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Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a type of rare and distinct entity of non-Hodgkin lymphoma with poor prognosis. It is important to evaluate the early treatment response accurately to decide further treatment strategy. 18F-FDG PET/CT plays an important role in response evaluation and prognostic prediction in some kinds of lymphomas. However, data available regarding patients with ENKTL are limited. Thus, in this prospective study, we analyzed the prognostic value of 18F-FDG PET/CT in ENKTL. Thirty-four patients with newly diagnosed ENKTL were enrolled in this phase 2 study (NCT02825147, July 7, 2016). The patients received pre-, mid-, and end-treatment 18F-FDG PET/CT scans. Deauville score (DS), maximal standardized uptake values (SUVmax), and the change in SUVmax (ΔSUVmax) were recorded for response assessment. The median follow-up period was 42.2 months. The 2-year overall survival (OS) and progression-free survival (PFS) were 82.4% and 73.5%, respectively. Univariate analysis revealed that Ann Arbor stage (P < 0.002), mid-treatment DS (P = 0.005), mid-SUVmax (P = 0.001), mid-∆SUVmax (P = 0.004), end-treatment DS (P < 0.001), and end-SUVmax (P = 0.014) were prognostic factors for OS. Ann Arbor stage (P = 0.001), mid-treatment DS (P = 0.008), mid-SUVmax (P = 0.029), mid-∆SUVmax (P < 0.001), and end-treatment DS (P =0.021) were of prognostic significance for PFS. Multivariate analysis showed that mid-SUVmax (P = 0.042) and DS at the middle (P = 0.050) and end (P = 0.044) of treatment were significant independent predictors of PFS. 18F-FDG PET/CT is useful for predicting the prognosis of ENKTL.

Purpose Nasal type extranodal natural killer/T-cell lymphoma (ENKTL) can be associated with hemophagocytic lymphohistiocytosis (NK/T-LAHLH), which is a rare and fatal disease with no effective therapy. We evaluated whether etoposide + dexamethasone-based chemotherapy regimens might be useful for treating NK/T-LAHLH. Methods This retrospective single-center study evaluated clinical data from 37 patients with NK/T-LAHLH who were treated between May 2008 and January 2020. Results Among 363 patients with ENKTL, the cumulative incidence of HLH was 11.9%. Among 43 patients with NK/T-LAHLH, 37 patients received etoposide + dexamethasone-based chemotherapy regimens, with an overall response rate of 45.9% for the HLH. The overall response rate was substantially higher for newly diagnosed NK/T-LAHLH than it was for relapsed or refractory NK/T-LAHLH (66.7% vs. 18.8%). The median overall follow-up time was 4 months, with overall survival rates of 81.1% at 1 month, 62.2% at 2 months, 56.8% at 3 months, and 34.4% at 6 months. Significantly better overall survival (all P

Extranodal NK/T-cell lymphoma (ENKTCL), nasal type is a very rare and aggressive non-Hodgkin lymphoma. Most commonly it occurs in the upper aerodigestive tract. But, it can also manifest at locations such as the skin, soft tissue, gastrointestinal tract (GI), lungs, testis, etc. These locations are designated as extranasal ENKTCL. The patients with the latter have often more adverse clinical features and poorer survival rate compared with nasal sites. We present a case of an 83-year-old patient with a primary ENKTCL, nasal type, with extranasal presentation in the right upper eyelid.Materials for the literature review was obtained by a comprehensive search on PubMed, which yielded 82 eligible cases with extranasal ENKTCL.Sixty-eight cases (83 %) were localized as primary ENKTCL in the lungs (17), central nervous system (CNS) (14), testis (11), GI-tract (7), skin (6), orbit and intraocular tissue (4), pancreas (2), adrenal gland (2), breast (1), etc. 14 cases (17 %) presented as extended or disseminated diseases involving exclusively organs outside the upper aerodigestive tract. There was no systematic pattern of organ involvement in the extended/disseminated ENKTCL. 63 % of the patient with localized extranasal ENKTCL and about 50% of patients with extended/disseminated disease were reported to have died of the disease. Treatment strategies varied with no preferred option. Among the used treatment options were chemotherapy, radiotherapy, surgery, stem cell transplantation alone or in different combinations.ENKTCL is a highly aggressive disease which may present in extranasal areas. Although the tumors respond to both chemotherapy and radiotherapy, durable complete remissions are very rare.

