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REVIEW
Male breast cancer
LEONARDO OLIVEIRA REIS, FERNANDO GF DIAS, MARCOS AS CASTRO, &
UBIRAJARA FERREIRA
School of Medical Sciences, Division of Urologic Oncology, Discipline of Urology, University of Campinas, UNICAMP, Brazil
(Received 3 April 2010; revised 10 October 2010; accepted 20 October 2010)
AbstractMale breast cancer (MBC) is a rare disease. However, as global populace ages, there is a trend to MBC increasing. Althoughaetiology is still unclear, constitutional, environmental, hormonal (abnormalities in estrogen/androgen balance) and genetic(positive family history, Klinefelter syndrome, mutations in BRCA1 and specially BRCA2) risk factors are already known.Clinic manifestation is painless hard and fixed nodule in the subareolar region in 75% of cases, with nipple commitmentearlier than in women. Breast cancer has similar prognostic factors in males and females, among which axillary adenopathy(present in 40–55% cases) is the most important one. Although mammography, ultrasonography and scintigraphy can beuseful tools in diagnosis; clinical assessment, along with a confirmatory biopsy, remains the main step in the evaluation ofmen with breast lesions. Infiltrating ductal carcinoma is the most frequent histological type. The established standard of careis modified radical mastectomy followed by tamoxifen for endocrine-responsive positive disease, although other options arebeing explored. While similarities between breast cancer in males and females exist, it is not appropriate to extrapolate datafrom female disease to the treatment of male. There is a need for specific multi-institutional trials to better understanding ofclinicopathologic features and establishment of optimal therapy for this disease.
Keywords: Breast cancer, male, mammary gland, urology, andrology
Introduction
Male breast cancer (MBC) is a rare and unique
disease presenting numerous particularities that
distinguish from female. However, most data regard-
ing treatment of MBC are, in nature, retrospective
and come from small single-institution series; thus,
the choice of treatment modalities is generally guided
by extrapolation of data from female breast cancer
(FBC).
We present a review of the literature presenting the
state of art in MBC, focusing on epidemiology,
aetiology, diagnosis, image workup, histopathology,
molecular markers, prognosis, treatment and psycho-
emotional aspects.
Epidemiology
MBC is rare, accounting for approximately 1% of all
cases of breast cancer, less than 1% of all cancers in
men and 0.17% of all cases of cancer in humans [1].
Prechtel & Prechtel [2] established a ratio of 1:175
men compared with women diagnosed with breast
cancer in Germany. Its prevalence is higher after 50
years, with a unimodal peak incidence between 60
and 70 years – average age of 68 years – 5 to 10 years
later than in women, which has a bimodal pattern of
involvement [1,3].
However, the involvement of children and young
adults under 30 years have been described [4]. The
geographic distribution is similar in both sexes.
Although it remains an uncommon disease in men,
incidence has been increasing over last decade. In
The United States of America, for instance, there has
been a 45% increase in the incidence of MBC since
1997 (from 1400 new cases in 1997–2030 in 2007)
[5].
Aetiology
Although aetiology of breast cancer in humans is not
completely established, a series of risk factors have
already been identified, mostly in women. While
epidemiological studies and basic research about
MBCs aetiology are still not numerous, some
conditions that can predispose men to breast cancer
are known, which can didactically be divided in
groups: genetic, constitutional, environmental and
hormonal.
Correspondence: Dr. Leonardo Oliveira Reis, M.D., M.Sc., R. Votorantim, 51, ap. 43, Campinas-SP, Brazil 13073-090. Phone/Fax: þ 55-19-35217481.
E-mail: [email protected]
The Aging Male, June 2011; 14(2): 99–109
ISSN 1368-5538 print/ISSN 1473-0790 online � 2011 Informa UK, Ltd.
DOI: 10.3109/13685538.2010.535048
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Genetic factors
They are found in cases of BRCA1 and BRCA2
mutations, positive family history and syndromes as
Klinefelter’s syndrome (KS).
Molecular and genetic knowledge related to breast
cancer’s aetiology is growing fast. Different gene
mutations are found in approximately 10% of cases
of MBC and FBC [6], particularly mutations in
BRCA1 (mapped in the region 17q21) and BRCA2
(mapped in the region 13q12q13), which are, by an
autosomal dominant transmission, responsible for
80% of hereditary cases [6–8].
