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42 Male Breast Cancer C 42 Male Breast Cancer C. Bernard-Marty, E. Azambuja, L. Dal Lago, M.J. Piccart, and F. Cardoso 42.1 Introduction The earliest reference to breast cancer (BC) in men dates from 3000–2500 BCE, on an Egyptian papyrus [11], and the first clinical report was described in the 14th cen- tury by John of Arderne [71]. Carcinoma of the male breast is a relatively rare disease that accounts for less than 1% of all cases of cancer in men. Therefore, BC in men has largely taken a back seat to the worldwide effort to control this disease in women. Similarly, the literature regarding male BC consists mainly of case-control and retrospective studies involv- ing small numbers of patients [28]. The statistical accuracy of the clinical character- istics of male BC is not fully established and knowledge relevant to specific aspects of the disease in men is still limited. Consequently, treatment strategies have been largely guided by extrapolation from experience in women. In this chapter, the available information on risk, prognostic factors, clinical fea- tures, and treatment modalities of male BC has been summarized. Tailored pro- spective clinical trials in this disease, through large Intergroup networks, should be initiated. 42.2 Incidence According to the American Cancer Society, of the 212,600 new cases of BC diag- nosed in 2003, 1,300 (1%) were diagnosed in men and resulted in 400 deaths (30%) [39]. In contrast to the increasing incidence of BC in women, the incidence of BC in men has remained stable over the past 4 decades [47]. The median age of diag- nosis is 68 years (range: 5–93 years), approximately 5–10 years later than in women [28, 71]. The incidence increases with age and the bimodal age distribution seen in women is absent in men [28]. The incidence of male BC varies by geographical location, higher in the USA and UK, and is lower in Finland and Japan. In parts of Africa, the high incidence of male BC, which runs parallel to the high female cervical cancer rate, has led to the hy- pothesis of a relationship with sexually transmitted disease(s), or could be explained by an increased incidence of liver disease (a known risk factor for male BC) in these countries [91]. 904 Male Breast Cancer 42.3 Risk Factors 42.3.1 Hormonal Factors A recent review of published literature by the MD Anderson Breast Cancer team has listed the main risk factors for male BC (Table 42.1) [28]. Many of them involve ab- normalities in estrogen and androgen balance (excess of estrogen and/or lack of an- drogen), which indicates that BC in men, as in women, may be hormonally driven [20, 28, 81]. An example of risk factors related to hormonal levels is obesity, which causes increased peripheral aromatization of estrogen. 42.3.2 Testicular Abnormalities An elevated risk of BC has been observed in patients with prior history of unde- scended testis, congenital inguinal hernia, orchidectomy, mumps orchitis, testicular injury, and infertility, although the association between these conditions and the development of BC in men remains unclear [91, 93]. The strongest known risk factor for male BC is Klinefelter’s syndrome, a con- dition that results from the inheritance of an additional X chromosome (47, XXY karyotype). These men have atrophic testis, gynecomastia, high levels of gonado- Table 42.1 Risk factors for male breast cancer (BC) Testicular abnormalities Obesity Undescended testis Liver conditions Congenital inguinal hernia Cirrhosis Orchidectomy Alcoholism Orchitis Schistosomiasis Testicular injury Drugs Infertility Digoxin Klinefelter’s syndrome Thioridazine Familial history Marijuana Benign breast conditions Exogenous estrogen Nipple discharge Amphetamines Breast cysts Environmental factors Breast trauma Heat exposure Radiation exposure Head trauma Jewish ancestry Smoking Occupational exposure 42.3 Risk Factors 905 tropins, and low levels of testosterone. Their BC risk is up to 50-fold higher than in men with a normal genotype [37]. 42.3.3 Benign Breast Conditions An increased risk of BC in men has also been associated with nipple discharge, breast cysts, or history of breast trauma [92]. Gynecomastia is probably not a signifi- cant risk factor [28, 60, 102] since its incidence in male BC patients (6–38%) [104] is not higher than in the general population (35% of clinical and 40% of pathological gynecomastia) [10, 97]. 42.3.4 Liver Conditions Men with chronic liver disorders such as cirrhosis, chronic alcoholism, and schisto- somiasis are at increased risk of BC. The liver dysfunction means that they are unable to metabolize endogenous estrogen, resulting in a relative hyperestrogenism [88]. 