Clear cell carcinoma of the ovary has distinct biology and clinical behavior. There are significant geographical and racial differences in the incidence of clear cell carcinoma compared with other epithelial ovarian tumors. Patients with clear cell carcinoma are younger, tend to present at an early stage, and their tumors are commonly associated with endometriosis, which is widely accepted as a direct precursor of clear cell carcinoma and has been identified pathologically in approximately 50% of clear cell carcinoma cases. The most frequent and important specific gene alterations in clear cell carcinoma are mutations of AT-rich interaction domain 1A () (~50% of cases) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha () (~50% cases). More broadly, subgroups of clear cell carcinoma have been identified based on C-APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and C-AGE (age-related) mutational signatures. Gene expression profiling shows upregulation of hepatocyte nuclear factor 1-beta () and oxidative stress-related genes, and has identified epithelial-like and mesenchymal-like tumor subgroups. Although the benefit of platinum-based chemotherapy is not clearly defined it remains the mainstay of first-line therapy. Patients with early-stage disease have a favorable clinical outcome but the prognosis of patients with advanced-stage or recurrent disease is poor. Alternative treatment strategies are required to improve patient outcome and the development of targeted therapies based on molecular characteristics is a promising approach. Improved specificity of the histological definition of this tumor type is helping these efforts but, due to the rarity of clear cell carcinoma, international collaboration will be essential to design appropriately powered, large-scale clinical trials.
© IGCS and ESGO 2020. Re-use permitted under CC BY. Published by BMJ.

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