HPV 6-associated HSIL/Squamous Carcinoma in the Anogenital Tract

Abstract

Human papillomavirus (HPV) type 6 is historically classified as low-risk HPV type and associates with low-grade squamous intraepithelial lesions of the anogenital tract. Rare squamous carcinomas have been reported in association with these HPV types but the mechanism(s) behind this carcinogenic sequence have been unclear. We report 4 cases of low risk anogenital HPV infections—3 cervical (immature low-grade squamous intraepithelial lesion with metaplastic phenotype) and one anal (exophytic condyloma) lesion—that manifested with high-grade squamous intraepithelial lesion/squamous cell carcinoma. Two were associated with invasion one of which metastasized to a regional node. Two cases exhibited strong p53 positivity in the high-grade squamous intraepithelial lesion/squamous cell carcinoma component analogous to that seen in HPV-negative differentiated intraepithelial lesions of the external genitalia. This series of cases adds to the literature on low risk HPV-associated cervical squamous carcinomas. It underscores the similarities between the baseline cyto-morphology and benign mimics (low-grade squamous intraepithelial lesions), the subtle cytologic and immunohistochemical (MIB1) features heralding biologic aggressiveness, and in some potential pathways (p53) not usually involved in HPV-related anogenital neoplasia.

Uterine cervical squamous cell carcinoma without p16 (CDKN2A) expression: Heterogeneous causes of an unusual immunophenotype

“…and Guimera et al also showed impressive findings that p16-negative HPV6-associated cervical SCCs were verruco-papillary lesions on gross and papillary 19 SIL or well-differentiated morphology according to a histological examination. 15, Our case was similar to these previously reported cases. These findings suggest that cervical SCCs with low-risk HPVs show a well-differentiated morphology and are difficult to diagnose.…”

“…The mechanism behind carcinogenesis with low-risk HPVs is unclear, but some cervical SCCs are reported to have an association with low-risk HPVs. 15,21 Liu et al reported three cases of p16 negative HPV6-associated HSIL/SCCs in the uterine cervix. 15 Guimera et al reported 6 9 cases of cervical SCCs with low-risk HPVs.…”

“…15,21 Liu et al reported three cases of p16 negative HPV6-associated HSIL/SCCs in the uterine cervix. 15 Guimera et al reported 6 9 cases of cervical SCCs with low-risk HPVs. 21 In a previous report by Sanjose et al, a single low-risk HPV infection was detected in 0.18% of cervical SCCs (16/8977).…”

“…In addition, while the Ki-67 expression is seen in over 75% of epithelial cells in carcinomas, its expression is concentrated in the basal third of the epithelium in LSIL/immature condyloma. 15 In such cases, CK7 can be another marker for HPV infection. CK7 contributes to viral episomal replication in high-risk HPV infected cells, 45 and CIN1 with CK7 expression is correlated with CIN2 progression.…”

“…The histological features and HPV infection status as well as the detection methods applied vary among evaluated lesions, and how SCCs are negative for p16 remains unclear. [10][11][12][13][14][15] 4…”