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Background/Objectives: The primary objective of this study was to investigate clinical manifestations, time to diagnosis, and number of biopsies in patients with extranodal natural killer T-cell lymphoma (ENKTL). The secondary objectives were to determine response rates, survival outcomes, prognostic factor for overall survival (OS), and validation of the Prognostic Index of Natural Killer Lymphoma (PINK), Ann Arbor staging system (AASS), and the CA system. Methods: This retrospective study included data pertaining to patients with newly diagnosed ENKTL in Chiang-Mai University Hospital from 2004 to 2020. Comparisons between the areas under the receiver operating characteristic curve (AUC) of prognostic models (PINK, AASS, and CA system) were made. Results: Sixty patients were enrolled (n = 60) with a mean age of 49.1 ± 13.4 years. The most frequent symptom of ENKTL was nasal obstruction (66%). The median time to diagnosis was 22 days (ranging from 3 to 84 days), with 36.7% requiring more than one biopsy for diagnosis. Most patients presented with limited stage disease (75%). The median OS was 49 months. Factors associated with increased mortality were advanced stage, bone marrow involvement, gastrointestinal tract involvement, and receiving chemotherapy. Following prognostic model validation, the CA system model scored the highest level of accuracy (AUC 0.61), followed by AASS (AUC 0.58) and PINK (AUC 0.54). Conclusions: Patients with ENKTL commonly presented with nasal obstruction, with 36.7% requiring more than one biopsy for diagnosis. An advanced stage, bone marrow involvement, or gastrointestinal tract involvement were associated with poor OS. The CA system model has the highest level of accuracy for prognostic determination. [ABSTRACT FROM AUTHOR]

Autologous hematopoietic stem cell transplantation (auto-HSCT) is considered optional consolidation therapy especially for relapsed/refractory extranodal NK/T-cell lymphoma (ENKL), but its applications to newly diagnosed advanced-stage ENKL is currently limited.

Purpose: Radiotherapy is a critical treatment for early-stage extranodal nasal-type NK/T-cell lymphoma (ENKTL) and has yielded favorable survival outcomes. However, their postradiotherapy quality of life (QOL) has not been investigated. Here, we conducted a cross-sectional study to assess the QOL of ENKTL patients with disease-free survival after definitive radiotherapy and to identify factors associated with QOL and treatment optimization. Methods: This cross-sectional study included 310 patients with stage I–II ENKTL of the upper aerodigestive tract (UADT) who had received simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) with a consistent design and achieved disease-free survival. The median postradiotherapy time was 47.2 months (range, 3.1–115.7). The EORTC QLQ-H&N35 questionnaire was used to assess symptom-related QOL, and nine additional items were added to incorporate nasal, optical, and aural-related symptoms. The scores indicate the severity of the symptoms. Results: The most common postradiotherapy symptoms among patients with ENKTL were nose problems (49.7%), dry mouth (44.8%), tooth problems (41.3%), sensory problems (32.6%), and less sexuality (25.8%). Tooth problems had the highest average score of 18.6, which is still acceptable. The severity of these symptoms decreased over time and reached a plateau in the second year after radiotherapy. Multivariable regression analysis showed that whole-neck irradiation was an independent predictive factor for xerostomia (P = 0.013, OR = 1.114), while age > 60 years was a predictive factor for lower sexuality (P < 0.001, OR = 1.32). Conclusion: The QOL of patients with early-stage ENKTL after radiotherapy was favorable, and most symptoms improved over time. Radiotherapy was correlated with specific symptoms, which may suggest a direction for further improvement in SIB-IMRT. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions The aim of this study was to develop a population pharmacokinetics model for sugemalimab, a monoclonal antibody that targets programmed death‐ligand 1 (PD‐L1), using data from Phase I–III trials and to assess clinical factors affecting sugemalimab exposure.A nonlinear mixed‐effect modelling approach was employed to analyse pooled data from nine studies involving 1628 subjects to characterize the PopPK of sugemalimab. This investigation examined the influence of various covariates on sugemalimab pharmacokinetics (PK), encompassing demographics, baseline hepatic and renal function‐related covariates, and others (including anti‐drug antibody [ADA], combination treatment, Eastern Cooperative Oncology Group [ECOG] performance score, tumour burden and tumour type). Estimation accuracy and predictive ability of the final model were evaluated using various methods. The influence of covariates on sugemalimab exposure was assessed by simulation from the final model.A two‐compartment model with first‐order elimination and time‐varying clearance effectively described the PK of sugemalimab. Covariate analyses revealed significant relationships between sugemalimab clearance and body weight, albumin, gender, ADA, tumour burden and tumour type. The statistically significant covariates on central volume were body weight, albumin, gender and tumour type. No significant relationships were found in the final model for age, race, alanine aminotransferase, aspartate aminotransferase, creatinine, total bilirubin, alkaline phosphatase, combination treatment, creatinine clearance, ECOG, renal function or hepatic function. All significant covariates demonstrated less than a 20% effect on sugemalimab exposure.The PopPK model adequately described the pharmacokinetic profile of sugemalimab with no clinically meaningful impact observed on its exposure across all covariates. Dose adjustment does not appear to be necessary. [ABSTRACT FROM AUTHOR]

Posttransplantation primary cutaneous T‐cell lymphomas (PT‐CTCL) are a rare complication of sustained immunosuppression in the posttransplant setting. When present, PT‐CTCLs are typically EBV− and exhibit features of mycosis fungoides/Sézary syndrome or CD30+ lymphoproliferative disorders. We present a case of a 75‐year‐old individual who developed skin lesions 30 years after liver transplantation. Pathologic evaluation of the skin biopsy revealed involvement by a clonal, EBV+ T‐cell population of gamma/delta lineage with no evidence of systemic disease. Comprehensive genomic profiling was performed, confirming focal one‐copy loss of 6q23.3, altogether consistent with the extremely rare and unusual diagnosis of primary cutaneous EBV+ extranodal NK/T‐cell lymphoma of gamma/delta T‐cell lineage in the posttransplantation setting. [ABSTRACT FROM AUTHOR]

Background and aimExtranodal NK/T-cell lymphoma (ENKTL) is a rare and aggressive subtype of non-Hodgkin’s lymphoma that most commonly affects the nasal cavity and nasopharynx. The lung is a rare site for ENKTL involvement, and its clinical behavior and prognostic factors are not well understood. This study aimed to analyze survival outcomes and identify prognostic factors in patients with primary lung ENKTL.MethodsA retrospective analysis was conducted using data from 20 cases of primary lung ENKTL, including four patients who were treated at Peking University Third Hospital in Beijing and 16 patients were extracted from the Surveillance, Epidemiology, and End Results Program database. Clinical characteristics, treatment modalities, and survival data were collected and analyzed using Kaplan–Meier and Cox regression models to identify potential prognostic factors.ResultsThe study cohort included 13 male (65%) and 7 female (35%) patients with a median age of 57 years. Sex was a significant predictor of survival (P = 0.030), with female patients having lower survival rates. Other factors, including age, race, and disease stage, were not significantly associated with survival. Most patients received chemotherapy (45%) or a combination of chemotherapy and radiotherapy (5%), but treatment data were incomplete for 40% of the cohort. The median overall survival was poor, reflecting the aggressive nature of primary lung ENKTL.ConclusionsPrimary lung ENKTL is a rare, aggressive malignancy with limited available data. In this cohort, sex was a significant prognostic factor, while other demographic and clinical variables did not show significant associations with survival. Future research should focus on understanding the molecular and immunological drivers of this disease, with an emphasis on discovering novel therapeutic approaches. Large-scale multicenter studies are needed to improve diagnostic and treatment strategies for primary lung ENKTL.