Mutation of BRCA1 is believed to occur in 45% of
cases of genetically transmitted breast cancer and
80% of cases where the family has a history of both
breast and ovarian cancer [9]. Gu et al. [10] have
demonstrated that in women with a mutated BRCA1
gene, the risk of breast cancer development prior to
age 50 years is 50% and increases to 80% by age 65
years. The frequency in men is considerably lower
[11].
Brose et al. [12] claim that the BRCA mutation
leads to an age-adjusted cumulative risk of 5.8% of
developing breast cancer vs. 0.1% for the normal
population.
Women with mutations or deletions of the BRCA1
gene have a cumulative life-time risk for the
incidence of breast cancer of approximately 90%,
while it is approximately 10% in the general
population.
The penetrance of these mutations in women aged
70 years or younger has been estimated to be 56–
70% for BRCA1 and 37–84% for BRCA2. In men,
the proportion attributable to mutations in the breast
cancer susceptibility genes varies with the population
studied. Much of the variation seen in mutation rates
may be due to the presence of a specific founder
mutation in isolated populations [11].
Interestingly, the mutation of the BRCA 2 appears
to be a risk factor for breast cancer in men more
important than BRCA 1 [13], leading to 6% risk of
developing the disease at age 70 [6]. Furthermore,
when present, the mutation of the BRCA 2 is
associated with diseases with more advanced histo-
logical grades, from which Paget’s disease is the most
frequent [14]. It was also described that an associa-
tion of BRCA2 mutation with positive protein c-
proto-2, which seems to be involved in promoting the
intra-epidermal spread of the tumour [11].
The association with other genes (CYP17, PTEN
and CHEK2) has been studied, however, with
inconclusive results [15].
First-degree family history of breast cancer is the
most widely known and well-established high-risk
factor for FBC [16]. For men, positive family history
is probably still more relevant (2.5 times increase
when a female family member is affected) [17,18].
Other studies found the prevalence of a positive
family history for breast cancer in a first- or second-
degree relative of MBC patients to be in the range of
13%–30% [19]. These values are significantly higher
than those reported for females with breast cancer,
where the highest estimate of the prevalence of a
positive family history, including distant relatives, has
been 19% [20]. This confirms the hypothesis that
MBC is more likely than FBC to be familial [11].
In 1942, Harry F. Klinefelter and colleagues
described a syndrome characterised by gynecomas-
tia, small testes, aspermatogenesis, hypoleydigism
and increased follicle-stimulating hormone (FSH).
In 1959, Jacobs and Strong reported the sex
chromosome genotype of 47, XXY in these patients,
defining the genetic basis for KS [21]. It is present in
3–7% of men with breast cancer and there is a 50-
fold increased risk of BC in men who has KS [6,22–
26]. Moreover, mean ages-at-diagnosis are younger
for KS (58 years) [19]. In these patients, the
disturbed estrogen/testosterone ratio may be a
causative factor for the development of MBC [27].
Some rare syndromes may account together
for51% of breast cancers. Approximately, 50% of
gene functions described so far have been involved in
the estrogen metabolism and function, but also
several other genes were suspicious [6]. A case of
MBC in kindred with hereditary non-polyposis
colorectal cancer syndrome (HNPCC) suggested an
association of the two diseases. The breast tumour
showed loss of heterozygosity for the MLH1 muta-
tion, which was shown to segregate with the disease
[28]. Some researchers regarded the breast cancer,
especially the MBC, as a part of the tumour spectrum
of HNPCC, and thought the breast cancer might be
an extracolonic manifestation of HNPCC [10].
Constitutional factors
They are ethnicity in addition to advanced age.
Black–white ethnic disparity appears to exist for
both male and FBCs. Overall breast cancer in-
cidence is 15% lower for black compared to white
women. Increased breast cancer incidence among
black men is especially intriguing given decreased
overall breast cancer incidence among black wo-
men. While white men have an incidence of 1.1 per
100,000, in black men it is of 1.8 per 100,000.
