Histopathology of breast cancer among African-American women†
This article is a US Government work and, as such, is in the public domain in the United States of America.
Although the overall incidence of breast cancer in African-American women is lower than in white women, African-American women younger than 50 years old have a higher incidence of breast cancer than white women. African-American women with breast cancer have a poorer survival rate than white women and are more likely to die of breast cancer in almost every age group. To explain this disparity, we studied a substantial body of literature that reported a biologic difference in the tumors found in African-American and white women. Specifically, more aggressive histopathologic patterns have been described among African-American patients with breast cancer when compared with white women. In addition, there are data that support an ethnicity-related variation in the expression of breast tumor hormonal markers. The objective of this study was to critically evaluate the existing published data on the histologic features of breast cancer to determine whether breast cancer in African-American women is a histologically more aggressive disease than in white women. We conclude that the aggressive tumor histology reported in African-American women has not been analyzed carefully with respect to the age of the patient at the time of diagnosis and the stage of disease at presentation. Furthermore, there is a need for central pathology review using accepted, published criteria for diagnosis of uncommon and controversial histologic subtypes of breast cancer. Cancer 2003;97(1 Suppl):253–7. Published 2003 by the American Cancer Society.
Age of Onset
Although the overall incidence of breast cancer is lower among African-American women than among white women, the incidence rates among African-American women younger than 50 years old are higher than among white women.1 In general, African-American women develop breast cancer 5–10 years earlier than white women.2, 3 In the Surveillance, Epidemiology, and End Results program, the median age at diagnosis of breast cancer for African-American women was 57.0 compared with 64.0 for white women.1 Newman and Alfonso4 evaluated breast cancer in women younger than 50 years old and found that significantly more African-American patients than white patients were diagnosed at a young age. Similarly, Kovi et al.5 reported that a higher percentage of African-American women (68%) younger than 54 years old were diagnosed with breast cancer compared with white women of the same age (53%). Their observation was based on data compiled by the Armed Forces Institute of Pathology experience with breast cancer from 1980 to 1983.
Disease Stage and Survival Rates
In addition to developing breast cancer earlier, African-American women with breast cancer present at a more advanced stage with larger tumor sizes and more positive lymph nodes.2, 4–10 African-American women present with an excess of Stage II disease and are twice as likely to be diagnosed with late-stage cancer than white women. Several studies reported a worse overall 5-year survival rate among African-American patients with breast cancer.8, 11 Stage for stage, African-American women have a worse survival rate than white women. The mortality rate of African-American women with breast cancer also exceeds that of white women.11 Numerous studies have evaluated tumor biology to explain the disparities in survival rates between African-American and white women. Several investigators found an increase in gross tumor size, high nuclear grade, and tumor necrosis among women with breast cancer.2, 3, 12–15 Elmore et al.2 found that tumors in African-American women were larger, contained necrosis, and were more likely to have lymphovascular invasion compared with tumors in white women. However, when confounding variables such as income, medical insurance, and screening mammography were controlled, most pathologic differences between the races were no longer significant. Aziz et al.3 found a higher incidence of nuclear Grade 3 tumors among African-American women with breast cancer than among white women. However, their sample size was small (323 patients) and the results were not statistically significant. In addition, age-specific comparisons were not performed in that study. In 1985, Ownby et al.13 completed a retrospective review of 1078 breast cancer patients from Detroit. They found that compared with white women, a higher percentage of African-American women with breast cancer were classified as nuclear Grade 3, had more lymph node involvement at the time of diagnosis, and had a greater percentage of Stage IV disease. These authors attributed some of these findings to a higher rate of obesity among African-American patients. This observation of a higher prevalence of obesity among African-American patients with breast cancer has been substantiated by Jones et al.16 They reported that severe obesity was significantly associated with advanced disease in African-American women with breast cancer.
Chen et al.12 reviewed 963 newly diagnosed breast cancer patients as part of the black/white cancer survival study. In this well designed study, not only was there a central pathology review, but the reviewing pathologist was blinded to patient demographics. The authors found that after adjusting for age, stage, and metropolitan area, African-American women were more likely than white women to have high-grade nuclear atypia and a higher mitotic activity. Although white women of high socioeconomic status (SES) had more favorable tumor histology compared with white women with a low SES, the same relationship was not observed for African-American women.
