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Obstetrics & Gynecology 1999;94:713-720
© 1999 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Race and Clinical Outcome in Endometrial Carcinoma

PHILIP P. CONNELL, MD, JACOB ROTMENSCH, MD, STEVE E. WAGGONER, MD and ARNO J. MUNDT, MD

From the Departments of Radiation and Cellular Oncology and Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago Hospitals, Chicago, Illinois.

Address reprint requests to: Arno J. Mundt, MD, Department of Radiation and Cellular Oncology, University of Chicago Hospitals, MC 9006, 5758 South Maryland Avenue, Chicago, IL 60637, E-mail: mundt{at}rover.uchicago.edu


   Abstract
Top
Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To compare the outcomes of black and white women who have surgically staged endometrial carcinoma.

Methods: We retrospectively compared the clinicopathologic factors, socioeconomic status, treatments, and outcomes of 70 black and 302 white women who were treated for surgically staged endometrial carcinoma at our institution.

Results: Black women had higher-grade tumors, less favorable histologic findings, more comorbid illnesses, and lower socioeconomic indices. A nonsignificant trend was also seen toward more advanced-stage disease. The extent of surgical staging and types of adjuvant therapies were similar. On univariate analysis, black women had worse 5-year disease-free survival than white women (52.8% versus 75.2%; P = .001). Other significant factors included stage, grade, lymph node status, extension to the uterine serosa, cervical involvement, histology, adnexal involvement, lymphovascular invasion, myometrial invasion, positive peritoneal cytology, level of education, and household income. After controlling for pathologic and socioeconomic differences in multivariate analysis, race remained a significant prognostic factor (P = .008; hazard rate 2.0; 95% confidence interval 1.2, 3.5).

Conclusion: In a large cohort of surgically staged and uniformly treated patients with endometrial carcinoma, black race was associated with significantly worse outcomes, even after controlling for clinicopathologic and socioeconomic factors.

Endometrial carcinoma is the most common gynecologic malignancy in the United States.1 In recent years, considerable interest has been focused on racial imbalances in this disease. Data from the U.S. Surveillance, Epidemiology, and End Results study between 1986 and 1990 showed that endometrial carcinoma is diagnosed approximately twice as frequently in white women as in black women, but black women are approximately twice as likely to die from this disease. The age-adjusted mortality rate of endometrial cancer for black women is 6.0 (per 100,000), versus 3.3 in white women.1

Several hospital2–6 and population-based7–17 studies have investigated this racial disparity in outcomes in women with endometrial cancer. Black women have been noted to present with more advanced stages of disease,2–5,9,10,14–17 higher tumor grades,2–4,6,10,15–17 less favorable histologic findings,5,6,9,15–17 and other adverse pathologic features.6,18 Black women also have lower socioeconomic status and more limited access to health care.6,9,10,15–17 Several investigators have argued that such differences explain the observed outcome disparity based on race.4–6 Others have found that outcome differences persisted even after controlling for imbalances in clinicopathologic factors.9,10,12,17 The published studies, however, have important limitations that may contribute to these contradictory results. Many included clinically staged women, and thus important pathologic prognostic factors were not known in all patients. Most studies did not describe the adjuvant therapy delivered, so uniformity of treatment between racial groups was not ensured. Finally, few controlled for differences in socioeconomic status.

At the University of Chicago, we care for a mixed racial population. Once in our system, all patients are staged and treated in a uniform manner. In this report, we present an analysis of the impact of race on outcome in women with surgically staged endometrial cancer. The goal of this study was to determine whether outcome differences exist between racial groups and whether such differences persist after controlling for imbalances in clinicopathologic and socioeconomic factors.


