ORIGINAL ARTICLE

Clinicopathologic characteristics and survival of male breastcancer

Dongying Liu • Guangru Xie • Ming Chen

Received: 16 January 2013 / Accepted: 26 March 2013

� Japan Society of Clinical Oncology 2013

Abstract

Backgrounds Male breast cancer (MBC) is a rare disease

and accounts for \1 % of all breast cancers.

Methods We retrospectively analyzed clinicopathologic

characteristics and prognosis of MBC patients who were

diagnosed in our hospital between March 2002 and March

2012.

Results The median age of diagnosis of MBC was

62 years, which was 9 years older than female breast

cancer (FBC) patients. The highest proportion of MBC

patients was in the 50–59-year age group. The percentage

of invasive ductal carcinoma in MBC was much higher

than in FBC (P = 0.000). The positive rate of estrogen

receptors in MBC patients (87.9 %) was significantly

higher than in FBC patients (P = 0.048), whereas HER-2

was positive in 17.2 % of MBC patients, which was sig-

nificantly lower than in FBC patients (P = 0.001). There

was a consistent significant difference in luminal subtypes

of FBC and MBC patients (P = 0.000). The overall

survival rates of MBC were significantly higher than

FBC (P = 0.004). HER-2-positive patients had a statisti-

cally worse prognosis than HER-2-negative patients

(P = 0.040). Lymph node metastasis and larger tumor size

were also associated with poorer prognosis (P = 0.056 and

P = 0.088). The level of hormones was examined in 7

patients, and abnormal hormone levels were detected in 4.

Conclusion The FBC patients were significantly different

from the MBC in clinicopathologic and prognostic char-

acteristics. HER-2 positivity was an important factor for

prognosis.

Keywords Male breast cancer � Prognosis � HER-2

Introduction

Male breast cancer (MBC) is a rare disease and accounts

for \1 % of all breast cancers worldwide [1, 2]. Because

of the rarity of this disease, little is known about its

precise etiology, such as hormonal [3, 4], environmental

[5] and genetic factors [6, 7], which are involved in the

pathogenesis of breast cancer in women as well as in

men. There is also little awareness of the accuracy of

clinical characteristics and optimal treatment [8–10],

which usually come from studies in female breast cancer

(FBC).

Although male and female breast cancers seem to be

similar with regard to clinical characteristics, there are

many differences between them which are associated with

the lower incidence and later onset of MBC [11, 12].

Unlike FBC, in which incidence rates are rising

throughout the world, the incidence of MBC has remained

relatively stable in most countries [13]; few studies

reported an increasing rate [14]. Its incidence varies greatly

in different geographical areas and ethnic groups. The

worldwide variation in MBC resembles that of FBC, with

higher rates in America and Europe [1, 2]. A substantially

D. Liu � G. Xie

Department of Integrated Traditional and Western Medicine,

Key Laboratory of Cancer Prevention and Therapy of Tianjin,

Tianjin Medical University Cancer Institute and Hospital,

Tianjin 300060, China

M. Chen (&)

Department of Digestive Medicine, Tianjin Nankai Hospital,

Tianjin 300060, China

e-mail: cmtjnk@sina.com

123

Int J Clin Oncol

DOI 10.1007/s10147-013-0555-4

high proportion of MBC cases also have been reported in

Africa [15]. However, its incidence was relatively low in

Asia [16, 17].

The prevalence of MBC increases with age. It is rare

before the age of 30 years, and the average age at diagnosis

is approximately 5–10 years older than that in females with

the disease [18, 19].

The predominant histological type of MBC is invasive

ductal carcinoma, which represents about 70 % of all

MBCs [20]. Much rarer tumor types include invasive

papillary, medullary carcinoma and Paget’s disease.

The proto-oncogene HER-2/neu (cerb-2) is a member

of the ErbB/HER type I tyrosine kinase receptor family.

Around 25–30 % of invasive FBCs over-express HER-2.

While HER-2 positivity is regarded as a prognostic factor

and therapeutic target for FBC, the role of HER-2 in

MBC is not well defined [21]. In previous studies, HER-2

over-expression in MBC, as measured by immunohisto-

chemistry, ranged from 1.7 to 23.4 % [21–24], but sur-

vival analysis was limited by small sample sizes. Bearing

in mind the importance of HER-2 in FBC, the HER-2

status of a MBC should be regarded as clinically

important.

MBCs have been shown to express estrogen receptors

(ERs) and progesterone receptor (PR) more frequently

(75–90 %) than FBCs [11, 12]. It was suggested that levels

of hormone receptors in MBC appear to closely approxi-

mate those found in breast cancers arising in post-meno-

pausal females [20].