Introduction: Extranodal NK/T-cell lymphoma (ENKTCL), a non-Hodgkin lymphoma, is known for its destructive local impact on nasal structures and systemic induction of inflammatory cytokines. Concurrent treatment with radiation and nonanthracycline-based chemotherapy has improved survival rates in patients with localized disease stages. However, survival outcomes vary significantly in advanced-stage and relapsed or refractory (R/R) cases. Methods: Therefore, we conducted a meta-analysis using random effects models to assess prognostic factors in advanced or R/R ENKTCL, employing a digital extractor on Kaplan-Meier graphs owing to the scarcity of published prospective trials for these patients. Results: We observed that patients with advanced ENKTCL treated with Lasparaginase had a median progression-free survival (PFS) of 14.3 months and an overall survival (OS) of 19 months. In R/R ENKTCL, PFS and OS were 11.7 and 15.6 months, respectively. Additionally, OS outcomes in advanced-stage ENKTCL were better in the asparaginase group than that in the non-asparaginase group, with PEG-asparaginase showing superior results compared with that using Lasparaginase. Epstein-Barr Virus (EBV)-DNA positivity in the bloodstream prior to treatment was associated with poor outcomes in advanced-stage ENKTCL, and similar trends were observed in patients with R/R ENKTCL and post-treatment EBV viremia. Discussion: Collectively, these findings suggest that chemotherapy with Lasparaginase or PEG-asparaginase can enhance survival in advanced or R/R ENKTCL. However, future strategies must be developed to effectively suppress EBV viremia and achieve a deep response toward tumor eradication. [ABSTRACT FROM AUTHOR]

The biological role of Ten‐11 translocation 2 (TET2) and the conversion of 5‐methylcytosine (5mC) to 5‐hydroxymethylcytosine (5hmC) in the development of extra‐nodal natural killer/T‐cell lymphoma (ENKTL) remains unclear. The level of 5mC and 5hmC was detected in 112 cases of ENKTL tissue specimens by immunohistochemical (IHC) staining. Subsequently, TET2 knockdown and the overexpression cell models were constructed in ENKTL cell lines. Biochemical analyses were used to assess proliferation, apoptosis, cell cycle and monoclonal formation in cells treated or untreated with L‐Ascorbic acid sodium salt (LAASS). Dot‐Blots were used to detect levels of genome 5mC and 5hmC. Additionally, the ILLUMINA 850k methylation chip was used to analyze the changes of TET2 regulatory genes. RNA‐Seq was used to profile differentially expressed genes regulated by TET2. The global level of 5hmC was significantly decreased, while 5mC was highly expressed in ENKTL tissue. TET2 protein expression was negatively correlated with the ratio of 5mC/5hmC (p < 0.0001). The 5mC/5hmC status were related to the site of disease, clinical stage, PINK score and Ki‐67 index, as well as the 5‐year OS. TET2 knockdown prolonged the DNA synthesis period, increased the cloning ability of tumor cells, increased the level of 5mC and decreased the level of 5hmC in ENKTL cells. While overexpression of TET2 presented the opposite effect. Furthermore, treatment of ENKTL cells with LAASS significantly induced ENKTL cell apoptosis. These results suggest that TET2 plays an important role in ENKTL development via regulation of 5mC and 5hmC and may serve as a novel therapeutic target for ENKTL. [ABSTRACT FROM AUTHOR]

Primary central nervous system (PCNS) extranodal NK/T‐cell lymphoma, nasal type (ENKTCL), is an exceedingly rare tumor. To the best of our knowledge, only 27 cases and only one reported aberrant CD20 expression have been documented in the literature. Here we present a second case of PCNS ENKTCL with aberrant CD20 expression in a 43‐year‐old immunocompetent Chinese female. The patient presented with tremors, weakness in the right upper limb, and a slow reaction. Magnetic resonance imaging revealed multiple brain lesions. A histological examination revealed a diffuse distribution of intermediate‐sized pleomorphic lymphocytes with angiocentric growth. The tumor cells expressed CD2, CD3, CD56, T‐cell intracellular antigen‐1, granzyme B, and Epstein–Barr virus‐encoded RNAs (EBERs), with additional partial and weak CD20 and CD30 expression. Despite a confirmatory pathological diagnosis, the patient refused treatment and was discharged, ultimately dying from the disease. In the literature review, the clinical, immunohistochemical, EBERs, treatment, and prognostic features of PCNS ENKTCL were summarized. Although PCNS ENKTCT is extremely rare, it does occur and should always be included in differential diagnoses. CD20 expression should be evaluated routinely with relevant markers. The accumulation of cases is crucial for developing an effective treatment strategy for this rare and aggressive malignancy. [ABSTRACT FROM AUTHOR]

ObjectiveSinonasal lymphomas are a rare entity that commonly present with nonspecific sinonasal symptoms and are often recognized immediately. Through this review, we aim to summarize important principles in diagnosis and treatment of sinonasal lymphomas, with the goal of disseminating the current knowledge of this under-recognized malignancy to otolaryngologists.MethodsSystemic review using PRISMA guidelines of foundational scholarly articles, guidelines, and trials were reviewed focusing on clinical characteristics of key sinonasal lymphoma subtypes, along with available treatments in the otolaryngology, medical oncology, and radiation oncology literature.ResultsSinonasal lymphoma are derived from clonal proliferation of lymphocytes at various stages of differentiation, of which diffuse large B-cell lymphoma (DLBCL) and extranodal natural killer/T-cell lymphoma (ENKTL) are the most common. Diagnosis and staging require biopsy with immunohistochemistry in conjunction with imaging and laboratory studies. Treatment is ever evolving and currently includes multi-agent chemotherapy and/or radiation therapy.ConclusionOtolaryngologists may be the first to recognize sinonasal lymphoma, which requires a comprehensive workup and a multidisciplinary team for treatment. Symptoms are nonspecific and similar to many sinonasal pathologies, and it is crucial for otolaryngologists to keep a broad differential.Level of evidence5.

This study aimed to explore the distribution, characteristics and prognostic value of baseline peripheral blood lymphocyte subsets in patients with extranodal NK/T-cell lymphoma (NKTCL). We conducted this cross-sectional study of 205 newly-diagnosed NKTCL patients receiving first-line chemotherapy and radiation at our institute between 2010 and 2020. Baseline peripheral blood lymphocytes were detected using flow cytometry, and the clinical value was analyzed. Compared with healthy controls, patients with NKTCL presented with a distinct peripheral immunity with higher levels of cytotoxic CD8+ T cells (33.230 ± 12.090% vs. 27.060 ± 4.010%, p < 0.001) and NKT cells (7.697 ± 7.219% vs. 3.550 ± 2.088%, p < 0.001) but lower proportions of suppressive regulatory T cells (Treg, 2.999 ± 1.949% vs. 3.420 ± 1.051%, p = 0.003) and CD4+ helper T cells (Th, 33.084 ± 11.361% vs. 37.650 ± 3.153%, p < 0.001). Peripheral lymphocytes were differentially distributed according to age, stage, and primary site in patients with NKTCL. The proportion of Th cells/lymphocytes was associated with tumor burden reflected by stage (p = 0.037), serum lactate dehydrogenase (p = 0.0420), primary tumor invasion (p = 0.025), and prognostic index for NK/T-cell lymphoma (PINK) score (p = 0.041). Furthermore, elevated proportions of T cells (58.9% vs. 76.4%, p = 0.005), Th cells (56.3% vs. 68.8%, p = 0.047), or Treg cells (49.5% vs. 68.9%, p = 0.040) were associated with inferior 5-year progression-free survivals (PFS) via univariable survival analysis. Multivariate cox regression revealed elevated Th cells as an independent predictor for unfavorable PFS (HR = 2.333, 95% CI, 1.030–5.288, p = 0.042) in NKTCL. These results suggested the proportion of Th cells positively correlated with tumor burden and was a potential non-invasive biomarker for inferior survival for patients with NKTCL. [ABSTRACT FROM AUTHOR]

