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Risk factors for lymph node metastasis in ovarian cancer: Implications for systematic lymphadenectomy
Accepted Manuscript Risk factors for lymph node metastasis in ovarian cancer: implications for systematic lymphadenectomy Juan Zhou, Jia-Yuan Sun, San-Gang Wu, Xuan Wang, Zhen-Yu He, Qiong-Hua Chen, Feng-Yan Li PII:
S1743-9191(16)00257-0
DOI:
10.1016/j.ijsu.2016.03.039
Reference:
IJSU 2683
To appear in:
International Journal of Surgery
Received Date: 14 January 2016 Revised Date:
6 February 2016
Accepted Date: 14 March 2016
Please cite this article as: Zhou J, Sun J-Y, Wu S-G, Wang X, He Z-Y, Chen Q-H, Li F-Y, Risk factors for lymph node metastasis in ovarian cancer: implications for systematic lymphadenectomy, International Journal of Surgery (2016), doi: 10.1016/j.ijsu.2016.03.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Risk factors for lymph node metastasis in ovarian cancer:
Juan Zhou
a,1
, Jia-Yuan Sun
b,1
, San-Gang Wu
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implications for systematic lymphadenectomy
c,1
, Xuan Wang d, Zhen-Yu He b,
a
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Qiong-Hua Chen a,*, Feng-Yan Li b,*
Xiamen Cancer Center, Department of Obstetrics and Gynecology, the First
b
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Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China Sun Yat-sen University Cancer Center, Department of Radiation Oncology, State
Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China
Xiamen Cancer Center, Department of Radiation Oncology, the First Affiliated
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c
Hospital of Xiamen University, Xiamen, People’s Republic of China d
Department of Basic Medical Science, Medical College, Xiamen University, Xiamen
Juan Zhou, Jia-Yuan Sun, and San-Gang Wu contributed equally to this work.
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1
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361003, People’s Republic of China
* Corresponding authors: Qiong-Hua Chen and Feng-Yan Li
Qiong-Hua Chen, Xiamen Cancer Center, Department of Obstetrics and Gynecology, the First Affiliated
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Hospital of Xiamen University, Xiamen, People’s Republic of China
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Tel. +86 592 2139531, Fax. +86 592 2139562, E-mail. [email protected]
Feng-Yan Li, Sun Yat-sen University Cancer Center, Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative
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Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China
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Tel. +86 20 87343543 Fax. +86 20 87343392 E-mail. [email protected]
Ethical approval
The study was approved by the ethics committee of the Sun Yat-sen University
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Cancer Center.
Sources of funding
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This work was supported by grants from the National Natural Science Foundation of China (No. 81571418), the Natural Science Foundation of Fujian Province (No.
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2015J01550, 2013D001), and the Foundation for Young Scholar of Fujian Provincial Health Department (No. 2014-ZQN-ZD-31).
Author contribution JZ, JYS, SGW, QHC and FYL performed the experiment. JZ, JYS and SGW drafted the article and interpret the data. XW and ZYH collected and analyzed the
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data. QHC and FYL design the study and critically revise the manuscript. All authors
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fi nally approved the submitted version
Guarantor
Conflict of interest disclosures
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Feng-Yan Li
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The authors have no conflicts of interest to disclose.
Research registration unique identifying number (UIN)
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Research registry 854.
Acknowledgment
This work was supported by grants from the National Natural Science Foundation
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of China (No. 81571418), the Natural Science Foundation of Fujian Province (No. 2015J01550, 2013D001), and the Foundation for Young Scholar of Fujian Provincial
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Health Department (No. 2014-ZQN-ZD-31).
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Risk factors for lymph node metastasis in ovarian cancer: implications for
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systematic lymphadenectomy
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Abstract Background: The purpose of this study was to assess the risk factors associated with lymph
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node metastases and to evaluate the role of systematic lymphadenectomy in ovarian cancer. Methods: We retrospectively reviewed patients diagnosed with ovarian cancer between
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January 2004 and January 2012. Demographics, pathologic findings, and correlations with lymph node metastases were assessed.
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Results: A total of 256 patients were identified. The mean number of removed lymph nodes was 20.5 (range, 2-57), and 84 patients (32.8%) had nodal metastases. The mean number of positive lymph nodes was 3 (range, 1-40) in patients with lymph node metastases. Univariate
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analysis showed that serous histology, histological grade 2-3, and CA-125 level at diagnosis >740 U/mL were significant risk factors for lymph node metastases. Multivariate analysis showed that serous histology (odds ratio [OR], 2.728; 95% confidence interval [CI],
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1.072-6.945; p = 0.035), histological grade 2-3 (OR 1.897; 95% CI, 1.209-2.977; p = 0.005),
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and CA-125 level at diagnosis >740 U/mL (OR, 3.858; 95% CI 2.143-6.947; p < 0.001) remain the most important risk factors for lymph node metastases. The nodal metastasis rates for 0 to 1 risk factors were significantly lower than those of 2 to 3 risk factors (3.7% vs. 40.6%; p < 0.001). Conclusions: The current study suggests that the decision making of systematic lymphadenectomy in ovarian cancer patients should be referred to the histological type, grade,
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and CA-125 level at diagnosis. Keywords: Ovarian cancer, Lymph node metastases, Lymphadenectomy, CA-125, Histology
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type
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1. Introduction Ovarian cancer is a highly fatal gynecologic cancer and the fifth leading cause of cancer
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mortality for women, with 21,980 new cases and 14,270 deaths occurring in the United States in 2014 [1]. In China, the incidence rate for ovarian cancer ranks 10th and was 7.95 per
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100,000 women during 2009 [2]. Most patients with ovarian cancer have advanced disease upon diagnosis owing to the asymptomatic nature of early-stage tumors, resulting in poor
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long-time survival [3,4].
