Mika Mizuno

Long-Term Prognosis of Stage I Ovarian Carcinoma

Objective: There are a few long-term follow-up studies of patients with stage I ovarian carcinoma. The objective of this study was to evaluate prognostic factors for long-term survival. Methods: Two hundred fourteen stage I ovarian carcinomas (registered by the Tokai Ovarian Tumor Study Group from 1988 to 1999) were analyzed. Staging according to the International Federation of Gynecology and Obstetrics was set without considering the pathologic findings of the lymph nodes. Stage Ic was divided into Ic(b) and other Ic. Results: Seventy-four patients were stage Ia, 2 were stage Ib, and 138 were stage Ic, consisting of 75 Ic(b) and 63 other Ic patients. The ratios of stage Ic to Ia and stage Ic(b) to Ic were highest in clear-cell adenocarcinoma among histologies analyzed. There were significant differences in disease-free survival curves between each group. In clear cell adenocarcinoma, there was a significant difference in disease- free survival curves between stage Ic(b) and other Ic (p = 0.0373), while this tendency was also observed in other histologies except for mucinous carcinoma. Multivariate analysis demonstrated that substage was a significant prognostic factor of both disease-free and overall survival. Conclusions: Stage Ic(b) patients showed poorer survival than stage Ia patients but better than survival in other Ic. Thus, cautious treatment of ovarian tumor during surgery is quite important to avoid rupture.

Survival impact of capsule rupture in stage I clear cell carcinoma of the ovary in comparison with other histological types

OBJECTIVE We analyzed a large number of stage I clear cell carcinoma of the ovary (CCC) patients to estimate the survival impact of the capsule status in stage I CCC patients, particularly in comparison with non-CCC patients. METHODS Clinicopathologic data on 564 patients with stage I epithelial ovarian cancer (EOC) collected under the central pathological review system were subjected to uni- and multivariable analyses to evaluate the disease-free survival (DFS) and overall survival (OS). RESULTS There was no significant difference in both the OS and DFS of CCC patients between IA and IC(ir) (intraoperative capsule rupture) {IA vs. IC(ir); OS: P=0.1402, DFS: P=0.2701}. In contrast, CCC patients at IC(non-ir) {IC excluding for IC(ir), such as preoperative capsule rupture, positive ascites/washing, and surface involvement} showed a poorer OS and DFS than those at IC(ir), or those at the corresponding stage in non-CCC. In multivariable analysis, the capsule status was an independent prognostic factor of a poor OS and DFS {OS: HR, 2.832; 95% CI 1.156-6.938; P=0.023; DFS: HR, 4.327; 95% CI, 1.937-9.667; P=0.0004)} {In contrast, non-CCC: N.S. (OS/DFS)}. Furthermore, in CCC patients, intraperitoneal recurrences were more frequently observed in IC(non-ir) CCC than IA or IC(ir) CCC (P=0.0083) {In contrast, non-CCC: N.S.}. CONCLUSION This study suggests that CCC patients other than those with intraoperative capsule rupture show a considerable risk for mortality despite adjuvant chemotherapy.

Fertility-sparing surgery in patients with clear-cell carcinoma of the ovary: Is it possible?

BACKGROUND Clear-cell carcinoma of the ovary (CCC) is often diagnosed at childbearing age, or sometimes during treatment for infertility. Therefore, most young women with early-stage CCC wish to preserve their reproductive and endocrine functions if possible. METHODS Clinicopathologic data collected under the central pathological review system were subjected to survival analyses. We analyzed patients with stage I CCC who underwent fertility-sparing surgery (FSS, n = 16) and compared their long-term survival with those receiving radical surgery (n = 205), or patients with non-CCC undergoing FSS (n = 64). RESULTS There was no difference in both the overall survival (OS) and disease-free survival (DFS) between patients with CCC who underwent FSS and those who received radical surgery [CCC/FSS (n = 16) versus CCC/radical (n = 205); OS: P= 0.519, DFS: P= 0.265]. Moreover, patients with CCC who underwent FSS did not show a poorer OS and DFS than non-CCC patients who underwent FSS (CCC/FSS versus non-CCC/FSS; OS: P= 0.584, DFS: P= 0.401), or those at the corresponding stage with no CCC. Furthermore, according to the series of patients with CCC in both the current study and four studies in the literature, there was no difference in the recurrence rate between patients with or without CCC who were treated conservatively (CCC/FSS: 13.2% versus non-CCC/FSS: 10.9%, P= 0.614). CONCLUSIONS Although our study did not have sufficient power to yield a definite conclusion, our data suggests that at least patients with stage IA CCC may be treated with FSS.

