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

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.

Serial genomic analysis of endometrium supports the existence of histologically indistinct endometrial cancer precursors

“…As expected for a heterozygous germline variant, AF was higher than other somatically acquired mutations and showed little fluctuation (Figure 2A). Thus, the HTS panel was able to detect classifying somatic mutations such as POLE and germline mutations that predispose to endometrial cancer [22].…”

“…Fixation, sectioning, antigen retrieval, blocking, and secondary detection were performed as previously described [21], with the following antibodies: ARID1A [#12354, rabbit monoclonal antibody (mAb); Cell Signaling Technology, Danvers, MA, USA; 1:200], PTEN (Dako #M326‐7, mouse mAb; Agilent Technologies, Santa Clara, CA, USA; 1:150), p53 (Dako #DO‐7, prediluted; Agilent), and β‐catenin (Dako #IR702, mouse mAb). IHC for four MMR proteins was performed as previously described [22]. Antigen retrieval was performed following the manufacturers' recommendations.…”

Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis

“…EAH/EIN is the precursor lesion of almost all endometrioid carcinomas and a subset of serous carcinomas [58]. The mutational profile of EAH/EIN and the concurrent EC is highly concordant [18,59–62] in the majority of cases; however, Li et al showed that, in 5 out of 30 EAH/EIC cases with concurrent EEC, the EAH/EIC and EC shared less than 5% of the mutations identified, indicating clonality but with a high degree of divergence [62]. Serous intraepithelial carcinoma (SEIC) is characterized by pre‐existing endometrial glands lined by markedly atypical glandular epithelial cells in the absence of invasive disease.…”

“…present in the low‐grade areas, or it can occur later and only be seen in the high‐grade serous component (Figure 2D,E). MMRd : These carcinomas are mostly of endometrioid histotype and there can be co‐existing EAH/EIN as the precursor lesion [60]. There is identical loss of MMR protein(s) in the EAH/EIN as in the associated carcinoma in most but not all cases (Figure 2F).…”

“…There is identical loss of MMR protein(s) in the EAH/EIN as in the associated carcinoma in most but not all cases (Figure 2F). In one study of more than 100 EAH/EINs, fewer than 5% were MMRd; thus, MMRd is much more commonly identified in EC than in the precursor lesion, suggesting that there is rapid transit through the in situ phase in these genomically unstable tumors [60]. This is similar to the situation in vulvar squamous cell carcinoma, where purely in situ lesions are predominantly HPV‐associated while invasive vulvar squamous cell carcinoma is predominantly HPV‐independent, an observation attributable, at least in part, to the more rapid progression of HPV‐independent VIN [72].…”