Extranodal Nasal-type NK/T-cell Lymphoma Research Articles

Extranodal nasal-type NK/T lymphoma treated with chemotherapy and radiotherapy: case series from aEuropean tertiary referral center and review of the literature.

Extranodal nasal-type NK/T-cell lymphoma (ENKTL) is very rare in western countries and few data are available regarding the prognosis and the outcome of patients treated for this disease. We aimed to evaluate the prognosis, the pattern and risk factors of disease failure after combined therapy and also performed areview of the literature. We retrospectively analyzed 20patients with (ENKTL) who underwent L‑Asparaginase based chemotherapy followed by (chemo-) radiotherapy between 2010 and 2020 in our center. Data on clinical characteristics and irradiation were collected. Failure patterns were recorded as local (tumor site), regional (regional lymph nodes) or distant failure (metastasis and/or nonregional lymph nodes). During amedian follow-up period of 46months, disease failure was observed in 8patients (40%). The 3‑year progression-free survival (PFS) and overall survival (OS) rates were 62.5 and 83.0%, respectively. The failure patterns were local (n = 6, 30%), regional (n = 3, 15%) and distant (n = 4, 20%). Among patients with local failure, all failures occurred within the radiation fields (100%). Univariate analysis showed that bilateral regional lymph node involvement (p = 0.0002), initial circulating EBV viral load ≥ 3.5 log (p = 0.03) and no negativation of EBV PCR after induction CT (p = 0.0497) were independent predictors of PFS. Patients with bilateral lymph node involvement and/or high EBV viral load have asignificant recurrence rate despite multimodal therapy. These results need to be confirmed by larger studies. Given the high rate of local recurrence within radiotherapy fields, the value of dose escalation should be considered. Patients at risk of relapse should be included in dedicated trials.

Development and Validation of CT-Based Clinical-Radiomics Nomogram for Early Stage Extranodal Nasal-Type NK/T Cell Lymphoma: A Multicenter Study

Most patients with extranodal nasal-type NK/T cell lymphoma (ENKTCL) had a localized disease with extensive primary tumor invasion at diagnosis (70-90%). Several clinical risk indexes, such as nomogram-revised risk index (NRI), international prognostic index (IPI), Korean Prognostic Index (KPI) and prognostic index of natural killer lymphoma (PINK), were used for ENKTCL patient stratification and providing information in clinical decision-making. However, they had low predictive power for early-stage patients with ENKTCL. This is the first study to construct a model with more predictive power through CT-based radiomics signature combined with traditional clinical risk indexes for overall survival (OS) of patients with early-stage ENKTCL. A total of 196 early stage ENKTCL patients were randomly assigned into the training (n = 147) and interval validation set (n = 49) in a 3:1 ratio. And 83 and 19 early stage ENKTCL patients from other two centers were used for external validation set (n = 62). All patients received radiotherapy after 2-3 cycles of chemotherapy. 1316 CT radiomic features before radiotherapy were extracted and selected to construct the radiomics signature (RS). A CT-based nomogram was established by integrating clinical indexes and radiomics signature in training set and was tested in two validation sets. With a median follow-up period of 59.9 months, 48 patients (24.1%) died. Compared with other prognostic index, NRI had better power to predict 5-year OS in the training cohort. The radiomics signature constructed by 11 selected radiomic features showed better prognostic performance than NRI for predicting 5-year OS in training set (C-index: 0.75 vs. 0.66), internal validation set (C-index: 0.71 vs. 0.62) and external validation set (C-index: 0.68 vs. 0.60). Patients were stratified into high- and low-risk groups by median radiomic signature. Patients in high-risk group had worse 5-year OS than patients in low-risk group (training set: 92% vs. 65%, P<0.001; internal validation set: 88% vs. 59%, P<0.05; external validation set 90% vs. 60%, P<0.05). The nomogram established by integrating radiomics signature with NRI showed optimal prognostic performance with C-index of 0.77 in training, 0.73 in internal and 0.71 in external validation set. Calibration curves showed good agreement. The clinical-radiomics nomogram integrating CT-based radiomics signature combined with traditional clinical risk index provided an excellent prognostic tool for OS, which could be helpful for personalized risk stratification and treatment in early stage ENKTCL patients.