Expression of CXCR4 indicates poor prognosis in patients with clear cell carcinoma of the ovary

Recent reports have shown that CXCR4 is expressed in various solid tumors and is involved in tumor development and metastasis. We examined the distribution and expression of this molecule in clear cell carcinoma of the ovary to elucidate its clinical significance. Paraffin sections from clear cell carcinoma of the ovary tissues (n = 42) were immunostained with CXCR4 antibody, and the staining intensities were evaluated. The clinicopathologic factors examined were age, FIGO (International Federation of Gynecology and Obstetrics) staging, preoperative value of cancer antigen 125 test, and residual tumor after cytoreductive surgery. Overall survival and progression-free survival were evaluated using the Kaplan-Meier method, and multivariate analysis was completed using Cox proportional hazards analysis. Of the 42 carcinomas, lower level CXCR4 immunoexpression was observed in 21 cases (50.0%) (CXCR4(low) group); and higher level immunoexpression, in 21 cases (50.0%) (CXCR4(high) group). Five-year overall survival was significantly poorer in the CXCR4(high) group than in the CXCR4(low) group (overall survival, CXCR4(low) group [90.2%], CXCR4(high) group [50.3%]; P = .0002). In addition, CXCR4(high) immunoexpression significantly predicted a poorer progression-free survival when compared with lower expression (5-year progression-free survival, CXCR4(low) group [90.5%], CXCR4(high) group [36.2%]; P < .0001). Furthermore, multivariate analyses including the age, preoperative cancer antigen 125 test value, FIGO stage, and CXCR4 expressions revealed that CXCR4(high) expression was an independent prognostic factor for poorer overall survival and progression-free survival of patients with clear cell carcinoma of the ovary (overall survival, P = .0011; progression-free survival, P = .0008, respectively). Our current study suggested that the assessment of CXCR4 immunoreactivity may be a useful prognostic indicator and that CXCR4 may play a critical role in the progression of clear cell carcinoma of the ovary.

Fertility-sparing surgery in young women with mucinous adenocarcinoma of the ovary

OBJECTIVES The purpose of this study was to clarify the clinical outcome of patients with stage IA mucinous epithelial ovarian cancer (mEOC) treated with fertility-sparing surgery (FSS). METHODS After a central pathological review and search of the medical records from multiple institutions, a total of 148 stage I mEOC patients were retrospectively evaluated in the current study. All mEOC patients were divided into three groups: group A (FSS; age, 40≥); groups B and C {radical surgery; age, 40≥ (B); 40< (C)}. Survival analysis was performed among these three groups using Kaplan-Meier methods. RESULTS The median follow-up time of all mEOC patients was 71.6 (4.8-448.3) months. Among the 41 patients in group A, 27 patients (65.9%) had IA disease, and 14 (34.1%) had IC disease. Five-year overall survival (OS) and disease-free survival (DFS) rates of patients in the groups were as follows: group A, 97.3% (OS)/90.5% (DFS); group B, 94.4% (OS)/94.4% (DFS); group C; 97.3% (OS)/89.3% (DFS). Collectively, there was no significant difference in OS or DFS among these groups even though they were stratified to each substage (IA/IC) (OS, P=0.180; DFS, P=0.445, respectively). Furthermore, in multivariate analyses, the surgical procedure was not an independent prognostic factor for either OS or DFS (OS, HR: 0.340, 95% CI: 0.034-3.775, P=0.352; DFS, HR: 0.660, 95% CI: 0.142-3.070, P=0.596). CONCLUSIONS Patients with stage I mEOC treated with FSS did not necessarily show a poorer prognosis than those receiving radical surgery.

