Pure-type clear cell carcinoma (CCC) has been recognized as a distinct subtype of ovarian cancer, showing resistance to conventional platinum-based chemotherapy and resulting in poor prognosis. The aim of the study was to evaluate the effects of complete surgical staging procedures for early-stage CCC patients in a retrospective multi-institutional analysis. During the period 1992 to 2002, a total of 199 patients with pT1 M0 CCC were identified. Survival analysis was estimated by Kaplan-Meier methods, and prognostic factors were evaluated using a Cox regression model. Among pT1 M0 tumors, retroperitoneal lymph node status was negative in 125 cases (pN0, 63%), positive in 10 cases (pN1, 5%), and unknown in 64 cases (pNx, 32%). Progression-free survival of pN1 was significantly worse than that of pN0 (P < 0.05), whereas there was no significant difference between pN1 and pNx. There was no significant difference of overall survival (OS) among the 3 groups. Multivariate analysis revealed that peritoneal cytology status was the only independent prognostic factor for progression-free survival (P = 0.04), but completion of surgical staging procedures was not a prognostic factor. There was no significant prognostic factor for OS. Our study implied that complete surgical staging enabled us to distinguish a high-risk group of recurrence in pT1 M0 CCC; however, the procedure could not improve OS. Although the study was a limited retrospective study, the impact of peritoneal cytology status was more important than complete surgical staging procedure in CCC patients. More effective treatment modality was warranted, especially for CCC cases positive for malignant peritoneal cytology.
*Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa; †Iwate Medical University School of Medicine, Morioka; ‡Tohoku University Graduate School of Medicine, Sendai; §Jichi Medical University School of Medicine, Shimotsuke; ∥Keio University School of Medicine, Shinjuku-ku; ¶JR Sapporo Railway Hospital, Sapporo; **Fujita Health University School of Medicine, Toyoake; ††Department of Gynecology, Kuzuya Clinic, Nagoya; ‡‡Cancer Center, Tottori University Hospital, Yonago; §§Department of Obstetrics and Gynecology, National Hospital Organization Kobe Medical Center, Kobe; ∥∥Department of Basic Pathology, National Defense Medical College, Tokorozawa; ¶¶Department of Pathology, Kawasaki Medical School, Kurashiki; and ***Department of Gynecology, Ohki Memorial Kikuchi Cancer Clinic for Women, Tokorozawa, Japan.
Address correspondence and reprint requests to Masashi Takano, MD, Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan. E-mail: email@example.com.
Despite recent improvement of treatment modality including chemotherapy, ovarian carcinoma is the leading cause of death in all gynecologic malignancy in the most developed countries.1,2 In several histological subtypes of ovarian cancers, clear cell carcinoma (CCC) is comparatively resistant to most of anticancer drugs including conventional platinum-based chemotherapy3-6 and paclitaxel-based regimen,7,8 resulting in poor prognosis, especially in advanced cases. On the other hand, approximately half of CCC tumors were diagnosed as stage I tumor.9 Surgical staging including retroperitoneal lymphadenectomy was inevitable for the FIGO (International Federation of Gynecology and Obstetrics) staging system.10 There have been several reports regarding the survival of stage I CCC patients11-15; however, it still remains unclear whether complete surgical staging procedure is clinically beneficial for survival of early-stage CCC. The aim of the present study was to evaluate the effect of complete surgical staging procedures upon survival of CCC tumors confined to the ovary (pT1 M0) in a large retrospective multi-intuitional analysis.
Patients and Tumors
Between 1992 and 2002, 334 patients with CCC of the ovary were identified by scanning the medical records of the collaborating institutions and central pathological review by 2 independent pathologists with no knowledge of the patients' clinical data. Tumors were diagnosed as CCC if typical clear or hobnail cells growing in a papillary, solid, or tubulocystic pattern are present in more than 90% of all pathological specimens. Patients received initial treatment and follow-up at 9 institutions belonging to Japan Clear Cell Carcinoma Study Group; National Defense Medical College Hospital, Tohoku University Hospital, Jichi Medical University Hospital, Osaka City General Hospital, Sapporo Medical University, Fujita Health University Hospital, Aichi Cancer Center Hospital, Tottori University Hospital, Kobe National Hospital, and Iwate Medical University Hospital. In those patients, 135 patients were excluded because of advanced FIGO stages more than stage II. The remaining 199 patients (60%) were enrolled on the present study.