Risk stratification and prognostic value of multi-modal MRI-based radiomics for extranodal nasal-type NK/T-cell lymphoma

BackgroundMagnetic resonance imaging (MRI) performs well in the locoregional assessment of extranodal nasal-type NK/T-cell lymphoma (ENKTCL). It’s important to assess the value of multi-modal MRI-based radiomics for estimating overall survival (OS) in patients with ENKTCL.MethodsPatients with ENKTCL in a prospectively cohort were systemically reviewed and all the pretreatment MRI were acquisitioned. An unsupervised spectral clustering method was used to identify risk groups of patients and radiomic features. A nomogram-revised risk index (NRI) plus MRI radiomics signature (NRI-M) was developed, and compared with the NRI.ResultsThe 2 distinct type I and II groups of the MRI radiomics signatures were identified. The 5-year OS rates between the type I and type II groups were 87.2% versus 67.3% (P = 0.002) in all patients, and 88.8% versus 69.2% (P = 0.003) in early-stage patients. The discrimination and calibration of the NRI-M for OS prediction demonstrated a better performance than that of either MRI radiomics or NRI, with a mean area under curve (AUC) of 0.748 and 0.717 for predicting the 5-year OS in all-stages and early-stage patients.ConclusionsThe NRI-M model has good performance for predicting the prognosis of ENKTCL and may help design clinical trials and improve clinical decision making.

Evidence of Cure for Extranodal Nasal-Type NK/T-Cell Lymphoma with Modern Treatment

<h3>Purpose/Objective(s)</h3> Statistically, a disease is considered curable when the mortality rate of survivors returns to the same level as that of the general population. We aimed to assess the curability of extranodal nasal-type NK/T-cell lymphoma (ENKTCL) in the modern treatment era. <h3>Materials/Methods</h3> The data of 1995 patients treated between 2000 and 2016 and registered in China Lymphoma Collaborative Group (CLCG) database were analyzed. We estimated cure fractions, median survival times, and the time point of cure using a non-mixture cure model. <h3>Results</h3> The relative survival curves attained plateau for the entire cohort and most subsets, indicating that the notion of cure was robust. The overall cure fraction was 72.1%. Median survival was 1.10 years in uncured patients. The cure time was 4.5 years, i.e., beyond this time, mortality in ENKTCL patients was equivalent to that in the general population. In multivariate analysis, cure probability was associated with stage, performance status, primary tumor invasion, and lactate dehydrogenase level. Elderly patients (>60 years) had cure fraction similar to that of younger patients. Five-year overall survival rate correlated well with the cure fraction across risk-stratified groups. Thus, statistical cure is possible in ENKTCL patients receiving modern treatment strategies. <h3>Conclusion</h3> Overall probability of cure is good, though it is affected by presence of risk factors. These findings provide the rationale for treatment and follow-up of patients with different cure probabilities.

Clinical characteristics and prognostic analysis of advanced-stage extranodal NK/T cell lymphoma

目的探讨非局限期结外鼻型NK/T细胞淋巴瘤（ENKTL）患者的临床特征及预后影响因素。方法回顾性分析北京协和医院2012年1月至2019年12月收治的51例Ⅲ~Ⅳ期ENKTL患者的临床资料。分析其临床特征、疗效、生存情况及预后影响因素，依据起病时是否存在鼻咽部受累分为鼻型与非鼻型，对比分析二者的差异，探讨EB病毒DNA（EBV-DNA）在疗效监测及预后评价中的意义。结果所有患者的中位发病年龄为42（14~67）岁，男女比例为2.9∶1。中位随访时间为30（1~78）个月，非局限期患者中位总生存（OS）时间为7个月，1年及3年无进展生存（PFS）率分别为34.1%和24.6%，1年及3年OS率分别为39.9%和26.6%。鼻型与非鼻型患者的比例为1.6∶1。非鼻型患者合并噬血细胞综合征的比例较鼻型患者高（65.0%对35.5%，P=0.039），非鼻型患者一线化疗的完全缓解（CR）率较鼻型患者低（10.0%对45.2%，P=0.008）。非局限期鼻型与非鼻型患者的中位OS时间分别为9个月和4个月，3年PFS率分别为36.0%和10.0%（P=0.029），3年OS率分别为37.9%和11.4%（P=0.050）。EBV-DNA的变化趋势与疗效有良好的相关性。基线EBV-DNA阴性与阳性患者生存曲线的差异无统计学意义。1个疗程化疗后EBV-DNA阴性与阳性患者的3年OS率分别为77.9%和8.1%，差异有统计学意义（P=0.002）。多因素分析结果显示，1个疗程化疗后EBV-DNA阳性为OS不良的独立预后因素。结论应用以培门冬酶为基础化疗方案的非局限期ENKTL患者的治疗有效率及远期生存仍较差。非鼻型患者在临床特征、化疗疗效及远期预后方面均较鼻型患者差。1个疗程化疗后EBV-DNA阳性为OS不良的独立预后因素，可用于早期预测疗效及预后。

