Prognostic Value of 18F-FDG PET/CT Radiomics in Extranodal Nasal-Type NK/T Cell Lymphoma.

OBJECTIVE: To investigate the prognostic utility of radiomics features extracted from 18F-fluorodeoxyglucose (FDG) PET/CT combined with clinical factors and metabolic parameters in predicting progression-free survival (PFS) and overall survival (OS) in individuals diagnosed with extranodal nasal-type NK/T cell lymphoma (ENKTCL). MATERIALS AND METHODS: A total of 126 adults with ENKTCL who underwent 18F-FDG PET/CT examination before treatment were retrospectively included and randomly divided into training (n = 88) and validation cohorts (n = 38) at a ratio of 7:3. Least absolute shrinkage and selection operation Cox regression analysis was used to select the best radiomics features and calculate each patient's radiomics scores (RadPFS and RadOS). Kaplan-Meier curve and Log-rank test were used to compare survival between patient groups risk-stratified by the radiomics scores. Various models to predict PFS and OS were constructed, including clinical, metabolic, clinical + metabolic, and clinical + metabolic + radiomics models. The discriminative ability of each model was evaluated using Harrell's C index. The performance of each model in predicting PFS and OS for 1-, 3-, and 5-years was evaluated using the time-dependent receiver operating characteristic (ROC) curve. RESULTS: Kaplan-Meier curve analysis demonstrated that the radiomics scores effectively identified high- and low-risk patients (all P < 0.05). Multivariable Cox analysis showed that the Ann Arbor stage, maximum standardized uptake value (SUVmax), and RadPFS were independent risk factors associated with PFS. Further, ß2-microglobulin, Eastern Cooperative Oncology Group performance status score, SUVmax, and RadOS were independent risk factors for OS. The clinical + metabolic + radiomics model exhibited the greatest discriminative ability for both PFS (Harrell's C-index: 0.805 in the validation cohort) and OS (Harrell's C-index: 0.833 in the validation cohort). The time-dependent ROC analysis indicated that the clinical + metabolic + radiomics model had the best predictive performance. CONCLUSION: The PET/CT-based clinical + metabolic + radiomics model can enhance prognostication among patients with ENKTCL and may be a non-invasive and efficient risk stratification tool for clinical practice.

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

BACKGROUND: Magnetic 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. METHODS: Patients 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. RESULTS: The 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. CONCLUSIONS: The NRI-M model has good performance for predicting the prognosis of ENKTCL and may help design clinical trials and improve clinical decision making.

Quality of life in patients with early-stage extra-nodal NK/T cell lymphoma of nasal type after definitive radiation therapy / 中华放射肿瘤学杂志

Objective:To investigate the quality of life in patients with early-stage extra-nodal NK/T cell lymphoma of nasal type (ENKTL) arising from the upper aerodigestive tract, who had remained progression-free survival (PFS) for over 3 months after definitive intensity-modulated radiation therapy (IMRT), and to analyze the factors related to main adverse symptoms.Methods:276 patients who received IMRT from March, 2012 to June, 2021 were included. There were 201 males and 75 females with a median age of 41.5 years (range: 13-81 years) upon diagnosis. Consistent target delineation schemes and similar dose gradients were adopted for IMRT, with a median prescribed dose of 54.6 Gy/26F. Cross-sectional investigation was performed with a modified EORTC QLQ-H&N35 questionnaire, the incidence and severity of adverse symptoms, severity of disease and their influencing factors at each time-point during their survival were statistically analyzed.Results:The median age of patients at the investigation was 46.2 years, and the median PFS after IMRT was 47.2 months (range: 3.1-115.7 months). The most common adverse symptoms included nasal symptoms (incidence rate 63.8%), dry mouth (50%), tooth diseases (47.1%), smell and taste alteration, and sexual apathy, etc. Most symptoms were mild (the average standardized score was 5.50, the full score of 100 indicating the most severe), and could be relieved remarkably over survival time, but some symptoms, such as tooth diseases and sexual apathy, were more obvious and recurred for several years. Age and anti-PD-1 immune therapy influenced the symptom scores, and tooth diseases were closely correlated with dry mouth. Conclusion:The quality of life in patients with early-stage ENKTL after definitive IMRT is high, and the most significant symptoms include nasal symptoms, tooth diseases, and sexual apathy, etc. , which need to be mitigated with more studies.

