Breast Cancer in Men

Carcinoma of the male breast is a relatively rare disease that accounts for less than 1% of all cases of cancer in men. Because of the rarity of the disease, most information has been obtained from small, single-institution, retrospective studies or by extrapolation from breast cancer trials in women. We have previously reviewed the literature on breast cancer in men (1) and now present an update that focuses on the molecular and pathology data that has been published over the past decade. Methods We identified articles published between 1942 and 2000 on breast cancer in men using CancerLit, MEDLINE, and bibliographies from other publications. We reviewed all retrospective series and studies that focused on the epidemiology, risk factors, genetics, pathology, molecular markers, prognostic factors, therapy, and outcomes of breast cancer in men. The project was supported in part by the Nellie B. Connally Breast Cancer Research Fund. The funding source had no role in the design of the study or in the preparation of or decision to publish the manuscript. Epidemiology and Risk Factors In 2002, approximately 1500 new cases of male breast cancer will be diagnosed in the United States, and 400 men will die of this disease (2). In contrast to the increasing incidence of breast cancer in women, the incidence of breast cancer in men has remained stable over the past four decades (3). The median age at diagnosis is 68 years compared with 63 years in women (4); however, the disease has been reported in males ranging from 5 to 93 years of age (5). The bimodal age distribution seen in women is absent in men; the incidence increases exponentially with age (6). In most western countries, men account for approximately 1% of cases of breast cancer. In Tanzania, by contrast, 6% of cases of breast cancer are diagnosed in men (7), and in countries in central Africa, a substantially higher proportion of cases of male breast cancer have been reported (8). The reasons for this geographic variability remain unclear. Many of the risk factors (Table 1) for breast cancer in men involve abnormalities in estrogen and androgen balance, which indicates that breast cancer in men, as in women, may be hormonally driven. An elevated risk has been seen in patients with undescended testes, congenital inguinal hernia, orchiectomy, orchitis, testicular injury, and infertility (8, 9). The Klinefelter syndrome, which is characterized by a 47,XXY karyotype, small testes, azospermia, and gynecomastia, is also a risk factor for breast cancer in men; affected men may have up to a 50-fold increased risk (10). Breast cancer in men may be a marker for the Klinefelter syndrome; between 4% and 20% of men with breast cancer have been unexpectedly found to have this syndrome, which affects only 0.1% of the general population (8, 10, 11). Other possible risk factors that relate to hormonal levels include obesity, which causes increased peripheral aromatization of estrogens, and cirrhosis, which results in a hyperestrogenic state (8, 9, 12, 13). Table 1. Risk Factors for Breast Cancer in Men A family history of breast cancer in female relatives has also been shown to be an important predisposing factor. Data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute showed that men with a positive family history have an odds ratio for developing breast cancer of 3.98 (14). The risk increases with increasing numbers of first-degree relatives affected and with young age at diagnosis in affected relatives. Benign breast conditions, such as nipple discharge, breast cysts, or history of breast trauma; radiation exposure; increasing age; and Jewish ancestry have also been associated with an increased risk for breast cancer in men (9). Gynecomastia probably does not represent a significant risk factor. Clinical gynecomastia has been reported in 6% to 38% of cases of breast cancer in men, which suggested that it could be a predisposing factor (15, 16). However, large reviews of gynecomastia in healthy men have found that 35% have clinical gynecomastia (17) and 40% have histologic evidence of gynecomastia (18). Thus, the rates in male patients with breast cancer do not seem to be higher than those in the general population. Genetics Approximately 15% to 20% of male patients with breast cancer have a positive family history, although only 7% of the general male population has an affected family member (15, 19-22). Therefore, researchers have suspected that some families may carry genetic mutations that provide an increased risk for breast cancer. In women, the breast cancer susceptibility genes BRCA1 and BRCA2 are thought to account for most hereditary breast cancers. Mutations in these genes confer a 40% to 70% risk for developing breast cancer by age 70 years. In men, BRCA1 does not appear to be associated with a significantly increased risk for breast cancer, although mutations in this gene have been described in affected men (23). However, men