immune microenvironment of NKTCL patients exhibited T-cell dysfunction and accumulation of inhibitory cell components, which may contribute to impaired antitumor immunity.
Topics: Humans; Epstein-Barr Virus Infections; Lymphoma, Extranodal NK-T-Cell; Herpesvirus 4, Human; Leukocytes, Mononuclear; Killer Cells, Natural; Tumor Microenvironment
PubMed: 37250921
DOI: 10.1080/2162402X.2023.2212532 -
Lancet (London, England) Sep 1978CT findings were reviewed in 68 patients with untreated head and neck lymphoma. More than half of the patients with either Hodgkin's disease or non-Hodgkin's lymphoma... (Comparative Study)
Comparative Study
CT findings were reviewed in 68 patients with untreated head and neck lymphoma. More than half of the patients with either Hodgkin's disease or non-Hodgkin's lymphoma were detected in the earlier stages (stage I or II). Four types of abnormalities were identified with CT: nodal involvement alone (type 1), extranodal involvement alone (type 2), a combination of extranodal and nodal disease (type 3), and multifocal extranodal disease with or without nodal involvement (type 4). In the 18 patients with Hodgkin's disease, a subgroup of mixed cellularity was most common; type 1 was the prevailing CT presentation, and no type 2 or 4 lesions were observed. In the 50 patients with non-Hodgkin's lymphoma, diffuse large-cell lymphoma was the most common histologic subtype, and the most common CT presentation was type 2, followed by type 3. Lymphomatous nodes may be extensive and confluent, but often they are smaller than 2 cm and rarely are necrotized. The most frequent extranodal sites of head and neck lymphomas are Waldeyer's ring, paranasal sinuses, and nasal cavity. Extranodal lymphoma cannot be differentiated reliably from the more commonly occurring carcinoma, although it is less often associated with invasion and destruction of adjacent bony structures. Multiple sites of extranodal involvement, with or without neck lymphadenopathy, may suggest a diagnosis of non-Hodgkin's lymphoma.
Topics: Enteral Nutrition; Evaluation Studies as Topic; Humans
PubMed: 80665
DOI: 10.1016/s0140-6736(78)92740-x