Giovanni Esposito

Focal lymphovascular space invasion: Friend or foe? A large retrospective analysis on stage I endometrioid endometrial carcinomas

Literature is inconsistent with respect to clinical value of lymphovascular space invasion (LVSI) semiquantitative assessment. We aim to investigate the prognostic role of LVSI extent in stage I endometrioid endometrial carcinomas (ECs) classified by immunohistochemistry (IHC) analysis. Patients with stage I endometrioid EC undergone primary surgery were retrospectively included. Following World Health Organization definition for LVSI pathologic evaluation, subjects were divided into: LVSI-negative; LVSI-focal; LVSI-substantial. An IHC-based model was utilized to classify patients into: p53-aberrant (p53abn); mismatch repair deficient (MMRd); mismatch repair proficient with positive estrogen receptors (MMRp-ERpos); and mismatch repair proficient with negative estrogen receptors (MMRp-ERneg). 2091 subjects were included and divided into: 78.0 % (n:1631) LVSI-negative, 10.6 % (n:221) LVSI-focal, and 11.4 % (n:239) LVSI-substantial. Presence of LVSI (any extent) was associated with older age, larger tumor size and deeper myometrial infiltration. Patients with LVSI-substantial presented with higher incidence of grade 3 tumors, p53abn and MMRd status. Conversely, most LVSI-negative and LVSI-focal cases were MMRp-ERpos. At multivariable regression, LVSI-substantial was independently associated with reduced 5-year disease-free survival (DFS) and overall-survival (OS). LVSI-negative and LVSI-focal groups had similar DFS (p = 0.42) and OS (p = 0.09), whereas comparison with LVSI-substantial demonstrated significantly poorer outcomes for patients with substantial invasion. These findings were confirmed in sub-analyses of cases with grade 1-2 endometrioid and myometrial infiltration, and in the MMRp-ERpos cohort. In stage I endometrioid ECs, LVSI-focal was not associated with reduced oncologic outcomes compared to LVSI-negative. In contrast, LVSI-substantial was associated with aggressive clinicopathologic and molecular features and behaved as an independent prognostic factor for reduced survival. Our results were further confirmed in two low-risk EC settings: grade 1-2 with myometrial infiltration, and the MMRp-ERpos group.

Are all mismatch repair deficient endometrial cancers created equal? A large, retrospective, tertiary center experience

One third of endometrial carcinomas (ECs) presents with mismatch repair deficiency (MMRd). Of these, 70 % are caused by somatic hypermethylation of MLH1 promoter; the remaining cases are determined by Lynch syndrome or double somatic inactivation of MMR genes. Although associated with good-intermediate prognosis, heterogeneity in treatment response and survival has been reported among MMRd ECs. We aim to investigate differences in pathologic aggressiveness and event-free survival (EFS) among three MMRd EC subtypes, classified by immunohistochemistry (IHC) and MLH1 methylation analysis. Subjects undergone surgical staging for EC were retrospectively included. IHC analysis was performed in all patients to assess MMR and p53 status. Methylation analysis was performed in MMRd patients with IHC-negative MLH1. The MMRd population was classified into: 1)MLH1-hypermethylated (MLH1-HyMet); 2)MLH1-unmethylated (MLH1-UnMet); 3)IHC-negative MSH2 and/or MSH6 or PMS2 alone (non-MLH1). Of 1171 patients undergoing surgical staging and IHC assessment, 362 (30.9 %) were classified as MMRd and included in the analysis. Among these, 59.7 % (n = 216) were MLH1-HyMet, 11 % (n = 40) MLH1-UnMet, and 29.3 % (n = 106) non-MLH1. Compared to MLH1-UnMet and non-MLH1, MLH1-HyMet was associated with older age, higher BMI, larger tumor size, deeper myometrial invasion, substantial lymphovascular space invasion, lower frequency of early-stage and low-risk disease. EFS was similar when comparing the MMRd subtypes, even after adjusting for stage and tumor histology. However, a trend of MLH1-HyMet toward poorer prognosis can be observed, particularly in the advanced/metastatic setting. MLH1-hypermethylated MMRd ECs display more aggressive clinicopathologic features compared to the other MMRd subgroups. However, although a suggestive trend toward poorer EFS was observed in the hypermethylated subset, particularly in the advanced setting, no significant differences in prognosis were detected among the MMRd subtypes.