Surgery is still an important treatment strategy for ovarian cancer, but the role of systematic lymphadenectomy for treating ovarian cancer is still controversial. Lymph node
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status may significantly affect the survival of patients with ovarian cancer and has been included as an important factor in the International Federation of Gynecology and Obstetrics (FIGO) staging system for ovarian cancer [5-7]. Ovarian cancer with lymph node metastasis
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is usually classified as stage III or higher [8,9]. Thus, systematic lymphadenectomy was
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included in the FIGO staging system guidelines because of recognition of the importance of the prognostic value of lymph node metastasis. Randomized studies indicated that analyses for systematic lymphadenectomy detected nodal metastases in 13.6%–30.3% of patients with ovarian cancer [10,11]. It was found that lymph node tumor involvement was 14.2% (range 6.1%-29.6%) for patients with clinical stage I–II ovarian cancer [12]. However, the predict factors for lymph node status in ovarian cancer patients are still lacking. In this retrospective
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study, we aimed to identify the incidence of lymph node metastases in FIGO stages I to III ovarian cancer, to determine the influence of risk factors on the incidence of lymph node
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metastases, and to evaluate the role of systematic lymphadenectomy.
2. Materials and methods
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2.1. Patients
From December 2004 to March 2012, a total of 256 patients with primary ovarian cancer who underwent cytoreductive surgery and lymphadenectomy at the XXXXXX (XXXXXX)
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were retrospectively analyzed. Cytoreductive surgery was considered to have achieved optimal debulking if the residual disease was < 1 cm. Patients with synchronous or metachronous tumors, borderline tumors, and advanced-stage (stage IV) ovarian cancer were
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excluded. Patients with missing data were also excluded. The study was approved by the
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ethics committee of XXXXXX. All patients provided written consent for storage of their information in the hospital database and for research use of the information.
2.2. Clinicopathologic factors Preoperative serum CA-125 levels were measured within 1 week of a staging laparotomy using a radioimmunoassay kit. The upper limit of normal for the serum CA-125 levels was
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defined as 35 U/mL. After being diagnosed with ovarian carcinoma, patients underwent surgical staging
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including a bilateral salpingo-oophorectomy and total abdominal hysterectomy; washing cytology; random multiple peritoneal biopsies; an omentectomy; and a systematic pelvic
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lymphadenectomy, para-aortic lymphadenectomy, or both.
Clinicopathologic factors were used to assess the risk of lymph node metastases.
CA-125 level at diagnosis.
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2. 3. Statistical analysis
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Examined factors included age, menopausal status, histological type, grade, and serum
Fisher’s exact and χ2 tests were used to analyze differences between qualitative data. The optimum cut-off point for CA-125 was determined using a receiver operating characteristic
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(ROC) curve. The independent effects of the clinical and pathological factors on lymph node
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metastases were then determined with a multiple logistic regression analysis, in which factors those were statistically significant in the univariate analysis were entered into a multiple logistic regression analysis. A p -value of <0.05 was considered significant in all analyses. All data were analyzed using the SPSS statistical software package, version 17.0 (IBM Corporation; Armonk, NY, USA).
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3. Results A total of 256 patients were identified in the present study. Table 1 summarizes the
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clinicopathologic characteristics of these patients. The median age was 56 years (range, 19-76 years); 57.8% (148/256) of the patients were premenopausal, while 81.3% (208/256) of the
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patients were diagnosed with serous carcinoma. According to the FIGO criteria, 32.0% (82/256) had stage I; 25.8% (66/256) had stage II; and 42.2% (108/256) had stage III.
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All patients received pelvic lymphadenectomy, and 144 (56.3%) patients received para-aortic lymphadenectomy. The mean number of removed lymph nodes was 20.5 (range, 2-57), and nodal metastases were found in 84 patients (32.8%). Of the 84 patients with lymph
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node positive, 38 (45.2%) patients with pelvic lymph node positive, 34 (40.5%) patients with pelvic and para-aortic nodal metastases, and 12 (14.3%) patients with para-aortic nodal metastase. The mean number of positive lymph nodes was 3 (range, 1-40) in patients with
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lymph node metastases.
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The median and mean values for the preoperative serum CA-125 levels were 330.3 U/mL and 1254.6 U/mL (range, 12-18277 U/mL), respectively. The optimal cut-off points for CA-125 were analyzed using an ROC curve. The results showed that 740 U/mL was the optimal cut-off point for lymph node metastases (area under ROC curve = 0.655; p < 0.001). Therefore, an optimal cutoff value of 740 was validated as a factor to assess the risk of lymph node metastasis.
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Table 1 shows the risk factors for lymph node metastases according to the univariate analysis. Serous histology, grade 2-3, and CA-125 level at diagnosis >740 U/mL were
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significant risk factors for lymph node metastases, while age and menopausal status were not. Serous adenocarcinoma had the highest incidence of node metastases if compared with other
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histological types (37.5% vs. 12.5%; p = 0.001). No lymph node metastases were found in patients with well-differentiated (grade 1) tumors. A significant difference in the incidence of
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lymph node metastases was observed among patients with moderately (grade 2) and poorly differentiated (grade 3) tumors, as compared with those with well-differentiated tumors (36.5%-37.3% vs. 0%; p < 0.001). Patients with a CA-125 level of ≤740 U/mL at diagnosis
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conferred a lymph node metastasis risk that was significantly lower than those with a CA-125 level of >740 U/mL at diagnosis (22.4% vs. 53.5%; p < 0.001). According to the multivariate analysis, serous histology (odds ratio [OR], 2.728; 95%
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confidence interval [CI], 1.072-6.945; p = 0.035), histological grade 2-3 (OR, 1.897; 95% CI,
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1.209-2.977; p = 0.005), and CA-125 level at diagnosis >740 U/mL (OR, 3.858; 95% CI, 2.143-6.947; p < 0.001) remain the most important risk factors for lymph node metastases (Table 2).