Extranodal natural killer/T cell lymphoma-nasal type (EN-NK/T-NT) is extremely rare in Western countries; however, it is the most common subtype of peripheral T cell lymphoma in China. Despite this, there are a limited number of clinicopathological research studies on Epstein-Barr virus (EBV)-negative EN-NK/T-NTs. EBV-negative EN-NK/T-NT is a rare disease type, which has not been fully investigated. If other diagnostic criteria are met, such as the lesions being located predominantly in the upper aerodigestive tract, the presence of angiocentricity or angioinvasion, necrosis and expression of NK/T-cell phenotype, EN-NK/T-NT may be diagnosed, even if EBV is negative. In the present study, 99 cases of EN-NK/T-NTs were analyzed retrospectively, among which seven cases were EBV-negative EN-NK/T-NTs and selected for further investigation. In addition, the present study reviewed previously published research into EN-NK/T-NT, highlighting that EBV-negative EN-NK/T-NT is rare and that its geographical distribution is mainly in countries in Asia, Central America and South America. Patients with EBV-negative EN-NK/T-NT were all of Chinese ethnicity, with a median age of 32 years and primarily female. Furthermore, these patients shared similar clinicopathological characteristics (such as the tumor occurring mainly in the upper aerodigestive tract, the presence of vascular destruction, necrosis and cytotoxic phenotypes) to patients with EBV-positive EN-NK/T-NT. Immunohistochemistry and molecular analysis results indicated that tumor cells were primarily of NK or cytotoxic T origin; however, EBV-encoded small RNAs were not detected in any of these cases. Among the immunochemistry markers, T-bet was statistical significantly different between EBV-positive and -negative cases. Fluorescence in situ hybridization was also performed in two EBV-negative cases, including one case with a co-deletion of 6q21 and PR/SET domain 1 genes. There was only available follow-up data in 3/5 patients who survived for 37–113 months (median, 40 months). As EN-NK/T-NT can be diagnosed, even when EBV is negative, awareness of this subtype may prevent misdiagnosis or delayed diagnosis.

Activation-induced cell death (AICD) mediated by the Fas/Fas ligand (FasL) system plays a key role in regulating immune response. Although normal natural killer (NK) cells use this system for their homeostasis, malignant NK cells seem to disrupt the process. Extranodal NK/T-cell lymphoma, nasal type (ENKL) is a rare but fatal disease, for which novel therapeutic targets need to be identified. We confirmed that ENKL-derived NK cell lines NK-YS and Hank1, and primary lymphoma cells expressed procaspase-8/FADD-like interleukin-1β-converting enzyme (FLICE) modulator and cellular FLICE-inhibitory protein (c-FLIP), along with Fas and FasL. Compared with Fas-sensitive Jurkat cells, NK-YS and Hank1 showed resistance to Fas-mediated apoptosis in spite of the same expression levels of c-FLIP and the death-inducing signaling complex (DISC) formation. Unexpectedly, the long isoform of c-FLIP (c-FLIPL ) was coimmunoprecipitated with Fas predominantly in both ENKL-derived NK cell lines after Fas ligation. Indeed, c-FLIPL was more sufficiently recruited to the DISC in both ENKL-derived NK cell lines than in Jurkat cells after Fas ligation. Knockdown of c-FLIPL per se enhanced autonomous cell death and restored the sensitivity to Fas in both NK-YS and Hank1 cells. Although ENKL cells are primed for AICD, they constitutively express and efficiently utilize c-FLIPL , which prevents their Fas-mediated apoptosis. Our results show that c-FLIPL could be a promising therapeutic target against ENKL.

Natural killer/T cell lymphoma (NKTCL) most frequently affects the nasal cavity and upper aerodigestive tract (UAT) and is often mistaken for reactive disease processes, such as chronic rhinosinusitis (CRS). Recently, alterations of the nasal resident microbiota have been found in CRS. However, nasal microbial features in NKTCL have never been reported. This case-control study collected 46 NKTCL patients, 25 CRS patients and 24 matched healthy controls (HCs) to analyze nasal microbial profiles via 16S rRNA sequencing technology to improve our understanding of changes in the nasal microbiota in NKTCL. We found that alpha diversity was significantly decreased, while beta diversity was significantly increased in NKTCL compared with those in CRS and HCs. The genus Corynebacterium was significantly depleted in CRS and NKTCL versus that in HCs, while genus Staphylococcus was the most abundant in the NKTCL compared to that in the other two groups. The nasal microbial community was significantly different between UAT-NKTCL and non-UAT NKTCL patients. Importantly, based on a panel of taxa, excellent classification power with an AUC of 0.875 between UAT-NKTCL and CRS was achieved. Furthermore, the alpha diversity of the nasal microbiota was associated with several clinical covariates of NKTCL. Finally, PICRUSt analysis implicated an array of distinct functions in NKTCL that might be involved in the pathogenesis of the disease. In conclusion, the nasal microbial profile was unique in NKTCL. The nose-microbiota-UAT NKTCL axis represents a panel of promising biomarkers for clinical practice and contributes to revealing the potential pathogenesis of this malignancy.