T-cell lymphomas (TCLs) are a rare and heterogeneous subgroup of non-Hodgkin lymphomas (NHLs), forming only 10 % of all NHL cases in Western countries. Resulting from their low incidence and heterogeneity, the current treatment outcome is generally unfavorable, with limited availability of novel therapeutic approaches. Therefore, the recent success of immune checkpoint inhibitors (ICIs) in cancer treatment motivated their clinical investigation in TCLs as well. Multiple studies showed promising results; however, cases of TCL hyper progression following ICI treatment and secondary T-cell-derived malignancies associated with ICI treatment of other cancer types were also reported. In our review, we first briefly summarize classification of T-cell-derived malignancies, general anti-tumor immune response, immune evasion, and immune checkpoint signaling. Next, we provide an overview of immune checkpoint molecule deregulation in TCLs, summarize available studies of ICIs in TCLs, and review the above-mentioned safety concerns associated with ICI treatment and T-cell-derived malignancies. Despite initial promising results, further studies are necessary to define the most suitable clinical applications and ICI therapeutic combinations with other novel treatment approaches within TCL treatment. ICIs, and their combinations, might hopefully bring the long awaited improvement for the treatment of T-cell-derived malignancies. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of different treatment strategies and risk factors on the prognosis of patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL) in a single medical center. Methods and analysis: The clinical features of 266 patients with ENKTL were retrospectively analyzed, among whom those in stages I and II received sandwich therapy, while those in stages III and IV underwent chemotherapy plus autologous hematopoietic stem cell transplantation. The Kaplan-Meier curves, univariate and multivariate Cox regression analyses were employed for survival and prognosis analysis. Statistical significance was set at P<0.05. Results: Following treatment, the post-intervention outcomes demonstrated a complete remission (CR) rate of 71.05% and a partial remission (PR) rate of 3.76%. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 70.4% and 70.9%, respectively. In addition, the PFS for patients in stage I/II was 79.8%, with an OS of 81.1%, whereas for those in stage III/IV, the PFS was 41.7% and the OS was 40.9%. Notably, the achievement of CR immediately after treatment was an independent prognostic factor (P<0.001). Patients in stage I/II depicted a favorable 5-year OS rate, while those in stage III/IV manifested a less favorable prognosis. Conclusion: Stages of the disease and whether CR was achieved following treatment are important factors determining the survival and prognosis of patients with ENKTL. Further researches focusing on disease onset and mechanisms of drug resistance will contribute to better management of ENKTL. [ABSTRACT FROM AUTHOR]

Extranasal natural killer/T-cell lymphoma arising in the heart is rare and typically presents with non-specific clinical symptoms, necessitating a biopsy for a definitive diagnosis. We report an unusual case of a 48-year-old male who initially presented with chest pain and shortness of breath. Subsequent diagnosis via pericardial fluid analysis, including flow cytometry and immunohistochemical stains, revealed extranasal NK/T-cell lymphoma without sinonasal involvement. The analysis identified neoplastic lymphoid cells expressing CD2, cytoplasmic CD3, Epstein-Barr virus, and CD56 and exhibiting increased Ki-67 staining. Additionally, the patient developed hemophagocytosis lymphocytosis secondary to NK/T cell lymphoma. Treatment included an interleukin-1 receptor antagonist (anakinra), dexamethasone, rituximab, and etoposide. Unfortunately, the patient's condition rapidly deteriorated, leading to multiorgan failure and eventual demise. Given the rarity of this lymphoma, early diagnosis based on a high suspicion level provides the best chance for improved overall survival. [ABSTRACT FROM AUTHOR]

Objective To evaluate the clinical value of red cell volume distribution width (RDW) to absolute lymphocyte count (ALC) ratio (RLR) in extranasal natural killer/T-cell lymphoma (ENKTL), and to provide information for better risk stratification.Method Clinical data of patients with ENKTL diagnosed in Zhongnan Hospital of Wuhan University from April 2013 to May 2022 were retrospectively analyzed. Kaplan-Meier curve and Cox proportional risk model were used to analyze the prognostic value of RLR. By integrating RLR, improved international prognostic index (IPI), Korean prognostic index (KPI), prognostic model of natural killer lymphoma (PINK) and nomogram-revision risk index (NRI) models were established respectively, and verified by subject operating characteristic curve.Results 72 ENKTL patients were included. There were statistically significant differences in age, ECOG PS score, IPI score, NRI score, LDH level and B symptoms (P

Background: Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive non-Hodgkin lymphoma that typically develops in the upper aerodigestive tract. Case presentation: We encountered an ENKTL patient who presented with purpura-like rashes and foot drops as initial symptoms and later developed other peripheral nerve involvement. The nerve conduction study of both the motor nerve and the sensory nerve showed axonal damage resembling mononeuropathy multiplex. Although the initial response to steroids was encouraging, the patient's symptoms reappeared and aggravated. A biopsy of the abdominal subcutaneous fat tissue with additional immunohistochemistry revealed neoplastic NK/T lymphocytes. Conclusion: We reported the first case presented as mononeuropathy multiplex as the initial clinical manifestation in ENKTL patients. Lymphoma should be considered in the diagnosis of atypical mononeuropathy in multiplex patients. [ABSTRACT FROM AUTHOR]

Abstract Background Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) of the small intestine, is a disease with extremely poor prognosis. We describe treatment in a case which is novel in that it demonstrated long-term survival. Case presentation A 68-year-old man was admitted to the emergency department of our hospital with the complaint of severe umbilical pain with tenderness and muscular defense. An abdominal computed tomography scan revealed a thick-wall mass on the small intestine and intra-abdominal free air. He was suspected of perforation of a small intestinal tumor and underwent emergency surgery. The surgery revealed a perforated tumor ulcer, and ENKL was diagnosed from the postoperative pathological findings. The patient’s postoperative course was uneventful. He was further treated with adjuvant chemotherapy by hematologist comprising six courses of dexamethasone, etoposide, ifosfamide, and carboplatin. The patient demonstrated long-term survival and was in remission at the time of writing, four years and five months after surgery. Conclusions We report a rare case of long-term survival of perforated ENKL of the small intestine achieved by surgery and adjuvant chemotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin. It is essential to consult with a hematologist to determine the most appropriate chemotherapy such as DeVIC if one encounters rare postoperative pathological findings of ENKL. To elucidate the pathophysiology of this disease and to prolong survival of affected patients, accumulation of cases of long-term survival and examination of associated characteristics is necessary.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), which is a rare form of mature T/NK cell lymphoma in children, currently lacks a standardized first-line treatment approach. However, a treatment protocol known as the "sandwich" regimen has been used in children newly diagnosed with ENKTL. This protocol combines the administration of methotrexate, ifosfamide, etoposide, pegaspargase, and dexamethasone (referred to as SMILE) with the addition of radiotherapy (RT). From September 2017 to December 2020, a total of five patients were included in the study, consisting of three males and two females. The median age of onset was 10.6 years (range, 9.8 to 14.0 years). Among the patients, four had nasal/nasopharyngeal disease at stage II, while one patient had extra nasal disease involving the skin at stage IV. The median EBV-DNA level in plasma was 1.68 × 103 copies/ml (range, 0.44 to 21.1 × 103copies/ml). All the patients had good overall response after 2 cycles of chemotherapy and radiotherapy, including 4 of the patients who had a complete response and 1 of the patients with partial remission. The patient with stage IV received allogeneic hematopoietic stem cell transplantation after the EBV-DNA level was elevated again during treatment. One patient in the low-risk group experienced grade 4 oral mucositis, while no other severe complications or treatment-related deaths were observed. The median follow-up period was 22 months (range, 5 to 57 months). All five patients successfully completed their treatment, with four patients achieving event-free survival, and one patient was lost to follow-up. The median OS time and EFS time was 33 months (range: 18–57 months) and 20 months (range: 5–47 months), respectively. The sandwich protocol has demonstrated a high response rate, good tolerance to chemotherapy, and no treatment-related fatalities. However, further confirmation is necessary through additional clinical studies involving larger sample sizes. Clinical trial registration number: Due to modified SMILE regimens with sandwiched radiotherapy yielded promising outcomes in children ENKTL, we have carried out a phase II multicenter clinical trial (ChiCTR220005954) for children ENKTL in China to further verify the efficacy and safety. [ABSTRACT FROM AUTHOR]