For these 3 independent risk factors, the nodal metastasis rates corresponding to 0, 1, 2, and 3 risk factors were 0, 4.0%, 29.9%, and 61.8%, respectively (p < 0.001) (Table 3) (Figure 1). Therefore, patients with 0 to 1 risk factors were considered a low-risk group, and patients
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with 2 to 3 risk factors were considered a high-risk group. The nodal metastasis rates for the low-risk group were significantly lower than those of the high-risk group (3.7% vs. 40.6%; p
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< 0.001). The predictive performance for the model was investigated. An ROC curve was
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constructed, and the calculated area under the curve was 0.740 (p < 0.001).
4. Discussion
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In the present study, risk factors affecting pelvic or para-aortic node metastases were investigated in patients with ovarian cancer. The results showed that histological type, grade, and CA-125 level at diagnosis were independent risk factors for lymph node metastasis for
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patients with ovarian cancer.
FIGO recommendations (1988) for surgical staging of ovarian cancer included pelvic and para-aortic lymph node sampling or lymphadenectomy. However, the benefit of
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lymphadenectomy for patients with ovarian cancer is still controversial. There are serious
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post-operative complications associated with lymphadenectomy, such as lower extremity lymphedema and pelvic lymph cysts with concomitant infection, and these can develop into chronic conditions [13-15]. A meta-analysis revealed that lymphadenectomy could improve the 5-year overall survival rate for advanced-stage (FIGO III-IV stage) epithelial ovarian cancer, but not early-stage (FIGO I-II stage) epithelial ovarian cancer or for residual tumors of ≤2 cm [16]. Randomized controlled studies have also failed to demonstrate that a
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lymphadenectomy might benefit patients with ovarian cancer [10]. After a lymphadenectomy, 5%–10% of patients with stage I–II ovarian cancer are diagnosed with lymph node
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metastases and are re-staged after surgery [17-19]. A systematic lymphadenectomy is essential for accurate staging and has a prognostic and
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possible therapeutic role. Chan et al. reported an increase in the percentage of patients who underwent systematic lymphadenectomy during surgical staging for ovarian cancer during the
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last decade using the Surveillance, Epidemiology, and End Results data [20]. Although lymph node status is important for the staging of ovarian cancer, not all patients with ovarian cancer require a lymphadenectomy. A randomized study showed that a systematic lymphadenectomy
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detected nodal metastases in 8/59 (13.6%) of women with no evidence of residual tumors and in 30/99 (30.3%) of women who had any residual tumors after primary surgery [10]. It was 22% in another randomized study [11]. In the present retrospective study, 32.8% had lymph
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metastases.
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node metastases. Thus, the majority of patients with ovarian cancer have no lymph node
Currently, for ovarian cancer, risk factors for lymph node metastases are still controversial.
Histological type, grade, bilateral adnexal disease, menopause status, preoperative serum CA-125 levels, and lymph node involvement on imaging studies have been found to be risk factors for lymph node metastases. However, the inclusion criteria and sample sizes varied among studies, and these risk factors were inconsistent among them [17,19,21-23]. Our
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results showed that histological type, grade, and CA-125 levels at diagnosis were independent risk factors for lymph node metastasis in ovarian cancer. have
shown
that
one-third
to
one-forth
of
patients
with
serous
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Studies
cystadenocarcinoma of the ovary develop lymph node metastases in the retroperitoneal space;
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however, few patients with mucinous adenocarcinoma of the ovary have no lymph node metastases [23]. Ditto et al. and Powless et al. found that 28%–30% of patients with serous
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cystadenocarcinoma of the ovary developed pelvic and/or para-aortic lymph node metastases, while 10.5% of patients with endometrioid adenocarcinoma of the ovary developed lymph node metastases, but patients with mucinous adenocarcinoma of the ovary had no lymph node
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metastases [19,23]. Takeshima et al. found that the proportion of patients with serous cystadenocarcinoma, clear-cell carcinoma, endometrioid adenocarcinoma, and mucinous adenocarcinoma who developed pelvic and/or para-aortic lymph node metastasis was 36.7%,
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16.9%, 15.6%, and 7.7%, respectively [24]. In the present study, 37.5% of patients with
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serous cystadenocarcinoma were diagnosed with lymph node metastases, while 12.5% with non-serous cystadenocarcinoma developed lymph node metastases, 20% with mucinous adenocarcinoma had lymph node metastases (4/20), and 11.1% (2/18) with endometrioid adenocarcinoma developed lymph node metastases; however, 10 patients with clear-cell carcinoma had no lymph node metastases. A multivariate analysis showed that serous cystadenocarcinoma was a risk factor for lymph node metastasis in ovarian cancer. Powless et
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al. and Bachmann et al. confirmed that serous cystadenocarcinoma was a risk factor for lymph node metastases [5,6,23], but pathological type was not found to be a risk factor for
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lymph node metastasis in other studies [19,21,22]. These findings and our results suggest that clinicians should consider risks for lymph node metastasis in their evaluation if serous
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cystadenocarcinoma was found upon a pathological examination.
