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Annals of Oncology Advance Access originally published online on March 19, 2008
Annals of Oncology 2008 19(7):1284-1287; doi:10.1093/annonc/mdn059
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

gynecologic tumors

Is there any association between retroperitoneal lymphadenectomy and survival benefit in ovarian clear cell carcinoma patients?

S. Suzuki1, H. Kajiyama1,*, K. Shibata1, K. Ino1, A. Nawa1, K. Sakakibara2, K. Matsuzawa3, A. Takeda4, Y. Kinoshita5, M. Kawai6, T. Nagasaka7 and F. Kikkawa1

1 Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
2 Department of Obstetrics and Gynecology, Okazaki City Hospital, Okazaki
3 Department of Obstetrics and Gynecology, Anjyo Kosei Hospital, Anjyo
4 Department of Obstetrics and Gynecology, Gifu Prefectural Tajimi Hospital, Tajimi
5 Department of Obstetrics and Gynecology, Ogaki Municipal Hospital, Ogaki
6 Department of Obstetrics and Gynecology, Toyohashi Municipal Hospital, Toyohashi
7 Division of Pathology, Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan

* Correspondence to: Dr H. Kajiyama, Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsuruma-cho 65, Showa-ku, Nagoya 466-8550, Japan. Tel: +81-52-744-2262; Fax: +81-52-744-2268; E-mail: kajiyama{at}med.nagoya-u.ac.jp


   Abstract
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 Abstract
introduction
 materials and methods
 results
 discussion
 References
 
Background: To estimate the survival impact of systemic retroperitoneal lymphadenectomy in patients diagnosed with International Federation of Gynecology and Obstetrics pTI–IIb clear cell carcinoma of the ovary (CCC).

Patients and Methods: Demographic and clinicopathologic data were obtained from the Tokai Ovarian Tumor Study Group between 1986 and 2006. Survival curves were calculated using the Kaplan–Meier method. Differences in survival rates were analyzed using the log-rank test.

Results: A total of 205 patients had clinical pTI–IIb CCC (median age: 52 years, range: 30–75). One hundred and four (50.7%) patients underwent systemic retroperitoneal lymphadenectomy. Lymphadenectomy was not associated with improved disease-free and overall survival in all patients (P = 0.353 and P = 0.645, respectively). Moreover, lymphadenectomy did not improve the overall survival in those with pTIc CCC (P = 0.433). Similarly, on univariate analysis, age, volume of ascites, preoperative CA 125 values, and regimen of chemotherapy were not significant factors. In addition, there was no significant difference in the ratio of positive lymph node metastases regardless of the completion of lymphadenectomy (P = 0.955).

Conclusion: Our data suggest that patients with pTI–IIb CCC who underwent lymphadenectomy did not show a significant improvement in survival. There was no significant difference in the overall and disease-free survival rates in pTI–IIb CCC patients regardless of the completion of surgical staging lymphadenectomy.

Key words: clear cell carcinoma of the ovary (CCC), epithelial ovarian carcinoma (EOC), lymphadenectomy, stage, survival


   introduction
Top
 Abstract
 introduction
materials and methods
 results
 discussion
 References
 
Clear cell carcinoma of the ovary (CCC) is the second most frequent subtype of epithelial ovarian cancer (EOC) in Japan, although CCC represents 8%–10% of all EOC in the United States [1, 2]. In addition, CCC is more likely to be diagnosed at an earlier stage, bilateral occurrence is rare, and it is frequently associated with endometriosis, hypercalcemia, and thromboembolic complications [2–5]. Generally, EOC cells such as serous adenocarcinoma are sensitive to antineoplastic agents. CCC, however, is comparatively resistant to most of these drugs [1]. Therefore, it is important to identify the prognostic factors of CCC to establish guidelines for its treatment and develop strategies to improve the prognosis [6].

In addition, it is needless to say that complete surgical resection of the tumor is required to improve the prognosis of CCC patients. With regard to nodal metastasis, a recent report from Takano et al. indicated that the positive rates of lymph node metastases in pTIa and pTIc CCC were 9.1% and 7.1%, respectively [7]. Especially for early-stage CCC, it remains unclear whether retroperitoneal lymphadenectomy is beneficial, although there have been several reports regarding survival of stage-I patients [8–10]. Ho et al. [11] demonstrated that disease-free and overall survival rates for patients who received lymphadenectomy including surgery were significantly greater than those for stage I EOC patients who underwent surgery without lymphadenectomy. It, however, still remains inconclusive with regard to survival in patients with CCC, possibly due to the small number of patients. In this context, to evaluate the benefit of lymphadenectomy, we need to analyze a larger number of CCC patients who have received the surgery without any residual tumors.

