Microcystic, elongated, and fragmented (MELF) pattern of myometrial invasion in grade 1–2 endometrioid endometrial carcinoma: clinicopathological associations, molecular profile, and prognostic significance under FIGO 2023 staging

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Background: The microcystic, elongated, and fragmented (MELF) pattern of myometrial invasion is a morphological feature of endometrioid endometrial carcinoma (EEC) with debated prognostic significance. Most prior studies evaluated MELF across heterogeneous histologic grades and predate the FIGO 2023 staging system. We assessed MELF prevalence in a uniform Grade 1-2 EEC cohort and its clinicopathological, molecular, and survival associations. Methods: We retrospectively reviewed 112 patients with Grade 1-2 EEC surgically treated at a tertiary center (2015-2023). MELF status was determined by pathology re-review, and molecular profiling used immunohistochemistry (IHC) for mismatch repair (MMR) proteins, p53, and hormone receptors. Associations were assessed with Fisher's exact and Mann-Whitney U tests; survival was analyzed by Kaplan-Meier, log-rank, and Cox regression with Firth penalization. Results: MELF was identified in 43/112 patients (38.4%). MELF-positive tumors were significantly associated with deep myometrial invasion (65.1% vs. 24.6%; OR 5.71, 95% CI 2.44-13.35), lymphovascular space invasion (LVSI: 58.1% vs. 11.6%; OR 10.59, 95% CI 4.01-27.95), cervical stromal invasion (32.6% vs. 10.1%; OR 4.28, 95% CI 1.55-11.82; all p ≤ 0.005), and larger tumor size (median 3.7 vs. 3.0 cm; p=0.015). MELF was not associated with deficient mismatch repair (OR 1.48, p=0.39) or p53 mutant-type expression (OR 0.96, p=1.00). At a median follow-up of 54.5 months (9 deaths), MELF-positive patients showed numerically worse overall survival that did not reach statistical significance (log-rank p=0.059). On Firth-penalized Cox regression, deep myometrial invasion was the only significant univariate predictor (HR 7.12, p=0.036); the MELF survival signal attenuated to near-unity when depth of invasion was added. Conclusions: In Grade 1-2 EEC, MELF is a frequent pattern (38.4%) that reliably flags aggressive local invasion, including cervical stromal invasion relevant to FIGO 2023 upstaging. Its survival association was largely shared with depth of myometrial invasion rather than independent of it; MELF is therefore best regarded as a morphological marker of an aggressive phenotype rather than an independent prognostic factor. Being independent of mismatch repair and p53 status, MELF may aid risk assessment within the presumed no-specific-molecular-profile (NSMP-like) subgroup. Routine pathological reporting of MELF can prompt assessment of depth of invasion and high-risk features.

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