In the study by Kleppe et al., the proportion of patients with grade 1, grade 2, and grade 3
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who developed lymph node metastases was 4.0%, 16.5%, and 20.0%, respectively [12]. Bachmann et al. also found that grade 3 was an independent risk factor for lymph node metastasis [5]; however, this was not observed in other studies [19,22]. Our results showed
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that grade 2–3 was an independent risk factor for lymph node metastases, and lymphadenectomy could be avoided for grade 1 disease. Serum CA-125 levels are known as a clinical prognostic factor for survival and response
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to treatment for patients with epithelial ovarian cancer [25-27]. Numerous studies have found
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that CA-125 may serve as a risk factor for lymph node metastasis in endometrial cancer [28-30]. Nevertheless, there have been few studies on the prediction of nodal metastasis in ovarian cancer using preoperative serum CA-125 levels. Kim et al. found that the preoperative serum CA-125 level (> 535 U/mL) was a risk factor for lymph node metastasis in patients with epithelial ovarian cancer [22]. Sudolmus et al. found that CA-125 could be used to predict lymph node metastasis for ovarian cancer and that the best cut-off point was
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72 U/mL [21]. However, Ditto et al. did not find that CA-125 was a risk factor for lymph node metastasis [19]. Our results showed that CA-125 was an independent risk factor for
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lymph node metastasis. Although the cut-off value was different from previous studies, the findings suggest that CA-125 is an important risk factor for the evaluation of lymph node
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metastasis in ovarian cancer.
Our results showed that the proportion of patients with 0, 1, 2, and 3 risk factors that
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developed lymph node metastasis was 0, 4.0%, 29.9%, and 61.8%, respectively (p < 0.001). According to the number of risk factors, patients were divided into a low-risk group (0-1 risk factor) and high-risk group (2-3 risk factors). The results showed that the risk of lymph node
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metastasis in the high-risk group was significantly higher than that of the low-risk group (40.6% vs. 3.7%; P < 0.001), suggesting that it is feasible to predict lymph node metastasis according to a number of risk factors, but more studies are required to confirm our results.
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The current study had some limitations. First, this was a single-center retrospective study
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and was subject to inherent biases. Second, patients enrolled in the present study underwent cytoreductive surgery, which achieved optimal debulking if the residual disease was <1 cm. Therefore, patients with metastatic FIGO stage IV disease were excluded in the present study. In addition, there were only 56.3% of patients received para-aortic lymphadenectomy, which would have a potential impact on the realistic number of positive lymph nodes.
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5. Conclusions In conclusion, as systematic lymphadenectomy for improving therapeutic efficacy and
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survival remains controversial. Our results suggest that the decision to perform complete surgical staging with systematic lymphadenectomy in ovarian cancer patients should be
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referred to the histological type, grade, and CA-125 level at diagnosis.
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Ethical approval
The study was approved by the ethics committee of the Sun Yat-sen University Cancer
Sources of funding
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Center.
This work was supported by grants from the National Natural Science Foundation of
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China (No. 81571418), the Natural Science Foundation of Fujian Province (No. 2015J01550,
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2013D001), and the Foundation for Young Scholar of Fujian Provincial Health Department (No. 2014-ZQN-ZD-31).
Author contribution JZ, JYS, SGW, QHC and FYL performed the experiment. JZ, JYS, and SGW drafted the article and interpret the data. XW and ZYH collected and analyzed the data. QHC and FYL
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design the study and critically revise the manuscript. All authors finally approved the
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submitted version
Guarantor
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Feng-Yan Li
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Conflict of interest disclosures The authors have no conflicts of interest to disclose.
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Research registration unique identifying number (UIN) Research registry 854.
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Acknowledgment
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This work was supported by grants from the National Natural Science Foundation of China (No. 81571418), the Natural Science Foundation of Fujian Province (No. 2015J01550, 2013D001), and the Foundation for Young Scholar of Fujian Provincial Health Department (No. 2014-ZQN-ZD-31).
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in endometria lcancer. Acta Obstet Gynecol Scand. (2006) 1501-1505.
[30] J. Y. Lee, D. C. Jung, S. H. Park, M. C. Lim, S.S. Seo, S. Y. Park, et al., Preoperative
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prediction model of lymph node metastasis in endometrial cancer. Int J Gynecol Cancer. (2010) 1350-1355.
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Figure legend
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Figure 1. Frequency of lymph node metastasis among the classified risk groups.
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Table 1. Clinicopathologic characteristics and univariate analysis for lymph node metastases. Characteristic
n (%)
Node-negative (%)
Node-positive (%)
p-value
≤ 50
134 (52.3)
92 (53.5)
42 (50.0)
0.600
> 50
122 (47.7)
80 (46.5)
42 (50.0)
Premenopausal
148 (57.8)
102 (59.3)
46 (54.8)
Postmenopausal
108 (42.2)
70 (40.7)
38 (45.2)
Serous
208 (81.3)
130 (75.6)
Non-serous
48 (18.7)
Grade
78 (92.9)
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Histology
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Menopausal status
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Age (years)
42 (24.4)
6 (7.1)
28 (16.3)
0 (0)
1
28 (10.9)
2
126 (49.2)
80 (46.5)
46 (54.8)
3
102 (39.9)
64 (37.2)
38 (45.2)
0.490
0.001
< 0.001
≤740
170 (66.4)
132 (76.7)
38 (45.2)
86 (33.6)
40 (23.3)
46 (54.8)
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>740
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CA-125 at diagnosis (U/mL )
< 0.001
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Table 2. Multivariate analysis of the association of clinicopathological characteristics with lymph node metastases. OR
95% CI
p-value
Histology
2.728
1.072-6.945
0.035
Histologic grade
1.897
1.209-2.977
CA-125 at diagnosis
3.858
2.143-6.947
0.005
< 0.001
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OR, odds ratio; CI, confidence interval.
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Characteristic
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Table 3. Frequency of lymph node metastasis among the classified risk groups. Node-negative (%)
Node-positive (%)
p-value
0 risk factor
4 (1.6)
4 (100)
0 (0)
< 0.001
1 risk factor
50 (19.5)
48 (96.0)
2 (4.0)
2 risk factors
134 (52.3)
94 (70.1)
40 (29.9)
3 risk factors
68 (26.6)
26 (38.2)
42 (61.8)
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n (%)
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Characteristic
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HIGHLIGHTS
Lymphadenectomy in ovarian cancer is still controversial.