However, the black to white incidence rate ratio is
reversed for women younger than age 40 years,
where breast cancer rates are 10–40% higher for
blacks than whites [19].
Besides developing more early-onset disease (540
years) than do white women, black women more
commonly develop aggressive breast cancer pheno-
types, as do black men. Black men also tend to have
poorer prognostic features, such as advanced-stage
disease, larger tumour sizes, more nodal involvement
and higher tumour grade, compared with their white
counterparts [19].
Although further analytic studies are clearly
needed to better understand ethnic disparity for both
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male and FBCs, the association of MBC with BRCA
mutations may partly explain the relationship of
MBC with Jewish ancestry [19]. The fact is that
frequencies of BRCA1 and BRCA2 mutations are
different in men from different ancestries and some
specific mutations are restricted to special popula-
tions, as was tested in large series, for example, in
Ashkenazi Jews [6].
Environmental factors
In women, environmental factors, such as diet and
body weight, probably account for the variation in
rates between different locations [16]. It has been
estimated that alcohol drinking increases the risk of
breast cancer in women by approximately 7% for
each increment of 10 g alcohol per day. The relative
risk of breast cancer in men is comparable to that in
women for alcohol intakes below 60 g per day. In
men, it continues to increase at high consumption
levels although it is not usually studied in women
[29].
Other recognised risk factors are smoking, thoracic
trauma and exposure to electromagnetic field
[29,30]. Regarding the exposure to ionising radia-
tion, important data were taken from a cohort of
atomic bomb survivors showing MBC rate of 1.8 per
100,000 person-years [31].
Hormonal factors
There is a large body of literature supporting an
important role of endogenous estrogen levels in the
development of FBC. Early menarche, late meno-
pause, nulliparity and late first gestation are known
risk factor for women [16]. There is some anecdotal
evidence suggesting that this may also be true for
MBC, there have been several reports of MBC
occurring after prolonged estrogen administration for
genitourinary cancers [32,33].
In men risk factors are related to abnormalities
in estrogen(surplus)-androgen(deficiency) imbal-
ance, which can be in association with KS,
gynecomastia, obesity, testicular and/or liver dys-
function, alcohol consumption, infertility and hy-
perprolactinemia, but these high-risk conditions
might only account for a small portion of MBC
cases [6,19,30,34]. Symmers has reported breast
cancer in two transsexuals after prolonged estrogen
use to induce female secondary sex characteristics
[35,36].
Gynecomastia alone is not considered a risk
factor [22,37], as well as intrauterine exposure to
high levels of estrogen [38]. However, some of the
factors associated with increased incidence of
gynecomastia are also related to breast cancer such
as KS, prostate cancer or transsexual patients
treated with exogenous estrogens. Overall, around
half of the cases of MBC present associated
gynecomastia [27,39].
Second cancer
The relative risk of a second breast cancer among
men is 30 times, while in women it is 2–4 times. The
risk of developing contralateral breast cancer is
highest in those men diagnosed with MBC at 50
years of age or younger, which is also the case in
women [30,40].
While, in FBC, sarcoma, lung and esophageal
cancers are known complications of radiotherapy, as
well as endometrial cancer secondary to the use of
tamoxifen [41], information about the risk of other
second primary cancer in men with breast cancer is
still inconsistent [41,42].
The incidence of breast cancer appears to be
higher in patients with prostate cancer than in the
general population [43]. Patients with breast cancer
were diagnosed with prostate cancer ranging from
15% to 17% [7]. Breast and prostate cancer can be
synchronic or methachronic (breast cancer manifest-
ing after estrogen therapy for prostate cancer)
[44,45]. However, Leibowitz et al. [46] studying
161 men with breast cancer, found no significant
differences regarding incidence, age at diagnosis and
aggressiveness of prostate cancer when compared
with the general population.
It is also important to emphasise that, in addition
to breast cancer, mutations also increase the risk of a
broader spectrum of cancers, including melanoma,
prostate, stomach, pancreas, colon and rectum,
among others; surveillance is indicated in these
patients after 40 years [47].
In the study of Haraldsson et al. [48], two of their
seven BRCA2 mutation carriers had another malig-
nancy preceding their breast cancer, a third patient
had a father with prostate cancer, and a fourth patient
had a daughter with melanoma.