Between January 1986 and December 2006, a total of 205 patients with International Federation of Gynecology and Obstetrics (FIGO) pTI–IIb CCC were registered and treated by the Tokai Ovarian Tumor Study Group, consisting of Nagoya University Hospital and affiliated hospitals. In the present study, we retrospectively analyzed a large number of CCC patients to estimate the survival impact of comprehensive staging surgeries in pTI–IIb CCC patients and to identify the important demographic and clinicopathologic prognostic factors in pTI–IIb CCC patients.


   materials and methods
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 Abstract
 introduction
 materials and methods
results
 discussion
 References
 
Two hundred and five patients with pTI–IIb pure type CCC diagnosed between 1986 and 2006 were registered and treated by the Tokai Ovarian Tumor Study Group, consisting of Nagoya University Hospital and affiliated hospitals. Data were collected from medical records and clinical follow-up visits. All patients were originally diagnosed with pure type CCC, and histological slides were reviewed by one of the authors with no knowledge of patients’ clinical data, under central pathological review system according to the World Health Organization classification. Tumors were classified as clear cell carcinoma if typical clear or hobnail cells were present in a papillary, solid, or tubulocystic pattern. None of the pTI–IIb patients had any residual tumors. Clinical staging was assessed according to FIGO (1985) criteria without considering the pathologic findings of the lymph nodes.

One hundred and four patients underwent total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic systemic lymphadenectomy as their initial operation (Group A). Patients in Group A received systemic lymphadenectomy, not lymph node exploration or sampling. Exploration of regional lymph nodes included systemic lymphadenectomy, the removal of palpable nodes, or the removal of all lymphatic tissue surrounding the retroperitoneal vessels, in the absence of clinically obvious disease. Para-aortic lymph node dissection was carried out from the bifurcation of the aorta to the origin of the renal vessels. Pelvic node dissection was done from the common, internal and external iliac, and obturator vessels to the femoral ring. One hundred and one patients underwent total hysterectomy and/or unilateral or bilateral salpingo-oophorectomy with or without omentectomy and sampling of lymph nodes (Group B). Lymph node exploration or sampling was added to the surgical procedure carried out in Group B. The current study was a long-term, multi-institutional retrospective analysis. Therefore, there was no evident criterion dividing these patients into each group. Selection of the surgical procedure was influenced by the patients’ physical condition, era of treatment, or decision of each institution.

In CCC patients, 171 were treated postoperatively with three to six cycles of adjuvant chemotherapy; 83 patients received platinum-based chemotherapy and 88 patients received platinum plus taxane chemotherapy. Three patients underwent other regimens. Thirty-one patients did not receive chemotherapy due to severe complications, patients’ wishes, advanced age, or decision of each institution. In the present study, the reminder of the CCC patients received first-line chemotherapy as follows: CAP [cyclophosphamide (300 mg/m2), adriamycin (30 mg/m2), and cisplatin (70 mg/m2)] (1986–1989); CAP or PVB [cisplatin (70 mg/m2), vinblastine (6 mg/m2), and bleomycin (12 mg/m2)] (1989–1991); PVB or PP [carboplatin (300 mg/m2) and cisplatin (70 mg/m2)] (1992–2000); TC {paclitaxel (180 mg/m2) and carboplatin [area under curve (AUC; mg.min/ml) 5]} (2000–2002); and TC or DC [docetaxel (70 mg/m2) and carboplatin (AUC 5)] (2003–2006).

Disease-free survival was defined as the interval from the date of primary surgery until that of recurrence. The overall survival duration was determined as the time from the date of primary surgery until death or that of the last follow-up. Disease-free and overall survival curves were calculated using the Kaplan–Meier method, and significance was determined using the log-rank test. Two-tailed tests at P values <0.05 were considered significant. The significance of differences in clinical characteristics between Groups A and B was determined by the chi-square test.


   results
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 Abstract
 introduction
 materials and methods
 results
discussion
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A total of 205 patients with pure pTI–IIb CCC were entered into this study. Patient characteristics of Groups A and B are summarized in Table 1. The median age at the time of diagnosis for patients in Group A was 52 years and ranged from 30 to 75, while that of Group B was 51 years and ranged from 32 to 75. There were no significant differences in age between Groups A and B (P = 0.549). The median follow-up for surviving patients was 49.6 months in Group A and 49.2 months in Group B. No patient was lost to follow-up. As shown in Table 1, among 104 Group A patients, 19 patients (18.3%) had pTIa–b disease, 76 (73.0%) had pTIc disease, and nine (8.7%) had pTIIa–b disease. Among 101 Group B patients, 27 patients (26.7%) had pTIa–b disease, 67 (66.3%) had pTIc disease, and 7 (7.0%) had pTIIa–b disease. The clinical characteristics of the two groups were similar, except for the rates of positive peritoneal cytology between Groups A and B (P = 0.0006). The median survival of all patients had not yet been reached.


