Epithelial ovarian cancer (EOC) is the common female cancer worldwide and one of the most lethal malignancies [1]. The incidence is reported to be relatively high in developed countries [2] and the incidence of ovarian cancer has been increasing in Korea according to the Korea Central Cancer Registry's nationwide cancer incidence monitor since 1999 [3]. Several reasons for poor prognosis related to EOC are suspected but the advanced disease at initial visit is presumed as major factor for poor survival in EOC. Stage is known for one of the powerful prognostic factor for survival and 5-year overall survival (OS) rates of stage I and II EOC is approximately 90% and 60%, respectively, and these rates decline to about 30% in more advanced stages (III and IV) [4].

Surgical exploration and pathological staging is standard procedure for classification of EOC and International Federation of Gynecology and Obstetrics (FIGO) classification is widely used. However, there have been debates on the issues that existing FIGO staging of EOC classifies heterogeneous groups of population as same stage [5,6]. For example, FIGO stage IIIC patients with only isolated lymph node metastasis have been shown better prognosis compared to the patients with stage IIIC with peritoneal carcinomatosis or abdominal metastatic lesion more than 2 cm [6,7,8,9,10,11,12]. Unfortunately FIGO staging classification of EOC has not been revised since 1988 under these critical issues but recently, FIGO announced revised FIGO staging classification [13] reflecting recent evidences. This study is designed to investigate the clinical relevance of new FIGO staging system and to compare revised classification with previous version of FIGO staging system in EOC.

Overall, we were able to enroll 878 patients with EOC. The basic characteristics of patients are presented in Table 1. The median age of the population was 51.9 years old with the range of 14 and 84. Most of the patients (66.9%, 587/878) were diagnosed as advanced disease (stage III and IV) and portion of stage II was the least (10.4% ,91/878). 92.3% of patients (811/878) had primary site from ovary, 5.6% (49/878) from fallopian tube, and 2.1% (18/878) from peritoneum. Serous adenocarcinoma (62.9%, 553/878) and grade III (54.8%, 481/878) was the most common type for histology and tumor grade, respectively. For treatment, 60 patients (6.8%) had neoadjuvant chemotherapy and 52 patients (5.9%) had surgical treatment alone without chemotherapy. Optimal surgical cytoreduction was achieved in 75.1% (660/878) in all patients and 63.4% (372/587) among stage III and IV. The median follow up time was 42.1 month with the range of 0.2 to 136.6.

Compared to previous FIGO staging system, revised one is divided into more sub-stages. Previous stage IC (98, 11.1%) subdivided into IC1 (9, 1.0%), IC2 (57, 6.4%), and IC3 (32, 4.1%). In addition, previous stage IV (94, 1.7%) was categorized into IVA (37, 4.2%) and IVB (57, 6.5%) in new staging classification. Stage IIC (66, 7.5%) has been eliminated and integrated into IIA (36, 4.1%) and IIB (55, 6.2%) in revised classification. Redistribution of stage III has been observed in new staging classification. Number of patients with stage IIIC in previous staging system (452, 51.8%) decreased in new staging system (384, 43,7%). Relatively, combined number of patients with stage IIIA1(i) (18, 2.1%), IIIA1(ii) (15, 1.7%), IIIA2 (18, 2.1%), IIIB (58, 6.6%) was increased in new staging system (Table 1).

In this study, we could find that revised 2013 FIGO staging classification in EOC is acceptable and has an independent prognostic role especially in IC3 and IIIC, which were not shown in IC and IIIC of previous FIGO stage. However, the prognostic significance remains uncertain in stage II and IV.

EOC is staged surgically and surgical staging should be confirmed based on pathological findings. The major role of staging system is not only to provide universal terminology to be able to use in different centers worldwide, but also to give information about the prognosis of the patients and outcome prediction after specific treatment. Since the last version of ovarian cancer FIGO staging classification in 1988, there have been concerns that FIGO staging cannot delineate the heterogeneity of EOC patients especially in IC and IIIC. For example, whether intra-operative iatrogenic rupture of ovary in stage I EOC might have an effect on the survival outcome or not is long standing controversy [14,15,16,17,18]. Recent meta-analysis reported that iatrogenic rupture might not decrease recurrence compared to early-stage EOC without rupture in which complete surgical staging followed by platinum-based chemotherapy [19]. This suggests that stage IC with iatrogenic rupture might have better prognosis than the other stage IC. In our study, there is no case of recurrence in stage IC1, which showed even better prognosis than stage IA EOC, and these findings also support that iatrogenic ruptured IC EOC should have been allocated to different category. In the revised FIGO stage classification, stage IC3 became significant independent prognostic factor, as previous FIGO stage IC with iatrogenic rupture was re-categorized to IC1.

