The Prognostic Value of HPV Status and p16 Expression in Patients with Carcinoma of the Anal Canal

Abstract

BackgroundIn anal cancer studies, the detection frequency of high-risk HPV (human papillomavirus) is variable, depending on the method used. There are limited data reporting results of different HPV detection techniques in the same clinical series, and very few correlating results with clinical outcome.ObjectivesTo evaluate tumor expression of p16/HPV16 using three different methods, and to determine their association with clinical outcome in patients with anal canal squamous cell carcinomas (SCC).DesignThis retrospective study included patients with anal canal SCC treated with definitive radiotherapy or chemoradiotherapy at a single institution between 1992 and 2005. Formalin-fixed paraffin–embedded tumor samples from 53 of the 89 (60%) patient pre-treatment biopsies were adequate for tissue microarray construction. HPV status was determined using: p16 expression by conventional immunohistochemistry (IHC) and quantitative IHC (AQUA), HPV genotype analysis by chromogenic in situ hybridization (CISH) and HPV linear array sub-typing. Expression status was correlated with clinical outcome.Results80% (28/35) of patient tumors had high p16 expression using conventional IHC. HPV16 CISH was positive in 81% (34/42) of tumors, and 78% (28/36) of tumors were HPV subtype 16. HPV16 CISH correlated with p16 evaluated by conventional IHC (correlation coefficient 0.46; p = 0.01) and by p16 AQUA score (correlation coefficient 0.49; p = 0.001). A subset of cases (15%) had very high p16 quantitative IHC scores (>244) and were associated with a higher incidence of local or distant recurrence (p = 0.04).ConclusionsThe vast majority (80%) of anal canal SCC in our series were positive for HPV16/p16, regardless of the testing method used. The exploratory analysis of automated quantitative IHC scoring was the only technique to define a subset of patients with a worse prognosis by p16 expression status on univariate analysis. Further exploration of the molecular mechanisms of treatment resistance in association with very high p16 expression is warranted.

Anal Canal Carcinoma in a Child With Disorders of Sex Development

“…Squamous cell carcinoma of the anal canal is known to be strongly linked with human papillomavirus (HPV) infection, as is the case in the development of cervical cancer and other gynecological cancers, as well as head and neck squamous cell carcinoma . HPV 16 has been reported to be the most frequently encountered genotype, detected in approximately 80% of cases . HPV infection is a highly suspicious causative factor for the carcinogenesis in our patient because overexpression of the cell cycle regulatory protein p16 (measured by immunohistochemistry) is often used as a surrogate marker for tumor HPV infection .…”

“…Salvage surgery was conducted because residual tumor cells were observed after radiotherapy. Recently, HPV+/p16+ status has been indicated as a strong predictor for favorable locoregional control and overall survival . On the other hand, HPV‐negative tumors frequently carry TP53 mutations, resulting in unresponsiveness to standard treatment .…”

“…[13,14] HPV 16 has been reported to be the most frequently encountered genotype, detected in approximately 80% of cases. [15,16] HPV infection is a highly suspicious causative factor for the carcinogenesis in our patient because overexpression of the cell cycle regulatory protein p16 (measured by immunohistochemistry) is often used as a surrogate marker for tumor HPV infection. [17] Prevalence of anogenital HPV infection in children prior to sexual debut has been reported to be just 1.6%.…”

“…Recently, HPV+/p16+ status has been indicated as a strong predictor for favorable locoregional control and overall survival. [15][16][17] On the other hand, HPV-negative tumors frequently carry TP53 mutations, resulting in unresponsiveness to standard treatment. [17] The present case might have favorable outcome on the basis of the HPV status.…”

Modulation of therapeutic sensitivity by human papillomavirus

“…The mixed etiology of head and neck cancer (HNC), however, provides an opportunity to study the influence of HPV on clinical outcomes. HPV-status is now a well-accepted prognostic biomarker in HNC and appears to have similar value in anal cancer [19–22]. Two recent meta-analyses by O’Rorke and Petrelli both confirm a remarkable survival advantage for patients with HPV-positive HNC as compared to those with HPV-negative disease (HR 0.46; 95% CI, 0.37–0.57 and HR = 0.33; 95% CI, 0.27–0.40, respectively) [23, 24].…”