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Background: Aggressive NK/T-Cell neoplasms are rare hematological malignancies characterized by the abnormal proliferation of NK or NK-like T (NK/T) cells. CD6 is a transmembrane signal transducing receptor involved in lymphocyte activation and differentiation. This study aimed to investigate the CD6 expression in these malignancies and explore the potential of targeting CD6 in these diseases., Materials and Methods: We conducted a retrospective study with totally 41 cases to investigate the expression of CD6 by immunohistochemistry, including aggressive NK-cell leukemia/lymphoma (ANKLL: N = 10) and extranodal NK/T-cell lymphoma (ENKTL: N = 31). A novel ANKLL model was applied for proof-of-concept functional studies of a CD6 antibody-drug-conjugate (CD6-ADC) both in vitro and in animal trial., Results: CD6 was expressed in 68.3% (28/41) of cases (70% (7/10) of ANKLL and 67.7% (21/31) of ENKTL). The median overall survival (OS) for ANKLL and ENTKL cases was 1 and 12 months, respectively, with no significant difference in OS based on CD6 expression (p > 0.05, Kaplan-Meier with log-rank test). In vitro exposure of the CCANKL cell line, derived from an ANKL patient, to an anti-CD6ADC resulted in dose dependent induction of apoptosis. Furthermore, CCANKL engraftment in NSG mice could be blocked by treatment with the anti-CD6 ADC., Conclusion: To date, this is the first report to explore the expression of CD6 in ANKLL and ENKTL and confirms its expression in the majority of cases. The in vitro and in vivo data support further investigation of CD6 as a potential therapeutic target in these aggressive NK/T-cell malignancies., Competing Interests: Disclosure EH: Abcon Therapeutics, Avalere Health, Novartis, Eli Lilly. FL: Abcon Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: T- and natural killer (NK)-cell lymphomas are neoplasms derived from immature T cells (lymphoblastic lymphomas), or more commonly, from mature T and NK cells (peripheral T-cell lymphomas, PTCLs). PTCLs are rare but show marked biological and clinical diversity. They are usually aggressive and may present in lymph nodes, blood, bone marrow, or other organs. More than 30 T/NK-cell-derived neoplastic entities are recognized in the International Consensus Classification and the classification of the World Health Organization (fifth edition), both published in 2022, which integrate the most recent knowledge in hematology, immunology, pathology, and genetics. In both proposals, disease definition aims to integrate clinical features, etiology, implied cell of origin, morphology, phenotype, and genetic features into biologically and clinically relevant clinicopathologic entities. Cell derivation from innate immune cells or specific functional subsets of CD4+ T cells such as follicular helper T cells is a major determinant delineating entities. Accurate diagnosis of T/NK-cell lymphoma is essential for clinical management and mostly relies on tissue biopsies. Because the histological presentation may be heterogeneous and overlaps with that of many benign lymphoid proliferations and B-cell lymphomas, the diagnosis is often challenging. Disease location, morphology, and immunophenotyping remain the main features guiding the diagnosis, often complemented by genetic analysis including clonality and high-throughput sequencing mutational studies. This review provides a comprehensive overview of the classification and diagnosis of T-cell lymphoma in the context of current concepts and scientific knowledge., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm preferentially involving the upper aerodigestive tract. Here we show that NK-cell-specific Trp53 disruption in mice leads to the development of NK-cell lymphomas after long latency, which involve not only the hematopoietic system but also the salivary glands. Before tumor onset, Trp53 knockout causes extensive gene expression changes, resulting in immature NK-cell expansion, exclusively in the salivary glands. Both human and murine NK-cell lymphomas express tissue-resident markers, suggesting tissue-resident NK cells as their cell-of-origin. Murine NK-cell lymphomas show recurrent Myc amplifications and upregulation of MYC target gene signatures. EBV-encoded latent membrane protein 1 expression accelerates NK-cell lymphomagenesis and causes diverse microenvironmental changes, particularly myeloid propagation, through interferon-γ signaling. In turn, myeloid cells support tumor cells via CXCL16-CXCR6 signaling and its inhibition is effective against NK-cell tumors in vivo. Remarkably, KLRG1-expressing cells expand in the tumor and are capable of repopulating tumors in secondary recipients. Furthermore, targeting KLRG1 alone or combined with MYC inhibition using an eIF4 inhibitor is effective against NK-cell tumors. Therefore, our observations provide insights into the pathogenesis and highlight potential therapeutic targets, including CXCL16, KLRG1, and MYC, in ENKTCL, which can help improve its diagnostic and therapeutic strategies., (© 2024. The Author(s).)

