Extracapsular extension of neck nodes and absence of human papillomavirus 16‐DNA are predictors of impaired survival in p16‐positive oropharyngeal squamous cell carcinoma

• Published in: Cancer 2020-05, Vol.126 (9), p.1856-1872
• Main Authors: Freitag, Josefine, Wald, Theresa, Kuhnt, Thomas, Gradistanac, Tanja, Kolb, Marlen, Dietz, Andreas, Wiegand, Susanne, Wichmann, Gunnar
• Format: Article
• Language: English
• Subjects: Adult; Aged; Cancer; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Deoxyribonucleic acid; DNA; DNA, Viral - genetics; extracapsular extension (ECE); Extranodal Extension - pathology; Female; Head & neck cancer; head and neck squamous cell carcinoma (HNSCC); Health hazards; Human papillomavirus; human papillomavirus (HPV); Human papillomavirus 16 - genetics; Humans; independent predictor; lymph node; Lymph nodes; Lymphatic system; Male; Metastases; metastasis (TNM) classification; Middle Aged; multivariate regression analysis; Neck; Neoplasm Staging; Nodes; Oncology; Oropharyngeal Neoplasms - metabolism; Oropharyngeal Neoplasms - pathology; Oropharyngeal Neoplasms - virology; oropharyngeal squamous cell carcinoma (OPSCC); Oropharyngolaryngeal carcinoma; p16 expression; Papillomavirus Infections - metabolism; Papillomavirus Infections - pathology; Prognosis; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; Squamous Cell Carcinoma of Head and Neck - virology; Surgery; Survival; Survival Analysis; Throat cancer; tumor; tumor staging; Tumors
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.32667

Background Human papillomavirus (HPV)‐driven oropharyngeal squamous cell carcinomas (OPSCCs) demonstrate superior outcome compared with HPV‐negative OPSCCs. The eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor, lymph node, metastasis (TNM) classification (TNM 2017) modifies OPSCC staging based on p16 positivity as a surrogate for HPV‐driven disease. In p16‐negative OPSCCs, lymph node (N) categories include extracapsular/extranodal extension (ECE); and, in p16‐positive OPSCCs, N categories are based on the number of positive neck lymph nodes omitting ECE status. The objective of the current study was to assess the prognostic impact of positive ECE status and the detection of HPV16 DNA in patients with p16‐positive OPSCC. Methods In a cohort of 92 patients with p16‐positive, lymph node (N)‐positive (stage III‐IVB) OPSCC who underwent surgery and neck dissection, allowing for a pathologic examination of positive lymph nodes, 66 of 92 patients (71.4%) were p16‐positive/HPV16 DNA‐positive, 62 of 92 (67%) were ECE‐positive, and 45 of 62 (72.6%) were ECE‐positive, p16‐positive, and HPV16 DNA‐positive. Differences in outcome were assessed using Kaplan‐Meier plots and Cox proportional hazard regression (CoxR) for tumor‐specific survival and overall survival (OS). Results The mean numbers of positive lymph nodes in ECE‐positive patients (5.0 positive lymph nodes; 95% CI, 3.8‐6.4 positive lymph nodes) and ECE‐negative patients (2.4 positive lymph nodes; 95% CI, 1.8‐2.9 positive lymph nodes) were different (P = .0007). ECE affected OS and tumor‐specific survival in p16‐positive patients (P = .007 and P = .047, respectively) and in p16‐positive/HPV16 DNA‐positive patients (P = .013 and P = .026, respectively). Related to the unequal distributions of ECE‐positive/HPV16 DNA‐negative tumors, the TNM 2017 failed to discriminate OS in patients with UICC stage I, II, and III disease (mean OS, 54.5, 73.4, and 45 months, respectively; median OS, 64.7 months, not reached, and 41.1 months, respectively). According to a univariate CoxR, the presence of ECE predicted impaired OS in patients with p16‐positive OPSCC (hazard ratio, 3.40; 95% CI, 1.17‐9.89; P = .025) and even greater impaired OS in those with p16‐positive/HPV16 DNA‐positive OPSCC (HR, 8.64; 95% CI, 1.12‐66.40; P = .038). Multivariate CoxR confirmed ECE and HPV16 DNA detection as independent predictors. Conclusions ECE and HPV16 DNA status should be inclu