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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Tottori University, Yonago, Japan; Kurume University, Kurume, Japan; National Defense Medical College, Tokorozawa, Japan; and Jichi Medical School, Utsunomiya, Japan.
Address reprint requests to: Junzo Kigawa, MD, PhD, Tottori University School of Medicine, Department of Obstetrics and Gynecology, 36-1 Nishimachi, Yonago, 6838504, Japan; E-mail: kigawa{at}grape.med.tottori-u.ac.jp.
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ABSTRACT |
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METHODS: Forty-one patients with clear cell carcinoma and 90 patients with serous adenocarcinoma, who had measurable disease after initial surgery, were examined. All patients underwent cytoreductive surgery followed by platinum-based chemotherapy. P-glycoprotein, multidrug resistance-associated protein, and Ki-67 expression were determined by immunohistochemical staining.
RESULTS: The 5-year survival rate for patients with clear cell carcinoma was significantly poorer, compared with serous adenocarcinoma (20.0% versus 31.9%). Response rate to chemotherapy was 14.6% for clear cell carcinoma and 72.2% for serous adenocarcinoma. The expression of P-glycoprotein and multidrug resistance-associated protein did not differ between responders and nonresponders in both tumor types. The Ki-67 labeling index (LI) in clear cell carcinoma was significantly lower than serous adenocarcinoma (18.4% versus 38.8%). The LI for responders was significantly higher than that for nonresponders in both tumor types. In clear cell carcinoma, the mean value of LI was 15.3% for nonresponders, but that for responders was 30.2%, which was similar to that for serous adenocarcinoma. When the cutoff value of LI was set at 18.4% (mean value), the 5-year survival rate for high LI (over 18.4%) patients was significantly greater than that for low LI patients (46.3% versus 9.2%). Multivariable analysis revealed that LI and residual tumor size were the independent prognostic factors.
CONCLUSION: Lower proliferation of tumor may be a behavior of clear cell carcinoma of the ovary that contributes to its resistance to chemotherapy.
Clear cell carcinoma of the ovary, which is recognized as a distinct histologic entity in the World Health Organization classification of ovarian tumors, demonstrates a distinctly different clinical behavior from the other epithelial ovarian cancers.1–7 The incidence of clear cell carcinoma among epithelial ovarian cancers is not high (3.7–12.1%), and several studies show that patients with clear cell carcinoma have a poor prognosis.2–6 Recently, we found that clear cell carcinoma has a more aggressive course and a poorer prognosis than does serous adenocarcinoma.8 In the literature, the low response of clear cell carcinoma to conventional platinum-based chemotherapy is associated with poor prognosis.5–8 However, the mechanism underlying clear cell carcinoma’s resistance to platinum-based chemotherapy is not yet understood.
Several mechanisms that may be involved in drug resistance have been proposed, including a decrease in the accumulation of the drug, an increase in detoxification of the drug within the cell, and an increase in DNA repair activity.9–14 Multidrug resistance is an important and well-defined mechanism of drug resistance. P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), which actively transport substrates across membranes into vesicles and out of cells, are important multidrug resistance factors.15,16 The P-gp expression has been considered a prognostic factor for ovarian cancer.17 In a previous study, we found that the expression of mRNAs of MRP increased in ovarian cancer that had been unresponsive to chemotherapy.14
Proliferative activity is known to be related to chemoresponse.18,19 Because the incidence of patients with stage I has been shown to be significantly higher in patients with clear cell carcinoma, the proliferative activity of clear cell carcinoma may differ from the other ovarian cancers, including serous adenocarcinoma.8 Also, Ki-67, a nuclear antigen, which is expressed in all states of the cell cycle except in resting cells in G0, is a reliable indicator of cell proliferative activity.20
We conducted the present study to estimate whether the biologic behavior of clear cell carcinoma includes a mechanism that precipitates chemoresistance. To do this, we examined the expression of P-gp and MRP and the proliferative activity with Ki-67 in clear cell carcinoma.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All patients underwent complete surgical staging, including intraperitoneal cytology, bilateral salpingo-oophorectomy, hysterectomy, omentectomy, pelvic-/paraaortic-lymphadenectomy, and aggressive cytoreductive surgery, followed by platinum-based chemotherapy. Seventy-two (55.0%) patients received postoperative chemotherapy, consisting of a combination of 50–75 mg/m2 cisplatin (Bristol Meyers-Squibb, Tokyo, Japan), 40–60 mg/m2 doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), and 400–600 mg/m2 cyclophosphamide (CAP) (Shionogi, Osaka, Japan). The remaining 59 patients received 50–75 mg/m2 cisplatin and 400–600 mg/m2 cyclophosphamide. Twenty-four of 41 (58.5%) patients with clear cell carcinoma and 48 of 90 (53.3%) patients with serous adenocarcinoma received CAP therapy. Paclitaxel was not used as first-line therapy in this study because it was not approved by the Ministry of Health and Welfare in Japan during the period of the study.
