OCCC is a rare pathological type of EOC, and there is geographic variance in the prevalence of OCCC, being more common in Asia(3–5). Prevalence also differs by race, being higher in Asians (11.1%) and lower in black, white, and other populations (3.1%, 4.8%, and 5.5%, respectively) (15). However, among patients analyzed from the SEER database in our research, only 15.08% of the 179 cases were Asians, with 78.21% of cases being white; this is likely related to the racial differences in the USA population. In the present study of 87 cases of OCCC in our hospital, most patients were diagnosed at an early stage (74.71%) and a younger age (49.28 ± 9.87), consistent to previous studies, showing the distinct epidemiology of OCCC from HGSC, which is more frequently diagnosed at an advanced stage and carries a poor prognosis(8).
Endometriosis is a common disease in women of reproductive age, which is recognized as a precancerous lesion of OCCC and is associated with triple the risk of OCCC(7, 16), approximately 18–43% of women with OCCC have a history of endometriosis(17, 18). Endometriotic lesions often carry multiple somatic mutations, such as high expression of HNF1β and mutations in ARID1A and PIK3CA, which are thought to occur early in the malignant transformation of OCCC(16). The risk of tumorigenesis in endometriosis is about 1% among premenopausal women and 1–2.5% among postmenopausal women(17, 19). A study by Ye et al. demonstrated that patients with OCCC and concurrent endometriosis were on average 8 years younger than those without, and were more likely to present at early stage (78.5%)(20). However, although patients with co-existing endometriosis tend to have better survival outcomes, endometriosis was not an independent predictor of survival(21). In the present study, OCCC patients with endometriosis also tended to be diagnosed at an early stage (87.50%) and were younger (average age of 45.50 ± 6.19) compared to patients without endometriosis, however this difference was not significant (P = 0.325 and P = 0.078, respectively). Unfortunately, due to the small sample of our research, survival analysis of OCCC patients with and without endometriosis could not be constructed.
Currently, there is no specific biomarker for OCCC, patients with OCCC usually present with a mild elevation of serum CA125(9). In the present study, 19.54% of the patients had a normal level of CA125, and 37.93% of the patients had a CA125 level of < 100U/mL. Thus, there is a need for novel diagnostic markers to improve early diagnosis of OCCC. Chronic inflammation appears to have an effect on tumorigenesis and response to therapy, as well as affecting prognosis(22). Several systemic inflammatory response (SIR) biomarkers have been investigated as potential biomarkers of OCCC, such as the neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR). Most OCCC patients diagnosed at an early stage showed complete response to initial treatment with decreased NLR levels, and NLR was found to return to preoperative high levels with recurrence, reflecting inflammation caused by the tumor(23). Low LMR has been shown to be associated with advanced stage disease, LN metastases, platinum-resistance, and poor prognosis, suggesting a decreased level of peripheral lymphocytes results in weakened immune surveillance and poor response to chemotherapy(22). In addition, genetic testing offers some potential diagnostic biomarkers for OCCC, such as HNF1β, which is expressed in almost all cases of OCCC and now used to distinguish histological subtypes by immunohistochemistry (IHC)(24). OCCC lesions tend to be positive for CK7 and negative for CK20, ER, PR, WT-1, and p53(10, 25). Testing negative for α-fetoprotein and CD10 can be used to exclude yolk cell tumors and renal cell carcinoma(26). We analyzed immunohistochemical results of our patients, and 55%(11/20) of them had positive HNF1β and negative WT-1, ER and PR. However, there remains an urgent need to discover novel biomarkers in peripheral blood or body fluids and validate their efficacy in the diagnosis of OCCC.