Lymphoproliferative disorders arising in a background of immune deficiency/dysregulation correspond to a spectrum of disorders ranging from non-noxious hyperplasias to aggressive lymphomas, mainly of B-cell type. We describe a case of an Epstein-Barr virus-positive T-cell lymphoma, with a cutaneous presentation and unusual pathological features in a patient under immunosuppression with infliximab. A 60-year-old patient, with a history of ankylosing spondylitis and autoimmune hemolytic anemia, treated with infliximab and low-dose prednisone since 2013, presented with a 7 cm ulcerated, well-demarcated tumor on his left lower back and a 20 cm scaly, well-demarcated erythematous patch in the left scapular region. A skin biopsy revealed a diffuse infiltration of the superficial and deep dermis by atypical, intermediate-size lymphocytes that expressed CD2, CD3, CD56, TIA-1, Granzyme B, TCRδ, and EBER. There was no evidence of epidermotropism, vasculotropism, or necrosis. The fluor-d-glucose positron emission tomography showed a large splenic, hepatic, bone marrow, and nodal uptake. A diagnosis of an extranodal NK/T-cell lymphoma in association with immunosuppression was rendered. With this article, we aim to add awareness to the difficulty of diagnosis, the careful use of immunomodulators, clinical suspiciousness, and surveillance of possible consequences warranted in all patients under prolonged immunosuppression. [ABSTRACT FROM AUTHOR]

Anti-SARS-CoV-2 vaccines were developed in response to the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the BNT162b2 mRNA vaccine is effective, adverse effects have been reported. Here, we report a case of extranodal NK/T-cell lymphoma, nasal type (ENKL), of the left arm following BNT162b2 mRNA vaccination. A 73-year-old male presented with a lump in the left arm, which was the site where he received the BNT162b2 mRNA vaccine 3 months prior. He was treated with topical corticosteroids and debridement, but the tumor progressed. Additionally, fever, night sweats, and general fatigue were observed. Laboratory findings included thrombocytopenia, elevated lactate dehydrogenase, and soluble interleukin-2 receptor levels. Skin biopsy led to a diagnosis of ENKL. The patient was treated with a 50% dose of SMILE therapy and radiotherapy, resulting in regression of the tumor. It seems that latent Epstein–Barr virus (EBV)-infected NK/T cells were reactivated by vaccination and contributed to the onset of ENKL. This is the first report of ENKL after BNT162b2 mRNA vaccination. The present case highlights the possible risk of development of malignant lymphoma, including ENKL at the injection site, after BNT162b2 COVID-19 vaccination. [ABSTRACT FROM AUTHOR]

EBV is a lymphotropic virus, member of the Herpesviridae family that asymptomatically infects more than 90% of the human population, establishing a latent infection in memory B cells. EBV exhibits complex survival and persistence dynamics, replicating its genome through the proliferation of infected B cells or production of the lytic virions. Many studies have documented the infection of T/NK cells by EBV in healthy individuals during and after primary infection. This feature has been confirmed in humanized mouse models. Together these results have challenged the hypothesis that the infection of T/NK cells per se by EBV could be a triggering event for lymphomagenesis. Extranodal NK/T-cell lymphoma (ENKTCL) and Epstein-Barr virus (EBV)-positive nodal T- and NK-cell lymphoma (NKTCL) are two EBVassociated lymphomas of T/NK cells. These two lymphomas display different clinical, histological and molecular features. However, they share two intriguing characteristics: the association with EBV and a geographical prevalence in East Asia and Latin America. In this review we will discuss the genetic characteristics of EBV in order to understand the possible role of this virus in the oncogenesis of ENKTCL and NKTCL. In addition, the main immunohistological, molecular, cytogenetic and epigenetic differences between ENKTCL and NKTCL will be discussed, as well as EBV differences in latency patterns and other viral molecular characteristics. [ABSTRACT FROM AUTHOR]

Background: To investigate the clinical features, pathological features and prognostic factors of cutaneous extranodal natural killer/T-cell lymphoma (CENKTL). Methods: A total of 20 cases with CENKTL from February 2013 to November 2021 were analysed retrospectively. Results: The patients included 15 men and five women, and their ages ranged from 19 to 92 (median age of 61) years. The most common lesions were on the extremities, followed by the trunk. Histopathological examination showed atypical lymphocyte infiltrate in dermis and subcutaneous fat. The tumour tissue showed vascular proliferation, vascular occlusion, and coagulation necrosis. In situ hybridisation revealed that 20 patients were positive for Epstein-Barr virus-coding ribonucleic acid. Immunohistochemistry showed that the tumour cells were positive for CD3ε (18/20 and 90%), CD56 (19/20 and 95%), T-cell intracellular antigen (TIA-1) (13/14 and 92.9%) and CD20 (5/20, 25%). About 20 patients were positive for Ki-67 with values of 30-90%. A total of 11 of the 20 patients died, and two patients were lost to follow-up. The 2-year overall survival was 24%, and the median overall survival was 17 months. Univariate analysis revealed that involvement of lymph nodes (P = 0.042) correlated with worse survival. Limitations: This is a retrospective study design and has a limited number of patients. Conclusion: CENKTL is rare and has a poor prognosis. Diagnosis is challenging due to non-specific clinical symptoms and histopathology results. A comprehensive judgement should be made based on related clinical manifestations and histopathological and molecular examination. Lymph node involvement is an independent prognostic factor for CENKTL. [ABSTRACT FROM AUTHOR]

Abstract Background Extranodal natural killer (NK)/T‐cell lymphoma (ENKTCL) is an aggressive lymphoma with marked heterogeneity, resulting in a distinct prognosis even in patients with the same disease stage. The nomogram‐revised risk index (NRI) has been proposed to stratify patients with ENKTCL. Numerous reports have revealed the prognostic role of serum ferritin in various cancers. Purpose We aimed to evaluate the role of NRI in our single cohort of patients with ENKTCL treated uniformly, explore the prognostic value of ferritin, and establish a new prognostic model to better stratify patients with ENKTCL. Methods We included 326 patients with ENKTCL with detailed data regarding clinical characteristics and survival outcomes. All patients were treated with asparaginase‐based chemotherapy with or without radiotherapy. Multiple R packages were used to analyze the prognostic factors and derive a novel prognostic model. Results In the training cohort comprising 236 patients with ENKTCL, NRI significantly correlated with progression‐free survival (PFS) and overall survival (p

Abstract Background Primary gastrointestinal natural killer (NK)/T‐cell lymphoma (PGINKTL) is a rare T‐/NK‐cell lymphoma subtype, and the clinical features and survival outcomes remain largely unknown. Methods To summarize the clinical features and survival outcomes of PGINKTL, PGINKTL cases diagnosed at our hospital from May 1999 to December 2020 were reviewed; and the clinical data, information on treatment strategies, and survival were collected. Survival analysis was performed using the Kaplan–Meier method and multivariable Cox proportional hazards regression. We constructed a nomogram to visualize the survival prediction of PGINKTL. The discriminative ability and calibration of the nomogram for prediction were tested using the concordance index (C‐index) and calibration plots. Results The cohort included 81 cases, the median age was 36 years (range, 7–80 years), and the male‐to‐female ratio was 1.7:1. The most common clinical symptom at the time of diagnosis was abdominal pain (71.6%). The most common lesion site was the colon (59.3%). During a median follow‐up period of 37.7 months, the median overall survival (OS) time of 81 patients was 4.0 months (95% confidence interval [CI], 3.1–4.9 months), and the 2‐year OS rate was 30.7% (95% CI, 20.3%–40.1%). The multivariate analyses indicated that patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≥2, serum lactic dehydrogenase (LDH) level ≥ the upper limit normal (ULN), and perforation had worse OS. We used these data to establish a nomogram to predict survival for PGINKTL. The nomogram displayed good accuracy, with a C‐index of 0.726. Conclusion The clinical features and poor outcomes of PGINKTL, which is a rare and fatal lymphoma type, are presented. The proposed nomogram provides an individualized estimate of survival for these patients. In the future, the study focused on exploring a better treatment strategy to improve survival is required in PGINKTL.