Several authors have reported an increased tumor nuclear grade among all women younger than 40 years old who have been diagnosed with breast cancer. Independent of race, they observed less well differentiated tumors among younger women.17–20 In a review of 1869 consecutive diagnoses of breast cancer patients, Fisher et al.20 found a statistically significant difference in the number of nuclear Grade 3 carcinomas in unselected women younger than 40 years old (P < 0.0001) when compared with older women. In the same study, lobular carcinoma was reported more frequently in women aged 70 years or older. In an evaluation of breast cancer in women 35 years of age or younger, Rosen et al.19 found a high incidence of poorly differentiated tumors (53%), medullary carcinomas (11%), and estrogen receptor (ER)-negative carcinomas in this young cohort. Kollias et al.17 reported similar findings in an evaluation of 2897 women with breast cancer: high nuclear grade, lymphovascular invasion, and an increase in medullary carcinoma were observed in women younger than 35 years of age when compared with older women.
Many authors have emphasized that medullary carcinoma comprises a large percentage of breast cancer subtypes in African-American women and point to the high nuclear grade of these tumors as evidence of an aggressive tumor histology in African-American women.5, 8, 14, 21, 22 Unfortunately, none of the aforementioned studies reported the diagnostic criteria used to make the diagnosis of medullary carcinoma. Moreover, most of the studies did not have a central pathologic review of the cases or age-matched controls. Natarajan et al.14 reviewed the cases of more than 40,000 women in the 1982 American College of Surgeons breast cancer curvey and found that 6.8% of African-American women had medullary histology compared with 2.7% of white women. In the same study, papillary carcinoma was identified in 2.1% of African-American patients compared with 1.1% of white women. Evaluating data from the Armed Forces Institute of Pathology's experience with breast cancer from 1980 to 1983, Kovi et al.5 found an excess of medullary, mucinous, and papillary carcinomas among African-American patients compared with white patients. However, only mucinous carcinoma occurred significantly more frequently among African-American women (4.8%) than among white women (2.1%; P ≤ 0.05).
In reviewing the University of Texas Health Science Center's experience with breast cancer, Elledge et al.8 found twice the frequency of medullary carcinoma in African-American women than in white women (5.2% vs. 2.6%, respectively). However, this information was obtained from both patients records and a review of their pathology reports, not from a central pathology review. In a retrospective review of 708 African-American patients treated at Harlem Hospital between 1964 and 1986, Freeman and Wasfie22 found that 9% of all types of breast cancers treated were medullary carcinomas. Unfortunately, a control group of white women was not used for comparison in this study. Claus et al.21 evaluated the data of 4071 patients with breast cancer. They found an increased incidence of medullary carcinoma in African-American women (11%) compared with white women (5%). Although medullary carcinoma was reported more frequently among African-American women compared with white women, the mean age at diagnosis of medullary carcinoma was significantly younger than the age at diagnosis of other histologic tumor types, adding the confounding variable of age to the interpretation of the data.
In most large series, medullary carcinoma accounts for less than 5% of all breast cancers and occurs most often in young women. In addition, the histologic diagnosis of medullary carcinoma is fraught with interobserver variability and the disease entity is frequently overdiagnosed.23–25 None of the studies that compared histopathologic observations and race mentioned the diagnostic criteria used to make the diagnosis of medullary carcinoma and most studies did not include a central pathology review.
Ownby et al.,13 Simon and Severson,9 Newman and Alfonso,4 Mittra et al.,26 and Chen et al.12 reported no variation in tumor histology by race. In addition, Williams et al.27 did not find an increase in medullary carcinoma among the 1270 African-American women studied at Howard University Hospital. Moreover, medullary, mucinous, and papillary carcinomas are tumors with a good prognosis, which would portend a good outcome and be antithetical to an aggressive tumor histology hypothesis. As illustrated by the data of Claus et al.,21 age at presentation was a confounding variable in the examination of patients with medullary carcinoma. They found that medullary carcinoma occurs most often among young women and that young African-American women are more likely to develop breast carcinoma than white women.
The findings on lobular carcinoma have been inconsistent. Studies have shown lobular carcinoma to be both more and less frequent in African-American women when compared with white women.5, 14, 15, 21, 27, 28 However, Newman and Alfonso4 and Elledge et al.8 reported no racial differences in the frequency of lobular carcinoma among African-American and white patients.
Hormonal Status of Tumors
Several historic studies have found that African-American women have less hormone-positive tumors than white women, a fact that has been linked to the clinical aggressiveness of breast cancer among African Americans. However, Newman and Alfonso,4 Muss et al.,28 and Ownby et al.13 found no significant differences in ER or progesterone receptor (PR) status in African-American women compared with white women.Similarly, Elmore et al.2 found no difference in ER expression in tumors involving African-American and white patients and Chen et al.12 reported no statistical difference in ER status between African-American and white patients. However, using data from the 1982 national survey of breast cancer, Natarajan et al.14 found that only 63% of African-American patients with breast cancer had ER-positive tumors compared with 74% of white women over the age of 50.In women younger than 50 years of age, 45% of African-American patients had ER-positive tumors compared with 58% of white women. Statistical analysis of these data was not reported. Similarly, Mohla et al.29 reported a low incidence of ER-positive tumors in a group of 142 African-American women who underwent surgery at Howard University Hospital. In that study, 46% of the tumors were positive for ER using tissue cytosol assays, compared with 56% ER positivity in the literature at that time (presumably for all races).