Recurrence-predicting prognostic factors for patients with early-stage epithelial ovarian cancer undergoing fertility-sparing surgery: a multi-institutional study

OBJECTIVES We reviewed the clinical outcomes of patients with early-stage epithelial ovarian cancer (EOC) who had undergone fertility-sparing surgery (FSS) to assess recurrence-free survival (RFS). STUDY DESIGN After central pathological review and scanning of the medical records of multiple institutions, a total of 94 patients with stage I EOC (IA: 43 and IC: 51) treated with FSS were analyzed. IC substages were defined as follows: intraoperative spillage (IC1), preoperative capsule rupture or surface invasion (IC2), and positive cytology results (IC3). RESULTS The median age was 30.5 (13-40) years. The median follow-up time was 66.6 months. Fourteen patients (14.9%) showed carcinoma recurrence. Eleven (11.7%) patients died of the disease. The total 5-year RFS rate including all women who received FSS was 84.3%. There was no significant difference in RFS between patients with IC1 and those with stage IA (P=0.9411). In contrast, the RFS rate of patients with IC2/3 was significantly poorer than in patients with stage IA (IA vs. IC2/3: P=0.0487, IC1 vs. IC2/3: P=0.0471). In further analyses according to each histological type and grade, the RFS rate of subjects with the mucinous type was the same as that of those with a clear-cell histology (P=0.3350). There was a significant difference in RFS of patients with grade 1 (G1) and G2-3 (P=0.0004). To eliminate selection bias from a number of clinicopathologic factors as thoroughly as possible, the age, FIGO stage, histological type, grade, and postoperative adjuvant chemotherapy were entered into multivariate RFS analyses. Cox multivariable analysis showed that the substage group and grade were independent prognostic factors for RFS. CONCLUSIONS Confined to young women with intraoperative rupture, FSS may be proposed, if without tumor-associated dense adhesion. However, those with preoperative rupture, surface invasion, and positive cytology showed a greater risk of recurrence, suggesting that they are not recommended candidates. Although patients with G2-3 tumors showed a poorer prognosis than those with G1, the number of these subjects was so small that the current results should be reconfirmed in the next study.

Diagnostic utility of CD117, CD133, SALL4, OCT4, TCL1 and glypican-3 in malignant germ cell tumors of the ovary

Aim:  Primary ovarian malignant germ cell tumors (OMGCTs) are rare and difficult to diagnose. Immunohistochemistry can help in the diagnosis and development of new management strategies. The aim of this study was to investigate the frequency of CD117, CD133, SALL4, OCT4, TCL1 and glypican‐3 marker expression in OMGCTs.

Postrecurrent oncologic outcome of patients with ovarian clear cell carcinoma.

Objectives To estimate the long-term clinical outcome of patients with recurrent clear cell carcinoma (RCCC) of the ovary in comparison with those with recurrent serous adenocarcinoma (RSAC). Patients and Methods In this study, 113 patients with RCCC and 365 patients with RSAC were analyzed. The pathological slides were evaluated under central pathological review. End points were the overall survival (OS), postrecurrence survival (PRS), and timing of death of mortality cases. Results The 5-year OS and PRS rates of patients with RCCC were 22.5 and 13.2%, respectively. In both OS and PRS, the prognosis of patients with RCCC was significantly poorer than that of the patients with RSAC (OS: P = 0.0007; PRS: P < 0.0001). Moreover, regardless of the status of the residual tumor (RT) at the initial surgery, the OS and PRS of the patients with RCCC were markedly shorter than those with RSAC (RT [−]: OS, P = 0.0005: PRS, P = 0.0002: RT [+]: OS, P < 0.0001: PRS, P < 0.0001). In multivariable analysis, the histological type was a significantly poorer prognostic indicator for OS and PRS (OS [RCCC vs RSAC]: hazard ratio, 2.302: 95% confidence interval, 1.723–3.076; P < 0.0001: PRS [RCCC vs RSAC]; hazard ratio, 2.353: 95% confidence interval, 1.756–3.155; P < 0.0001). Even in the deceased patients (n = 350), the rate of patients with RCCC dying within 12 months of recurrence was higher than that of RSAC (RCCC, 67.8%; RSAC, 40.7%; [P < 0.0001]). Conclusions The long-term clinical outcome of patients with RCCC was extremely poor. We confirmed that RCCC should be investigated as a different malignancy compared with RSAC.

