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Histopathological evaluation including subtyping and grading is the current cornerstone for endometrial cancer (EC) classification. This provides clinicians with prognostic information and input for further treatment recommendations. Nonetheless, patients with histologically similar ECs may have very different outcomes, notably in patients with high‐grade endometrial carcinomas. For endometrial cancer, four molecular subgroups have undergone extensive studies in recent years: POLE ultramutated (POLEmut), mismatch repair‐deficient (MMRd), p53 mutant (p53abn) and those EC lacking any of these alterations, referred to as NSMP (non‐specific molecular profile). Several large studies confirm the prognostic relevance of these molecular subgroups. However, this 'histomolecular' approach has so far not been implemented in clinical routine. The ongoing PORTEC4a trial is the first clinical setting in which the added value of integrating molecular parameters in adjuvant treatment decisions will be determined. For diagnostics, the incorporation of the molecular parameters in EC classification will add a level of objectivity which will yield biologically more homogeneous subclasses. Here we illustrate how the management of individual EC patients may be impacted when applying the molecular EC classification. We describe our current approach to the integrated diagnoses of EC with a focus on scenarios with conflicting morphological and molecular findings. We also address several pitfalls accompanying the diagnostic implementation of molecular EC classification and give practical suggestions for diagnostic scenarios. [ABSTRACT FROM AUTHOR]

Simple Summary: HER2 testing in endometrial cancer (EC) has gained renewed interest as a therapeutic target. However, HER2 status has not been investigated in the context of the molecular EC classification. Here, we aimed to determine the clinicopathological features and prognostic significance of the HER2 status in the molecularly classified PORTEC-3 trial population of patients with high-risk EC. HER2 status of 407 high-risk EC was determined by HER2 immunohistochemistry and HER2 dual in situ hybridization. Twenty-four (5.9%) HER2-positive EC of various histological subtypes were identified, including serous (n = 9, 37.5%), endometrioid (n = 6, 25.0%), and clear cell (n = 5, 20.8%). HER2 positivity was highly associated with the p53-abnormal subgroup (p53abn, 23/24 cases; p < 0.0001). The correlation between p53abn and the HER2 status (ρ = 0.438; p < 0.0001) was significantly stronger (p < 0.0001) than between serous histology and the HER2 status (ρ = 0.154; p = 0.002). HER2 status did not have independent prognostic value for survival after correction for the molecular classification. Our study strongly suggests that molecular subclass-directed HER2 testing is superior to histotype-directed testing. HER2 status has not been investigated in the context of the molecular endometrial cancer (EC) classification. Here, we aimed to determine the clinicopathological features and prognostic significance of the HER2 status in the molecularly classified PORTEC-3 trial population of patients with high-risk EC (HREC). HER2 testing was performed on tumor tissues of 407 molecularly classified HREC. HER2 status was determined by HER2 immunohistochemistry (IHC; all cases) and subsequent HER2 dual in situ hybridization for cases with any (in) complete moderate to strong membranous HER2 IHC expression. The Χ2 test and Spearman's Rho correlation coefficient were used to compare clinicopathological and molecular features. The Kaplan–Meier method, log-rank test, and Cox proportional hazards models were used for survival analysis. We identified 24 (5.9%) HER2-positive EC of various histological subtypes including serous (n = 9, 37.5%), endometrioid (n = 6, 25.0%), and clear cell (n = 5, 20.8%). HER2 positivity was highly associated with the p53-abnormal subgroup (p53abn, 23/24 cases; p < 0.0001). The correlation between p53abn and the HER2 status (ρ = 0.438; p < 0.0001) was significantly stronger (p < 0.0001) than between serous histology and the HER2 status (ρ = 0.154; p = 0.002). HER2 status did not have independent prognostic value for survival after correction for the molecular classification. Our study strongly suggests that molecular subclass-directed HER2 testing is superior to histotype-directed testing. This insight will be relevant for future trials targeting HER2. [ABSTRACT FROM AUTHOR]