Expression of mTOR and 4E-BP1 in extranodal Nasal-type NK/T-cell Lymphoma and implication for prognosis

Objective: To study the expression of mTOR and 4E-BP1 in extranodal Nasal-type NK/T-cell Lymphoma(ENKTCL) and the correlation with the clinicopathological factors and prognosis of ENKTCL.Method: Immunohistochemistry was used to detect the expresstion of mTOR and 4E-BP1 in the tissues of ENKTCL and nasal pharyngeal lymphoid hyperplasia. The relationship between the expression of mTOR and 4E-BP1 and clinicopathological features was analyzed using the Chi-square test, which including sorting clinical stage, general condition score and international prognostic index(IPI). Result: The expression rates of mTOR and 4E-BP1 in ENKTCL were 63.9% and 58.3% respectively, and significantly higher than those（15.0% and 10.0%）in patients with nasal pharyngeal lymphoid hyperplasia(χ ²=12.355, P=0.0001; χ ²=12.410, P=0.0001). The positive expression rate of mTOR was linked to clinical staging, and the positive protein expressions in Stage Ⅲ and Ⅳwere higher than those in stageⅠand Ⅱ(χ ²=17.902, P=0.0001). mTOR expression was related to 4E-BP1(r=0.655,P=0.001). The positive expression rates of 4E-BP1were linked to IPI of lymphoma(χ ²=4.051, P=0.044). Conclusion: High-expressions of mTOR and 4E-BP1 in patients with ENKTCL are related to the biological progression and recurrence of ENKTCL and are malignant indicators to identify ENKTCL from nasal pharyngeal lymphoid hyperplasia. mTOR and 4E-BP1 may play important roles to assess ENKTCL prognosis..

Current status for the treatment of extranodal nasal type NK/T cell lymphoma

The most of extranodal nasal type NK/T-cell lymphoma (ENKTL) are in the Ⅰ/Ⅱ stage. Radiotherapy alone is insufficient to achieve a high cure rate for the early stage patients with ENKTL due to frequent local and systemic relapse. Concomitant/sequential chemotherapy and radiotherapy is the standard treatment for the early stage patients with ENKTL. For the patients with stage Ⅲ/Ⅳ ENKTL, regimens containing L-asparaginase are most effective. For the patients with advanced stage ENKTL or refractory recurrent ENKTL, hematopoietic stem cell transplantation may be considered when the remission is achieved. Key words: Lymphoma, extranodal NK-T-cell; Radiotherapy; Drug therapy; Hematopoietic stem cell transplantation

Internal medical management of extranodal nasal type NK/T cell lymphoma

Extranodal nasal type NK/T cell lymphoma (ENKTL) is a highly aggressive non-Hodgkin lymphoma. Due to its low occurrence even in prevalent areas, there has been no large sample randomized controlled clinical trials. Therefore, no standard therapeutic strategy is currently identified in this disease. Tumor cells are insensitive to conventional anthracyclines-containing chemotherapy because of high expression of multi-drug resistant gene 1. Regimens that incorporate the use of L-asparaginase or gemcitabine result in substantial improvements in overall response rate and are promising treatment for ENKTL. Targeted therapy, immunomodulatory therapy and hematopoietic stem cell transplantation are still under research. Key words: Lymphoma, extranodal NK-T-cell; Drug therapy; Hematopoietic stem cell transplantation

Clinicopathologic, Immunophenotypic, and EBER in situ Hybridization Study of Extranodal Natural Killer/T-cell Lymphoma, Nasal Type in Xinjiang Multi-Ethnic Groups

