The prognostic significance of tumor human papillomavirus status for patients with anal squamous cell carcinoma treated with combined chemoradiotherapy

Abstract

The prognostic relevance of tumor human papillomavirus (HPV) status in anal squamous cell carcinoma (SCC) had not been previously investigated, although its relevance to cervical, head and neck SCC is known. We retrospectively evaluated outcomes in 47 patients with anal SCC treated with combined chemoradiotherapy (CCRT) and determined tumor HPV status by HPV DNA chip method and p16 expression by immunohistochemistry (IHC) from paraffin-embedded tumor tissues. The median age was 65 years (range, 44-90 years). Sixteen (34%) patients were diagnosed with T stage 3 to 4, and 18 (38%) patients had regional nodal disease (N-positive). Thirty-five (75%) patients were HPV positive, and 31 (66%) patients were genotype 16 (HPV16-positive). Thirty-nine (83.0%) patients were positive for p16. After median follow-up of 51.7 months (range, 5.1-136.0 months), HPV16-positive group had significantly better 4-year progression-free survival (PFS, 63.1% vs. 15.6%, p < 0.001) and overall survival (84.6% vs. 39.8%, p 5 0.008) than HPV genotype 16 negative (HPV16-negative) group. Patients with p16-positive tumor also had a better 4-year PFS (52.5% vs. 25.0%, p 5 0.014) than those with p16-negative tumor. In multivariate analysis for PFS, N-positive and HPV16-negative were independent prognostic factors for shorter PFS. Comparing patterns of failure, time to loco-regional failure was statistically superior in HPV16-positive over HPV16-negative groups (p 5 0.006), but time to systemic failure was not different (p 5 0.098). Tumor HPV genotype 16 status is a prognostic and predictive factor in anal SCC treated with CCRT, and p16 expression determined by IHC might be advocated as a surrogate biomarker of HPV integration in anal SCC. Further studies are warranted.Anal squamous cell carcinoma (SCC) is an uncommon malignancy of the anal canal and perianal skin area. The clinical biology of anal SCC is distinct from other gastrointestinal tract cancers. It is mostly a loco-regional disease at diagnosis, with metastasis in only 15% of patients.1 Therefore, in managing anal cancer, the concerns of treatment strategies include improving loco-regional control and preserving sphincter function. Combined chemoradiotherapy (CCRT)

High-sensitivity human papilloma virus genotyping reveals near universal positivity in anal squamous cell carcinoma: Different implications for vaccine prevention and prognosis

“…For prognostic modelling, our results are similar to recently published series of patients with ASCC treated with CRT [22][23][24]. In particular, our results mirror those from the Danish treatment series of 146 patients with ASCC, where HPV positivity (almost all HPV 16 positive) was significantly prognostic for disease-free survival in univariate analysis, but not in multi-variate analysis.…”

“…Similar patterns are noted for cervical carcinoma [21]. A number of studies are emerging in which HPV positivity and/or p16 expression are prognostic for improved survival in patients with ASCC treated by CRT [17,[22][23][24].…”

“…Whilst p16 immunohistochemistry consistently performs better than HPV 16 positivity alone [17,[22][23][24], only a quarter of recurrences are p16 negative tumours. Future work should focus on the mechanisms of p16 positivity (or otherwise) within the context of HPV infection.…”

Influence of human papillomavirus and p16INK4a on treatment outcome of patients with anal cancer

“…Accordingly, patients with HPV-associated anal SCC appear to have a better outcome than HPV-negative anal SCC [18,19] -similar to what has been shown for head and neck cancers. However, the number of studies addressing the prognostic relevance of HPV in anal SCC is still limited.…”

New Insights into the Role of Human Papillomavirus in Anal Cancer and Anal Wart Development

“…HPV positivity in anal SCC seems to have a prognostic value, with a better survival in patients with HPV-positive tumors [35, 39], similar to what was documented in cervical cancers [40] and head and neck SCC [41]. TP53 (gene encoding p53) mutations, which are frequent in HPV-negative anal SCC, have been claimed as one of the reasons for a low rate of response to standard treatment [42].…”