Impact of surgery and molecular classification in stage IV endometrial cancer

Evidence supporting the role of surgery after neoadjuvant chemotherapy in advanced endometrial cancer remains limited. Additionally, the prognostic relevance of molecular classification in this setting is poorly defined. We aimed to evaluate overall survival in patients with peritoneal and/or extra-abdominal spread, focusing on surgical approach and molecular sub-type. We retrospectively analyzed all patients with Fédération Internationale de Gynécologie et d'Obstétrique 2009 stage IVB (Fédération Internationale de Gynécologie et d'Obstétrique 2023 IIIB2, IVB, IVC) endometrial cancer treated between January 2012 and September 2023. Patients were stratified according to immunohistochemistry-based molecular classification, intra-abdominal disease extension, and treatment strategy. Kaplan-Meier and Cox regression analyses were used to assess overall survival. Differences across groups were evaluated using appropriate nonparametric and categorical statistical tests. Among 363 eligible patients, 229 (63.1%) underwent primary cytoreduction, 52 (14.3%) had interval debulking surgery, 55 (15.2%) received chemotherapy alone, and 27 (7.4%) were untreated. Patients receiving neoadjuvant or exclusive chemotherapy more frequently had extra-abdominal (p < .001) and upper abdominal disease (p < .001). In patients with extra-pelvic disease, overall survival was comparable between primary and interval surgery (p = .82). Among those treated with neoadjuvant treatment, surgical cytoreduction was strongly associated with improved overall survival (p < .001). Mismatch repair-deficient patients had better overall survival than those with p53 abnormal tumors (34 vs 21 months, p = .026). No specific molecular profile-estrogen receptor positive tumors showed longer overall survival than both p53 abnormal and no specific molecular profile-estrogen receptor negative sub-types (60 vs 34 and 21 months, p = .018 and p = .041, respectively). In multivariate analysis, extra-pelvic disease (p = .042) and exclusive chemotherapy (p < .0001) were independent negative prognostic factors. In advanced endometrial cancer, surgery remains a key component of management. Our findings suggest a potential survival advantage for patients who undergo surgery-either as primary treatment or following neoadjuvant chemotherapy-compared to those treated with chemotherapy alone. Molecular classification may offer prognostic insight even in stage IV disease, although further validation is required. These findings provide a benchmark for future studies in the evolving landscape of immunotherapy and personalized treatment.

ENDOESTRO score: Where is the dark side? Evaluation of estrogen receptor expression cutoff in endometrial cancer molecular classification, an ambispective study

Estrogen receptor (ER) expression has prognostic value in endometrial cancer (EC), also in the context of molecular classification. However, a standardized cutoff to define ER positivity is lacking. To identify the ER expression cutoff that best correlates with survival outcomes overall and within each molecular subgroup. We conducted an ambispective study comprising a retrospective phase (Feb 2017-Feb 2022) and a prospective phase (Mar 2022-Jan 2024), including patients with EC who underwent surgery at our institution. In the retrospective cohort, molecular subgroups were defined by immunohistochemistry (IHC): 1) MMRp Among 2084 patients, ER < 10 % was the strongest cutoff for prognosis based on disease-free survival (DFS). Patients with ER < 10 % and < 1 % shared similar unfavorable clinicopathological and molecular features, while ER ≥ 10 % was associated with more favorable profiles. ER < 10 % was an independent adverse prognostic factor in uni- and multivariate analyses for DFS and overall survival, particularly in MMRp ER < 10 % expression is a robust prognostic indicator, associated with worse outcomes and may serve as a clinically meaningful cutoff in endometrial cancer risk stratification. Further prospective validation is warranted.