Virchows Archiv (2022) 480:85–93

https://doi.org/10.1007/s00428-021-03190-7

REVIEW

Male breast cancer: an update

Stephen Fox1 · Valerie Speirs2 · Abeer M. Shaaban3

Received: 31 March 2021 / Revised: 23 July 2021 / Accepted: 3 August 2021 / Published online: 30 August 2021
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Male breast cancer (MBC) is rare, accounting for less than 1% of all breast cancer but the incidence has increased world-
wide. Risk factors include increased longevity, obesity, testicular diseases and tumours, and germline mutations of BRCA2.
BRCA2 carriers have 80 times the risk of the general population. Men generally present with breast cancer at an older age
compared with women. Histologically, MBC is often of grade 2, hormone receptor positive, HER2 negative, and no special
type carcinoma although in situ and invasive papillary carcinomas are common. Reporting and staging are similar to female
breast cancer. Metastatic lesions to the male breast do occur and should be differentiated from primary carcinomas. Until
recently, MBC was thought to be similar to the usual ER positive post-menopausal female counterpart. However, advances
in MBC research and trials have highlighted significant differences between the two. This review provides an up to date
overview of the biology, genetics, and histology of MBC with comparison to female breast cancers and differential diagnosis
from histological mimics.

Keywords Male breast · Male breast cancer · BRCA2 · Genomics · Gynaecomastia · Prognosis

Development and embryology of the male
breast
Breast develops from ectodermal and mesodermal elements
developing into mammary epithelium and stroma, respec-
tively. The early mammary development is largely under
non-hormonal stimulation. The embryonic development
of male and female breast starts as early as 4–5 weeks of
gestation. Bilateral epidermal crests (milk lines) are formed
in the first trimester and extend from the axilla to ingui-
nal region, which later undergo atrophy leaving mammary
buds. Well-defined mammary buds with two distinct epithe-
lial and myoepithelial layers penetrating into the underlying
mesenchyme are seen towards the end of the first trimester.
* Abeer M. Shaaban
abeer.shaaban@uhb.nhs.uk; a.shaaban@bham.ac.uk
1
Department of Pathology, Peter MacCallum Cancer Centre
and University of Melbourne, Melbourne 3000, Australia
2
Institute of Medical Science, School of Medicine,
Medical Sciences and Nutrition, University of Aberdeen,
Aberdeen AB24 2ZD, Scotland
3
Department of Cellular Pathology, Queen Elizabeth
Hospital Birmingham and Cancer and Genomic Sciences,
University of Birmingham, Mindelsohn Way, Edgbaston,
Birmingham B15 2GW, UK
Simultaneously, the mesenchyme differentiates into fibro-
blasts, adipose tissue, smooth muscles, and capillaries. A
basic framework of tubular glands within fibrous stroma is
formed by the 6th month of gestation [60]. These continue to
branch, and at birth, approximately 15–20 mammary lobes
are present; each drained by a lactiferous duct connected to
the mammary pit (inverted nipple). After birth, the nipple
becomes everted due to the mesenchymal growth. The mam-
mary gland remains quiescent till puberty where it devel-
oped under hormonal stimulation in females. No further
development occurs in men due to the rising testosterone
levels during puberty. The normal adult male breast, there-
fore, comprises a small amount of mammary epithelium in
the form of mammary ducts, without well-developed lob-
ules, sat in a large amount of predominantly fatty stroma.
Background and epidemiology of male
breast cancer
Male breast cancer (MBC) is a rare disease accounting for
less than 1% of all breast cancers and a reported population
incidence of 0.4 per 1­ 05 person-years in men compared with
66.7 per 1­ 05 person-years in women [45]. The incidence
has increased worldwide over the last few decades [50, 58].

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We have reviewed data produced annually by the American
Cancer Society [20, 27] [28, 55] [56] which showed a rise in
the number of men receiving a breast cancer diagnosis over
the last 20 years. This parallels what is seen in female breast
cancer over the same period.
MBC is more common in certain racial groups such as the
black African American men [10] and Israelis [52]. Unlike
the female counterpart, MBC shows a unimodal age distri-
bution [4] similar to post-menopausal female breast cancer
(FBC) and typically presents at an older age compared with
FBC.
