Clinicopathologic association and prognostic impact of microcystic, elongated and fragmented pattern invasion, combined with tumor budding in endometrioid endometrial cancer

Abstract

Aim As a special invasive pattern seen in low‐grade endometrial carcinoma, microcystic, elongated and fragmented (MELF) pattern is related to lymph node metastasis. Tumor budding (TB) is another histological marker in many cancers associated with tumor aggressiveness. Herein, we evaluated the impact of MELF pattern combined with TB about clinicopathological features and prognosis in endometrioid endometrial cancer (EEC). To verify the relationship between the two morphological markers and microsatellite status in EEC, the primary mismatch repair (MMR) proteins were detected by immunohistochemistry. Methods One hundred and seventy‐two cases of ECC diagnosed between 2011 and 2016 were reviewed with a median follow up of 47.5 months. MELF pattern and TB were examined on all H&E‐stained slides. Primary MMR proteins (MLH1, MSH2, MSH6, and PMS2) were also detected. Results Based on MELF pattern and TB, 172 patients were divided into the following four groups: MELF(−)/TB(+) (n = 41), MELF(+)/TB(−) (n = 15), MELF(+)/TB(+) (n = 20), and MELF(−)/TB(−) (n = 96). Adverse pathological features were observed in the MELF(+)/TB(+) group: 70% presented deep muscular infiltration, 65% were lymphovascular space invasion, and 25% suffered lymph node metastasis. The proportion of MMR deficient in MELF(+)/TB(−) group was the highest (66.7%). The progression‐free survival (PFS) and overall survival (OS) among the four groups were significantly different. MELF(+)/TB(+) group showed the worst PFS and OS. As univariate and multivariate survival analyses revealed, the combination of MELF pattern and TB was confirmed as an independent predictor of poor prognosis. Conclusions Our research demonstrates that MELF pattern combined with TB, as an independent predictor of adverse outcome, is associated with adverse pathological features, which facilitates better understanding of EEC tumor behavior and more precise prognosis without additional medical expense.

Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients

“…These results are in line with previous publications reporting inferior outcomes for tumors with high TB compared to tumors with low TB for several tumor entities like colorectal adenocarcinomas, head and neck squamous cell carcinomas and non-small cell lung cancer [17]. Up to date, there are only a few publications reporting inferior outcomes of patients with high TB in endometrial cancer [19,20]. In general, TB is supposed to be associated with at least partial epithelial to mesenchymal transition (EMT), causing cancer invasion and leading to lymph node metastases and distant metastases [44].…”

“…As Qi. et al [20] previously proposed a grading system including MELF and TB, we included these parameters (TB and MELF) in a subsequent multivariate analysis to probe their independent impact in a Cox regression model. Here, only TB was shown to be an independent variable (HR: 12.19, p < 0.001, Supplementary Table S6).…”

“…The prognostic relevance of TB could be shown, e.g., in colorectal cancer, lung cancer and head and neck cancer [17]. For endometrial cancer, so far, only a few studies have evaluated TB (reviewed in [18]); however, those studies differed regarding the cutoffs applied for scoring TB [19,20]. Furthermore, while Qi et al analyzed a grading scheme composed of TB and the "microcystic, elongated, fragmented" (MELF) pattern and obtained the worst outcomes for patients whose tumors show both TB and MELF; analysis was conducted irrespective of TCGA-defined molecular subgroups [20].…”

Clinical-grade endometrial cancer detection system via whole-slide images using deep learning

“…The deep learning model successfully flagged these subtle regions, alerting pathologists to re-examine the case. MELF invasion was an independent prognostic factor closely related to the risk of lymph node metastasis ( 28 ), indicating poor prognosis. Omitting deep muscular infiltration leads to a lower stage (from IA2 to IA1).…”

Microcystic Elongated and Fragmented Pattern Invasion in Endometrial Cancer: Possible Prognostic Value to Precise and Individualized Therapeutic Strategies

“…Recently, Qi et al 2 demonstrated that the combination of MELF and tumor budding is a histological marker associated with tumor aggressiveness and can be an independent predictor of adverse outcomes. Moreover, Tahara et al 3 reported a strong expression of programed death-ligand 1 (PD-L1) in the invasive front of the MELF pattern and concluded that programed cell death protein 1/PD-L1 immunotherapy demonstrated significant therapeutic effect on the management of patients with endometrial cancer and grade 1 MELF.…”