GENERAL DISCUSSION 183 8 DISCUSSION In this thesis, the aim was to evaluate the prognostic relevance of histomorphology, immunohistochemical (IHC) and clinical biomarkers within the new era of molecular profiling in endometrial cancer (EC). In this general discussion the main findings and clinical relevance of the different studies are presented. Furthermore, a clinical decision tool for primary treatment is proposed optimizing the use of biomarkers beholding current histomorphology, decreasing diagnostic costs and further improving prognostication of EC patients. Diagnosis of endometrial cancer EC is commonly diagnosed by endometrial sampling (pipelle biopsy, hysteroscopic biopsy or dilatation and curettage (D&C). Previous studies indicated that preoperative diagnoses based on endometrial sampling is only moderately (≤67%) correlated with final tumor grade and histological subtype.1-4 The lowest concordance was found for grade 2 EC (61.0%).4 Explanations for discordance on histological diagnosis include 1) the limited amount of tissue obtained by preoperative endometrial sampling 2) sampling errors leading to missed tumor components, 3) interobserver disagreement due to subjective interpretation of defined criteria. In chapter 2 it is shown, that the amount of preoperative endometrial tissue surface is not related to the degree of concordance with final classification in low- and high-grade EC, based on retrospective analysis of a large study cohort. Interestingly, concordant diagnoses revealed a significant lower median endometrial tissue surface compared to discordant diagnoses. Even the sampling method (pipelle biopsy, hysteroscopic biopsy or D&C) did not influence the degree of concordance between pre- and postoperative diagnoses. Therefore, sampling errors that occur due to heterogeneous and/or mixed tumors or sampling of only superficial tumor tissue, will remain and cannot be resolved by the use of a different sampling method. Based on the study of Mota et al. genetic analysis out of pipelle biopsy material (uterine aspirates) might be a solution, even in samples that are not histologically classifiable. With this approach tumor heterogeneity might be captured as well.5 In some cases discordance of grading can be caused by a misjudgment of the percentage solid growth or a missed tumor component. Unintentional misjudgment by the pathologist, including interobserver disagreement, may be reduced by the binary grading classification and/or the additional use of immunohistochemical (IHC) or molecular biomarkers. The use of a binary grading system (low- vs. high-grade EC) is preferred by the most recent ESGO/ESTRO/ ESP (European Society of Gynaecological Oncology / European SocieTy for Radiotherapy and Oncology / European Society of Pathology) guideline and World Health organization (WHO) classification of Female Genital tumors over the FIGO (International Federation of Gynecology and Obstetrics) three-tiered grading system with respect to reproducibility.4, 6-8
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