Objective
Clinicopathological characteristics and possible prognostic factors among women with endometrioid epithelial ovarian cancer (EEOC) with or without concurrent endometriosis were investigated.
Study Design
A search of medical charts at Peking Union Medical College Hospital from 2000 through 2012 identified patients with EEOC with or without endometriosis.
Results
Of 188 patients with EEOC, concurrent endometriosis was identified in 32 (17.0%). Patients with concurrent endometriosis were approximately 5 years younger, more likely to be premenopausal, more likely to have an early stage of EEOC, and less likely to have high-grade tumors compared to those without endometriosis. The univariate analysis showed that concurrent endometriosis was a significant prognostic factor for disease-free survival, but this association did not remain in the multivariate analysis.
Conclusion
Women with EEOC and concurrent endometriosis showed distinct characteristics and had longer disease-free survival when compared to those without endometriosis.
The association between endometriosis and endometrioid epithelial ovarian cancer (EEOC) has long been known; however, the published data that focus specifically on endometrioid cancer are comparatively few. The limited reports have stated that endometriosis-associated ovarian cancer might be an entity distinct from typical EEOC. It was also proposed that endometriosis might be the precursor disorder for EEOC. However, controversy remains regarding the correlation between EEOC and its uterine counterpart, synchronous endometrial endometrioid cancer. For that purpose, we aimed to compare a sequential set of patients with EEOC who were treated at Peking Union Medical College Hospital, Beijing, China, over a period of 12 years with respect to the clinicopathological features and survival outcomes (overall survival [OS] and disease-free survival [DFS]).
Materials and Methods
By reviewing the medical charts, we retrospectively identified 188 patients with EEOC who were primarily treated and received surgery at the Division of Gynecological Oncology of the Department of Obstetrics and Gynecology at Peking Union Medical College Hospital from January 2000 through March 2012. This study was approved by the university institutional review board. The clinical and pathological characteristics are presented in Table 1 .
| Variable | Group 1 | Group 2 | P value |
|---|---|---|---|
| Total | 32 (17.0%) | 156 (83.0%) | |
| Age, y, mean ± SD (range) | 45.8 ± 11.2 (28–79) | 51.2 ± 12.7 (24–82) | .028 a |
| Premenopause | 23 (69.7%) | 76 (48.7%) | .028 a |
| Gravid | |||
| <2 | 11 (34.4%) | 54 (34.6%) | .979 |
| ≥2 | 21 (65.6%) | 102 (65.4%) | |
| Symptoms | |||
| Abdominal pain | 6 (18.8%) | 52 (33.3%) | .104 |
| Abdominal distension | 4 (12.5%) | 32 (20.5%) | .294 |
| Palpable mass | 10 (31.3%) | 39 (25.0%) | .463 |
| Incidental finding | 4 (12.5%) | 18 (11.5%) | 1.0 |
| Irregular menstruation | 7 (21.9%) | 14 (9.0%) | .071 |
| Postmenopausal bleeding | 1 (3.1%) | 10 (6.4%) | .758 |
| Others and unclear | 0 (0%) | 7 (4.5%) | .478 |
| Ca125, U/mL, mean ± SD (range) | 521.5 ± 1238.9 (30.8–6505) n = 27 | 988.3 ± 2402.7 (5.2–24242) n = 137 | .327 |
| Ca125 in normal range (<35 U/mL) | 1 (3.1%) | 12 (7.7%) | .586 |
| Tumor size, cm, mean ± SD (range) | 10.9 ± 5.3 (4–25) n = 31 | 10.1 ± 5.6 (0.5–30) n = 127 | .466 |
| Side of ovarian tumor | .134 | ||
| Left | 14 (43.7%) | 39 (25%) | |
| Right | 8 (25%) | 55 (35.3%) | |
| Bilateral | 9 (28.2%) | 49 (31.4%) | |
| Unclear | 1 (3.1%) | 13 (8.3%) | |
| Breast cancer history | 0 (0%) | 6 (3.8%) | .131 |
| Stage | |||
| I | 23 (71.9%) | 55 (35.3%) | |
| II | 7 (21.9%) | 24 (15.4%) | |
| III | 2 (6.2%) | 67 (42.9%) | |
| IV | 0 (0%) | 10 (6.4%) | |
| Stage categories | < .001 | ||
| Early (I + II) | 30 (93.8%) | 79 (49.1%) | |
| Late (III + IV) | 2 (6.2%) | 77 (50.9%) | |
| Residual disease | .005 | ||
| No or <1 cm | 30 (93.8%) | 109 (69.9%) | |
| >1 cm | 2 (6.2%) | 47 (30.1%) | |
| Grade | < .001 | ||
| G1 | 16 (50%) | 29 (18.6%) | < .001 |
| G2 | 9 (28.1%) | 50 (32.0%) | .663 |
| G3 | 7 (21.9%) | 77 (49.4%) | .004 |
| Mixed with other subtypes | |||
| Clear cell | 1 (3.1%) | 16 (10.3%) | .346 |
| Brenner | 0 (0%) | 1 (0.6%) | |
| Endometrial disorders | |||
| Endometrial carcinoma | 2 (6.3%) | 16 (10.3%) | .710 |
| Endometrial hyperplasia | 1 b (3.1%) | 1 a (0.6%) | |
| Endometrial polyps | 2 c (6.3%) | 10 (6.4%) | 1.0 |
a One case with atypical hyperplasia of mild and moderate grade
b One case with complex hyperplasia
c Including 1 case with ordinary polyp and another with adenomyomatous polyp.