Among enrolled patients, 134 patients underwent complete surgical staging procedures including hysterectomy, bilateral salpingo-oophorectomy, peritoneal washing, omentectomy, pelvic lymphadenectomy, and paraaortic lymphadenectomy. Pelvic lymphadenectomy was done from the common, external and internal iliac node, and obturator vessel to the femoral ring. Paraaortic lymphadenectomy was done from the bottom of the left renal vessel including the left infrarenal lymph nodes to the bifurcation of the aorta. Cases that underwent hysterectomy and bilateral salpingo-oophorectomy with only lymph node exploration or sampling were regarded as pNx tumors. Selection of the surgical procedure was determined by the physicians' preference. The resected lymph node counts were not considered for the completion of the lymphadenectomy. A pN1 case was determined as having 1 or more lymph node metastases in pelvic or paraaortic lymph nodes.
One hundred eighty-four patients (92%) received 3 to 6 cycles of postoperative chemotherapy after initial surgery. The regimen of the chemotherapy was as follows: paclitaxel and platinum in 77 cases, other platinum-based regimens in 106 cases, and no chemotherapy in 15 cases. Paclitaxel and platinum regimen consisted of an infusion of 175 to 180 mg/m2 of paclitaxel and 50 to 75 mg/m2 of cisplatin or carboplatin (area under concentration curve = 5-6). Other regimens included CAP (cyclophosphamide [500 mg/m2], doxorubicin [50 mg/m2], and cisplatin [50-70 mg/m2], every 3-4 weeks), CP (cyclophosphamide [500 mg/m2] and cisplatin [50-70 mg/m2], every 3-4 weeks), and CPT-P (irinotecan hydrochloride [50-60 mg/m2, on days 1, 8, and 15] and cisplatin [50-60 mg/m2, on day 1], every 4 weeks).
Progressive disease was defined as the appearance of a new lesion evaluated by computed tomography of chest/abdomen or pelvic magnetic resonance images. Serum levels of tumor markers including CA-125 were not used for survival analysis in the present study. The time to progression was defined as the interval from the date of primary surgery until the date of progressive disease. Survival duration was determined as the time from the date of primary surgery until death or the date of last follow-up contact.
Kaplan-Meier method was used for calculation of patient survival distribution. The significance of the survival distribution in each group was tested using the log-rank test. The χ2 test and Student t test for unpaired data were used for statistical analysis. P < 0.05 was considered statistically significant. The StatView software version 5.0 (SAS Institute Inc, Cary, NC) was used to analyze the date.
A total of 199 pT1 M0 CCC patients were enrolled on the study. Among them, retroperitoneal lymph node status was negative in 125 cases (pN0, 63%), positive in 10 cases (pN1, 5%), and unknown in 64 cases (pNx, 32%). Median follow-up time was 48 months (range, 6-130 months) in pN0 group, 50 months (range, 5-83 months) in pN1 group, and 57 months (range, 5-150 months) in pNx group. Characteristics of the patients are summarized in Table 1. There were no statistical differences among 3 groups according to age, performance status, pT status, ascites/malignant washing, and postoperative chemotherapy.
Five-year progression-free survival (PFS) rate was 84% in pN0 group, 75% in pNx group, and 51% in pN1 group. Progression-free survival of pN1 was significantly worse than that of pN0 (Fig. 1A, P = 0.001), whereas there was no significant difference between pN1 and pNx (P = 0.06). There is no significant prognostic difference between pN0 group and pNx group (P = 0.16). Five-year overall survival (OS) rate was 88% in pN0 group, 84% in pNx group, and 79% in pN1 group (Fig. 1B). There were no statistical differences of OS among the 3 groups: pN0 versus pNx, P = 0.52; pNx versus pN1, P = 0.46; pN0 versus pN1, P = 0.22.
Multiple regression analysis was performed to detect prognostic factors for PFS of stage I CCC. Values of age, performance status, pT and pN status, ascites or peritoneal washing status, and chemotherapy were compared. As a result, ascites or peritoneal cytology status was the only independent prognostic factor for PFS of CCC tumors confined to the ovary (Table 2, P = 0.04). Although pN status showed a marginal difference (P = 0.05), it was not an independent prognostic factor. Other variables were not prognostic factors for PFS including pT status and chemotherapeutic regimen. In addition, the same variables as described in Table 2 were analyzed for OS of CCC patients; however, there were no significant prognostic factors for OS (data not shown). Progression-free survival and OS curves according to peritoneal cytology status are shown in Figure 2. Progression-free survival of the patients with malignant ascites/positive peritoneal washing was significantly worse than those with negative cytology (P = 0.02), but there was no difference in OS (P = 0.28).
It has been reported that the incidence of lymph node metastasis in stage I (pT1) ovarian cancer was approximately 20%.16-19 Previous reports demonstrated that serous tumors had a higher incidence of lymph node metastasis than nonserous tumors including CCC tumors.20,21 The incidence of lymph node involvement of CCC disease was 9.1% in pT1a and 7.1% in pT1c tumors in a large retrospective case series.9 Lower incidence of lymphatic involvement in CCC has been suggested in comparison with other histological subtypes, especially serous tumors.