Extranodal nasal-type NK/T-cell lymphoma (ENKTCL) is a common and geographic predominant disease in China. We observed the clinical and pathologic features of this tumor type and its relationship to Epstein-Barr virus (EBV), and focused on the epidermology and prevalence of ENKTCL in Xinjiang, in order to improve the diagnostic and differential diagnosis ability. 103 cases with nasal-type NK/T-cell lymphoma were recruited and assessed. All cases were submitted for histological assessment, immunophenotyping, in situ hybridization detection of EBV-encoded RNA (EBER), and clinical information analysis. Male patients, aged between 40 and 50 years, were predominantly of Han ethnicity outnumbering those of Uyghur ethnicity. 80 cases of ENKTCL involved the nasal cavity or other areas of the upper respirodigestive tract whereas the remaining ones involved other extranodal sites. All cases exhibited similar histological changes: necrosis and inflammatory infiltration were frequently present. Cytologic atypical as well as angiocentric and angiodestructive growth patterns of the tumor cells were consistently noted, although the sizes and contours of the tumor cells varied considerably. All cases expressed one or several T-cell markers and at least one cytotoxic molecule. 86 cases (84%) expressed CD56, and 97 cases submitted for EBER detection showed positive results. ENKTCL affects predominantly middle-aged Han Chinese in the Xinjiang region, with a predilection to involvement of the nasal cavity and a strong association with a high EBV load. Early and correct identification of the disease in daily practice depends on the combination of morphologic evaluation, immunophenotypic assessment, and EBER detection.

Comparison of clinical characteristics and prognoses between primary Waldeyer's ring diffuse large B-cell lymphoma and extranodal nasal-type NK/T-cell lymphoma

Objective This study aimed to compare the clinical characteristics and prognoses of primary Waldeyer's ring diffuse large B-cell lymphoma (DLBCL) and extranodal nasal-type NK/T-cell lymphoma ( ENKTCL).Methods From 2000 to 2008,122 patients with primary Waldeyer's ring DLBCL and 44 patients with primary Waldeyer' s ring ENKTCL consecutively diagnosed were retrospectively compared.Patients with DLBCL usually received 4-6 cycles of CHOP-based chemotherapy followed by involved-field radiotherapy.Patients with early stage ENKTCL usually received extended-field radiotherapy with or without subsequent chemotherapy,or short courses ( 1 - 3 cycles ) of chemotherapy followed by radiotherapy.Kaplan-Meier method was used for survival analysis.Logrank method was used for univariate analysis.Results The follow-up rate was 82％.The number of patients followed 5 years were 32 and 15 in DLBCL and ENKTCL.DLBCL mainly presented with stage Ⅱ tonsillar disease with regional lymph node involvement.ENKTCL occurred predominately in young males,as nasopharyngeal stage I disease with B symptoms and involving adjacent structures.The 5-year overall survival (OS) and progression-free survival (PFS) rates were 74％ and 67％ in DLBCL,and 68％ and 59％ in ENKTCL (x2=0.53,1.06,P=0.468,0.303),respectively.In stage Ⅰ and Ⅱ diseases,the 5-year OS and PFS rates were 79％ and 76％ for DLBCL compared to 72％ and 62％ for ENKTCL (x2 =1.20,2.46,P=0.273,0.117).On univariate analysis,age ＞ 60 years,elevated lactate dehydrogenase,eastern cooperative oncology group performance status ＞ 1,international prognosis index ( IPI ) score ≥ 1,stage Ⅲ/Ⅳ diseases and bulky disease were associated with unfavorable survival for DLBCL (x2=9.40,12.72,6.15,10.36,12.48,5.53,P=0.002,0.000,0.013,0.001,0.000,0.019),and only age＞60 years and IPI score ≥ 1 were associated with poor survival for ENKTCL (x2 =3.98,8.41,P =0.046,0.004).Conclusions These results indicate that remarkable clinical disparities exist between DLBCL and ENKTCL in Waldeyer's ring. Different treatment strategies for each can result in similarly favorable prognoses. Key words: Lymphoma,diffuse large B-cell,Waldeyer's ring/radiotherapy; Lymphoma,diffuselarge B-cell,Waldeyer's nng/chemotherapy; Lymphoma,extranodal nasal-type NK/T-cell,Waldeyer's ring/radiotherapy; Lymphoma,extranodal nasal-type NK/T-cell,Waldeyer's ring/cheomotherapy; Prognosis

E3330 Enhanced Antitumor Effect of Adrinmycin on Human Extranodal Nasal-Type NK/T Cell Lymphoma Xenografted–Nude Mice