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is prevalent in the Asian population; however, little is known about its molecular characteristics. In this study, we examined the CD30 expression in ENKTLs and then performed whole exome sequencing on ten CD30 + ENKTL and CD30 - ENKTL paired samples. CD30 was positive in 55.74% of the ENKTLs. Single nucleotide and insertion/deletion polymorphism analyses revealed that 53.41% of the somatic mutations in CD30 + ENKTLs were shared with CD30 - ENKTLs, including mutations in SERPINA9, MEGF6, MUC6, and KDM5A. Frequently mutated genes were primarily associated with cell proliferation and migration, the tumor microenvironment, energy and metabolism, epigenetic modulators, vascular remodeling, and neurological function. PI3K-AKT, cAMP, cGMP-PKG, and AMPK pathways were enriched in both CD30 + and CD30 - ENKTLs. Copy number variation analysis identified a unique set of genes in CD30 + ENKTLs, including T-cell receptor genes (TRBV6-1 and TRBV8), cell cycle-related genes (MYC and CCND3), immune-related genes (GPS2, IFNA14, TTC38, and CTSV), and a large number of ubiquitination-related genes (USP32, TRIM23, TRIM2, DUSP7, and UBE2QL1). BCL10 mutation was identified in 6/10 CD30 + ENKTLs and 7/10 CD30 - ENKTLs. Immunohistochemical analysis revealed that the expression pattern of BCL10 in normal lymphoid tissues was similar to that of BCL2; however, its expression in ENKTL cells was significantly higher (67.92% vs. 16.98%), implying the potential application of BCL10 inhibitors for treating ENKTLs. These results provide new insights into the genetic characteristics of CD30 + and CD30 - ENKTLs, and could facilitate the clinical development of novel therapies for ENKTL., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Extranodal natural killer/T cell lymphoma (ENKTL) shows a high rate of recurrence after chemoradiotherapy. Drug resistance can be mediated by the cargo of small extracellular vesicles (sEVs). Here, we show that high abundance of the transmembrane glycoprotein CD98hc in tumor cells and serum sEVs was associated with ENKTL progression and drug resistance. Mechanistically, PEGylated-asparaginase (PEG-asp) treatment, a common therapy against ENKTL, promoted the translocation of the transcription factor ATF4 to the nucleus, where it was stabilized by USP1 and subsequently increased CD98hc expression. CD98hc delivered in tumor cell-derived sEVs increased tumor cell proliferation and drug resistance in a cultured human NK lymphoma cell line, animal models, and samples from patients with refractory/relapse ENKTL. Moreover, inhibiting both USP1 and EV secretion synergistically enhanced the cytotoxicity of PEG-asp. These data suggest that targeting CD98hc in the treatment of ENKTL may be beneficial in overcoming drug resistance.

The current clinical management of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the prognostic index of NK cells lymphoma with Epstein-Barr virus (PINK-E) prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA sequencing used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-sequencing data upon MYC knockdown with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.

Objective: To investigate the clinical manifestations, endoscopic characteristics, and prognostic factors of patients with colorectal extranodal NK/T cell lymphoma. Methods: The clinical data of 52 patients with colorectal extranodal NK/T cell lymphoma admitted to the First Affiliated Hospital of Zhengzhou University from January 2013 to January 2023 were retrospectively analyzed. Their clinical manifestations and endoscopic characteristics were summarized, and the prognostic factors were analyzed by Cox regression model. Results: Among the 52 patients with colorectal extranodal NK/T cell lymphoma, there were 35 males and 17 females, with a male-to-female ratio of 2.06∶1. Among the general symptoms, abdominal pain was the most common (39 cases), and B symptoms occurred in 47 patients, among which fever was the most common lymphoma B symptom (42 cases), and gastrointestinal perforation was the most common complication (18 cases). Forty-three patients underwent colonoscopy, and the main manifestations under endoscopy were the ulceration type (24 cases). The ulcers were irregular at the edges and often covered with moss at the bottom. The median survival time was 4.3 months. Multivariate Cox regression analysis showed that hemocytic syndrome ( HR =8.50,95% CI : 1.679-8.328, P =0.001), serum albumin ( HR =3.59,95% CI : 1.017-6.551, P =0.048), and with or without chemotherapy ( HR =0.31, 95% CI : 0.246-1.061, P =0.025) were independent factors influencing the overall survival of patients with colorectal extranodal NK/T cell lymphoma. Conclusions: Colorectal extranodal NK/T cell lymphoma is a rare disease with a very poor prognosis. When patients present with abdominal pain and lymphoma B symptoms, and when ulcers with irregular edges and moss covering the bottom are found under endoscopy, the disease should be considered, and endoscopic biopsy should be taken in time for pathological diagnosis. The prognosis of patients with hemophagocytic syndrome and hypoproteinemia is poor. This disease should be treated with chemotherapy and surgery, and on this basis, hemophagocytic syndrome and hypoproteinemia should be treated to improve the prognosis of patients.

Natural killer/T cell lymphoma (NKTCL) exhibits highly aggressive clinical behavior, and the outcomes for relapsed/refractory patients are still poor. Recently, the mechanism underlying the effect of Epstein-Barr virus (EBV) infection, which has not been fully defined in NKTCL, has attracted great attention. We explored how LMP1 promoted aerobic glycolysis via metabolic sequencing combined with mRNA sequencing and immunoprecipitation coupled to mass spectrometry. Experimental assays were used to determine the effects of LMP1 and its downstream pathway on the function and glucose metabolism of NKTCL cells. The correlations between LMP1 expression in patients and their clinical features, treatment response, and prognosis were analyzed. Results show that LMP1 enhances NKTCL cell proliferation in vitro and in vivo, inhibits apoptosis, and decreases gemcitabine sensitivity. In addition, LMP1 also enhances aerobic glycolysis in NKTCL cells, as indicated by increases in glucose uptake, lactate production, and extracellular acidification rate. Clinically, LMP1 expression is correlated with risk stratification, treatment response, and prognosis, and higher LMP1 expression indicates greater SUVmax for NKTCL patients. Mechanistically, LMP1 competitively binds to TRAF3 to promote cell proliferation and aerobic glycolysis by regulating the noncanonical NF-κB pathway. The application of an NF-κB pathway inhibitor or reactivation of the NF-κB pathway affects aerobic glycolysis and the biological function of NKTCL cells. In summary, this study is the first to describe and define in detail how LMP1 affects glucose metabolism in NKTCL and might provide a novel perspective for further treatment., (© 2024. The Author(s).)

