Mismatch Repair Protein Expression in Endometrioid Intraepithelial Neoplasia/Atypical Hyperplasia: Should We Screen for Lynch Syndrome in Precancerous Lesions?

Elena Lucas, Hao Chen, Kyle Molberg, Diego H. Castrillon, Glorimar Rivera Colon, Long Li, Stacy Hinson, Joel Thibodeaux, Jayanthi Lea, David S. Miller, Wenxin - Zheng

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalInternational Journal of Gynecological Pathology
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Hereditary Nonpolyposis Colorectal Neoplasms
DNA Mismatch Repair
Hyperplasia
Endometrial Neoplasms
Neoplasms
Proteins
Carcinoma
Mutation
Curettage
Genetic Testing
Immunohistochemistry
Biopsy

Keywords

  • Atypical hyperplasia
  • Endometrioid intraepithelial neoplasia
  • Lynch syndrome
  • Mismatch repair proteins
  • MLH1 promoter hypermethylation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Obstetrics and Gynecology

Cite this

Mismatch Repair Protein Expression in Endometrioid Intraepithelial Neoplasia/Atypical Hyperplasia : Should We Screen for Lynch Syndrome in Precancerous Lesions? / Lucas, Elena; Chen, Hao; Molberg, Kyle; Castrillon, Diego H.; Rivera Colon, Glorimar; Li, Long; Hinson, Stacy; Thibodeaux, Joel; Lea, Jayanthi; Miller, David S.; Zheng, Wenxin -.

In: International Journal of Gynecological Pathology, 01.01.2018.

Research output: Contribution to journalArticle

Lucas, Elena ; Chen, Hao ; Molberg, Kyle ; Castrillon, Diego H. ; Rivera Colon, Glorimar ; Li, Long ; Hinson, Stacy ; Thibodeaux, Joel ; Lea, Jayanthi ; Miller, David S. ; Zheng, Wenxin -. / Mismatch Repair Protein Expression in Endometrioid Intraepithelial Neoplasia/Atypical Hyperplasia : Should We Screen for Lynch Syndrome in Precancerous Lesions?. In: International Journal of Gynecological Pathology. 2018.
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abstract = "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.",
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AU - Molberg, Kyle

AU - Castrillon, Diego H.

AU - Rivera Colon, Glorimar

AU - Li, Long

AU - Hinson, Stacy

AU - Thibodeaux, Joel

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AU - Miller, David S.

AU - Zheng, Wenxin -

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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.

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