GENERAL DISCUSSION 185 8 recurrence-free survival.37 Low-grade EC has generally a favorable prognosis with a 5-year survival rate of 85-95%.9, 38, 39 Due to the overall favorable outcome of patients with lowgrade EC, standard histomorphology analysis remains the cornerstone in the preoperative risk stratification of EC. In chapter 3 the relevance of molecular profiling within patients with low-grade EC has been analyzed. It was shown that patients with low-grade EC have an excellent prognosis independent of their molecular subgroup. This was confirmed by external validation within the study cohort of Kandoth et al. In multivariable analyses high-grade EC was independently associated with decreased DSS along with TP53mut and FIGO stage IIIIV, again supporting the relevance of tumor grading in EC. Patients with preoperative grade 2 EC and TP53mut did show a decreased disease-specific survival compared to grade 1 EC and TP53mut, confirming our previous hypothesis that so called doubtful preoperative grade 2 EC should be considered as high-grade EC. Approximately 20.0% of the patients are diagnosed with high-grade EC (grade 3 EEC and NEEC), with an overall poor prognosis (5-year survival rate of 58.8%), which is mainly attributed to the presence of regional and/or distant metastases and have a high risk of recurrence even after adjuvant treatment.38, 40 Discordance for high-grade EC is likely supported by poor interobserver reproducibility of diverse morphological classification, different NEEC subtypes and the intratumoral heterogeneity of NEEC subtypes (mixed tumors). Molecular classification has shown to improve prognostication in high-grade tumors and an IHC panel for high-grade EC with PR and IMP3 has shown to improve concordance.14, 32, 41 The improved prognostication by molecular classification in high-grade EC was confirmed in chapter 3 and chapter 4. Furthermore the prognostic and intratumoral heterogeneity of one of the NEEC subtypes (clear cell carcinoma (CCC)) was shown in chapter 4. We demonstrated that pure and mixed CCC are two entities with different molecular background and clinical outcome. Frequent TP53 mutations were found in pure uterine CCCs whereas microsatellite instability (MSI)/mismatch repair deficient (MMRd) was more frequently present in mixed uterine CCCs. This may explain the different outcome in pure vs. mixed uterine CCC. Results were comparable to Köbel et al., in which patients with mixed uterine CCC had improved outcome, compared to patients with pure uterine CCC.42 Similar findings were reported in serous EC in which mixed serous EC had a superior prognosis compared to pure serous EC.43 Expected that the etiology and pathogenesis of mixed serous EC differs from the pure serous EC. These studies support that histomorphology remains the cornerstone and that molecular classification or IHC is of additional value in high-grade EC patients to refine prognostication. In Table 1 the association of morphological and clinical characteristics with immuno- and molecular markers is shown.
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