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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]

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]

2021 ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma (EC) encourage molecular classification and propose a new prognostic risk stratification based on both pathologic and molecular features. Although deep myometrial invasion (DMI) has been considered as a crucial risk factor in EC, it is unclear if its prognostic value is independent from The Cancer Genome ATLAS (TCGA) groups. To assess if the prognostic value of DMI is independent from the TCGA groups in EC patients. A systematic review and meta-analysis was performed by searching through 5 electronic databases, from their inception to March 2021, for all studies that allowed to assess DMI as a prognostic factor independent of the TCGA groups in EC patients. Pooled hazard ratio (HR) of DMI for overall survival (OS) and disease-free survival (DFS) was calculated at multivariable analyses including TCGA groups as a variable. Superficial myometrial invasion (<50% of myometrial thickness) was considered as a reference. In DFS analyses, locoregional and distant recurrence were separately considered for one study. Five studies with 2469 patients were included in the systematic review and 3 studies with 1549 patients in the meta-analysis. Pooled HR of DMI was 1.082 (CI 95% 0.85–1.377; p = 0.524) for OS, 1.709 (CI 95% 1.173–2.491; p = 0.005) for DFS, 1.585 (CI 95% 1.154–2.178; p = 0.004) for DFS additionally considering locoregional recurrence for one study, and 1.701 (CI 95% 1.235–2.344, p = 0.001) for DFS additionally considering distant recurrence for the same study. DMI does not appear as an independent prognostic factor for OS in EC patients; instead, it seems to affect the risk of recurrence independently from the TCGA groups. Further studies are necessary to confirm these findings and to assess the prognostic impact of DMI separately in each TCGA group. • Deep myometrial invasion (DMI) has been considered as a crucial risk factor in endometrial carcinoma (EC). • It is unclear if DMI prognostic value is independent from TCGA molecular groups. • This may be the first systematic review and meta-analysis in the field. • DMI does not appear as an independent prognostic factor for overall survival in EC patients. • DMI seems to affect the risk of recurrence independently from the TCGA groups. [ABSTRACT FROM AUTHOR]