Genital Human Papillomavirus (HPV) Infections and Their Associations with Squamous Cell Cancer: Reappraisal of the Morphologic, Epidemiologic and DNA Data

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The reliable assessment of epidemiology of genital human papillomavirus (HPV) infections is hampered by a number of technical problems. Because of the lack of tissue-culture systems, methods based on morphological approaches (colposcopy, cytology, and histopathology) play a central role in HPV diagnosis. Even the DNA-hybridization techniques and the recently introduced DNA amplification with PCR are extremely difficult to standardize, and they are thus subject to major interlaboratory variation. The situation is further complicated by the complex biological behavior of HPV infections. As established by the long-term prospective follow-up study run in Kuopio since 1981 for over 500 women, clinical progression and regression seem to be significantly related to grade of the lesion when first diagnosed (p > 0.00001, and p = 0.0005, respectively), as well as to the type of HPV (p = 0.0012). Most importantly, however, genital HPV infections seem to run an extremely fluctuating course, a transition from a manifest to a subclinical or latent infection frequently being encountered in individual patients when examined at 6-month intervals for prolonged periods. This explains the highly divergent prevalence figures reported in different series (ranging from a few percent to 80%), which are completely dependent on the technique used to analyze the presence of HPV, i.e., whether by (1) PAP smear, (2) biopsy, (3) DNA hybridization, or (4) PCR amplification. The first two are capable of disclosing only manifest (clinical) infections, the latter two also the subclinical and latent ones, respectively. Because of major practical relevance, the criteria for subclinical and latent HPV infections are defined in this paper for the first time. In an unselected population of 22-year-old Finnish females, the prevalence of clinical HPV infections was 3%, and the adjusted annual incidence was 8%. According to estimates for the life-time risk, up to 79% of Finnish females would contract at least one HPV infection between ages 20 to 79 years. When related to long-term trends in invasive cervical cancer in Finland, it is evident that this 79% life-time risk of getting HPV-infected or the observed 15% clinical progression rate for HPV infections during a long-term prospective follow-up are far above the established risk (5/105, annual incidence) for the development of cervical cancer (ie, 0.79 × 0.15 = 11%). A theoretical model was constructed to explain the complex biological behavior of genital HPV infections, according to which clinical lesions represented only a small minority (2%-5%) of the problem, subclinical and latent infections accounting for over 90% of all HPV infections. It seems clear that in countries where effective mass-screening programs exist (and precancerous lesions are traced), the increasing prevalence of clinical HPV infections is not necessarily reflected as increased prevalence and incidence figures of invasive cervical carcinomas. As long as HPV infections are not associated with a morphologically manifest epithelial lesion, they are probably of lesser clinical significance (ie, subclinical and latent). Accordingly, our major attempts should be focused on the clinical HPV lesions to develop accurate means by which to predict the lesions at risk for malignant transformation from those regressing spontaneously. This would have major implications in therapeutic considerations of genital HPV infections.