SUMMARY 203 9 SUMMARY In this thesis, we investigated the role of classical tumor morphology and existing biomarkers in the context of the new era of molecular classification. This to optimize the use of all available biomarkers and apply the best care for patients with endometrial cancer (EC). There is only moderate concordance between pre- and postoperative histological diagnosis in EC (67%) which may lead to under- and overtreatment. In Chapter 2, we investigated whether the amount of preoperative tissue and the sampling method (pipelle biopsy, dilation & curettage or hysteroscopy biopsy) affects the concordance. For this purpose, within the ENITEC (European Network of Individual Treatment in Endometrial Cancer) network, 573 tumor samples were collected in which we measured the area of preoperative endometrial tissue by digital imaging of the sections. In 60.0% of the samples, there was agreement between pre- and postoperative tumor grade and histology. When using binary grading, i.e. low- (grade 1 and 2 EC) and high-grade EC (grade 3 and non-endometrioid EC) the agreement was 88.8%. The amount of preoperative endometrial tissue surface was unrelated to the concordance of pre- and postoperative diagnosis. In contrast, the amount of endometrial tissue surface was significantly lower when pre- and postoperative diagnoses were concordant (18.7 mm2 vs. 23.5 mm2 , respectively P=0.022). The sampling method was also unrelated to the degree of concordance between pre- and postoperative diagnosis. Immunohistochemical (IHC) or molecular markers can be used to improve the agreement between pre- and postoperative diagnosis. In Chapter 3, we investigated the added value of molecular classification within the group of patients with low-grade EC in an ENITEC retrospective cohort. The four molecular subgroups were determined by next-generation sequencing (NGS) or a combination of NGS and IHC: (1) polymerase epsilon (POLE) mutation, (2) microsatellite instable (MSI), (3) TP53 mutation and (4) no specific molecular profile (NSMP). A total of 393 patients were included, POLE mutation was present in 8.4%, MSI in 19.8%, TP53 mutation in 18.3% and NSMP in 53.4%. In all molecular subgroups, patients with low-grade EC had an excellent 5-year disease-specific survival of 85-100%, and this was confirmed in the external validation cohort. Patients with high-grade EC had a significantly worse 5-year disease-specific survival within TP53 mutation and NSMP subgroup (40% and 68%, respectively). In the multivariable analysis, high-grade EC, TP53 mutation and FIGO stage III-IV were independently associated with reduced disease-specific survival. The relevance of molecular classification in high-grade tumors was demonstrated in Chapter 4. We investigated whether pure clear cell carcinoma (CCC) differs from mixed type CCC in terms of molecular, IHC markers and prognosis. In a retrospective cohort study of 43 patients
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