[Outcome of radiotherapy for low-risk early-stage patients with extranodal NK/T-cell lymphoma, nasal-type].

Objective: To evaluate the prognosis and determine the failure patterns after radiotherapy for low-risk early-stage patients with extranodal NK/T-cell lymphoma, nasal-type (ENKTCL). Methods: A total of 557 patients from 2000-2015 with low-risk early-stage ENKTCL who received radiotherapy (RT) with or without chemotherapy (CT) from China Lymphoma Collaborative Group were retrospectively reviewed. Among them, 427 patients received combined modality therapy, whereas 130 patients received RT alone. Survivals were calculated by Kaplan-Meier method and compared with Log-rank test. Overall survival (OS) was compared with age and sex-matched general Chinese population using expected survival and standardized mortality ratio (SMR). Cox stepwise regression model was used for multivariate analysis. Results: The 5-year OS and progression-free survival (PFS) were 87.2% and 77.2%. The SMR was 3.59 (P<0.001) at 1 year after treatment, whereas it was 1.50 at 4 years after treatment, without significant difference between ENKTCL group and country-matched general population (P=0.146). Compared with RT alone, CMT did not result in significantly superior 5-year OS (87.0% vs 87.4%, P=0.961) or PFS (76.1% vs 80.7%, P=0.129). Local failure (11.5%, 64/557) and distant failure (10.8%, 60/557) were the main failure modes, while regional failure was rare (2.9%, 16/557). The 5-year locoregional control rate (LRC) was 87.2% for the whole group, with 89.5% for ≥50 Gy versus 73.7% for <50 Gy (P<0.001). Radiotherapy dose was an independent factor affecting LRC(P<0.05). Conclusions: Radiotherapy achieves a favorable prognosis in patients with low-risk early-stage ENKTCL. The incidence of either locoregional or distant failure is low. Radiation dose still is an important prognostic factor for LRC.

Relation Between EB Virus Infection and Curative Effect, Prognosis of Patients with Early-stage Extranodal Nasal-type NK/T-cell Lymphoma / 肿瘤防治研究

Objective To explore the correlation of pretreatment EBV DNA load, EBV EA-IgA and VCA-IgA antibodies levels with the clinical characteristics, curative effect and prognosis of the patients with early-stage extranodal nasal-type NK/T-cell lymphoma (ENKTCL). Methods We analyzed the clinical features and prognostic factors of 78 ENKTCL patients. Results Positive rates of pretreatment EBV DNA, VCA-IgA and EA-IgA were 43.6%, 20.5% and 14.1%, respectively. EBV DNA was significantly associated with Ann Arbor stage, primary site, PTI and non-CR (all P < 0.05). VCA-IgA and EA-IgA were related to positive EBV DNA and non-CR (all P < 0.05). Multivariate analysis showed that age, EBV DNA and non-CR were independent prognostic factors for OS (all P < 0.05); age, EBV DNA, primary site and non-CR were independent prognostic factors for PFS (all P < 0.05). Conclusion The pretreatment positive EBV DNA is related to advanced Ann Arbor stage, PTI, primary extra-nasal subtypes of upper aerodigestive tract and poor response to treatment. The elevated levels of EA-IgA and VCA-IgA are related to positive EBV DNA and poor response to treatment. Pretreatment EBV DNA could be used for risk stratification and prognosis prediction of ENKTCL, while EA-IgA and VCA-IgA play limited role in guiding the prognosis of ENKTCL.

Efficacy and toxicities of chemoradiotherapy in the treatment of early stage extranodal nasal-type NK/T-cell lymphoma / 中华放射医学与防护杂志