Long-term clinical outcome of patients with recurrent epithelial ovarian carcinoma: is it the same for each histological type?

Objective This study was conducted to estimate the long-term clinical outcome of patients with recurrent ovarian carcinoma (ROC). Methods Six hundred three patients with ROC were analyzed in this study. The pathological slides were evaluated under central pathological review. The prognostic significances of clinicopathologic factors were evaluated using both univariate and multivariate analysis. Results The 5-year overall survival (OS) and postrecurrence survival (PRS) rates were 31.1 and 16.9%, respectively. On stratifying to treatment periods, the PRS has been prolonged over the last decade (year ≥2000) compared with before this period (year ≤1999) (P = 0.0002). In contrast, on stratifying to histological types and treatment periods, in both OS and PRS, the prognosis of patients with the nonmucinous/clear-cell histology, including serous, endometrioid, and other histological types, was significantly improved after 2000 compared with before (year ≤1999) (OS, P = 0.0009; PRS, P < 0.0001). In contrast, that of patients with the mucinous/clear-cell histology did not significantly differ regardless of the treatment period (≥2000 vs ≤1999: OS, P = 0.3887; PRS, P = 0.7617). In multivariate analysis, the stage, period of starting initial treatment, histological type, and the treatment-free interval were independent prognostic factors of a poor OS and PRS (OS/PRS: histological type: mucinous/clear-cell vs nonmucinous/clear-cell: hazard ratio, 1.300/1.498; 95% confidence interval [CI], 1.039–1.626/1.197–1.874). Conclusions Despite the continuous administration of treatment for ROC, survival is poor, and the extent of therapeutic progress differs according to the histological type.

Adjuvant chemotherapy for stage i ovarian clear cell carcinoma: is it necessary for stage IA?

Background It is controversial whether patients with stage I ovarian clear cell carcinoma (CCC) benefit from postoperative chemotherapy. This study was designed to evaluate the postoperative outcomes associated with the inclusion or exclusion of adjuvant therapy in these patients. Methods A total of 185 patients who were treated for stage I CCC between 1991 and 2007 were retrospectively evaluated. All of the patients had received comprehensive surgical staging, and their condition had been diagnosed by a central pathological review system. Only one patient with stage IB was excluded from this study. Results Median follow-up time was 62 months (range 7–191 months). Median age was 52 years (30–75 years). There were 41, 93, and 50 patients in stage IA, intraoperative capsule ruptured IC (rupture-IC), and all other-IC groups, respectively. The 5-year recurrence-free survival rates for the substage were 97.6%, 87.8%, and 70.4% (P < 0.001), respectively. Among 134 patients consisting of those in the stage IA and rupture-IC groups, 91 patients received adjuvant chemotherapy (AC) and 43 patients did not (non-AC). There was no significant survival difference in each substage group between the non-AC and AC groups in 5-year recurrence-free survival rate (stage IA, 100% vs 93.8%; rupture-IC, 94.1% vs 86.6%). Multivariate analysis demonstrated that there was no significant prognostic factor for both recurrence and survival among the IA and rupture-IC groups. Postoperative therapy, regimen, and chemotherapy cycles were not significantly affected. Conclusions This study indicates that adjuvant chemotherapy does not contribute to the improving prognosis of stage IA ovarian CCC. Whereas the histological type is CCC, the routine adjuvant chemotherapy after comprehensive surgical staging may be unnecessary for patients with at least stage IA.