Epithelial ovarian cancer (EOC) is the second most common cancer of the female reproductive system and the leading cause of death associated with gynecologic cancers in developed countries [1]. EOC has four main histological types: serous, mucinous, endometrioid, and ovarian clear cell carcinoma (OCCC). The latter is a special tissue type characterized by a relatively young age of onset compared with other EOC subtypes. The average age of onset reported in foreign literature is 55 years old. Moreover, the incidence of OCCC has been reported to be around 11% in the majority of Asian populations, up to 10% in Caucasian women, and even as high as 29.1% in Japan. Although the clinical diagnosis is mostly established early, prognosis evaluation is still controversial [2]. There has been a study suggest that the tumor stage of the International Federation of Gynecology and Obstetrics (FIGO) is the main independent factor affecting the prognosis of OCCC [3]. The 5-year overall survival rate (OS) of FIGO stage I and II is 80%–89%, and that of FIGO stage III and IV is reduced to 52% [4]. Currently, the standard treatment for OCCC includes comprehensive staging or tumor reduction surgery, which requires total hysterectomy, bilateral appendages, and platinum-based combined chemotherapy [5].

FIGO staging system, which is widely used in clinical practice, has been established as a relatively important indicator for evaluating tumor prognosis. However, most researchers and clinicians believe that other important, relevant factors, such as demographic characteristics, residual tumor, venous thrombosis, and surgical methods, should be considered when predicting cancer survival [2]. In recent years, different prediction models after surgery, which are more advantageous than the existing FIGO staging, have emerged, helping clinicians to better predict disease recurrence and the benefit of adjuvant therapy [6]. However, nomograms are rarely used in OCCC. Most previous studies only considered the overall survival (OS) based on Kaplan Meier and COX survival analysis, rarely focusing on cancer-specific survival (CSS).

At present, initial tumor debulking surgery combined with platinum-based chemotherapy is considered the standard treatment for epithelial ovarian cancer. However, the general direction for diagnosing and treating ovarian clear cell carcinoma is still based on high-grade serous ovarian cancer. As this form of cancer is rare, the efficacy of various surgical modalities has not yet been prospectively evaluated [7]. In a previous study that compared the clinicopathological features and survival of OCCC patients with other EOCs, OCCC patients had worse 5-year CSS than serous carcinomas [8]. In a Japanese multicenter retrospective study, Sugiyama et al. [9] also reported that 48.5% of OCCCs were diagnosed as stage I, but only 16.6% of serous carcinomas were diagnosed as stage I. The recurrence rate of IC stage OCCC was as high as 37%, and the survival rate was lower than IC stage serous carcinoma [9]. After entering the advanced stage, OCCC disease progresses rapidly, the chemotherapy resistance rate is high, and the prognosis is worse [4]. Therefore, synchronizing the treatment for OCCC with other epithelial ovarian cancers has certain limitations. Hence, it is necessary to summarize the clinical characteristics of OCCC and identify more accurate solutions for diagnosis, treatment, and follow-up. Retrospective analyses through the surveillance, epidemiology, and end results (SEER) database and real-world research are effective methods for studying low-incidence diseases such as OCCC.

This study selected 11 indicators. FIGO stage is the most clearly prognostic risk factor. Studies have shown that age, race, preoperative carbohydrate antigen 125 (CA125) level, postoperative chemotherapy, and surgical method have a certain correlation with OS, while tumor laterality has rarely been studied. Log odds of positive lymph nodes (LODDS) is a new indicator that can better reflect the condition of lymph nodes. It has not been seen in OCCC prognostic studies.