Extranodal NK/T-Cell Lymphoma, nasal type (ENKTL-NT) has some salient aspects. The lymphoma is commonly seen in Eastern Asia, has progressive necrotic lesions in the nasal cavity, makes midfacial destructive lesions, and shows poor prognosis. The lymphoma cell is originated from either NK- or γδ T-cells, which express CD56. Since the authors first demonstrated the existence of Epstein–Barr virus (EBV) DNA and EBV oncogenic proteins in lymphoma cells, ENKTL-NT has been recognized as an EBV-associated malignancy. Because the angiocentric and polymorphous lymphoma cells are mixed with inflammatory cells on a necrotic background, the diagnosis of ENKTL-NT requires CD56 immunostaining and EBER in situ hybridization. In addition, serum the EBV DNA level is useful for the diagnosis and monitoring of ENKTL-NT. Although ENKTL-NT is refractory lymphoma, the prognosis is improved by the development of therapies such as concomitant chemoradiotherapy. The basic research reveals that a wide variety of intracellular/cell surface molecules, cytokines, chemokines, and micro RNAs are involved in lymphomagenesis, and some of them are related to EBV. Understanding lymphoma behavior introduces new therapeutic strategies, such as the usage of immune checkpoint inhibitors, peptide vaccines, and molecular targeting therapy. This review addresses recent advances in basic and clinical aspects of ENKTL-NT, especially its relation to EBV features.

Peripheral T cell lymphomas constitute nearly 15% of all cases on non-Hodgkin lymphoma. Of these, NK-T cell lymphoma nasal type is a rare and aggressive form. We present our experience of 16 patients of NK/T cell lymphoma which constituted approximately 1% of all lymphoma (N = 1590) cases treated at our center. Male to female ratio was 4.3:1. Median age of presentation was 42 years. Early Stage patients (n = 11) were treated with DeVIC regimen (n = 10) and SMILE (n = 1) chemotherapy and RT to all the patients. Advanced stage patients were treated with SMILE regimen (n = 4) and ICE and local RT (n = 1) with one treatment related mortality. The presence of B-symptoms adversely affected survival. The estimated median PFS and OS were 39 and 49 months respectively. Overall survival was not reached in Limited Stage patients (stage 1 and 2) and 8 months in patients with advanced stage (stage IV) (p = 0.001). According to the new CSWOG staging (retrospectively applied), comparing the Limited versus Extensive Stage, the earlier group has a significantly better estimated PFS (p = 0.020) and OS (p = 0.007). ENKTL is a rare malignancy with aggressive course. B-symptoms portend a poor prognosis to patients with this aggressive lymphoma. The new staging system helps estimate survival better.

Objective Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is an aggressive extranodal lymphoma of NK-cell or T-cell lineage. Its clinical features overlap with those of several sinonasal mass lesions. While the histopathological features are well described, diagnosis is often difficult, owing to presence of extensive coagulative necrosis, so that repeated biopsies may sometimes be necessary for correct diagnosis. Literature on cytological findings of ENKTL is limited. Methods Cytomorphological features of cases of histologically confirmed ENKTL having corresponding cytology samples were reviewed retrospectively, to identify distinctive features that could possibly suggest this entity. Results Aspirates from five patients were studied: four from cervical nodes, one from cheek swelling and one from pleural fluid. Two aspirates were reported as positive for malignancy, two as atypical lymphoid proliferation and one was non-diagnostic. Pleural fluid was reported as malignant, favouring a diagnosis of carcinoma. On cytology, aspirates showed medium to large cells with folded, indented nuclei and abundant pale cytoplasm, some with tongue-like cytoplasmic protrusions. A distinctive feature was presence of large loose clusters of tumour cells with arborising capillaries running through them. Interestingly, necrosis was consistently absent. Subsequent biopsies from palate (three cases) and nasal masses (two cases) confirmed the diagnosis of ENKTL. Conclusions Suspicion of ENKTL on cytology is crucial for timely diagnosis to avoid diagnostic delay, especially when only highly necrotic biopsy samples are available. Awareness of distinctive cytomorphological features is required to make fine needle aspiration an effective diagnostic tool for initial diagnosis and for evaluation of possible recurrences.

