PURE AND MIXED CLEAR CELL CARCINOMA 79 4 INTRODUCTION Endometrial carcinoma (EC) is the fourth leading cancer in female patients in Europe, with 121 600 new cases and 29 600 deaths in 2018 1. The most common histological type of EC is endometrioid endometrial carcinoma (EEC), which accounts for 80% of all cases and generally shows a favorable prognosis 2. Less than 5% of EC consists of uterine clear cell carcinoma (CCC), an aggressive subtype of non-endometrioid endometrial carcinoma (NEEC) 3-5. Uterine CCC is frequently diagnosed in older, postmenopausal women, with 4045% presenting with extra-uterine disease 6, 7. The 5-year overall survival is 63%, compared to 83% in the EEC population 8. The Society of Gynecologic Oncology recommends comprehensive surgical staging and the use of adjuvant radiotherapy and/or chemotherapy for patients with uterine CCC, given the high incidence of recurrence 9, 10. In addition to pure clear cell histology, it is not uncommon for uterine CCC to display other histological components. These so-called mixed uterine CCCs usually show an additional component of endometrioid or serous carcinoma 11. In serous EC, it is known that carcinomas with mixed histology have a significantly better prognosis than patients with serous histology only 12. Whether mixed uterine CCCs display a better clinical outcome than pure uterine CCCs remains unclear. Major advances in characterization of the molecular background of ECs have been made in recent years 13. The Cancer Genome Atlas (TCGA) has defined four distinct molecular subtypes each with prognostic relevance. These molecular subtypes have been modified for clinical use by, amongst others, the Proactive Molecular Risk classifier for Endometrial Cancer (ProMisE) classification 14, 15. Molecular profiling has demonstrated to be supportive in high grade EC, yet for CCC, data are limited. Molecular subtypes in EC include an “ultramutated” subgroup with mutations in the exonuclease domain of polymerase-ε (POLE) and an excellent prognosis; a “hypermutated” subgroup with microsatellite instability (MSI); a “copy-number high” subgroup characterized by TP53 mutations and generally unfavorable outcome; and the copy number-low subgroup 13. Recent studies have shown that pure uterine CCC is a molecularly heterogeneous disease which encompasses different molecular subtypes 16-20. Due to this heterogeneous molecular background, clinical behavior and prognosis of uterine CCC may be more varied than generally thought, which could have consequences for the extent of (adjuvant) therapy. The primary aim of this study was to identify and compare the molecular and immunohistochemical (IHC) background of pure and mixed uterine CCC. The secondary aim was to evaluate whether histological classification, molecular and IHC features affect clinical outcome.
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