title: Endometrial carcinomas in women aged 40 years and younger: tumors associated with loss of DNA mismatch repair proteins comprise a distinct clinicopathologic subset.
abstract: Endometrial carcinomas (ECs) in young women (< or = 40 y) are usually managed conservatively in selected patients. Whether oophorectomy with total hysterectomy is mandated for patients failing hormonal therapy is controversial. Recognition of features that might discourage conservative management and ovarian preservation are currently poorly characterized. We evaluated these patients for DNA mismatch repair (MMR) protein defects to assess whether the MMR status had an impact on therapeutic decision making. Seventy ECs in women of 40 years of age or younger (n=70) were identified from review of institutional databases (1993-present). All available slides were reviewed and DNA MMR immunohistochemistry was performed using 4 markers (MLH1, PMS2, MSH2, and MSH6) in cases with available blocks (n=54). ECs were predominantly endometrioid (65/70), and most were low grade (1988 International Federation of Gynecology and Obstetrics grades 1 or 2, 83%). Five (7%) were undifferentiated carcinomas. Most patients presented at early stage (stages I to II, 90%). A significant number of patients also had synchronous ovarian carcinomas (9 of 70, 13%), predominantly endometrioid (7 of 9), whereas 2 were ovarian clear cell carcinomas. Sixty-six of the 70 patients are alive with no evidence of disease, whereas 4 patients (6%) died of disease. Immunohistochemistry for DNA MMR showed loss of at least 1 protein in 9 of 54 cases (16%) with slight predominance of MSH2/MSH6 abnormalities (5 of 9) compared with loss of MLH1/PMS2. Tumors with MMR loss frequently occurred in women with low body mass index; these tumors were of higher grade and associated with worse clinical outcomes. They frequently showed tumor characteristics associated with microsatellite instability, including tumor infiltrating lymphocytes, undifferentiated or dedifferentiated histology, and lower uterine segment origin. These tumors also showed lower estrogen receptor/progesterone receptor expression compared with tumors with retained staining for MMR proteins. None of the cases with synchronous ovarian and endometrial endometrioid carcinomas showed loss of MMR proteins, whereas 1 of 2 ECs with synchronous CCC of ovary showed loss of MSH2/MSH6.As young women with endometrioid carcinomas who show loss of mismatch proteins are at risk for high-grade tumors with worse clinical outcomes and lower estrogen receptor/progesterone receptor expression, they may not be appropriate candidates for conservative management. Although young EC patients are at increased risk for synchronous endometrioid ovarian carcinomas, this does not seem to be associated with MMR loss.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Karuna
authors.initials: K
authors.lastname: Garg
authors.forename: Karin
authors.initials: K
authors.lastname: Shih
authors.forename: Richard
authors.initials: R
authors.lastname: Barakat
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
authors.forename: Alexia
authors.initials: A
authors.lastname: Iasonos
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D018262:Adenocarcinoma, Clear Cell / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000251:Adenosine Triphosphatases / Q000032:analysis; D000328:Adult; D000367:Age Factors; D001706:Biopsy; D018269:Carcinoma, Endometrioid / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000032:analysis; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000032:analysis; D009367:Neoplasm Staging; D009378:Neoplasms, Multiple Primary; D009687:Nuclear Proteins / Q000032:analysis; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018579:Patient Selection; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes