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The aim of this study is to assess the clinical reproducibility and the potential oncological validity of the molecular information provided by the immunohistochemistry (IHC) to properly stratify the endometrial cancer patients. Retrospective IHC analyses were conducted in a large series of 778 pre-operative uterine-confined ECs, studying the presence/absence of MLH1, MSH2, MSH6 and PMS2 to define the mismatch repair (MMR) stable or instable phenotype; the presence of p53 mutations and other molecular features. The molecular profile was correlated with histological, clinical and prognostic data. Based on IHC assessment , we defined 3 EC populations: stable MMR patients (MMRs), instable patients (MMRi) and p53 mutated patients (p53+). Our result demonstrated that the IHC stratification statistically correlated with the most relevant pathologic-clinical features: FIGO stage (p < 0.001), grading (p < 0.001), histotype (p < 0.001), presence of LVSI (p < 0.001), myometrial invasion and tumor dimension (p = 0.003 for both). These 3 IHC populations statistically reflected the EC risk class ESGO-ESMO-ESP classification 2021 (p < 0.001). These results were also confirmed in the Kaplan-Meier curves in terms of overall survival (OS) and disease-free survival (DFS) (p < 0.0001). The multivariate analyses demonstrated that absence of estrogen receptor (ER) impacted the OS (p = 0.011) and, the Age > 60 years and the ER-status the DFS (p = 0.041 and p = 0.004). In this large series , we demonstrated that the pragmatic and systematic use of IHC may have an important role to properly stratify, in terms of histological features and clinical outcomes, the EC patients. • The aim of the study is to assess the oncological validity of IHC to properly stratify the endometrial cancer patients (EC). • The IHC statistically stratifies EC patients according to the most relevant pathologic-clinical and survival outcomes. • The systematic use of IHC properly stratifies, in terms of histological features and clinical outcomes, the EC patients. [ABSTRACT FROM AUTHOR]

The 2020 ESGO/ESTRO/ESP guidelines stratify the prognosis of endometrial carcinoma (EC) patients combining The Cancer Genome ATLAS (TCGA) molecular signature and pathological factors, including lymphovascular space invasion (LVSI). However, little is known about the prognostic independence of LVSI from molecular signature. To assess whether the prognostic value of LVSI is independent from the TCGA signature. A systematic review and meta-analysis was performed by searching 5 electronic databases from their inception to March 2021. All peer-reviewed studies reporting assessing LVSI as a prognostic factor independent from the TCGA groups in EC were included. Multivariate HRs with 95% confidence interval (CI) were pooled separately for overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS). The absence of LVSI was considered as a reference. In DFS analyses, locoregional and distant recurrence were separately considered for one study. Six studies with 3331 patients were included in the systematic review and three studies with 2276 patients in the meta-analysis. LVSI showed a pooled multivariate HR of 1.818 (CI 95%, 1.378–2.399) for OS, 1.849 (CI 95%, 1.194–2.863) for DSS, 1.377 (CI 95%, 1.008–1.880) for DFS excluding one study, 1.651 (CI 95%, 1.044–2.611) for DFS additionally considering locoregional recurrence from one study, and 1.684 (CI 95%, 1.05–2.701) for DFS additionally considering distant recurrence from the same study. LVSI has a prognostic value independent of TCGA signature, as well as age and adjuvant treatment, increasing the risk of death of any cause, death due to EC and recurrent or progressive disease by 1.5–2 times. • The 2020 ESGO/ESTRO/ESP guidelines stratify EC prognosis combining TCGA signature and pathological factors, including LVSI. • However, little is known about prognostic independence of LVSI from TCGA signature. • We aimed to assess whether the prognostic value of LVSI is independent from the TCGA signature. • LVSI has a prognostic value independent of TCGA signature, as well as age and adjuvant treatment. • LVSI increases the risk of death of any cause, death due to EC and recurrent or progressive disease by 1.5–2 times. [ABSTRACT FROM AUTHOR]