Due to the absence of screening programs, MBCs are

diagnosed at an older age than in women and with a more

severe clinical presentation, such as greater tumor size and

more frequent lymph node metastases [25]. Prognosis in

MBCs was also worse than in female patients [20], prob-

ably because of the advanced stage at diagnosis together

with the older age of male patients, often leading to the

coexistence of serious morbidities.

Patients and methods

Patients

A total of 71 male patients diagnosed with breast cancer at

Tianjin Medical University Cancer Institute and Hospital

between March 2002 and March 2012 were analyzed ret-

rospectively. In the same period, 16,796 female breast

cancers were diagnosed in our center. The ratio of males to

females was 42:10,000. Data regarding clinicopathologic

characteristics (including age, presenting signs and symp-

toms, tumor site and location), histopathology, chemo-

therapy, radiotherapy, surgery modalities and overall

survival time were extracted from medical records.

Histopathology was reviewed for each case to confirm the

diagnosis of MBC and to assess TNM stage, histologic

subtype, tumor size, lymph node involvement, hormone

receptor status (ER and PR) and HER-2 protein over-

expression.

The median age at diagnosis of MBC was 62 years

(ranging from 43 to 84 years). The most frequent symptom

before diagnosis was painless palpable retroareolar lump,

followed by nipple discharge. The tumor was located in the

left breast in 36 (50.7 %) patients and in the right breast in

35 (49.3 %) patients. All 71 cases were verified by path-

ologic diagnosis.

Immunohistochemistry

Both estrogen receptor (ER) and progesterone receptor

(PR) were determined by immunohistochemistry. 10 % or

more of positively stained cells was used as the cut-off for

hormonal receptor positivity.

HER-2 status was determined by either immunohisto-

chemistry or fluorescent in-situ hybridization (FISH).

Tumors with 3? IHC score and FISH positivity were

considered to be HER-2-positive. Tumors with 2? IHC

scores were assayed with FISH. Tumors with 1? and/or 0

IHC and FISH negativity were considered to be HER-2-

negative.

Hormone levels

The levels of hormones in blood, including estradiol (E2),

prolactin (PRL), testosterone (T), luteinizing hormone

(LH), follicle-stimulating hormone (FSH) and progesterone

(P), were examined in 7 cases.

Follow-up plan

Clinical follow-up included history, physical examination,

laboratory tests and radiologic imaging tests every

6–12 months for detection of relapse.

Statistical analysis

For statistical methods, the chi-squared and Fisher’s exact

tests were used for categorical variables. Student’s t test

and the Mann–Whitney U test were used for continuous

variables, and data are presented as median (range). Sur-

vival curves and univariate analysis were calculated

according to the Kaplan–Meier method and the log-rank

test was used to evaluate statistically significant differ-

ences. Cox regression was applied in multivariate prog-

nostic analysis. A value of P \ 0.05 (two-sided) was

regarded as statistically significant. All analyses were

performed using SPSS version 17.0.

Int J Clin Oncol

123

Results

We investigated the differences in clinicopathologic fea-

tures between FBC and MBC. The median age of MBC

was 62 years, which was significantly older than FBC

patients (P = 0.000). We also observed that a higher pro-

portion of the MBC patients were in the 50–59-year age

group while only 27.5 % of FBC patients were in this age

group.

Histologic type and stage

The predominant histologic type of MBC was invasive

ductal carcinoma; other histologic types included ductal

carcinoma in situ in 5 patients, secretory carcinoma in 1

patient, papillary carcinoma in 5 patients, mucinous car-

cinoma in 4 cases, and lipid-rich carcinoma in 1 patient.

The percentage of invasive ductal carcinoma in MBC was

much higher than in FBC (P = 0.000). The MBCs were

detected at advanced stage more frequently than FBCs

(P = 0.037).

ER, PR and HER-2 expression

66 patients underwent hormonal receptor analysis: ER was

positive in 58 patients while 53 patients were PR-positive,

and HER-2 was positive in 11 patients. ER was positive in

87.9 % of MBC patients, which was higher than in FBC

patients. However, HER-2 was positive in 17.2 % of MBC

patients, which was significantly lower than in FBC

patients. Overall, 53 patients were classified as luminal A

subtype (ER? or PR?, and HER-2-), 9 patients were

luminal B subtype (ER?, PR? and HER-2?), 2 patients

were HER-2 over-expressing subtype (ER-, PR- and

HER-2?) and 2 patients were basal-like subtype (ER-,

PR- and HER-2-) (Table 1). Consistently, there was a

significant difference in luminal subtypes of FBC and MBC

patients (P = 0.000). Of the 11 HER-2-positive patients,

only 2 received trastuzumab treatment.