Objective: N6-methyladenosine (M6A) is the most prevalent epigenetic alteration. Methyltransferase-like 3 (METTL3) is a key player in the control of M6A modification. Methyltransferase promote the processing of mature miRNA in an M6A-dependent manner, thereby participating in disease occurrence and development. However, the regulatory mechanism of M6A in NK/T cell lymphoma (NKTCL) remains unclear., Patients and Methods: We determined the expression of METTL3 and its correlation with clinicopathological features using qRT-PCR and immunohistochemistry. We evaluated the effects of METTL3 on NKTCL cells using dot blot assay, CCK8 assay and subcutaneous xenograft experiment. We then applied M6A sequencing combined with gene expression omnibus data to screen candidate targets of METTL3. Finally, we investigated the regulatory mechanism of METTL3 in NKTCL by methylated RNA immunoprecipitation and RNA immunoprecipitation (RIP) assays., Results: We demonstrated that METTL3 was highly expressed in NKTCL cells and tissues and indicated poor prognosis. The METTL3 expression was associated with NKTCL survival. Functionally, METTL3 promoted the proliferation capability of NKTCL cells in vitro and in vivo. Furthermore, EBV-miR-BART3-3p was identified as the downstream effector of METTL3, and silencing EBV-miR-BART3-3p inhibited the proliferation of NKTCL. Finally, we confirmed that PLCG2 as a target gene of EBVmiR-BART3-3p by relative assays., Conclusions: We identified that METTL3 is significantly up-regulated in NKTCL and promotes NKTCL development. M6A modification contributes to the progression of NKTCL via the METTL3/EBV-miR-BART3-3p/PLCG2 axis. Our study is the first to report that M6A methylation has a critical role in NKTCL oncogenesis, and could be a potential target for NKTCL treatment., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manscript entitled., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The interaction between CD47 and signal-regulatory protein-alpha (SIRPα) inhibits phagocytosis, and their clinicopathological characteristics have been evaluated in various diseases. However, the significance of CD47 and SIRPα expression, as well as the combined effect, in Extranodal Natural killer/T-cell Lymphoma (ENKTL) remains uncertain., Methods: In total, 76 newly diagnosed ENKTL patients (mean age 49.9 years, 73.7% male) were included in this study. CD47 and SIRPα expression were examined by immunohistochemistry. Survival analyses were conducted through Kaplan-Meier curves and the Cox regression model., Results: Seventy-one (93.4%) cases were categorized as the CD47 positive group and 59 (77.6%) cases were categorized as the SIRPα positive group. CD47-negative cases had more advanced-stage illness (P = 0.001), while SIRPα-positive cases showed significantly lower levels of high-density lipoprotein (P < 0.001). In univariable analysis, CD47, SIRPα expression, and their combination were significantly associated with prognosis (P < 0.05). In multivariable analysis, only positive SIRPα expression remained significantly associated with superior overall survival (Hazard ratio [HR] 0.446; 95% confidence interval [CI] 0.207-0.963; P = 0.004). Furthermore, SIRPα expression could re-stratify the survival of patients in ECOG (< 2), advanced CA stage, PINK (HR), CD38-positive, PD1-positive, and CD30-positive groups., Conclusions: SIRPα status was a potential independent prognostic factor for ENKTL. The prognostic significance of CD47 expression and the interaction between CD47 and SIRPα in ENKTL need further investigation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Neurolymphomatosis (NL) describes an infiltration of cranial and peripheral nerves by lymphoma cells, most frequently in non-Hodgkin B-cell lymphoma. This clinical entity is rare and poses a challenging diagnosis. We describe a case of a 64-year-old female patient with NL associated with extra-nodal NK/T-cell lymphoma (ENKTL), nasal type, presenting as a painful progressive mononeuropathy multiplex with an oral cavity lesion. ENKTL is usually associated with Epstein-Barr virus (EBV) infection and rarely affects the central and peripheral nervous system. Lumbar puncture, magnetic resonance imaging (MRI), nerve biopsy, and 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) help to establish the diagnosis. Thereby, NL should be considered in the differential diagnosis of painful progressive multiple neuropathies, even in patients without previous history of cancer., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: Extranodal natural killer/T-cell lymphoma (ENKTL) with tonsil involvement is not common, especially in children., Case Presentation: A 13-year-old girl presented with an unexplained sore throat for more than 2 months, together with intermittent fever and suppurative tonsilitis. Nasopharyngoscopy revealed a pharyngeal mass. Enhanced computed tomography (CT) scan showed tonsillar hypertrophy and punctate calcification. Chronic pyogenic granulomatous inflammation with pseudoepithelial squamous epithelial hyperplasia was observed in left tonsil, and pyogenic granulomatous inflammation and a small number of T-lymphoid cells were detected in the right tonsil. The immunohistochemical results showed CD2 + , CD3 + , CD4 + , CD5 + , CD8 + , granzyme B + , and TIA-1 + . The Ki-67 proliferation index was 20%. The case showed T cell receptor gene rearrangement. Finally, the case was diagnosed as ENKTL of stage II with tonsil involvement. The patient received 6 cycles of chemotherapy with SMILE regimen, and showed complete response with no recurrence in the follow-up., Conclusion: We presented a rare case of ENKTL with tonsil involvement in a child. The patient showed complete response to the SMILE chemotherapy with no recurrence., (© 2024. The Author(s).)

