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ORIGINAL RESEARCH |
From The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Address reprint requests to: Susan C. Modesitt, MD, University of Texas M. D. Anderson Cancer Center, Department of Gynecologic Oncology, Box 440, 1515 Holcombe Bovlevard, Houston, TX 77030; E-mail: smodesit{at}mdanderson.org.
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ABSTRACT |
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METHODS: A search of medical records at The University of Texas M. D. Anderson Cancer Center from 1970 to 1999 identified patients who had synchronous endometriosis and intraperitoneal cancer. Demographic and clinicopathologic characteristics were evaluated for differences based on the relationship of the cancer to the endometriosis and for correlation with survival.
RESULTS: One hundred fifteen patients were identified: 25 patients with ovarian cancer arising in endometriosis, 21 with an extraovarian cancer arising in endometriosis, 33 patients with endometriosis and ovarian cancer in the same location but without a definite transition point, and 36 patients with ovarian cancer and incidental endometriosis. Women with extraovarian cancers arising in endometriosis were more likely to be postmenopausal (P < .001) and use hormone replacement (P < .001). The median age was 47 years, the most common histological tumor types were clear cell and endometrioid (23% each), and the most common stage was stage I (31%). The median survival was 35 months. Univariate survival analysis revealed that gravidity (P < .038), grade (P < .001), stage (P < .001), histology (P < .01), and type of chemotherapy (P < .011) correlated with survival. Multivariable analysis revealed that stage and gravidity independently predicted survival.
CONCLUSION: Women with endometriosis-associated cancers are typically premenopausal, have a high incidence of endometrioid and clear cell histologies, and have early stage disease. Stage and gravidity independently predicted survival.
Endometriosis is a common gynecologic problem, with an estimated prevalence of 5–15% in women of reproductive age and 3–5% in postmenopausal women.1 A relationship between endometriosis and malignancy is well documented in the literature; however, whether the relationship is causal remains controversial. Prior studies have found an increased overall cancer incidence in women with endometriosis,2 and many studies have documented an increased rate of endometriosis in women with ovarian cancer, especially endometrioid and clear cell histologies.3–12 Despite the association of endometriosis with certain types of ovarian cancer, there are several problems in delineating the actual relationship. In women with intraperitoneal cancers, an invasive cancer may obliterate the endometriosis, or small implants of endometriosis might be missed on pathologic evaluation. Because the diagnosis of endometriosis is quite common, it is sometimes unclear whether the endometriosis has undergone malignant transformation or simply coexisted with the cancer. Additionally, although several retrospective studies have attempted to evaluate the relationship between endometriosis and intraperitoneal cancer, the number of patients has been small and definitive conclusions are thus difficult.
The purpose of this study was to evaluate all of the women treated at The University of Texas M. D. Anderson Cancer Center who had both endometriosis and an intraperitoneal cancer to understand better the relationship between the two conditions. The first objective was to determine the clinical characteristics of women with endometriosis-associated cancers and to assess whether the clinical characteristics differed among women depending upon the relationship of the cancer to the endometriosis. The second objective was to assess factors associated with survival in this patient population.
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MATERIALS AND METHODS |
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Statistical analysis was performed using Statistical Package for the Social Sciences 10.1 (SPSS Inc., Chicago, IL) and StatXact 5 (Cytel Software Corp., Cambridge, MA). The Pearson 
2 test and the Fisher-Freeman-Halton test were used to assess the relationships between endometriosis diagnostic category and demographic and clinicopathologic characteristics. The Kaplan-Meier method and the log rank statistic were used to analyze survival, and the Cox proportional hazard model was used for multivariable analysis. Hazards ratios and 95% confidence intervals (CIs) were used to calculate the relative risk of death for each variable of interest while adjusting for other covariates. In all cases, a P value of less than .05 was considered statistically significant and all P values were two sided.
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RESULTS |
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). The first group of patients had positive identification of ovarian cancer arising within the endometriosis (25 patients). The second group had cancer arising in endometriosis in an extraovarian site (21 patients). Of note, 18 (86%) of the 21 patients in this group had undergone a prior hysterectomy and bilateral salpingo-oophorectomy, and the other three had normal ovaries with the cancer arising in either the bowel or the bladder. The third group of patients had endometriosis and ovarian cancer in the same location but a definite transition point was not identified (33 patients). Finally, the last group had essentially incidental endometriosis where the endometriosis and ovarian cancer were in anatomically separate locations (36 patients).
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2= 18, P < .001) and use HRT (2= 37, P < .001) (Table 2).
