Objective
The objective of the study was to evaluate the prognosis of ovarian cancer arising in endometriosis.
Study Design
We retrospectively compared 42 cases of endometriosis-associated ovarian cancer (EAOC) with 184 cases of ovarian carcinoma without endometriosis (OC).
Results
The median age in the EAOC group was 52 vs 59 years in OC ( P < .05). In comparison with OC, the EAOC patients were more likely to have low-grade (21% vs 8%; P = .04) and early-stage tumors (International Federation of Gynecology and Obstetrics I and II combined) (49% vs 24%; P = .002). Clear cell (21% vs 2%) and endometrioid (14% vs 3%) tumors were more frequent in EAOC, whereas mucinous tumors were more prevalent in OC ( P = .001). The median survival (199 vs 62 months) and the 5 year survival (62% vs 51%) were better for EAOC when compared with OC ( P = .038). After controlling for age, stage, grade, and treatment, association with endometriosis was not an independent predictor of better survival in ovarian cancer.
Conclusion
As such, EAOC has a much better survival rate than OC. This could be explained by the higher prevalence of early-stage and low-grade tumors in EAOC when compared with OC.
Ovarian cancer is the gynecologic malignancy with the highest case fatality ratio. The high mortality of ovarian cancer is due to the fact that the vast majority of cases would have already disseminated to the extraovarian sites at the time of diagnosis. The late detection has been partly attributed to the nonspecific signs and symptoms of this disease in early phases of cancer growth.
Endometriosis is characterized by proliferation of endometrial glands and stroma at an ectopic site, other than the endometrium. It affects approximately 3-10% women in the reproductive age group, 2-5% of postmenopausal women, and 25-80% of infertile women. Endometrioid and clear cell subtypes of ovarian cancer are both known to be closely associated with endometriosis. Although endometriosis has not been classified as a premalignant condition, the association of endometriosis and ovarian cancer has been well described.
Endometriosis exhibits phenotypic features of both a benign and malignant disease. The features of endometriosis, which resemble that of cancer, are local and distant spread, loss of control of cell proliferation, and in some circumstances, invasion. Brinton et al in 2004 reported that patients suffering from endometriosis have a standard incidence ratio (SIR) of 4.19 (95% confidence interval [CI], 2.0–7.7) for ovarian cancer, when compared with patients with no endometriosis. Other investigators have reported a much higher risk associated with endometriosis, as depicted by the study by Kobayashi et al in 2007 in which SIR for ovarian cancer was 8.95 (95% CI, 4.12–15.3).
It is also evident from these studies that the longer the duration of endometriosis, the greater is the risk for developing ovarian cancer. Numerous studies document the progression of endometriosis from a benign histological lesion to a frankly invasive malignant tissue. However, the precise mechanism for transformation from endometriosis to ovarian cancer remains to be elucidated.
One keenly debated issue in the literature is whether endometriosis-associated ovarian cancer (EAOC) is a distinct disease entity or whether it is similar to the ovarian cancer not associated with endometriosis (OC). The existing literature on this issue has several limitations. Some investigators have reported a better overall survival when ovarian cancer is associated with endometriosis, whereas others have failed to find such a difference.
The histology reporting for EAOC is extremely heterogeneous, making comparisons between the various reports suboptimal. For example, some authors specifically focused on clear cell tumors or endometrioid tumors, whereas others included nonclear cell and nonendometrioid histology types as well. Furthermore, the criteria for diagnosis of EAOC has varied between different groups.
Some authors considered the tumors as EAOC when there was evidence of malignant transformation in the endometriosis glands leading to carcinoma, whereas others included cases if either the transition point was identified or merely endometriosis was found within the surgical specimen coexisting with cancer. The clarification of the issue weather EAOC carries a better prognosis and whether it represents a distinct clinicopathologic entity is of great clinical importance.
The objective of this study was to evaluate the clinical and pathologic features and patients outcome in EAOC and compare them with that of OC.
Materials and Methods
Wayne State University Institutional Review Board approval was obtained for this study. After protocol approval, we identified all patients diagnosed with cancer of the ovary from our departmental database in the Division of Pathology and the Division of Gynecologic Oncology. This study included patients treated between 1992 and 2002. The following data were collected in a tabulated manner: patient and tumor characteristics, International Federation of Gynecology and Obstetrics (FIGO) stage, treatment, and follow-up status. For survival analysis, patients were censored if they were alive at the date of last follow-up.
