Stratified mucin-producing intraepithelial lesion with invasive carcinoma: 12 cases with immunohistochemical and ultrastructural findings.

Stratified mucin-producing intraepithelial lesion (SMILE) is considered to be a variant of adenocarcinoma in situ (defined as intraepithelial malignant glandular epithelium without invasion) or adenosquamous carcinoma in situ of the uterine cervix. However, recent study suggested that SMILE is more similar to high-grade squamous epithelial lesion by their immunohistochemical findings. An invasive form of SMILE "invasive stratified mucin-producing carcinoma (ISMC)" has been also proposed, but immunohistochemical features are not well documented. Therefore, this study aimed to clarify the immunohistochemical characteristics of SMILE and ISMC. Twelve cases of SMILE were found among 445 patients (2.7%) with high-grade intraepithelial lesions or invasive carcinomas, 3 of whom had solely intraepithelial disease with SMILE component (mean age, 37 years; range, 30-48 years) and 9 with invasive carcinomas (mean age, 47 years; range, 37-66 years; including ISMC). Immunohistochemically, SMILE and ISMC were diffusely positive for p16 and CAM5.2, focally for IMP3, and almost negative or only focally positive for p63. Nuclear signals in SMILE and invasive carcinomas were detected by human papillomavirus (HPV) in situ hybridization; 5 cases showed HPV16 and/or HPV18 polymerase chain reaction products. The ultrastructural study of 1 case showed surface microvilli and small vacuolar structure in SMILE; ISMC had mucous-like vacuoles, many mitochondria and intracytoplasmic lumen but lacked tonofilament. These findings were more similar to adenocarcinoma in situ or adenocarcinoma than squamous intraepithelial lesion or squamous cell carcinoma. We suggest that SMILE is an intraepithelial neoplasm and ISMC is an invasive form of SMILE.