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The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75–86), 62% (55–70), and 25% (20–34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)—which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories—significant associations with overall survival were noted (81% [95% CI 75–87%], 55% (44–66), and 28% (18–40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. Samsung Biomedical Research Institute.

Aggressive NK-cell leukemia (ANKL) shares common clinicopathological features with extranodal NK/T-cell lymphoma with bone marrow (BM) involvement (ENKTL-BM), making their distinction challenging in BM examination. Despite numerous studies, genetic differences between the two diseases remained largely unclear. To investigate the genetic and clinical differences between ANKL and ENKTL-BM, we performed targeted sequencing of 282 genes and survival analyses on 15 ANKL and 5 ENKTL-BM patients. Mutation frequency of FAT family genes was higher in ANKL than in ENKTL-BM (80.0% vs. 0.0%, P  = 0.004), and FAT1 gene mutations were associated with significantly lower survival rates in ANKL patients ( P  = 0.002). Copy number alterations including 11q loss and 4q loss were detected exclusively in ANKL. The interval from symptom onset to death was significantly shorter (113.0 vs. 440.5 days, P  = 0.027) and survival rate was significantly lower ( P  = 0.004) in ANKL than in ENKTL-BM. In conclusion, ANKL exhibited a higher mutation frequency of FAT family genes, a more acute fulminant clinical course, and worse prognosis than ENKTL-BM, indicating that ANKL and ENKTL-BM can be distinguished both genetically and clinically. We expect the identified FAT1 gene mutations to serve as novel prognostic factors for ANKL.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is highly invasive. Its etiology and pathogenesis may be related to Epstein-Barr virus infection. In this article, we report a case of a man with ENKTL affecting the right vocal cord and right lung. Initially, the lesion was misdiagnosed as a pulmonary infection. However, subsequent histopathological examinations confirmed the diagnosis through analysis of a surgically resected specimen. Following 14 cycles of immune therapy and chemotherapy, the lesion in the right lung significantly shrank. This case underscored the importance of obtaining surgically resected specimens for pathology when ENKTL is suspected, which can improve diagnostic accuracy and mitigate misdiagnosis.

Programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) pathway blockade has emerged as a promising strategy for cancer therapy. Extranodal natural killer/T cell lymphoma (ENKTL) is an aggressive disease characterized by a strong association with Epstein–Barr virus (EBV), and chronic EBV infection is known to induce PD-L1 expression. However, the PD-1/PD-L1 pathway status in ENKTL remains elusive. Thus, the expression pattern of PD-1 and PD-L1 was investigated in 73 ENKTL cases, and its clinicopathological features and prognostic significance were analyzed. Most ENKTLs had few PD-1 + lymphocytes in the tumor microenvironment. PD-L1 was positive in 56 % ( n  = 41/73) with a cutoff value of ≥10 % of tumor cells and in 62 % ( n  = 45/73) with a cutoff value of ≥10 % of total cells including malignant and non-malignant cells. PD-L1 expression on tumor cells was mostly correlated with PD-L1 expression on non-malignant cells. PD-L1 positivity showed no significant relationship with clinicopathological features. However, patients with PD-L1 + ENKTL exhibited better 5-year overall survival (OS) and a trend for longer 5-year progression-free survival. Moreover, in the subgroups with clinically advanced parameters including late stage III/IV, higher International Prognostic Index scores of 2–5 or non-upper aerodigestive tract involvement PD-L1 positivity was also associated with favorable OS. PD-L1 expression was the only significant independent predictor for longer OS in patients with advanced stage (III/IV) ENKTL. These results suggest that PD-L1 might be used as a novel prognostic marker.

This study aimed to investigate the feasibility and safety of low-dose radiotherapy (RT) (< 50 Gy) in patients with stage I/II Extranodal NK/T-cell lymphoma (ENKTCL). Clinical and treatment data from 158 stage I/II ENKTCL patients who received combined chemoradiotherapy at the First Affiliated Hospital of Zhengzhou University from 2020 to 2022 were retrospectively analyzed to compare locoregional control (LC) and survival outcomes between high-dose (≥ 50 Gy) and low-dose (< 50 Gy) RT groups. All patients achieved an objective response (OR) after treatment, with a median follow-up of 51 months. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 90.1% and 81.7% in the high-dose group ( n  = 130), compared to 84.0% and 68.2% in the low-dose group ( n  = 28), with no significant statistical differences between the two groups. Notably, no local recurrence was observed in the low-dose group (100% local control rate), and the incidence of grade ≥ 3 RT-related adverse events (AEs) was significantly lower in the low-dose group than in the high-dose group. Preliminary evidence suggests that for newly diagnosed stage I/II ENKTCL patients receiving combined chemoradiotherapy, low-dose radiotherapy may not compromise LC and survival outcomes while reducing the incidence of grade 3–4 adverse events, with 40–45 Gy appearing to be the optimal dose range within the examined parameters.

