CHAPTER 1 12 curettage (D&C). Performing office-based endometrial sampling as a first-line diagnostic procedure is recommended. When histopathological findings are inconclusive to rule out cancer, hysteroscopic biopsy or D&C is recommended.5 The obtained tissue is subjected to histopathological evaluation including tumor typing and grading.6 Histology Historically, EC was subdivided into two histopathological subtypes, type 1 and type 2 EC (Figure 1). Type 1, comprising grade 1 and 2 endometrioid EC (EEC), is associated with high immunohistochemical (IHC) expression of estrogen receptor (ER) and a favorable prognosis. Type 2, comprising of grade 3 EEC and non-endometrioid EC (NEEC), generally shows low ER expression, mainly TP53 mutation and an unfavorable prognosis.7 Non-endometrioid histology includes most commonly serous and clear cell histology.8 Serous carcinoma has a poor prognosis with extra-uterine disease in 37% of EC patients.9 Uterine clear cell carcinoma (CCC) also often presents with extra-uterine disease (40-45%), has a high recurrence rate (50% at 3-years) and a 5-year overall survival of only 63%.8, 10 Besides pure also mixed EC occurs, being a tumor composed of two or more different histological types of EC, for example components of endometrioid, serous and/or clear cell histology.11 The mixed form of uterine CCC can display apart from clear cell, endometrioid and/or serous carcinoma histological components.12 It is questioned whether pure CCC presents with another molecular and IHC background compared to the mixed form of uterine CCC, and affecting clinical outcome. The most recent ESGO/ESTRO/ESP (European Society of Gynaecological Oncology/ European SocieTy for Radiotherapy and Oncology/European Society of Pathology guideline) and WHO (World Health Organization) Classification of Tumors, recommends a modified binary FIGO (Federation International of Gynecology and Obstetrics) grading, considering both FIGO grade 1 and 2 lumped as low-grade EC and FIGO grade 3 EEC, and NEEC as high-grade EC.6, 12, 13 Most patients (80%) are diagnosed with low-grade EC and an overall favorable prognosis with a 5-year survival rate of 85%. About 20% of the patients are diagnosed with high-grade EC, associated with increased risk of regional or distant metastases and have a poor prognosis with a 5-year survival rate of 58%.4 Numerous studies state that preoperative endometrial sampling is poorly to moderately correlated with final tumor grade and histological subtype.14-17 Within a meta-analysis, the lowest concordance was found for grade 2 EC (only 61.0%).17 Since the primary treatment of EC is mainly based on preoperative tumor histology, disagreement in grading between preoperative and final diagnosis may therefore result in either under- or overtreatment and subsequently impact outcome.18, 19 Currently, sampling errors and interobserver variability
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