Prognostic analysis

We then compared the prognosis of MBC and FBC. We

found that the survival rates of MBC (3-, 5- and 10-year

survival rates of 89.6, 81.2 and 74.1 %, respectively) were

significantly higher than FBC (v2 = 8.205, P = 0.004)

(Fig. 1). We observed clinicopathologic differences

between FBC and MBC, which may have resulted in the

significant prognostic difference between them. We there-

fore applied Cox regression to adjust for clinicopathologic

factors. Table 2 shows that sex was still an independent

prognostic factor for all breast patients.

Table 1 Clinicopathologic differences between FBC and MBC

Factors MBC FBC v2 P

Median age 62 (43–84) 53 (25–87) 6.355 0.000

Age group (years) 48.400 0.000

\40 0 (0.0) 57 (13.7)

40–49 8 (11.3) 155 (37.3)

50–59 34 (47.9) 114 (27.5)

60–69 13 (18.3) 62 (14.9)

C70 16 (22.5) 27 (6.5)

Histology 29.875 0.000

Invasive ductal carcinoma 53 (74.6) 120 (28.9)

Invasive lobular carcinoma 0 (0.0) 23 (5.5)

Others 18 (25.3) 272 (65.5)

Tumor size (cm) 4.031 0.133

B2 35 (49.3) 163 (39.2)

2–5 30 (42.2) 228 (54.9)

[5 6 (8.4) 24 (5.8)

Lymph node metastasis 0.015 0.902

No 35 (49.3) 224 (53.9)

Yes 36 (50.7) 191 (46.0)

Stage 13.377 0.037

I 12 (16.9) 66 (15.9)

IIA 23 (32.3) 177 (42.6)

IIB 14 (3.4) 110 (26.5)

IIIA 11 (15.4) 38 (9.1)

IIIB 8 (11.2) 16 (3.8)

IIIC 1 (1.4) 2 (0.4)

IV 2 (2.8) 6 (1.4)

ER 3.741 0.048

Negative 8 (12.1) 90 (22.6)

Positive 58 (87.9) 308 (77.4)

PR 1.909 0.167

Negative 13 (19.6) 111 (28.2)

Positive 53 (80.3) 283 (71.8)

HER-2 12.845 0.001

Negative 55 (82.8) 244 (61.0)

Positive 11 (17.2) 156 (39.0)

Luminal subtypes 36.597 0.000

Luminal A 53 (80.3) 161 (42.3)

Luminal B 9 (13.6) 63 (16.5)

HER2 over-expressing 2 (3.0) 81 (21.3)

Basal-like subtype 2 (3.0) 76 (19.9)

Chemotherapy 0.162 0.730

Yes 58 (81.7) 347 (83.6)

No 13 (18.3) 68 (16.4)

Radiotherapy 0.202 0.701

Yes 39 (54.9) 216 (52.0)

No 32 (45.1) 199 (48.0)

Surgery 1.339 0.512

Radical mastectomy 17 (23.9) 127 (30.6)

Modified radical mastectomy 48 (67.6) 253 (61.0)

Tumorectomy 6 (8.5) 35 (8.4)

Int J Clin Oncol

123

We applied the Kaplan–Meier method and log-rank test

to detect the important prognostic factors for MBC (shown

in Table 3). Only the HER-2-positive patients had a sta-

tistically worse prognosis than HER-2-negative patients

(v2 = 4.219, P = 0.040), as shown in Fig. 2. Lymph node

metastasis and larger tumor size were also associated with

poor prognosis (v2 = 3.656, P = 0.056 and v2 = 4.851,

P = 0.088, respectively) (Figs. 3 and 4), but both P values

were greater than 0.05. A lower number of MBC patients

were enrolled and only 16 of them had the end point of

cancer death in this study. These two reasons may result in

the lack of statistical significance in these two factors.

Hormone levels

Of the 7 patients whose hormone levels were examined, 4

had an imbalance in hormone levels, as shown in Table 4.

3 patients had higher levels of PRL, 3 patients had higher

levels of LH, 1 patient with secretory carcinoma had lower

levels of E2, P and LH, 2 patients had abnormal levels of

both PRL and LH, and another patient had an abnormal

level of only 1 hormone.