Objective:To assess the efficacy and toxicity of chemoradiotherapy in the treatment of early stage extranodal nasal-type NK/T-cell lymphoma (ENKTCL).Methods:Retrospective review was conducted for 174 patients with pathological proved early stage ENKTCL who were treated in the Department of Radiation Oncology, Peking University Cancer Hospital & Institute. The Kaplan-Meier survival analysis was adopted to calculate the local-regional control (LRC), overall survival (OS), and progression free survival (PFS), and the Log-rank test COX regression model were applied to univariate and multivariate analyses.Results:The patients in this study included 102 and 72 patients diagnosed with Ann Arbor stage-Ⅰ and stage-Ⅱ, respectively. Among them, two patients received radiotherapy alone and 172 patients were treated with combined chemoradiotherapy. The overall response rate of all the patients was 94.2%, with a complete response (CR) rate of 87.9% (153). Furthermore, the rates of 5-year OS, PFS, and LRC were 87.3%, 83.1%, and 91.9%, respectively. The most common toxicities during the chemotherapy and radiotherapy included myelosuppression and oral mucositis, with grade ≥ 3 myelosuppression and grade ≥ 3 oral mucositis accounting for 62.1% and 10.9% of all patients, respectively. As shown by multivariate analysis, the adverse prognostic factors for OS included age > 60, B symptoms, and stage Ⅱ, while the adverse prognostic factors for PFS included age > 60 and stage Ⅱ. Meanwhile, the PFS rate was significantly improved by increasing the radiation dose (≥ 50 Gy vs.<50 Gy), and the 5-year PFS rates of the two groups were 83.5% and 76.5%, respectively [hazard ratio ( HR) 0.374; 95% CI, 0.169-0.826; P=0.015]. Conclusions:A good therapeutic effect can be achieved for early stage NK/T-cell lymphoma and the toxicities after combined chemoradiotherapy can be tolerated.

[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..

TP53 mutations in peripheral mature T and NK cell lymphomas: a whole-exome sequencing study with correlation to p53 expression.

Peripheral mature T and NK cell lymphomas consist of a heterogeneous group of neoplasms with cytogenetic and molecular diversities. TP53 mutation is involved in the events of tumorigenesis and present in a variety of cancer subtypes. However, TP53 mutation in peripheral mature T and NK cell lymphomas has not been extensively investigated. In this study, 57 formalin-fixed paraffin-embedded samples were collected for whole-exome sequencing and immunohistochemical study. Ten cases had TP53 mutation variant allele frequency (VAF) of more than 5%, predominantly in intestinal T-cell lymphoma (60%), peripheral T-cell lymphoma, not otherwise specified (22.2%), and extranodal nasal-type NK/T-cell lymphoma (21.7%). Six of 16 (37.5%) cases with 72Pro homozygous genotype showed higher frequency of TP53 mutation VAF > 5% than did those with 72Arg homozygous genotype (P = .044). To a variable extent, overexpression of p53 was observed in 11 of 56 (19.6%) tumors. The percentage of tumor cells with strong p53 staining was positively correlated with TP53 mutation VAF (R2 = 0.95, P < .001). TP53 mutation and p53 expression tended to indicate poor prognosis (P = .054 and P = .009, respectively). In conclusion, we demonstrated TP53 mutation and p53 expression in subtypes of peripheral mature T and NK cell lymphomas and found positive correlation of this immunostaing pattern with the status of TP53 mutation.

The prognostic role of level of involved regional lymph node in patients with stage Ⅱ extranodal nasal-type NK/T-cell lymphoma of the upper aerodigestive tract / 中华放射肿瘤学杂志

Objective This study aimed to evaluate the prognostic value of regional lymph node spread in patients with stage Ⅱ nasal-type NK/T-cell lymphoma of the upper aerodigestive tract (UADT-NKTCL).Methods From 1987 to 2013,a total of 97 patients with newly-diagnosed stage Ⅱ UADT-NKTCL were retrospectively reviewed.Primary tumors were located in the nasal cavity (n=52) or extranasal UADT sites (n=45).The majority of patients were treated with primary radiotherapy.Sixty-five patients were treated with combined modality therapy (CMT),and 32 patients were treated with radiotherapy alone (n=27) or chemotherapy alone (n=5).The Kaplan-Meier method was used to calculate the survival rate,and the log-rank test was used for survival difference analysis and monovariate prognostic analysis.The Cox regression model was used to multivariate prognostic analysis.Results The 5-year overall survival (OS) and progression-free survival (PFS) rates for all stage Ⅱ patients were 57% and 49%,respectively.The presence of a lower neck lymph node (defined as extension below the caudal border of the cricoid cartilage) was significantly associated with poor outcomes on univariate analysis and maintained significance on multivariate analysis.The median survival for patients with lower neck lymph node was 19.3 months and the 2-,5-years OS rates were 28% and 11%(P=0.000).For stage Ⅱ patients,CMT significantly improved survival.The 5-year OS and PFS rates were 64% and 52% for CMT,compared with 40.4%(P=0.006) and 42% for single modality therapy (P=0.088).Conclusion The level of regional lymph node is a powerful prognostic factor for stage Ⅱ UADT-NKTCL.The involvement of low neck lymph node is significantly associated with poorer survival outcomes.