All patients received surgery and chemotherapy and were followed up at our institution. With the exception of 2 women who underwent hysterectomy and bilateral salpingo-oophorectomy resection and who, respectively, had stage-IB, grade-2 and stage-IIC, grade-1 tumors, all patients received staging surgery if they were at an early stage (I-II) or cytoreductive surgery if they were at an advanced stage (III-IV).
We defined EEOC with concurrent endometriosis as the presence of ovarian cancer and endometriosis identified histologically in the same ovary, the presence of endometriosis in one ovary and of ovarian cancer in the contralateral ovary, or the presence of ovarian cancer and extraovarian pelvic endometriosis (eg, peritoneal endometriosis).
According to the pathological criteria listed above, we identified 32 of 188 patients as having EEOC with concurrent endometriosis (group 1). The remaining 156 patients had no pathological evidence of endometriosis (group 2).
The collected clinicopathological data were compared between 2 groups as shown in Table 1 . For statistical analysis, International Federation of Gynecology and Obstetrics (FIGO) stage categories were classified into early stage (FIGO stages I-II) and late stage (FIGO stages III-IV). Synchronous tumors of the ovary and endometrium were found and analyzed in this series ( Table 2 ). The criteria of Young and Scully were used for interpretation of synchronous primary tumors of both organs or of metastasis from one organ to the other. When the pathologic study reveals similar types, the differentiation between the 2 separate primary cancers or 1 single advanced cancer with metastasis is much more difficult. Herein, we apply standardized criteria to differentiate the 2 synchronous cancers, rather than 1 cancer metastases [(1) both tumors are confined to primary sites; (2) no direct extension between the tumors; (3) no lymphovascular tumor emboli; (4) no or only superficial myometrial invasion of the endometrial lesion; and (5) no distant metastasis].
| Ovarian cancer | Endometrial cancer | |||
|---|---|---|---|---|
| Total | G1 | G2 | G3 | |
| G1 | 12 | 11 a | 1 | 0 |
| G2 | 4 | 2 | 2 | 0 |
| G3 | 2 | 0 | 1 | 1 |
DFS was defined as the time interval from the date of primary surgery to the date of disease progression and/or recurrence. OS was defined in months as the date of the primary surgery to the date of death or censoring at the date of last contact.
Statistical associations between 2 groups and the clinicopathological variables were examined with χ 2 or Fisher exact tests as indicated. Survival comparisons were obtained using the log rank test in an unadjusted Kaplan-Meier model. Cox proportional hazards regression was used for multivariate analysis. Variables included in this analysis were those found to be statistically significant in the univariate analyses. Hazards ratios and 95% confidence intervals were used to calculate the relative risk of death or relapse for each variable of interest while adjusting for other covariates. All P values reported are 2 tailed, and a P value of ≤ .05 was considered to be statistically significant.
Results
Clinical and morphological features
Of 188 patients with EEOC whose medical records and pathologic reports were available, 32 (17.0%) had pathologically confirmed coexisting endometriosis, and 156 (83.0%) had no endometriosis. Specifically, 4 patients in group 1 had been previously diagnosed as endometriosis surgically (n = 2) or clinically (n = 2).