VTE, i.e. deep vein thrombosis (DVT) and pulmonary embolism (PE), are common in patients with OCCC, with a 2.5–4 times higher risk than in other subtypes of EOC(20, 27). VTE is more commonly seen in advanced stage OCCC (21.9%) compared with early stage (8.2%) disease, and occurred most commonly prior to primary surgery (36.4%), or with recurrence or progression (33.3%)(20). There are some measurable biomarkers of increased risk of VTE in ovarian cancer, such as elevated platelet count, white blood cell counts, d-dimer and CA125 level, decreased hemoglobin and albumin levels preoperatively, and elevated d-dimer and decreased albumin postoperatively(28). In our study, 8 patients developed VTE (Table 2), 4 preoperatively and 4 postoperatively. The low occurrence of VTE in our research might be associated with the use of appropriate prophylaxis. In spite of prophylaxis, patients with OCCC can still develop VTE, suggesting that an aggressive postoperative anticoagulation regimen and prolonged post-discharge VTE prophylaxis should be considered for patients with OCCC.
Staging surgery or optimal cytoreduction combined with chemotherapy is a common therapeutic strategy recommended for OCCC, however, only 11–27% of patients with OCCC respond to conventional platinum-based chemotherapy, resulting in a poor prognosis(29, 30). Disorder of the cell’s detoxification effects of the glutathione system, low proliferation activity of OCCC and overexpression of EGFR, HNF1β, and HER2 may be involved in chemoresistance(31). In our clinical practice, OCCC patients often developed resistance characterized by a slow decline or elevation of tumor markers during postoperative chemotherapy. However, in the absence of more effective treatments, platinum-based chemotherapy remains the first line adjuvant therapy for OCCC patients, and more effective therapies are urgently needed. Recently, several targeted therapies and immunotherapies have been investigated for use in OCCC, such as PARP, EZH2, and ATR inhibitors combined with synthetic lethality of ARID1A-deficiency, and MAPK/PI3K/HER2, VEGF/bFGF/PDGF, HNF1β, and PD-1/PD-L1 inhibitors. Some regimens have demonstrated efficacy and revealed a potential therapeutic benefit for OCCC patients, but further research is required(32–35).
Survival analysis of our clinical data identified CA199 level and massive ascites as independent prognostic factors of OS, as well as HE4 level and massive ascites as independent prognostic factors of PFS in OCCC. Elevated postoperative CA199 has been reported as an independent risk factor for reduced survival outcomes in OCCC patients with normal postoperative CA125 levels(36). HE4 is not commonly used in OCCC prediction, however, Mckinnon found that since HE4 is sensitive to hormonal treatment and menstrual cycle variation, it may be potentially superior to CA125 as an endometriosis marker and therefore has potential as a marker for the risk of developing ovarian cancer(37). Suboptimal cytoreduction and advanced stage have been found to be associated with less favorable survival outcomes in univariate analysis, however, neither is an independent prognostic factor in the present study, which may be related to the small sample size. In our survival analysis of 179 cases of OCCC from the SEER, we found that positive LN is an independent prognostic factor. OCCC tends to metastasize most frequently via the lymphatic system(38). However, among patients in our hospital, only 4.48% of patients had metastatic LNs, which may be due to the fact that most (89.55%) of the 67 patients who received lymphadenectomy were at an early stage. Mueller found that 4.4–20% of clinically stage I OCCC had lymph node involvement, and this rate will be higher with positive cytology or ovarian surface involvement, accounting for 37.5% of metastases(39). Therefore, systematic pelvic and para-aortic lymphadenectomy is vital to accurately determine disease stage, provide prognostic information, and guide adjuvant therapy, especially for patients at early stage.
In conclusion, our study presents the clinicopathological features, treatment regimens and prognosis of OCCC in China, and confirms that OCCC typically presents at an early stage and at a younger age, with a mild elevation in CA125 level. Positive HNF1β, and negative WT-1, ER, and PR are reliable immunohistochemical indicators of OCCC. Patients with early stage OCCC tend to have a better OS and PFS, with CA199, HE4, massive ascites and positive lymph nodes being independent prognostic indicators. The present study confirms the unique features of OCCC, and further research is required to illustrate the molecular mechanisms and discover novel diagnostic biomarkers and targeted therapies, in order to benefit early diagnosis and therefore prognosis of OCCC.