Background Extranodal natural killer (NK) cell/T-cell lymphoma (NKTCL), a rare type of non-Hodgkin's lymphoma, has strongly been associated with Epstein-Barr virus (EBV) infection. However, there are no EBV genomes isolated from NKTCL, and the roles the variations of EBV strains play in the pathogenesis of NKTCL are still unclear. Materials and Methods In this study, whole EBV genomes from eight primary NKTCL biopsy specimens were obtained using next-generation sequencing, designated NKTCL-EBV1 to NKTCL-EBV8. Results Compared with the six mostly referenced EBV strains, NKTCL-EBVs closely resemble the GD1 strain but still harbor 2,072 variations, including 1,938 substitutions, 58 insertions, and 76 deletions. The majority of nonsynonymous mutations were located in latent and tegument genes. Moreover, the results from phylogenetic analysis of whole NKTCL genomes and specific genes demonstrated that all the NKTCL-EBVs were related to Asian EBV strains. Based on the amino acid changes in certain residues of latent membrane protein 1 (LMP1) and EBV-determined nuclear antigen 1 (EBNA1), all the NKTCL-EBVs were sorted to China 1 and V-val subtype, respectively. Furthermore, changes in CD4+ and CD8+ T-cell epitopes of EBNA1 and LMP1 may affect the efficacy for a cytotoxic T lymphocyte (CTL)-based therapy. Conclusion This is the first large study to our knowledge to obtain EBV genomes isolated from NKTCL and show the diversity of EBV genomes in a whole genome level by phylogenetic analysis. Implications for Practice In this study, the full-length sequence of Epstein-Barr virus (EBV) isolated from eight patients with nasal natural killer/T-cell lymphoma (NKTCL) was determined and further compared with the sequences previously reported isolated from other malignancies. Phylogenetic analysis showed that NKTCL-EBV strains are close to other Asian subtypes instead of non-Asian ones, leading to the conclusion that EBV infections are more likely affected by different geographic regions rather than particular EBV-associated malignancies. Therefore, these data have implications for the development of effective prophylactic and therapeutic vaccine approaches targeting the personalized or geographic-specific EBV antigens in these aggressive diseases.

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) is a lymphoid malignancy that mainly affects the nasopharynx and is associated with the Epstein-Barr virus (EBV). Increased incidence is seen in some Latin American and Asian countries. In this study, we describe a case series of 86 Guatemalan patients with ENKTCL-NT from a single diagnostic head and neck center. We emphasize the distinctive clinical, microscopic, and immunohistochemical (IHC) features, as well as EBV positivity by in situ hybridization (ISH). Most of the patients (90.6%) were of Mayan descent and low socioeconomic status (SES). Males were more often affected than females, comprising 68.3% of cases. Patient age ranged from 8 to 71, with a mean of 34.7 years. All cases arose in the upper aerodigestive tract and mainly presented as a rapidly progressive, necrotizing midfacial process affecting the nasal, nasopharyngeal, sinonasal, palatal, and oropharyngeal structures. Microscopically, ENKTCL-NT showed a diffuse polymorphic and atypical lymphoid infiltrate. Angiocentric and angiodestructive growth patterns were present with associated necrosis. Peripheral hyaline necrosis of blood vessels was a histologic hallmark. The ISH and IHC profiles included positivity of EBV, LCA, CD3, CD45RO, CD30 (focal in 39.2%), granzyme-B, TIA-1, perforin (in 82.3%), and CD56 (in 83.7%). CD20 was negative, and the Ki-67 index ranged from 70 to 90%. In Guatemala, this lymphoma is strongly associated with people of low SES and indigenous ethnicity. When affected, the palatal mucosa provides the best site to obtain a representative biopsy. Since ENKTCL-NT is highly aggressive, it is extremely important to recognize the spectrum of clinical presentations and microscopic features in order to avoid misdiagnosis and treatment delay.

