Evaluation of Clinical Criteria for the Identification of Lynch Syndrome among Unselected Patients with Endometrial Cancer

Abstract

Clinical criteria, primarily young age of cancer onset and family history of signature cancers, have been developed to identify individuals at elevated risk for Lynch Syndrome with the goals of early identification and cancer prevention. In 2007, the Society of Gynecologic Oncology (SGO) codified criteria for women presenting with gynecologic cancers. These criteria have not been validated in a population-based setting. For 412 unselected endometrial cancers, immunohistochemical expression of DNA mismatch repair proteins and MLH1 methylation were assessed to classify tumors as sporadic or probable Lynch Syndrome. In this cohort, 10.5% of patients were designated as probable Lynch Syndrome based on tumor testing. The sensitivity and specificity of SGO criteria to identify these same cases were 32.6% (95% CI 19.2–48.5) and 77% (95% CI 72.7–81.8), respectively. With the exception of tumor location in the lower uterine segment, multivariate analysis of clinical features, family history, and pathologic variables failed to identify significant differences between the sporadic and probable Lynch Syndrome groups. A simplified cost-effectiveness analysis demonstrated that SGO clinical criteria and universal tissue testing strategies had comparable costs per probable Lynch Syndrome patient identified. In conclusion, SGO criteria successfully identify probable Lynch Syndrome cases among women with endometrial cancer who are young or have significant family history of signature tumors. However, a larger proportion of probable Lynch Syndrome patients who are older and have less significant family history are not detected by this screening strategy. Universal tissue testing may be necessary to capture more individuals at risk for having Lynch Syndrome.

Identifying Lynch Syndrome in Women Presenting With Endometrial Carcinoma Under the Age of 50 Years

“…24 A simplified cost-effectiveness analysis from a large retrospective cohort showed similar costs for universal testing versus triage using the SGO 5% to 10% risk-of criteria. 32 Prediction models support preselecting cases of EC using family pedigree criteria but not age cutoffs. 23 A prospective study of 179 women with EC revealed that 92% of suspected LS women received a diagnosis at older than 50 years.…”

Clinical Challenges Associated with Universal Screening for Lynch Syndrome–Associated Endometrial Cancer

“…For women with Lynch Syndrome, the lifetime risk of EC is 64%, and the lifetime risk of colorectal cancer is 54% (3). Prior studies have shown that use of clinical screening (patient age and family history of cancer) alone misses a substantial subset of endometrial cancer patients that may harbor a germline Lynch Syndrome mutation (4, 5). …”

“…Tumors with high levels of microsatellite instability (MSI-H) or immunohistochemical loss of expression of DNA MMR proteins in the absence of MLH1 gene methylation are suggestive of Lynch Syndrome. Many recently published studies have advocated for universal screening of endometrial carcinomas with MSI and/or IHC (4, 6, 7). The American College of Obstetricians and Gynecologists and the Society of Gynecologic Oncology have recently issued a practice bulletin recommending that universal tissue testing as a rational approach for identifying women at risk for Lynch-associated endometrial cancer (8).…”

Importance of PCR-based Tumor Testing in the Evaluation of Lynch Syndrome–associated Endometrial Cancer

“…14 A study performed by our group evaluated 412 sequential, unselected endometrial cancer patients, comparing SGO clinical screening criteria to universal tumor testing, and found the sensitivity and specificity for detecting tumors at elevated risk for Lynch Syndrome were 32.6% and 77%, respectively. 15 The clinically based screening criteria performed better at identifying women with increased risk for MLH1 and MSH2 mutations and performed poorly at identifying tumors with increased risk for MSH6 and PMS2 mutations. Other studies have also shown that individuals with germline mutations in MSH6 and PMS2 are more likely to have an older age at diagnosis and family histories that are dominated by gynecologic cancer or have less prevalent colon cancers.…”

“…Other studies have also shown that individuals with germline mutations in MSH6 and PMS2 are more likely to have an older age at diagnosis and family histories that are dominated by gynecologic cancer or have less prevalent colon cancers. 15–18 In addition to the limitations of these available screening criteria, patients with concerning family histories for Lynch Syndrome are not being universally screened by providers. 19 …”