Invasive stratified mucin-producing carcinoma (i-SMILE) represents a recently recognized subtype of cervical adenocarcinoma (AC) developing in a background of a stratified mucin-producing intraepithelial lesion (SMILE). Clinical and prognostic data on i-SMILE are limited.

We report a series of five cases with histopathological, immunohistochemical (p16) and PCR analyses. The cases as well as the patients previously published in the literature were reviewed for follow-up information.

Thirteen cases were identified. The mean age of 47.1 years (range 34–66) was not different from the usual type of cervical AC. 10/13 cases presented with tumors > 2 cm and a polypoid-exophytic appearance. Regardless of tumor size and stage of the disease, 7 out of 11 patients developed recurrent disease after a mean of 7.8 months (range 6 weeks–36 months). Five patients developed distant metastases (three of them in the lungs). Five out of the 11 informative cases died of the disease. All reported cases were positive for high-risk HPV (mainly HPV type 18) and associated with p16-overexpression.

i-SMILE represent a distinct subtype of invasive endocervical AC, associated high-risk HPV infection and strong p16-overexpression. Clinically, i-SMILE may represent an aggressive tumor with early recurrent disease and substantial risk of distant metastatic disease, especially to the lungs.