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Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
09, 2021;34 (9): 1738-1749.

Immunohistochemical and genetic characteristics of HPV-associated endocervical carcinoma with an invasive stratified mucin-producing carcinoma (ISMC) component.

Eunhyang Park, Young Tae Kim, Sunghoon Kim, Eun Ji Nam, Nam Hoon Cho
Author Information
  1. Eunhyang Park: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea. ORCID
  2. Young Tae Kim: Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea. ORCID
  3. Sunghoon Kim: Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.
  4. Eun Ji Nam: Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.
  5. Nam Hoon Cho: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea. cho1988@yuhs.ac.
PMID: 34103667 DOI: 10.1038/s41379-021-00829-3

Abstract

Invasive stratified mucin-producing carcinoma (ISMC) is a recently described entity of human papillomavirus (HPV)-associated endocervical adenocarcinoma with phenotypic plasticity and aggressive clinical behavior. To identify the cell of origin of ISMC, we investigated the immunohistochemical expression of cervical epithelial cell markers (CK7, PAX8, CK5/6, p63, and CK17), stemness markers (ALDH1 and Nanog), and epithelial-mesenchymal transition (EMT) markers (Snail, Twist, and E-cadherin) in 10 pure and mixed type ISMCs with at least 10% of ISMC component in the entire tumor, seven usual type endocervical adenocarcinomas (UEAs), and seven squamous cell carcinomas (SCCs). In addition, targeted sequencing was performed in 10 ISMCs. ISMC was significantly associated with larger tumor size (p = 0.011), more frequent lymphovascular invasion and lymph node metastasis (p < 0.001), higher FIGO stage (p = 0.022), and a tendency for worse clinical outcomes (p = 0.056) compared to other HPV-associated subtypes. ISMC showed negative or borderline positivity for PAX8, CK5/6, and p63, which were distinct from UEA and SCC (p < 0.01). Compared to UEA and SCC, ISMC showed higher expression for ALDH1 (p = 0.119 for UEA and p = 0.009 for SCC), Snail (p = 0.036), and Twist (p = 0.119), and tended to show decreased E-cadherin expression (p = 0.083). In next-generation sequencing analysis, ISMC exhibited frequent STK11, MET, FANCA, and PALB2 mutations compared to conventional cervical carcinomas, and genes related to EMT and stemness were frequently altered. EMT-prone and stemness characteristics and peripheral expression of reserve cell and EMT markers of ISMC suggest its cervical reserve cell origin. We recommend PAX8, CK5/6, and p63 as diagnostic triple biomarkers for ISMC. These findings highlight the distinct biological basis of ISMC.

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MeSH Term

Adenocarcinoma
Adult
Aged
Biomarkers, Tumor
Female
Humans
Immunohistochemistry
Middle Aged
Neoplasms, Cystic, Mucinous, and Serous
Papillomavirus Infections
Uterine Cervical Neoplasms

Chemicals

Biomarkers, Tumor
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 4

Word Cloud

Created with Highcharts 10.0.0ISMCp = 0cellexpressionmarkerscarcinomaendocervicalcervicalPAX8CK5/6p63stemnessEMTUEASCCstratifiedmucin-producingclinicaloriginALDH1SnailTwistE-cadherin10typeISMCscomponenttumorsevencarcinomassequencingfrequentp < 0highercomparedHPV-associatedshoweddistinct119characteristicsreserveInvasiverecentlydescribedentityhumanpapillomavirusHPV-associatedadenocarcinomaphenotypicplasticityaggressivebehavioridentifyinvestigatedimmunohistochemicalepithelialCK7CK17Nanogepithelial-mesenchymaltransitionpuremixedleast10%entireusualadenocarcinomasUEAssquamousSCCsadditiontargetedperformedsignificantlyassociatedlargersize011lymphovascularinvasionlymphnodemetastasis001FIGOstage022tendencyworseoutcomes056subtypesnegativeborderlinepositivity01Compared009036tendedshowdecreased083next-generationanalysisexhibitedSTK11METFANCAPALB2mutationsconventionalgenesrelatedfrequentlyalteredEMT-proneperipheralsuggestrecommenddiagnostictriplebiomarkersfindingshighlightbiologicalbasisImmunohistochemicalgeneticinvasive

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