Human papillomavirus and oropharyngeal cancer, the epidemics, and significance of additional clinical biomarkers for prediction of response to therapy (Review)

Abstract

In 2007, the International Agency for Research against Cancer (IARC) recognized human papillomavirus (HPV), especially HPV16, besides smoking and alcohol, as a risk factor for oropharyngeal squamous cell carcinoma (OPSCC), where tonsillar and base of tongue cancer dominate. Moreover, during the past decade, in many Western countries, a sharp rise in the incidence of OPSCC, more specifically of HPV-positive OPSCC has been observed. Notably, patients with HPV-positive OPSCC, where the majority are men, particularly never-smokers have a better clinical outcome than patients with HPV-negative OPSCC and other head neck cancer (roughly 80 vs. 40% disease-free survival with conventional radiotherapy and surgery). This suggests that many patients with HPV-positive OPSCC may not require the more aggressive intensified chemo-radiotherapy given to head neck cancer patients today, and could with somewhat tapered treatment maintain excellent survival, avoiding some of the severe side effects along with intensified treatment. However, before de-intensified treatment is administered additional biomarkers are necessary in combination with HPV-positive status in order to predict and select patients that will respond favorably to therapy. In conclusion, noteworthy issues within this field with an increasing cohort of patients with HPV-positive OPSCC are better-tailored therapy and prevention. Patients with HPV-positive OPSCC, with biomarkers for good response to therapy e.g., low MHC class I, or CD44 expression or high numbers of CD8+ tumor infiltrating lymphocytes, could be included in randomized trials with less severe therapy. Furthermore, possibilities to screen for HPV-positive OPSCC and to vaccinate boys against HPV infection should be further investigated.

Figure 1.

HPV genome and viral proteins, from Tommassino (21) with permission of the publisher.

Figure 2.

The estimated age standardized incidence rate with 95% CI of HPV-positive and HPV-negative tonsillar cancer SCC cases per 100,000 person-years in the County of Stockholm, between 1970–2006, from Näsman et al, 2009 (11), with permission from the publisher.

Figure 3.

Kaplan-Meier curves for disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) in patients with HPV-positive oropharyngeal squamous cell carcinoma (OSCC) with known MHC class I expression, where HCA-2 and HC-10 are two antibodies against HLA class I (the human MHC class I). (A) DFS stratified for HCA-2 intensity; (B) DSS stratified for HCA-2 intensity; (C) OS stratified for HCA-2 intensity; (D) DFS stratified for HC-10 intensity; (E) DSS stratified for HC-10 intensity; and (F) OS stratified for HC-10 intensity. HPV_DNA⁺ OSCC with absent HLA class I intensity had a significant better clinical outcome than tumors with strong HLA class I intensity, while weak intensity staining presented an intermediate survival (HCA-2: DFS p<0.001; DSS p=0.060; OS p=0.022; HC-10: DFS p=0.003; DSS p=0.021; and OS p=0.009, with the log-rank test). Notably, the difference observed in the HCA-2 DSS analysis did not reach significance, although the trend was similar. From Näsman et al (46), with permission from the publisher.