Low etiologic fraction for human papillomavirus in larynx squamous cell carcinoma

Human Papillomavirus (HPV) is a cause of oropharyngeal squamous cell carcinoma (OPSCC), but its pathogenic role in larynx squamous cell carcinoma (LSCC) remains unclear.

A single-institutional, retrospective case-series was performed to estimate the etiological fraction (EF) for HPV in LSCC. Eligible cases included 436 consecutive cases of LSCC diagnosed (2005-2014) at The Ohio State University Medical Center. HPV DNA presence was detected by consensus primer PCR (Inno-LiPa) and HPV type-specific qPCR. HPV E6/E7 mRNA expression was detected by type-specific qRT-PCR. Tumor p16 expression was evaluated by immunohistochemistry (IHC).

HPV DNA was detected by Inno-LiPa in 54 of 404 (13.4%, 95% CI 10.2-17.1) evaluable samples but was confirmed by HPV type-specific qPCR in only 14 (3.5%, 95% CI 1.9-5.7). Only 7 of 404 (1.7%, 95% CI 0.7-3.5) LSCC were positive for HPV E6/E7 mRNA expression, including HPV16 (n=4) and 1 each for 11, 26 and 33. In the HPV11-positive tumor, Sanger sequencing discovered 6 nucleotide mutations in the upstream regulation region, E6 and E7. Of 404 LSCC, 18 had strong and diffuse p16 expression. In comparison to a gold standard of HPV E6/E7 mRNA expression, p16 expression had a sensitivity of 71.4% (95% CI 29.0-96.3), specificity of 96.7% (95% CI 94.5-98.3), positive-predictive-value (PPV) of 27.8% (95% CI 9.7-53.5) and negative-predictive-value of 99.5% (95% CI 98.1-99.9).

The EF for HPV in LSCC is low (1.7%) in a geographic region with high EF for OPSCC. Low-risk HPV may rarely cause LSCC. Finally, p16 expression has poor PPV for HPV in LSCC.