Breast carcinoma is an uncommon neoplastic condition in men, accounting for not more than 1% of all breast carcinomas and for less than 0.1% of male cancer deaths.^1,2,3,4,5 Worldwide, the incidence is generally less than 1 case per 100,000 men per year.

Hodgson et al.⁶ analyzed 1,396 cases of male breast carcinoma diagnosed in the state of Florida between 1985 and 2000. The age-adjusted incidence rose from 0.9 to 1.5 cases per 100,000 men between 1990 and 2000. The highest incidence (12.5 per 100,000) occurred in men aged 85 years or older. These results are consistent with a nationwide rise in incidence recorded by Giordano et al.,⁷ who analyzed data from the Surveillance Epidemiology and End Results (SEER) program from 1973 to 1998. During this period, the incidence of male breast carcinoma rose from 0.86 to 1.08 per 100,000 (p < 0.001). In a California-based study,⁸ the number of cases of male breast carcinoma diagnosed per year rose from 87 in 2005 to 139 in 2009. The rising incidence of male breast carcinoma is probably a function of overall aging of the population, but the contribution of other factors cannot be excluded. More recently, Anderson et al.⁵ reported that breast carcinoma incidence and mortality rates for men and women in the United States decreased from 1996 to 2005, with a decline of 28% among men and 42% among women in the adjusted hazard rate for breast cancer death.

On the basis of data from the SEER program, Siegel et al.⁹ estimated that there would be 2,190 new cases of male breast carcinoma and 410 deaths from the disease in 2012 in the United States. By comparison, the projected number of women diagnosed with breast carcinoma in 2012 was estimated to be 226,870, with 39,510 breast carcinoma deaths. An international population-based study using data for 459,846 women and 2,665 men with breast carcinoma from six countries reported standardized incidence of 66.7 and 0.4 per 100,000 person-years for women and men, respectively.¹⁰

Racial variations have been described, with the incidence reportedly lower among Japanese¹¹ and higher among Blacks in West Africa¹² and the United States¹³ when compared with Whites in the United States. The average annual ageadjusted breast carcinoma death rate is higher among non-White men in the United States⁴ and lower among Japanese men in Japan¹¹ than among White men in the United States, Canada, Europe, or Scandinavia. A higher incidence of breast carcinoma has been found in Israel¹⁴ and among Jewish men when compared with other White ethnic subgroups.^2,4,15,16 The incidence and age-specific death rate for male breast carcinoma increase in a linear fashion with advancing age among different racial and ethnic groups.^1,4,11,15 This straight-line relationship between incidence and age among men differs from that of female breast carcinoma, which is characterized by a less steep slope after age 50 among postmenopausal women.¹⁷ Ethnicity of men with breast carcinoma was evaluated in detail in a California-based population study.⁸ Most (431/606; 71%) patients were non-Hispanic White men, 45/606 (7.4%) non-Hispanic Blacks, 67/606 (11.1%) Hispanics, and the remaining 63/606 (10.4%) were Asian/Pacific Islanders or of other ethnicities. Most (82.8%) non-Hispanic White men had hormone receptor-positive carcinomas, 14.6% had HER2-positive tumors, and only 2.6% were reported to have triple negative carcinomas. Among non-Hispanic Blacks, 73.3% of carcinomas were hormone receptor-positive, 17.8% HER2-positive, and 8.9% triple negative carcinomas. Among Hispanic men, 77.6% of the carcinomas were hormone receptor-positive, 16.4% HER2-positive, and 6% triple negative. Despite these differences, race and ethnicity did not affect patient survival.

Some investigators¹⁸ have found increased levels of estradiol and other estrogenic hormones in men with breast carcinoma, but others have not detected increased or abnormal estrogen concentrations.^19,20 Case-control studies by Schottenfeld et al.⁴ and Mabuchi et al.² found a relatively high frequency of antecedent mumps orchitis among men with breast carcinoma. It was suggested that testicular atrophy after orchitis causes relative hyperestrogenism. A follow-up study of 132 men who had mumps orchitis in one community revealed that the median age of patients with mumps was 8 years and that of patients with mumps orchitis was 29 years.²¹ Follow-up of 20 years or more was
obtained for 36% of the patients, revealing testicular neoplasms in two. The absence of subsequent male mammary carcinoma in this cohort may reflect the relative youth of the patients at follow-up and the lack of information about most of the men. Nicolis et al.²² described a patient who developed breast carcinoma 30 years after mumps orchitis that resulted in testicular atrophy. Casagrande et al.²³ found no relationship between mumps in adulthood and male breast carcinoma, but they did not evaluate orchitis as a specific factor. An association with antecedent testicular trauma was observed by Mabuchi et al.² Further evidence that testicular dysfunction might contribute to male breast carcinoma risk was reported by Thomas et al.,²⁴ who studied 227 patients and 300 controls. The strongest association was detected for undescended testes, but orchitis, injury, late puberty, and infertility were also relevant factors.

