TY - JOUR
T1 - Mismatch Repair Protein Expression in Endometrioid Intraepithelial Neoplasia/Atypical Hyperplasia
T2 - Should We Screen for Lynch Syndrome in Precancerous Lesions?
AU - Lucas, Elena
AU - Chen, Hao
AU - Molberg, Kyle
AU - Castrillon, Diego H.
AU - Colon, Glorimar Rivera
AU - Li, Long
AU - Hinson, Stacy
AU - Thibodeaux, Joel
AU - Lea, Jayanthi
AU - Miller, David S.
AU - Zheng, Wenxin
N1 - Funding Information:
Supported by the Department of Pathology, UTSW Medical Center (intramural funding). The authors declare no conflict of interest.
Funding Information:
Acknowledgments: The authors acknowledge the assistance of the University of Texas Southwestern Tissue Resource, a shared resource at the Simmons Comprehensive Cancer Center, which is supported in part by the National Cancer Institute under award number 5P30CA142543. The authors thank Sara Blacketer and the staff of the Parkland Hospital Anatomic Pathology Laboratory for technical assistance.
Publisher Copyright:
© 2018 International Society of Gynecological Pathologists.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Screening for Lynch syndrome (LS) is routinely performed in patients with endometrial carcinoma. Currently, no screening recommendations exist for LS in precancerous lesions. The study goal was to determine the incidence of abnormal protein expression in endometrioid intraepithelial neoplasia/atypical hyperplasia (EIN/AH). We analyzed mismatch repair (MMR) protein expression by immunohistochemistry in EIN/AH concurrent with MMR-deficient endometrial carcinomas, and in endometrial biopsy/curettage specimens with EIN/AH from an unselected group of patients. Of 63 patients with MMR-deficient endometrial carcinoma, 34 demonstrated loss of MLH1/PMS2 expression; 1 showed loss of PMS2 alone; 12 showed loss of MSH2/MSH6, and 15 had loss of MSH6 alone. Genetic testing identified deleterious mutations in 14 cases (LS). 15 tumors demonstrated MLH1 promoter hypermethylation. Abnormal MMR expression in EIN/AH and adjacent carcinoma was concordant in 100% of LS cases and 71% of MLH1 promoter hypermethylation cases. Of 118 patients from the unselected group with EIN/AH, 4 (3%) cases demonstrated absent expression of one or more MMR proteins. Of these, 2 patients were later confirmed to have deleterious mutations in subsequent specimens with endometrial carcinoma. The prevalence of abnormal MMR expression in EIN/AH adjacent to carcinoma and in the unselected group of patients with EIN/AH is similar to the reported prevalence of LS in endometrial carcinoma. Identifying patients at high risk for LS through abnormal MMR expression in EIN/AH provides the benefit of early surveillance, treatment and timely diagnosis for the patient and affected family members.
AB - Screening for Lynch syndrome (LS) is routinely performed in patients with endometrial carcinoma. Currently, no screening recommendations exist for LS in precancerous lesions. The study goal was to determine the incidence of abnormal protein expression in endometrioid intraepithelial neoplasia/atypical hyperplasia (EIN/AH). We analyzed mismatch repair (MMR) protein expression by immunohistochemistry in EIN/AH concurrent with MMR-deficient endometrial carcinomas, and in endometrial biopsy/curettage specimens with EIN/AH from an unselected group of patients. Of 63 patients with MMR-deficient endometrial carcinoma, 34 demonstrated loss of MLH1/PMS2 expression; 1 showed loss of PMS2 alone; 12 showed loss of MSH2/MSH6, and 15 had loss of MSH6 alone. Genetic testing identified deleterious mutations in 14 cases (LS). 15 tumors demonstrated MLH1 promoter hypermethylation. Abnormal MMR expression in EIN/AH and adjacent carcinoma was concordant in 100% of LS cases and 71% of MLH1 promoter hypermethylation cases. Of 118 patients from the unselected group with EIN/AH, 4 (3%) cases demonstrated absent expression of one or more MMR proteins. Of these, 2 patients were later confirmed to have deleterious mutations in subsequent specimens with endometrial carcinoma. The prevalence of abnormal MMR expression in EIN/AH adjacent to carcinoma and in the unselected group of patients with EIN/AH is similar to the reported prevalence of LS in endometrial carcinoma. Identifying patients at high risk for LS through abnormal MMR expression in EIN/AH provides the benefit of early surveillance, treatment and timely diagnosis for the patient and affected family members.
KW - Atypical hyperplasia
KW - Endometrioid intraepithelial neoplasia
KW - Lynch syndrome
KW - MLH1 promoter hypermethylation
KW - Mismatch repair proteins
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U2 - 10.1097/PGP.0000000000000557
DO - 10.1097/PGP.0000000000000557
M3 - Article
AN - SCOPUS:85056191699
SN - 0277-1691
VL - 38
SP - 533
EP - 542
JO - International Journal of Gynecological Pathology
JF - International Journal of Gynecological Pathology
IS - 6
ER -