Diagnosis
Hittmair et al. [49] and Donegan [50] described the
similarity of signs and symptoms of breast cancer in
both sexes. The duration of symptoms before
diagnosis is declining [51], with geographical varia-
tions. It is more frequently manifested by painless
hard and fixed nodule in the subareolar region (75%
of cases). Others signs and symptoms may be
present: ulceration (27%) [52], bloody or serous
nipple discharge (up to one-third of cases) [52,53],
nipple retraction, axillary adenopathy (40–55%)
[54,55] and pain [1,37,56,57].
The nipple tends to be affected earlier in men [58],
given the fact that the tumour develops just below the
nipple, where the rudimentary breast ducts are
located, and not in the superolateral quadrant, as it
is characteristic of women. Bilateral MBC may occur
from 0 to 1.9% [59] in comparison with an incidence
of 4.3% in women [60].
Approximately 2–5% of the cases manifest as the
Paget’s disease of the nipple [61]. There is no
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evidence that Paget’s disease manifest in different
ways in males and females, although the survival is
lower (20–30% in men versus 30–50% in women)
[62].
Imaging workup
Although mammography, ultrasonography (US) and
scintigraphy can be useful tools in diagnosis; clinical
assessment, along with a confirmatory biopsy,
remains the main step in the evaluation of men with
breast lesions. Magnetic resonance imaging has not
been used [27,30].
Mammography
The role of mammography in the evaluation of male
breast is controversial due to the lack of specific
information regarding its true diagnostic accuracy
[63]. An American study obtained the following
results: 92% sensitivity, 90% specificity, 55% positive
predictive value, 99% negative predictive value and
90% accuracy [3,64]. Nevertheless, it has been
routinely used as a complement to clinical examina-
tion, and it should be the first imaging examination
in the evaluation of suspicious lesions [65].
The presence of solid masses eccentric to the
nipple should raise suspicions of malignancy, being
speculated the most common pattern [66]. Lesions
may be round, oval and located in the subareolar
region. Calcifications are present in only approxi-
mately 7–10% of cases [67,68]. In males, the
margins of the lesions are often more defined and
calcifications are less frequent and coarser [69].
Microcalcifications occur primarily in ductal carci-
noma in situ (DCIS), which is not frequent in males
[49,65]. It should be emphasised the importance of
the bilateral examination, since the risk factors that
predisposed the emergence of the disease in one
breast have acted similarly in the contralateral breast
[65].
Ultrasonography
The US characteristics of MBC are usually the same
found in female breast, and hypoechoic lesions with
margins are the most frequent [70]. Margins can be
angled, microlobulated or spiculated. By using
Doppler, intralesional flow can be evidenced [69];
however, this information and the assessment of
posterior acoustic changes contribute little to the
differential diagnosis between benign and malignant
lesions [65]. Secondary signs of malignancy may
include greater echogenicity, considering changes in
the subcutaneous fat layer and structural distortion of
normal breast tissue [71]. The examination should
be extended to the armpits when evaluating a
suspicious breast lesion [72].
Complex cystic lesions (more than one compart-
ment within the cyst) were estimated to be reported
in approximately 5% of breast ultrasound examina-
tions and should be biopsied due to the risk of
malignancy. Ultrasound features associated with a
higher risk of cancer are: thickened walls, thick
internal septations, a mix of cystic and solid
components, and an imaging classification of in-
determinate.
Very few studies have examined complex breast
cysts and quantified the associated cancer detection
rate. In most of these studies, subjects have been
selected on the basis of progress to intervention,
which would overestimate the likelihood of malig-
nancy. The only study to examine complex cysts
from all consecutive ultrasounds reported one case of
non-invasive cancer from 308 lesions – 0.3% (95%
confidence interval, 0.01–1.84).
Yang et al. [72] reported a series on the sono-
graphic features of MBC, in which a complex cystic
mass was seen in four (50%) of eight men with breast
cancer. Three of the four complex cystic lesions in
this series were proven to represent DCIS at
histopathology. These findings are consistent with
data from a recent large retrospective clinicopatholo-
gic study of 114 male patients with DCIS [49].
