p16‐positive lymph node metastases from cutaneous head and neck squamous cell carcinoma: No association with high‐risk human papillomavirus or prognosis and implications for the workup of the unknown primary

Abstract

BACKGROUND:The incidence of p16 overexpression and the role of human papillomavirus (HPV) in cutaneous head and neck squamous cell carcinoma (cHNSCC) are unclear. METHODS: One hundred forty-three patients with cHNSCC lymph node metastases involving the parotid gland were evaluated for p16 expression by immunohistochemistry. The detection of 18 high-risk HPV subtypes was performed with HPV RNA in situ hybridization for a subset of 59 patients. The results were correlated with clinicopathological features and outcomes. RESULTS: The median follow-up time was 5.3 years. No differences were observed in clinicopathological factors with respect to the p16 status. p16 was positive, weak, and negative in 45 (31%), 21 (15%), and 77 cases (54%), respectively. No high-risk HPV subtypes were identified, regardless of the p16 status. The p16 status was not prognostic for overall (hazard ratio, 1.08; 95% confidence interval [CI], 0.85-1.36; P 5 .528), cancer-specific (hazard ratio, 1.12; 95% CI, 0.77-1.64; P 5 .542), or progression-free survival (hazard ratio, 1.03; 95% CI, 0.83-1.29; P 5 .783). Distant metastasis-free survival, freedom from locoregional failure, and freedom from local failure were also not significantly associated with the p16 status. CONCLUSIONS: p16 positivity is common but not prognostic in cHNSCC lymph node metastases. High-risk HPV subtypes are not associated with p16 positivity and do not appear to play a role in this disease. HPV testing, in addition to the p16 status in the unknown primary setting, may provide additional information for determining a putative primary site. Cancer 2016;122:1201-8. V C 2016 American Cancer Society.KEYWORDS: head and neck cancer, human p16 protein, papillomavirus infections, skin neoplasms, squamous cell neoplasms, unknown primary neoplasms. INTRODUCTIONCutaneous head and neck squamous cell carcinoma (cHNSCC) is a common malignancy in Caucasians living in areas of high ultraviolet exposure. 1,2 The majority of cutaneous squamous cell carcinomas (cSCCs) can be considered low-risk and are cured by local treatment, most often excision. 3,4 However, despite surgery, a proportion of patients with aggressive tumor biology will develop locoregional and/or distant recurrences, which are associated with a poor prognosis. Pathologic features such as grade, perineural invasion, and anatomic location are currently used to identify those primary high-risk lesions at increased risk for nodal metastases. 3,4 Working at a tertiary referral center, we manage a disproportionate number of node-positive cHNSCCs. The incidence and relevance of p16 positivity in cSCC became an issue when we were revising our unknown primary (UKP) management policy to reflect the increasing incidence of p16-positive/human papillomavirus (HPV)-associated oropharyngeal cancer and the increasing role of robotic surgery in the management of UKP/oropharyngeal cancer.The p16 status has been used to direct management in patients with cervical squamous cell carcinoma lymph node metastases from a UKP because p16 positi...

Comprehensive management of HPV‐related squamous cell carcinoma of the head and neck of unknown primary

“…55 HPV-RNA assessment using the E6/E7 mRNA in situ hybridization identifies transcriptionally active HPV which might be considered the gold standard for high-risk HPV detection. [64][65][66][67] Therefore, the use of p16 expression as a surrogate biomarker to OPSCC has limitations in SCCUP. 57 Immunohistochemical p16 expression as an indicator of HPV infection has gained wide popularity after the development of commercially available and low-cost antibodies.…”

Unilateral radiotherapy treatment for p16/human papillomavirus–positive squamous cell carcinoma of unknown primary in the head and neck

“…We do advise caution in using p16 positivity alone to direct patient management. Our institution has published a series of patients with parotid SCC that were highly likely to have originated from a skin primary . We found that 31% of these cases were p16 positive but HPV negative.…”

“…Testing for HPV was also performed on both p16‐positive and negative cases using HPV RNA in situ hybridization (ISH) testing. Our method for testing for p16 and HPV are outlined in a prior publication …”

Molecular mechanisms of perineural spread of cutaneous carcinoma: a potential role for receptor tyrosine kinases and other biomarkers

“…(172) As to whether it is viral or UVR associated dysregulation in the p16 pathway that has led to significant overexpression in a subset of perineural spread cSCCHN, it is difficult to say. Unlike other studies, we did not perform FISH or PCR for the presence of high-risk HPV subtypes.…”