The mean age at diagnosis among the entire population was 50.3 ± 12.6 years (range, 24–82 years). The comparisons of clinical and morphological characteristics between EEOC patients with or without endometriosis are shown in Table 1 . The mean age at diagnosis for patients with endometriosis (group 1) was approximately 5 years younger than those without endometriosis (group 2), which was statistically significant. Patients in group 2 were more likely to be premenopausal. As listed in Table 1 , the common presenting symptoms at initial presentation did not differ significantly between the 2 groups, including for gravidity, preoperative cancer antigen 125 (Ca125) level, and prevalence of preoperative Ca125 level in the normal range.
Additionally, no statistically significant difference was found in tumor size or laterality of ovary between the 2 groups. In the aggregate series, history of breast cancer was found in 6 (3.2%) patients, 4 of whom had received tamoxifen (TAM) following breast cancer surgery. Surprisingly, none of the 6 had coexisting endometriosis.
In general, as seen in Table 1 , 58% of patients with EEOC were at an early stage (I-II) of disease, while 42% were at a late stage (III-IV). In comparison, those in group 1 were more likely to present with early-stage disease. More patients in group 1 were debulked to <1 cm of residual disease. Additionally, well-differentiated tumors (grade 1) were more likely to be seen in group 1; conversely, poorly differentiated tumors (grade 3) were less likely to be found in group 1. Finally, the features of mixed clear cell components did not differ significantly between the 2 groups, in spite of a trend for a greater proportion in group 2 (10.3% vs 3.1%).
Overall, concurrent endometrial pathology was documented in 32 patients (17.0%) ( Table 1 ). There was no statistically significant difference in the prevalence of either endometrial malignant or benign disorders between the 2 groups. Interestingly, synchronous tumors of the ovary and endometrium were of identical histological grade in 77.8% of cases ( Table 2 ). Low-grade ovarian cancer was seen in 66.7% of the cases with synchronous tumors.
Survival analysis
After a median follow-up time of 40.5 months (range, 1-265), the entire study cohort observed 26 (13.8%) deaths due to disease, and 162 (86.2%) patients were censored at last follow-up. During the comparable period of follow-up time for groups 1 and 2 (with and without endometriosis), the survival rate was significantly higher in group 1 (96.9% vs 84%, P = .027). Similarly, the tumor relapse or death rate was significantly lower in group 1 (18.8% vs 56.4%, P < .001).
Univariate survival analysis showed age at diagnosis (< or ≥50 years), menopausal status, FIGO stage, residual disease, and histological grade to be significant prognostic factors ( Table 3 and Figure 1 ). However, after these factors were entered into the multivariate analysis, menopausal status and FIGO stage were the only independent predictors of OS ( Table 4 ). There was no difference in OS between the subgroups stratified by gravidity, mixed clear cell cancer, coexisting endometriosis, or concurrent endometrial carcinoma.
| Variable | No. | % | 5-y OS | P value | 2-y DFS | 5-y DFS | P value | |
|---|---|---|---|---|---|---|---|---|
| Age, y | <50 | 91 | 48.4 | 87% | .027 a | 68% | 48% | .001 a |
| ≥50 | 97 | 51.6 | 79% | 47% | 30% | |||
| Menopausal status | Pre | 99 | 52.7 | 87% | .003 a | 67% | 48% | .001 a |
| Post | 89 | 47.3 | 64% | 46% | 29% | |||
| Gravidity | <2 | 65 | 34.6 | 79% | .352 | 60% | 45% | .126 |
| ≥2 | 123 | 65.4 | 75% | 56% | 36% | |||
| Stage | Early (I + II) | 109 | 58.0 | 90% | < .001 a | 83% | 63% | < .001 a |
| Late (III + IV) | 79 | 42.0 | 53% | 23% | 7% | |||
| Residual disease | None or <1 cm | 139 | 73.9 | 84% | .001 a | 70% | 51% | < .001 a |
| >1 cm | 49 | 28.4 | 52% | 23% | 9% | |||
| Grade | G1 | 45 | 23.9 | 97% | .016 a | 92% | 80% | < .001 a |
| G2 | 59 | 31.4 | 75% | 52% | 37% | |||
| G3 | 84 | 44.7 | 65% | 42% | 18% | |||
| Mixed clear cell | Yes | 17 | 9.0 | 56% | .322 | 41% | 16% | .002 a |
| No | 171 | 91.0 | 79% | 59% | 41% | |||
| Endometriosis | Yes | 32 | 17.0 | 100% | .056 | 87% | 66% | .001 a |
| No | 156 | 83.0 | 72% | 52% | 34% | |||
| EC | Yes | 18 | 9.6 | 80% | .629 | 89% | 81% | .006 a |
| No | 170 | 90.4 | 76% | 54% | 35% |
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