In early-stage ovarian cancer, clinical significance of complete surgical staging procedures upon survival was not determined. Some reports showed a positive relationship between node status and survival,18,22-24 whereas others showed survival similarity between node positive and negative tumors.25,26 However, the results in these reports were derived from retrospective analysis with relatively small numbers of patients. A prospective randomized clinical trial to assess the value of systematic lymphadenectomy in comparison with lymph node sampling was conducted by Maggioni et al,27 enrolling a total of 268 cases. The incidence of positive nodes was significantly higher in the lymphadenectomy group: 22% versus 9%, P = 0.007; however, there were no significant differences in 5-year OS and PFS between both groups. In our present analysis, pN status showed only a marginal significance upon PFS and no significance upon OS. Together, it is possible that there are only small advantages in systemic lymphadenectomy upon survival of early-stage ovarian cancers including CCC. However, sentinel node detection methods have not been established yet18; comprehensive lymphadenectomy is still recommended as an essential procedure for accurate staging and prediction of recurrence in early-stage ovarian cancers.
In the present analysis, malignant peritoneal cytology was an independent prognostic factor for increased risk of recurrence for CCC tumors confined to the ovary (pT1 M0). Previous studies have demonstrated that positive peritoneal washing was associated with a poorer prognosis in patients with ovarian cancers.28,29 The significant impact of peritoneal cytology upon survival was observed in the cases with CCC. Because CCC tumors generally showed resistance to conventional chemotherapy including platinums and taxans, these observations suggested the existence of intra-abdominal microdissemination, which included chemoresistant clones when the patients were positive for peritoneal washing. Further studies are needed to establish more effective regimens for CCC of the ovary.
In the aspects of molecular biologic characteristics as well as clinical behavior, it is hypothesized that CCC belongs to a different entity from other histological subtypes of ovarian carcinoma. There are many publications supporting this hypothesis, showing that the expression pattern was completely different in several molecular markers such as HNF-1β,30,31 WT1,32 ABCF2.33 These molecules might be candidates used for targeting therapy for CCC in the near future.
The present study was, to our knowledge, 1 of the largest study including CCC tumors confined to the ovary, although it was retrospectively analyzed. The results implied that complete surgical staging enabled us to distinguish a high-risk group of recurrence in pT1 M0 CCC; however, we could not draw the conclusion that the procedures could improve OS of these patients.
For further evaluation, the study using the same chemotherapeutic regimen would be needed to eliminate the chemotherapy bias. In addition, definition of lymphadenectomy should be determined for adequate lymph node assessment. Approximately 81 lymph nodes (range, 49-128 lymph nodes) were reported to be located between the pelvis and the aortic area: 50 at the pelvis and 31 at the aorta.34 Removal of 25 pelvic lymph nodes and 13 aortic lymph nodes was recommended for adequate detection of nodal involvement in epithelial ovarian cancer.35 The definition like this would be extremely helpful not only for comparing retrospective analyses but also for designing prospective studies.
Although the study was a limited retrospective study, it was suggested that the impact of peritoneal cytology is more important than that of complete surgical staging procedure in CCC patients. More effective treatment modality was warranted, especially for cases positive for malignant peritoneal cytology. In addition, further efforts to elucidate the therapeutic effects of comprehensive staging procedures are needed in a large prospective study.
1. Bray F, Loos AH, Tognazzo S, et al. Ovarian cancer in Europe: cross-sectional trends in incidence and mortality in 28 countries, 1953-2000. Int J Cancer
2. Edwards BK, Brown ML, Wingo PA, et al. Annual report to the nation on the status of cancer, 1975-2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst
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
4. Recio FO, Piver MS, Hempling RE, et al. Lack of improved survival plus increase in thromboembolic complications in patients with clear cell carcinoma of the ovary treated with platinum versus nonplatinum-based chemotherapy. Cancer
5. Sugiyama T, Kamura T, Kigawa J, et al. Clinical characteristics of clear cell carcinoma of the ovary. Cancer
6. Pectasides D, Fountzilas G, Aravantinos G, et al. Advanced stage clear-cell epithelial ovarian cancer: the Hellenic Cooperative Oncology Group experience. Gynecol Oncol
7. Enomoto T, Kuragaki C, Yamasaki M, et al. Is clear cell carcinoma and mucinous carcinoma of the ovary sensitive to combination chemotherapy with paclitaxel and carboplatin? Proc Am Soc Clin Oncol
. 2003;22:447. Abstract 1797.