2.
CA-125 level are significantly associated with lymph node metastases in ovarian
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1.
cancer.
Lymphadenectomy could be avoided for patients with lower risk for lymph node
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3.
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metastases.
S1743-9191(16)00257-0
DOI:
10.1016/j.ijsu.2016.03.039
Reference:
IJSU 2683
To appear in:
International Journal of Surgery
Received Date: 14 January 2016 Revised Date:
6 February 2016
Accepted Date: 14 March 2016
Please cite this article as: Zhou J, Sun J-Y, Wu S-G, Wang X, He Z-Y, Chen Q-H, Li F-Y, Risk factors for lymph node metastasis in ovarian cancer: implications for systematic lymphadenectomy, International Journal of Surgery (2016), doi: 10.1016/j.ijsu.2016.03.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Risk factors for lymph node metastasis in ovarian cancer:
Juan Zhou
a,1
, Jia-Yuan Sun
b,1
, San-Gang Wu
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implications for systematic lymphadenectomy
c,1
, Xuan Wang d, Zhen-Yu He b,
a
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Qiong-Hua Chen a,*, Feng-Yan Li b,*
Xiamen Cancer Center, Department of Obstetrics and Gynecology, the First
b
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Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China Sun Yat-sen University Cancer Center, Department of Radiation Oncology, State
Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China
Xiamen Cancer Center, Department of Radiation Oncology, the First Affiliated
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c
Hospital of Xiamen University, Xiamen, People’s Republic of China d
Department of Basic Medical Science, Medical College, Xiamen University, Xiamen
Juan Zhou, Jia-Yuan Sun, and San-Gang Wu contributed equally to this work.
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1
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361003, People’s Republic of China
* Corresponding authors: Qiong-Hua Chen and Feng-Yan Li
Qiong-Hua Chen, Xiamen Cancer Center, Department of Obstetrics and Gynecology, the First Affiliated
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Hospital of Xiamen University, Xiamen, People’s Republic of China
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Tel. +86 592 2139531, Fax. +86 592 2139562, E-mail. [email protected]
Feng-Yan Li, Sun Yat-sen University Cancer Center, Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative
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Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China
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Tel. +86 20 87343543 Fax. +86 20 87343392 E-mail. [email protected]
Ethical approval
The study was approved by the ethics committee of the Sun Yat-sen University
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Cancer Center.
Sources of funding
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This work was supported by grants from the National Natural Science Foundation of China (No. 81571418), the Natural Science Foundation of Fujian Province (No.
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2015J01550, 2013D001), and the Foundation for Young Scholar of Fujian Provincial Health Department (No. 2014-ZQN-ZD-31).
Author contribution JZ, JYS, SGW, QHC and FYL performed the experiment. JZ, JYS and SGW drafted the article and interpret the data. XW and ZYH collected and analyzed the
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data. QHC and FYL design the study and critically revise the manuscript. All authors
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fi nally approved the submitted version
Guarantor
Conflict of interest disclosures
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Feng-Yan Li
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The authors have no conflicts of interest to disclose.
Research registration unique identifying number (UIN)
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Research registry 854.
Acknowledgment
This work was supported by grants from the National Natural Science Foundation
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of China (No. 81571418), the Natural Science Foundation of Fujian Province (No. 2015J01550, 2013D001), and the Foundation for Young Scholar of Fujian Provincial
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Health Department (No. 2014-ZQN-ZD-31).
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Risk factors for lymph node metastasis in ovarian cancer: implications for
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systematic lymphadenectomy
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Abstract Background: The purpose of this study was to assess the risk factors associated with lymph
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node metastases and to evaluate the role of systematic lymphadenectomy in ovarian cancer. Methods: We retrospectively reviewed patients diagnosed with ovarian cancer between
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January 2004 and January 2012. Demographics, pathologic findings, and correlations with lymph node metastases were assessed.
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Results: A total of 256 patients were identified. The mean number of removed lymph nodes was 20.5 (range, 2-57), and 84 patients (32.8%) had nodal metastases. The mean number of positive lymph nodes was 3 (range, 1-40) in patients with lymph node metastases. Univariate
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analysis showed that serous histology, histological grade 2-3, and CA-125 level at diagnosis >740 U/mL were significant risk factors for lymph node metastases. Multivariate analysis showed that serous histology (odds ratio [OR], 2.728; 95% confidence interval [CI],
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1.072-6.945; p = 0.035), histological grade 2-3 (OR 1.897; 95% CI, 1.209-2.977; p = 0.005),
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and CA-125 level at diagnosis >740 U/mL (OR, 3.858; 95% CI 2.143-6.947; p < 0.001) remain the most important risk factors for lymph node metastases. The nodal metastasis rates for 0 to 1 risk factors were significantly lower than those of 2 to 3 risk factors (3.7% vs. 40.6%; p < 0.001). Conclusions: The current study suggests that the decision making of systematic lymphadenectomy in ovarian cancer patients should be referred to the histological type, grade,
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and CA-125 level at diagnosis. Keywords: Ovarian cancer, Lymph node metastases, Lymphadenectomy, CA-125, Histology
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type
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1. Introduction Ovarian cancer is a highly fatal gynecologic cancer and the fifth leading cause of cancer
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mortality for women, with 21,980 new cases and 14,270 deaths occurring in the United States in 2014 [1]. In China, the incidence rate for ovarian cancer ranks 10th and was 7.95 per
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100,000 women during 2009 [2]. Most patients with ovarian cancer have advanced disease upon diagnosis owing to the asymptomatic nature of early-stage tumors, resulting in poor
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long-time survival [3,4].
