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Background: Mismatch repair (MMR)-deficiency analysis is increasingly recommended for all endometrial cancers, as it identifies Lynch syndrome patients, and is emerging as a prognostic classifier to guide adjuvant treatment. The aim of this study was to define the optimal approach for MMR-deficiency testing and to clarify discrepancies between microsatellite instability (MSI) analysis and immunohistochemical (IHC) analysis of MMR protein expression. Patients and methods: Six hundred ninety- six endometrial cancers were analyzed for MSI (pentaplex panel) and MMR protein expression (IHC). Agreement between methodologies was calculated using Cohen's Kappa. MLH1 promoter hypermethylation, dinucleotide microsatellite markers and somatic MMR and POLE exonuclease domain (EDM) gene variants (using next-generation/Sanger sequencing) were analyzed in discordant cases. Results: MSI was found in 180 patients. Complete loss of expression of one or more MMR proteins was observed in 196 cases. A PMS2- and MSH6-antibody panel detected all cases with loss of MMR protein expression. The results of MSI and MMR protein expression were concordant in 655/696 cases (kappa=0.854, P<0.001). Ambiguous cases (n=41, 6%) included: subclonal loss of MMR protein expression (n=18), microsatellite stable or MSI-low cases with loss of MMR protein expression (n=20), and MSI-low or MSI-high cases with retained MMR protein expression (n=3). Most of these cases could be explained by MLH1 promoter hypermethylation. Five of seven cases with solitary loss of PMS2 or MSH6 protein expression carried somatic gene variants. Two MSI-high cases with retained MMR protein expression carried a POLE-EDM variant. Conclusion: MSI and IHC analysis are highly concordant in endometrial cancer. This holds true for cases with subclonal loss of MMR protein expression. Discordant MMR-proficient/MSI-high cases (<1%), may be explained by POLE-EDM variants. [ABSTRACT FROM AUTHOR]

Background L1 cell adhesion molecule (L1CAM) expression has been implicated as risk factor for disease recurrence in endometrial cancer (EC), most likely due to its role in promoting tumour cell motility. We tested the performance of L1CAM expression in predicting the risk of recurrence in the randomised post operative radiation therapy in endometrial carcinoma (PORTEC)-1 and -2 trials. Methods In the PORTEC trials, stage I EC patients were randomised to external beam radiotherapy (EBRT) versus no additional treatment (PORTEC-1, n = 714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n = 427). Tumour samples of 865 (75.8%) patients were available for L1CAM expression analysis by immunohistochemistry. An established scoring system for EC was used, with >10% L1CAM staining defined as positive. Results Positive L1CAM expression was significantly correlated with risk of distant recurrence, with a hazard ratio (HR) of 5.1 (95% confidence interval (CI) 3.1–8.7) but not with vaginal relapse, while a trend for pelvic nodal relapse was found. Tumours with the highest expression levels (>50% positive) had the strongest risk of distant recurrence (HR 5.3, CI 2.7–10.4). In multivariate Cox analysis with the risk factors age, depth of invasion, grade, lympho-vascular space invasion (LVSI) and treatment, L1CAM expression remained an independent prognostic factor for distant recurrence (HR 3.5, CI 1.92–6.30) and overall survival (HR 2.1, CI 1.41–2.98). Conclusion L1CAM expression is a strong independent predictor for distant recurrence and overall survival in stage I endometrial cancer. These results warrant prospective validation of L1CAM as marker for selecting patients who could benefit from more extensive diagnostic and/or therapeutic procedures. [ABSTRACT FROM AUTHOR]