Updates of Pathogenesis, Diagnostic and Therapeutic Perspectives for Ovarian Clear Cell Carcinoma

Abstract

Ovarian clear cell carcinoma (OCCC) is a special pathological type of epithelial ovarian carcinoma (EOC) and has a high prevalence in Asia without specific molecular subtype classification. Endometriosis is a recognized precancerous lesion that carries 3-fold increased risk of OCCC. Ovarian endometrioid carcinoma, which also originates from endometriosis, shares several features with OCCC, including platinum resistance and younger age at diagnosis. Patients with OCCC have about a 2.5 to 4 times greater risk of having a venous thromboembolism (VTE) compared with other EOC, and OCCC tends to metastasize through lymphatic vesicular and peritoneal spread as opposed to hematogenous metastasis. There is only mild elevation of the conventional biomarker CA125. Staging surgery or optimal cytoreduction combined with chemotherapy is a common therapeutic strategy for OCCC. However, platinum resistance commonly portends a poor prognosis, so novel treatments are urgently needed. Targeted therapy and immunotherapy are currently being studied, including PARP, EZH2, and ATR inhibitors combined with the synthetic lethality of ARID1A-dificiency, and MAPK/PI3K/HER2, VEGF/bFGF/PDGF, HNF1β, and PD-1/PD-L1 inhibitors. Advanced stage, suboptimal cytoreduction, platinum resistance, lymph node metastasis, and VTE are major prognostic predictors for OCCC. We focus on update pathogenesis, diagnostic methods and therapeutic approaches to provide future directions for clinical diagnosis and treatment of OCCC.

Keywords: Ovarian clear cell carcinoma; endometriosis; epithelial ovarian carcinoma; targeted treatment.

Figure 1

Schematic overview of ovarian clear cell carcinoma development. Shed menstrual endometrium leaves the cavity and retrograde along the fallopian tube to the ovary and into the pelvic or abdominal cavity (red arrow), it may then form endometriosis under multiple factors. Several genetic alterations, such as ARID1A, PIK3CA mutations and HNF1β overexpression, as well as some microenvironmental change, were suspected to be associated with early carcinogenic events of ovarian clear cell carcinoma. BMDCs: Bone marrow-derived dendritic cells; CAFs: Cancer-associated fibroblasts; ECM: Extracellular matrix.

Figure 2

Distributions of metastatic lesions and the commonly complication (venous thromboembolism, VTE) of ovarian clear cell carcinoma. Patients with ovarian clear cell carcinoma especially at advanced stages have high recurrence rates, hematogenous, lymphatic and peritoneal spread are general routes to metastasis. The most frequent sites of metastasis are lymph node and pelvic cavity, rarely in brain, bone and spleen. VTE, consist of deep vein thrombosis (DVT) and pulmonary embolism (PE), is the common complication in epithelial ovarian carcinomas especially in ovarian clear cell carcinoma.

Figure 3

Potential therapeutic targets for ovarian clear cell carcinoma. Five mechanisms of potential therapeutic target have been characterized in ovarian clear cell carcinoma, including synthetic lethality with ARID1A loss, suppression of hyper-activation of RTKs, formation of tumor vasculature and glucose metabolism disturbances, and immune checkpoint blockade therapeutics. MDSCs: Myeloid-derived suppressor cells; BMDCs: Bone marrow-derived dendritic cells; CAFs: Cancer-associated fibroblasts.