   Materials and Methods
Top
Abstract
 Materials and Methods
Results
 Discussion
 References
 
We reviewed the outcomes of 372 women (70 black, 302 white) with endometrial carcinoma who underwent primary surgery at our institution between 1980 and 1995. Patient, tumor, and treatment characteristics were abstracted from the hospital records and pathology reports. Each woman had total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO). Adjuvant postoperative therapies included radiation therapy, chemotherapy, and hormonal therapy. Adjuvant radiation primarily consisted of external-beam whole-pelvic or intracavitary radiation therapy. Chemotherapy varied over the years of study but was predominantly cisplatin-based. Hormonal therapy consisted of megestrol acetate or tamoxifen. Adjuvant therapy typically was administered to women with documented extrauterine disease, high-risk early-stage disease, and unfavorable histologies. All cancer stages were reviewed and updated to reflect the 1988 International Federation of Gynecology and Obstetrics criteria.19 Clear-cell, adenosquamous, and papillary serous histologies were defined as unfavorable. Papillary serous and clear-cell tumors were not graded, but were considered grade 3 in the multivariate analysis. Socioeconomic information was not routinely recorded in our hospital charts, so average values for median family income, mean highest levels of education, and percentage below the poverty level were taken from the census tract of residence. These values were assigned as proxy measures for each woman. Follow-up data were obtained from hospital records, contacts with the patients’ physicians, and tumor registries.

Disease-free survival was defined as the interval from diagnosis to disease recurrence or death. Disease recurrence and cancer-related deaths were considered events in the analysis. Subjects were censored for death due to intercurrent disease. Actuarial curves were calculated using the method of Kaplan and Meier20 and compared by the log-rank test.21 The {chi}2 test was used for analysis of the distribution of prognostic factors between racial groups. Variables found to be significant on univariate analysis (P <= .05) were entered into a multivariate Cox proportional hazards model.22


   Results
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Abstract
 Materials and Methods
 Results
Discussion
 References
 
Characteristics of black and white women are compared in Table 1Go. No significant differences were seen in median subject age, weight, or nulliparity. Black women had more frequent comorbid illnesses, including hypertension and diabetes. Significant differences were noted in all three socioeconomic measures, including median income, likelihood of completing high school, and likelihood of living below the poverty level.


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  		Table 1. Patient and Tumor Characteristics
 
Table 1Go also compares the tumor characteristics. Black women had more advanced stages of disease, but this difference was not statistically significant. Black women also had a higher frequency of unfavorable histologies, particularly papillary serous tumors. Even after excluding unfavorable histologic findings, black women had more high-grade lesions. No significant differences were seen in the depth of myometrial invasion, positive peritoneal cytology, extension to the serosa, vaginal involvement, lymphovascular invasion, or lymph node involvement.

All women underwent TAH-BSO with abdominopelvic exploration, and lymph node sampling was done in the majority of both groups. Among the 225 women at high risk for nodal involvement (more than half myometrial invasion, cervical involvement, and extrauterine disease), we found no differences in the frequency of nodal sampling between black and white women (64.6% versus 61.6%; P = .7). Peritoneal fluid sampling was done somewhat less frequently in black than in white subjects (62.9% versus 75.2%; P = .04).

Adjuvant therapies (radiation therapy, chemotherapy, and hormonal therapy) are summarized in Table 2Go. The percentages of women who received adjuvant therapies were similar between groups. In addition, no significant differences were seen in the adjuvant therapies delivered when analyzed by stage and histologic process.


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  		Table 2. Comparison of Adjuvant Therapy
 
The median follow-up times for all patients and all surviving patients were 40.1 months (range 1–185) and 42.3 months (range 1–185), respectively. We found no difference in median follow-up between the racial groups (P = .50). As shown in Figure 1Go, black women had a worse 5-year actuarial disease-free survival compared with white women (52.8% versus 75.2%; univariate hazard rate 2.4). When analyzed by stage, grade, and histology, this outcome difference was most prominent in stages II–III disease and in grades 2–3 tumors with favorable histology. This is shown graphically in Figures 2Go and 3Go; however, these curves should be interpreted with caution because each represents a limited subgroup with relatively few subjects.



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  		Figure 1. Disease-free survival of black (1) versus white (0) women (P < .001).

 


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  		Figure 2. Disease-free survival of black (1) versus white (0) women with A) stage I (P = .24), B) stage II (P = .02), C) stage III (P < .001), and D) stage IV disease (P = .42).

 


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  		Figure 3. Disease-free survival of black (1) versus white (0) women with favorable histology of A) grade 1 (P = .48), B) grade 2 (P = .08), or C) grade 3 (P = .05), and D) unfavorable histology (P = .63).