Objectives: Previous studies have been inconsistent concerning the association between the prognostic value of CD30 expression and extranodal natural killer/T-cell lymphoma (ENKTL)., Methods: CD30 expression in 82 patients with newly diagnosed ENKTL (mean age, 50 years; 73.2% male) was assessed by immunohistochemistry on paraffin-embedded sections. The level of CD30 expression was categorized into negative (0%, no staining) and positive groups., Results: Sixty-seven cases exhibited positive CD30 expression, and the main between-group difference was the Chinese Southwest Oncology Group and Asia Lymphoma Study Group (CA) ENKTL stage and Eastern Cooperative Oncology Group (ECOG) performance status. The cutoff point for CD30 expression was 40% by restricted cubic splines analysis. The overall survival of patients with high expression (>40%) was statistically superior to negative (0%) and low-expression groups. A positive correlation was observed between CD30 and Epstein-Barr virus-encoded small RNA status (r = 0.305). Multivariable analysis suggested that positive CD30 expression (hazard ratio, 0.420 [95% CI, 0.193-0.914]; P = .029) and CA advanced stage (hazard ratio, 2.844 [95% CI, 1.371-5.896]; P = .005) were independent prognostic factors for ENKTL., Conclusions: Positive CD30 expression was a favorable prognostic factor for ENKTL, and CD30 expression could restratify the survival of patients in clinical subgroups., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1. Among them, CD274 (24%) was the most frequently altered, followed by TP53 (20%), CDKN2A (19%), ARID1A (15%), HLA-A (15%), BCOR (14%), and MSN (14%). Chromosome X losses were the most common arm-level CNAs in females (∼40%), and alterations of four X-linked driver genes (MSN, BCOR, DDX3X, and KDM6A) were more frequent in males and females harboring chromosome X losses. Among X-linked drivers, MSN was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines showed that MSN disruption promoted cell proliferation and NF-κB activation. Moreover, MSN inactivation increased sensitivity to NF-κB inhibition in vitro and in vivo. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, nonnegative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognoses irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL. Significance: Integrative genetic analyses and functional studies in extranodal NK/T-cell lymphoma identify frequent disruptions of X-linked drivers, reveal prognostic molecular subgroups, and uncover recurrent MSN alterations that confer sensitivity to NF-κB inhibition., (©2024 American Association for Cancer Research.)

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., (© 2024 John Wiley & Sons Ltd.)

Immunotherapy with programmed cell death 1 ligand 1 (PD-L1) blockade was effective in patients with NK/T-cell lymphoma. In addition to PD-L1, indoleamine 2,3-dioxygenase-1 (IDO1) is one of the most promising immunotherapeutic targets. High proportions of PD-L1 and IDO1 proteins were observed by immunohistochemistry (IHC) from 230 newly diagnosed patients with NK/T lymphoma with tissue samples from three cancer centers and were associated with poor overall survival (OS) in patients with NK/T lymphoma. Importantly, the coexpression of PD-L1 and IDO1 was related to poor OS and short restricted mean survival time in patients with NK/T lymphoma and was an independent prognostic factor in the training cohorts, and which was also validated in 58 NK/T lymphoma patients (GSE90597). Moreover, a nomogram model constructed with PD-L1 and IDO1 expression together with age could provide concise and precise predictions of OS rates and median survival time. The high-risk group in the nomogram model had a positive correlation with CD4 + T-cell infiltration in the validation cohort, as did the immunosuppressive factor level. Therefore, high PD-L1 and IDO1 expression was associated with poor OS in patients with NK/T lymphoma. PD-L1 and IDO1 might be potential targets for future immune checkpoint blockade (ICB) therapy for NK/T lymphoma., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Because of its low frequency in adult populations and clinical and laboratory overlap with hemophagocytic lymphohistiocytosis and other T-cell lymphomas, T-cell/natural killer (NK) cell systemic, chronic, active Epstein-Barr virus (EBV) (T/NK sCAEBV) infection remains underdiagnosed, preventing critical, prompt therapeutic interventions., Methods: We report a 5-case series that included 2 adult patients with T/NK sCAEBV and 3 additional adult patients with T/NK lymphomas with concomitant systemic EBV infection to review these entities' overlapping diagnostic and clinical features., Results: Approximately 95% of the world population has been infected with EBV during their lifetime, and infection is usually asymptomatic, with symptomatic cases eventually resolving spontaneously. A small subset of immunocompetent patients develops CAEBV, a life-threatening complication resulting from EBV-infected T-cell or NK cell neoplastic lymphocytes. The sites of end-organ damage in T/NK sCAEBV demonstrate pathologic findings such as reactive lymphoid proliferations, making the diagnosis difficult to establish, with the only curative option being an allogeneic hematopoietic stem cell transplant., Conclusions: This diagnosis is most prevalent in Asia, with few cases reported in Western countries. Adult age is an independent risk factor for poor outcomes, and most cases are diagnosed in pediatric populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Extranodal NK/T-cell lymphoma (ENKTL) is a rare lymphoma subtype associated with Epstein-Barr virus (EBV) infection, portending a poor prognosis despite systemic chemotherapy. We present the unusual case of an 85-year-old man receiving ibrutinib for mantle cell lymphoma, who developed a erythematous, subcutaneous nodule on the forehead, featuring a proliferation of pleomorphic CD8 + /CD56 - /EBV + cells. Given the negative staging and comorbidities, a watchful waiting strategy was performed, experiencing a benign course with self-resolution and complete remission over a 4-year follow-up. The literature on primary cutaneous ENKTL has been discussed, with particular attention to clinical and histological prognostic factors., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Nodal T-follicular helper cell lymphoma (TFHL) is a subset of T-cell lymphoma and frequently co-occurs with Epstein-Barr virus (EBV)-positive B-cell lymphoma but not with T/NK-cell lymphoma. Recently, a new entity with a worse prognosis, called EBV-positive nodal T/NK-cell lymphoma (NTNKL) has been established. Here, we report an autopsy case of synchronous multiple lymphomas, including TFHL and NTNKL. The patient was a 78-year-old female admitted with pneumonia. Although pneumonic symptoms were improved, fever, pancytopenia, and disseminated intravascular coagulation emerged, implicating lymphoma. She died on the 21st hospital day without a definitive diagnosis. The autopsy revealed the enlargement of multiple lymph nodes throughout her body. Histological analysis revealed three distinct regions in the left inguinal lymph node. The first region consists of small-sized lymphocytes with T-follicular helper phenotype and extended follicular dendritic cell meshwork, indicating TFHL. The second region included EBV-positive large B cells. The third region comprised EBV-positive large cells with cytotoxic T/NK cell phenotype, indicating NTNKL. Clonality analysis of the first and the third regions showed different patterns. Since various hematopoietic malignancies progress from common clonal hematopoiesis according to existing literature, this case may help to understand TFHL and NTNKL., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Extranodal natural killer/T-cell lymphoma is a distinct subtype of non-Hodgkin lymphoma that originates from natural killer cells or cytotoxic T cells. Its diagnosis is challenging due to the rarity and lack of awareness, especially in cases where osteomyelitis of the jawbone is the initial symptom. This paper reports a case of extranodal natural killer/T-cell lymphoma presenting primarily with oral ulcers. Through analyzing the clinical and pathological characteristics, differential diagnosis, treatment and prognosis, and reasons for misdiagnosis of the disease, this study aims to provide references for clinical diagnosis and treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

