The role of high-risk human papillomavirus infections in laryngeal squamous cell carcinoma

The contribution of human papillomavirus (HPV) to the development and clinical outcome of oropharyngeal cancers has been well documented. The association of HPV in laryngeal squamous cell carcinoma (LSCC) has been examined in several studies, but controversy exists regarding its role in carcinogenesis, the outcome of the patients and thus, clinical significance of HPV testing in LSCC. In this review, we give an update of known associations between HPV-positive testing and carcinogenesis in laryngeal cancer. In an early study, the HPV-DNA detection rate in LSCC was documented being 24.0% with significant regional differences. Non-HPV-16 types were more often detected in LSCC when compared to the oropharynx. Later, single institution case series revealed markedly fewer amounts (<10%) of HPV DNA in LSCC and the results suggested that high-risk HPV infections seem to be biologically irrelevant in most LSCC. The significance of p16INK4a (p16) expression as a surrogate marker towards high-risk HPV infection and the outcome in LSCC is doubtful, since only few p16-positive LSCC samples are HPV RNA positive and accordingly there was poor correlation of p16-test results towards the outcome in LSCC. Recent meta-analysis (n = 2739) and large case series (n = 1042) of LSCC revealed the true rate of HPV-driven LSCC being 8.6%, respectively, <5%. In the latter the rate of DNA-, DNA/RNA-, DNA/p16, and DNA/RNA/p16 positivity was 5.7, 3.1, 1.9, and 1.5%, respectively. These results indicate relevant amounts of insignificant/transient HPV infection in LSCC specimen. However, in the same study the rate of transforming HPV infections increased since 2000, and younger patients had higher amounts of HPV-driven LSCC. Serologic testing of E6/E7 antibodies additionally revealed odds ratios between 2 and 5 as a hint for a weak contribution of high-risk HPV infection and the development of LSCC. The contribution of HPV for the development of LSCC needs future investigations, to date, routine HPV testing of LSCC specimen is not warranted.