Synchronous cancers of the endometrium and ovary account for 50% to 70% of all synchronous female genital tract malignancies.1 In previous case series reports with a small number of patients, synchronous endometrial/ovarian cancers occurred in 5% of women with endometrial cancer and in 10% of women with ovarian cancer.2,3 Earlier studies suggested that synchronous endometrial/ovarian cancers are more prevalent in younger (median age, 44 years), obese, premenopausal, and nulliparous women.4–9 They reported that women with synchronous cancer have a better overall prognosis than if their disease was classified as single-organ disease with metastasis.10,11
However, most studies thus far have involved a small number of patients, and therefore, predictors for tumor recurrence and survival have not yet been clearly established. The Korean Gynecologic Oncology Group therefore undertook a multicenter retrospective study to determine the prognostic factors for women with synchronous endometrial and ovarian cancers.
After obtaining the approval from the institutional review board of each of the participating institution, women with endometrial cancer drawn from 7 participating institutions (Asan Medical Center, CHA Gangnam Medical Center, National Cancer Center, Samsung Medical Center, Seoul National University Hospital, SMG-SNU Boramae Medical Center, and Seoul St Mary’s Hospital) were screened for enrollment for this study.
Inclusion criteria were pathologically proven synchronous endometrial/ovarian cancer from January 1995 to December 2010 with available medical records for pretreatment evaluation, primary treatment, and follow-up from each institution. Exclusion criteria were as follows: borderline ovarian tumor histologic finding, uterine sarcoma histologic finding, or application of chemotherapy or/and radiotherapy before primary surgery.
Patients with cancers of both the endometrium and the ovary can be classified into 3 following groups: (a) endometrial cancer with metastasis to the adnexa, (b) ovarian cancer with metastasis to the endometrium, or (c) synchronous primary cancers of the endometrium and ovary. In 1985, Ulbright and Roth12 delineated a set of pathologic criteria to help distinguish metastatic disease from synchronous primary tumors. Scully et al13 described a similar but more extensive list of clinicopathologic features used to differentiate endometrial cancer with metastasis to the ovary (Fig. 1A), ovarian cancer with metastasis to the endometrium (Fig. 1B), and independent primary cancers of the endometrium and ovary (Fig. 1C). The diagnosis of independent primary cancers is made when the pathologic findings favor the characteristics in Figure 1C when compared with the characteristics in Figures 1A and B. At 7 institutions involved in this study, gynecologic pathologists use these criteria to determine whether cancers of the endometrium and ovary represent metastatic disease or synchronous primary cancers.
Information regarding patient age, body mass index (BMI), reproductive history, preoperative work-up, intraoperative findings, adjuvant treatment, and follow-up were abstracted from their medical records. All patients’ stages were reviewed and updated based on the endometrial and ovarian cancer staging criteria set by the International Federation of Gynecology and Obstetrics.14 Categorical variables were summarized with percentages, and numerical variables were summarized with median and range or mean and SD after confirming the normality of the data by the Kolmogorov-Smirnov test. The progression-free survival (PFS) was defined as the number of months from the date of surgery to the date of disease recurrence or the date censored. Overall survival (OS) was calculated from the date of surgery to the date of death or last contact. Patients with death from causes other than synchronous endometrial/ovarian cancer were considered as lost follow-up, and therefore, their survival times were censored at the date of death. Survival curves and rates were calculated using the Kaplan-Meier method. The differences in survival were assessed using the log-rank test. Estimates of the hazards ratio (HR) with corresponding 95% confidence intervals were calculated using the Cox proportional hazards model. Multivariate analysis to determine independent prognostic factors was performed using the Cox regression model. A P value of less than 0.05 in a 2-sided test indicated a significant difference. Statistical analyses were performed with SPSS software (version 12.0; SPSS, Inc, Chicago, IL).
