Human papillomavirus DNA and p16 expression in Japanese patients with oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV) is a major etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC). However, little is known about HPV-related OPSCC in Japan. During the study, formalin-fixed, paraffin-embedded OPSCC specimens from Japanese patients were analyzed for HPV DNA by the polymerase chain reaction (PCR) and for the surrogate marker p16 by immuno-histochemistry. For HPV DNA-positive, p16-negative specimens, the methylation status of the p16 gene promoter was examined by methylation-specific PCR. Overall survival was calculated in relation to HPV DNA and p16 status and was subjected to multivariate analysis. OPSCC cell lines were examined for sensitivity to radiation or cisplatin in vitro. The study results showed that tumor specimens from 40 (38%) of the 104 study patients contained HPV DNA, with such positivity being associated with tumors of the tonsils, lymph node metastasis, and nonsmoking. Overall survival was better for OPSCC patients with HPV DNA than for those without it (hazard ratio, 0.214; 95% confidence interval, 0.074-0.614; P = 0.002). Multivariate analysis revealed HPV DNA to be an independent prognostic factor for overall survival (P = 0.015). Expression of p16 was associated with HPV DNA positivity. However, 20% of HPV DNA-positive tumors were negative for p16, with most of these tumors manifesting DNA methylation at the p16 gene promoter. Radiation or cisplatin sensitivity did not differ between OPSCC cell lines positive or negative for HPV DNA. Thus, positivity for HPV DNA identifies a distinct clinical subset of OPSCC with a more favorable outcome in Japanese.

Kawakami H ，Okamoto I ，Terao K ，Sakai K ，Suzuki M ，Ueda S ，Tanaka K ，Kuwata K ，Morita Y ，Ono K ，Nishio K ，Nishimura Y ，Doi K ，Nakagawa K ... -  《Cancer Medicine》

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

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. 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). 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. 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.

Freitag J ，Wald T ，Kuhnt T ，Gradistanac T ，Kolb M ，Dietz A ，Wiegand S ，Wichmann G ... -  《-》

Prognostic significance of cell cycle-associated proteins p16, pRB, cyclin D1 and p53 in resected oropharyngeal carcinoma.

Plath M ，Broglie MA ，Förbs D ，Stoeckli SJ ，Jochum W ... -  《Journal of Otolaryngology-Head & Neck Surgery》

Human Papillomavirus DNA Detection by Droplet Digital PCR in Formalin-Fixed Paraffin-Embedded Tumor Tissue from Oropharyngeal Squamous Cell Carcinoma Patients.

Schiavetto CM ，de Abreu PM ，von Zeidler SV ，de Jesus LM ，Carvalho RS ，Cirino MT ，Carloni AC ，Oliveira C ，Scapulatempo-Neto C ，de Almeida GC ，de Menezes NS ，Carvalho AL ，Reis RM ，de Carvalho AC ... -  《-》

High-risk HPV genotypes and P16INK4a expression in a cohort of head and neck squamous cell carcinoma patients in Singapore.

Tan LS ，Fredrik P ，Ker L ，Yu FG ，Wang Y ，Goh BC ，Loh KS ，Lim CM ... -  《Oncotarget》