Elsevier

Human Pathology

Volume 55, September 2016, Pages 174-181
Human Pathology

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

https://doi.org/10.1016/j.humpath.2016.05.007Get rights and content

Summary

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.

Introduction

High-grade squamous intraepithelial lesion (HSIL) and adenocarcinoma in situ (AIS) are precursor lesions for invasive carcinomas [1], [2]. Stratified mucin-producing intraepithelial lesion (SMILE) is a rare columnar cell cervical neoplasm, first described in 2000 [3]. It overlaps morphologically with HSIL and AIS and is considered to be a variant of AIS [4] or adenosquamous carcinoma in situ [5]. IMP3 is a member of insulin growth factor II protein and is a useful marker for AIS, HSIL, and invasive carcinomas [6]. Recently, Boyle and McCluggage [7] suggested that SMILE is more similar to squamous epithelial tumor than adenocarcinoma because SMILE and HSIL were negative for IMP3 in their study.

A few studies have reported the association between SMILE and invasive carcinomas. Park et al [3] reported 12 cases (67%) of SMILE with invasive carcinomas (4 invasive adenocarcinomas, 1 adenocarcinoma and separated squamous cell carcinoma, 5 adenosquamous carcinomas, and 2 papillary lesions) but did not describe their morphological findings in detail. Lastra et al [8] recently reported the similarity in appearance between invasive components and SMILE and proposed the invasive form of SMILE to be “invasive stratified mucin-producing carcinoma” (ISMC). However, the immunohistologic features of SMILE and ISMC have not been well documented.

Therefore, we studied the immunohistochemically characteristics of 12 cases of SMILE with or without invasive carcinoma components, and the ultrastructural study of 1 case was also described.

Section snippets

Materials and methods

This study was approved by the Ethics Committee of the University of Miyazaki (approval no. 2014-05). We retrospectively reviewed specimens obtained from 445 patients (mean age, 44 years; age range, 19-80 years) with uterine cervical tumors, diagnosed as HSIL, AIS, SMILE, or invasive carcinoma, who were treated at the University of Miyazaki Hospital between 2004 and 2014. Of the 445 patients, 250 (56%; mean age, 39 years) had only intraepithelial lesions, and 195 patients (44%; mean age, 50

Clinical features

Of 445 patients, 12 showed SMILE histologically (2.7%; mean age, 44 years; age range, 30-66 years; Fig. 1; Table 1). Of 12 patients, 3 (25%; mean age, 37 years; range, 30-48 years) had only intraepithelial lesions, and 9 patients (75%; mean age, 47 years; range, 37-66 years) had invasive cancer elements. In the group with only intraepithelial tumors, 1 patient presented with genital bleeding; and 2, with abnormal cytology; in the invasive group tumor, 6 patients presented with genital bleeding;

Discussion

SMILE is an uncommon intraepithelial lesion. Determining its incidence and clinicopathological features from the few reports in the literature is difficult. The initial 2000 proposal by Park et al [3] and the recent 2014 World Health Organization classification [4] described SMILE as a cervical glandular premalignant lesion; however, SMILEs are probably still underrecognized or misclassified. Actually, we could not make the diagnosis of SMILE for 6 cases in the original diagnoses. We documented

Acknowledgments

The authors thank Dr Tohru Hayashi for his valuable advice and Takako Tokumitsu, Kyoko Ohashi, and Ritsuko Sotomura for their excellent technical assistance.

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    Disclosures: There is no relationship with industry to declare, and no authors have competing financial interests or conflicts of interest.

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