Seventy-five percent of the tumours in the study were
of the papillary subtype, and the typical presentation
for papillary DCIS was a partially cystic palpable
mass.
While complex breast cysts in men seem to carry
higher risk of cancer, additional studies are needed to
delineate the frequency of complex cystic masses in
men with breast cancer [72].
Errors in diagnostic imaging can occur, since
gynecomastia and cancer can mimic each other in
both ultrasound and mammography. False positive
results occur in cases of inflammation, gynecomastia,
fat necrosis, lipoma, epidermal inclusion cyst, in-
traductal papilloma and pseudoangiomatous stromal
hyperplasia.
B-mode US alone is considered a poorer diag-
nostic option [73]; however, accuracy can be
increased when it is combined with mammography
[70]. Chen et al. [65] has described a better
correlation of sonographic findings in transverse
and oblique sagittal planes with craniocaudal and
medial lateral oblique images of mammography.
Moreover, it is useful to characterise the lesion in
relation to the nipple, in order that a retroareolar
mass seen on mammography can be clearly identified
in a position eccentric to the nipple when seen on US
[65].
Scintigraphy
It is another diagnostic tool that can be used in
indeterminated cases by US and mammography,
utilising thallium – Tl-201. In a study comparing the
methods: US, mammography and thallium scinti-
graphy; mammography was the most sensitive (92%)
and scintigraphy was the most specific (75%) [74].
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Histopathology
Fine-needle aspiration cytology is a very reliable
diagnostic method, which may reduce the need for
biopsy for histopathological evaluation. According to
some studies, it presents sensitivity, specificity,
negative and positive predictive values of 100%
[75,76]. The study by John Hopkins Institute showed
a sensitivity of 95.3%, specificity of 100% and
diagnostic accuracy of 98% [77].
Conventional aspiration cytology is usually suffi-
cient; however, sometimes, the analysis with mono-
clonal antibodies can be a useful tool [78]. In cases in
which fine-needle aspiration cytology is inadequate,
core biopsy is indicated [79]. Considering that
stereotactic-guided biopsies are not feasible due to
the small size of the male breast, US-guided biopsies
are performed [65]. In special situations, cytology of
breast secretions may show neoplastic cells, particu-
larly ductal carcinoma [80]; however, there are false
positive cases due to increased cellularity and atypia
in some patients with gynecomastia [81].
Bearing in mind that males have only breast duct
tissue, without terminal lobes [7], the most frequent
histological type is infiltrating ductal carcinoma,
approximately 85% of cases, which mostly is moder-
ately undifferentiated. The second most common
type is papillary [3,51,82]. The great difference bet-
ween male and FBC histopatology is that, while in
women, lobular represents 10% of the total [58,83],
in men is rare, and lobular in situ carcinoma has only
been reported in association with infiltrating lobular
carcinoma [84]. Others subtypes of carcinoma obser-
ved in women can also be found very rarely (1%),
such as DCIS, intraductal papillary carcinoma [4].
Tumours metastatic to the breast are rare. They
account for approximately 2% of mammary malig-
nancies. Melanomas and lymphomas are common
sources of metastases as are carcinomas of the lung,
ovary or stomach [85]. Metastatic breast cancer from
renal, prostate, leukaemia, phyllode tumour has also
been reported [86,87]. Except for ovary and phyllode
for women and prostate for men the sites of
metastases are similar across the sexes.
Molecular markers
Numerous molecular markers have been studied,
including estrogen receptor (ER), progesterone
receptor (PR), androgen receptor (AR), p53, HER-
2/neu (human epidermal growth factor-2), gelati-
nases, p27 gene, MIB-1 (kit67) gene and Bcl-2 gene
(B-cell lymphoma-2) [3].
A retrospective study by Giordano et al. [83] with
2537 men and 383,146 women found 90.6%
positivity of estrogen receptors in men compared
with 76% in women, and on the progesterone
receptor, the positivity rates were 81.2% in men
versus 66.7% in women. Moreover, as it occurs
in women, ER positivity in men also increases
significantly with age, from 75% in the age range of
30–34 years for up to 94% after 85 years of age [83].