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., (© 2023 Japanese Society of Neuropathology.)

Accurate diagnosis and prognosis prediction are conducive to early intervention and improvement of medical care for natural killer/T cell lymphoma (NKTCL). Artificial intelligence (AI)-based systems are developed based on nasopharynx magnetic resonance imaging. The diagnostic systems achieve areas under the curve of 0.905-0.960 in detecting malignant nasopharyngeal lesions and distinguishing NKTCL from nasopharyngeal carcinoma in independent validation datasets. In comparison to human radiologists, the diagnostic systems show higher accuracies than resident radiologists and comparable ones to senior radiologists. The prognostic system shows promising performance in predicting survival outcomes of NKTCL and outperforms several clinical models. For patients with early-stage NKTCL, only the high-risk group benefits from early radiotherapy (hazard ratio = 0.414 vs. late radiotherapy; 95% confidence interval, 0.190-0.900, p = 0.022), while progression-free survival does not differ in the low-risk group. In conclusion, AI-based systems show potential in assisting accurate diagnosis and prognosis prediction and may contribute to therapeutic optimization for NKTCL., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population., (© 2024. The Author(s).)

Competing Interests: We declare no competing interests.

Background: Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored., Methods: Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels., Results: Our study not only confirmed previously reported common NKTCL mutational targets like STAT3, TP53, and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9, DST, and RBMX. In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0-C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole., Conclusions: The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine., (© 2024. The Author(s).)

Abstract: Extranodal nasal-type natural killer (NK)/T-cell lymphoma is a type of non-Hodgkin lymphoma. Neoplastic lymphocytes are positive for CD4, CD56, and CD20, a specific B-cell marker. CD20 positive NK/T-cell lymphoma is rare, with only nine reported cases. This paper reports a case of nasal-type NK/T-cell lymphoma with CD20 positivity in a 47-year-old woman. The patient presented with bilateral nasal congestion and bloody nasal cavity secretions for 2 months. Computed tomography revealed thickening of the nasal mucosa and posterior wall of the nasopharyngeal crest, and the left and right cervical lymph nodes were enlarged. On histopathology, the lesion was composed of medium-sized atypical lymphoid cells and vascular infringement. Immunohistochemical staining showed that the tumor cells were positive for CD20, CD3, CD56, and Epstein-Barr virus (EBV)-encoded RNA in situ hybridization. The patient was treated with radiotherapy for 2 months and is currently well., (Copyright © 2023 Copyright: © 2023 Indian Journal of Pathology and Microbiology.)

Natural killer/T-cell lymphoma (NKTCL) is an aggressive and malignant condition with a high mortality rate. Prognostic factors may assist to evaluate the outcome of the disease and may also be useful in selecting appropriate therapeutic strategies for patients. The study aims to describe NKTCL in terms of its clinical features, laboratory examinations, and immunophenotypes and to analyze relevance affecting patient survival outcomes. The patients diagnosed as NKTCL in Jinling Hospital from Jan. 2012 to Dec. 2022 were reviewed retrospectively in this study basing on histopathology. The analysis was performed to evaluate overall survival (OS). A total of 125 NKTCL patients were included, which mainly affected male more than female with the onset median age of 51.00 years old (range, 14 ~ 85 y). NKTCL commonly affects the nasopharynx and upper aerodigestive tract, intestines, and skin. The median overall survival was 13.00 months (range, 2-156 m), and the 5-year survival rate was 9.8%. Under univariable analysis revealed the following factors at diagnosis age: serum total IgEAb ≥ 54.6 IU/mL, IL-6 ≥ 32.445 ng/L, elevated PINK score, smoking, and extranasopharyngeal site were statistically significant predictors for OS. Compared to the patients who received radiotherapy alone or chemotherapy alone, the patients who received combined chemoradiotherapy had longer OS. We found that IL-6 and total IgEAb were significant prognostic factors in NKTCL patients. Also, extranasopharyngeal site was correlated with advanced disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Extranodal Natural killer/T (NK/T) cell lymphoma nasal type is an aggressive non-Hodgkin lymphoma and has a constant association with Epstein-Barr virus (EBV) infection. Approximately more than 75% cases are located in upper aero-digestive tract, of which stomach is a very rare site. Very few cases of gastric extranodal NK/T cell lymphoma have been reported in the literature. A 22-year-old male patient presented with complaints of abdominal pain and hematemesis. Endoscopy showed a large ulcer in the stomach. Partial gastrectomy done and histopathology showed transmural infiltration by intermediate size atypical lymphoid cells which are immunopositive for CD3, CD56, TIA, EBV-encoded RNA (EBER) and negative for CD4, CD8, CD20. A diagnosis of extranodal NK/T cell lymphoma nasal type was made., (Copyright © 2023 Copyright: © 2023 Indian Journal of Pathology and Microbiology.)

