Insights from the Pre-Molecular Era in Advanced Endometrial Cancer: Benchmarking Prognostic Indicators in High-Risk Tumours

<b>Background/Objectives</b>: Although the binarism between type I and II endometrial cancer was dismissed and substituted with molecular classification, histopathological features remain of paramount importance. Hence, analysing survival outcomes according to histological type, our aim is to clarify whether the morphological features of the tumour retain prognostic relevance in the context of advanced disease. <b>Methods</b>: This is a retrospective analysis led within the Thames Valley Cancer Alliance Network. <b>Results</b>: We include 148 FIGO 2009 stage III-IV patients affected by endometrioid endometrial cancer (EEC) G1, G2, and G3, carcinosarcoma (CS), serous carcinoma (SC), and clear cell carcinoma (CCC) of the uterus. Five year overall survival (OS) is distinct among the histological groups (<i>p</i>-value < 0.001), being 73.3% for G2 endometrioid, 49.2% for G3 endometrioid, 8.3% for CS, and 28.4% for SC. The divergence was marked also for 5 year progression-free survival (PFS) (<i>p</i>-value < 0.001) as follows: for G2 endometrioid, was 76.4%; for G3 endometrioid, 52.7%; and for carcinosarcoma, 5.9%. PFS after 18 months for serous carcinoma was 5.7%. The multivariate analysis found G3 endometrioid (HR 2.91, 95% CI 1.20-7.11, <i>p</i>-value 0.018), carcinosarcoma (HR 12.15, 95% CI 5.07-29.11, <i>p</i>-value < 0.001), and serous carcinoma (HR 4.84, 95% CI 2.16-10.83, <i>p</i>-value < 0.001) as independent predictors of poor survival, as well as cervical invasion (HR 1.83, 95% CI 1.10-3.05, <i>p</i>-value 0.020) as the only histopathological feature confirmed. Regarding progression-free only carcinosarcoma (HR 14.91, 95% CI 5.28-41.11) and serous carcinoma (HR 17.68, 95% CI 6.41-48.75) were associated with an increased risk of recurrence. <b>Conclusions:</b> Our findings testify that, beyond the disease stage, histological subtype remains a major determinant of survival outcome. Cervical involvement is associated with a more aggressive disease, possibly correlated to death beyond relapse. Prospective trials involving advanced stage endometrial cancer, stratified by histological subtype and integrated with the molecular classification, are required.