Evaluation of Microcystic, Elongated, and Fragmented (MELF) Invasion Pattern inEndometrioid Endometrial Carcinoma: Prognostic Parameters and ImmunohistochemicalProfile

Title: Evaluation of Microcystic, Elongated, and Fragmented (MELF) Invasion Pattern in Endometrioid Endometrial Carcinoma: Prognostic Parameters and Immunohistochemical Profile Abstract: Objective: In our study, we aimed to assess the prevalence of microcystic, elongated, and fragmented (MELF) invasion pattern in cases of endometrioid endometrial carcinoma, investigate its association with prognostic parameters such as tumor grade, pathological stage, lymphovascular invasion, lymph node metastasis, recurrence, and survival impact. Additionally, we explored the immunohistochemical profile according to the new integrated histomolecular classification. Materials and Methods: We reviewed the files of 560 women diagnosed with endometrioid adenocarcinoma who underwent total abdominal hysterectomy, bilateral salpingo- oophorectomy, omentectomy, pelvic, and paraaortic lymph node dissection at Başkent University Ankara Hospital between December 2011 and January 2023. Hematoxylin and eosin (H&E) stained slides of the cases were retrieved from the archives. Sections containing the tumor were re-evaluated for MELF invasion pattern, and 136 cases demonstrating MELF invasion were included in the study. Cases were categorized into "focal" and "widespread" groups based on the number of MELF foci, and both groups were evaluated for prognostic parameters such as tumor size, lymphovascular invasion, lymph node metastasis, depth of myometrial invasion, and endocervical involvement. Immunohistochemical staining for ER, PR, p53, MSH2, MSH6, MLH1, and PMS2 antibodies was also performed in both groups. Results: The study included 136 patients divided into two groups based on the prevalence of MELF invasion pattern. There were 53 patients in the focal MELF invasion group and 83 patients in the widespread MELF invasion group. The widespread MELF invasion group showed a significantly higher proportion of advanced stage and high-risk cases (p<0.001). Significant associations were found between the widespread MELF invasion group and tumor size (p=0.037), depth of myometrial invasion (p<0.001), endocervical involvement (p=0.029), and uterine serosal involvement (p=0.030). Lymph node metastasis (p=0.005) and the presence of macrometastasis (p=0.015) were significantly higher in the widespread MELF invasion group. Para-aortic lymph node metastasis was significantly associated with widespread MELF invasion (p=0.032). No significant relationship was found between lymphovascular invasion and MELF invasion (p=0.34). ER positivity was 92.4% in the focal MELF invasion group and 97.6% in the widespread MELF invasion group, with no significant difference between the two groups (p=0.155). PR positivity was 88.7% in the focal MELF invasion group and 97.6% in the widespread MELF invasion group, and a statistically significant association was observed between MELF prevalence and PR positivity (p=0.031). Additionally, a significant association was found between MELF prevalence and immunohistochemical mutant-type p53 expression (p=0.045). There was no statistically significant correlation between MELF prevalence and immunohistochemical expression of DNA mismatch repair (MMR) proteins, including MSH2, MSH6, MLH1, PMS2, and microsatellite status. Overall, MELF prevalence did not significantly impact overall and disease-free survival. Conclusion: Our study observed associations between widespread MELF invasion pattern and adverse prognostic parameters in endometrioid endometrial carcinoma. Furthermore, all cases with mutant-type p53 staining pattern were found in the widespread MELF invasion group. The study concludes that the prevalence of MELF invasion pattern does not significantly affect disease-free and overall survival. However, more extensive studies with a larger number of cases and long-term follow-ups, exploring all categories of molecular classification, are needed for definitive evaluations. We believe that our current study and future research in this field will shed light on the developments in the treatment and prognosis of endometrioid endometrial carcinomas demonstrating MELF invasion pattern.