Surgery is still an important treatment strategy for ovarian cancer, but the role of systematic lymphadenectomy for treating ovarian cancer is still controversial. Lymph node
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status may significantly affect the survival of patients with ovarian cancer and has been included as an important factor in the International Federation of Gynecology and Obstetrics (FIGO) staging system for ovarian cancer [5-7]. Ovarian cancer with lymph node metastasis
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is usually classified as stage III or higher [8,9]. Thus, systematic lymphadenectomy was
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included in the FIGO staging system guidelines because of recognition of the importance of the prognostic value of lymph node metastasis. Randomized studies indicated that analyses for systematic lymphadenectomy detected nodal metastases in 13.6%–30.3% of patients with ovarian cancer [10,11]. It was found that lymph node tumor involvement was 14.2% (range 6.1%-29.6%) for patients with clinical stage I–II ovarian cancer [12]. However, the predict factors for lymph node status in ovarian cancer patients are still lacking. In this retrospective
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study, we aimed to identify the incidence of lymph node metastases in FIGO stages I to III ovarian cancer, to determine the influence of risk factors on the incidence of lymph node
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metastases, and to evaluate the role of systematic lymphadenectomy.
2. Materials and methods
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2.1. Patients
From December 2004 to March 2012, a total of 256 patients with primary ovarian cancer who underwent cytoreductive surgery and lymphadenectomy at the XXXXXX (XXXXXX)
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were retrospectively analyzed. Cytoreductive surgery was considered to have achieved optimal debulking if the residual disease was < 1 cm. Patients with synchronous or metachronous tumors, borderline tumors, and advanced-stage (stage IV) ovarian cancer were
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excluded. Patients with missing data were also excluded. The study was approved by the
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ethics committee of XXXXXX. All patients provided written consent for storage of their information in the hospital database and for research use of the information.
2.2. Clinicopathologic factors Preoperative serum CA-125 levels were measured within 1 week of a staging laparotomy using a radioimmunoassay kit. The upper limit of normal for the serum CA-125 levels was
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defined as 35 U/mL. After being diagnosed with ovarian carcinoma, patients underwent surgical staging
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including a bilateral salpingo-oophorectomy and total abdominal hysterectomy; washing cytology; random multiple peritoneal biopsies; an omentectomy; and a systematic pelvic
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lymphadenectomy, para-aortic lymphadenectomy, or both.
Clinicopathologic factors were used to assess the risk of lymph node metastases.
CA-125 level at diagnosis.
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2. 3. Statistical analysis
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Examined factors included age, menopausal status, histological type, grade, and serum
Fisher’s exact and χ2 tests were used to analyze differences between qualitative data. The optimum cut-off point for CA-125 was determined using a receiver operating characteristic
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(ROC) curve. The independent effects of the clinical and pathological factors on lymph node
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metastases were then determined with a multiple logistic regression analysis, in which factors those were statistically significant in the univariate analysis were entered into a multiple logistic regression analysis. A p -value of <0.05 was considered significant in all analyses. All data were analyzed using the SPSS statistical software package, version 17.0 (IBM Corporation; Armonk, NY, USA).
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3. Results A total of 256 patients were identified in the present study. Table 1 summarizes the
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clinicopathologic characteristics of these patients. The median age was 56 years (range, 19-76 years); 57.8% (148/256) of the patients were premenopausal, while 81.3% (208/256) of the
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patients were diagnosed with serous carcinoma. According to the FIGO criteria, 32.0% (82/256) had stage I; 25.8% (66/256) had stage II; and 42.2% (108/256) had stage III.
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All patients received pelvic lymphadenectomy, and 144 (56.3%) patients received para-aortic lymphadenectomy. The mean number of removed lymph nodes was 20.5 (range, 2-57), and nodal metastases were found in 84 patients (32.8%). Of the 84 patients with lymph
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node positive, 38 (45.2%) patients with pelvic lymph node positive, 34 (40.5%) patients with pelvic and para-aortic nodal metastases, and 12 (14.3%) patients with para-aortic nodal metastase. The mean number of positive lymph nodes was 3 (range, 1-40) in patients with
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lymph node metastases.
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The median and mean values for the preoperative serum CA-125 levels were 330.3 U/mL and 1254.6 U/mL (range, 12-18277 U/mL), respectively. The optimal cut-off points for CA-125 were analyzed using an ROC curve. The results showed that 740 U/mL was the optimal cut-off point for lymph node metastases (area under ROC curve = 0.655; p < 0.001). Therefore, an optimal cutoff value of 740 was validated as a factor to assess the risk of lymph node metastasis.
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Table 1 shows the risk factors for lymph node metastases according to the univariate analysis. Serous histology, grade 2-3, and CA-125 level at diagnosis >740 U/mL were
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significant risk factors for lymph node metastases, while age and menopausal status were not. Serous adenocarcinoma had the highest incidence of node metastases if compared with other
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histological types (37.5% vs. 12.5%; p = 0.001). No lymph node metastases were found in patients with well-differentiated (grade 1) tumors. A significant difference in the incidence of
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lymph node metastases was observed among patients with moderately (grade 2) and poorly differentiated (grade 3) tumors, as compared with those with well-differentiated tumors (36.5%-37.3% vs. 0%; p < 0.001). Patients with a CA-125 level of ≤740 U/mL at diagnosis
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conferred a lymph node metastasis risk that was significantly lower than those with a CA-125 level of >740 U/mL at diagnosis (22.4% vs. 53.5%; p < 0.001). According to the multivariate analysis, serous histology (odds ratio [OR], 2.728; 95%
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confidence interval [CI], 1.072-6.945; p = 0.035), histological grade 2-3 (OR, 1.897; 95% CI,
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1.209-2.977; p = 0.005), and CA-125 level at diagnosis >740 U/mL (OR, 3.858; 95% CI, 2.143-6.947; p < 0.001) remain the most important risk factors for lymph node metastases (Table 2).
