Current concepts in the relationship of human papillomavirus infection to the pathogenesis and classification of precancerous squamous lesions of the uterine cervix

Pathologic and epidemiologic studies performed over the past three decades have provided evidence that the development of squamous cell carcinoma of the cervix is a multistep process involving a precursor preinvasive stage. The results of recent molecular analyses now suggest that the human papillomavirus (HPV) plays a role in this process and is an important but insufficient factor in the development of invasive carcinoma. Infection by a variety of HPV types may result in active viral intranuclear replication without integration into the cellular genome. This episomal form of infection is manifested morphologically by the development of mild dysplasia, cervical intraepithelial neoplasia (CIN) 1 with koilocytosis and acanthosis. Approximately 20 different HPV types have been associated with CIN 1 lesions, whereas high-grade dysplasia and carcinoma in situ (CIN 2 and 3) are associated with only a few viral types (mainly HPVs 16, 31, 33, and 35). Low-grade lesions are differentiated and have a low risk of progression to cancer, whereas high-grade lesions are characterized by nearly complete or complete loss of squamous maturation and a higher risk of progression to invasive cancer. Based on the biologic dichotomy of an infectious and a neoplastic process and the segregation of HPV types into two groups, a modification of the CIN classification into low-grade and high-grade squamous intraepithelial lesions in accordance with the Bethesda System is proposed. Although HPV plays a significant role in the development of cervical neoplasia, the value of identifying HPV DNA by such molecular techniques as Southern blot analysis, in situ hybridization, and the polymerase chain reaction in the early detection of preinvasive lesions has not been determined and their routine use is not at present recommended.