An international comparison of age-standardized incidence for prostatic and male breast carcinomas revealed a direct relationship between the two diseases.²⁵ On the other hand, the actual reported frequency of both diseases in individual patients was quite low, occurring in less than 1% of 397 men with breast carcinoma in a 1995 report.²⁶

Leibowitz et al.²⁷ found a prostatic carcinoma in 10 (6.2%) of 161 men with breast carcinoma treated at two centers in Boston between 1977 and 2000. In eight patients, breast carcinoma was diagnosed prior to prostatic carcinoma. The mean ages for the diagnosis of mammary and prostatic carcinomas were 65.7 years (47 to 72 years) and 68.0 years (51 to 76 years), respectively. Seven patients had a history of breast carcinoma in a first-degree female relative, and one had a family history of prostatic carcinoma. The fact that mammary carcinoma preceded prostatic carcinoma in most of the cases reported by Leibowitz et al.²⁷ makes it unlikely that prostate carcinoma treatment played a role in the development of breast carcinoma.

Among 62 male patients with breast carcinoma studied by Kiluk et al.,²⁸ 18 (29%) had a family history of breast, ovarian, or colon carcinoma. Seven (11.3%) of the patients had previously been treated for prostatic carcinoma.

There is limited evidence that the administration of exogenous estrogens to treat prostatic carcinoma might contribute to the development of male breast carcinoma. Epidemiologic studies have failed to demonstrate an excess frequency of subsequent breast carcinoma among men with prostatic carcinoma,²⁹ despite the fact that most patients treated for this disease with estrogens develop gynecomastia. The duration of treatment rarely exceeds 10 years, and the exposure may not be sufficient for mammary carcinogenesis to become apparent. Schlappack et al.³⁰ described two men who had breast carcinoma diagnosed after 12 years of estrogen therapy for prostatic carcinoma, Wilson and Hutchinson³¹ described another man with a 7-year interval between estrogen therapy and diagnosis of breast carcinoma, and Carlsson et al.³² reported four patients who developed carcinoma after estrogen therapy. Some case reports of breast carcinoma that developed in men with prostatic carcinoma are difficult to evaluate because of the well-known predilection of the latter to metastasize to the breast. The sporadic occurrence of primary concurrent prostatic and mammary carcinomas has been reported.³³ Breast carcinoma has been described in transsexuals after castration and prolonged estrogen treatment.^34,35,36 Benign histologic changes in the breast associated with this therapy include fully formed lobules, apocrine metaplasia, and pseudolactational hyperplasia.

Traumatic injury of the breast has been cited in some older studies as a possible predisposing event.⁴ The fact that most patients who have related their carcinoma to trauma report a single incident rather than sustained or repeated injury has led most investigators to discount this as a significant factor. In many instances, documentation that the carcinoma arose at the site of injury is not available. Occupational exposure as a potential source of injury has not been explored in most studies. An association with employment in steel works, blast furnaces, and rolling mills was noted by Mabuchi et al.² Other occupations reportedly associated with excess risk were work as a butcher and employment with exposure to high environmental temperatures.^37,38 Cocco et al.³⁹ carried out a case-control study that compared 178 male breast carcinoma patients with 1,041 controls. There was a significantly increased risk of breast carcinoma among men employed in occupations with exposure to blast furnaces, steel works, and rolling mills (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.1 to 10.1) and in motor vehicle manufacturing (OR, 3.1; 95% CI, 1.2 to 8.2). Breast cancer risk was not significantly related to exposure to electromagnetic fields, herbicides, pesticides, high temperatures, and organic solvents.

Radiation exposure has been implicated as a risk factor. In some instances, radiation was administered to the breast to treat gynecomastia or other local conditions, or for intrathoracic diseases.^{17,40,41,42,43} Male breast carcinoma has also been associated with a source of radiation linked to increased breast carcinoma risk among women, multiple fluoroscopic examinations,⁴⁴ but not to atomic bomb explosions.⁴⁵ Although not statistically significant, Casagrande et al.²³ found a trend toward more frequent breast carcinoma in men who had the greatest thoracic radiation exposure by fluoroscopy or during therapeutic irradiation. One patient received radiotherapy for chondrosarcoma of a rib prior to developing breast carcinoma.²⁶

An excess risk of breast carcinoma has been reported among men treated with medications that cause hyperprolactinemia.³⁷ Bilateral breast carcinoma has been described
in a man treated for a prolactin-secreting pituitary adenoma.⁴⁶ Olsson et al.²⁰ found that plasma prolactin levels in 15 male patients with breast carcinoma were elevated when compared with those in controls with other neoplasms. Concurrent breast carcinoma and pituitary prolactinoma were described in a 68-year-old man who did not have gynecomastia.⁴⁷ Lactational change was not evident in the carcinoma.

