Human Papillomavirus The cytologic changes of HPV were first recognized by Koss and Durfee in 1956 and given the term koilocytosis (6). Their significance was not recognized until 20 years later, when Meisels and colleagues reported these changes in mild dysplasia (7) (Fig. 19.6). Molecular biologic studies showed high levels of HPV DNA and capsid antigen, indicating productive viral infection in these koilocytic cells (8). The HPV genome is found in all grades of cervical neoplasia (9). Infection with HPV is the primary cause of cervical cancer (10). As the CIN lesions become more severe (Fig. 19.7), the koilocytes disappear, the HPV copy numbers decrease, and the capsid antigen disappears, indicating that the virus is not capable of reproducing in less differentiated cells (11). Instead, portions of the HPV DNA become integrated into the host cell. Integration of the transcriptionally active DNA into the host cell appears to be essential for malignant transformation (12). Malignant transformation requires the expression of E6 and E7 HPV oncoproteins (13). Because HPV will not grow in cell culture, there is no direct evidence of the carcinogenesis of HPV. However, a cell culture system for growing keratinocytes was described that allows for stratification and differentiation of specific keratinase types (14). When normal cells are transfected with the plasmid-containing HPV-16, the transfected cells produce cytologic abnormalities identical to those seen in intraepithelial neoplasia. The E6 and E7 oncoproteins are identifiable in the transfected cell lines, providing strong laboratory evidence of a cause-andeffect relationship (15). Cervical cancer cell lines that contain active copies of HPV-16 or -18 (SiHa, HeLa, C 4-11, Ca Ski) express HPV-16 E6 and E7 oncoproteins (16).
HPV DNA can be detected in most women with cervical neoplasia (17,18). There are more than 120 types of HPV identified, with 30 of these HPV types primarily infecting the squamous epithelium of the lower anogenital tract of men and women (19,20). Detection of HPV is associated with a 250-fold increase risk of high-grade CIN (21). The percentage of intraepithelial neoplasia attributed to HPV infection approaches 90% (18).
Only certain types of HPV account for about 90% of high-grade intraepithelial lesions and cancer (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59 and -68) (18). Type 16 is the most common HPV found in invasive cancer and in CIN 2 and CIN 3, and it is found in 47% of women with cancer in all stages (22). It is the most common HPV type found in women with normal cytology.
CHAPTER 19 Intraepithelial Disease of the Cervix, Vagina, and Vulva
Figure 19.7 Cervical biopsy showing normal cells, cervical intraepithelial neoplasia 2 and 3 (CIN 2, CIN 3). In CIN 3, the normal maturation is lost.
HPV-16 infection is not very specific; it can be found in 16% of women with low-grade lesions and in up to 14% of women with normal cytology. Human papillomavirus type-18 is found in 23% of women with invasive cancers, 5% of women with CIN 2 and CIN 3, 5% of women with HPV and CIN 1, and fewer than 2% of patients with negative findings (18). Therefore, HPV-18 is more specific than HPV-16 for invasive tumors.