Among 596 OCCC patients included in the present study, the age of clinical diagnosis, which was mainly 55–59 years old, was relatively lower than in patients with other epithelial ovarian cancers. In addition, the onset was often in the early stage of the disease (namely stage I and II), and the tumor volume of $>$80 mm was large. These results are consistent with previous studies [10, 11] and suggest the uniqueness of OCCC compared to other EOCs. In addition to the distinctive clinical features, ovarian clear cell carcinoma (OCCC) is also unique in terms of histopathological and genetic features. First, the incidence varies by ethnicity; however, the cause remains unclear. Also, Asians, especially Japanese women, have the highest incidence reaching the OCCC rate of 23% [12]. Second, tumors are often high-grade and have a relatively poor prognosis, which is in line with the fact that OCCCs in our study population was mostly differentiated tumors.

Through previous literature reading, we selected 11 relevant variables for current research. Following COX survival analysis, the final modeling variables were FIGO stage, race, tumor location, age, and LODDS. As the most definitive diagnosis and treatment basis for EOC, FIGO tumor staging is still feasible in OCCC [13] for prognosis prediction [14]. FIGO staging also has an important role in our CSS prediction model. Because the onset of OCCC is mostly in the early stage, there are many studies on patients with stage I. Herein, we subdivided stage I into IA/B and IC stages, after which it was found that patients with IC stage had high CSS scores. FSS is feasible and whether postoperative chemotherapy is required remain research topics of interest with a certain degree of interpretation and inclination. In terms of incidence research, OCCC has a high specificity in Asian populations. In terms of mortality prediction, although some studies have reported that race is not an important indicator of progression-free survival (PFS) and OS of the disease [15], our model clearly showed that African Americans had higher 3-year and 5-year cancer-specific mortality rates, which may be related to many social, economic, and even cultural reasons, and may also be related to the population included in the SEER database. In our follow-up studies, we plan to continue to focus on the effect of race on mortality risk. Multivariate analysis showed no significant difference between the tumor located on the left and right sides; however, compared with bilateral ovarian tumors, the 3-year and 5-year survival rates of OCCC confined to one ovary were significantly improved. A larger tumor burden was associated with a greater tumor burden, which we believe is closely related to the FIGO stage of the disease; thus, future studies could subdivide stages IA and IB. Previous studies have suggested that age is a high-risk factor for a prognosis for EOC, and the study has suggested that age $\ge$70 years is associated with a 1.4-fold increased risk of CSS [16]. Our results showed that those who were 50 years old had a worse prognosis, which may be related to the trend of younger onset of OCCC and the faster disease progression in younger patients compared with older patients. Other studies have shown that the prognosis of OCCC has a certain correlation with the tumor size and the marital status of the patients [17], but in our study, patients with tumors $>$80 mm had a worse prognosis in the survival curve, and the marital status of the patients showed a worse prognosis. However, the effect was not obvious. It has been reported that lymph node metastasis is not common in OCCC patients with the limited disease to the ovary, but compared with node-negative patients, node-positive patients were more likely to die and more extensive. Lymphadenectomy has an important role in providing accurate staging and prognostic information [18]. Some researchers argued that for stage I OCCC, the number of resected lymph nodes $\ge$35 is an independent predictor of improving recurrence-free survival (RFS) [19]. However, a previous study showed that compared with no lymphadenectomy, systematic pelvic and para-aortic lymphadenectomy was not associated with longer OS or PFS but with a higher incidence of postoperative complications [20]. In the present study, we included LODDS, which is a quantifiable indicator that can reflect the number of positive and negative lymph nodes in general. It is suitable for advanced patients who underwent systematic lymph node dissection. The cutoff value related to survival status was obtained by X-tile. It can be seen in the nomogram that the 3-year and 5-year cancer-specific survival of LODDS I grades were significantly reduced, suggesting that pelvic and para-aortic lymph node resection in the early stage of the disease had obvious advantages for cancer-specific survival. Although the surgical method, preoperative CA125 level, and postoperative chemotherapy did not result as independent risk factors in the multivariate regression analysis, we can see the trend of different choices in the Kaplan-Meier survival curve, which may be limited by OCCC incidence. It is also possible that due to the clear deletion of unknown data from the database, we selected the small sample size; however, it could still provide preliminary ideas for the study of predictors of OCCC. Because the age of onset of OCCC is younger than other EOCs, it is particularly important for early OCCC patients who have not completed childbirth and have a strong desire to bear children and wish to undergo FSS. Also, the research on surgical methods for stage I patients has become particularly popular in recent years. Because OCCC is mostly a tumor with poor pathological differentiation, some studies have pointed out the controversy of FSS in OCCC patients [21], while others have suggested that compared with FSS and radical surgery, there is no difference in OS between the two groups of patients, after adjusting for lymph node resection. Moreover, disease staging or FSS did not affect OS [22]. In our survival curve, we can see that the prognosis of patients who underwent intermediate and advanced tumor debulking surgery was significantly worse, while there seemed to be no significant difference between patients who underwent FSS and complete hysterectomy and bilateral adnexa, as the choice of surgical method was also closely related to disease stage. Therefore, we consider that the poor prognosis of patients undergoing debulking surgery is related to the later stage of FIGO to a certain extent. In a Japanese study on stage I-IIB OCCC patients, univariate analysis revealed that neither preoperative CA125 value nor chemotherapy regimen was a prognostic risk factor [23]. In stage I patients, adjuvant chemotherapy did not affect 5-year PFS, but in stage IC OCCC, adjuvant chemotherapy was associated with improved OS [24]. Another study showed that compared with other EOCs, OCCC preoperative CA125 levels were mostly negative [25]. In the present study, preoperative CA125 was elevated in 72.82% of patients, and 85.91% of patients chose postoperative chemotherapy, which was not completely consistent with previous studies. Existing research suggested that OCCC is associated with endometriosis [25], and patients with endometriosis are often accompanied by elevated CA125 levels, thus further adding credibility to our results. Moreover, the survival curve showed that the patients with preoperative CA125 elevation and postoperative chemotherapy were more likely to die.