Prognostic value of pretreatment serum hemoglobin level in early-stage extranodal nasal-type NK/T-cell lymphoma / 中华放射肿瘤学杂志

Objective To investigate the effect of pretreatment serum hemoglobin (Hb) level on the prognosis of early-stage extranodal nasal-type NK/T-cell lymphoma.Methods A retrospective analysis was performed on the clinical data of 175 patients with stage Ⅰ or Ⅱ extranodal nasal-type NK/T-cell lymphoma who were admitted to The Tumor Hospital Affiliated to Shanxi Medical University from 2000 to 2015.The inclusion criteria included Ann Arbor Ⅰ/Ⅱ stage, the primary tumor located in the upper aerodigestive tract, without other malignant diseases, and complete clinical information and follow-up data.Of the 175 patients, 67 received chemotherapy alone, 8 received radiotherapy alone,100 received radiotherapy and chemotherapyed.The survival rate was calculated using the Kaplan-Meier method.The log-rank test was used for univariate prognostic analysis.The Cox regression model was used for multivariate prognostic analysis.Results The univariate analysis showed that pretreatment serum Hb level (≥120 g/L), lactate dehydrogenase (LDH) level (normal), Eastern Cooperative Oncology Group (ECOG) score (0-1), Ann Arbor stage (IE), and radiotherapy were associated with significantly improved progression-free survival (PFS) and overall survival (OS)(P=0.000-0.046).The multivariate analysis showed that pretreatment serum Hb level, LDH level, ECOG score, and Ann Arbor stage were independent prognostic factors for PFS and OS (P=0.000-0.040).Conclusion Patients with a high pretreatment serum Hb level (≥120 g/L) have a better prognosis than those with a low pretreatment serum Hb level (<120 g/L).

Linfoma Extranodal de Células NK/T tipo Nasal / Extranodal Nasal type NK/T-Cell Lymphoma / Extranodal Nasal type NK/T-Cell Lymphoma

O Linfoma Extranodal de Células NK/T tipo Nasal tem uma distribuição geográfica peculiar, ocorrendo mais frequentemente em países orientais e na população nativa de alguns países da América Central e da América do Sul. Sua localização preferencial é na cavidade nasal e nos seios paranasais, mas pode acometer outras estruturas da chamada região médio-facial. Tem um padrão de disseminação com "homing" característico, incluindo pele, testículo, SNC e trato digestivo. Este linfoma, menos frequentemente, pode acometer primariamente estas regiões. A maioria destas neoplasias apresenta um fenótipo NK, mas alguns poucos casos podem ter sua origem em células T verdadeiras, por este motivo é designado "linfoma NK/T". O genoma do vírus Epstein-Barr é detectado na maioria dos casos, sugerindo uma relação etiológica. Embora este linfoma seja sensível à radioterapia, apresenta mais frequentemente resistência a agentes quimioterápicos que outros linfomas. Uma possível explicação para a resistência é a usual expressão de glicoproteína-p. O prognóstico destes linfomas é pobre, sendo necessária a investigação de novas modalidades terapêuticas.

Extranodal Nasal type NK/T-Cell Lymphoma has a peculiar geographic distribution, occurring more frequently in Eastern countries and in the native populations of some Central and South American countries. It is commonly found in the nasal cavity and paranasal sinuses, but may also compromise other structures in the mid-facial region. The disease has a characteristic homing dissemination pattern, including skin, testis, CNS and digestive tract. This lymphoma can, less frequently, primarily compromise these regions. The majority of these neoplastic diseases present an NK phenotype, but a few cases can be truly of T-cell origin, because of which it is designed "NK/T-cell lymphoma". The Epstein-Barr virus genome can be detected in most of the cases, suggesting an etiological relationship. Although this lymphoma is responsive to radiotherapy, it is more resistant to conventional chemotherapy than other lymphomas. A possible explanation for this is the frequent expression of the p-glycoprotein. The prognosis of these lymphomas is still poor, making further investigation of new therapies imperativ.