The differential diagnosis of a breast mass in a male includes gynaecomastia, pseudogynaecomastia/lipomastia, infection/breast abscess, lipoma, pseudoangiomatous stromal hyperplasia (PASH), granular cell tumour, desmoid tumour, schwannoma, myofibroblastoma, haemangioma, metastases to the breast and other non-breast cancer primary tumours such as sarcomas [9, 37]. Fibroadenomas of the male breast are very rare due to the absence of breast lobules.

All men diagnosed with BC should be referred for genetic counselling and, if indicated, BRCA mutation testing. Currently, the National Comprehensive Cancer Network recommends consideration of BRCA1/2 testing in men with a personal history of BC [38]. Also risk counselling should be given to healthy men with Klinefelter’s syndrome. Although routine mammographic screening is not advocated, breast self-examination and regular physical breast examination are recommended in men with Klinefelter’s syndrome [33].

After a diagnosis of MBC is established, the extent of disease should be determined with a bone scan and CT scan of the chest, abdomen and pelvis, as clinically appropriate according to the same guidelines as in females. MBC is classified according to the tumour, nodes, metastasis (TNM) staging system [38] which does not differentiate between male and female diseases.

Although most histologic subtypes of female BC also present in men, there is still a need to better understand the pathology of MBC.

The predominant histological type of MBC is invasive ductal cancer which constitutes more than 90% of cases. Lobular cancer is less common in males than females and accounts for only 1.5% of cases (compared to 10% in females) because the male breast is rudimentary and lacks acini and lobules. Neither differentiation nor lobule formation occurs unless the breast is exposed to increased concentrations of endogenous or exogenous oestrogen. Other rare histological types include papillary and mucinous cancers [39]. Regarding ductal carcinoma in situ (DCIS), there are differences in men when compared to women. DCIS constitutes a larger proportion of female BCs than in MBCs overall (20% vs. 7–11%, respectively). DCIS in men tend to occur in more elderly males, often as an intraductal papillary form with a low grade [40]. More than half of DCIS cases present as intermediate grade. Only 17–33% of cases were found to be high grade [9]. Registry data has shown that MBC patients have significantly more nodal involvement than female BC patients and therefore MBC cases present with more advanced disease [41] (◘ Table 45.1).

As in postmenopausal women, the most common subtype of MBC is oestrogen receptor-positive (ER+) tumours. SEER database findings revealed that more than 90% of MBC were oestrogen receptor (ER) positive which is more common than it is in female BC where 70% ER+ is the normal proportion. The ER positivity rate increases with age in MBC as it does in females. Also, 92–96% of MBCs are progesterone receptor (PR) positive. [23, 41]. Men also have higher mean expressions of ER, PR and proliferation genes such as Ki-67, MYBL2, Survivin, Cyclin B1 and STK15 [42].

Studies using standardized methodology by both immunohistochemistry and fluorescence in situ hybridization showed lower rates of Her2-neu overexpression in MBC (2–15%) when compared to the rate observed in female BC (18–20%) [9, 43].

Findings from several studies showed that MBCs from patients with BRCA1/BRCA2 mutations display different pathologic characteristics when compared to female BC with BRCA1/BRCA2 mutations. MBC with BRCA1 mutations seemed to have a lower grade when compared to female BC with BRCA1 mutations, but grade distribution was more likely to be similar between female and male BC cases with BRCA2 mutations. Also, MBC patients with either BRCA1 or BRCA2 mutations had more advanced disease at presentation when compared to those with female BC carrying mutations. Also, ER and PR expressions in MBC patients with BRCA1 and BRCA2 mutations were higher than those observed in female BC cases with same gene mutations (◘ Table 45.2) [13, 44].

In female BC, DNA microarray studies have identified five molecular subtypes which are normal breast-like, Luminal A and B type, Her2 overexpressing and basal-like [45]. Although data on genomic subtyping of MBC is scarce, the frequency of subtypes is different than that of those in female BC cases. In MBC cases, Luminal A subtype (83–98%) is the most common type, followed by Luminal B (0–17%). The Her2-overexpressing subtype and basal-like tumours are infrequent in MBC (0–5%) [46]. Furthermore, the basal-like MBC expresses ER in 75% of cases in contrast to female BC in which only 30% of basal-like cases have ER expression [47].

Considering the possibility that MBC is a different disease than female BC by recognizing the dissimilarity of frequency of standard intrinsic subtypes in MBC and female BC, studies with more comprehensive methods revealed different subtypings of MBC. One of these studies was based on high-resolution genomic profiling. In this methodology, two genomic subgroups with significantly different aberrant copy number levels were identified among MBC: male-complex and male-simple cancers. The male-simple cancer subgroup consists of 20% of MBC cases and appeared to be comprised of less aggressive and small tumours. These cancers were remarkably different from those of previously described six BC subgroups and seemed to represent a new subgroup seen only in males [48, 49]. Male-complex cancers which were found to be more aggressive were overall similar to those in luminal-complex subgroup of female BC [49]. In another study, MBC was grouped using global gene expression profiles, and here again two distinct subgroups were identified: Luminal M1 and Luminal M2. Across the study’s dataset, Luminal M1 cancers consisted of 70% of cases and the rest were Luminal M2 cancers [50]. Luminal M1 cancers had low correlation to genes associated with ER signalling and were found to carry more aggressive phenotype with worse prognosis, whereas Luminal M2 cancers had high expression of genes associated with ER signalling. When comparing these two new subtype groupings of MBC to standard intrinsic groups defined for female BC, MBC cases in each subgroup did not fit completely into previously described intrinsic subtypes [50]. On the other hand, newly described above subtypes overlap partly with each other in which nearly 90% of the Luminal M1 tumours were found to be male-complex, whereas nearly half of the Luminal M2 cancers were male-simple [50, 51].

N-acetyltransferase-1NAT1, a xenobiotic metabolizing enzyme, was identified as a promising prognostic biomarker for MBC. NAT1 positivity was associated with better outcome [50].

Cell cycle regulatory proteins are also aberrantly expressed in MBC. The tumour suppressor gene tp53 is mutated in 3.7–54% of MBC cases. The oncogene c-myc is overexpressed in 12–100% of MBC. The proto-oncogene bcl-2 which inhibits apoptosis and promotes cell growth was found to be significantly higher in MBC than in female BC. Cyclin D1, related to cell cycle regulation, is overexpressed in approximately 50% of MBC. Upregulation of p21waf1 and cdk inhibitor p27Kip1 is more frequent in MBC than that in women with BC [2]. Intratumoural aromatase expression is shown in 27% of MBC patients, and its expression was found to be associated with improved 5-year overall survival [52].

As it is in female BC patients, the treatment strategy for MBC involves surgery, radiation therapy (RT) and systemic treatments.

In reports comparing MBC and female BC, matched for age at diagnosis, grade and stage did not show a worse survival in men when compared to that in women [9]. Blacks with MBC have a worse prognosis than whites in the USA based on historic SEER database data (however socioeconomic factors relating to health funding may impact on US data) [67]. Significant prognostic factors of MBC are identical to those in the female, namely, tumour size, nodal status and immunophenotype (ER+). The prognostic value of AR expression is still controversial [22, 63]. Also, whether Her2 overexpression is a marker for poor prognosis in MBC remains uncertain. Until now there is limited data regarding the role of multigene prognostic and predictive profiling tests in MBC. Only study which analysed a small cohort from Israel found that distribution of 21-gene recurrence score in ER-positive MBC patients is similar to that of female BC patients [68]. But profiling tests’ accuracy in MBC cases was not studied yet.