Performance characteristics of screening strategies for Lynch syndrome in unselected women with newly diagnosed endometrial cancer who have undergone universal germline mutation testing

Abstract

BACKGROUND: Immunohistochemistry (IHC) for mismatch repair protein expression, microsatellite instability (MSI) testing, tumor morphology, and family history were compared to determine which screening strategy is superior in identifying Lynch syndrome (LS) in unselected women with newly diagnosed endometrial cancer (EC) who have undergone universal germline mutation testing. METHODS: A prospective cohort study was performed that recruited women with newly diagnosed EC. Participants completed a family history assessment with molecular characterization of EC with IHC and MSI testing and EC assessment for LS-associated morphologic features and underwent universal germline mutation testing for mutations in the mismatch repair pathway. The sensitivity, specificity, and positive and negative predictive values were compared between the screening strategies. RESULTS: A total of 118 (65%) of 182 consecutive women with EC participated. Of these, 34 women (29%) had tumors that were IHC deficient and 27 women (23%; N 5 117) had tumors that were positive for MSI. Twenty women (17%) met IHC criteria and 16 women (15.2%, N 5 105) met family history criteria based on Ontario Ministry of Health Criteria for the genetic assessment for LS. Seven women (5.9%) had a germline mutation: 4 had MLH1 (mutL homolog 1), 2 had MSH6 (mutS homolog 6), and 1 had MSH2 (mutS homolog 2). IHC in women aged <60 years had the best performance characteristics, with a sensitivity of 100%, a specificity of 86.1%, a positive predictive value of 58.3%, and a negative predictive value of 100%. Family history and tumor morphology both had the lowest sensitivity at 71.4%. Overall tumor morphology had the poorest performance, with a specificity of 42.1%. CONCLUSIONS: The mutation rate of 5.9% was higher than expected in this unselected cohort of women with EC. The superior screening strategy to identify women presenting with EC is universal IHC screening in women aged <60 years. Cancer 2014;120:3932-9.

Differences in Microsatellite Instability Profiles between Endometrioid and Colorectal Cancers

“…Another study documented that 21% of IHCdeficient EMC tumors were MSS by the MSI PCR assay. 12 However, a recent study by McConechy et al 13 showed 93% concordance between the two methods, with 4% MSI-H EMCs missed by IHC, yet only 1% of IHC-deficient EMCs were missed by the MSI assay. Furthermore, the correlation of MSI status with pathologic features of EMCs is also controversial.…”

Efficient Screening Strategy for Lynch Syndrome in Japanese Endometrial Cancer

“…Clinicians have been overlooking most of LS cases accounting for 2-6% of EC patients (Hampel et al 2006;Ferguson et al 2014). To efficiently identify LS in all EC patients and to provide them with appropriate surveillance, we seek a sensible screening strategy for clinical practice.…”

“…The first problem is its costeffectiveness. Considering the fact that LS accounts for 2-6% of all EC patients (Hampel et al 2006;Ferguson et al 2014), opinions on the cost-effectiveness of US are divided. In a comparative study using a simulation model of several LS screening strategies, the strategy that adds an IHC assessment for EC patients who have at least one firstdegree relative with LS-associated cancer has better costeffectiveness than US (Kwon et al 2011).…”

“…If the social environment and medical systems that provide genetic information and support for patients are not properly maintained, the benefits that US can bring to patients will be much less extensive than the theoretical benefits. The third problem is that the positive predictive value of US is lower than those of other screening strategies (Buchanan et al 2014;Ferguson et al 2014), implying that the ratio of patients with suspected LS without germline mutations is relatively high. In the group of suspected LS patients without germline mutations, the incidence of LS-associated cancers is lower than that in the group of LS patients, but significantly higher than that in the general population.…”

“…LS-associated cancers include the cancer of stomach, ovaries, small intestine, liver, gallbladder ducts, upper urinary tract, brain, and skin. Recent studies have shown that women with LS account for 2-6% of all EC patients (Hampel et al 2006;Ferguson et al 2014) and that their lifetime risk of developing CRC is 43-48%, while that of developing EC is 40-62% (Aarnio et al 1999;Lu and Broaddus 2005;Boilesen et al 2008;Stoffel et al 2009). In cases of women with LS who developed both primary CRC and gynecologic cancer, EC or ovarian cancer plays a role equal to or greater than that of CRC as a sentinel cancer of LS ).…”