The close relationship between genital HPV infection and genital malignancies, described below, underscores the potential importance for developing more effective management of this disease. Cervical cancer is the second leading cause of cancer deaths in women worldwide (6). In many developing countries, it is the leading cause of death from cancer in women. In developed countries, the extensive use of the Pap (Papanicolaou) smear as a screening test for precursor lesions of the cervix has resulted in a substantial reduction in the incidence of cervical cancer (7). The incidence of cervical cancer may be severalfold higher in developing countries where the Pap smear has been employed more sparingly (2).

RELATIONSHIP BETWEEN HPV INFECTION AND CERVICAL CANCER

HPVs cannot be routinely cultivated, and serotypes have not been defined. Instead, HPVs are typed by molecular hybridization of their genomes. By this analysis, >70 distinct HPV genotypes (types) have been recognized and defined since the 1970s (8). Significant clinicopathological correlations can be made for many HPV types. It is useful to divide the HPVs into three broad classes: genital-mucosal types, nongenital types, and epidermodysplasia verruciformis (EV)-specific types. EV is a rare skin condition in which patients develop widespread, chronic nongenital cutaneous HPV lesions (9). Almost one-half of the known HPV types have been identified principally in EV patients. As with other HPV types, the EV-specific types have a worldwide distribution in spite of the small number of EV patients. The nongenital HPV types infect the nongenital skin of the general population and induce common and plantar warts. These lesions have an extremely low probability of oncogenic progression. Clinical infection by the genital-mucosal HPV types (called genital types below) is found most commonly in the internal and external genitalia, although these types may also cause lesions in the upper aerodigestive tract, especially the mouth, pharynx, and larynx.

Two major classes of genital HPV types have been identified, depending upon their association with cervical cancer (reviewed in ref. 10). The "low-risk" types, especially HPV6 and HPV11, are almost never found in cervical malignancies. They are most frequently isolated from external genital warts (condylomata acuminata) or from benign cervical lesions. Viral DNAs from the "high-risk" types, by contrast, are identified in most cervical cancers, although the vast majority of lesions in which they are found are nonmalignant (reviewed in ref. 11). HPV16 and HPV18 are the types most frequently identified in cervical cancers. In



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