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16 September 2020 - Case of the Month #495

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Thanks to Dr. Tanner Storozuk and Dr. Jennifer A. Bennett, University of Chicago, Illinois (USA), for contributing this case and writing the discussion.


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Case of the Month #495

Clinical history:
A 34 year old woman was found to have atypical glandular cells of undetermined significance on Pap smear. She underwent a cervical biopsy and the results are depicted below. She had a hysterectomy afterwards that showed residual disease. Pap smears for the following 3 years were negative.

Histopathology images:

What is your diagnosis?

Click here for diagnosis, test question and discussion:

Diagnosis: Invasive stratified mucin producing carcinoma (iSMILE)

Test question (answer at the end):
Which morphologic feature may help distinguish stratified mucin producing lesions (SMILE) / invasive stratified mucin producing carcinomas (iSMILE) from more common HPV related cervical malignancies?

A. Brisk mitotic activity and apoptotic bodies
B. Large nuclear / cytoplasmic ratio
C. Mucin vacuoles throughout the full thickness of the epithelium
D. Quantity of cytoplasmic mucin

Invasive stratified mucin producing carcinoma (iSMILE) of the cervix is a recently described entity that is favored to arise from transdifferentiation of embryonic cells at the cervical transformation zone during high risk HPV infection (Am J Surg Pathol 2016;40:262). Analogous to other HPV associated cervical lesions, iSMILE has an in situ precursor, stratified mucin producing lesion (SMILE), which may coexist with high grade squamous intraepithelial lesion or endocervical adenocarcinoma in situ. SMILE is comprised of stratified columnar epithelium with hyperchromatic nuclei, mitoses and apoptotic bodies (Histopathology 2015;66:658). Mucin vacuoles are noted throughout the full thickness of the epithelium and p16 shows diffuse "block type" expression. When desmoplasia, destructive / infiltrative growth or notable architectural complexity is present, a diagnosis of iSMILE can be rendered. The invasive component often consists of nests of stratified columnar cells with bland nuclei, peripheral nuclear palisading and an associated neutrophilic infiltrate (Am J Surg Pathol 2016;40:262). For both SMILE and iSMILE, “mucin rich” and “mucin poor” subtypes can occur. STK11 mutations have recently been identified in 40% (2/5) of iSMILEs (Int J Gynecol Pathol 2019 Dec 18 [Epub ahead of print]).

Mucinous differentiation is seen in a variety of endocervical adenocarcinomas, including both HPV associated and HPV independent types. However, the 2014 WHO Classification of Tumors of Female Reproductive Organs groups all mucinous carcinomas together, irrespective of HPV status. Thus, the 2017 International Endocervical Adenocarcinoma Criteria and Classification (IECC) system was developed to link morphology and etiology (Am J Surg Pathol 2018;42:214). The IECC system has two primary groups: HPV associated adenocarcinoma (HPVA) and non-HPV associated adenocarcinoma (NHPVA). HPVAs are further classified into usual, villoglandular, mucinous NOS, mucinous intestinal, mucinous signet ring cell and iSMILE; NHPVAs into gastric, endometrioid, serous, clear cell, mesonephric and invasive NOS. HPVAs are associated with improved overall, disease specific and progression free survival compared with NHPVAs, with mucinous HPVAs having a worse progression free survival than usual type HPVAs (Am J Surg Pathol 2019;43:466). Decreased disease free and disease specific survival has also been reported for iSMILEs compared with other HPVA subtypes (J Clin Pathol 2019;72:347).

Test question answer:
Mucin vacuoles throughout the full thickness of the epithelium

Image 01 Image 02