Risk factors
Similar to other cancers, age increases male breast cancer
risk. Factors leading to hormonal imbalance and a relative
excess of oestrogen also increase the risk of MBC. These
include obesity, Klinefelter’s syndrome, drugs, and exog-
enous hormone (e.g. for gender reassignment). Lesions
and tumours impairing testicular function such as mumps,
cryptorchidism, and testicular malignancy also predispose to
MBC. A recent Dutch study showed a 46 fold increased risk
of MBC in trans women (male sex at birth, female gender
identity) compared with cis men [12]. There is no estab-
lished link between gynaecomastia and increased MBC risk.
Data from the Nordic Occupational Cancer Study
(NOCCA) reported a 20–25% protective effect of physical
workload that was stronger with increased levels of physical
activity in a dose–response fashion [62]. A similar protec-
tive effect of physical activity was reported by the Canadian
Occupational Disease Surveillance System (ODSS) where
men with managerial, administrative, and teaching roles had
higher incidence of the disease [59]. Changes in the adipose
microenvironment of male breast are a potential contributor
to increased MBC rates [37].
Germline mutations
Germline susceptibility is a significant contributor to the
pathogenesis of male breast cancer [15] with up to 20% aris-
ing in a background of familial breast and ovarian cancer,
the majority of cases being associated with BRCA2 suscep-
tibility gene [63] [5]. A summary of the genetic mutations
of male breast cancer and their prevalence is provided in
Table 1
BRCA​
Breast cancer 2 (BRCA2) is the strongest risk factor for
MBC with incidence rates of up to 10% in BRCA2 male car-
riers [19] [14] and a relative risk of 80 times in the general
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Virchows Archiv (2022) 480:85–93
Table 1  The genetic mutations in male breast cancer (MBC)
Relative risk of MBC Ref
BRCA2 × 80–100 [56]
BRCA1 × 3.2 [56]
ATM × 1.4–2.14 [51, 55]
PALB2 × 6.6–11.2 [51, 55]
CHEK2 (all) × 1.47 [22, 51]
RAD51D × 10.18 [55]
*as there is limited research in male breast cancer, many risk esti-
mates are imprecise and variable.
population [39]. Somatic BRCA2 mutations, including loss
of heterozygosity, have also been reported in about 12% of
sporadic MBCs, in about 10% of unselected MBC cases and
up to 13% of unselected MBC cases in founder populations.
Significantly fewer invasive lobular carcinomas among male
BRCA2 mutation carriers than among female BRCA2 muta-
tion carriers have been observed [57]. In addition, compared
with BRCA2-associated FBCs, BRCA2-associated MBCs
were of higher stage and grade, and were more likely to be
node positive and be ER and PR positive.
Others
Partner and localizer of BRCA2 (PALB2) interacts closely
with BRCA1 and BRCA2 in the homologous recombination
DNA repair pathway suggesting that it might have similar
cancer risks. However, the estimated relative risk for male
breast cancer was 7.34 with an absolute risk of 0.9% devel-
oping MBC to age 80 years [68].
There is also evidence supporting that germline Check-
point Kinase 2 (CHEK2) 1100delC mutation in certain
populations confers an up to tenfold increase of MBC risk,
although other studies have failed to show any increased
incidence above the baseline population [22, 61, 67], sug-
gesting significant country to country variation which again
might be accounted for by modifiers.
MBC has been observed in patients with Li-Fraumeni,
Cowden, and Lynch syndromes [7] [18, 48] but as these
and MBC are rare, it is difficult to ascertain any difference
in risk for MBC.
Tumour alterations
There is a paucity of data from genomic, transcriptomic,
proteomic, or methylomic data studies, but the few that have
been performed support the notion that MBC is distinct from
FBC.
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic
subunit Alfa, PIK3CA (20–36%) and GATA3 (15%) are
Virchows Archiv (2022) 480:85–93
most commonly mutated genes with a significantly lower
(1–3%) frequency of p53 [13, 46, 49] compared with FBC.
Some of the genetic changes including PIK3CA and Ataxia
Telangiectasia Mutated (ATM) have also shown an associa-
tion with higher grade tumours [46].
