Sonia Gatius

Molecular features for timely cancer diagnosis and treatment – tumors of the ovary, fallopian tube and endometrium

Gynecologic pathology has moved, within only a few years, from being a diagnostic area devoid of molecular testing into a diagnostic discipline in which such analyses are becoming routine. The direct relevance of molecular characterization to the choice of treatment of patients with carcinomas originating in both the uterus and adnexae makes it likely that such testing will only expand along with our understanding of the molecular make-up of these tumors. As a consequence, gynecologic pathologists have become an integral part of patient management, rather than lab personnel providing external services.In parallel, molecular testing is expanding as a tool for diagnosing rare tumors affecting these organs, including soft tissue tumors, sex cord-stromal tumors and germ cell tumors, as well as other rare entities. Increased knowledge in this area bears directly on the ability to diagnose these tumors in a reproducible manner, as well as recognize and consult on genetic diseases. Hopefully, despite the inherent difficulty in studying rare cancers, it will also translate into new therapeutic options for the malignant ones among these rare cancers.

EPM2 AIP1 immunohistochemistry as a surrogate of promoter methylation analysis in endometrial carcinoma

Abstract Mismatch repair (MMR) status in endometrial carcinoma (EC) is crucial for diagnosis, prognosis, treatment, and Lynch syndrome pre-screening. MLH1 loss is the most frequent cause of MMR deficiency and usually by promoter hypermethylation. We tried to confirm the role of EPM2 AIP1 immunohistochemistry as a surrogate of MLH1 promoter methylation in EC. Case series from two different institutions were analyzed by comparable methods using immunohistochemistry for MMR proteins and EPM2 AIP1, and pyrosequencing for MLH1 methylation. In the first series of 70 cases, concordance was 100%, after reassessing three cases with methylation scores close to cut-off, by tumor cell enrichment. In the second series of 29 MLH1-deficient ECs, concordance was 96.5%, while in the control group of 30 MMR-proficient EC, one MLH1-positive case was EPM2 AIP1-negative. EPM2 AIP1 immunoreactivity was qualitatively superior in curettages and biopsies compared to hysterectomy. We conclude that EPM2 AIP1 immunohistochemistry is a good surrogate for MLH1 promoter methylation analysis, cost-effective with short turnaround time, but needs attention regarding preanalytical handling, normal tissue contamination, or low tumor percentage.

The importance of the pseudocapsule in the management of uterine myoma: State of the art and expert recommendations

Abstract The pseudocapsule corresponds to specialized myometrium that surrounds and nourishes the fibroid. This entity has a neurovascular structure and particular fibrotic tissue and has gained recognition as a critical factor in the management of these prevalent tumors. This article provides a comprehensive review of the current understanding of the pseudocapsule's anatomy, function, and implications for clinical practice. By synthesizing current literature and considering expert opinions, this article emphasizes the need to incorporate the pseudocapsule into the clinical framework for uterine fibroids, ultimately aiming to improve patient care.

In Vivo Intra‐Uterine Delivery of TAT‐Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53‐Deficient Endometrial Cancers

AbstractPhosphatase and TENsin homolog (Pten) and p53 are two of the most frequently mutated tumor suppressor genes in endometrial cancer. However, the functional consequences and histopathological manifestation of concomitant p53 and Pten loss of function alterations in the development of endometrial cancer is still controversial. Here, it is demonstrated that simultaneous Pten and p53 deletion is sufficient to cause epithelial to mesenchymal transition phenotype in endometrial organoids. By a novel intravaginal delivery method using HIV1 trans‐activator of transcription cell penetrating peptide fused with a Cre recombinase protein (TAT‐Cre), local ablation of both p53 and Pten is achieved specifically in the uterus. These mice developed high‐grade endometrial carcinomas and a high percentage of uterine carcinosarcomas resembling those found in humans. To further demonstrate that carcinosarcomas arise from epithelium, double Pten/p53 deficient epithelial cells are mixed with wild type stromal and myometrial cells and subcutaneously transplanted to Scid mice. All xenotransplants resulted in the development of uterine carcinosarcomas displaying high nuclear pleomorphism and metastatic potential. Accordingly, in vivo CRISPR/Cas9 disruption of Pten and p53 also triggered the development of metastatic carcinosarcomas. The results unfadingly demonstrate that simultaneous deletion of p53 and Pten in endometrial epithelial cells is enough to trigger epithelial to mesenchymal transition that is consistently translated to the formation of uterine carcinosarcomas in vivo.