Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. In 2020, the estimated number of deaths was 13 940 in the USA, which ranks fifth in cancer deaths among women (1). Ovarian clear cell cancer (OCCC) is a lethal histological subtype with an incidence rate ranging from 5%–25% according to geographical area and race (2).

Although the distinct biological and clinical behavior of OCCC differs extensively from serous ovarian cancer, such as younger age and earlier International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, greater chemoresistance, and higher rate of thromboembolic complications, the surgical treatment of these different EOC subtypes is similar (2, 3). According to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for ovarian cancer/Fallopian tube cancer/primary peritoneal cancer (Version 1. 2021, available at NCCN.org), standard surgical staging procedures, including systematic retroperitoneal lymphadenectomy (para-aortic and pelvic lymph nodes) should be performed in ovarian cancer patients with early FIGO stage (apparent FIGO stage IA–IIA). For patients with advanced ovarian cancer involving the pelvis and upper abdomen (FIGO stage ≥ IIB), optimal cytoreductive surgery, including resection of suspicious and/or enlarged nodes, should be performed, while this is not required for patients with clinically negative nodes.

Previous studies have shown inconsistent results regarding the prognostic impact of retroperitoneal lymphadenectomy for ovarian cancer in both early- and advanced-stage patients (4–8). Furthermore, different ovarian cancer subtypes have distinct biological and clinical behavior, which is especially true for OCCC; therefore, the subtypes should be studied separately. We conducted this retrospective study to estimate the prognostic impact of retroperitoneal lymphadenectomy in patients with OCCC.

Recent studies focusing on the role of retroperitoneal lymph node dissection have emerged following the results of the LION study (4). For advanced ovarian cancer patients, Fang et al. found that systematic lymphadenectomy did not improve survival in patients with no gross residual disease (NGR) or residual tumors measuring < 1 cm (5). Ting et al. showed that retroperitoneal lymph node dissection was not associated with a gain in overall- (OS) and progression-free survival (PFS) for patients with early-stage ovarian cancer (6). Chen et al. showed that retroperitoneal lymph node dissection was not significantly associated with improved prognosis for most stage I EOC patients, but may be necessary for the stage IC subtype (7). Bizzarri et al. showed that pelvic and para-aortic lymphadenectomy improved disease-free survival while having no impact on OS in apparent early-stage ovarian cancer patients (8). In our study, the results suggested that retroperitoneal lymphadenectomy provided no survival benefit in patients diagnosed with OCCC, no matter in the whole cohort or when subgroup analysis were performed stratified by early and advanced stage, or in patients with clinically negative nodes.

Although the results of an earlier study (9) showed that complete surgical staging involving pelvic and para-aortic lymphadenectomy appeared to improve survival in patients with stage I OCCC, more recent research showed no benefit (10). The recent studies including ours seem reasonable for the following reasons: First, for early-stage OCCC patients, the frequency of lymph node metastasis was much lower than other tumor subtypes according to previous studies. Heitz et al. studied the frequency of lymph node metastasis in patients with different tumor stages and histological subtypes who underwent pelvic and paraaortic lymphadenectomy. The results showed that 3.6% of OCCC patients with stage pT1a-pT2aM0 tumors had lymph node metastasis, while the rate was 71.6% in patients with high-grade serous ovarian cancer and 47.4% for high-grade endometrial cancer (11). Mahdi et al. estimated the prevalence of lymph node involvement in stage I OCCC patients from data from the SEER database, and the results showed that 61 (4.5%) of 1359 stage I OCCC patients were upstaged to FIGO stage III (12). In our study, the rate of lymph node metastasis was 4.3% in patients with stage pT1 disease ( Table 3 ), similar to findings in these two previous studies. Second, regarding postoperative adjuvant chemotherapy, except for stage IA OCCC patients, for whom observation is feasible, both stage I and stage IIIA OCCC patients should receive postoperative chemotherapy, meaning that postoperative adjuvant therapy is almost unaffected by retroperitoneal lymphadenectomy. Furthermore, the rate of lymph node metastasis for all pT1 stage patients (< 5%) may also suggest a lower frequency in OCCC patients with stage pT1A tumors. Therefore, lymphadenectomy may accurately upstage only a small percentage (< 5%) of early-stage OCCC patients, indicating an extremely limited therapeutic role.

