Increased coexpression of PD-L1 and IDO1 is associated with poor overall survival in patients with NK/T-cell lymphoma.

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.

Sintilimab (anti-PD-1 antibody) plus chidamide (histone deacetylase inhibitor) in relapsed or refractory extranodal natural killer T-cell lymphoma (SCENT): a phase Ib/II study.

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.

Artificial intelligence for diagnosis and prognosis prediction of natural killer/T cell lymphoma using magnetic resonance imaging.

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.

Mandibular Osteomyelitis as the Earliest Clinical Manifestation of Maxillary Sinus Lymphoma.

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.

Full-spectral genome analysis of natural killer/T cell lymphoma highlights impacts of genome instability in driving its progression.

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.

Extranodal NK/T-cell lymphoma with localized relapse in bone marrow of lower leg detected using PET-CT.

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.

Clinicopathologic features and survival outcomes of CD30 expression in extranodal natural killer/T-cell lymphoma.

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.

Characterization of T-/natural killer cell lymphoproliferative neoplasms associated with systemic, chronic, active Epstein-Barr virus in adults: A report of 5 cases in a Western population.

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.

Primary extranodal NK/T cell lymphoma of stomach: A case report and review of literature.

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.

Extranodal nasal-type NK/T-cell lymphoma with CD20 positive: A case report and review of literature.

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.

Extranodal natural killer/T cell lymphoma nasal type simulating osteoradionecrosis with metachronic B lymphoma in the pelvis: Case report.

Extranodal Natural Killer/T Cell Lymphoma Nasal Type (EN-NK/T-CL-NT) is a non-Hodgkin extranodal lymphoma of unfavorable prognosis due to its aggressive nature. This neoplasm mainly affects the paranasal sinuses, nasopharynx, oropharynx, oral cavity, palate, and rarely intestinal, gastric and skin regions. 50-year-old female with a history of lymphoma in nasal and pelvic region. At four years of tumors-free, has facial asymmetry, accompanied by sub-palpebral, nasal and lip edema. Intraoral examination revealed a large ulceration suggestive of osteoradionecrosis. Gum biopsy shows Extranodal NK/T Cell Lymphoma Nasal Type (EN-NK/T-CL-NT). In this case we highlight the characteristics of EN-NK/T-CL-NT with a presentation of osteoradionecrosis-like. Unfortunately, the nature of this tumor led to the patient's death. Clinical follow-up of patients with cancer is imperative to mend and/or decrease treatment complications, as well as to identify second primary tumors or the spread of the underlying disease.

Comparative analysis of upper aerodigestive tract and non-upper aerodigestive tract in NK/T-cell lymphoma

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 (AU)

Histone methyltransferase KMT2D inhibits ENKTL carcinogenesis by epigenetically activating SGK1 and SOCS1.

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.

Comparative analysis of upper aerodigestive tract and non-upper aerodigestive tract in NK/T-cell lymphoma.

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.

Elevated serum IL-6 and total IgEAb are associated with poor survival in natural killer/T-cell lymphoma.

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.

A case of extranodal NK/T-cell lymphoma, nasal type, diagnosed by scraping cytology of the maxillary gingiva.

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.

Molecular and clinicopathological features of granzyme B-negative extranodal NK/T-cell lymphoma.

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.