Discussion

Characteristics of patients

The incidence of MBC varies by geographical location,

accounting for 1 % of breast cancers in the USA and UK

[1, 2], compared with a significantly higher male-to-female

ratio of 3.9 % in Africa [15]. However, considering that

blacks living in the USA also had a higher male-to-female

ratio than their white counterparts, it is possible that

genetic background plays an important role in the higher

incidence [26]. In Asian patients the annual incidence of

MBC is significantly lower than the average global level

[2, 16]. In conformity with previous studies in Japan and

China, the male-to-female ratio was 42:10,000 in our

center [16, 17].

Because of the rarity of breast cancer in males, most

reported series involved small numbers of patients. The

statistical accuracy of clinical characteristics of MBC is

therefore not fully obtained. However, the mean age of

diagnosis in most reports spans 60–65 years, with a range

from the mid-20s to the early 90s [12, 18]. This is

approximately 10 years older than the corresponding mean

age for breast cancer in women. The incidence of MBC

increases with age and the bimodal age distribution seen in

women is absent in men, showing instead a peak incidence

Fig. 1 Comparison of survival in MBC and FBC

Table 2 Multivariate analysis of prognostic factors of MBC and

FBC patients

Factors HR 95 % CI Wald

statistic

P

Lower Upper

Age 0.996 0.970 1.024 0.071 0.789

Sex (male/female) 1.832 1.007 3.512 3.991 0.046

Histology (invasive

ductal carcinoma/

other)

0.688 0.296 1.599 0.754 0.385

Tumor size (cm) 0.919 0.632

B2 0.709 0.281 1.790 0.530 0.467

2–5 0.583 0.164 2.074 0.694 0.405

[5 1

Lymph node metastasis

(no/yes)

1.692 0.478 5.986 0.666 0.414

Stage 7.627 0.019

I 0.269 0.099 0.729 6.658 0.010

II 0.583 0.348 0.978 4.177 0.041

III 0.302 0.140 0.653 9.250 0.002

IV 1

ER (-/?) 1.014 0.629 1.635 0.003 0.955

PR (-/?) 1.034 0.554 1.931 0.011 0.917

HER-2 (-/?) 0.547 0.057 0.139 4.340 0.037

Luminal subtypes 1.855 0.173

Luminal A 0.897 0.784 1.027 2.496 0.114

Luminal B 2.302 0.383 13.845 0.830 0.362

HER2 over-expressing 0.123 0.008 1.901 2.252 0.133

Basal-like subtype 1

Chemotherapy (yes/no) 1.671 0.754 1.978 1.375 0.196

Radiotherapy (yes/no) 1.864 0.794 4.386 1.932 0.154

Surgery 1.820 0.401

Radical mastectomy 0.806 0.442 1.470 1.828 0.477

Modified radical

mastectomy

1.002 0.846 1.162 0.593 0.672

Tumorectomy 1

Int J Clin Oncol

123

in the sixth decade. In our study also, the median age of

MBC was 9 years older than FBC patients.

MBCs differ from FBCs in the predominance of inva-

sive ductal carcinoma, which accounted for about 70 % of

MBC cases in the literature [22, 23]. Meanwhile, the much

less frequent incidence of invasive lobular carcinoma can

be explained by the absence of lobules in the rudimentary

male breast [27]. In this study, the frequencies of invasive

ductal carcinoma and invasive lobular carcinoma were 74.6

and 0.0 %, respectively.