 
The significance of other subject and tumor-related variables is summarized in Table 3Go. Significant prognostic factors included stage, grade, nodal status, cervical invasion, extension to the serosa, histology, adnexal involvement, lymphovascular invasion, myometrial invasion, peritoneal washings, completion of high school, and median household income.


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  		Table 3. Five-Year Actuarial Disease-Free Survival: Univariate Analysis
 
Multivariate analysis was done to determine whether race would remain an independent prognosticator. This model included all subject and tumor-related variables found to be significant on univariate analysis. The results are summarized in Table 4Go. Stage (P = .005) and grade (P < .001) were strong predictors of recurrence. However, race also remained a significant prognostic factor (P = .008; hazard rate 2.0; 95% confidence interval 1.2, 3.5).


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  		Table 4. Multivariate Analysis of Disease-Free Survival
 

   Discussion
Top
Abstract
 Materials and Methods
 Results
 Discussion
References
 
Analyses of outcome in patients with endometrial carcinoma are complicated by numerous interrelated prognostic variables. Observed racial disparities in survival could be due to imbalances in stage, grade, histology, socioeconomic status, extent of staging, adjuvant therapy, or confounding medical conditions.23–25 It is crucial to identify all potential explanatory factors and to understand their relative importance. Only after accounting for these factors can one make meaningful conclusions regarding the impact of race on outcome.

All women in our study were seen in a single hospital system, underwent primary surgery, and were staged and treated equivalently. Clinicopathologic and socioeconomic factors were accounted for in all subjects. Our analysis revealed significant differences in outcome based on race, and these remained even after controlling for imbalances in prognostic factors. As shown in Table 5Go, several investigators have analyzed the effect of race on endometrial carcinoma.2–10,12–14,17 All noted marked differences in pathologic features and outcomes between black and white women, consistent with our results. Of the series that included multivariate analyses, four found that race remained a significant prognostic factor after controlling for imbalances in clinicopathologic features9,10,12,17 and three did not.4–6 Many series included clinically staged subjects who did not undergo surgery2,3,5,7–10,12,14,17 or patients who received preoperative irradiation.13 Therefore, pathologic prognostic factors including depth of myometrial invasion and extrauterine involvement were not known in many patients and thus could not be accounted for in multivariate models. In the National Cancer Institute’s Black/White Cancer Survival Study, for example, 70.5% of the black women had surgery compared with 95.4% of the white women.16,17 This is an important limitation because pathologic features are major prognostic factors in endometrial cancer.26 Two recent series included only surgically staged women.4,6 However, both included small numbers of black women (fewer than 40), limiting statistical power.


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  		Table 5. Race and Outcome Studies: Endometrial Carcinoma
 
Many investigators have suggested that outcome differences based on race are due to a greater frequency of high-grade tumors with unfavorable histology in black women.4,5,15–17 In the present study, we too noted large differences in grade and histology between the groups. Nevertheless, race remained a significant prognostic factor on multivariate analysis after controlling for these differences. It remains unclear why a greater percentage of black women present with high-grade tumors with unfavorable histology. In a recent review of the California Cancer Registry, Plaxe and Saltzstein27 found that although black women present with a greater percentage of high-grade or unfavorable-histology tumors, the annual population-based risk of developing such lesions was equivalent between groups. This finding suggests that the observed racial imbalances are attributable to a relatively high incidence of low-grade or favorable-histology tumors in white women, possibly due to differences in exogenous hormone use,27 which is more common in white women4,15 and results in the development of low-grade, superficially invasive, favorable-histology tumors.28

Other frequently cited explanations for racial disparities in outcomes are differences in socioeconomic status, resulting in impaired access to health care, and delays in diagnosis.23–25 Women without a usual health care source present with more advanced stages and higher tumor grades.15,16 Significant differences have been reported between black and white women in terms of the source of health care,15–17 family income,6,15–17,29 poverty index,15–17,29 and educational level.15–17,29 In our study, race remained a significant prognosticator after controlling for differences in socioeconomic indices. Other investigators have found that socioeconomic factors explain only part of the observed differences in outcome based on race.10,15,17

The extent of staging and treatment is also an important consideration in endometrial cancer. Unfortunately, most series did not detail these factors or reported marked imbalances between racial groups. Axtell and Myers7 found that black women were more likely to receive no treatment; others have found that black women were less likely to undergo surgery.10,15–17 In one of the few series comparing adjuvant therapy, Bain et al10 found that adjuvant treatment was given less often to black women. Such discrepancies may have contributed to the observed differences in outcomes between racial groups in these series. In our study, all patients underwent surgery, were similarly staged, and received comparable adjuvant treatment. It is unlikely that staging and treatment factors explain the outcome differences observed in our series.