A histologic review of all cases was performed by 2 of the authors (R.A.-F. and H.A.). Sampson’s criteria along with Scott’s modification were used to make a diagnosis of EAOC. These included the following: (1) there must be clear endometriosis in proximity to the tumor, (2) no other primary site for the tumor can be found, and (3) there must be the presence of tissue resembling endometrial stroma surrounding epithelial glands in addition to the demonstration of histologically proven transition from endometriosis to cancer.
For statistical analysis, subjects were classified into 2 surgical stage categories: FIGO stages I and II subjects were considered early stage, whereas FIGO stages III and IV were late stage. Subjects were also classified according to surgical outcome after cytoreduction surgery: (1) complete cytoreduction in subjects with no macroscopic residual disease; (2) optimal cytoreduction for residual disease less than 1 cm; and (2) suboptimal cytoreduction for residual disease greater than 1 cm. Disease-free survival was defined as the time interval from the date of primary surgery to the date of disease progression and/or recurrence. Overall survival was defined as the date of the primary surgery to the date of death or censored at the date of last contact in months.
Comparisons between EAOC and OC were performed using χ 2 test and parametric Student t tests. Survival comparisons were obtained using the log-rank test in an unadjusted Kaplan-Meier model. Cox proportional hazards model in a forced entry format was first used to screen for variables likely to affect survival. Subsequently in a second analysis, Cox proportional hazards model in a forward stepwise method (conditional logistic regression) was used to determine independent effect of association of ovarian cancer to endometriosis on the survival, after controlling for other potential confounding variables such as age of diagnosis, race, histology type, grade, and FIGO stage. The validity of the proportional hazards assumption was assessed from log survival curves. All P values reported are 2 tailed, and a P value of .05 or less was considered to be statistically significant.
Results
Medical records and pathology slides were available on 226 patients in a time interval of 1992-2002. Of these 226 patients, 42 were EAOC and 184 patients were OC. The mean age of diagnosis in EAOC was 54 years as compared with 59 years in OC ( P = .05). Sixty-one patients (27%) were African Americans as compared with 165 whites (73%). Only 11% of African Americans (n = 7) had EAOC, whereas 21% of whites (n = 35) had EAOC, but this difference was statistically nonsignificant ( P = .06; Table 1 ). For the total study population, mean body mass index (BMI) was 23.3 vs 27.6 kg/m 2 for the EAOC and OC subgroups, respectively ( P = .031). None of the patients received hormone therapy after diagnosis of cancer in our cohort. Prior to the diagnosis of cancer, 24% of patients in EAOC had hormone therapy.
| Variable | EAOC | % | OC | % | P value |
|---|---|---|---|---|---|
| Age | |||||
| Mean | 54 | 59 | .05 | ||
| Median | 52 | 60 | |||
| Race | |||||
| White | 35 | 83 | 130 | 71 | .07 |
| African American | 7 | 17 | 54 | 29 | |
| FIGO stage | |||||
| I | 19 | 45 | 28 | 15 | |
| II | 1 | 2 | 16 | 9 | |
| III | 16 | 38 | 121 | 66 | |
| IV | 5 | 12 | 15 | 8 | |
| Unknown | 1 | 2 | 4 | 2 | |
| Stage comparison a | |||||
| Early stage (I and II) | 20 | 49 | 44 | 24 | .002 |
| Late stage (III and IV) | 21 | 51 | 136 | 76 | |
| Grade | |||||
| Low | 7 | 17 | 12 | 7 | |
| High | 26 | 62 | 132 | 70 | |
| Borderline | 9 | 21 | 39 | 21 | |
| Unknown | 0 | 0 | 1 | 0.4 | |
| Grade comparison b | |||||
| Low | 7 | 21 | 12 | 8 | .04 |
| High | 26 | 79 | 132 | 92 | |
| Histology | |||||
| Serous | 23 | 55 | 148 | 80 | .001 |
| Clear cell | 9 | 21 | 4 | 2 | |
| Mucinous | 4 | 10 | 27 | 15 | |
| Endometrioid | 6 | 14 | 5 | 3 | |
| Status | |||||
| Alive | 28 | 67 | 88 | 48 | .007 |
| Dead | 13 | 31 | 96 | 52 | |
| Unknown | 1 | 2 | 0 | 0 |
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