Somatic chromosomal and copy number changes in MBC
have shown similarities with FBCs apart from gains within
the X chromosome in male breast cancer [63]. Interest-
ingly, a lower frequency of copy number changes has been
reported in Klinefelter’s Syndrome [46].
Presentation and macroscopic features
Male breast cancer often presents with a unilateral pain-
less retro-areolar slightly eccentric mass. Less commonly,
it presents with nipple discharge or nipple ulceration. The
Fig. 1  Macroscopic and microscopic features of male breast cancer.
a Typical macroscopic specimen is an orientated mastectomy includ-
ing the nipple. b Core biopsy of a grade 2 no special type carcinoma.
c No special type carcinoma in a mastectomy specimen comprising
nests of moderately pleomorphic cells within a fibrous stroma. Peri-
87
standard macroscopic specimen is a mastectomy with senti-
nel node or axillary clearance (Fig. 1a).
Microscopy and criteria for diagnosis
Almost half of the patients (48.7%) present with tumours
less than 20 mm. The commonest type of invasive carcinoma
in the male breast is carcinoma of no special type (NST)
(Fig. 1b, c). Papillary carcinomas are the second common-
est cancers, whereas the lobular and metaplastic types are
extremely rare. Most MBCs are of grade 2 differentiation
and more than 90% of cancers are oestrogen receptor (ER)
positive and human epidermal growth factor 2 (HER2) nega-
tive [25] (Fig. 1d–f).
A retrospective analysis of 1483 patients reported ER
and progesterone receptor (PR) positivity in 99% and 82%,
respectively [9]. HER2 positivity is uncommon ranging from
neural invasion is present. Male breast cancer is typically ER positive
(d), PR positive (e), and HER2 negative (f). g Encapsulated papillary
carcinoma of the male breast showing a cystic haemorrhagic lesion
with malignant cells exhibiting a papillary architecture. h HER2 posi-
tive Paget’s disease of the nipple in a male patient
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88
0 to 9% [54] [9, 25]. A basal phenotype is reported in 1–3%
of cases [2, 54]. Androgen receptor (AR), GATA3, mamma-
globin, and gross cystic disease fluid protein 15 (GCDFP-15)
are expressed in the majority of MBCs and maintained in
the metastases [6, 35]. Axillary nodal metastasis is reported
in 40.6% of cases.
Ductal carcinoma in situ (DCIS) exists in association
with invasive MBC and less commonly in the pure form.
Encapsulated papillary carcinoma (Fig. 1g) and Paget’s dis-
ease (Fig. 1h) have been reported [3] and lobular carcinoma
in situ is extremely rare (< 1%) [17].
The classification, diagnostic criteria, and reporting of
in situ and invasive carcinomas in men are the same as in the
female breast. Staging is performed following the Union for
International Cancer Control (UICC) TNM staging system,
eighth edition [26].
Differential diagnosis
Invasive MBC should be differentiated from metastatic
lesions to the male breast including prostate cancer. Fea-
tures that support primary breast cancer include the pres-
ence of DCIS (Fig. 2a), typical luminal A profile, GATA3
(Fig. 2b) positivity, and androgen receptor expression. MBC
Fig. 2  Features of primary male breast cancer (MBC), metastases to
the male breast and benign mimics. a Primary invasive male breast
cancer with associated ductal carcinoma in situ (DCIS). The identifi-
cation of DCIS confirms the primary origin. b MBC showing strong
GATA3 nuclear positivity. Note that GATA3 positivity is a sensitive
but not specific marker that can be expressed in several other malig-
nancies. c MBC is typically CK7 positive. d Metastatic squamous
cell carcinoma to male breast showing strong diffuse CK5 positiv-
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is typically broad spectrum and cytokeratin (CK7) positive
(Fig. 2c). A panel of immunohistochemistry depending on
the suspected primary origin should be used in combination
with morphology, thorough history, and clinical examination
(Fig. 2d).
Metastases from MBC generally maintain the same
immunoprofile. However, a recent case report highlighted
a switch in the molecular phenotype from a triple positive
primary tumour to ER/PR positive, HER2 negative profile
in the subsequent brain metastasis [47].