Extranodal NK/T-cell lymphoma (ENKTL) is a non-Hodgkin lymphoma associated with the Epstein-Barr virus that primarily affects individuals in East Asia and indigenous populations in Central and South America. Morphologically, ENKTL typically consists of medium-sized cells or a combination of small and large cells. This report presents 10 cases characterized by predominantly anaplastic cells with diffuse expression of CD30, resembling anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK-negative ALCL) and demonstrating highly aggressive behavior. The cohort included 9 males and 1 female, ranging in age from 29 to 65 years (median age: 47 y). Eight patients presented with nasal disease, while 2 had non-nasal disease. Five patients had stage I/II disease, and the remaining 5 had stage III/IV disease. Morphologically, necrosis was observed in 9 cases, angiocentric-angiodestructive growth in 3 cases, and pseudoepitheliomatous hyperplasia in 2 cases. Anaplastic cells predominated in all cases, with some displaying eccentric, horseshoe-shaped, or kidney-shaped nuclei (referred to as "Hallmark" cells). The morphology profile was monomorphic in 3 cases and polymorphic in 7 cases. Immunohistochemically, all cases tested positive for cytotoxic granule markers (TIA1 and granzymeB) and Epstein-Barr virus-encoded RNA. Cytoplasmic expression of CD3ε and CD56 was observed in 9 of 10 cases. Interestingly, most cases (7 of 8) exhibited variable expression of MuM1, ranging from 10% to 90%. All cases showed diffuse positivity for CD30 but were negative for ALK, resulting in 3 cases being initially misdiagnosed as ALK-negative ALCL. Compared with nonanaplastic cases, anaplastic cells predominant ENKTL had a significantly higher frequency of "B" symptoms, bone marrow involvement, hemophagocytic lymphohistiocytosis, and higher Ki67 proliferative index. These findings provide valuable information for pathologists, expanding their understanding of the cytologic spectrum of ENKTL. This rare variant of ENKTL, characterized by the predominance of anaplastic cells and diffuse CD30 expression, exhibits high aggressiveness and should be differentiated from ALK-negative ALCL. Awareness of this uncommon variant is crucial in preventing misdiagnosis and ensuring the timely initiation of therapy., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL), is characterized by Epstein-Barr virus infection and poor prognosis. We established a novel cell line, ENKL-J1, from bone marrow cells of an ENKL patient. We found that ENKL-J1 cells express the ganglioside GD2 (GD2) and that GD2-directed chimeric antigen receptor T cells exhibit cytotoxicity against ENKL-J1 cells, indicating that GD2 would be a suitable target of GD2-expressing ENKL cells. Targeted next-generation sequencing revealed TP53 and TET2 variants in ENKL-J1 cells. Furthermore, single-cell RNA sequencing in ENKL-J1 cells showed high gene-expression levels in the oncogenic signaling pathways JAK-STAT, NF-κB, and MAPK. Genes related to multidrug resistance (ABCC1), tumor suppression (ATG5, CRYBG1, FOXO3, TP53, MGA), anti-apoptosis (BCL2, BCL2L1), immune checkpoints (CD274, CD47), and epigenetic regulation (DDX3X, EZH2, HDAC2/3) also were expressed at high levels. The molecular targeting agents eprenetapopt, tazemetostat, and vorinostat efficiently induced apoptosis in ENKL-J1 cells in vitro. Furthermore, GD2-directed chimeric antigen receptor T cells showed cytotoxicity against ENKL-J1 cells in vivo. These findings not only contribute to understanding the molecular and genomic characteristics of ENKL; they also suggest new treatment options for patients with advanced or relapsed ENKL., Competing Interests: Conflict of interest disclosures J.A. received research grants and honoraria from AbbVie. M.A. received research funding from Century Therapeutics and Daiichi-Sankyo and received research grants from Sumitomo Pharma, Chugai Pharmaceutical, Kyowa Kirin, AbbVie, Shionogi, Eisai, and Daiichi Sankyo., (Copyright © 2023 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Extranodal NK/T-cell lymphoma (ENKTL), nasal type, is often seen in the head and neck region, but there have been rare instances of this disease with initial presentation as a lesion in the oral mucosa. The patient, a woman in her seventh decade of life, presented with an ulcer in the maxillary gingiva, and scraping cytology and biopsy were performed. Cytological specimens showed solitary or small aggregating cells with marked atypia in a necrotic background. Tumor cells were detected that had various nuclear shapes and azure granules in the cytoplasm. Biopsy showed that the tumor cells had diffusely infiltrated or interdigitated into the subepithelium. Immunohistochemistry revealed that the tumor cells had T- and NK cell phenotypes and were Epstein-Barr virus-encoded small RNA (EBER) positive, leading to a diagnosis of ENKTL. Thus, when nonepithelial tumor cells in a necrotic background and prominent atypia are found, as in this case, it is important to carefully observe for azurophil granules in the cytoplasm for differential diagnosis considerations., (© 2023 Wiley Periodicals LLC.)

