Pathogenesis of combined high-grade squamous intraepithelial lesion and adenocarcinoma in situ of the uterine cervix: human papillomavirus genotype and methylation status and immunohistochemical study.

To determine the etiology of combined high-grade squamous intraepithelial lesion (HSIL) and adenocarcinoma in situ (AIS) of the uterine cervix, we examined human papillomavirus (HPV) subtypes, methylation status of the HPV-16 L1 gene, and immunohistochemical staining pattern of Krt7 in 8 cases of combined HSIL and AIS. Overall, 6 (75%) of 8 patients with combined HSIL and AIS were infected by the same subtype of HPV in both HSIL and AIS (cases 1-5, HPV-16; and case 6, HPV-18), whereas 2 (25%) patients showed infection with different subtypes of HPV (case 7, HPV-31 and -18; and case 8, HPV-52 and -16, in HSIL and AIS, respectively). The degrees of methylation at CpG islands within the HPV-16 L1 gene were almost equivalent between HSIL and AIS in cases 1-4, whereas a great difference in CpG methylation patterns between two was seen in only 1 case (case 5). In addition, both patients infected with different subtypes of HPV between HSIL and AIS were positive for Krt7 only within the AIS component. Based on these results, we propose two distinct developmental pathways of combined HSIL and AIS of the uterine cervix, the common pathway and the individual pathway.