The presence of high‐risk HPV combined with specific p53 and p16^INK4a expression patterns points to high‐risk HPV as the main causative agent for adenocarcinoma in situ and adenocarcinoma of the cervix

Abstract

Adenocarcinoma in situ (ACIS) and adenocarcinoma (AdCA) of the cervix are frequently missed in population-based screening programmes. Adding high-risk HPV (hrHPV) testing to cervical cancer screening might improve the detection rate of ACIS and AdCA. Since the exact proportion of AdCAs of the cervix that can be attributed to hrHPV infection is still a matter of debate, a comprehensive study was performed of hrHPV presence in ACIS and AdCA of the cervix. Archival formalin-fixed specimens of indisputable ACIS (n=65) and AdCA (n=77) of the cervix were tested for hrHPV DNA by GP5+/6+ PCR-enzyme immunoassay (EIA) and type-specific E7 PCR for 14 hrHPV types. Further immunostaining for p16INK4A and p53 was performed to assess alternative pathways of carcinogenesis potentially unrelated to HPV. hrHPV DNA was found in all (100%) ACISs and 72 (94%) cervical AdCAs, whereas none of 20 endometrial AdCAs scored hrHPV-positive. HPV 18 was most prevalent and found as single or multiple infection in 68% of ACISs and 55% of cervical AdCAs. Diffuse immunostaining for p16INK4a, a potential marker of hrHPV E7 function, was significantly more frequent in hrHPV-positive cervical AdCAs (19/20; 95%) than in those without hrHPV (1/5; 20%; p<0.001). Immunostaining for p53, pointing to stabilized wild-type or mutant p53 protein, was significantly more frequent in hrHPV cervical AdCAs negative for hrHPV (p=0.01). No difference in p16INK4a and p53 immunostaining was found between hrHPV-negative cervical AdCAs and endometrial AdCAs. Hence, only a minority of cervical AdCAs displayed absence of HPV DNA and immunostaining profiles suggestive of an aetiology independent of HPV. Since all ACISs and nearly all cervical AdCAs were hrHPV-positive, the incorporation of hrHPV testing in cervical cancer screening programmes is likely to decrease markedly the incidence of cervical AdCA.

Relationship among human papillomavirus infection, p16INK4a, p53 and NF-κB activation in penile cancer from northern Thailand

“…Therefore, overexpression of p16 INK4a is suggested to be a useful marker for evaluating HPV activity in cancer lesions and its precursors (6,9). The overexpression frequency of p16 INK4a was reported to be 55-97% in cervical squamous cell carcinoma (6-8) and 48-80% in cervical adenocarcinoma (28,29). The overexpression frequency of p16 INK4a was previously reported to be 29-50% in penile squamous cell carcinoma (9,10).…”

Prevalence of human papillomavirus DNA in various histological subtypes of cervical adenocarcinoma: a population-based study

“…5,6 However, the recent more sensitive techniques have made it possible to identify the higher rate of HPV infection in adenocarcinoma with a frequency of 85% or more. [19][20][21] In this study, we used a recently developed HPV DNA Chip for the detection of HPV DNA in 82 of 135 cases. This method is based on the polymerase chain reaction with an advantage to detect single and multiple infection of 22 HPV genotypes at once and has reported to be a very sensitive method comparable with Hybrid Capture II assay.…”

Sequential gene promoter methylation during HPV-induced cervical carcinogenesis

“…Although hrHPVs can be detected in virtually all cervical SCCs and AdCAs (Walboomers et al, 1999;Zielinski et al, 2003;Castellsague et al, 2006), progression of an hrHPV-positive premalignant lesion to invasive cancer is a rare event. Consistent with the multistep nature of human carcinogenesis, additive host cell alterations drive progression to invasive cancer .…”