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). Mixed epithelial adenocarcinomas included tumors with any combination of two or more of the epithelial histological types. The most common stage at presentation was stage I (31%), followed closely by stage III (30%). Twenty-three percent of patients were un-staged. The unstaged patients fell into two categories: patients who were unstaged because the malignancy was not recognized until the final pathologic examination and patients with an extraovarian cancer for which no defined staging system exists. With regard to histological grade, the most common grade was grade 3 (46%), followed by grade 2 (26%) and grade 1 (23%). There were no significant differences between the groups with regard to grade, but there was a significant difference when evaluating stage (Fisher-Freeman-Halton test = 22, P < .016) and histological type (Fisher-Freeman-Halton test = 30, P < .004). Patients with a diagnosis of extraovarian cancer arising in endometriosis were more likely to be unstaged, whereas patients in the other diagnostic categories were more likely to be diagnosed at an earlier stage, particularly women with a diagnosis of incidental extraovarian endometriosis. The various histological types were fairly evenly distributed among the four groups, except that patients with extraovarian cancer arising in endometriosis were less likely to have serous or clear cell types and were the only ones to have an adenocarcinoma that was not otherwise specified.
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The chemotherapy used changed over the period studied. In the 1970s, melphalan was the chemotherapeutic agent of choice, and this gradually evolved to platinum agents and finally to paclitaxel and platinum in the 1990s. Of the 82 patients who received chemotherapy as a postoperative therapy, 35 (43%) received platinum (alone or with an agent other than paclitaxel), 26 (32%) received paclitaxel and platinum, 15 (18%) received melphalan, and the remaining six (7%) had other agents.
At the completion of initial therapy, 74% of patients were clinically disease free. Disease status at the time of last contact was known for 111 patients; the remaining four were lost to follow-up. Fifty patients had no evidence of disease, and the median length of follow-up for these patients was 59 months (range 3–348 months). Forty-three patients were dead of disease, 12 patients were alive with disease, and six patients died of other causes. Among the group as a whole, 61 patients (55%) had a recurrence of cancer, the median disease-free interval for the entire group was 21 months, and median survival was 35 months.
No relationship between overall survival and endometriosis/cancer relationship, age at diagnosis, HRT use, menopausal status, family history of cancer, initial surgery type, OC pill use, smoking, and postoperative treatment modality (chemotherapy versus radiation) was observed. However, tumor grade (P < .001), stage (P < .001), and histology (P < .01) as well as gravidity (P < .038) and type of postoperative chemotherapy (P < .011) were statistically significant predictors of overall survival by the Kaplan-Meier method and log rank statistic pooled over the different strata (Figure 1). The survival data were then compared in a pairwise fashion over the different classifications and demonstrated that patients with stage III or IV tumors, grade 3 tumors, serous or clear cell type histology, and a history of two or more pregnancies and who received platinum postoperative chemotherapy correlated with a poor overall survival. Table 4 presents the results of the multivariable Cox proportional hazard model for overall survival. Variables included in this analysis were those found to be statistically significant in the univariate analysis. After controlling for the effect of other predictive factors, only stage and gravidity remained as independent predictors of overall survival. Although grade was found to be a significant predictor of survival in the univariate analysis, we were unable to assess the independent effect of this variable because there were no deaths in women with grade 1 cancers. Patients with stage III or IV disease and unstaged tumors were at a higher risk of dying, compared with women with a diagnosis of stage I or II disease. Women with a diagnosis of stage III or IV tumors had a four-fold increased risk of dying (hazards ratio 4.05, 95% CI 1.174, 9.63), whereas women with unstaged tumors had a 2.4-fold higher risk of dying (hazards ratio 2.43, 95% CI 0.83, 7.11) Women with two or more pregnancies had a two-fold increased risk of death when compared with women with no or one pregnancy (hazards ratio 2.28, 95% CI 1.14, 4.54). Of note, lower gravidity was significantly associated with an increased number of grade 1 and 2 tumors relative to higher gravidity (2 = 11.77, P < .008); the percentage of grade 3 tumors was essentially the same for both groups. Histology and chemotherapy type were no longer found to be significantly associated with survival in the multivariable model.
