Validating And Refining The 8th Edition Tnm N-Classification For Hpv Negative Oropharyngeal Cancer

The 8th edition TNM (TNM-8) re-introduced “overt clinical extranodal extension (cENE)” as an N-classification (cN) modifier for HPV-negative (HPV–) oropharyngeal cancer (OPC), although independent validation of outcome prediction over TNM-7 is not yet available. Emerging data shows that radiologic ENE (rENE) has a high specificity to predict pathological ENE (pENE) with similar prognostic importance. This study evaluates the performance of the TNM-8 vs TNM-7 N-classifications and explores the potential role of rENE in future cN classification. All HPV– OPC patients (n = 361) treated with definitive IMRT between 2005-2016 were included. cENE was retrospectively ascertained based on unambiguous “fixation” of neck mass or “skin involvement” detected by clinical examination. Pre-treatment CT/MR of cN+ cases were reviewed by a head-neck radiologist (EY) to determine rENE, defined as unequivocal evidence of tumor invading beyond the nodal capsule. Disease-free survival (DFS) and overall survival (OS) were compared between cENE-positive (cENE+) vs cENE-negative (cENE–) and rENE-positive (rENE+) vs rENE-negative (rENE–) patients. The prognostic value of cENE and rENE was confirmed by multivariable analyses (MVA). A refined cN-classification incorporating both cENE and rENE parameters was developed and then included in a revised TNM proposal. The performance of the revision was next compared to TNM-8 and TNM-7 using established criteria examining hazard consistency within each stage, hazard distinctiveness across stages, prognostic importance of the stage schema and sample size balance. A total of 48 cENE+ and 72 rENE+ cases were identified. Of cENE+ cases, 42 were rENE+ and 6 were rENE– due to excessive time lapse between CT and clinical evaluation, or subjectivity including primary tumor misinterpretation as nodal disease. The cENE+ and rENE+ proportion increased with higher N-category (N1/N2/N3: 2%/14%/87% and 7%/23%/100%, respectively p < 0.001). Median follow-up was 5.4 years. Compared to cENE–, cENE+ patients had lower 5-year OS (25% vs 42%, p = 0.006) and DFS (17% vs 37%, p < 0.001). Compared to rENE–, rENE+ patients had lower 5-year OS (30% vs 42%, p = 0.037) and DFS (36% vs 24%, p = 0.015). MVA confirmed a prognostic impact of cENE for OS (HR = 2.3, p = 0.001) and DFS (HR = 2.8, p < 0.001). We propose a refined N-categorization that reclassifies any cENE– case with rENE+ to one N stratum higher while any cENE+ still occupies the most adverse cN3b category. The revised stage schema with the refined N-categorization, that included both cENE and rENE elements, outperformed TNM-8 and both outperformed TNM-7 in OS prediction. We confirm the prognostic value of cENE and rENE. TNM-8 N-classification with the inclusion of cENE has improved outcome prediction compared to TNM-7 in HPV-negative OPC. rENE incorporation into TNM-8 appears to additionally augment the existing N classification to facilitate clinical trial design and decision making.