8. Ho CM, Huang YJ, Chen TC, et al. Pure-type clear cell carcinoma of the ovary as a distinct histological type and improved survival in patients treated with paclitaxel-platinum-based chemotherapy in pure-type advanced disease. Gynecol Oncol
9. 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
10. FIGO Cancer Committee. Staging announcement. Gynecol Oncol
11. Kennedy AW, Markman M, Biscotti CV, et al. Survival probability in ovarian clear cell adenocarcinoma. Gynecol Oncol
12. O'Brien ME, Schofield JB, Tan S, et al. Clear cell epithelial ovarian cancer (mesonephroid): bad prognosis only in early stages. Gynecol Oncol
13. Jenison EL, Montag AG, Griffiths CT, et al. Clear cell adenocarcinoma of the ovary: a clinical analysis and comparison with serous carcinoma. Gynecol Oncol
14. 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
15. Suzuki S, Kajiyama H, Shibata K, et al. Is there any association between retroperitoneal lymphadenectomy and survival benefit in ovarian clear cell carcinoma patients? Ann Oncol
16. Cass I, Li AJ, Runowicz CD, et al. Pattern of lymph node metastases in clinically unilateral stage I invasive epithelial ovarian carcinomas. Gynecol Oncol
17. Morice P, Joulie F, Camatte S, et al. Lymph node involvement in epithelial ovarian cancer: analysis of 276 pelvic and paraaortic lymphadenectomies and surgical implications. J Am Coll Surg
18. Negishi H, Takeda M, Fujimoto T, et al. Lymphatic mapping and sentinel node identification as related to the primary sites of lymph node metastasis in early stage ovarian cancer. Gynecol Oncol
19. Sakai K, Kamura T, Hirakawa T, et al. Relationship between pelvic lymph node involvement and other disease sites in patients with ovarian cancer. Gynecol Oncol
20. Baiocchi G, Raspagliesi F, Grosso G, et al. Early ovarian cancer: is there a role for systematic pelvis and para-aortic lymphadenectomy? Int J Gynecol Cancer
21. Takeshima N, Hirai Y, Umayahara K, et al. Lymph node metastasis in ovarian cancer: difference between serous and non-serous primary tumors. Gynecol Oncol
22. Kanazawa K, Suzuki T, Tokashiki M. The validity and significance of substage IIIC by node involvement in epithelial ovarian cancer: impact of nodal metastasis on patient survival. Gynecol Oncol
23. Sakuragi N, Yamada H, Oikawa M, et al. Prognostic significance of lymph node metastasis and clear cell histology in ovarian carcinoma limited to the pelvis (pT1M0 and pT2M0). Gynecol Oncol
24. Chan JK, Munro EG, Cheung MK, et al. Association of lymphadenectomy and survival in stage I ovarian cancer. Obstet Gynecol
25. Onda T, Yoshikawa H, Yasugi T, et al. Patients with ovarian carcinoma upstaged to stage III after systematic lymphadenectomy have similar survival to stage I/II patients and superior survival to other stage III patients. Cancer
26. Cliby WA, Aletti GD, Wilson TO, et al. Is it justified to classify patients to stage IIIc epithelial ovarian cancer based on nodal involvement only? Gynecol Oncol
27. Maggioni A, Benedetti Panici P, Dell'Anna T, et al. Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br J Cancer
28. Mizuno M, Kikkawa F, Shibata K, et al. Long-term prognosis of stage I ovarian carcinoma. Prognostic importance of intraoperative rupture. Oncology
29. Chan JK, Tian C, Monk BJ, et al. Prognostic factors for high-risk early-stage epithelial ovarian cancer: a Gynecologic Oncology Group study. Cancer
30. Tsuchiya A, Sakamoto M, Yasuda J, et al. Expression profiling in ovarian clear cell carcinoma: identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma. Am J Pathol
31. Kato N, Sasou S, Motoyama T. Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary. Mod Pathol
32. Kaneuchi M, Sasaki M, Tanaka Y, et al. WT1 and WT1-AS genes are inactivated by promoter methylation in ovarian clear cell adenocarcinoma. Cancer
33. Tsuda H, Ito YM, Ohashi Y, et al. Identification of overexpression and amplification of ABCF2 in clear cell ovarian adenocarcinoma by cDNA microarray analysis. Clin Cancer Res
34. Panici PB, Scambia G, Baiocchi G, et al. Anatomical study of para-aortic and pelvic lymph nodes in gynecologic malignancies. Obstet Gynecol
35. Pereira A, Magrina JF, Victoria R, et al. Pelvic and aortic lymph node metastasis in epithelial ovarian cancer. Gynecol Oncol
Keywords:Copyright © 2009 by IGCS and ESGO
Ovarian cancer; Clear cell carcinoma; Surgical staging; Lymphadenectomy; Washing cytology