Chemotherapy was evaluated by computed tomography. A complete response (CR) was defined as the complete disappearance of all clinically detectable disease for at least 4 weeks. A partial response (PR) was defined as a 50% or greater decrease in tumor size for at least 4 weeks without an increase in the size of any other known lesion or the appearance of a new lesion. Tumor size was determined by product of the maximum diameter and the length perpendicular to the maximum diameter. Static disease was defined as the absence of any significant change in measurable lesions for at least 4 weeks. Progressive disease was defined as the appearance of a new lesion or a greater than 25% increase in tumor size. For this study, the responders consisted of patients showing a CR or PR.
Before chemotherapy, samples were collected from non-necrotic cancer tissue during the initial surgery. Each sample was fixed with 10% formalin and embedded in paraffin. For routine histologic studies, 3 µm of paraffin sections were stained with hematoxylin and eosin. Immunohistochemical staining by the streptavidin-biotin-peroxidase complex method was done using paraffin-embedded tissue. Samples were heated in a microwave oven for 20 minutes at 94C. Anti-P-gp monoclonal antibody and anti-MRP polyclonal antibody were C494 (DAKO, Glostrup, Denmark) and C-20 (Santa Cruz Biotechnology, Santa Cruz, CA), respectively. For the negative control, the primary antibodies were replaced with phosphate buffer saline. The specimens, in which the expression of P-gp or MRP had been confirmed by reverse transcription-polymerase chain reaction or RNase protection assay in our previous studies,14,21 were used for the positive control. Based on a previous study,22 P-gp or MRP expression were considered positive when 10% or more of the tumor cells were stained.
The primary anti-Ki-67 monoclonal antibody used was MIB-1 (Immunotech, Marseille, France). For Ki-67 staining slides, the labeled and unlabeled cells were counted in five hyper views (x400). The total cell count was 500 cells in each specimen. The Ki-67 labeling index (LI) was determined by the following formula: LI (%) = 100 x labeled cell/labeled and unlabeled cells.
Patient survival distribution was calculated using the Kaplan-Meier method. The significance of the survival distribution in each group was tested by a generalized Wilcoxon test and log rank test. A 
2 test and unpaired t test were used for statistical analysis. In addition, multivariable analysis was done with a Stat view 5.0-J program (Hulinks Inc., Tokyo, Japan) to fit a Cox proportional hazards model including age, FIGO stage, tumor size, Ki-67 LI, and nuclear grading. A P value of < .05 was considered statistically significant.
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RESULTS |
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. The mean age of patients with clear cell carcinoma was significantly younger than that of those with serous adenocarcinoma (P < .05). Distribution of FIGO stages did not differ between clear cell carcinoma and serous adenocarcinoma (Table 1). The estimated 5-year survival rate for patients with clear cell carcinoma was significantly poorer than that for those with serous adenocarcinoma (20.0% versus 31.9%, P < .001) (Figure 1). The median survival times were 13.7 months for clear cell carcinoma and 23.2 months for serous adenocarcinoma.
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Figure 2 shows a representative case of immunohisto-chemical staining for P-gp, MRP, and Ki-67 in tumor of clear cell carcinoma. The overall positive rates of P-gp and MRP were 41.5% (17/41) and 19.5% (8/41) for clear cell carcinoma, and 46.7% (42/90) and 27.8% (25/90) for serous adenocarcinoma, respectively. The expression of P-gp or MRP did not differ between clear cell carcinoma and serous adenocarcinoma. There were no significant differences in the expression of P-gp and MRP between responders and nonresponders in both tumors (Table 2).
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). The LI for responders was significantly higher than that for nonresponders with serous adenocarcinoma. The LI for responders was also significantly higher in clear cell carcinoma (Table 2
). In the present study, the cutoff value of LI was set at 18.4% (mean value for clear cell carcinoma). The 5-year survival rate for high LI (over 18.4%) patients was significantly greater than that for low LI (less than 18.4%) patients (46.3% versus 9.2%, P < .05) (Figure 4). Multivariable analysis revealed that LI and residual tumor size were the independent prognostic factors, but nuclear grading was not (Table 3).