For these 3 independent risk factors, the nodal metastasis rates corresponding to 0, 1, 2, and 3 risk factors were 0, 4.0%, 29.9%, and 61.8%, respectively (p < 0.001) (Table 3) (Figure 1). Therefore, patients with 0 to 1 risk factors were considered a low-risk group, and patients
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with 2 to 3 risk factors were considered a high-risk group. The nodal metastasis rates for the low-risk group were significantly lower than those of the high-risk group (3.7% vs. 40.6%; p
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< 0.001). The predictive performance for the model was investigated. An ROC curve was
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constructed, and the calculated area under the curve was 0.740 (p < 0.001).
4. Discussion
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In the present study, risk factors affecting pelvic or para-aortic node metastases were investigated in patients with ovarian cancer. The results showed that histological type, grade, and CA-125 level at diagnosis were independent risk factors for lymph node metastasis for
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patients with ovarian cancer.
FIGO recommendations (1988) for surgical staging of ovarian cancer included pelvic and para-aortic lymph node sampling or lymphadenectomy. However, the benefit of
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lymphadenectomy for patients with ovarian cancer is still controversial. There are serious
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post-operative complications associated with lymphadenectomy, such as lower extremity lymphedema and pelvic lymph cysts with concomitant infection, and these can develop into chronic conditions [13-15]. A meta-analysis revealed that lymphadenectomy could improve the 5-year overall survival rate for advanced-stage (FIGO III-IV stage) epithelial ovarian cancer, but not early-stage (FIGO I-II stage) epithelial ovarian cancer or for residual tumors of ≤2 cm [16]. Randomized controlled studies have also failed to demonstrate that a
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lymphadenectomy might benefit patients with ovarian cancer [10]. After a lymphadenectomy, 5%–10% of patients with stage I–II ovarian cancer are diagnosed with lymph node
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metastases and are re-staged after surgery [17-19]. A systematic lymphadenectomy is essential for accurate staging and has a prognostic and
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possible therapeutic role. Chan et al. reported an increase in the percentage of patients who underwent systematic lymphadenectomy during surgical staging for ovarian cancer during the
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last decade using the Surveillance, Epidemiology, and End Results data [20]. Although lymph node status is important for the staging of ovarian cancer, not all patients with ovarian cancer require a lymphadenectomy. A randomized study showed that a systematic lymphadenectomy
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detected nodal metastases in 8/59 (13.6%) of women with no evidence of residual tumors and in 30/99 (30.3%) of women who had any residual tumors after primary surgery [10]. It was 22% in another randomized study [11]. In the present retrospective study, 32.8% had lymph
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metastases.
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node metastases. Thus, the majority of patients with ovarian cancer have no lymph node
Currently, for ovarian cancer, risk factors for lymph node metastases are still controversial.
Histological type, grade, bilateral adnexal disease, menopause status, preoperative serum CA-125 levels, and lymph node involvement on imaging studies have been found to be risk factors for lymph node metastases. However, the inclusion criteria and sample sizes varied among studies, and these risk factors were inconsistent among them [17,19,21-23]. Our
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results showed that histological type, grade, and CA-125 levels at diagnosis were independent risk factors for lymph node metastasis in ovarian cancer. have
shown
that
one-third
to
one-forth
of
patients
with
serous
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Studies
cystadenocarcinoma of the ovary develop lymph node metastases in the retroperitoneal space;
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however, few patients with mucinous adenocarcinoma of the ovary have no lymph node metastases [23]. Ditto et al. and Powless et al. found that 28%–30% of patients with serous
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cystadenocarcinoma of the ovary developed pelvic and/or para-aortic lymph node metastases, while 10.5% of patients with endometrioid adenocarcinoma of the ovary developed lymph node metastases, but patients with mucinous adenocarcinoma of the ovary had no lymph node
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metastases [19,23]. Takeshima et al. found that the proportion of patients with serous cystadenocarcinoma, clear-cell carcinoma, endometrioid adenocarcinoma, and mucinous adenocarcinoma who developed pelvic and/or para-aortic lymph node metastasis was 36.7%,
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16.9%, 15.6%, and 7.7%, respectively [24]. In the present study, 37.5% of patients with
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serous cystadenocarcinoma were diagnosed with lymph node metastases, while 12.5% with non-serous cystadenocarcinoma developed lymph node metastases, 20% with mucinous adenocarcinoma had lymph node metastases (4/20), and 11.1% (2/18) with endometrioid adenocarcinoma developed lymph node metastases; however, 10 patients with clear-cell carcinoma had no lymph node metastases. A multivariate analysis showed that serous cystadenocarcinoma was a risk factor for lymph node metastasis in ovarian cancer. Powless et
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al. and Bachmann et al. confirmed that serous cystadenocarcinoma was a risk factor for lymph node metastases [5,6,23], but pathological type was not found to be a risk factor for
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lymph node metastasis in other studies [19,21,22]. These findings and our results suggest that clinicians should consider risks for lymph node metastasis in their evaluation if serous
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cystadenocarcinoma was found upon a pathological examination.