Composite lymphoma (CL) is defined as the occurrence of two distinct types of lymphoma within the same patient. Most cases of CL involve Hodgkin and non-Hodgkin lymphomas or two distinct types of B-cell lymphomas; true CL is a composite B-cell and T-cell lymphoma, and is rare. We herein report a case involving concurrent extranodal NK/T-cell lymphoma, nasal-type and diffuse large B-cell lymphoma, which has not been previously reported. As the mechanisms and treatments of composite B-cell and T-cell lymphomas are unclear, further studies are required to improve the prognosis.

Summary Enhancer of zeste homolog 2 (EZH2), an H3K27-specific histone methyltransferase, has been shown to be frequently overexpressed in various human cancers including lymphoma. Here we investigate the expression and functionality of EZH2 and H3K27me3 in extranodal NK/T-cell lymphoma, nasal type (ENKTL). Results of NanoString analysis revealed that EZH2 and related histone H3 families were up-regulated genes in ENKTL tissues. Results of immunohistochemistry demonstrated that EZH2 and trimethylation of Lys-27 in histone (H3K27me3) were highly expressed in 55.2% and 78.0% of patients with ENKTL, respectively. EZH2 overexpression was significantly associated with higher tumor cell proliferation (r = 0.582, P = .000), advanced stage (P = .012), and predicted poorer overall survival (P = .016) in ENKTL. H3K27me3-positive expression was correlated with lower tumor cell proliferation (r = −0.623, P = .036), earlier stage (P = .043), and predicted better overall survival (P = .020). In addition, EZH2 and H3K27me3 showed inverse correlations (r = −0.652, P = .002) in clinical samples by immunohistochemistry. Furthermore, inhibition of EZH2 by 3-deazaneplanocin A significantly suppressed tumor cell growth. Interestingly, pharmacologic suppression of the JAK3/STAT3 pathway effectively reduced EZH2 and enhanced H3K27me3 in NK/T tumor cell lines. Our data suggest that EZH2 and H3K27me3 are important prognostic markers and potential therapeutic targets in ENKTL.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL-NT) is a rare type of Non-Hodgkin’s lymphoma, which usually presents with extranodal involvement and affects the nasal/upper aerodigestive tract in the classical presentation. Herein, we report the case of a 31-year-old, previously healthy, male patient diagnosed with ENKTL-NT with the involvement of the lung parenchyma and heart. Unfortunately, due to the rapid disease progression, the diagnosis was performed only at the autopsy. The authors highlight the rare clinical presentation of this type of lymphoma, as well as the challenging anatomopathological diagnosis in necrotic samples.

NK/T-cell lymphomas are extremely rare lymphomas in the western world. The population of CD3+CD56+ NK/T-cells that seems to be the progenitor cells for those types of lymphomas is not homogeneous, which may explain the reason for polymorphic presentation. Several functionally distinct NK/T-cell subsets diverge after their development in the thymus. Organ-specific antigen-presenting cells may modulate NK/T-cell function and post-thymic development. The organs with the highest content of NK/T cells are tonsils, lymph nodes, spleen, skin, testis, and stomach. Not surprisingly, those are the places of the most frequent localization of NK/T-cell lymphoma. The Waldeyer’s tonsillar ring is involved most commonly. The patient sometimes may present with a single cutaneous nodule, but the asymptomatic nasal involvement could be detected on PET/CT frequently, still placing the patient into “the nasal” category. Extranasal presentation comprises around 20% of all cases and most likely arises from the dermal NK/T cells in contrast to tonsillar NK/T cells in “the nasal” cases. Unusual cases of such rare cancer are characterized by the unusual expression of non-NK/T-cell markers and rare morphologic presentations. The aberrant expression of γδ TCR on EBV+ CD56+ cells is still a matter of debate of appropriate classificational categorization. Despite semantics, the prognosis is universally gravid.

