Papillary Squamous Intraepithelial Lesion Outside the Uterine Cervix

Papillary immature metaplasia, originally described in the uterine cervix, is increasingly recognized as a distinctive squamous intraepithelial lesion rather than a true metaplastic process. Accordingly, the term papillary squamous intraepithelial lesion (PSIL) has been proposed. PSIL occurring outside the uterine cervix is exceedingly rare. In this study, we characterize the clinicopathologic, immunophenotypic, and virologic features of 25 cases of PSIL involving non-cervical sites (vagina, vulva, anus, and endometrium). All lesions demonstrated exophytic papillary architecture lined by uniform immature squamous cells with limited surface maturation. Mitotic figures were frequently identified in the lower half of the epithelium. Low-risk HPV E6/E7 mRNA was detected in 76% of cases, whereas none harbored high-risk HPV. HPV transcripts exhibited a distinctive punctate distribution throughout the epithelium, contrasting with the superficial clustered pattern seen in condyloma/LSIL. Non-block p16 immunostaining pattern was seen in all PSILs, while Ki-67 labeling indices were increased (median 50%), predominantly involving the lower half to two-thirds of the epithelium. Clinical follow-up (median 32 months) demonstrated recurrence in 43% of cases, most commonly with incomplete excision. Our study shows that non-cervical PSIL shares morphologic, immunophenotypic, and virologic features with cervical PSIL. Despite the absence of block-type p16 expression, PSIL demonstrates high proliferative activity, frequently leading to diagnostic confusion with HSIL. Given its distinctive papillary architecture, unusual HPV distribution pattern, and tendency for recurrence, PSIL represents a unique low-risk HPV-associated intraepithelial lesion distinct from conventional LSIL and HSIL. Adoption of the term papillary squamous intraepithelial lesion is recommended in accordance with LAST terminology.