with BRCA2 mutations are predisposed to breast cancer. This gene was first identified by Wooster, who localized it to 13q12-13 and described multiple cases of breast cancer in men that showed linkage to this area (24). Families in which breast cancer has occurred and at least one male has been affected have been reported to have a 60% to 76% chance of carrying BRCA2 mutations (25, 26). Thus, the presence of breast cancer in men within a family with documented breast cancer indicates a high likelihood of a BRCA2 mutation. The frequency of BRCA2 mutations in men without a strong family history is much lower. A population-based study from California found that only 2 of 54 cases (4%) had BRCA2 mutations (21). Other series (Table 2) report that between 11% and 40% of men with breast cancer carry this mutation (27-32). The highest known prevalence of BRCA2 mutations in male patients with breast cancer is in Iceland, where a founder mutation accounts for 40% of all cases (28). Little is known about the distinguishing characteristics of breast cancer in men with BRCA2 mutations, although men with a mutation may present with disease at an earlier age (33). Table 2. BRCA2 Mutations in Breast Cancer in Men Pathology Almost all of the histologic subtypes of breast cancer that have been described in women have also been reported in men. Approximately 90% of all breast tumors in men are invasive carcinomas; the remaining 10% are noninvasive (34). The proportion of noninvasive cancers is higher than that seen in women before the introduction of mammography and may be due to the small size of the male breast, which simplifies the detection of small breast masses (34). Almost all of the noninvasive cancers are ductal carcinoma in situ. Lobular carcinoma in situ is extremely rare because of the absence of terminal lobules in the normal male breast; it has only been reported in conjunction with invasive lobular carcinoma (15, 35, 36). Ductal carcinoma in situ of the male breast differs from that of the female breast in that almost 75% of cases are a papillary subtype and almost all cases are low to intermediate grade (37). In men, the predominant histologic subtypes of invasive carcinoma are infiltrating ductal carcinoma, which accounts for more than 80% of all tumors (38-45), and papillary carcinoma, which makes up about 5% (22, 38, 39, 45-47). Lobular carcinoma is much less common in men than in women and represents only 1% of all cases (15, 22, 44). The rarer subtypes, such as medullary, tubular, mucinous, and squamous carcinomas, have all been reported in men, although they may be slightly more uncommon than in women (34, 43-45). Inflammatory carcinoma and Paget disease are seen with similar frequency in men and women (34, 45, 46). Carcinomas of the male breast have a higher rate of hormone receptor positivity than do carcinomas of the female breast when matched for tumor stage, grade, and patient age (48-50). Our review of the literature indicates that 81% of breast cancers in men are estrogen receptor positive, and 74% are progesterone receptor positive (Table 3) (11, 15, 22, 34, 41-45, 48, 51-82). In contrast to women, men do not have a higher incidence of estrogen receptorpositive tumors with advancing age (34, 51, 60, 61). Table 3. Pathologic Features of Breast Cancer in Men Molecular Markers C-erbB-2, p53, Bcl-2, cyclin D1, and epidermal growth factor receptor (EGFR) are important in the pathogenesis and prognosis of breast cancer in women. Recent literature has evaluated their role in carcinoma of the male breast, and we present a synthesis of these data (Table 3). The c-erbB-2 protooncogene encodes for a transmembrane receptor of the tyrosine kinase family, which is closely related to EGFR. This protein is expressed in 20% to 30% of breast cancers in women and may be associated with a poor prognosis (95). Pooled data indicate that 37% of tumors overexpress c-erbB-2 as detected by immunohistochemistry (48, 50, 58-61, 73, 76, 79, 83-88). Although these data are the best available, they must be interpreted with caution because antibody preparations and the definitions for positive staining were not standardized and varied considerably among studies. Recently, Bloom and colleagues presented data on 58 male patients who were tested for c-erbB-2 overexpression (88). Twenty-six of these patients had been evaluated in an earlier study, and 35% were reported as overexpressing c-erbB-2 (79). When the same tumors were reevaluated by using stricter criteria to define positive immunohistochemistry staining, only one sample had either 2+ or 3+ staining. This study suggests that the older data may have been overestimating the rate of c-erbB-2 expression. Bloom and colleagues' study also evaluated the patient's tumors by using fluorescent in situ hybridization and found that none of the 58 tumors had gene amplification. This is the only study to date that has used fluorescent in situ hybridization to evaluate c-erbB-2