Objectives The present study aims to compare the diagnostic efficacy of MR, 18F-FDG PET/CT, and 18F-FDG PET/MR for the local detection of early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTL). Patients and Methods Thirty-six patients with histologically proven early-stage ENKTL were enrolled from a phase 2 study (Cohort A). Eight nasopharyngeal anatomical regions from each patient were imaged using 18F-FDG PET/CT and MR. A further nine patients were prospectively enrolled from a multicenter, phase 3 study; these patients underwent 18F-FDG PET/CT and PET/MR after a single 18F-FDG injection (Cohort B). Region-based sensitivity and specificity were calculated. The standardized uptake values (SUV) obtained from PET/CT and PET/MR were compared, and the relationship between the SUV and apparent diffusion coefficients (ADC) of PET/MR were analyzed. Results In Cohort A, of the 288 anatomic regions, 86 demonstrated lymphoma involvement. All lesions were detected by 18F-FDG PET/CT, while only 70 were detected by MR. 18F-FDG PET/CT exhibited a higher sensitivity than MR (100% vs. 81.4%, χ2 = 17.641, P < 0.001) for local detection of malignancies. The specificity of 18F-FDG PET/CT and MR were 98.5 and 97.5%, respectively (χ2 = 0.510, P = 0.475). The accuracy of 18F-FDG PET/CT was 99.0% and the accuracy of MR was 92.7% (χ2 = 14.087, P < 0.001). In Cohort B, 72 anatomical regions were analyzed. PET/CT and PET/MR have a sensitivity of 100% and a specificity of 92.5%. The two methods were consistent (κ = 0.833, P < 0.001). There was a significant correlation between PET/MR SUVmax and PET/CT SUVmax (r = 0.711, P < 0.001), and SUVmean (r = 0.685, P < 0.001). No correlation was observed between the SUV and the ADC. Conclusion In early-stage ENKTL, nasopharyngeal MR showed a lower sensitivity and a similar specificity when compared with 18F-FDG PET/CT. PET/MR showed similar performance compared with PET/CT.

Background: Extranodal NK/T-cell lymphoma, nasal type, is a rare subtype of non-Hodgkin lymphoma, origin from natural killer (NK) cells and T cells. This is a rare, fast-growing and poor prognosis disease. Currently there have been not many studies in Vietnam on this issue. We conduct this research with two objects: to describe characteristics of patients and evaluate premininary results of treatment extranodal NK/T cell lymphoma, nasal type, stage I to II at K hospital. Methods: Retrospective study. From January 2017 to June 2020, we enrolled 26 patients with extranodal NK/T cell lymphoma, nasal type, stage I to II. Patients were treated concurrent chemoradiotherapy with cisplatin, followed by 3 cycles of VIPD adjuvant regimen. Results: Patient characteristics: The average age was 43.2. Male/female ratio was 1.36. The most common symptoms were stuffy of nose 84.6%; runny nose 65.4%. Peripheral lymph nodes observed in 19.2%; 50% with B symptom. Staged I was dominated with 73.1%. Treatment results: Concurrent chemoradiotherapy phase: completed response was 26.9%, partial response 53.8% and progression disease 19.2%. At the end of treatment course, the overall response rate was 73% (including 61.5% completed response and 11.5% partial response), 26.9% cases with disease progression. Toxicity: Leukopenia was the most common toxicity (61.1%). Grade III and IV leukopenia were observed in 18.4%. Conclusions: Concurrent chemoradiotherapy followed by adjuvant VIPD regimen with stage I, II is effective regimen and acceptable toxicity.

T-cell lymphomas are infrequently encountered in the head and neck area, with the most common subtype being Extranodal NK/T cell lymphoma, nasal type (ENKTL-NT). ENKTL-NT shows a predilection for midline facial structures presenting with ulcerative destructive lesions, whereas palatal involvement is one of the most prominent signs from the oral cavity. Herein, we describe a case of a 76-year-old Greek man with nasal obstruction and an extensive painful necrotic ulcer with ragged borders on the left distal portion of the soft palate and palatine tonsil of 4-months duration. After an initial non-diagnostic biopsy from the nasopharynx, a second incisional biopsy from the palatal lesions was performed. Histopathology was suggestive of an angiocentric lymphoproliferative neoplasm and immunohistochemical examination and in situ hybridization for EBV RNA led to a final diagnosis of ENKTL-NT. The patient was placed under combined chemotherapy and radiotherapy and no recurrence has been noted. Additionally, a retrospective review of the cases in the English literature with an established diagnosis of ENTKL-NT between 2000 and 2019, based on the latest WHO classification of Head and Neck tumors, is performed.