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  		Table 1. Patient characteristics

 
The 5-year disease-specific survival rate of all Group A patients was 84.7%, compared with 85.3% in Group B. On Kaplan–Meier analysis, the difference in overall survival between these groups was nonsignificant (Figure 1). Moreover, since 143 of 205 patients had stage pTIc disease, we examined the difference in the survival of patients with pT1c CCC patients. However, confining analysis to pTIc patients, systemic lymphadenectomy did not improve the 5-year survival {84.2% (Group A) compared with 86.8% (Group B); P = 0.433; Figure 2}. Furthermore, Figures 3 and 4 show the disease-free survival curves of patients with pTI–IIb or pTIc CCC according to the surgical procedure. Similarly, systemic lymphadenectomy did not improve the 5-year disease-free survival of patients with CCC in both analyses [pTI–IIb: 79.7% (Group A) compared with 73.5% (Group B), P = 0.353; pTIc: 77.2% (Group A) compared with 78.0% (Group B), P = 0.926].


Figure 1
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  		Figure 1. Kaplan–Meier estimated overall survival of patients with pTI–IIb pure clear cell carcinoma (CCC). Group A (solid line), 104 patients receiving systemic retroperitoneal lymphadenectomy; Group B (dotted line), 101 patients who did not receive systemic lymphadenectomy. There was no significant difference in survival between Groups A and B patients with pTI–IIb CCC (P = 0.645).

 

Figure 2
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  		Figure 2. Kaplan–Meier estimated overall survival of patients with pTIc clear cell carcinoma of the ovary (CCC). Group A (n = 76), solid line. Group B (n = 67), dotted line. There was no significant difference of survival between Groups A and B patients with pTIc CCC (P = 0.433).

 

Figure 3
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  		Figure 3. Disease-free survival curves of patients with pTI–IIb clear cell carcinoma of the ovary. Five-year disease-free survival was 79.7% in Group A and 73.5% in Group B (P = 0.353).

 

Figure 4
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  		Figure 4. Disease-free survival curves of patients with pTIc clear cell carcinoma of the ovary. Five-year disease-free survival was 77.2% in Group A and 78.0% in Group B (P = 0.926).

 
Finally, in recurrence cases, we examined whether there was a difference in the distribution of recurrence sites. As a result, in Group A, recurrence was observed in 20 of 104 (19.2%) cases and nodal metastasis was found in 6 cases among the 20 recurrent cases. In contrast, in Group B, recurrence was observed in 26 of 101 (25.7%) cases and nodal metastasis was found in 8 cases among the 26 recurrent cases. In both groups, there was no difference in the distribution of nodal recurrence (*P = 0.955, Table 2). Accordingly, nodal metastasis was not always more frequently observed in Group B than Group A.


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  		Table 2. Pelvic and/or para-aortic lymph node metastasis in recurrent cases

 

   discussion
Top
 Abstract
 introduction
 materials and methods
 results
 discussion
References
 
In spite of the implementation of a surgical staging scheme for EOC including lymphadenectomy from the FIGO, there have been limited examinations showing its survival benefit in those patients with early-stage disease. Indeed, an adequate staging procedure will help physicians provide the most appropriate adjuvant treatment. In addition, several reasons may be supposed for the possible improvement in survival associated with systemic lymphadenectomy. For example, a thorough lymphadenectomy may improve survival by removing micrometastatic disease within the node that was not detected on routine hematoxylin and eosin analyses. Or, because of the high probability of developing chemoresistance during therapy, it is likely that the survival benefit experienced by patients who underwent lymphadenectomy may be attributable to the removal of resistant clones of cells and regions of poor blood supply. These explanations emphasize the equivocal benefit of systemic lymphadenectomy in EOC. On the other hand, if there are invisible micrometastases in lymph nodes, it is probable that further micrometastases may expand to other lymph nodes or distant organs through a variety of lymph vessels, or which their surgical removal is a limited. In addition, it is very hard to remove all micrometastases by subsequent platinum- or taxane-based chemotherapies since CCC is generally resistant to these agents. Therefore, the existence of nodal metastasis in itself may hardly contribute to the survival improvement of patients with CCC.

Our present study retrospectively analyzed 205 patients with pTI–IIb CCC to evaluate the efficacy of lymphadenectomy. The reason why we chose pTI–IIb CCC patients for the current analysis was that all the pTI–IIb patients received macroscopically complete tumor resection without any residual tumor on initial surgery. Consequently, we demonstrated that lymphadenectomy did not improve the disease-free and overall survival rates of patients with pTI–IIb CCC. Furthermore, regardless of the completion of lymphadenectomy, there was no difference in the rate of following nodal recurrence.