42.3.5 Drugs Chronic use of drugs such as digoxin and thioridazine, chronic marijuana use, in- gestion of exogenous estrogen for treatment of prostate cancer [82], or hormonal replacement therapy in transsexuals [70] increases the risk of BC in men [71, 93]. 42.3.6 Environmental Factors The testicular function of workers in steel mills, blast furnaces, and rolling mills can be suppressed by chronic heat exposure [16]. Radiation exposure of men who work in electromagnetic fields or who are exposed to repeated fluoroscopy increases their risk of BC. Recently, a statistically significant association between ionizing radiation and male BC incidence has been shown in a population of Japanese atomic bomb survivors [77]. Employers with more than 3 months exposure to gasoline and com- bustion products have an odds ratio for BC of 2.5 (1.3–5.4) [34]. 42.3.7 Other Risk Factors Other reported risk factors include head trauma through increased prolactin pro- duction and local chest trauma [61, 72]. A meta-analysis of seven case-controlled studies has revealed the characteristics of men “at high-risk” to be: never married, benign breast disease, Jewish ancestry, or history of BC in first-degree relatives [81]. 906 Male Breast Cancer There is no evidence that male twins are at increased risk of BC when compared to the general population [96]. 42.4 Genetics Familial male BC was first described in 1889 [21, 44, 78, 98]. The genetic aberrations related to male and female BC are very similar. 42.4.1 BRCA1 and BRCA2 A positive family history is observed in 15–20% of male BC patients, compared to 7% of their female counterparts [28]. In women, mutations of the BRCA1 and BRCA2 genes are associated with a 50 and 80% risk of developing BC by the age of 60 years, respectively [101]. Numerous series of BRCA1 and BRCA2 mutations have been reported [12, 26, 35, 46, 62]. Male BC is a characteristic element of the BRCA2 phenotype. The lifetime risk of BC in male BRCA2 mutation carriers is approximately 80–100 times higher than in the general population, and BRCA2 mutations account for roughly 15% of all male BC [49]. Male BC is also reported in families with BRCA1 mutations, but the associ- ated risk seems to be lower [7]. Genetic testing criteria for men should perhaps be somewhat less strict than those for women, due to the rarity of the disease and the higher frequency of gene mutations. Men without cancer might be considered for testing if they have a fam- ily history of breast or ovarian cancer in a first- or second-degree relative, with BC diagnosed before age 50 years. Men with a diagnosis of BC should also be eligible for testing regardless of family history [49]. 42.4.2 Other Alterations Germline mutations in exons 2 and 3 encoding the DNA binding domain of the an- drogen receptor (AR) have been described (point mutation change Arg607 into Gln and Arg608 into Lys). These AR gene mutations suppress the activity of androgen in the breast cells, possibly leading to the development of BC as a result of loss of the protective effect of androgen [50]. A polymorphism of the CYP17 gene, a key regulator of the synthesis of andro- gens and estrogens, occurs significantly more frequently in male BC patients than in male controls (p = 0.038). The odds ratio for risk of developing BC in males with an allele C is 2.10 (95% confidence interval, CI = 1.04–4.27) [105]. However, no as- sociation has been described between this polymorphism of the CYP17 gene and BC in women. 42.5 Diagnosis 907 42.5 Diagnosis 42.5.1 Clinical Presentations As reported above, the mean age of presentation of male BC is 68 years. Its most common presentation is a painless subareolar mass (50–97%), which is centrally located in 50–70% of cases, followed by the upper outer quadrant [33]. There is a slight predilection for the left breast (1.07:1) [28] and bilateral forms are rare (less than 2%) [13]. The median diameter of these masses is 3.0–3.5 cm (range: 0.5–12.5 cm) [71]. Others signs and symptoms are nipple retraction (10–51%), lo- cal pain (4–20%), nipple ulceration (4–17%), nipple discharge (1–12%), and nipple bleeding (2–9%) [28]. Edema and eczema can occur in 17–30% of cases, and Paget disease is present in 5%. Suspect axillary nodes are detected clinically in 40–55% of patients at the time of diagnosis [71]. The mean duration of symptoms before the diagnosis was 1–21 months in the earlier series, declining to 1–8 months in a more recent one [71]. A population-based analysis of 2,524 cases of male BC and 380,856 cases of fe- male BC showed that men were significantly older at diagnosis (p < 0.0001), more likely to present with later stage disease (p < 0.0001), had larger tumors (p < 0.0001), nodal involvement (p < 0.0001), ductal histology (p < 0.0001), and estrogen receptor (ER)-positive tumors (p < 0.0001) [29].
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