Nicoletta D’Alessandris

Interobserver Agreement in Immunohistochemical Evaluation of Folate Receptor Alpha (FRα) in Ovarian Cancer: A Multicentre Study

Folate receptor alpha (FRα) is a high-affinity folate transporter overexpressed in various epithelial malignancies, particularly high-grade serous ovarian carcinoma. Given its restricted expression in normal tissues and accessibility in tumors, FRα is an emerging therapeutic target. Immunohistochemistry (IHC) is the standard method for FRα assessment; however, interpretation is semi-quantitative and prone to interobserver variability. This study aimed to evaluate interobserver agreement among 12 pathologists in the IHC assessment of FRα in ovarian cancer, focusing on internal control adequacy, staining intensity, and the percentage of FRα-positive tumor cells. Thirty-seven high-grade serous ovarian carcinoma cases were stained using the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay. A reference panel of four expert pathologists established consensus diagnoses. Twelve pathologists independently assessed the slides, recording internal control adequacy, staining intensity (positive vs. negative), and percentage of FRα-positive tumor cells. Interobserver agreement was measured using Fleiss’ kappa and intraclass correlation coefficient (ICC). Agreement on internal control adequacy was almost perfect (κ = 0.84). Substantial agreement was observed for staining intensity (κ = 0.76), while percentage estimation showed almost perfect concordance (ICC = 0.89). Discrepancies were primarily confined to borderline cases (65–85% positivity) and tumors with intermediate staining, reflecting interpretive challenges near clinical decision thresholds. Pathologists demonstrated high reproducibility in FRα IHC assessment, particularly in estimating percentage positivity and control adequacy. These findings support the clinical utility of FRα IHC but underscore the need for standardized scoring criteria and potential integration of digital tools to enhance consistency, especially in borderline cases.

A Case Report to Reflect on the Origins of MMRd Mesonephric-like Ovarian Adenocarcinoma: Can It Be Defined as a Mϋllerian Neoplasm?

Mesonephric-like adenocarcinoma (MLA) of ovaries is a new and rare neoplastic entity, recently classified by the World Health Organization. Its morphological and immunohistochemical profile is similar to primitive cervical mesonephric adenocarcinoma, but its origin has not been determined yet. Some authors believe that this neoplasm originates from Wolffian remnants in the ovarian hilum, while others suggest an origin from the Mϋllerian epithelium, followed by a mesonephric trans-differentiation. Starting from a recently diagnosed mismatch repair-deficient ovarian MLA, we try to further develop this line of research. A detailed molecular analysis of the studied tumor helps clarify our ideas. In fact, the typical KRAS mutation was not present. We found mutations in numerous other genes, which are rarely described in the literature or are already described in the endometrioid histotype. We reached some interesting conclusions, which, if supported by future studies, will clarify the true nature of these tumors, allowing for better stratification and a better therapeutic framework.

Folate Receptor Alpha in Advanced Epithelial Ovarian Cancer: Diagnostic Role and Therapeutic Implications of a Clinically Validated Biomarker

Folate receptor alpha (FRα), a glycosylphosphatidylinositol-anchored glycoprotein encoded by the FOLR1 gene, plays a crucial role in folate transport during cell growth and development. While minimally expressed in most normal adult tissues, FRα is frequently overexpressed in several epithelial malignancies, particularly in high-grade serous ovarian carcinoma. An immunohistochemical (IHC) evaluation of FRα expression using the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay is now approved as a companion diagnostic for selecting patients eligible for mirvetuximab soravtansine, an FRα-targeted antibody–drug conjugate. Clinical trials such as SORAYA and MIRASOL have demonstrated significant clinical benefit in platinum-resistant epithelial ovarian cancer patients with high FRα expression (≥75% of tumor cells with moderate to strong membrane staining). This review summarizes the biological significance of FRα in ovarian cancer progression, its predictive value for targeted therapy, and the technical aspects of IHC assessment, including scoring interpretation and pre-analytical variables. We also discuss heterogeneity in FRα expression across histological subtypes and tumor sites, as well as the impact of archival versus fresh tissue. Understanding FRα expression patterns across histologic subtypes and tissue samples is critical for optimizing clinical decision-making and expanding the role of FRα-targeted therapies in gynecologic oncology.