OCCC accounts for 5–25% of ovarian cancers, with obvious ethnic and regional differences in incidence [26]. During the development of OCCC, ARID1A and PIK3CA genes frequently mutate, unlike the common mutations in serous carcinoma BRCA1/2. Therefore, standard high-grade serous ovarian cancer treatment is not fully applicable to OCCC [26]. Studying epidemiology, clinical characteristics, diagnosis, and treatment of OCCC in order to obtain a more specific diagnosis and treatment plan is of urgent importance. Also, due to the ethnic differences in its pathogenesis, we need to pay more attention to exploring disease-targeted therapy.

First of all, this study is a retrospective study, and only death and non-death outcomes were assessed, which has some inevitable bias. Tumor reduction satisfaction rates vary widely across cancer centers, and the lack of detailed information on preoperative evaluation and postoperative complications prevents more rigorous comparisons of surgical procedures and their impact. Secondly, chemotherapy data in the SEER database only recorded whether chemotherapy was performed, but there was no detailed protocol and cycle, and it was not clear whether preoperative neoadjuvant chemotherapy was performed.

The incidence of OCCC is low, and the overall prognosis is poor. The prediction model based on tumor FIGO stage, race, tumor location, age, and LODDS performed well in validation and could ideally divide postoperative patients into high-risk and low-risk groups, thus achieving certain clinical reference values.

The data we used were obtained from the publicly available SEER database (https://seer.cancer.gov/).

All authors contributed to the concept and design of the study. Material preparation, data collection and analysis were performed by MH, LL, YLiu and YLi. The first draft of the manuscript was written by MH and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

All procedures performed in these studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was deemed exempt by the Ethics Committee of Nanjing First Hospital, China, since the data we used were obtained from the publicly available SEER database. Written informed consents were exempt since the data we used were obtained from the publicly available SEER database.

We would like to express our gratitude to all those who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.

This research received no external funding.

The authors declare no conflict of interest.