Klinefelter syndrome, a genetic abnormality that usually becomes evident during or after puberty, has been associated with an increased risk of the development of male breast carcinoma. The majority of patients with Klinefelter syndrome have at least two X chromosomes and a Y chromosome. Prominent clinical manifestations are gynecomastia and testicular atrophy. Abnormal hormonal findings include reduced testosterone production, low plasma testosterone, and a high estradiol-to-testosterone ratio, at least partially augmented by increased testicular estrogen secretion. Microscopic examination of the testes reveals hyalinization of spermatic tubules with disappearance of germ cells and Sertoli cells. Hyperplasia with pleomorphism of interstitial cells develops concurrently.⁴⁸ The extra X, or 47th, chromosome is identified cytologically as the nuclear Barr body.

Most papers relating male breast carcinoma to Klinefelter syndrome have been individual case reports in which the chromosomal abnormality has been documented by genetic studies.^48,49,50,51 The reported incidence of breast carcinoma among patients with Klinefelter syndrome varies from 1% to 3%.^52,53 Breast carcinoma has also been described in a phenotypic male with an XX genotype.⁵⁴

It has been estimated that 1% to 3% of male breast carcinoma patients have Klinefelter syndrome.^55,56 Using fluorescence in situ hybridization (FISH) to examine tissues from men with breast carcinoma, Hultborn et al.⁵⁷ found the prevalence of Klinefelter syndrome to be 7.5%. The authors concluded that individuals with Klinefelter syndrome had a 50-fold increased risk of developing breast carcinoma when compared with men without this genetic syndrome. Klinefelter syndrome did not have a significant effect on the median age at diagnosis or on survival after diagnosis.

Cutuli et al.²⁶ found a positive family history of breast carcinoma in 5.6% of 397 men with breast carcinoma. A twofold increased risk of breast carcinoma among firstdegree relatives of male breast carcinoma patients, largely due to an excess of carcinoma in sisters, was reported by Casagrande et al.²³ Rosenblatt et al.⁵⁸ reported that the increased risk associated with sisters having breast carcinoma was significantly greater among men with carcinoma diagnosed before age 60. The relative risk (RR) of male breast carcinoma among men with an affected sister was 3.93. The RR in men whose mothers had breast carcinoma was also increased (2.33). Gough et al.⁵⁹ found that a positive family history of breast carcinoma was associated with 27% of male breast carcinomas treated at the Mayo Clinic. Olsson et al.⁶⁰ have also reported a lower incidence of prostatic carcinoma among male relatives of men with breast carcinoma.

Several instances of the familial occurrence of male breast carcinoma have been described in which father and son,^58,61,62,63 brothers,^58,64,65 and other groups of male relatives^{58,66,67,68,69} have been affected. Multiple female and male relatives have been affected in some kindreds.⁶⁶ One family included an individual with Klinefelter syndrome.⁶¹ Genetic analysis of two brothers who developed breast carcinoma at ages 55 and 75, respectively, revealed a mutation consisting of a G-to-A substitution in exon 3 of the androgen receptor (AR) gene.⁷⁰ Both men were born with penoscrotal hypospadias and undescended testes. A study of DNA extracted from the tumor tissue of 12 male breast cancer patients who did not have clinical features of androgen insensitivity failed to reveal comparable mutations of the AR gene.⁷¹