Abstract Objective Sinonasal lymphomas are a rare entity that commonly present with nonspecific sinonasal symptoms and are often recognized immediately. Through this review, we aim to summarize important principles in diagnosis and treatment of sinonasal lymphomas, with the goal of disseminating the current knowledge of this under‐recognized malignancy to otolaryngologists. Methods Systemic review using PRISMA guidelines of foundational scholarly articles, guidelines, and trials were reviewed focusing on clinical characteristics of key sinonasal lymphoma subtypes, along with available treatments in the otolaryngology, medical oncology, and radiation oncology literature. Results Sinonasal lymphoma are derived from clonal proliferation of lymphocytes at various stages of differentiation, of which diffuse large B‐cell lymphoma (DLBCL) and extranodal natural killer/T‐cell lymphoma (ENKTL) are the most common. Diagnosis and staging require biopsy with immunohistochemistry in conjunction with imaging and laboratory studies. Treatment is ever evolving and currently includes multi‐agent chemotherapy and/or radiation therapy. Conclusion Otolaryngologists may be the first to recognize sinonasal lymphoma, which requires a comprehensive workup and a multidisciplinary team for treatment. Symptoms are nonspecific and similar to many sinonasal pathologies, and it is crucial for otolaryngologists to keep a broad differential. Level of Evidence 5

Purpose: To investigate the prognostic value of gross tumor volume (GTV) in early-stage extranodal NK/T-cell lymphoma (ENKTCL) treated with intensity-modulated radiation therapy (IMRT) and explore the interactive effect of GTV and radiotherapy (RT) dose on locoregional recurrence (LRR). Methods: The data of 319 early-stage ENKTCL patients who underwent IMRT were reviewed retrospectively. Overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) were estimated using Kaplan–Meier method and compared using the log-rank test. Cox proportional hazards regression was performed to identify independent risk factors for survival outcomes. Penalized spline regression was used to flexibly model the association of continuous predictors (GTV and RT dose) with mortality, progression, and relapse. Results: The 5-year OS, PFS, and LRC for the entire cohort were 72.9, 64.4, and 89.9%, respectively. The risks of disease mortality, progression, and recurrence increased steadily with increasing GTV. Patients with GTV < 35 mL had significantly higher 5-year OS (83.0% vs. 59.4%; P < 0.001), PFS (76.7% vs. 48.4%; P < 0.001), and lower 5-year cumulative LRR rate (4.9% vs. 14.5%; P = 0.004), than patients with GTV ≥ 35 mL. The risk of LRR was low with RT doses of 50-56 Gy, independent of GTV. For patients with GTV ≥ 35 mL, dose ≥ 56 Gy was not associated with decreased LRR. Conclusion: Larger GTV is associated with worse survival and higher LRR in early-stage ENKTCL patients treated with IMRT. A dose of 50–56 Gy may be appropriate to achieve lower risk of LRR, regardless of GTV. [ABSTRACT FROM AUTHOR]

The engagement of CD27 on lymphocytes with its ligand, CD70, on tumors is believed to mediate tumor immune evasion and the elevation of serum soluble CD27 (sCD27) levels in patients with CD70-positive malignancies. We previously showed that CD70 is expressed in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), an Epstein–Barr virus (EBV)-related malignancy. However, little is known about serum sCD27 expression and its association with the clinical characteristics of, and the CD27/CD70 interaction in, ENKL. In the present study, we show that serum sCD27 is significantly elevated in the sera of patients with ENKL. The levels of serum sCD27 provided excellent diagnostic accuracy for discriminating patients with ENKL from healthy subjects, correlated positively with the levels of other diagnostic markers (lactate dehydrogenase, soluble interleukin-2 receptor, and EBV-DNA), and decreased significantly following treatment. Elevated serum sCD27 levels also correlated significantly with advanced clinical stage and tended to correspond with shorter survival, in patients with ENKL. Immunohistochemistry indicated that CD27-positive tumor-infiltrating immune cells exist adjacent to CD70-positive lymphoma cells. In addition, serum sCD27 levels in patients with CD70-positive ENKL were significantly higher than those in patients with CD70-negative ENKL, suggesting that the intra-tumoral CD27/CD70 interaction boosts the release of sCD27 in serum. Furthermore, the EBV-encoded oncoprotein latent membrane protein 1 upregulated CD70 expression in ENKL cells. Our results suggest that sCD27 may serve as a novel diagnostic biomarker and also may serve as a tool for evaluating the applicability of CD27/CD70-targeted therapies by predicting intra-tumoral CD70 expression and CD27/CD70 interaction in ENKL. [ABSTRACT FROM AUTHOR]

Background: Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) of the small intestine, is a disease with extremely poor prognosis. We describe treatment in a case which is novel in that it demonstrated long-term survival. Case presentation: A 68-year-old man was admitted to the emergency department of our hospital with the complaint of severe umbilical pain with tenderness and muscular defense. An abdominal computed tomography scan revealed a thick-wall mass on the small intestine and intra-abdominal free air. He was suspected of perforation of a small intestinal tumor and underwent emergency surgery. The surgery revealed a perforated tumor ulcer, and ENKL was diagnosed from the postoperative pathological findings. The patient's postoperative course was uneventful. He was further treated with adjuvant chemotherapy by hematologist comprising six courses of dexamethasone, etoposide, ifosfamide, and carboplatin. The patient demonstrated long-term survival and was in remission at the time of writing, four years and five months after surgery. Conclusions: We report a rare case of long-term survival of perforated ENKL of the small intestine achieved by surgery and adjuvant chemotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin. It is essential to consult with a hematologist to determine the most appropriate chemotherapy such as DeVIC if one encounters rare postoperative pathological findings of ENKL. To elucidate the pathophysiology of this disease and to prolong survival of affected patients, accumulation of cases of long-term survival and examination of associated characteristics is necessary. [ABSTRACT FROM AUTHOR]

EBV is a lymphotropic virus, member of the Herpesviridae family that asymptomatically infects more than 90% of the human population, establishing a latent infection in memory B cells. EBV exhibits complex survival and persistence dynamics, replicating its genome through the proliferation of infected B cells or production of the lytic virions. Many studies have documented the infection of T/NK cells by EBV in healthy individuals during and after primary infection. This feature has been confirmed in humanized mouse models. Together these results have challenged the hypothesis that the infection of T/NK cells per se by EBV could be a triggering event for lymphomagenesis. Extranodal NK/T-cell lymphoma (ENKTCL) and Epstein-Barr virus (EBV)-positive nodal T- and NK-cell lymphoma (NKTCL) are two EBV-associated lymphomas of T/NK cells. These two lymphomas display different clinical, histological and molecular features. However, they share two intriguing characteristics: the association with EBV and a geographical prevalence in East Asia and Latin America. In this review we will discuss the genetic characteristics of EBV in order to understand the possible role of this virus in the oncogenesis of ENKTCL and NKTCL. In addition, the main immunohistological, molecular, cytogenetic and epigenetic differences between ENKTCL and NKTCL will be discussed, as well as EBV differences in latency patterns and other viral molecular characteristics.

