Utility of MLH1 Methylation Analysis in the Clinical Evaluation of Lynch Syndrome in Women with Endometrial Cancer

Abstract

Clinical screening criteria, such as young age of endometrial cancer diagnosis and family history of signature cancers, have traditionally been used to identify women with Lynch Syndrome, which is caused by mutation of a DNA mismatch repair gene. Immunohistochemistry and microsatellite instability analysis have evolved as important screening tools to evaluate endometrial cancer patients for Lynch Syndrome. A complicating factor is that 15-20% of sporadic endometrial cancers have immunohistochemical loss of the DNA mismatch repair protein MLH1 and high levels of microsatellite instability due to methylation of MLH1. The PCR-based MLH1 methylation assay potentially resolves this issue, yet many clinical laboratories do not perform this assay. The objective of this study was to determine if clinical and pathologic features help to distinguish sporadic endometrial carcinomas with MLH1 loss secondary to MLH1 methylation from Lynch Syndrome-associated endometrial carcinomas with MLH1 loss and absence of MLH1 methylation. Of 337 endometrial carcinomas examined, 54 had immunohistochemical loss of MLH1. 40/54 had MLH1 methylation and were designated as sporadic, while 14/54 lacked MLH1 methylation and were designated as Lynch Syndrome. Diabetes and deep myometrial invasion were associated with Lynch Syndrome; no other clinical or pathological variable distinguished the 2 groups. Combining Society of Gynecologic Oncology screening criteria with these 2 features accurately captured all Lynch Syndrome cases, but with low specificity. In summary, no single clinical/pathologic feature or screening criteria tool accurately identified all Lynch Syndrome-associated endometrial carcinomas, highlighting the importance of the MLH1 methylation assay in the clinical evaluation of these patients.

Clinical challenges associated with universal screening for Lynch syndrome associated endometrial cancer

“…The demographic and pathologic characteristics in this study population are similar to published national data, thus findings from this study can presumably be applied to other EC patients (15). Results from this cohort also show tumor testing results of MSI-H in 25.1% of cases, with 93.5% of these with MLH1 promoter methylation, a finding consistent with other published literature evaluating both colorectal and endometrial carcinomas (12,(16)(17)(18)(19)(20)(21). Using the universal tumor screening approach, clinical and diagnostic challenges in definitively designating an endometrial cancer patient as sporadic or Lynch Syndrome would be expected to occur in approximately 13.6% of patients.…”

“…Endometrial carcinomas exhibiting loss of MSH2, MSH6, or PMS2 were considered suggestive of a Lynch Syndrome (LS) associated tumor. For cases in which there was IHC loss of MLH1 protein expression, the PCR-based MLH1 promoter methylation assay was utilized to distinguish between sporadic epigenetic silencing of MLH1, methylated, and suspected MLH1 loss due to LS, unmethylated as previously described (12).…”

Recent Developments in Surgical Pathology of the Uterine Corpus

“…The MSI-high ECs tend to be associated with higher tumor grade, unusual morphology, the presence of lymphovascular invasion, deeper myometrial invasion, a high number of tumor-infiltrating lymphocytes, the origin of tumor in the lower uterine segment, and synchronous carcinoma of the ovary and endometrium (Table 5). 36,37 On the other hand, in the study by Bruegl et al 38 multivariate analysis failed to identify any specific associations other than the tumor location in the lower uterine segment between the sporadic and LS groups. Mills et al 39 found that at least 41% of patients with LS-associated germline mutations are not associated with any of the demographic or morphologic indicators.…”

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…Alternatively, immunohistochemistry (IHC) can confirm the presence or absence of MMR proteins. Sporadic MSI occurs in both CRC and extracolonic malignancies, particularly endometrial cancer (Bruegl et al, 2014;Haraldsdottir et al, 2014). Lynch syndrome (formerly hereditary non-polyposis colorectal cancer [HNPCC]) is the most common heritable cancer predisposition syndrome and is characterised by an increased predisposition to certain cancers, most notably CRC (Vasen et al, 2007).…”