Precancer of the Human Cervix

Cancer Surv. 1998;32:201-29.

Abstract

The tumour biology of cervical precancer is unusual. A large variety of individually distinct forms crudely divided into slight, moderate, severe dysplasia and carcinoma in situ exist. Virtually all contain genital human papillomavirus (HPV) either as infectious virions or as episomal or integrated DNA. HPV, which occurs as hundreds of types, subtypes and variants, has a high prevalence in all human populations. Most males are symptomless reservoirs, whereas a proportion of infected women develop condyloma, precancer and subsequently, in a minority, invasive cancer. HPV has unequivocal features of a sexually transmitted infectious agent. Risk of precancer is statistically related to infection with genital HPV, but differences in risk between populations with high and low prevalence of HPV are larger than expected from a direct correlation. Findings fit with HPV as a major risk factor, but other factors must also be operative. These may include shifts in number of target cells, depending on regeneration and infection by various micro-organisms, hormones, smoking and immunity. Final proof of necessity of HPV infection for precancer can probably be delivered only after its elimination by successful vaccination. Genital condyloma, which is not precancerous, is caused by HPV low risk types, typically 6 or 11, in analogy with papilloma formation in skin and mucosa in a large variety of species. This benign lesion is the hallmark of mammalian HPV pathology and a source of interindividual spread of virus. Slight dysplasia is heterogeneous. Many lesions seem to be polyclonal, self limited cell proliferative responses to infection with low grade HPV. A small proportion are associated with either simultaneous presence or subsequent development of higher grades of dysplasia, in situ or invasive cancer. Evidence exists for two mechanisms: clonal selection of cells with increasingly undifferentiated phenotypes, and independent development of different morphological types of precancer. The relative importance of the two is unknown. High risk HPV, typically 16 or 18, is preferentially associated with high grade dysplasia and in situ cancer, either because it increases risk of clonal progression to these forms or induces them de novo. Severe dysplasia, in situ and invasive cancer always present as monoclonal lesions. Genetic links indicate that these pathologies arise by clonal selection from less advanced precursors. The number of potential target cells for precancer confined to a narrow transformation zone is small. Risk of precancer and malignant transformation per target cell is therefore probably far higher than in any other human tissue subject to cancer. Spontaneous mutation rate and physicochemical carcinogens seem insufficient for the creation of a malignant phenotype in cells of the transformation zone. Currently HPV is the only strong candidate for such a feat. Any or all of the following mechanisms may play a role: overexpression of viral E6 and E7 genes, often triggered by disruption of control elements upon integration of viral DNA into the cellular genome, activity of specific (E6?) configurations in certain HPV variants, inactivation of TP53 with decreased capacity for DNA repair and enhanced likelihood of accumulation of "transforming" mutations and viral integration at sites controlling function of cellular oncogenes and/or suppressor genes. Target cells within the transformation zone have the capacity for bidirectional (squamous and/or glandular) differentiation. HPV types seem to drive cells preferentially in different directions after infection/transformation. Low risk types are almost always associated with squamous differentiation, HPV 16 usually also with squamous differentiation and HPV 18 with adenosquamous or adenomatous differentiation. (ABSTRACT TRUNCATED)

Publication types

  • Review

MeSH terms

  • Carcinoma in Situ / genetics
  • Carcinoma in Situ / pathology
  • Carcinoma in Situ / virology
  • Cervical Intraepithelial Neoplasia / genetics
  • Cervical Intraepithelial Neoplasia / pathology
  • Cervical Intraepithelial Neoplasia / virology
  • Condylomata Acuminata / pathology
  • DNA, Viral / genetics
  • Female
  • Genes, Viral / genetics
  • Genes, p53 / genetics
  • Humans
  • Male
  • Papillomaviridae / classification
  • Papillomaviridae / genetics
  • Papillomavirus Infections
  • Phenotype
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology*
  • Precancerous Conditions / virology
  • Risk Factors
  • Tumor Virus Infections
  • Uterine Cervical Dysplasia / genetics
  • Uterine Cervical Dysplasia / pathology
  • Uterine Cervical Dysplasia / virology
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / pathology*
  • Uterine Cervical Neoplasms / virology

Substances

  • DNA, Viral