Human Papillomavirus Infections of the Genital Tract: Clinical Significance and Diagnosis by Polymerase Chain Reaction

Summary

Current data implicate that human papillomavirus (HPV) lesions in the genital tract are frequently associated with precancer lesions and invasive squamous cell carcinomas. Almost 70 different HPV types have been recognized during the past 10 years, and a significant risk for the development of an invasive cancer has been ascribed to infections of the high risk HPV types. On the other hand, spontaneous regression has been histologically confirmed in a significant proportion of genital HPV infections in prospective cohort studies. Of special importance from the epidemiological point of view is the mode of transmission of this virus by sexual contact, thus conferring a potential risk for the development of genital precancer lesions to both sexual partners. Recently, HPV DNA has been detected by different hybridization techniques and PCR in normal squamous epithelium of the genital tract in both sexes, suggesting that these sites of latent HPV infections might act as a reservoir for such infections. In the present review, the clinical significance of genital HPV infections is discussed. The importance of making a distinction between (1) clinically manifest, (2) subclinical, and (3) latent HPV infections is emphasized, and the potentially precancerous nature of the manifest HPV infections is underlined. The applicability and limitations of different diagnostic techniques are discussed with special emphasis on the important role of PCR as the only method capable of disclosing also the subclinical and latent HPV infections. The significance of detecting minute amounts (a few molecules) of HPV DNA is unknown. Many of these PCR-positive results may not represent an infection per se, but rather a tissue surface contamination. Extensive studies are still needed to establish the clinically relevant amounts of viral DNA. Thus, caution should be exercised in labelling as an HPV infection those cases where HPV DNA is detected by PCR alone. It seems clear that the examination and treatment of all patients with even a clinically manifest HPV infection will be an overwhelming task. In the light of the epidemiological data and substantiated by the current PCR results, it is equally obvious that patients with subclinical and latent HPV infections cannot be traced and treated by the currently available facilities. It should be borne in mind, however, that it is not the HPV itself which is harmful to the patients, but the precancer (and cancer) lesions that it causes at various anatomic sites. Thus, in countries where nation-wide mass-screening programmes are effective, the means are available to prevent the development of invasive cervical carcinomas by tracing and eradicating the precancer lesions. The old concept on early detection of cervical precancer lesions still remains valid, despite the role of HPV in genital carcinogenesis. In prevention of cervical cancer worldwide, it will be enormously much more effective to first establish covering mass-screening programmes in the high-risk countries than to introduce sophisticated DNA technology (hybridization tests) or PCR amplification procedures to screen large populations for subclinical and latent HPV infections. It will be of major importance to promptly elucidate the risk factors predisposing the clinically manifest HPV lesions for rapid progression. Although some of these factors are well established by now (i.e., lesion grade and HPV type), additional factors involved in the regulation of the viral life cycle within the cell certainly exist which, hopefully, could be used to better predict the disease outcome of the genital HPV infections in the future.

Our original studies included in this review have been supported in part by a research grant from the Finnish Cancer Society, a research grant from Sigrid Juselius Foundation, a PHS grant no. 5 RO1 CA 42010-03 awarded by the Natlonal Cancer Institute, DHHS, a research grant from the Social Insurance Institution of Finland, a joint research grant from Fabriques de Tabac Reunies S.A., and British-American Tobacco Company Ltd, and by a research contract (#1041051) from the Medical Research Council of the Academy of Finland.