Background: Epigenetic alteration plays an essential role in the occurrence and development of extranodal natural killer/T cell lymphoma (ENKTL). Histone methyltransferase (HMT) KMT2D is an epigenetic regulator that plays different roles in different tumors, but its role and mechanism in ENKTL are still unclear., Methods: We performed immunohistochemical staining of 112 ENKTL formalin-fixed paraffin-embedded (FFPE) samples. Then, we constructed KMT2D knockdown cell lines and conducted research on cell biological behavior. Finally, to further investigate KMT2D-mediated downstream genes, ChIP-seq and ChIP -qPCR was performed., Results: The low expression of KMT2D was related to a decreased abundance in histone H3 lysine 4 mono- and trimethylation (H3K4me1/3). In KMT2D knockdown YT and NK-YS cells, cell proliferation was faster (P < 0.05), apoptosis was decreased (P < 0.05), the abundance of S phase cells was increased (P < 0.05), and the level of H3K4me1 was decreased. Notably, ChIP-seq revealed two crucial genes and pathways downregulated by KMT2D., Conclusions: KMT2D is a tumor suppressor gene that mediates H3K4me1 and influences ENKTL proliferation and apoptosis by regulating the cell cycle. Moreover, in ENKTL, serum- and glucocorticoid-inducible kinase-1 (SGK1) and suppressor of cytokine signaling-1 (SOCS1) are downstream genes of KMT2D., (© 2023. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Introduction: Although there is now a consensus on asparaginase-based chemotherapy regimens in the treatment of advanced-stage extranodal natural killer/T-cell lymphomas (ENKTCLs), patient survival in the real-world setting is still not optimistic according to previous literature reports, and the optimal chemotherapeutic regimens and integration of different therapeutic methods under the concept of combined-modality treatment still need to be further explored and verified., Methods: Newly diagnosed stage Ⅲ/Ⅳ ENKTCL patients from Chinese National Cancer Center in the last two decades were retrospectively collected and analyzed. Overall survival (OS) and progression-free survival (PFS) were determined as primary endpoints. Log-rank tests and Cox proportional hazard models were performed to test for survival differences between subgroups and examine the univariable and multivariable associations., Results: The study included 83 newly diagnosed stage Ⅲ/Ⅳ ENKTCL patients and reported a median OS of 26.07 months and an estimated 5-year OS of 41.3% with a median follow-up of 82.13 months. First-line asparaginase-based regimens compared to non-asparaginase-based regimens significantly prolonged PFS (p = 0.007; HR = 0.48, p = 0.020) and showed a tendency to improve OS (p = 0.064; HR = 0.74, p = 0.359). Gemcitabine-based regimens also exhibited a trend toward improved PFS (p = 0.048; HR = 0.59, p = 0.164) and OS (p = 0.008; HR = 0.67, p = 0.282) compared to non-gemcitabine-based ones. The asparaginase and gemcitabine combinations yielded a 5-year OS of 55.0% and led to significantly superior PFS (p = 0.020; HR = 0.40, p = 0.022) and slightly better OS (p = 0.054; HR = 0.79, p = 0.495) compared to the remaining regimens. First-line combined-modality treatment integrating chemotherapy and radiotherapy improved PFS (p = 0.051) and OS (p = 0.036) compared to chemotherapy alone. Four autologous hematopoietic stem cell transplantation recipients reached a median OS of 58.34 months., Conclusion: Asparaginase and gemcitabine alone brought a favorable impact on PFS and OS; and the asparaginase and gemcitabine combination chemotherapy yielded the optimal efficacy, response duration, and survival outcomes. Combined-modality treatment including potent chemotherapy supplemented by radiotherapy and/or consolidative transplantation could improve prognosis in newly diagnosed advanced-stage ENKTCLs., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objective: Nasal or extranasal natural killer/T-cell lymphoma (NKTCL) is a very rare aggressive lymphoma, but it is increasingly diagnosed. To evaluate some specificity by comparative analysis between primary upper aerodigestive tract (UAT) and non-upper aerodigestive tract (NUAT)NKTCL., Methods: A retrospective analysis was performed on NKTCL patients from January 2013 to November 2022 in our cancer center., Results: The majority of the lesions were UAT-NKTCL 70 cases (92.1%), the primary NUAT occurred in 6 cases. Patients in the UAT group were mainly in the early stage and in the low and medium risk, while those in the NUAT group were late stage and in high risk (p = 0.000). The expressions of CD3 and TIA-1 in UAT group were higher than those in NUAT group (p = 0.031, p = 0.003), while CD7 was dominant in NUAT group (p = 0.009). For early stage NKTCL, multivariate analysis suggested that gender and PINK score were independent factors affecting PFS and OS (p < 0.05). The 3 year OS rate in initial CR group was 90.1% versus 46.4% in non-CR group (p = 0.000). In advanced stage, KI67% and bone marrow involvement were independent factors affecting OS (p = 0.022, p = 0.038)., Conclusion: It was difficult to distinguish between UAT and NUAT-NKTCL from histopathology. NUAT-NKTCL patients did have advanced stage and poor outcome. The prognostic value of PINK score and bone marrow involvement was proposed. We aimed to improve initial CR rates, as well as to find new predictive models to predict the whole population., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Aim: This multicenter retrospective study aimed to develop a novel prognostic system for extranodal natural killer/T-cell lymphoma (ENKTL) patients in the era of pegaspargase/L-asparaginase. Materials & methods: A total of 844 newly diagnosed ENKTL patients were included. Results: Multivariable analysis confirmed that Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, Chinese Southwest Oncology Group and Asia Lymphoma Study Group ENKTL (CA) system, and albumin were independent prognostic factors. By rounding up the hazard ratios from four significant variables, a maximum of 7 points were assigned. The model of Huaihai Lymphoma Working Group-Natural killer/T-cell Lymphoma prognostic index (NPI) was identified with four risk groups and the 5-year overall survival was 88.2, 66.7, 54.3 and 30.5%, respectively. Conclusion: Huaihai Lymphoma Working Group-NPI provides a feasible stratification system for patients with ENKTL in the era of pegaspargase/L-asparaginase.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma (NHL) with poor prognosis, particularly in relapsed or refractory patients. Thus, timely detection of relapse and appropriate disease management are crucial. We present two patients with ENKTL, wherein positron emission tomography-computed tomography (PET-CT) with total-body coverage after induction therapy, detected newly relapsed regions in the bone marrow of the lower leg prior to progression. Case 1: A 47-year-old woman with nasal obstruction, showing 18F-fluoro-deoxyglucose (FDG) uptake in the nasal cavity (Lugano stage IE). After induction therapy (RT-2/3 DeVIC), PET-CT revealed abnormal uptake only in the right fibula. Case 2: A 68-year-old man with a skin nodule/ulcer and an enlarged right inguinal lymph node was diagnosed with advanced ENKTL. A PET-CT scan revealed abnormal uptake in the subcutaneous mass of the right medial thigh, lymph nodes, and descending colon (Lugano stage IV). After induction therapy, PET-CT revealed new abnormal uptake only in the left tibia. In both patients, CT-guided biopsy confirmed ENKTL recurrence. Moreover, PET-CT with whole-body coverage was useful for the timely assessment of relapse and detection of asymptomatic bone involvement. This approach allowed for modifications to treatment strategies in certain patients.

