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

Abstract

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 included in the prognostic staging of patients with p16-positive OPSCC because several lines of evidence demonstrate their impact on survival.

Standardized Diagnostics Including PET-CT Imaging, Bilateral Tonsillectomy and Neck Dissection Followed by Risk-Adapted Post-Operative Treatment Favoring Radio-Chemotherapy Improve Survival of Neck Squamous Cell Carcinoma of Unknown Primary Patients

“…Besides improved outcome in the oropharyngeal cancers presenting initially as NSCCUP (data not shown), we provide evidence that a standardized diagnostic workup followed by riskadapted treatment described improves the outcome even in definitive NSCCUP-P without detection of primary lesions (Table 1 and Figures 2-5). The evidence-based decisionmaking for further diagnostic and the standardized treatment planning for CRT, Op + PORT or risk-adapted cisplatin-based Op + PORCT improve outcome as demonstrated in oropharyngeal cancer (29). The diagnostic step carrying a substantial therapeutic effect improving survival was ND.…”

Significance of Extranodal Extension in Surgically Treated HPV-Positive Oropharyngeal Carcinomas

“…Among other things, they showed that microscopic or macroscopic ENE results in a significantly worse OS when compared to positive lymph nodes without ENE (5J-OS: 91% vs. 78%; p < 0.0001) ( 43 ). In addition, Freitag et al recently published their analysis of a cohort of 92 patients with surgically treated HPV-mediated OPSCC (IC+OP+RT: n = 8, OP: n = 21, OP+RT: n = 23, OP+RCT: n = 39, OP+RT+Cetuximab: n = 1) ( 44 ). Their multivariate analysis showed that ENE represents an independent predictor for decreased OS ( p = 0.033), tumor-specific survival ( p = 0.165), progression-free survival ( p = 0.42), and DFS ( p = 0.04) ( 44 ).…”

“…In addition, Freitag et al recently published their analysis of a cohort of 92 patients with surgically treated HPV-mediated OPSCC (IC+OP+RT: n = 8, OP: n = 21, OP+RT: n = 23, OP+RCT: n = 39, OP+RT+Cetuximab: n = 1) ( 44 ). Their multivariate analysis showed that ENE represents an independent predictor for decreased OS ( p = 0.033), tumor-specific survival ( p = 0.165), progression-free survival ( p = 0.42), and DFS ( p = 0.04) ( 44 ). The results of their investigation as a whole led them to the conclusion that ENE (as well as HPV16 DNA status) should be integrated in the prognostic staging algorithm of HPV-mediated OPSCC ( 44 ).…”

“…Their multivariate analysis showed that ENE represents an independent predictor for decreased OS ( p = 0.033), tumor-specific survival ( p = 0.165), progression-free survival ( p = 0.42), and DFS ( p = 0.04) ( 44 ). The results of their investigation as a whole led them to the conclusion that ENE (as well as HPV16 DNA status) should be integrated in the prognostic staging algorithm of HPV-mediated OPSCC ( 44 ). Furthermore, Gal et al recently showed a decreased survival in the presence of clinical and pathological ENE compared to the absence of ENE.…”

Lymph Node Yield and Ratio in Selective and Modified Radical Neck Dissection in Head and Neck Cancer—Impact on Oncological Outcome

“…The presence of LNMs bears a major prognostic influence, with an estimated 50% reduction in overall survival in nodal negative vs. nodal positive HPV-negative HNSCC [ 6 , 7 , 8 ]. Features such as number, size, location in the neck, and the presence of extracapsular extension (ECE) among others equally have a negative impact on survival and oncological outcome [ 9 , 10 , 11 , 12 ].…”