Abstract
The invasive tumor front (the tumor–host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.
Highlights
Uterine endometrial adenocarcinoma is the fourth most common cancer among women in the Western world, with an estimated incidence of 10–20 per 100,000 women
We found a high degree of similarity between the 5 × 4 mm region of interest (ROI) of Uterine endometrial adenocarcinoma (uADC) and Uterine leiomyosarcoma (uLMS) invasive tumor front (ITF) (Figures 1A,B); the only significant differences observed in the cases studied were in area size and deformity of the individual or meshwork fibers
Large uADC ROIs with reticular fibers occupying a higher proportion of stained area than uLMS were detected
Summary
Uterine endometrial adenocarcinoma (uADC) is the fourth most common cancer among women in the Western world, with an estimated incidence of 10–20 per 100,000 women. The World Health Organization (WHO) tumor classification distinguishes several histopathological types of uADC, based on microscopic appearance (Cree et al, 2020): (1) endometrioid carcinoma, low grade (grades I–II) or high grade (grade III), (2) serous carcinoma, (3) clear cell carcinoma, (4) mixed carcinoma, (5) undifferentiated carcinoma, (6) carcinosarcoma, (7) neuroendocrine carcinomas, and (8) other unusual types These types have different histological and molecular features, precursor lesions, and natural history (Matias-guiu et al, 2001; Yeramian et al, 2013). They are stratified by Tumor Cancer Genome Atlas (TCGA)-based molecular classification into four risk groups combining gene encoding DNA polymerase ε (POLE) mutational analysis with IHC analysis of p53 and mismatch repair (MMR) proteins (PMS-2 and MSH-6) (Getz et al, 2013). This provides additional prognostic information to complement the microscopic features
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