Abstract

Molecular classification of endometrial carcinoma (EC) has represented a breakthrough ever since the TCGA (The Cancer Genome Atlas) project published it in 2013. Four distinct molecular subgroups were recognized based on somatic copy number alterations and tumor mutational burden: POLE (polymerase-epsilon) ultramutated, MSI (microsatellite instability) hypermutated (MSI-H), copy number low (CNL) and copy number high (CNH). However, implementing a standardized algorithm in current practice is far from being definitive. Our purpose in this study was to determine different molecular subgroups in a cohort of Romanian patients using cost effective and available immuno-histochemistry markers and outline statistical associations with different parameters. Tissue microarrays encompassing 50 cases with previously diagnosed ECs were tested for ER, PR, HER2, p53, MSH6 and PMS2 and results showed 68% MSI-H cases with statistical correlation with tumor size ] 2 cm (p=0.028) and no association with overall survival. CNH ECs were reported in 26% of cases and showed important statistical significance with TILs (p=0.041) and no correlations with overall survival. The CNL subgroup was reported in 74% of ECs cases and showed statistical significance with the histopathological subtype (p=0.006), pT (removal of primary tumor according to AJCC/UICC convention) (p=0.033), risk category according to ESMO (European Society of Medical Oncology) criteria (p=0.022) and ER expression (p=0.002). Five-year overall survival was 84%. Molecular classification is an important additional tool in current pathology guidelines for reporting ECs, but it is not currently standardized or available in all laboratories. Its importance in evolving treatment strategies for this disease is well documented so we strongly recommend routine testing for molecular prognostic factors.

Highlights

  • Endometrial carcinoma (EC) represents the most frequent gynecological neoplasia in developed countries, in which the incidence of cervical cancer has decreased significantly due to screening methods and prophylaxis

  • New staging guidelines do not include positive peritoneal cytology as a parameter and prognosis remains uncertain, one recent study [4] performed on a large cohort of patients proved that positive peritoneal cytology was associated with decreased overall survival for women with Federation of Gynecology and Obstetrics (FIGO) I/II stage, including those with low-grade endometrioid endometrial carcinoma. 64% of our cases showed tumor size >2 cm with 14% associated lymph node metastasis and 5% of cases with previous histopathological diagnosis of endometrial hyperplasia without or with atypia

  • We found a much larger percentage of MSI-H endometrial carcinomas (68%) which should represent a red flag and prompt further investigation to exclude genetic syndromes (Lynch syndrome), since endometrial carcinoma is often considered asentinel cancerand patients often have other digestive malignancies

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Summary

Introduction

Endometrial carcinoma (EC) represents the most frequent gynecological neoplasia in developed countries, in which the incidence of cervical cancer has decreased significantly due to screening methods and prophylaxis. The prevalence of EC has been on an increased trend over the years and the age at diagnosis is usually 60-64 years, there have been numerous reports of younger female patients diagnosed with this disease. We have come a long way as pathologists from the moment Bokhman published his epidemiological studies [3, 23] that classified endometrial carcinoma in two clinicopathological entities: type I endometrial carcinoma (low-grade endometrioid histology and association with unopposed estrogen) and type II endometrial carcinoma (unrelated to estrogen exposure and serous histology). Standardized guidelines for pathological reporting focus mainly on histological parameters: tumor grade, histopathological subtype, disease extension, LVSI etc. Since the moment new genetic and molecular techniques were introduced all over the world, we were offered the opportunity to study cancer biology and diversity on a deeper level

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