Florid gynaecomastia (Fig. 2e) should also be differenti-
ated from DCIS. Attention to the typical architecture and
cytological atypia of DCIS should establish the diagnosis. It
is important not to mistake the normal tri-layered expression
of basal and luminal cytokeratins in male mammary ducts
for atypia (Fig. 2f). This pattern is distinct from the inner
luminal and outer myoepithelial/basal layer seen in female
mammary ducts.
Prognosis
Similar to FBC, the outcome of male breast cancer depends
on tumour stage, nodal status, and molecular subtype. Stage
for stage, MBC outcome is similar to the female counterpart.
ity. The patient had a past history of skin squamous cell carcinoma.
The basal phenotype is extremely rare in primary MBC. e Active
gynaecomastia showing hyperplasia of mammary ducts with nuclear
stratification and micropapillary pattern. The adjacent stroma is loose
and oedematous and shows pseudoangiomatous stromal hyperplasia.
f CK5 immunohistochemistry of male type mammary ducts showing
a positive outer and inner basal layer and a negative middle layer of
luminal epithelial cells
Virchows Archiv (2022) 480:85–93
ER, PR, and AR status correlated with overall and relapse
free survival [9]. Negative nodal status and the lymph node
ratio were associated with better prognosis [1]. The Sur-
veillance, Epidemiology, and End Results (SEER) data for
2005–2010 showed that male breast cancer patients were
associated with an overall worse outcome compared with
women, a reduced 5-year survival rate for male compared to
female patients (82.8% vs. 88.5%), and a risk of death 43%
greater in men than in women during the follow-up period,
after other variables were accounted for [41]. A recent SEER
data analysis for 2010–2017 showed that patients with triple
negative breast cancer, a rare occurrence in men, comprised
2.3% of all patients and had the worst breast cancer specific
survival (BCSS, p = 0.001) with race, tumour type, and stage
significantly associated with overall and BCSS in multivari-
ate analysis [38].
Distant metastasis on presentation is uncommon occur-
ring in only 5.7% of patients [21]. Low socioeconomic status
and poor access to insurance and health care were associ-
ated with higher mortality. Of note, married men with breast
cancer had a better survival compared with those who were
not married [40].
There are limited data investigating the Oncotype DX
recurrence score (RS) derived from a 21-gene mRNA assay
that has shown no significant difference in the average RS
in male breast cancer compared with female breast cancer
although significantly more men than women had high
RS ≥ 31 [44]. In their study of 848 male and 110,898 female
breast cancer patients, Wang et al. showed the RS to be pre-
dictive of mortality in men but at a much lower score (> 21)
compared with FBC [66]. Mammographic screening for
men at increased breast cancer risk has been suggested and
showed a cancer detection rate similar to that in women [43].
Male breast cancer research and trials
Historically, research on male breast cancer has been oppor-
tunistic, using descriptive biomarker studies, with small
numbers of cases from single hospitals. Fuelled largely by
a growing recognition that the disease is becoming diag-
nosed more frequently and is associated with unfavourable
outcome [50, 58], more robust research studies examining
larger numbers of samples have been conducted.
Over the last decade, data from biomarker and gene
expression studies has shown differences in the underlying
biology of male and female breast cancer. In a comparative
biomarker study, Shaaban and colleagues identified gender-
specific biological differences, with AR-positive luminal A
male breast cancer showing improved overall survival over
female breast cancer of the same phenotype, while hierar-
chical clustering showed gender-specific clustering of ERα
and ERβ; in female breast cancer, ERα clustered with PR,
89
while in male breast cancer, ERα clustered with ERβ and
AR [54]. Gender-specific differences have also been shown
at the genomic level [46]. One of the first of these stud-
ies analysed 37 male and 53 matched female breast can-
cer, showing differential expression of nearly 1000 genes
between female and male patients, with gender-associated
differences in genes associated with energy metabolism,
matrix remodelling, immune cell recruitment, and transla-
tional regulation [8]. In line with observations from Shaaban
[54], a key role for AR was implicated and metastatic male
breast cancer patients who expressed AR responded well
to the anti-androgen cyproterone acetate, either as a mono-
therapy or combined with a gonadotropin hormone-releasing
hormone (GnRH) analogue [16].
