Introduction/Background*Microcystic, elongated fragmented (MELF) pattern of myometrial invasion is a distinct histologic feature occasionally seen in low-grade endometrial carcinomas (EC). The prognostic relevance of the presence of MELF is uncertain due to conflicting data and has not appropriately been studied in the context of the novel molecular EC classification. We aimed to determine the relation of MELF pattern of invasion with clinicopathological and molecular characteristics, and define its prognostic relevance in early stage (high)intermediate risk EC.

Methodology Single haematoxylin and eosin (H&E) stained whole tumour slides of 929 of the 1141 early stage (high)intermediate risk EC of patients included in the post-operative radiation therapy in endometrial carcinoma (PORTEC)-1/-2 trials were available for review for the presence of MELF. Histological type, stage and grade, presence and extent of lymph-vascular-space-invasion (LVSI), molecular subclass, L1-cell-adhesion-molecule (L1CAM) overexpression, and β-catenin exon-3 (CTNNB1) and KRAS mutational status were compared between MELF-positive and negative cases. Differences in patient and tumour characteristics were analysed with chi-square or Fisher’s exact test for categorical and Mann-Whitney U test for continuous variables. Time-to-event analyses were done using the Kaplan-Meier method, log-rank tests and Cox’ proportional hazards models.

Result(s)*MELF pattern of invasion was identified in 129 (16%) cases, and was associated with grade 1-2 and deep myometrial invasion (table 1). MELF positive tumours were significantly more often found in the no-specific-molecular-profile (NSMP) subclass (n=95, 84.8%). Of these NSMP MELF positive tumours 91.1% were CTNNB1-wildtype (n=82) and 26.5% KRAS-mutated (n=22). Uncorrected survival analysis showed a significantly favourable impact of MELF on risk of recurrence (p=0.031). After correction for stage, grade, LVSI, molecular EC class, L1CAM and CTNNB1, MELF pattern of invasion did not significantly impact clinical outcome (HR 0.63 95%CI 0.28 – 1.41, p=0.26), table 2.

Conclusion*MELF-pattern of invasion was identified in 16% of early stage (high)intermediate risk EC, and had no independent prognostic impact. However, our results show that MELF pattern of invasion is more frequently found in NSMP KRAS-mutated EC without CTNNB1 mutations. These distinct molecular features could contribute to further refinement of the NSMP-subgroup of EC pointing to potential novel treatment targets.