Maria Consiglia Giuliano

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.

MIRaGE (Minimally Invasive suRGery in recurrent Endometrial cancer)

Endometrial cancer is one of the most common gynecologic malignancies. Recurrence occurs in 10% to 15% of early-stage and up to 70% of advanced-stage cases. Secondary cytoreductive surgery is critical when complete gross resection is achievable. Minimally invasive surgery may offer perioperative advantages, but data on patient selection and oncologic outcomes are limited. This retrospective study included patients with first abdominal recurrence of endometrial cancer who underwent secondary cytoreductive surgery at Fondazione Policlinico Universitario A. Gemelli IRCCS between 2010 and 2023. Patients were grouped by surgical approach (minimally invasive surgery [MIS]: laparoscopy/robotic-assisted vs open surgery). The primary endpoint was the identification of clinical and radiological preoperative predictors of successful MIS, defined as complete gross resection. Secondary endpoints included intraoperative and perioperative outcomes, and survival outcomes (overall survival and progression-free survival). Among 192 patients with abdominal recurrence, 74 (38.5%) underwent MIS. The 2 groups were not fully homogeneous, differing mainly in relapse site and recurrence pattern; nevertheless, complete gross resection was achieved in 97.3% of minimally invasive procedures and 94.9% of open surgeries (p = .42). Minimally invasive surgery was associated with lower blood loss (p < .001), fewer transfusions (p = .030), shorter operative times (p < .001), and reduced hospital stays (p < .001). Independent predictors of successful MIS were body mass index ≥30, early-stage disease, single-site relapse, and loco-regional or lymph-node recurrence. No significant differences were observed in survival outcomes, with comparable overall survival (p = .47) and progression-free survival (p = .43) between groups. Minimally invasive surgery may represent a feasible option for selected patients with recurrent endometrial cancer, providing perioperative advantages with comparable survival outcomes. Prospective multicenter studies are needed to confirm oncologic safety and to refine patient selection, also in the context of integration with novel therapies.

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.

Exploring isolated tumor cells entity in endometrial cancer

Endometrial cancer (EC) management includes nodal staging and molecular classification. Despite molecular advancements, the biological significance of isolated tumor cells (ITC) in EC remains unclear. This study aimed to characterize ITC in the context of pathological and molecular features MATERIALS AND METHODS: A multicenter, retrospective analysis included EC patients diagnosed between June 2018 and May 2024 who underwent surgical staging via sentinel lymph node (SLN) biopsy and molecular profiling. ITC cases detected through SLN ultrastaging or One Step Nucleic Acid Amplification (OSNA) were compared with N0 and N + (micro-/macrometastasis) groups. Among the 1821 patients included, nodal status was N0 in 84.5 %, ITC in 5.1 %, micrometastases in 5.3 %, and macrometastases in 4.5 %. ITC patients exhibited deep myometrial invasion in 67.7 % of cases vs. 28.7 % in N0 (p < 0.001). Diffuse lymphovascular space invasion (LVSI) was significantly higher in ITC (52.1 %) than N0 (12.2 %, p < 0.001). MMR deficiency was more frequent in ITC (33.3 %) vs. N0 (25.0 %, p = 0.07). POLE mutations were more common in N0 (4.2 %) and ITC (3.1 %) vs. N + (1.1 %), though not statistically significant. p53-abnormal tumors were significantly associated with N + status (19.4 %) compared to ITC (7.3 %, OR 0.33, p = 0.008). No relapses occurred among ITC patients with low-risk features. These findings suggest that ITC may represent an early form of nodal involvement, biologically distinct from micro- and macrometastases. The association with MMR deficiency and the absence of aggressive markers such as p53 abnormalities support a less aggressive profile. Integrating molecular and pathological features may refine risk stratification and inform management strategies for EC patients with ITC.