AimsThe aim of this study is to investigate the expression profiles of cell cycle related proteins in nasal extranodal NK/T cell lymphoma, nasal type (ENKTCL).MethodsThe expression profiles of cell cycle related proteins were assessed with a cell cycle antibody array and validated by immunohistochemistry. Correlations between the expression levels of proteins and clinical outcomes of patients with nasal ENKTCL were evaluated.ResultsThe expression of full length ataxia telangiectasia mutated (ATM) in nasal ENKTCL significantly decreased compared with that in nasal benign lymphoid proliferative disease (NBLPD), but the expression levels of p-ATM, CHK2 and RAD51 significantly increased in nasal ENKTCL compared with that in NBLPD. Kaplan-Meier analysis showed that the expression levels of p-ATM and CHK2 in nasal ENKTCL were inversely related to overall survival (p=0.011 and p=0.025, respectively).ConclusionAbnormalities in the ATM pathway may play a crucial role in the oncogenesis and chemoradiotherapy resistance of nasal ENKTCL.

Common T-cell leukemias/lymphomas frequently involving the spleen and liver include entities such as T-cell prolymphocytic leukemia, aggressive NK-cell leukemia, and hepatosplenic T-cell lymphoma. The involvement of the spleen and liver by other nodal or extranodal T-cell or NK-/T-cell lymphomas is less common and mostly as part of disseminated disease. The clinicopathologic features of these uncommon mature T-cell lymphomas in the spleen and liver, including peripheral T-cell lymphoma, NOS, adult T-cell leukemia/lymphoma, angioimmunoblastic T-cell lymphoma, ALK-positive and ALK-negative anaplastic large cell lymphoma, and extranodal NK-/T-cell lymphoma, nasal type, are discussed in this chapter. Spleen and liver biopsies are typically not obtained in these lymphomas, as diagnosis is typically made on lymph node or other primary sites of involvement.

Background Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is a rare aggressive subtype of non-Hodgkin lymphoma characterized by angioinvasion, angiodestruction, necrosis and strong association with Epstein-Barr virus (EBV). ENKTCL-NT occurs worldwide and is more prevalent in Asian and the Native American populations of Mexico, Central and South America. It represents approximately 10% of all peripheral T-cell lymphomas worldwide. The aim of this report is to present a rare case of ENKTCL-NT with an unusually indolent clinical course and low-grade histopathologic features. Case presentation A 71-year-old Asian woman with a long-standing history of seasonal rhinosinusitis presented with persistent nasal congestion, cough, and fever unresponsive to antihistamines and antibiotics. Histopathological evaluation of a polypoid nasal mass revealed an atypical infiltrate with predominantly small lymphoid cells that were CD2+, surface CD3-, cytoplasmic CD3+, CD5(dim)+, CD7(dim)+, cytotoxic markers (granzyme B and perforin)+, EBER+ and CD56-. The Ki-67 proliferative index was very low ( T). A diagnosis of low-grade ENKTCL-NT was rendered. Conclusions Our case of ENKTCL-NT is unusual due to (1) an indolent clinical course (2) low-grade histopathologic features including a low proliferative index (3) lack of CD56 expression and (4) a novel KIT mutation. This case raises awareness of the existence of a subset of cases of ENKTCL-NT that can potentially be misdiagnosed as a reactive process, particularly in patients with recurrent chronic rhinosinusitis.

Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a subtype of mature T- and natural killer cell lymphomas characterized by its association with Epstein-Barr virus and extranodal involvement. Although there is geographic variance in the frequency of ENKL, its clinical features are similar between Western countries and endemic areas, such as East Asia. Anthracycline-containing chemotherapy is not recommended to treat ENKL. No standard treatment has been established based on the results of randomized controlled trials. In patients with localized disease, radiotherapy is a core component of the recommended first-line therapy. Radiotherapy administered at 50 to 54 Gy, extended involved-site radiotherapy considering tumor invasiveness, and the use of intensity modulated radiation therapy or volumetric modulated arc therapy are associated with efficacy of radiotherapy. Although the use of concurrent chemoradiotherapy has been supported by the results of clinical trials, accumulating evidence supports the use of sequential chemoradiotherapy with non-anthracycline-containing regimens that include l-asparaginase and/or platinum anticancer agents. l-asparaginase-containing chemotherapy is a key component of first-line treatments for systemic ENKL. Hematopoietic stem cell transplantation is recommended as a front-line consolidation therapy for newly diagnosed advanced-stage ENKL. Newer agents including immune checkpoint inhibitors are being investigated for treating ENKL. In this modern ENKL treatment era, multidisciplinary efforts are needed to identify the best timing and sequencing of radiotherapy, l-asparaginase, platinum, newer agents, and hematopoietic stem cell transplantation.