During the study period, a total of 3240 women with endometrial cancer were identified at 7 participating institutions. Of them, 3117 women were excluded from the study primarily because of no ovarian malignancy (n = 2938) or endometrial cancer with metastasis to the ovary (n = 179), and 123 women were deemed eligible. Thus, the incidence of synchronous endometrial/ovarian cancer was 3.8% (123/3240 women).15 In addition, the incidence of metastasis to the ovary in women with endometrial cancer was 5.5% (179/3240 women), and the incidence of coexisting ovarian malignancy in women with endometrial cancer was 9.3% (302/3240 women).
Table 1 shows the baseline characteristics of the study population of 123 women with synchronous endometrial/ovarian cancer. The mean (±SD) age and BMI were 50.4 (±13.2) years (range, 22–87 years) and 24.1 (±3.4) kg/m2 (range, 16.5–33.3 kg/m2) at the time of diagnosis, respectively. A fair number of women were nulliparous (38.2%) and premenopausal (43.9%). Elevated CA-125 level was found in 76 (61.8%) women. Synchronous cancer was detected simultaneously in most of the cases (118/123 cases, 95.9%); in the remaining 5 women, it was identified within 6 months.
Table 2 displays the histologic types of endometrial and ovarian cancer. Of the 123 women analyzed in this study, 55 (44.7%) women were determined to have independent histologic types of endometrial and ovarian malignancies. The remaining 68 women had identical histologic types of both tumors and were determined to have synchronous primary cancer based on the Ulbright and Roth criteria12 and the Scully criteria.13 In the 56 (45.5%) women, histologic findings of endometrial and ovarian cancers were both of endometrioid.
Table 3 lists the histopathologic characteristics of synchronous endometrial/ovarian cancer. The major histologic type of ovarian and endometrial cancers was endometrioid (81.3% of endometrial cancer and 50.4% of ovarian cancer). Grade 3 differentiations were found in 28.5% of endometrial cancer and 36.6% of ovarian cancer. Eighty-six (69.9%) women had stage I endometrial cancer and 37 (30.1%) women had stage II to IV endometrial cancer. Only 36 (29.3%) women had both stage I endometrial and stage I ovarian cancers.
After primary surgery, 104 (84.6%) women received adjuvant therapy. Of them, 75 (61.0%) women were treated with chemotherapy, 12 (9.8%) women with radiation, and 17 (13.8%) women received a combination of chemotherapy and radiation. During the 66 months of median follow-up (range, 1–186 months), 41 (33.3%) women developed recurrent disease (Fig. 2A). Although 26 (26.1%) women were deceased because of their cancer, 3 women died of noncancer-related problems such as traffic accident or suicide (Fig. 2B). During the follow-up, other primary tumors were detected in 5 cases; thyroid tumors were noted in 3 cases, colon cancer in 1 case, and breast cancer in 1 case.
The 5-year PFS and 5-year OS for all 123 women were 66.9% and 80.0% (Fig. 2). Women older than 40 years seemed to have better survival than younger woman, but the difference was not statistically significant (P = 0.085 in PFS). Pretreatment CA-125 had an influence on prognosis, with PFS and OS in women with a normal CA-125 value being significantly better than those with an elevated CA-125 value (P = 0.022 in PFS and P = 0.005 in OS; Table 4). Body mass index did not show relation to PFS or OS. Endometrioid histologic finding showed significantly better prognosis than nonendometrioid histologic finding in endometrial cancer (P = 0.027 in PFS and P = 0.045 in OS) but not in ovarian cancer (P = 0.085 in PFS and P = 0.110 in OS). Histologic grade 3 endometrial and/or ovarian cancer had a more aggressive prognosis than lower-grade cancers. Interestingly, staging showed a significant prognostic impact in ovarian cancer (P = 0.019 in PFS and P = 0.003 in OS) but not in uterine cancer (P = 0.534 in PFS and P = 0.651 in OS). The presence of stage I at both sites had a statistical significance for good prognosis (P = 0.008 in PFS and P = 0.002 in OS).
