HPV RNA CISH score identifies two prognostic groups in a p16 positive oropharyngeal squamous cell carcinoma population

Abstract

HPV-related and HPV-unrelated oropharyngeal squamous cell carcinomas are two distinct entities according to the Union for International Cancer Control, with a better prognosis conferred to HPV-related oropharyngeal squamous cell carcinomas. However, variable clinical outcomes are observed among patients with p16 positive oropharyngeal squamous cell carcinoma, which is a surrogate marker of HPV infection. We aimed to investigate the prognostic value of RNA CISH against E6 and E7 transcripts (HPV RNA CISH) to predict such variability. We retrospectively included 50 histologically confirmed p16 positive oropharyngeal squamous cell carcinomas (p16 positive immunostaining was defined by a strong staining in 70% or more of tumor cells). HPV RNA CISH staining was assessed semi-quantitatively to define two scores: RNA CISH "low" and RNA CISH "high". Negative HPV RNA CISH cases were scored as RNA CISH "low". This series contained 29 RNA CISH low cases (58%) and 21 RNA CISH high cases (42%). Clinical and pathologic baseline characteristics were similar between the two groups. RNA CISH high staining was associated with a better overall survival in both univariate and multivariate analyses (p = 0.033 and p = 0.042, respectively). Other recorded parameters had no prognostic value. In conclusion, HPV RNA CISH might be an independent prognostic marker in p16 positive oropharyngeal squamous cell carcinomas and might help guide therapeutics.

RNA in situ hybridization for human papillomavirus testing in oropharyngeal squamous cell carcinoma on a routine clinical diagnostic platform

“…The inclusion of this additional quality control measure may also explain why there were no p16−RNAISH+ cases in our cohort, an observation reported in studies utilizing magnification‐based interpretation methods alone 19,20 . Nevertheless, further work is required to define low‐end RNA ISH signal threshold cut‐offs validated against qRT‐PCR reference standards and clinical outcomes 29 …”

In situ hybridization for high-risk HPV E6/E7 mRNA is a superior method for detecting transcriptionally active HPV in oropharyngeal cancer

“…Our study revealed 15 cases with p16 IHC positivity but HPV-mRNA ISH negativity. Patients with a discordant (p16 IHC+/HPV-) tumor have been related to significantly worse prognosis compared with patients who has a confirmed HPV-positive (p16 IHC+/HPV+) tumor [9,33]. Thus, the use of p16 IHC as a stand-alone test for HPV detection can mislead diagnostics and treatment approaches, particularly when considering treatment deescalation [9].…”

<p>DNMT1 Enhances the Radiosensitivity of HPV-Positive Head and Neck Squamous Cell Carcinomas via Downregulating SMG1</p>

“…The binding of DNA cis-acting elements activates transcription of p16 gene, resulting in high activation of p16 protein. 15 The expression level of p16 and Ki-67 is increased, which causes cell cycle disorder and causes cell malignant transformation. Recent studies have shown that E6 and E7 can also bind to other proteins, such as Bak and p21, leading to their genetic instability.…”