Abstract Background There is a great geographic variation of extranodal natural killer (NK)/T-cell lymphoma, nasal type (NNKTL) prevalence, with a much higher prevalence in the Asian and South American populations. According to our knowledge and searches, only one other case report/study of NNKTL has been published in South Africa. Case presentation We present a southern-African 31-year-old male residing in a township in the south of Johannesburg, South Africa. He presented with signs and symptoms similar to those of benign upper airway diseases. Further work-up of persisting signs and symptoms yielded a diagnosis of NNKTL. He was treated with the SMILE (steroids — dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide) chemotherapy regimen, and sandwich radiotherapy was planned. He had a partial response to chemotherapy but unfortunately demised due to overwhelming sepsis prior to radiation therapy. Conclusion Making a diagnosis of NNKTL in resource-limited settings is challenging as the diagnosis requires not only the demonstration of NK-cell markers but also to have a positive Epstein-Barr virus (EBV) in situ hybridization (EBER-ISH). Collaboration of smaller centres with larger and better equipped centres is required to diagnose and document NNKTL more accurately in the African setting.

An 18-year-old male presented with a non-healing penile ulcer, initially diagnosed as a syphilitic chancre but later confirmed to be extranodal NK/T-cell lymphoma. The patient had a history of nasopharyngeal NK/T-cell lymphoma and was undergoing chemotherapy and radiotherapy. Extranodal NK/T-cell lymphoma is rare, aggressive, and associated with Epstein-Barr virus infection, commonly affecting the upper aerodigestive tract. Skin involvement can mimic other conditions, and penile involvement is rare with a poor prognosis and potential resistance to conventional chemotherapy. [Extracted from the article]

Purpose: Anti-PD-1 antibody (anti-PD-1 mAb) showed favorable outcomes in some patients with relapsed/refractory (r/r) extranodal NK/T-cell lymphoma (ENKTL). However, the role of anti-PD-1 antibody in NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHS) remains unclear. Here, we evaluated the efficacy and toxicity of anti-PD-1 antibody-based treatment in NK/T-LAHS patients. Methods: The clinical data of 98 patients diagnosed with NK/T-LAHS at Sun Yat-sen University Cancer Center and the First Affiliated Hospital of Guangdong Pharmaceutical University from May 2014 to November 2021 were retrospectively analyzed. All patients received anti-HLH [HLH-2004 (etoposide, dexamethasone, cyclosporine A) or DEP-based (liposomal doxorubicin, etoposide, methylprednisolone)] regimen and sequential anti-ENKTL chemotherapy (ChT) combined with anti-PD-1 antibody or not. Results: The overall response rate (ORR) of the anti-PD-1 mAb plus ChT regimens was higher than that of the ChT regimens (73.3% vs. 45.5%, P = 0.041). The toxicity of the anti-PD-1 mAb plus ChT regimens was tolerable. Except for higher rate of neutropenia, no significant difference in adverse events (AEs) was observed between the two groups. When the optimal response to anti-ENKTL was achieved, the median EBV DNA levels in patients who received anti-PD-1 mAb plus ChT were significantly lower than patients who received ChT only (878 copies/mL vs. 18,600 copies/mL, P = 0.001). With a median follow-up of 26.6 months (range 0–65.9 months), the median overall survival (mOS) was 3.5 months (95% CI：2.3–4.7 months). Patients treated with anti-PD-1 mAb plus ChT experienced a longer mOS than those who received ChT only [5.2 months (95% CI: 2.5–7.8 months) vs. 1.5 months (95% CI: 0.5–2.6 months), P = 0.002]. Cox multivariate analysis found that anti-PD-1 mAb was an independent prognostic factor for all NK/T-LAHS patients. Conclusion: In conclusion, anti-PD-1 mAb combined with ChT regimens seemed to be associated with prolonged survival in NK/T-LAHS patients and may represent a potentially promising treatment strategy for this population. [ABSTRACT FROM AUTHOR]

Background: Extranodal natural killer (NK)/T‐cell lymphoma (ENKTCL) is an aggressive lymphoma with marked heterogeneity, resulting in a distinct prognosis even in patients with the same disease stage. The nomogram‐revised risk index (NRI) has been proposed to stratify patients with ENKTCL. Numerous reports have revealed the prognostic role of serum ferritin in various cancers. Purpose: We aimed to evaluate the role of NRI in our single cohort of patients with ENKTCL treated uniformly, explore the prognostic value of ferritin, and establish a new prognostic model to better stratify patients with ENKTCL. Methods: We included 326 patients with ENKTCL with detailed data regarding clinical characteristics and survival outcomes. All patients were treated with asparaginase‐based chemotherapy with or without radiotherapy. Multiple R packages were used to analyze the prognostic factors and derive a novel prognostic model. Results: In the training cohort comprising 236 patients with ENKTCL, NRI significantly correlated with progression‐free survival (PFS) and overall survival (p < 0.0001). Using a ferritin level of 400 μg/L as the cutoff value, patients with high ferritin levels had significantly inferior PFS (p = 0.00028). Integrating the NRI score and four easily accessible clinical parameters, namely ferritin, hemoglobin, albumin, and D‐dimer, a new prognostic model was constructed, stratifying patients with ENKTCL into three risk groups. This new prognostic model was independent of disease stage and NRI and performed better than NRI. Furthermore, this model helped to stratify patients within the same NRI risk groups. Finally, the role of this novel prognostic model was validated in the external validation cohort comprising 90 patients with ENKTCL. Conclusions: Serum ferritin level could be a novel prognostic factor in patients with ENKTCL. The new prognostic model combining NRI and clinical parameters could better predict the prognosis of ENKTCL, thereby warranting further validation and potentially guiding individualized treatment in future prospective clinical trials. [ABSTRACT FROM AUTHOR]

Patients with central nervous system (CNS) involvement at initial diagnosis of extranodal NK/T-cell lymphoma (ENKTL) are exceedingly rare, and the clinicopathologic features of CNS involvement have not been well characterized. In this study, we reviewed 662 patients with ENKTL from August 2008 to September 2019. Their clinical and pathological features, treatments, and survival outcomes were analyzed. The median follow-up time was 72 months. Nine of 662 (1.4%) patients were diagnosed with CNS involvement. Among them, the median age was 37 years, and seven patients were male. All patients had positive EBV-DNA, and three patients were asymptomatic at the time of diagnosis with CNS involvement. Common extranodal involved sites included bone, paranasal sinuses, breast, kidney, adrenal gland, and bone marrow. All patients were positive for cytoplasmic CD3ε, cytotoxic granule proteins, and EBER and negative for CD20. All patients received intrathecal chemotherapy and at least one cycle of systemic chemotherapy. Seven patients had died and two were still alive by the last follow-up. The median overall survival (OS) in patients with CNS involvement at initial diagnosis of ENKTL was 9 months, and the 1-year OS was 44.4%. Five patients achieved a complete response after asparaginase-based chemotherapy; two were still alive, one died of systemic progression, one died of ENKTL-associated hemophagocytic syndrome, and one died of treatment-related infections. In conclusion, CNS involvement at initial diagnosis of ENKTL is extremely rare with poor prognosis. There is no standard treatment, and asparaginase-based chemotherapy combined with intrathecal chemotherapy might yield good efficacy. [ABSTRACT FROM AUTHOR]