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DISCUSSION |
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Our study suffers from the same limitations inherent in any retrospective study. The long study period encompasses treatment changes; however, endometriosis-associated cancers remain rare, and the only way to study adequate numbers of patients is to expand the time frame or the number of institutions involved. Our study suggests that women with endometriosis-associated cancers may represent a different subset of patients than the traditional ovarian cancer patients with regard to histological distribution and prognostic factors. One of our main hypotheses was that women with cancer arising in endometriosis might have an improved survival relative to women with incidental endometriosis, yet we were not able to demonstrate a survival difference. This may have been due to the fact that all of the women in our study had endometriosis and that even if the cancer did not arise within the endometriosis, it still may have behaved differently than traditional ovarian cancer, a finding supported by other investigators.16
Our study demonstrates the increased incidence of clear cell and endometrioid cancer histologies in women with coexisting endometriosis. In the 1998 International Federation of Gynecology and Obstetrics report, 55% of epithelial ovarian cancers were serous, whereas 13% were endometrioid and 6% were clear cell.17 This is in direct contrast to our study, in which the endometrioid and clear cell subtypes each accounted for 23% of the cases. In the literature, the percentage of women with endometrioid ovarian cancer and associated endometriosis has ranged from 8% to 38%, and the percentage of women with clear cell ovarian carcinoma and associated endometriosis has ranged from 21% to 55%.3,4,8–12,15–21 The increased incidence of endometriosis with certain subtypes of ovarian cancer may support the hypothesis that various subtypes of ovarian cancers evolve by different mechanisms. Several studies have evaluated pathways believed to be important in carcinogenesis and determined that endometrioid and clear cell tumors differ from the traditional serous tumors with regard to the presence of p53 mutations, PTEN expression, estrogen receptors, galactose-1-phosphate uridyl transferase, and glutathione S-transferase activity.22–24 Further work is required to determine whether the differences translate into a causal relationship.
Our study did not demonstrate a difference in survival based on histology. On univariate analysis, endometrioid histology was associated with an improved survival relative to serous and clear cell histological types. However, on multivariable analysis, once stage was held constant, this apparent survival benefit was no longer applicable. Prior retrospective reviews of patients with ovarian clear cell carcinoma have demonstrated both a decreased survival and a less favorable response to platinum-based chemotherapy when compared with patients with papillary serous ovarian carcinoma.19–21 Prior studies evaluating endometriosis and ovarian cancer have found mixed results in terms of a potential survival benefit in women with endometriosis-associated ovarian cancer.10,16,19–21
Several authors have tried to address the question of whether the cancer results from malignant transformation of the ovarian endometriosis or whether the two conditions simply coexist. In several articles, the authors were able to demonstrate a transition point on the slides from benign endometriosis to a malignant tumor in 36–42% of cases, similar to the 40% of cases in which we identified such a transition point.4,11,12 Another way to address this question is to look for common genetic alterations like loss of heterozygosity, X chromosome inactivation, or p53 mutations. Jiang et al25 did so and suggested that the ovarian cancer resulted from transformation of the endometriosis in over half of the patients. In the cases in which a common defect was not found, 80% had the endometriosis and cancer on different ovaries. These studies strongly support the concept that endometriosis does undergo malignant transformation but that such a transformation does not account for all of the cancers that are associated with endometriosis.
An unexpected finding of this study was the fact that decreased gravidity was associated with a survival benefit. Our initial hypothesis to explain this correlation on the univariate analysis was that patients with lower gravidity and endometriosis-associated cancers might have come to medical attention earlier with infertility complaints and thus might have been diagnosed at an early stage. However, on the multivariable analysis, in which stage was held constant, this finding persisted. Grade could not be included in the multivariate analysis because no women with grade 1 cancer died of their disease. Of note, more women with lower gravidity had grade 1 tumors than would be expected, and this propensity for a lower grade in women of lower gravidity might partially explain the survival benefit. Another possible explanation that merits further exploration is the effect of pregnancy-related hormonal changes on the growth of endometriosis and possibly endometriosis-associated cancers. Increasing gravidity would logically increase exposure to hormones and growth factors and theoretically decrease survival if these factors play any role in cancer development.
Another area of speculation is the role of HRT in the genesis of endometriosis-associated cancers. An association has been noted between unopposed estrogen therapy and the development of endometrioid or clear cell epithelial ovarian tumors.5,26,27 The use of unopposed estrogen in women with an intact endometrium is contraindicated because of the increased risk of endometrial adenocarcinoma; should it be contraindicated in women with known endometriosis as well? Further, should women with significant endometriosis who undergo surgical therapy with removal of the uterus and ovaries also be cautioned with regard to hormonal therapies? Of the 21 women in our study with extraovarian cancers arising in endometriosis, 62% received HRT, compared with 10% of the other groups, and the majority who received HRT received unopposed estrogen. Although HRT use was not associated with a difference in survival in our study, the increased association of HRT use with extraovarian cancer arising in endometriosis raises interesting questions that should prompt further investigation.
Our study raises numerous questions that require further analysis. Women with endometriosis-associated cancers most likely represent a different class of patients than traditional ovarian cancer patients and may require different therapeutic options. Further investigation must focus on delineating the genetic differences between women with endometriosis-associated intraperitoneal cancer, women with ovarian cancer, and women with endometrial cancer; this will help guide both cancer treatment and hormone replacement strategies in women with endometriosis.
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Footnotes |
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Received December 28, 2001. Received in revised form April 10, 2002. Accepted April 25, 2002.
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REFERENCES |
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