Why then do racial differences in outcome exist? One possibility is that tumors arising in black women are biologically more aggressive. Kohler et al18 noted that p53 mutations occurred more frequently in endometrial tumors arising in black women. This finding is important because p53 alterations are early events in the pathogenesis of papillary serous lesions.30 Hicks et al6 noted that black women had a higher percentage of tumors with high S-phase fractions and a trend toward more aneuploidy. It is unclear whether these findings demonstrate a worse tumor biology or are simply markers of more advanced disease.

Alternatively, outcome differences may be due to unidentified patient-related factors. We and others15–17 have noted marked differences in the prevalence of comorbid illnesses between racial groups. Dietary differences were also noted. On average, diets of black women are higher in fat and lower in fiber.31 Such differences might adversely affect the host immune status or alter tumor cell proliferation.32 Several investigators have also reported racial differences in endogenous hormones.33,34 These and other host factors might affect the natural history of endometrial carcinoma.

Several limitations of this study should be noted. This report includes a 16-year observation period, during which staging and treatment philosophies have changed. Because of the retrospective nature of this analysis, certain subject and treatment details were unknown, ie, exogenous hormone use, body mass index, frequency of follow-up visits, and smoking history. Our socioeconomic indices were not obtained from the individual subjects and were only gross measures of socioeconomic status. It is possible that more subtle issues associated with low socioeconomic status, including treatment compliance problems and delays in diagnosis, may have contributed to the poor outcomes seen in black women. Nonetheless, our results suggest that imbalances in traditional prognostic factors do not explain differences in outcome based on race. Further investigation is needed to explain and correct this racial disparity.


   Footnotes
 
PII S0029-7844(99)00381-6

Received February 1, 1999. Received in revised form April 9, 1999. Accepted April 15, 1999.


   References
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 Materials and Methods
 Results
 Discussion
 References
 
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6. Hicks ML, Kim WS, Abrams J, Johnson CC, Blount AC, Parham GP. Racial differences in surgically staged patients with endometrial cancer. J Natl Med Assoc 1997;89:134–40.[Medline]

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8. Young JL, Ries LG, Pollack ES. Cancer patient survival among ethnic groups in the United States. J Natl Cancer Inst 1984;73:341–52.

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16. Hill HA, Coates RJ, Austin H, Correa P, Robboy SJ, Chen V, et al. Racial differences in tumor grade among women with endometrial cancer. Gynecol Oncol 1995;56:154–63.[Medline]

17. Hill HA, Eley JW, Harlan LC, Greenberg RS, Barrett RJ II, Chen VC. Racial differences in endometrial cancer survival: The Black/White Cancer Survival Study. Obstet Gynecol 1996;88:919–26.[Abstract]

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20. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81.

21. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50:163–70.[Medline]

22. Cox DR, Oakes D. Analysis of survival data. London: Chapman & Hall, 1984.

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24. Schottenfeld D. Determinants of black/white survival differences among women with endometrial cancer [editorial]. Gynecol Oncol 1995;56:151–3.[Medline]

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26. Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al. Relationship between surgical-pathological risk and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group study. Gynecol Oncol 1991;40:55–65.[Medline]

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28. Shapiro S, Kelly JP, Rosenberg L, Kaufan DW, Helmrich SP, Rosenshein NB, et al. Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med 1985;313:969–72.[Abstract]

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34. Wright NM, Papadea N, Willi S, Vendhuis JD, Pandey JP, Key LL, et al. Demonstration of a lack of racial differences in secretion of growth hormone despite a racial difference in bone mineral density in pre-menopausal women—a Clinical Research Center study. J Clin Endocrinol Metab 1996;81:1023–6.[Abstract]




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