Extranodal natural killer/T-cell lymphoma (ENKTCL) is almost always fatal after the failure of asparaginase. This phase II study aimed to investigate the efficacy and safety of tislelizumab combined with gemcitabine and oxaliplatin (Tisle-GemOx) in patients with ENKTCL failing asparaginase. Eligible patients received Tisle-GemOx as initial induction for 6–8 cycles at 21-day intervals. Responders continued tislelizumab maintenance every two months for two years. The primary endpoint was the best complete response rate (CRR). As of September 2023, 32 patients were enrolled in our study. Among the 30 efficacy-evaluable patients, the best CRR was 60 %, meeting the primary efficacy endpoint. With a median follow-up of 22.6 months, the median progression-free survival (PFS) was 7.4 months and the 1-year PFS rate was 46.4 %. Subgroup analyses showed that shorter PFS was associated with previous lines of chemotherapy ≥ 2 (P = 0.034) and concomitant hemophagocytic lymphohistiocytosis (P = 0.040). Pseudo-progression was observed in three patients (10 %). The most common grade ≥ 3 toxicities were lymphopenia (25 %) and anemia (15.6 %). Tisle-GemOx exhibits promising anti-tumor activity and manageable toxicities as a salvage therapy for ENKTCL failing asparaginase. Further long-term follow-up is necessary to evaluate the durability of the response with tislelizumab maintenance in this patient population. • Tisle-GemOx combination shows promise in treating ENKTCL post-asparaginase failure. • Best complete response rate of 60 % achieved in this phase II study. • 1-year PFS rate of 46.4 % with manageable toxicities observed. [ABSTRACT FROM AUTHOR]

Chronic active Epstein-Barr virus disease (CAEBV) is a systemic lymphoproliferative disorder that is closely linked to Epstein-Barr virus (EBV) infection. The clinical course and severity of CAEBV can vary, and in some cases, it can progress to overt lymphoma, which is characterized by extranodal natural killer/T-cell lymphoma (ENKTL) and has a poor clinical outcome. Although anti-programmed cell death protein-1 (PD-1) therapy has shown effectiveness in some patients with EBV-associated disease, it has been less successful in others, and the exact mechanism of action of PD-1 inhibitor therapy in these diseases remains unclear. In this report, we describe a patient who was diagnosed with ENKTL secondary to CAEBV and experienced rapid disease progression accompanied by hyperinflammation after receiving PD-1 inhibitor therapy. Single-cell RNA sequencing revealed a significant increase in the patient’s lymphocyte count, especially in natural killer cells, with increased activity following PD-1 inhibitor therapy. This case raises questions about the efficacy and safety of PD-1 inhibitor therapy in patients with EBV-associated diseases.

Extranodal NK/T-cell lymphoma (ENKTCL) is the most common subtype of T/NKcell lymphoma in Asia and Latin America, but very rare in North American and Europe. Patient survival has improved significantly over the past two decades. However, standard treatment has not yet been established, although dozens of prospective trials have been conducted. To help understand how the treatment of ENKTCL has evolved in the past and what trends lie ahead, we have comprehensively reviewed the treatment of this aggressive malignancy, with a particular focus on neglected or unanswered issues, such as the optimal staging method, the best partner of asparaginase (Asp), the individualized administration of Asp, the preferred sequence of CT and RT and so on. Overall, the 5-year overall survival (OS) of patients with Ann Arbor stage I/II disease increased from< 50% in the early 20th century to > 80% in recent years, and the median OS of patients with Ann Arbor stage III/IV disease increased from < 1 year to more than 3 years. The improvement in patient survival is largely attributable to advances in radiation technology and the introduction of Asp and anti-PD-1/PD-L1 immunotherapy into practice. Radiotherapy is essential for patients with early-stage disease, while Asp-based chemotherapy (CT) and PD-1/PD-L1 inhibitors significantly improved the prognosis of patients with advanced-stage disease. ENKTCL management is trending toward simpler regimens, less toxicity, and higher efficacy. Novel drugs, such as manufactured T cells, monoclonal antibodies, and small molecule inhibitors, are being intensively investigated. Based on the fact that ENKTCL is highly resistant to cytotoxic drugs except Asp, and aggressive CT leads to higher toxicity rather than better outcomes, we recommend it is unnecessary to expend additional resources to compare different combinations of Asp with cytotoxic agents. Instead, more efforts should bemade to optimize the use of Asp and immunotherapy to maximize efficacy and minimize toxicity, explore ways to overcome resistance to Asp and immunotherapy, identify novel treatment targets, and define subpopulations who may benefit more fromspecific treatments. [ABSTRACT FROM AUTHOR]

Background: Primary gastrointestinal natural killer (NK)/T‐cell lymphoma (PGINKTL) is a rare T‐/NK‐cell lymphoma subtype, and the clinical features and survival outcomes remain largely unknown. Methods: To summarize the clinical features and survival outcomes of PGINKTL, PGINKTL cases diagnosed at our hospital from May 1999 to December 2020 were reviewed; and the clinical data, information on treatment strategies, and survival were collected. Survival analysis was performed using the Kaplan–Meier method and multivariable Cox proportional hazards regression. We constructed a nomogram to visualize the survival prediction of PGINKTL. The discriminative ability and calibration of the nomogram for prediction were tested using the concordance index (C‐index) and calibration plots. Results: The cohort included 81 cases, the median age was 36 years (range, 7–80 years), and the male‐to‐female ratio was 1.7:1. The most common clinical symptom at the time of diagnosis was abdominal pain (71.6%). The most common lesion site was the colon (59.3%). During a median follow‐up period of 37.7 months, the median overall survival (OS) time of 81 patients was 4.0 months (95% confidence interval [CI], 3.1–4.9 months), and the 2‐year OS rate was 30.7% (95% CI, 20.3%–40.1%). The multivariate analyses indicated that patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≥2, serum lactic dehydrogenase (LDH) level ≥ the upper limit normal (ULN), and perforation had worse OS. We used these data to establish a nomogram to predict survival for PGINKTL. The nomogram displayed good accuracy, with a C‐index of 0.726. Conclusion: The clinical features and poor outcomes of PGINKTL, which is a rare and fatal lymphoma type, are presented. The proposed nomogram provides an individualized estimate of survival for these patients. In the future, the study focused on exploring a better treatment strategy to improve survival is required in PGINKTL. [ABSTRACT FROM AUTHOR]

Methotrexate, skin ulcer, extranodal NK/T-cell lymphoma, , Epstein-Barr virus Keywords: extranodal NK/T-cell lymphoma; ; methotrexate; Epstein-Barr virus; skin ulcer EN extranodal NK/T-cell lymphoma methotrexate Epstein-Barr virus skin ulcer 849 852 4 11/11/22 20221201 NES 221201 I Sir, i Immunosuppressive therapies such as methotrexate (MTX) can cause oligoclonal or monoclonal lymphoproliferative disorder, which is categorized as other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) in the current WHO classification.1 Most MTX-associated LPDs, including skin lesions, are of B-cell lineage, and only four cases of primary cutaneous MTX-associated T-cell LPD have been reported.2,3 The histologic subtypes of these four cases were angioimmunoblastic T-cell lymphoma, primary cutaneous anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and MTX-associated T-cell LPD (not further specified), all of which regressed after MTX was discontinued. 4 Yu WW, Hsieh PP, Chuang SS. Cutaneous EBV-positive T-cell lymphoma vs. extranodal NK/T-cell lymphoma: a case report and literature review. [Extracted from the article]

Gene expression profiling studies have shown the pathogenetic role of oncogenic pathways in extranodal natural killer/T-cell lymphoma (ENKL). In this study, we aimed to identify the microRNAs (miRNAs) playing potential roles in ENKL, and to evaluate the genes and biological pathways associated to them. Gene expression profiles of ENKL patients were acquired from the gene expression omnibus (GEO) database. Most differentially expressed (DE)-miRNAs were identified in ENKL patients using limma package. Gene targets of the DE-miRNAs were collected from online databases (miRDB, miRWalk, miRDIP, and TargetScan), and used in Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses on Database for annotation, visualization, and integrated discovery database, and then used in protein–protein interaction (PPI) analysis on STRING database. Hub genes of the PPI network were identified in cytoHubba, and were evaluated in Biological networks gene ontology. According to the series GSE31377 and GSE43958 from GEO database, four DE-miRNAs were screened out: hsa-miR-363-3p, hsa-miR-296-5p, hsa-miR-155-5p, and hsa-miR-221-3p. Totally 164 gene targets were collected from the online databases, and used in the GO and KEGG pathway analyses and PPI network analysis. Ten hub genes of the PPI network were identified: AURKA, TP53, CDK1, CDK2, CCNB1, PLK1, CUL1, ESR1, CDC20, and PIK3CA. Those hub genes, as well as their correlative pathways, may be of diagnostic or therapeutic potential for ENKL, but further clinical evidence is still expected.