Some studies evaluating the number of resected lymph nodes in early OCCC, such as the study by Yuji et al. (13) showed that for patients with stage I OCCC, the group with ≥ 35 resected lymph nodes were correlated with better recurrence-free survival than those with < 35 resected lymph nodes. Harder et al. found a trend toward improved survival when more extensive lymphadenectomy (> 10 nodes) was performed, although there was no statistical significance (12). Matsuo et al. found that adequate lymphadenectomy was associated with a 15%–25% reduction in ovarian cancer mortality compared with inadequate lymphadenectomy (14). In our study, there was no survival difference between patients with < 20 vs ≥ 20 resected lymph nodes ( Supplementary Figure 1 ).

A recent study of 410 advanced-stage ovarian cancer patients (including both serous and non-serous cancer) showed no significant difference in 5-year OS and 2-year PFS between the lymphadenectomy group and no lymphadenectomy group, while patients in the lymphadenectomy group had a higher incidence of infection (5). The study included patients with negative (n=288, 70.2%) and positive lymph nodes, and the results indicated no benefit with lymphadenectomy for both the entire cohort and when patients were stratified by lymph node clinical evaluation. ours is the first study investigating the therapeutic role of retroperitoneal lymphadenectomy in advanced-stage OCCC patients. As shown in Table 3 , almost 60% of patients with stage pT3 OCCC had retroperitoneal lymph node metastasis, which was much higher than in patients with stage pT1 disease. Our results showed a negative prognostic role of lymphadenectomy in these patients.

In addition to advanced ovarian cancer patients undergoing primary debulking surgery, several recent studies have evaluated the role of lymphadenectomy in patients who underwent interval debulking surgery. A systematic literature review from Seidler et al, that included 1094 patients from six retrospective series, suggested no benefit of systematic lymphadenectomy during interval debulking surgery procedure on survival in node-negative, advanced-stage ovarian cancer patients (15). He et al. retrospectively analyzed the role of lymphadenectomy in advanced-stage ovarian cancer patients who underwent interval debulking surgery. Of the 303 patients included in the study, 163 (53.8%) patients achieved NGR, and 127 (41.9%) patients underwent lymphadenectomy. The results suggested no therapeutic value of lymphadenectomy, with both PFS and OS showing no statistical difference between the lymphadenectomy group and no lymphadenectomy group (16). In our study, we did not include patients received neoadjuvant chemotherapy for analysis to avoid bias.

Several limitations existed in our study. The first weakness was the low cases number. A more concrete analysis could be achieved with more cases enrolled, especially when subgroup analysis was performed in the study. Another limitation was that our study included patients with early-and advanced stage, optimal and sub-optimal surgery, and clinically positive and negative lymph nodes. The heterogeneity of the sample may also weaken the conclusion of our study. However, the results of the current study may provide evidence for designing a randomized clinical trial specifically for patients with ovarian clear cell cancer.

In this retrospective study, we found no survival benefit of retroperitoneal lymphadenectomy in OCCC patients, both in the entire cohort and when subgroup analysis was performed. A prospective clinical trial is needed to confirm the present results.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Medical ethics committees of both Fudan University Zhongshan Hospital and Zhejiang Cancer Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

SY, WG, and JZ contributed to conception and design of the study. PS, HS, and MX organized the database. SY and WG performed the statistical analysis. SY wrote the first draft of the manuscript. WG, PS, and WT wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

The study was funded by Zhongshan Development Program (XK-066).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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