Freeman and Wasfie22 reported a lower percentage of ER-positive tumors in African-American women compared with white women in their study of 703 patients with breast cancer treated at Harlem Hospital (50% vs. 66%). However, less than 10% of their patient population of 703 (70 women total) was examined for ER status. Pegoraro et al.30 reported that 49% of black women with breast cancer in South Africa had ER-positive tumors compared with 67% of South African white women. Yet it is known that nuclear grade and hormone positivity are inversely related independent of racial origin. ER positivity is strongly associated with age at diagnosis, being more prevalent among postmenopausal women. Some researchers adjusted for age or stratified by age group when comparing hormone receptor status between African-American and white women, which may account for the inconsistent study findings. Elledge et al.8 stratified ER status by age and race of patients with breast cancer. For women younger than 35, there was no significant difference in ER or PR hormone status by ethnicity. However, in women older than 35, white women had a higher percentage of ER-positive tumors compared with African-American women (P < 0.001). Gordon31 reported a clear association between social class (measured as educational level) and the diagnosis of ER-negative tumors after controlling for age, race, and other known risk factors of breast cancer.
No clinically significant difference in Her-2/neu status between African-American and white women with breast cancer has been identified.8, 10, 32 In addition, Wu et al.32 found no difference in the plasma level of Her-2/neu in African-American and Hispanic women. A higher S-phase fraction in tumors of African-American women has been described by both Elledge et al.8 and Shiao et al.33 S-phase fraction, an indicator of proliferative activity, correlates with the degree of histologic differentiation, nuclear grade, and ER immunoreactivity. However, S-phase fraction is not an independent indicator and adds little additional prognostic information. Both Elledge et al.8 and Shiao et al.33, 34 found no difference in DNA ploidy or p53 expression in African-American women compared with white women. Shiao et al.34 identified p53 genetic alterations in 20.0% and 19.2% of African-American and white patients with breast cancer, respectivelyAlthough the proportion of patients with p53 gene alteration was similar, the location and types of genetic mutations were different between African-American and white women. Expression of CYP1A1, a gene that produces an enzyme that can metabolize some carcinogens, is increased in African-American women with breast cancer. In a small pilot study evaluating 21 African-American women and 30 white women, a microsatellite polymorphism was identified in the African-American patients with breast cancer, but not in the white women.35 However, another study found no association of this polymorphism among women with breast cancer.36
This critical literature review suggests that the aggressive tumor histology reported in African-American women has not been analyzed carefully with respect to the age of the patient at diagnosis and the stage at presentation. Any association with age at presentation is problematic as it is difficult to obtain adequate matched control cases because breast cancer is relatively uncommon in young women (e.g., 4% in the Kollias et al. study17). Advanced stage at presentation and early age at diagnosis remain real race-related differences between African-American and white women and can explain many of the observed adverse histopathologic findings (increased nuclear grade, cell turnover and necrosis, and hormonal receptor status). Therefore, we conclude that independent evaluation of race will require age-matched, stage-matched, treatment-matched, and SES-matched studies to eliminate many of the confounding variables. In essence, it is extremely difficult to rule out nonbiologic factors in the assessment of histopathology in African-American women. In addition, ease of availability of medical care (including insurance coverage and income) and the availability of screening mammography are linked to clinical outcome and have been reported, in at least one study,2 to account for most pathologic differences.
Genetic epidemiologic evidence does not support that there is sufficient racial heterogeneity to expect profoundly different disease histopathology or treatment response strictly on the basis of race. In fact, more than 80% of genetic variability is identified within individuals of the same population.37
One major observation from this review is that there is a need for central pathology review using accepted published criteria for diagnosis of uncommon and controversial histologic subtypes of breast cancer, i.e., medullary carcinoma in African-American women. There is also a need for central review of tumor nuclear grade for standardization and consistency. It is difficult to make recommendations based on historical studies of breast cancer in African-American women because most studies reporting on tumor histopathology and race had no central pathology review. In addition, many studies had small sample sizes, which could be addressed by future multiinstitutional research on breast cancer in special populations.