Aetiology, pathogenesis, and pathology of cervical neoplasia.

Abstract

Early epidemiological studies of cervical neoplasia suggested a causal relation with sexual activity and human papillomaviruses (HPVs) have emerged as prime suspects as venerally transmitted carcinogens. HPVs fall into two broad camps: low risk types, associated with cervical condylomas and CIN 1; and high risk types (mostly 16 and 18), found in 50-80% of CIN 2 and CIN 3 lesions, and 90% of cancers. This association with cancer is very strong, with odds ratios of > 15 (often much higher) in case-control studies that are methodologically sound. An infrequently detected third group of intermediate risk type HPVs is associated with all grades of CIN and occasionally with cancers. HPVs have also been detected in a wide range of asymptomatic controls, indicating that other events are required for development of neoplasia such as viral persistence and/or altered expression of viral genes, often following integration of the viral genome. This leaves the two major viral oncogenes, E6 and E7, directly coupled to viral enhancers and promoters, allowing their continued expression after integration. High risk HPV E7 proteins bind and inactivate the Rb protein, whereas E6 proteins bind p53 and direct its rapid degradation. A range of putative cofactors has been implicated in progression: HLA type, immunosuppression, sex steroid hormones, and smoking; most of these cofactors appear to influence progression to CIN 3. The natural history includes progression to CIN 3 in 10% of CIN 1 and 20% of CIN 2 cases, whereas at least 12% of CIN 3 cases progress to invasive carcinoma. Cervical glandular intraepithelial neoplasia (CGIN) often coexists with squamous CIN, and the premalignant potential of high grade CGIN is not in doubt, but the natural history of low grade CGIN remains uncertain. A high proportion of CGIN lesions and adenocarcinomas are HPV positive, and HPV18 has been implicated more in glandular than in squamous lesions. A strong clinical case for the application of HPV typing of cells recovered from cervical scrapes can be made; however, a rigorous cost-benefit analysis of introducing HPV typing into the cervical screening programme is required. Prophylactic and therapeutic HPV vaccines are under development. This article reviews the aetiology, pathogenesis, and pathology of cervical neoplasia, emphasising the role of HPVs. (J Clin Pathol 1998;51:96-103) Keywords: human papillomavirus; cervical neoplasia This review is based on three presentations by the authors to the first National Cervical Screening Conference organised by Marie Curie Cancer Care and held in Oxford, UK in September 1996. It also includes several more recent developments. It is important to emphasise that the cervical screening programme aims to detect women who have an epithelial abnormality that might, if untreated, lead to the development of cervical carcinoma. The screening programme is not designed to detect small or early invasive carcinomas, but no screening system will detect all women at risk and it is inevitable that in a small prop...

Detection of cancer‐related gene expression profiles in severe cervical neoplasia

“…Also, patients with CIN3 from branches B and C were significantly younger than those from branch A (27.7 Ϯ 4.1 vs. 37.8 Ϯ 8.2; p ϭ 0.011, Student's t-test). No statistically significant association was found for women with CIN3 from branch A vs. branches B and C with respect to hormonal contraception (p ϭ 0.644, Fisher's exact test) and parity status (p ϭ 0.785, Pearson's 2 test), 30,31 both of which are discussed as cofactors for progression of CIN3. 32 Fifty percent of women in both groups practised hormonal contraception.…”

Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

“…The majority of HPV-induced cancers are squamous cell carcinomas (SCCs) which arise in a multistep fashion from precursor cervical intraepithelial lesions (CIN) (Ostor, 1993;Arends et al, 1998). The life cycle of HPV is unique in that the virus infects replicative competent cells of the basal and parabasal layer but requires terminally differentiating cells for its replication.…”

Molecular biology of prostate cancer

“…The wild-type p53 function may be lost when viral oncoproteins such as SV40 T-antigen, adenovirus E1B or human papilloma virus oncoprotein E6 bind and degrade it. 111 More classically it is inactivated by point mutations. 112 Wild-type p53 suppresses growth of human PC cells containing mutant p53 alleles, suggesting a functional role in suppressing prostatic tumorigenesis.…”