Ovarian clear cell carcinoma accounts for 5% to 25% of EOC with obvious regionality. OCCC incidence was markedly higher in Asia than in other regions.4 The rate of early detection of OCCC is also higher than that of HGSOC. However, although a high proportion of patients with OCCC are detected early, much literature has reported that the prognosis of patients with OCCC is similar to or worse than that of patients with HGSOC.5-9 Compared with other histologic types of EOC, OCCC is more aggressive and less sensitive to platinum-based chemotherapy.10
Oliver et al. enrolled 544 patients with OCCC and 7054 patients with serous carcinoma. They found that patients with OCCC were younger and had a higher proportion of early stage.4 FIGO stages Ⅰ-Ⅱ accounted for more than 50% (57-81%) of patients with OCCC. OCCC also has some special clinical features, such as frequent presentation as a large pelvic mass, association with endometriosis, vascular thrombotic events, and hypercalcemia.2 Although no patients with OCCC were found to have hypercalcemia in our study, this may be related to our relatively small sample size. The lower incidence of bilaterality of OCCC compared to HGSOC observed in this study has been confirmed by other authors.11 Strong evidence for an association between ovarian endometriosis and OCCC has been established in many studies.11-14 Patients with ovarian endometriosis have a higher risk of developing ovarian cancer, and the risk was particularly elevated in subjects with a long-standing history of ovarian endometriosis.12 Park et al.14 even proposed that ovarian endometriosis may be a precancerous lesion of OCCC. In the present study, 36% of OCCC patients were complicated with ovarian endometriosis, compared with 1.0% of HGSOC patients (P<0.01), which fully demonstrated the association between ovarian endometriosis and OCCC.
Compared with other types of EOC, OCCC lacks effective tumor biomarkers. CA125, which plays a vital role in other types of ovarian cancer, has less clinical significance in OCCC.15 In recent years, some scholars have studied the clinical significance of CA199 in OCCC. Nakagawa et al.16 reported that 54% of OCCC patients were associated with elevated CA199. Zhu et al.17 suggested that CA199 may help to distinguish the prognosis of patients. The clinical value of CA199 in patients with OCCC is worthy of further investigation. Hypercalcemia is one of the most common paraneoplastic syndromes in malignant tumors. However, ovarian cancer with hypercalcemia is rarely reported. Japanese scholars Fujino et al.18 proposed that OCCC is most closely related to hypercalcemia in patients with ovarian cancer. For patients with OCCC complicated with hypercalcemia, recurrence is often accompanied by an increase in serum calcium. However, none of the 50 OCCC patients included in this study were complicated with hypercalcemia, which is inconsistent with the above reports and may be related to the insufficient sample size.
OCCC has been generally accepted as unfavorable when compared with other types of EOC, which has been supported by several retrospective studies.19-21 However, Oliver et al.4 found that patients with OCCC had a better overall prognosis compared with serous carcinoma. Oliver et al. believed that this difference was related to younger age, earlier stage, and better performance status of patients with OCCC. The study also found that, after adjusting the age, stage, and performance status, the prognosis of OCCC was significantly better than serous carcinoma in stages I–II. At the same time, it was significantly worse in stages Ⅲ-Ⅳ. In our study, we used HGSOC as the control group. We found no statistically significant difference in OS and PFS between the two groups in stages I–II. However, in stages Ⅲ-Ⅳ patients, OCCC patients displayed worse OS and PFS.
The factors affecting the prognosis of patients with OCCC continue to be a topic of hot debate in medicine. The sample size of the clinical studies on OCCC by Nasioudis et al. was relatively large. Nasioudis et al.22 evaluated the effect of chemotherapy on prognosis in 2325 OCCC patients with stage I. They found that the survival benefit of chemotherapy on patients with OCCC in the early stage might only be apparent when the lesion was confined to the ovary. Jenison et al.11 found that incomplete capsules had a significant adverse effect on the prognosis of patients with OCCC in stage I. Therefore, to improve the prognosis of patients with OCCC, we should try our best to avoid iatrogenic upgrading.
In conclusion, there are many differences in clinical features and prognosis between OCCC and HGSOC. Most of the OCCC showed a large unilateral cystic solid tumor. The detection of CA199 is more critical in patients with OCCC than in patients with HGSOC. OCCC has a high incidence of early stage. OCCC patients have a significantly worse prognosis than those with HGSOC in the advanced stage (FIGO Ⅲ-Ⅳ). Clinically, we should try to maintain the integrity of the tumor envelope during surgery. R0 resection is an essential factor that can improve the prognosis of patients with both OCCC and HGSOC.
Our study was a retrospective single-center study; a larger prospective multi-center study is needed for further prospective external validation.