Unveiling Commonalities: Exploring Shared Characteristics in Clear-Cell Carcinomas of the Gynecologic Tract

Abstract Clear-cell carcinomas (CCC) arising from the gynecologic tract (including from the ovary, endometrium, cervix, vulva, or vagina) represent rare but clinically significant entities with intriguing overlapping characteristics. Epidemiologically, CCCs exhibit a predilection for women of Asian ethnicity and are often associated with a previous or synchronous diagnosis of endometriosis. Pathologically, despite originating from different primary organs, CCCs of the gynecologic tract show similar morphologic and immunophenotypic features on traditional histopathology, such as the expression of napsin A and hepatocyte nuclear factor 1β on IHC, without the expression of Wilms tumor 1. Well-described molecular characteristics of these cancers include recurrent mutations in genes such as ARID1A, PIK3CA, and/or PTEN, although significant variations exist across the different anatomic sites. Therapeutically, optimal management remains challenging due to the relative rarity of CCCs and limited subtype-specific clinical trials. Surgery remains the cornerstone of treatment, often complemented by systemic chemotherapy. However, promising drugs targeting angiogenesis or the immune microenvironment have emerged in recent years, leading to clinical successes, and are likely to reshape the therapeutic landscape of gynecologic CCC. This review summarizes the commonalities and disparities in terms of epidemiology, pathology, molecular features, and therapeutic approach, among CCCs of different anatomic origin, offering a foundation for further research and dedicated therapeutic interventions for these malignancies.