Ovarian endometrioid carcinoma (OEC) shares morphological and molecular features with endometrial endometrioid carcinoma (EEC). Several studies assessed the four TCGA groups of EEC, i.e. POLE-mutated (POLEmut), mismatch repair-deficient (MMRd), no specific molecular profile (NSMP) and p53-abnormal (p53abn), in OEC; however, it is unclear whether the TCGA groups have the same distribution and clinicopathological features between OEC and EEC. To assess the distribution and clinicopathological features of the TCGA groups in OEC. A systematic review and meta-analysis was carried out by searching 7 electronic databases from January 2013 to April 2021 for studies assessing the TCGA classification in OEC. Prevalence of each TCGA group in OEC and of FIGO grade 3 and stage>I was pooled using a random-effect model. Prevalence of TCGA groups was compared between OEC and EEC, extracting EEC data from a previous meta-analysis. Kaplan-Meier and Cox regression survival analyses were performed for progression-free survival (PFS). A significant p -value<0.05 was adopted. Four studies with 785 patients were included. The frequency of the TCGA groups in OEC vs EEC was: POLEmut = 5% vs 7.6% (p = 0.594); MMRd = 14.6% vs 29.2% (p < 0.001); p53abn = 14% vs 7.8% (p = 0.097); NSMP = 66.4% vs 55.4% (p = 0.002). The pooled prevalence of FIGO grade 3 was: POLEmut = 19.2%; MMRd = 18.3%; p53abn = 38.1%; NSMP = 14.5%. The pooled prevalence of FIGO stage >I was: POLEmut = 31.6%; MMRd = 42.8%; p53abn = 48.5%; NSMP = 24.6%. Two-, 5- and 10-year PFS was: POLEmut = 100%, 100%, and 100%; MMRd = 89.1%, 82.2% and 73.3%; p53abn = 61.7%, 50.2% and 39.6%; NSMP = 87.7%, 79.6% and 65.5%. The hazard ratio for disease progression (reference = NSMP) was: POLEmut = not estimable (no events); MMRd = 0.825 (p = 0.626); p53abn = 2.786 (p = 0.001). The prognostic value of the TCGA groups was similar between OEC and EEC, despite the differences in the frequency and pathological features of each group. • The TCGA groups differ in distribution and pathological features between ovarian and endometrial endometrioid carcinoma. • The prognostic value of the TCGA groups appears similar between ovarian and endometrial endometrioid carcinoma. • The TCGA groups might be used to guide the management of ovarian endometrioid carcinoma. [ABSTRACT FROM AUTHOR]

In the ESGO/ESTRO/ESP guidelines for endometrial carcinoma management, the risk category of clear cell carcinoma (CCC) is not well defined. In fact, while p53-abnormal (p53abn) CCC are known to be aggressive, the prognosis of mismatch repair-deficient (MMRd) and p53-wild-type (p53wt) CCCs is less clear. To assess the prognostic value of the MMRd and p53wt groups in CCC through a systematic review and meta-analysis. Electronic databases were searched from their inception to February 2021. All studies reporting p53 expression, MMR proteins expression and survival outcomes in endometrial CCC (either pure or mixed) were included. Kaplan-Meier and Cox regression survival analyses with hazard ratio (HR) for overall survival (OS) were performed by using the p53abn group as reference; a significant p -value<0.05 was adopted. Six studies with 136 CCC (114 pure and 22 mixed) were included. Five-year OS was 95.7 ± 4.3% in the MMRd group, 48.4 ± 8.4% months in the p53wt group and 40.6 ± 10.4% in the p53abn group. The hazard of death was significantly lower in the MMRd group than in the p53abn group (HR = 0.062; p = 0.007), while it did not significantly differ between the p53wt and the p53abn group (HR = 0.673; p = 0.222). The POLEmut group could not be analyzed due to the absence of deaths. Similar results were observed in the pure CCC and mixed CCC subgroups. MMRd CCCs seem to have a favorable prognosis and might be lumped together with MMRd endometrioid carcinoma for management purpose. On the other hand, p53wt CCCs appear prognostically more similar to p53abn CCCs. • The prognosis of mismatch repair-deficient (MMRd) and p53-wild-type (p53wt) clear cell carcinoma (CCC) is not well defined • We aimed to assess the prognostic value of the MMRd and p53wt groups in CCC • This may be the first systematic review and meta-analysis assessing the prognostic value of the TCGA groups in endometrial CCC • MMRd CCCs have a favorable prognosis and might be lumped together with MMRd endometrioid carcinoma for management purpose • P53wt CCCs appear prognostically more similar to p53abn CCCs. with a 5-year overall survival <50% [ABSTRACT FROM AUTHOR]