However, it was shown that although ER and PR
are more expressed in MBC than FBC, the proteins
under estrogen control (such as pS2, heat shock
protein 27 and cathepsin D) are more frequent in
FBC than MBC, suggesting that ERs in MBC do not
have the same function as in FBC [88,89]. This
could also explain the variable success reported for
anti-hormonal treatment of MBC [90].
Few studies exist on the role of ARs in breast
cancer. ARs have been detected in 31–91% FBCs
[91]. No association was found with tumour size,
lymph node status or tumour stage [92], although
high AR levels seem to predict lymph node metas-
tases [92]. AR-positive patients respond better to
hormone therapy [93] and have longer disease-free or
overall survival rates [90,91].
Data concerning androgen receptors positivity in
MBC vary a lot, from negativity to 95% positivity.
The discrepancy may be due in part to the different
methodologies used for AR demonstration. Its
relationship with clinicopathological factors and
survival is still uncertain [90].
Pitch et al. [90] found no significant association
between AR and age, tumour size or lymph node
status. A trend towards association (p¼ 0.08) was
observed for histological grade: 42.8% G1, but only
8.3% G3 were AR positive, in agreement with studies
on FBCs showing that hormone receptors are
expressed at higher rates in well-differentiated
tumours. Androgen action in breast cancer cell lines
may not be solely mediated by binding of androgen
to the AR. For example, metabolites of DHT with
estrogenic activity, or androgen binding to receptors
other than the AR, may explain the divergent
responses to androgens observed in different breast
cancer cell lines. One study suggested that a decrease
in AR action in breast development may predispose
to early cancer [94].
Conversely, the p53 gene is present in 21–95% of
cases of men affected by the disease [95,96] and it is
associated with higher recurrence and worse prog-
nosis in some patients [97].
According to a review by Giordano et al. [84],
HER-2 expression was present in 37% of men with
breast cancer. However, other studies show a lower
rate of HER-2 overexpression ranging from 1.1% to
15% [98–100] and less frequently expressed than in
women [30,39]. Its presence denotes more advanced
staging and histological grades [98,101].
Although current data suggest more similarities
than differences between MBC and FBCs, additional
research on molecular characteristics of MBC is
critical.
Staging
The classification by the TNM system does not
differentiate the corresponding one in females.
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At diagnosis, 45% of these tumours are localised,
33% have regional extension, 7% present with distant
metastasis and 15% are uncertain [102]. Axillary
lymph node involvement is very common (40–55%),
being 1.6 times more common in men than in
women [103]. However, primary axillary lymph node
as first manifestation of the disease is rare, represent-
ing less than 1% of all cases of breast cancer in men
[104].
The main metastatic sites are, as in women, liver,
lungs, brain and bone [29]. Rare cases of involve-
ment of the choroid and orbit have been reported
[105].
Prognosis
Breast cancer has similar prognostic factors and
behaviour in males and females [106]. The most
important independent prognostic factors include
tumour size (42 cm), histological grade of differ-
entiation, the absence of hormone receptors [7],
older age, clinical stage [30,107] and, highlighting
among them, the presence of axillary lymph nodes
[7,83,108,109].
The five-year survival rate is near 100% in stage I,
86% in stage II and 67% in stage III patients [73].
In metastatic disease (bone, lungs, liver, brain, etc.),
the median survival from diagnosis is 26.5 months
[110].
Mortality appears to be greater in men because,
given the rarity of the disease and the lack of a
prevention culture, diagnosis is usually made at later
stages in males [111,112]. However, when evaluating
patients of similar age and stage, the survival rate is
similar to women [30,83].
The established method in prognosis of breast
cancer includes detection of molecular markers,
such as the ER, PR and HER-2/neu. These
markers are routinely checked via immunohisto-
chemistry (IHC). Flow cytometry is a new method
for detecting these markers, providing quantitative
data on expression patterns of important prognostic
markers [113]. However, the use of flow cytometry
to evaluate the prognostic significance has ques-
tionable value yet [73]. There is no evidence as
strong as there is in women that the status of ER
and C-Erb-B2 is an important prognostic factor in
men [83].