Analysis of 22 families with at least one male and multiple female breast carcinomas revealed no linkage to the BRCA1 locus.⁷² The carcinomas in approximately 16% of families with multiple women and one or more men affected are attributable to BRCA1 mutation.⁷³ In the same study, analysis of 26 families with one or more male breast carcinomas revealed that 76% were associated with BRCA2 mutations. Male carriers of BRCA2 mutations were found to have a cumulative risk of 6.3% to develop breast carcinoma by age 70.⁷⁴ Analysis of 111 families with BRCA2 mutations revealed that 11% of breast carcinomas diagnosed in these families occurred in men.⁷⁵ Among 18 Hungarian men with breast carcinoma, 6 (33%) had truncating mutations in the BRCA2 gene.⁷⁶ None of the six patients with BRCA2 mutations reported a family history of breast or ovarian carcinoma, but four other men without BRCA2 mutations had such a history. A study of Icelandic men with breast carcinoma revealed that 40% had a BRCA2 mutation.⁷⁷ Linkage to mutations in the BRCA2 region on chromosome 13q has been demonstrated in one family with multiple cases of male breast carcinoma.⁷⁸ Others have reported finding loss of heterozygosity (LOH) on chromosome 11q13 in 13 (68.4%) of 19 male breast carcinomas⁷⁹ and on chromosome 8 in 19 (83%) of 23 cases⁸⁰ studied. Data from a Danish cancer registry revealed that the RR of developing breast carcinoma in daughters of affected men was 16.4 (95% CI, 3.3 to 47.7).⁸¹ Deb et al.⁸² studied the clinical and pathologic characteristics of 60 patients with familial male breast carcinomas. Most patients (25/60; 41.7%) were BRCA2 germline mutation carriers, only 3/60 (5%) were BRCA1 mutation carriers, and the remaining 32/60 (53.3%) had no known BRCA1 or BRCA2 gene mutation. Ottini et al.⁸³ studied 382 breast carcinomas in Italian men, including 4 in BRCA1 and 46 in BRCA2 germline mutation carriers. Men with BRCA2-associated carcinoma were diagnosed at a mean age of 58.9 years, and 12 (26.1%)
had other carcinomas (prostate carcinoma and contralateral breast carcinoma). BRCA2-associated carcinomas were mostly grade 3 invasive ductal carcinomas 62.5% presented at stage I to II and 56.7% had positive lymph nodes. BRCA2-associated carcinomas were HER2-positive in 63.2% of cases and 56.2% had high Ki67. HER2 positivity in male breast carcinoma was significantly associated with BRCA2 germline mutation carrier status (p = 0.001).

Other genes implicated in the etiology of male breast carcinoma include RAD51B⁸⁴ and CHEK2*1100delC,^85,86 both of which are involved in ensuring fidelity of DNA doublestrand break repair, and the tumor suppressor PTEN, which is associated with Cowden syndrome.⁸⁷ An association with polymorphism in the CYP17 gene encoding cytochrome p450, a key enzyme in the conversion of steroids in peripheral tissues, has also been described.⁸⁸

Increased urinary estrogen excretion has been reported among male relatives of male patients with breast carcinoma. Many of these families have had relatives with other malignant neoplasms.^{61,62,64,65,68} The incidence of breast carcinoma and other malignant neoplasms in wives of men with breast carcinoma is similar to that in the general population.⁶⁰

The relationship between gynecomastia and the development of male breast carcinoma is not clear. A major factor that has contributed to the problem is differing definitions of gynecomastia, including the distinction between clinical and pathologic manifestations of the condition. Gynecomastia has florid or proliferative and quiescent phases, but the histologic diagnosis is sometimes limited to the former pattern. Nonetheless, clinical manifestations may be as prominent when the process is inactive. Evidence linking gynecomastia to the pathogenesis of male breast carcinoma includes epithelial atypia in gynecomastia, relatively lower mean age at diagnosis of breast carcinoma when associated with gynecomastia, the association of gynecomastia and carcinoma with Klinefelter syndrome, and the finding of microscopic gynecomastia associated with 5% to 40% of carcinomas.^89,90 Histologic transitions from usual or florid epithelial hyperplasia in gynecomastia to intraductal carcinoma have very rarely been described.^90,91 Satisfactory long-term follow-up studies of men who have gynecomastia with atypical ductal hyperplasia (ADH) are not available.

Finasteride, a medication employed since 1992 to treat prostatic hyperplasia, interferes with the conversion of testosterone to dihydrotestosterone by blocking AR, thereby causing an increase in the ratio of estrogen to androgen. Gynecomastia has been a frequent adverse side effect of finasteride therapy,⁹² and there have been rare cases of breast carcinoma arising in finasteride-related gynecomastia.

Gynecomastia associated with breast carcinoma has been observed in young men who employed androgenic steroids to enhance muscle development. Staerkle et al.⁹³ reported the diagnosis of bilateral synchronous DCIS in a 30-year-old man who developed bilateral gynecomastia after the administration of an androgenic steroid for bodybuilding. It seems likely that the coexistence of male breast carcinoma and gynecomastia is due to the fact that both conditions are often related to one or more common predisposing factors. However, current evidence suggests that gynecomastia rarely serves as a precancerous condition and that the epithelial hyperplasia in gynecomastia is not usually an intermediate step in the development of carcinoma (See Chapter 35).