Extranodal NK/T-cell lymphoma (ENKTL) generally expresses cytotoxic molecules, including granzyme B (GZMB), T-cell-restricted intracellular antigen-1 (TIA-1), and perforin; however, the expression of these molecules varies across cases. We performed gene expression profiling and identified unique biological and clinicopathological features of GZMB-negative ENKTL. We reviewed the clinicopathological characteristics of 71 ENKTL samples. Gene expression profiling on nine ENKTLs using multiplexed, direct, and digital mRNA quantification divided ENKTLs into Groups A (n = 7) and B (n = 2) through hierarchical clustering and t-distributed stochastic neighbor embedding. Group B was characterized by downregulation of genes associated with IL6-JAK-STAT3 signaling and inflammatory responses. GZMB mRNA expression was significantly downregulated in Group B. GZMB protein expression was evaluated with immunohistochemistry in all 71 ENKTLs, and expression data of Tyr705-phosphorylated STAT3 (pSTAT3) and MYC from our previous study was utilized. T-cell receptor gamma (TRG) gene rearrangement in the selected samples was also assessed using PCR. GZMB expression was higher in pSTAT3-positive (p = 0.028) and MYC-positive (p = 0.014) ENKTLs. Eighteen percent (13/71) of all ENKTLs were negative for GZMB (defined by positivity <10 %); patients with GZMB-negative ENKTLs were often in a higher clinical stage (p = 0.016). We observed no other correlations with clinical parameters or TRG rearrangement and no significant association between GZMB expression and survival. In conclusion, GZMB expression is highly heterogeneous in ENKTLs and is associated with the activation of the JAK-STAT3 pathway and higher MYC expression. GZMB-negative ENKTLs correlate with an advanced clinical stage, suggesting the potential utility of GZMB immunohistochemistry as a biomarker of ENKTL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract: Extranodal nasal-type natural killer/T-cell lymphoma may arise anywhere outside the lymph nodes, predominantly including the nasal cavity, nasopharynx, oropharynx, upper respiratory tract, gastrointestinal tract, skin, testes, and salivary glands, whereas primary tumor arising in muscle is rarely documented. We report FDG PET/CT findings of primary extranodal nasal-type natural killer/T-cell lymphoma in the muscles of the right lower limb in an 82-year-old man., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Aspartate aminotransferase (AST), an indicator of liver cell damage, was related to the prognosis of certain malignant tumors., Objective: This study examined the predictive value of AST in patients with extranodal natural killer/T cell lymphoma (ENKTL)., Methods: We reviewed 183 cases diagnosed with ENKTL and selected 26 U/L as the optimum cut-off value of AST. We used the univariate and multivariate Cox regression to compare the different AST groups' overall survival (OS) and progression-free survival (PFS)., Results: Prior to propensity score matching (PSM), Kaplan-Meier analysis showed that patients in the low AST subgroup had better OS and PFS than the high AST subgroup. Multivariate analysis revealed that AST was an independent indicator for prognosis. After PSM, the low AST subgroup maintained a significantly better OS and PFS than the high AST subgroup., Conclusion: AST might represent a significant prognostic marker for ENKTL patients.

In this case report, a 61-year-old male presented with odynophagia and ulceration in palatum durum after inhalating dust from machinery containing a weak acid. It was at first diagnosed as an acidic ulcer due to two biopsies verifying this. Because of progressing ulceration a third biopsy was taken - this time with the diagnosis extranodal NK/T-cell lymphoma, nasal type. This illustrates the diagnostic challenges of the illness, typically requiring multiple biopsies, and one should have this differential diagnosis in mind in case of progressing ulceration., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Extranodal NK/T-cell lymphoma (ENKTL), nasal type and aggressive NK cell leukemia are rare in Western World been less than 1% in USA to 8% in Asia among Non-Hodgkin's lymphomas. It is aggressive, with poor outcome and optimal treatment is unclear. A combination therapy that includes Peg-Asparaginase (SMILE) has been employed in young patients. An 85-year-old Puerto Rican male presented with anorexia, epistaxis, vertigo and involuntary facial movements. He was treated with injectable Onabotulinum toxin A due to suspicion of a hemifacial spasm. However, a CT scan demonstrated a left maxillary sinus lesion extending into the left middle turbinate with biopsy consistent with ENKTL. We adjusted therapy to patient's age and performance receiving Gemcitabine-Oxaliplatin (Gemox) with radiation obtaining a complete response with persistent negative Epstein Barr DNA titers. ENKTL is a rare disease initially misdiagnosed in our elderly patient, who demonstrated adequate response with a modified therapeutic regime.