Treatment
Despite a wealth of small retrospective studies on
MBC, its relative low incidence contributes to the
lack of prospective randomised controlled treatment
trials with resultant relative lack of tailor-made
management of breast cancer in males. Although in
men it has aetio-pathological differences from that of
women, treatment regimes are comparative, being
multimodal, including surgery, hormone, che-
motherapy and radiotherapy.
Surgery
The established standard of care for MBC is
modified radical mastectomy. According to Patey,
modified radical mastectomy and simple mastectomy
are the most appropriate surgical interventions.
There is no difference in survival when comparing
patients who underwent modified radical or simple
mastectomy [59,99,114,115].
Lumpectomy combined with radiotherapy is
rarely indicated. A Canadian study found worse
local control of disease with lumpectomy when
compared with mastectomy [116,117]. In addition,
the nodule excision may not be adequate for
complete tumour excision due to the small volume
of breast tissue in males. Nevertheless, it can be
used in patients with impaired general condition
[84,116].
Axillary lymph node dissection is recommended in
case of positive clinical examination, and the sentinel
node study, using blue dye or radioisotope, seems to
be feasible and accurate in cases of absence of
clinically affected ganglia [30].
Studies by means of lymphoscintigraphy, using
technetium-99 injection around the tumour, for
sentinel lymph node resection with intraoperative
gamma camera has shown encouraging results,
avoiding unnecessary axillary dissection and its
consequences, such as lymphedema, pain and loss
of sensibility of upper limb [118,119]. In experienced
hands, success rates are similar to female patients
[120,121], however, it is recommended to avoid the
use of frozen sections because of false-negative
results, up to 10% [60].
Reconstructions can be done using fasciocuta-
neous flaps with local or distant flaps depending on
the stage of the disease [122]. Possible options are
deltopeitoral [123], transverse thoracoepigastric skin
[124] and external oblique flaps.
Hormone
Hormone suppression therapy may be indicated
because of the high positivity of estrogen and
progesterone, which are higher than in women [7].
The use of tamoxifen as a form of complementary
therapy in stage II patients has demonstrated
improved overall [45] and disease-free survivals
[114,116,125] compared to the control group. It
appears to be associated with limited side effects,
such as decreased libido, weight gain, hot flashes,
mood swings, depression, insomnia and deep vein
thrombosis in men compared to women [7]. It is
not yet defined whether the therapy duration
should be 5 years, like in women [3].
Recently, another drug called Anastrozole de-
monstrated impact on disease-free survival in
postmenopausal women with localised breast can-
cer [126]; however, the use of aromatase inhibitors
alone in men is questionable [127], since 20% of
104 L. O. Reis et al.
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circulating estrogen in men are produced by the
testes and are independent of the aromatase
enzyme [30].
Patients with overexpression of the oncogene C-
erb-B2 can benefit from humanised anti-HER 2
monoclonal antibody (Trastuzumab), especially in
negative ER cases, extrapolating the results in female
patients [106].
In metastatic disease, endocrinotherapy using
tamoxifen is the first-line treatment, with beneficial
effects either on visceral, bone or soft tissue
metastases, with response rates of up to 80% in
positive ER cases [87,128]. The second line treat-
ment is orchiectomy or the use of GnRH agonists
with or without antiandrogens [129].
Diethylstilbestrol has been prescribed for patients
with metastatic involvement of soft tissue with
response rate of 38% [130]. There are case reports
demonstrating the efficacy of using aromatase
inhibitors alone or combined with GnRH agonists
in advanced disease [131].
Others hormonal agents under investigation are
antiestrogens (Fulvestrant) [132], ketoconazole, cy-
proterone, corticosteroids, androgens [110,133,134]
with duration of response to these medications
ranging from 3 to 12.5 months [135].
Chemotherapy
Neoadjuvant chemotherapy can be used in locally
advanced forms.
Adjuvant chemotherapy should be offered in cases
of negative ER or endocrine non-responsive disease
and in patients with positive axillary lymph nodes
[64] and locally advanced disease – stage II [136],
using the same drugs used in women, i.e. metho-
trexate, 5-fluorouracil or 5-fluoracil, adriamycin and
cyclophosphamide [68]. However, it should be
remembered that approximately 30% of patients are
older than 70 years when the toxicity associated with
drugs increases [137].
