Stratified Mucin-Producing Lesions of the Anal Canal: Expanding the Spectrum of a Newly Recognized Entity

Context: Stratified mucin-producing intraepithelial lesions (SMILEs) and invasive stratified mucin-producing carcinoma (ISMC) are well studied in the uterine cervix. These lesions have recently been described in the anorectal canal; however, understanding about their clinicopathologic features and clinical implications is limited. Objective: -To investigate the clinicopathologic features and behavior of SMILE/ISMC in the anorectal canal. Design: We identified 4 cases containing SMILE/ISMC in the anorectal canal between 2013 and 2024. Clinical data and histopathologic slides were reviewed. Results: The SMILE/ISMC component was associated with conventional adenocarcinoma (n = 1), squamous cell carcinoma (n = 2), or adenosquamous carcinoma (n = 1). We observed SMILE in 2 of 4 cases, ISMC in 1 of 4 cases, and both components in 1 of 4 cases. Histopathologic features included intracytoplasmic mucin, pseudostratification (all cases), various degrees of peripheral palisading, apoptosis, intratumoral neutrophils (all cases), and mitoses (3 of 4 cases). A p16 immunohistochemical stain showed diffuse positivity (3 strong and 1 weak) in all SMILE/ISMC, and in situ hybridization for human papillomavirus 16/18 RNA was positive in 2 cases. Three of 3 cases were mismatch repair proficient, p53 wild type, and HER2 negative. All 4 patients were alive on follow up (median, 16.5 months). One patient was found to have a separate focus of human papillomavirus-driven invasive adenocarcinoma 4 months post-excision of SMILE/adenocarcinoma. None showed residual/recurrent disease at the site. Conclusions: SMILE is often associated with invasive carcinoma and may be a harbinger of neoplasia similar to its cervical counterpart. Close examination is necessary for accurate diagnosis, and further study is warranted to determine the potential benefits of closer follow-up.