Factors shown to be of prognostic significance using the univariate Cox regression model were subsequently evaluated with the multivariate Cox regression model (Tables 4 and 5). Pretreatment CA-125 and tumor stage of the ovary were determined as independent prognostic factors of PFS and OS. In fact, women with elevated CA-125 level and women with stage II to IV ovarian cancer had an increased risk of recurrence compared with those with normal CA-125 level (HR = 2.02 and P = 0.043) and those with stage I ovarian cancer (HR = 3.33 and P = 0.027), respectively, after adjusting for other factors. Women with elevated CA-125 level and women with stage II to IV ovarian cancer also had an increased risk of death compared with those with normal CA-125 (HR = 2.33 and P = 0.047) and those with stage I ovarian cancer (HR = 2.76 and P = 0.031), respectively.
The main result of the current study is that pretreatment CA-125 was an independent prognostic factor in women with synchronous endometrial and ovarian cancers. Tumor stage of ovarian cancer also showed a significant prognostic impact. This is the largest study on women with synchronous gynecologic cancers and the first study to evaluate the role of CA-125 as a prognostic factor for these women. Our results suggest that the identified factors may provide prognostic information in patients with synchronous endometrial/ovarian cancer and allow individualization of patient care.
Little is known about the role of CA-125 as a prognostic marker in women with synchronous endometrial and ovarian cancers. Since its first introduction as a glycoprotein epithelial surface tumor marker in epithelial ovarian cancer with particular use for follow-up monitoring of disease activity,16 serum CA-125 has widely been used as an important biomarker in the management of women with ovarian cancer.17 Elevated CA-125 levels were also shown to be a strong predictor of poor prognosis in patients with endometrial cancer.18 These findings support our result that CA-125 is a prognostic factor even in synchronous endometrial and ovarian cancers.
Our large multicenter study found that staging had a significant prognostic impact on ovarian cancer but not in uterine cancer. This is consistent with a study by Caldarella et al,4 which showed that unlike tumor stage of the endometrium (P = 0.30), tumor stage of ovarian cancer (P < 0.001) had a prognostic importance for survival. A possible explanation of these findings could be that ovarian cancer is generally more aggressive than endometrial cancer. According to the Surveillance, Epidemiology, and End Results data,19 the overall 5-year survival rates of endometrial cancer and ovarian cancer were 84% and 50%, respectively.
We found that 45.5%, 43.9%, 38.2%, and 17.1% of women had endometrioid/endometrioid histologic finding and were premenopausal, nulliparous, and younger than 40 years, respectively. This means that women with synchronous endometrial/ovarian cancer had distinct characteristics such as young age, premenopausal state, and nulliparity. This suggests that a hormonal “field effect” may account for the development of these simultaneous endometrioid cancers. Eifel et al10 also suggested that the response of the uterine corpus, fallopian tubes, and ovarian epithelium as a morphologic unit may explain the development of synchronous endometrioid tumors in different components of the mullerian system. Future studies are needed to further evaluate the role of estrogen in these synchronous endometrioid endometrial/ovarian tumors.
A major strength of this study is its large sample size based on a multicenter design, which gave us power to detect independent prognostic factors using multivariate analysis. However, our study also has limitations. First, its retrospective design raises the possibility of selection bias and the problem of missing data. Second, the current study did not assess other parameters that may affect prognosis. Further investigation is needed to evaluate whether parameters, such as findings of computed tomography or positron emission tomography, have a prognostic importance. Third, pathology specimens were not centrally reviewed, which introduced the possibility of interobserver variability.
In summary, our study represents a large cohort of women with synchronous endometrial and ovarian cancers. We found that pretreatment CA-125 is significantly associated with recurrence and survival in patients with synchronous endometrial and ovarian cancers. Tumor stage of ovarian cancer also showed a significant prognostic impact. Our results suggest that the assessment of prognostic factors may allow identification of a subset of patients with a particularly poor prognosis. This aspect should be investigated a larger clinical trial that includes other biologic parameters in multivariate analysis.
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