It has been also suggested that Stage IIIC in previous FIGO stage may be consisted of heterogeneous groups [5]. The most important issue that has been raised is the differences in prognosis between stage IIIC with intra-abdominal metastasis and IIIC with isolated lymph node metastasis without coelomic metastasis which is reported to be associated with better prognosis [6,7,8,9,10,11,12]. Allegedly, less than 10% of EOC extends beyond the pelvis with only retroperitoneal lymph node metastasis [20]. In our study, overall 3.9% of patients turned out to be the case which is relatively lower than previously reported. This lower rate might have been associated with comprehensive surgical approaches in clinically early stage and 37.5% patients with stage I EOC might not had complete lymph node dissection in our study. However, we found that survival benefits of stage IIIA1 and 2 are clear when compared to FIGO stage IIIC in revised FIGO stage. Stage IIIC was an independent prognostic factor for PFS in revised version but not in previous version of FIGO stage. These findings support that revised FIGO staging classification may be more feasible to predict prognosis of patients with EOC.

For stage II, we could not find any clinical benefits to predict prognosis with revised FIGO staging classification. The previous substage IIC (i.e., IIA or IIB but with tumor on surface, capsule ruptured, or ascites or positive peritoneal washing) was considered redundant and eliminated [13]. Clinically it is hard to distinguish stage IIA and IIB because serosa of fallopian tubes, uterus, and ovaries are continuum of pelvic peritoneum. And we often see the cases with peritoneal involvement not completely excluded due to severe adhesions even though peritoneal involvement was not proven pathologically. More on that, stage II is relatively rare. For example, a nationwide study [21] reported that less than 10% of the patients with EOC were stage II disease at initial diagnosis and in our data, we could also find that 10.4% (91/878) was stage II for 10 years which is less than 10 patients per year on average. And the event for recurrence or death was relatively rare which might be associated with low power to detect any survival difference in this group. Stage IV disease may be more heterogeneous than we expected. For example, a study demonstrated that OS for stage IV patients was significantly different between 2 groups based on supraclavicular lymph node metastasis (HR, 0.22; 95% CI, 0.08 to 0.63; P=0.005) and bone metastasis (HR, 3.49; 95% CI, 1.10 to 11.08; P=0.034). As the overall prognosis was extremely poor in stage IV, it might also be hard to see the survival differences between IVA and IVB in revised FIGO staging classification.

To our best knowledge, this is the first study to see the clinical relevance of revised FIGO staging classification in EOC in large population during relatively short period of time (10 years). Because EOC is known to have proven clinical factors associated with prognosis, including various biological behaviors based on different histology, tumor grade, and the amount of cytoreduction [16,17,22,23], we adjusted these factors to see the independent role of sub-stages through multivariate analysis. However, there are limitations in this study. First, there could be misplaced classification due to factors necessarily arise from retrospective study design. Comprehensive or fertility sparing surgery was permitted in this study, and there might be cases with microscopic metastasis on retroperitoneal lymph node that would be upstaged to stage IIIA1 instead of stage I. For the similar circumstances, stage III patients who did not have pleural tapping, because of asymptomatic pleural effusion, would have been changed into stage IVA. According to preoperative evaluation protocols for ovarian cancer of our department, pleural tapping was performed for cytologic result of malignancy in patients with pleural effusion observed in chest X-ray or computed tomography. However, possibility of improper classification of stage IVA as stage III, in patients with pleural effusion not shown in chest X-ray or computed tomography possibly due to minimal amount, cannot be excluded. Also, substage IC1 was decided by fact that whether the iatrogenic rupture had occurred during operation, indicated in operation record which was separately recorded by operator. However, possibility of not having recorded by operator leading to false classification still exist. That could be limitation of our study as retrospective design. Second, our positive results in PFS for revised FIGO staging classification were not seen in OS. Conversely, the opposite result was observed in OS for previous FIGO stage III. Stage IIIC was associated with better survival (in OS) than stage IIIA in multivariate analysis. It is unclear but we can assume that small number of patients with stage IIIA (1.8%, 16/878) and various subsequent therapies after progression, which was not considered in this study, might be associated with this result. For example, PFS can be sometimes used as a surrogate for OS but statistical modeling has suggested that the association between OS and PFS becomes weaker in diseases with longer survival post progression [24].

In conclusion, revised FIGO staging system of EOC has more progressed utility for informing prognosis than previous staging system, especially in stage I and III. For stage II and IV, further validation should be needed in large population based study in the future.