title: The presence of high-risk HPV combined with specific p53 and p16INK4a 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.
authors.affiliation: Department of Pathology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: G Denise
authors.initials: GD
authors.lastname: Zielinski
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rozendaal
authors.forename: Nathalie Fransen
authors.initials: NF
authors.lastname: Daalmeijer
authors.forename: Elle K J
authors.initials: EK
authors.lastname: Risse
authors.forename: Feja J
authors.initials: FJ
authors.lastname: Voorhorst
authors.forename: N Medi
authors.initials: NM
authors.lastname: Jiwa
authors.forename: Hans C
authors.initials: HC
authors.lastname: van der Linden
authors.forename: Frits A
authors.initials: FA
authors.lastname: de Schipper
authors.forename: Arnold P
authors.initials: AP
authors.lastname: Runsink
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000328:Adult; D002278:Carcinoma in Situ / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004273:DNA, Neoplasm / Q000032:analysis; D004279:DNA, Viral / Q000032:analysis; D016889:Endometrial Neoplasms / Q000209:etiology / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D019942:Genes, p16; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction / Q000379:methods; D012307:Risk Factors; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm; D004279:DNA, Viral