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is an aggressive malignancy primarily affecting the sinonasal region, with a strong association with Epstein-Barr virus (EBV) infection. The disease is significantly more prevalent in Asian and Latin American populations. Diagnosis is particularly challenging in nonendemic regions. We present the case of a 78-year-old male with a one-year history of nasal lesions, later diagnosed with ENKTCL-NT. The patient was treated with curative-intent radiotherapy, achieving a complete clinical response. Radiation therapy, particularly utilizing advanced techniques such as Volumetric Modulated Arc Therapy (VMAT), resulted in favorable outcomes with minimal toxicity. This case emphasizes the importance of early diagnosis, accurate staging, and personalized radiotherapy in the management of ENKTCL-NT. Ongoing research into the molecular pathogenesis, treatment strategies, and prognostic factors is crucial for improving outcomes, particularly in advanced-stage disease.

Although different types of prognostic indices have been applied in extranodal NK-/T-cell lymphoma (ENKTL), they are based mainly on clinical characteristics before treatment. Moreover, these methods lack early assessment and tumor metabolic parameters. It remains unclear whether changes in the plasma Epstein–Barr virus DNA (EBVDNA) status and SUVmax after two cycles of chemotherapy may predict disease prognosis. We retrospectively analyzed the clinical records of 119 patients with ENKTL. According to the multivariate analysis, limited stage (LS), interim EBVDNA (I-EBVDNA) negativity and a ≥ 50% decrease in the sum of the SUVmax for the target lesion (DSSTL) were significantly associated with complete remission after two cycles of chemotherapy ( p  = 0.005, p  = 0.016 and 0.026, respectively). LS disease, I-EBVDNA negativity and ≥ 50% DSSTL were strongly associated with prolonged PFS (HR = 2.953, 95% CI 1.433–6.009, p  = 0.003; HR = 2.479, 95% CI 1.239–4.958, p  = 0.01; and HR = 2.048, 95% CI 1.037–4.405, p  = 0.039, respectively). Based on these predictors of PFS, a preliminary scoring system was developed. Patients with scores of 1 and 2/3 had poorer survival outcomes than those with a score of 0 (HR = 2.030, 95% CI 0.816–5.048, p  = 0.044, and HR = 2.377, 95% CI 1.663–3.396, p  = 0.000, respectively). This scoring system also applied well to overall survival (OS) and appeared to be superior to the revised Ann Arbor staging system ( p  < 0.001, vs. p  = 0.205). By assessing the early response to chemotherapy, interim changes in the SUVmax and I-EBVDNA could be used to predict disease prognosis and better stratify patients into subgroups with different prognoses of ENKTL. Further prospective studies are needed to verify these findings.

AimsTo characterise the karyotypic abnormalities and heterogeneities in intravascular lymphoma (IVL).MethodsG-banded karyotyping was performed on biopsy specimens from a single-centre IVL cohort comprising intravascular large B-cell lymphoma (IVLBCL, n=12) and NK/T-cell lymphoma (IVNKTCL, n=1).ResultsFive IVLBCL cases and one IVNKTCL case (total 46%) were found to have normal karyotypes, and the cytogenetic abnormalities observed in the other seven IVLBCL cases (54%) were investigated further. These seven karyotypes were uniformly complex with an average of 13 aberrations. The seven cases all had abnormalities involving chromosome 6, with 57% involving structural abnormalities at 6q13, and chromosome 8, with 43% involving abnormalities at 8p11.2. In addition, 71% had aberrations at 19q13. On average, 4.4 chromosomal gains and losses were detected per case. Cytogenetic heterogeneities were observed in six cases (86%) and tetraploidy in three cases (43%). There was no significant difference in progression-free survival (p=0.92) and overall survival (p=0.61) between the IVLBCL cases with complex and normal karyotypes.ConclusionApproximately half of IVLBCL cases had a highly heterogeneous pattern of karyotypes with different clonal numerical and structural chromosome aberrations.

Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3′-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.

Extranodal natural killer (NK)/T-cell lymphoma is an aggressive malignancy of putative NK-cell origin, with a minority deriving from the T-cell lineage. Pathologically, the malignancy occurs in two forms, extranodal NK/T-cell lymphoma, nasal type; and aggressive NK-cell leukaemia. Lymphoma occur most commonly (80%) in the nose and upper aerodigestive tract, less commonly (20%) in non-nasal areas (skin, gastrointestinal tract, testis, salivary gland), and rarely as disseminated disease with a leukemic phase. Genetic analysis showed mutations of genes involved in the JAK/STAT pathway, RNA assembly, epigenetic regulation, and tumor suppression. In initial clinical evaluation, positron emission tomography computed tomography, and quantification of plasma EBV DNA are mandatory as they are useful for response monitoring and prognostication. In stage I/II diseases, combined chemotherapy and radiotherapy (sequentially or concurrently) is the best approach. Conventional anthracycline-containing regimens are ineffective and should be replaced by non-anthracycline-containing regimens, preferably including L-asparaginase. Radiotherapy alone is associated with high systemic relapse rates and should be avoided. In stage III/IV diseases, non-anthracycline-regimens-containing L-asparaginase are the standard. In relapsed/refractory cases, blockade of the programmed death protein 1 has recently shown promising results with high response rates. In the era of effective non-anthracycline-containing regimens, autologous haematopoietic stem cell transplantation (HSCT) has not been shown to be beneficial. However, allogeneic HSCT may be considered for high-risk or advanced-stage patients in remission or relapsed/refractory patients responding to salvage therapy. Prognostic models taking into account presentation, interim, and end-of-treatment parameters are useful in triaging patients to different treatment strategies.