ER, PR and HER-2 expression

Several series have consistently reported a higher per-

centage of hormonal receptor positivity in MBC. ER was

more likely to be positive in MBC than in FBC

Table 3 Prognostic factors of MBC

Factors n Survival rate (%) v2 P

3 years 5 years 10 years

Age 0.792 0.851

40–49 years 8 83.3 62.5 62.5

50–59 years 34 87.0 75.4 57.6

60–69 years 13 83.3 83.3 0.00

C70 years 16 73.1 73.1 48.8

Histology 0.061 0.970

Invasive ductal

carcinoma

53 82.8 77.3 28.3

Others 18 83.1 71.3 57.6

Tumor size (cm) 4.851 0.088

B2 35 89.0 78.6 67.3

2–5 30 77.4 77.4 55.3

[5 6 66.7 50.0 16.7

Lymph node

metastasis

3.656 0.056

No 35 91.2 79.8 53.2

Yes 36 56.0 56.0 29.9

Stage 4.622 0.202

I 12 75.0 58.3 50.0

II 8 87.2 81.4 53.1

III 1 80.0 80.0 80.0

IV 2 50.0 50.0 0.0

ER 1.114 0.291

Negative 8 51.4 51.4 51.4

Positive 58 87.0 76.1 52.7

PR 1.876 0.121

Negative 13 80.0 66.7 35.6

Positive 53 83.3 76.1 52.7

HER-2 4.219 0.040

Negative 55 82.7 78.8 55.4

Positive 11 80.8 60.6 26.9

Luminal subtypes 4.788 0.198

Luminal A 53 81.0 78.3 50.1

Luminal B 9 87.2 81.4 43.1

HER2 over-

expressing

2 100.0 100.0 100.0

Basal-like subtype 2 100.0 50.0 50.0

Chemotherapy 1.214 0.371

Yes 58 82.9 77.8 32.3

No 13 80.0 69.3 47.0

Radiotherapy 2.528 0.102

Yes 39 79.8 70.5 46.1

No 32 83.1 82.0 50.0

Surgery 0.973 0.615

Radical

mastectomy

17 93.3 74.7 0.0

Modified radical

mastectomy

48 79.3 75.7 63.4

Tumorectomy 6 100.0 50.0 0.0

Fig. 2 Impact of HER-2 expression on survival in MBC

Fig. 3 Impact of tumor size on survival in MBC

Int J Clin Oncol

123

(80–90 % vs. 75 %), as well as PR (73–81 % vs. 65.9 %)

[24, 28]. The ER and PR positivity rates in our study were

also, as expected, higher than those seen in the FBC group.

Increase in hormone receptor expression with age has been

reported in MBC, as occurs in post-menopausal women

[20]. However, it is still controversial whether the

expression of ER or PR in MBC is associated with therapy

response or prognosis of MBC [29, 30].

While HER-2 positivity is regarded as a prognostic

factor and therapeutic target for female breast cancer,

HER-2 over-expression and its prognostic significance in

MBC is still controversial [21]. In this study, over-

expression of HER-2 was associated with worse prognosis.

The over-expression of HER-2 activates the downstream

pathway and promotes proliferation of cancer cells,

resulting in growth and metastasis of tumor. Analysis of

FBC suggests that amplification and/or over-expression of

HER-2 is a strong predictive factor for the response to

treatment with the monoclonal antibody trastuzumab alone

or in combination with cytotoxic agents [31]. In accor-

dance to these findings, the HER-2 status of a MBC tumor

may be of clinical importance. Due to the relatively rare

incidence, data on the predictive relevance of HER-2 and

clinical benefit of trastuzumab in MBC are lacking. In our

study, only 2 patients received trastuzumab treatment in

recent years, so the benefit of trastuzumab in MBC needs

more research for clarification in the future.

Prognosis

The overall survival for MBC patients varied in series

studies, ranging between 36 and 75 % at 5 years. In gen-

eral, it has an more unfavorable outcome than breast

cancer in women [32]. In our study, overall survival rates

were also significant lower for men. The reasons for the

Fig. 4 Impact of lymph node metastasis on survival in MBC

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Int J Clin Oncol

123

worse prognosis of breast cancer in men are unclear.

Borgen et al. [25] suggested that this was due to an older

age at diagnosis and more advanced stage at diagnosis,

which can be seen in this study. However, in Foerster

et al.’s [23] report, when age- and stage-matched MBC and

FBC were compared, MBC patients still had worse prog-

nosis than FBC patients.

Ravandi et al. [5] suggested that the aggressive behavior

and poor prognosis of MBC may also be the result of the

anatomical differences between the male and female

breast. The sparseness of breast tissue in men places even a

small tumor close to the overlying skin and underlying

pectoral fascia without the great bulk of intervening breast

tissue in women. It has been shown that in men the breast

tissue close to the skin is drained by lymphatics into the

subareolar lymphatic plexus and axilla [33, 34].

Hormone levels of MBC patients

Imbalance in the estrogen–testosterone ratio is deemed to

be a risk factor for MBC. Hormonal alterations due to

testicular disease may be an etiology implicated in MBC

[35, 36]. Cirrhosis of the liver, by virtue of increased

estrogen levels, may predispose to MBC [36]. Calabresi

et al. [37] found that serum levels of estradiol and estrone

were higher in MBCs. However, Ballerini et al. [4] did not

find any differences between hormone levels in MBC

patients and in matched controls. In our study, 4 patients

had higher levels of PRL and LH, but in 1 patient with

secretory carcinoma differing alterations (lower levels of E,

P and LH) were observed. Thus, the importance of hor-

monal changes may vary in MBC patients with different

histological types.

Conclusion

There were significant clinicopathologic and prognostic

differences between FBC and MBC. Over-expression of

HER-2 may be an important prognostic factor for MBC.

However, many factors of etiology in MBC, such as hor-

monal, environmental, genetic factors and prognosis, were

unclear. Large-scale multi-center prospective clinical trials

would be necessary to verify these factors.

Conflict of interest The authors declare that they have no conflicts

of interest.

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