Abstract 2723 Abstract:Extranodal Nasal-Type NK/T Cell Lymphoma (EN-NK/T-L) is a distinct clinicopathological entity of non-Hodgkin’s lymphoma, which is characterized by a highly aggressive clinical process and poor prognosis especially when disseminated or recurrent after radiotherapy. Human purinic/apyrimidinic endonuclease/redox factor-1 (hAPE/Ref-1) is a multifunctional protein involved in the repair of DNA damaged by oxidative. Because of its involvement in DNA repair and apoptosis-related signaling mechanisms, APE/Ref-1 is also being discussed as a novel target for tumor-therapeutic approaches. In studies, high level of APE1 expression is associated with an resistance to chemotherapeutic agents and adverse prognosis. And recent studies show that E3330, a small molecule inhibitor of the Ape-1/Ref-1 redox domain, induce inhibition of growth in cancer cell in vitro by specific inhibiting the function of APE/REF-1. E3330 blocks the in vitro growth of pancreatic cancer-associated endothelial cells(J Cell Physiol. 2009 Apr;219(1):209–18.) and of the NK/T-cell lineage in our sdudy already and provides a potential therapeutic strategy in tumor. Thus far, no study has reported the experimental research on E3330 combined with chemotherapy in treating NK/T cell lymphoma. Therefore, we try to establish xenografted-nude mice model of human extranodal nasal type NK/T cell lymphoma and to investigate the effect of E3330 combined with adrinmycin on the human EN-NK/T-L xenografted-nude mice and its mechanism. Methods: EN-NK/T-L Xenografted-nude mice model was established by intraperitoneal injection of NK/T cell lymohoma cells SNK-6. IC50 of E3330 for SNK-6 was calculated according to the result of MTT assay. Xenografted- nude mice were divided into four groups: Control group were given equal volume sodium,po,d1-7□ G E3330 group were given E3330, 6mg/kg, po, d1-7□ GADM group were given ADM, 0.5mg/kg, ip,d1,4,7□ GE3330 + ADM group were given both E3330 and ADM, E3330, 6mg/kg, po, d1-7, ADM 0.5mg/kg, ip, D1,4,7. The tumor weight and the survival rate of tumor–bearing mice were assayed, the apoptosis cells were determined by TdT-mediated Dutp Nick-end-Labeling(Tunel). Immunohistochemistry were used to study the expression of ki-67. Immunofluorescence were used to study the expression of APE/REF-1. Results: Nude mice model of human extranodal nasal type NK/T cell lymphoma was established successfully. The results showed that the expression level of APE/REF-1 was higher in tumor tissues compared with that in normal tissues (Fig 1 A 1B). The transplanted tumor volumes of mice were significantly smaller in E3330 + ADM group than those in other three groups(p<0.05)(Table 1). The expression of ki-67 in E3330 + ADM group was lower than other groups(p<0.05) (Fig 2 A 2B 2C 2D) and the apoptosis cells were increased in the same group (Table 2). Conclusion: Our study showed that E3330 + adrinmycin can significantly inhibit the growth of transplanted tumor of extranodal nasal type NK/T cell lymphoma Xenografted-nude mice. Disclosures:No relevant conflicts of interest to declare.

Preliminary Results of Concurrent Chemoradiation Therapy in Patients with Early Stage Extranodal Nasal Type NK/T-cell Lymphoma

Extranodal nasal type NK/T-cell lymphoma (ENKTCL) is a peculiar pathological type of NHL with higher incidence in south China. Though most of the diseases can be diagnosed at early stage, the prognosis after combined radiotherapy (RT) and chemotherapy (CT) is generally poor, and optimal treatments remain unclear. We investigated concurrent chemoradiation therapy (CCRT) in a group of patients and here report the feasibility and preliminary outcome of this treatment.

Expression of p33ING1 proteins in extranodal nasal type NK/T cell lymphoma

Objective To study expressions of p33ING1 proteins in extranodal nasal type NK/T cell lymphoma(ENKL). Methods p33ING1 were detected by immunohistochemistry in 37 cases of ENKL and 37 cases of benign lymphoid tissue proliferation. Results Expressions of p33ING1 and in ENKL were 67.57%, lower than that in benign lymphoid tissue proliferation. Low expression of p33ING1 in ENKL was correlation to patients' high level LDH. Conclusions Low or lost expression of p33ING1 may play on important role on the development and progression of ENKL. Key words: ENKL; p33ING1 ; Clinicopathological features