IMMUNOHISTOCHEMICAL BIOMARKERS IN EC 121 5 used instead of final tumor sections in which L1CAM can be expressed focally and/or at the invasive front predominantly25. Our results are in line with a study reporting that patients with L1CAM+ had significantly reduced survival also in the ESMO-ESGO-ESTRO ‘high and advanced/metastatic’ risk group compared with normal L1CAM expression24. A more recent study reported reduced overall survival (OS) and progression-free survival (PFS) in patients with FIGO stage III and L1CAM+ when compared with L1CAM- patients26. This is in line with our results since FIGO stage III is included in the ‘high’ risk group. Multiple studies have investigated ER/PR expression in relation to outcome in EC reporting conflicting results18, 27, 28. In our study, ER/PR- was not significantly related to RFS in the multivariate analysis, contrary to previous studies18, 27, 28. In line with the study by Trovik et al. ER/PR- was related to DSS and LNM17. In a previous ENITEC study of our study group, mainly loss of PR predicted disease recurrence18. Biologically, loss of ER is preceded by loss of PR and therefore PR might be the most relevant to outcome. In the current study, we did not analyze ER/PR separately. Interestingly, loss of PR was mainly present in the ‘advanced/ metastatic’ risk group, underlining the possible relevance for distant spread. The expression of ER/PR was studied in relation to the different TCGA groups and although ER and PR biomarkers were both predictive for outcome in the univariate analysis, only the ProMisE subtypes maintained significant associated with outcome in the multivariate analysis. It was suggested that the prognostic significance of single biomarkers could be explained by being a covariable with the ProMisE molecular subtype16. Similar was shown in the study of Stelloo et al29. Due to the used cut-offs for ER/PR of 5% and 1% respectively in one study, the prognostic value might have been underestimated when compared with the 10% cut-off that was used in our study and by Trovik et al16, 17. Stelloo et al. did used the 10% cut-off, however they only included early stage EEC patients hampering comparison to our study29. There is an ongoing debate about routine surgical staging with LN dissection or sampling in EC, especially after the introduction of molecular profiling. LN status as determined by either lymphadenectomy or SLN remains an important prognosticator for survival and guiding adjuvant treatment in the current ESMO-ESGO-ESTRO risk classification5, 30-33. The study of Ouldamer et al. concluded, that even patients within the ‘high-intermediate’ risk group should receive systematic nodal staging for a significant better survival34. This is in line with recent paper of Weelden et al. that demonstrated that patients with FIGO IIIA-B had significant improved outcome if LN were sampled and negative35. Our results show the prognostic relevance of IHC expression in addition to LN status, similar to other studies17, 19. The importance of both IHC biomarkers and LN status is shown since patients with LNM and normal IHC expression had comparable RFS/DSS with patients without LNM and abnormal IHC expression.
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