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DISCUSSION |
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Drug resistance represents a complex problem for the treatment of ovarian cancer. The reliability of biologic assay is important. As biologic assay, we carried out immunohistochemical staining. The specimens, which confirmed the expression of P-gp or MRP by a molecular assay, were used for the positive control in our series.14,21 Additionally, the incidence of the expression of those proteins was similar to previous findings.17,23 Therefore, our data were considered to be reliable.
Although it is known that P-gp maintains the intracellular concentration of drug at low levels,15,16 the relation between P-gp expression and chemoresponse has been controversial.24 Amplification of the mdr1-gene, encoding P-gp, was not observed in chemoresistant ovarian cancer.25 Other authors have shown the prognostic value of P-gp in ovarian cancer patients undergoing chemotherapy.17 In our study, P-gp expression did not differ between responders and nonresponders in either clear cell carcinoma or serous adenocarcinoma. Overexpression of MRP occurs in several human cancers, such as leukemia and lung, breast, and ovarian cancer.26 In neuroblastoma, a significant association was found between a high level of MRP expression and poor clinical outcome.27 Additionally, MRP was shown to be an important predictor of a poor prognosis in breast cancer patients receiving chemotherapy.28,29 However, the present study failed to demonstrate a correlation between MRP expression and chemoresponse in ovarian cancer. Izquierdo et al22 also showed that positive immunostaining for MRP was not associated with response to chemotherapy in ovarian cancer patients. We previously found that MRP gene expression after chemotherapy was significantly higher in nonresponders than in responders.14 It is noteworthy that cellular detoxification enzymes are induced by cytotoxic agents.30–32 These results suggest that the expression of MRP before chemotherapy does not affect chemosensitivity, although MRP may be associated with a chemoresistance mechanism in ovarian cancer. Arts et al23 examined the expression of MRP1 and canalicular multispecific organic anion transporter (c-MOAT/MRP2) by immunohisto-chemistry of 115 ovarian cancer patients and their response to chemotherapy. In their study, P-gp expression was observed in 20 of 115 (17%), MRP1 in 51 (44%), and MRP2 in 19 (16%) tumors, but assessment of P-gp, MRP1, or MRP2 did not allow prediction of response to chemotherapy. These results suggest that neither P-gp nor MRP expression, at least before chemotherapy, is associated with chemoresistance in ovarian cancer. Therefore, these multidrug resistance proteins are not contributing factors to chemoresistance in clear cell carcinoma.
We next examined proliferation activity of tumor. Higher LI for clear cell carcinoma was significantly lower compared with serous adenocarcinoma (P < .01), indicating lower proliferation activity of clear cell carcinoma. This finding may cause the high incidence of stage I patients with clear cell carcinoma. To our knowledge, this is the first clinical report to examine proliferation activity of clear cell carcinoma. Interestingly, LI is associated with chemoresponse in both clear cell carcinoma and serous adenocarcinoma. It is known that rapidly proliferating cells are the most sensitive, whereas cells that slowly proliferate are generally less sensitive to cytotoxic agents. Intracellular drug accumulation decreases in resting cells.33 We found that the mean value of LI for nonresponders with clear cell carcinoma was 15.3%. In contrast, the mean value of LI for responders was 30.2%, which was similar to that for serous adenocarcinoma.
The survival rate for high LI patients with clear cell carcinoma was significantly greater. Multivariate analysis revealed that LI was an independent prognostic factor in clear cell carcinoma. The present study did not show correlation between LI and nuclear grade, although indices such as proliferative cellular nuclear antigen and Ki-67 antigen are considered to correlate with nuclear grade.34 Those findings suggest that low proliferation activity may contribute to chemoresistance and poor prognosis in clear cell carcinoma.
The information about patients with optimally cytoreduced disease might be interesting. However, we could not observe any relationship between proliferation activity and prognosis in those patients (data not shown). Most patients with optimally cytoreduced disease were included in stages I–II and then showed excellent prognosis.8 Additionally, chemoresponse could not be evaluated in patients with optimally cytoreduced disease. Although further studies are necessary to draw a conclusion, the present study showed that clear cell carcinoma had low tumor proliferation activity and that low proliferation activity in clear cell carcinoma could be associated with chemoresistance.
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Footnotes |
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Received December 18, 2001. Received in revised form February 22, 2002. Accepted March 14, 2002.
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REFERENCES |
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