Transcriptional profiling revealed two genomic subgroups
of male breast cancer, termed male-complex and male-sim-
ple, with the former similar to luminal female breast cancer
and the male-simple subgroup unique to men [31]. Further
work by the same group identified two subgroups of the
luminal phenotype in men, termed luminal M1 and lumi-
nal M2 [30]. The former was more aggressive with inferior
outcome while the latter expressed a higher proportion of
immune response genes. The mutational landscape and copy
number variation also differs between genders [32, 49] with
differences also reflected at the epigenetic level [29, 34].
Interrogation of the chromatin binding landscapes of ster-
oid hormone receptors revealed both gender-selective and
genomic location-specific hormone modifications, which
could stratify male breast cancers for survival [53]. In a case-
matched comparative transcriptomic analysis, compared
with female breast cancer, eukaryotic translation initiation
factor 4E (eIF4E) and eukaryotic translation initiation factor
5 (eIF5) genes, involved in the translational initiation path-
way, were overexpressed in male breast cancer, validated by
in silico analysis and immunohistochemistry [24].
Specific phenotypic features and biomarkers have also
been compared between genders. Counter-intuitively, ER
expression is more common in male than female breast
cancer [25]. Recognising that stromal elastosis correlated
strongly with ER expression in female breast cancer, this
was examined in male breast cancer. Surprisingly, signifi-
cantly less stromal elastosis was observed in male compared
to matched ER-positive female breast cancer [65]. Similarly,
connective tissue growth factor, a multifunctional protein
found in endothelial cells and fibroblasts, was strongly
expressed in male but not in female breast cancer[36]. Stan-
niocalcin 2 (STC2) was overexpressed in a transcriptomic
screen of male and female breast cancers and when assessed
by immunohistochemistry, was an independent prognostic
factor for survival in men [11]. Reduced expression of the
programmed death-ligand 1 (PD-1) but not PDL-1 check-
point inhibitor has been reported in male breast cancer,
suggesting there could be different responses to immune
13
90
checkpoint inhibitors [42]. While the presence of CD8-
positive lymphocytes in male breast cancer was associated
with poorer survival [37], when tumour-infiltrating lympho-
cyte (TIL) density was examined, there was generally a low
density and where TILs were present, this correlated with
favourable outcome, similar to female breast cancer [64].
Collectively, these observations point strongly to the
notion that male and female breast cancers are different
diseases.
Until recently, men were excluded from breast cancer
clinical trials but this is gradually changing with a male-spe-
cific trial planned by the International Male Breast Cancer
Program [33]. A male-only phase 2 trial in Germany exam-
ining the efficacy of endocrine treatment in men has recently
reported, showing that tamoxifen or aromatase inhibitors
plus GnRHa versus tamoxifen alone decreased circulating
estradiol, resulting in diminished sexual function and quality
of life [51]. Guidelines have recently been published con-
cerning the management of male breast cancer [23].
Conclusions
Male breast cancer is a rare and traditionally understudied
disease but its incidence has increased globally. The diagno-
sis and differentiation from potential benign and malignant
mimics can be challenging. Careful attention to the morpho-
logical features, immunohistochemical profile together with
the history and imaging information should establish the
diagnosis. Over the last few decades, there has been marked
progress in the understanding of the biology, pathology,
outcome, and optimal management of this disease and its
distinction from female breast cancer.
Author contribution All authors contributed to the writing and editing
of the manuscript; SF: wrote the genetics aspects; VS: covered research
and trials data; AMS: covered the rest of the sections, provided the
manuscript figures, and oversaw the write up. All authors approved
the final submitted draft.
Funding VS receives support from Friends of Anchor, NHS Grampian
and the University of Aberdeen Development Trust. AMS is supported
by Birmingham Cancer Research UK Centre (C17422/A25154).
Data availability Not applicable.
Code availability Not applicable.
Declarations
Ethics approval Not applicable.
Consent to participate Not applicable.
13
Virchows Archiv (2022) 480:85–93
Consent for publication All authors approved the final manuscript and
consented for publications.
Competing interests The authors declare no competing interests.
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