The cellular lineage of extranodal NK/T-cell lymphoma, nasal-type (ENKTL), is determined by expression of T-cell receptor (TR) or TR gene rearrangement. In ENKTL, from TR immunohistochemistry, it may often be difficult to decide whether TR-positive cells are tumor cells or not, especially when TR is expressed in a subset of tumor cells. To analyze TR expression pattern and TR rearrangement in T-lineage ENKTL, we performed double immunofluorescence staining for Epstein-Barr virus-encoded small RNAs (EBER)/T-cell receptor (TCR) βF1 and CD56/TCR βF1 in 12 cases of ENKTL that showed TCR βF1 expression in immunohistochemistry. TR gene rearrangement was analyzed using a commercial BIOMED-2 multiplex polymerase chain reaction system. Immunohistochemistry showed that all 12 cases expressed TCR βF1 in a wide range of infiltrating cells from 100% to

Introduction: Despite many studies reporting on the optimal therapies for early stage ENKTL-N in the front-line setting, this area continues to be subject to a significant controversy regarding single modalities versus combination or sequential approaches. All these comparative studies were small non-randomized studies that combined stages I & II. The results were often inconclusive and occasionally conflicting. In the absence of direct head-to-head randomized controlled trials in this clinical setting, a network meta-analysis was conducted to compare these therapeutic approaches and their respective impact on 5-year survival in stage I/IE ENKTL-N. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of stage I/IE ENKTL-N, treatment with chemotherapy (CT), radiation (RT), sequential CT and RT (SEQ), and chemoradiotherapy (CRT), comparative studies that reported predominantly (>70%) I/IE 5-year overall survival (OS) and disease-free survival (DFS) rates. Studies that reported on mixed samples of early and advanced ENKTL were excluded. A frequentist network meta-analysis was conducted using the netmeta package and random-effects model. Results: Seven studies comprising a total of 397 participants were included. Our network meta-analysis revealed that upfront RT tended to have better 5-year OS and DFS than CRT, SEQ, though it did not reach statistical significance. However, RT had a significantly superior 5-year OS when compared to CT (RR=0.43, 0.19-0.97). Based on the pair-wise and network meta-analyses, RT was ranked as the most effective first-line treatment approach followed by CRT, SEQ, and CT in decreasing order. Analysis of the 5-year DFS yielded similar findings. Inconsistency analysis did not reveal any significant differences between direct and indirect estimates. Conclusion: This is the first network meta-analysis to compare all commonly utilized upfront treatment modalities in stages I/IE ENKTL-N. It indicates that upfront RT alone may be sufficient as there was no signal that chemotherapy added any OS or DFS advantages. Adequately powered randomized trials are warranted. Disclosures No relevant conflicts of interest to declare.

Extranodal NK/T-cell lymphoma, nasal type, is an unusual Epstein-Barr Virus (EBV)-related lymphoma that carries a poor prognosis. Most cases affect upper aerodigestive tract, and secondarily may extend to skin, lungs, testis, and other sites. Extranodal NK/T-cell lymphoma, nasal type, presenting primarily as intestinal lymphoma is rare, and not recognized as a distinct entity and neither is considered as a special subtype of intestinal lymphoma of T-cell lineage. Here, we describe a 36-year-woman who presented with abdominal pain and acute-onset diarrhea. Her clinical course was complicated by intestinal perforation and peritonitis. She died one month later of sepsis. Pathologic examination revealed extranodal NK/T-cell lymphoma, nasal type, confined to the intestine. Immunophenotypically, the neoplastic cells expressed CD3 and Granzyme B, and were positive for EBV-encoded RNA (EBER) by in situ hybridization. From the practical point of view, we highlight the clinical, pathologic and immunophenotypic features that can be useful in the differential diagnosis from other intestinal lymphomas of T-cell lineage.

A 39-year-old man presented with bilateral nasal obstruction for 4 months and associated with hyposmia and foul-smelling nasal discharge. Nasal endoscopy showed irregular mucosa of the nasal cavity with easily bleeding. Nasal biopsy reported as extranodal Natural Killer/T cell lymphoma, nasal type. In-situ hybridisation for Epstein-Barr encoding region was positive. He was treated with six cycles of gemcitabine, oxaliplatin and L-asparaginase and peripheral blood stem cell transplant. After the treatment, he was asymptomatic until 9 months where he had splenic abscess and undergone splenectomy. He was asymptomatic of the disease for 2 years.