According to a recent report by Chan et al. [12] regarding the association of systemic lymphadenectomy and survival, although women with non-clear cell EOC showed significantly improved 5-year disease-specific survival with lymphadenectomy, CCC patients did not show significantly improved survival following lymphadenectomy. Their results were consistent with our current data. Of course, we did not think that these retrospective results would immediately lead to the possibility of omitting lymphadenectomy since our study was limited because of the lack of information on the extent of lymphadenectomy, such as the number of resected lymph nodes, subsequent surgical procedures, and complications. Moreover, one of the major problems of our study was the inconsistency of adjuvant chemotherapy between both groups. It is, however, widely accepted that CCC is resistant to a variety of chemotherapeutic agents, including platinum or taxane compounds, and complete surgical resection is crucial for prognostic improvement. Thus, although the distribution of chemotherapy was not significant between both groups, we estimated that the impact of chemotherapy might be less. To completely eliminate the influence of chemotherapy, we should compare patients receiving same regimen and dose. We position our current study as a step towards the next randomized control trial. To verify the actual legitimacy, further investigations should be conducted with a larger scale prospective clinical trial in the future.

The strengths of the current examination include the fact that, to our knowledge, this is one of the largest studies on surgically completely resected CCC evaluating the effect of lymphadenectomy, although it was a retrospective analysis.

Indeed, we understand that a sufficient surgical procedure with systemic lymphadenectomy is required for adequate surgical staging at present. It is, however, possible that the importance of lymphadenectomy may be different in CCC since its biological nature or chemosensitivity differs from other histological types. A more precise analysis of surgical procedures including lymphadenectomy is required to improve the prognosis of CCC patients.

Received for publication December 9, 2007. Revision received February 10, 2008. Accepted for publication February 11, 2008.


   References
Top
 Abstract
 introduction
 materials and methods
 results
 discussion
 References
 
1. Sugiyama T, Kamura T, Kigawa J, et al. Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer (2000) 88:2584–2589.[CrossRef][Web of Science][Medline]

2. Kennedy AW, Biscotti CV, Hart WR, et al. Ovarian clear cell adenocarcinoma. Gynecol Oncol (1989) 32:342–349.[CrossRef][Web of Science][Medline]

3. Goff BA, Sainz de la Cuesta R, Muntz HG, et al. Clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease. Gynecol Oncol (1996) 60:412–417.[CrossRef][Web of Science][Medline]

4. Czernobilsky B, Silverman BB, Enterline HT. Clear-cell carcinoma of the ovary. A clinicopathologic analysis of pure and mixed forms and comparison with endometrioid carcinoma. Cancer (1970) 25:762–772.[Medline]

5. Matsuura Y, Robertson G, Marsden DE, et al. Thromboembolic complications in patients with clear cell carcinoma of the ovary. Gynecol Oncol (2007) 104:406–410.[CrossRef][Web of Science][Medline]

6. Mizuno M, Kikkawa F, Shibata K, et al. Long-term prognosis of stage I ovarian carcinoma. Prognostic importance of intraoperative rupture. Oncology (2003) 65:29–36.[Web of Science][Medline]

7. Takano M, Kikuchi Y, Yaegashi N, et al. Clear cell carcinoma of the ovary: a retrospective multicentre experience of 254 patients with complete surgical staging. Br J Cancer (2006) 94:1369–1374.[CrossRef][Web of Science][Medline]

8. Kennedy AW, Markman M, Biscotti CV, et al. Survival probability in ovarian clear cell adenocarcinoma. Gynecol Oncol (1999) 74:108–114.[CrossRef][Web of Science][Medline]

9. O'Brien ME, Schofield JB, Tan S, et al. Clear cell epithelial ovarian cancer (mesonephroid): bad prognosis only in early stages. Gynecol Oncol (1993) 49:250–254.[CrossRef][Web of Science][Medline]

10. Jenison EL, Montag AG, Griffiths CT, et al. Clear cell adenocarcinoma of the ovary: a clinical analysis and comparison with serous carcinoma. Gynecol Oncol (1989) 32:65–71.[CrossRef][Web of Science][Medline]

11. Ho CM, Chien TY, Shih BY, et al. Evaluation of complete surgical staging with pelvic and para-aortic lymphadenectomy and paclitaxel plus carboplatin chemotherapy for improvement of survival in stage I ovarian clear cell carcinoma. Gynecol Oncol (2003) 88:394–399.[CrossRef][Web of Science][Medline]

12. Chan JK, Munro EG, Cheung MK, et al. Association of lymphadenectomy and survival in stage I ovarian cancer patients. Obstet Gynecol (2007) 109:12–19.[CrossRef][Web of Science][Medline]


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