p16 expression in cutaneous squamous cell carcinoma of the head and neck is not associated with integration of high risk HPV DNA or prognosis

Abstract

Head and neck cutaneous squamous cell carcinoma (HNcSCC) can present with cervical metastases without an obvious primary. Immunohistochemistry for p16 is established as a surrogate marker of human papillomavirus (HPV) in oropharyngeal cancer. p16 expression in HNcSCC needs to be elucidated to determine its utility in predicting the primary site. The aim of this study was to evaluate the rate of p16 expression in HNcSCC and its association with prognostic factors and survival. p16 immunohistochemistry was performed on 166 patients with high risk HNcSCC (2000-2013) following histopathology review. Chromogenic in situ hybridisation (CISH) for HPV was performed. Fifty-three (31.9%) cases showed strong, diffuse nuclear and cytoplasmic p16 expression including 14 (41%) non-metastatic and 39 (29.5%) metastatic tumours (p=0.21). HPV CISH was negative in all cases. p16 expression significantly increased with poorer differentiation (p=0.033), but was not associated with size (p=0.30), depth of invasion (p=0.94), lymphovascular invasion (p=0.31), perineural invasion (p=0.69), keratinisation (p=0.99), number of involved nodes (p=0.64), extranodal extension (p=0.59) or survival. Nearly 32% of HNcSCCs, particularly poorly differentiated HNcSCCs, show p16 expression. A primary HNcSCC should be considered in p16 positive neck node metastases in regions with high prevalence of HNcSCC. p16 expression is not associated with improved survival in HNcSCC.

Review of emerging biomarkers in head and neck squamous cell carcinoma in the era of immunotherapy and targeted therapy

“…7 Furthermore, results of biomarker analyses can be notoriously inconsistent, making it difficult to draw robust conclusions. 8 Some studies might show negative or discrepant results, while the same biomarker might clearly demonstrate positive associations in other studies-for example, CCND1, 9 cMET, 10 p16, [10][11][12] EGFR, 13 and ERCC1. 14 challenges.…”

“…Furthermore, results of biomarker analyses can be notoriously inconsistent, making it difficult to draw robust conclusions . Some studies might show negative or discrepant results, while the same biomarker might clearly demonstrate positive associations in other studies—for example, CCND1, cMET, p16, EGFR, and ERCC1 . Plausible reasons for such discrepancies might include (a) small sample sizes with inadequate controls; (b) differing study populations with true clinical variability; (c) differing treatment modalities; (d) variations in the biomarker assay, for example, different technological platforms used for detection and measurement; (e) differences in the biomarker source, for example, tissue vs liquid biopsy, or fresh vs fixed tissue; (f) varied antibody specificities and binding affinities among different batches or vendors; (g) biomarker instability, with a risk of false positivity or false negativity; (h) differing statistical testing methods; and (i) other methodological differences between studies, for example, evaluation of mRNA vs protein expression …”

“…Of the many biomarkers with a prognostic role in HNSCC, the most well established and validated is p16, which plays an essential role in HNSCC . Approximately one third of HNSCCs express p16.…”

“…p16 also appears to be an important prognostic marker in cutaneous HNSCC, which commonly presents as cervical metastases secondary to CUP. High p16 expression has been shown to be indicative of primary HNSCC with better survivals; however, p16 expression was not associated with improved survival in this specific subgroup of HNSCC . In theory, p16 positivity would not be exclusively associated with HPV infection, considering p53 and retinoblastoma ( RB ) gene involvement .…”

“…Of the many biomarkers with a prognostic role in HNSCC, the most well established and validated is p16, which plays an essential role in HNSCC. 10,80 Approximately one third of HNSCCs express p16. p16 is a widely used clinical biomarker for HPV-a well-known cause of HNSCC-and HPV status, in turn, is an important prognostic marker used for patient stratification in HNSCC.…”