Abstract Background There is no unified treatment standard for patients with extranodal NK/T-cell lymphoma (ENKTL). Cancer neoantigens are the result of somatic mutations and cancer-specific. Increased number of somatic mutations are associated with anti-cancer effects. Screening out ENKTL-specific neoantigens on the surface of cancer cells relies on the understanding of ENKTL mutation patterns. Hence, it is imperative to identify ENKTL-specific genes for ENKTL diagnosis, the discovery of tumor-specific neoantigens and the development of novel therapeutic strategies. We investigated the gene signatures of ENKTL patients. Methods We collected the peripheral blood of a pair of twins for sequencing to identify unique variant genes. One of the twins is diagnosed with ENKTL. Seventy samples were analyzed by Robust Multi-array Analysis (RMA). Two methods (elastic net and Support Vector Machine-Recursive Feature Elimination) were used to select unique genes. Next, we performed functional enrichment analysis and pathway enrichment analysis. Then, we conducted single-sample gene set enrichment analysis of immune infiltration and validated the expression of the screened markers with limma packages. Results We screened out 126 unique variant genes. Among them, 11 unique genes were selected by the combination of elastic net and Support Vector Machine-Recursive Feature Elimination. Subsequently, GO and KEGG analysis indicated the biological function of identified unique genes. GSEA indicated five immunity-related pathways with high signature scores. In patients with ENKTL and the group with high signature scores, a proportion of functional immune cells are all of great infiltration. We finally found that CDC27, ZNF141, FCGR2C and NES were four significantly differential genes in ENKTL patients. ZNF141, FCGR2C and NES were upregulated in patients with ENKTL, while CDC27 was significantly downregulated. Conclusion We identified four ENKTL markers (ZNF141, FCGR2C, NES and CDC27) in patients with extranodal NK/T-cell lymphoma.

Simple Summary: Soluble and exosomal programed death-ligand 1 can be upregulated in extranodal natural killer/T-cell lymphoma. We investigated the association between pre-treatment soluble and exosomal programed death-ligand 1 and outcomes in extranodal natural killer/T-cell lymphoma patients who received pembrolizumab as a salvage treatment. Treatment outcomes and overall survival after pembrolizumab were significantly better in patients with low soluble and exosomal programed death-ligand 1. Thus, soluble and exosomal programed death-ligand 1 can predict responses to pembrolizumab, making it a useful pre-treatment biomarker for extranodal natural killer/T-cell lymphoma patients receiving pembrolizumab. Soluble and exosomal programed death-ligand 1 (PD-L1) can be upregulated in extranodal natural killer/T-cell lymphoma (ENKTL). However, its clinical role in predicting outcomes after pembrolizumab treatment has yet to be studied in ENKTL patients. We investigated the association between pre-treatment soluble and exosomal PD-L1 and outcomes in ENKTL patients who received pembrolizumab as a salvage treatment. The production of soluble and exosomal PD-L1 was analyzed in vitro using an etoposide-resistant ENKTL cell line. Serum levels of soluble and exosomal PD-L1 were measured in patients with relapsed or refractory ENKTL prior to treatment with pembrolizumab. Relapsed or refractory ENKTL patients who received pembrolizumab as a salvage therapy between May 2017 and March 2021 were analyzed at our institute. Soluble and exosomal PD-L1 was significantly higher in serum samples of relapsed or refractory ENKTL patients compared with healthy controls, which is consistent with increased production of soluble and exosomal PD-L1 in an etoposide-resistant ENKTL cell line (SNK6R), which was found to show increased expression of soluble and exosomal PD-L1. Serum-soluble PD-L1 levels were significantly correlated with exosomal PD-L1, and were significantly lower in responders to pembrolizumab compared with non-responders. Longitudinal analysis after pembrolizumab also revealed a relationship between PD-L1 levels and responses. Treatment outcomes and overall survival after pembrolizumab were significantly better in patients with low soluble and exosomal PD-L1. In conclusion, soluble and exosomal PD-L1 can predict responses to pembrolizumab in ENKTL patients, making it a useful pre-treatment biomarker for ENKTL patients receiving pembrolizumab. [ABSTRACT FROM AUTHOR]

Simple Summary: Intravascular lymphoma is a neoplasm with tumor cells localized exclusively within blood vessel lumina. Most cases are of B-cell origin; only rare cases of NK or T-cell lineage. Unlike intravascular large B-cell lymphoma, which is a well-recognized entity in the WHO classification, intravascular NK/T-cell lymphoma is not considered a specific entity and there is still a debate about whether it is closer to aggressive NK leukemia or to extranodal NK/T-cell lymphoma. Our aim was to summarize the clinical, pathological, and molecular data on intravascular NK/T-cell lymphoma, which is a challenge both in terms of diagnosis and treatment. Recent molecular studies improved our understanding of the mechanism of lymphomagenesis, showing that multiple genetic events associated with EBV infection are required for the pathogenesis of this aggressive lymphoma. Promising therapeutic results may be offered by immune checkpoint inhibitors due to the high PD-L1 expression, which is possibly related to EBV infection. Intravascular lymphoma is a form of lymphoid malignancy characterized by neoplastic cells growing almost exclusively within the lumina of small- to medium-sized blood vessels. Most cases are of B-cell origin with rare cases of natural killer or T-cell lineage. Extranodal sites are affected, mainly the skin and central nervous system, although any organ may be involved. Intravascular NK/T-cell lymphoma deserves special attention because of its clinicopathologic features and the need for adequate immunophenotyping combined with clonality test for a proper diagnosis. Moreover, intravascular NK/T-cell lymphoma is strongly linked to Epstein–Barr virus (EBV), which is considered to play a role in tumorigenesis and to be responsible for the aggressive behavior of the disease. In this paper, we review the current knowledge on this rare lymphoma and, in particular, the most recent advances about its molecular landscape. The main distinguishing features with other EBV-related entities, such as extranodal NK/T-cell lymphoma, EBV-positive primary nodal T/NK-cell lymphoma, and aggressive NK-cell leukemia, are discussed to help pathologists obtain the correct diagnosis and consequently develop an adequate and prompt therapy response. [ABSTRACT FROM AUTHOR]

The nasal type of extranodal natural killer (NK)/T-cell lymphoma (ENKL) is an aggressive form of non-Hodgkin's lymphoma. Although ENKL is most commonly seen in the midline of the nose, face and Waldeyer's ring, it can also occur in the skin, gastrointestinal tract, soft tissues and other parts of the body. Severe ENKL cases are accompanied by hemophagocytosis, with clinical manifestations such as high fever, hepatosplenomegaly, and decreased blood cell count. ENKL at different locations exhibits similar histological features and immunophenotypes, such as a strong affinity for T cell markers CD2 and CD56, cytotoxic molecules, as well as a strong positive for EBER after in situ hybridization. Although indolent ENKL is extremely rare, we hereby present a case study of primary NK/T cell lymphoma in the spinal canal with the initial manifestation of a diffuse growth of small cells, and the survival and recurrence details after 11 years, accompanied by CD30-positive large cell transformation. The patient's condition after treatment has improved and is currently in good health. [ABSTRACT FROM AUTHOR]