Chemotherapy (doxorubicin) in metastatic disease
is indicated in negative ER and cases resistant to
hormone therapy [129,136] or with a disease-free
interval less than one year [138]. Although men
present an apparently faster response to chemother-
apy, it may be shorter compared to women [135].
One study reported response rates of 67% for 5-
fluoracil, doxorubicin and cyclophosphamide; 55%
for doxorubicin and vincristine; 53% for cyclopho-
sphamide and methotrexate and 13% for 5-fluorour-
acil [139].
Radiotherapy
Adjuvant radiotherapy appears to reduce the risk of
local recurrence in large tumours with lymph node
and muscle involvement [140]. However, the real
impact of adjuvant radiotherapy in reducing local
recurrence has not been fully established [7] and, in
some series, did not have a positive impact on
survival [39,140]. Considering the small size of the
Table I. Main differences between male and female breast cancer.
Male breast cancer Female breast cancer
Epidemiology Unimodal Bimodal
5–10 years later (68 years)
Etiology BRCA 1: less frequent
BRCA 2: more important
Second cancer Breast: 306 Breast: 2–46Prostate Endometrial (pos tamoxifen)
Sarcoma, lung, esophageal (RT)
Clinic aspects Nipple affected earlier Superolateral quadrant
Bilateral: 0–1.9% Bilateral: 4.3%
Axillary lymph node: 40–55%
(1.66 more common)
Radiology Mammography: controversial Mamography: essential
Margins: more defined Microcalcification: frequent in
ductal carcinoma in situCalcifications: less frequent and coarser
Histopathology Lobular : rare Lobular: 10%
Molecular markers ER, PR Positivity: Greater
ER (90%); PR (81%) ER (76%); PR (66%)
HER-2: less frequent
Prognosis Status ER e C-Erb –B2: unclear Important factor
Mortality: greater (later diagnosis)
Treatment Tamoxifen: less side effects Tamoxifen:
Duration: unclear Duration 5 years
Aromatase inhibitors alone: questionable
Radiotherapy: include internal mammary
lymph node chain
Screening High risk: BRCA, Klinefelter All,440 years
Psychoemotional Disease specific stress: higher
Male breast cancer 105
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male breast, Gennari et al. [141] indicate radio-
therapy after mastectomy in cases of tumour 41 cm
and/or presence of 41 positive lymph node, as well
as in cases of more conservative surgery. Since male
breast tumours are predominantly central in location,
adjuvant radiotherapy can include, in addition to the
routine fields of women, the internal mammary
lymph node chain [110,142,143].
Psycho-emotional aspects
The disease impact on men regarding psycho-
emotional aspects should be emphasised. In addition
to being more vulnerable to social constraints in
relation to women, these men find themselves
suffering from a disease in a sexual organ typically
associated with the opposite sex [144], leading to
high levels of disease-specific stress (over 23%)
[145].
Screening
The incidence of breast cancer is too low among men
to justify a screening programme. Therefore, breast
cancer screening for males has been indicated only
for high risk population, as in families with BRCA
mutations and patients with KS. It is also recom-
mended for patients with a previous diagnosis of
breast cancer because of the risk of a second primary
cancer [45].
Future perspectives
It appears that males have derived lesser benefit from
the substantial advances in breast cancer therapy
made over the past several decades. Although
similarities between breast cancer in males and
females exist, it is not appropriate to extrapolate
data from female disease to the treatment of male
(Table I).
Recently, the development of a collaborative task
through the Multidisciplinary Meeting on Male
Breast Cancer [146] put forward that treatment of
MBC should be driven by data collected from studies
that include male participants.
Ongoing studies to define the molecular and
genetic profile of MBC may yield other relevant
biomarkers and therapeutic targets. Current efforts at
pooling epidemiologic data, clinical information and
tumour specimens will lead to a greater under-
standing of the aetiology of this disease [146].
Education of both patients and providers is needed
to increase awareness of MBC, to guide evidence-
based treatment and to encourage enrolment onto
future clinical and biologic studies aimed at optimis-
ing treatment for this rare disease.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are respon-
sible for the content and writing of the paper.
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