In the study by Kleppe et al., the proportion of patients with grade 1, grade 2, and grade 3
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who developed lymph node metastases was 4.0%, 16.5%, and 20.0%, respectively [12]. Bachmann et al. also found that grade 3 was an independent risk factor for lymph node metastasis [5]; however, this was not observed in other studies [19,22]. Our results showed
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that grade 2–3 was an independent risk factor for lymph node metastases, and lymphadenectomy could be avoided for grade 1 disease. Serum CA-125 levels are known as a clinical prognostic factor for survival and response
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to treatment for patients with epithelial ovarian cancer [25-27]. Numerous studies have found
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that CA-125 may serve as a risk factor for lymph node metastasis in endometrial cancer [28-30]. Nevertheless, there have been few studies on the prediction of nodal metastasis in ovarian cancer using preoperative serum CA-125 levels. Kim et al. found that the preoperative serum CA-125 level (> 535 U/mL) was a risk factor for lymph node metastasis in patients with epithelial ovarian cancer [22]. Sudolmus et al. found that CA-125 could be used to predict lymph node metastasis for ovarian cancer and that the best cut-off point was
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72 U/mL [21]. However, Ditto et al. did not find that CA-125 was a risk factor for lymph node metastasis [19]. Our results showed that CA-125 was an independent risk factor for
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lymph node metastasis. Although the cut-off value was different from previous studies, the findings suggest that CA-125 is an important risk factor for the evaluation of lymph node
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metastasis in ovarian cancer.
Our results showed that the proportion of patients with 0, 1, 2, and 3 risk factors that
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developed lymph node metastasis was 0, 4.0%, 29.9%, and 61.8%, respectively (p < 0.001). According to the number of risk factors, patients were divided into a low-risk group (0-1 risk factor) and high-risk group (2-3 risk factors). The results showed that the risk of lymph node
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metastasis in the high-risk group was significantly higher than that of the low-risk group (40.6% vs. 3.7%; P < 0.001), suggesting that it is feasible to predict lymph node metastasis according to a number of risk factors, but more studies are required to confirm our results.
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The current study had some limitations. First, this was a single-center retrospective study
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and was subject to inherent biases. Second, patients enrolled in the present study underwent cytoreductive surgery, which achieved optimal debulking if the residual disease was <1 cm. Therefore, patients with metastatic FIGO stage IV disease were excluded in the present study. In addition, there were only 56.3% of patients received para-aortic lymphadenectomy, which would have a potential impact on the realistic number of positive lymph nodes.
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5. Conclusions In conclusion, as systematic lymphadenectomy for improving therapeutic efficacy and
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survival remains controversial. Our results suggest that the decision to perform complete surgical staging with systematic lymphadenectomy in ovarian cancer patients should be
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referred to the histological type, grade, and CA-125 level at diagnosis.
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Ethical approval
The study was approved by the ethics committee of the Sun Yat-sen University Cancer
Sources of funding
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Center.
This work was supported by grants from the National Natural Science Foundation of
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China (No. 81571418), the Natural Science Foundation of Fujian Province (No. 2015J01550,
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2013D001), and the Foundation for Young Scholar of Fujian Provincial Health Department (No. 2014-ZQN-ZD-31).
Author contribution JZ, JYS, SGW, QHC and FYL performed the experiment. JZ, JYS, and SGW drafted the article and interpret the data. XW and ZYH collected and analyzed the data. QHC and FYL
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design the study and critically revise the manuscript. All authors finally approved the
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submitted version
Guarantor
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Feng-Yan Li
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Conflict of interest disclosures The authors have no conflicts of interest to disclose.
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Research registration unique identifying number (UIN) Research registry 854.
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Acknowledgment
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This work was supported by grants from the National Natural Science Foundation of China (No. 81571418), the Natural Science Foundation of Fujian Province (No. 2015J01550, 2013D001), and the Foundation for Young Scholar of Fujian Provincial Health Department (No. 2014-ZQN-ZD-31).
References
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Figure legend
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Figure 1. Frequency of lymph node metastasis among the classified risk groups.
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Table 1. Clinicopathologic characteristics and univariate analysis for lymph node metastases. Characteristic
n (%)
Node-negative (%)
Node-positive (%)
p-value
≤ 50
134 (52.3)
92 (53.5)
42 (50.0)
0.600
> 50
122 (47.7)
80 (46.5)
42 (50.0)
Premenopausal
148 (57.8)
102 (59.3)
46 (54.8)
Postmenopausal
108 (42.2)
70 (40.7)
38 (45.2)
Serous
208 (81.3)
130 (75.6)
Non-serous
48 (18.7)
Grade
78 (92.9)
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Histology
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Menopausal status
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Age (years)
42 (24.4)
6 (7.1)
28 (16.3)
0 (0)
1
28 (10.9)
2
126 (49.2)
80 (46.5)
46 (54.8)
3
102 (39.9)
64 (37.2)
38 (45.2)
0.490
0.001
< 0.001
≤740
170 (66.4)
132 (76.7)
38 (45.2)
86 (33.6)
40 (23.3)
46 (54.8)
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CA-125 at diagnosis (U/mL )
< 0.001
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Table 2. Multivariate analysis of the association of clinicopathological characteristics with lymph node metastases. OR
95% CI
p-value
Histology
2.728
1.072-6.945
0.035
Histologic grade
1.897
1.209-2.977
CA-125 at diagnosis
3.858
2.143-6.947
0.005
< 0.001
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OR, odds ratio; CI, confidence interval.
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Characteristic
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Table 3. Frequency of lymph node metastasis among the classified risk groups. Node-negative (%)
Node-positive (%)
p-value
0 risk factor
4 (1.6)
4 (100)
0 (0)
< 0.001
1 risk factor
50 (19.5)
48 (96.0)
2 (4.0)
2 risk factors
134 (52.3)
94 (70.1)
40 (29.9)
3 risk factors
68 (26.6)
26 (38.2)
42 (61.8)
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n (%)
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Characteristic
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HIGHLIGHTS
Lymphadenectomy in ovarian cancer is still controversial.
2.
CA-125 level are significantly associated with lymph node metastases in ovarian
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1.
cancer.
Lymphadenectomy could be avoided for patients with lower risk for lymph node
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3.
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metastases.