and Aysegul A. Sahin2
Division of Pathology, Singapore General Hospital, Singapore, Singapore
The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
KeywordsMale breastGynaecomastiaEpithelial hyperplasiaPseudoangiomatous stromal hyperplasiaInvasive carcinomaDuctal
The structure of the male breast is almost identical to that of the female breast, yet both benign and malignant breast neoplasms are rare in males [1–3]. Until puberty, the male and female breasts are identical, composed of lactiferous ducts and fibrofatty stroma . In males, testosterone levels increase during puberty, causing involution and atrophy of the ducts. In females, both stroma and ducts proliferate and lobular units develop in response to oestrogen and progesterone. The normal adult male breast is composed primarily of a small nipple-areolar complex, subcutaneous adipose tissue, stromal elements, and a few poorly developed ductal structures that end blindly (Fig. 14.1). Cooper ligaments are absent, and terminal ductal lobular unit formation is rare, which explains the rarity of many lesions such as cysts, fibroadenomas, phyllodes tumours, and lobular neoplasia. Most lesions in the male breast are of ductal origin [5, 6].
Comparison of male and female breasts. (a) Male breast composed predominantly of stromal elements, including fibrous and adipose tissue, with poorly developed ducts and without any lobular units. (b) Adult female breast, showing ducts connected to lobular units
Gynaecomastia is the non-neoplastic enlargement of the male breast, resulting from a proliferation of both epithelial and mesenchymal components of the breast.
Clinical and Epidemiological Features
Asymptomatic gynaecomastia is a relatively common, usually self-limited disorder. It is reported in 30–40 % of men [7–14]. The pathophysiology of gynaecomastia is poorly understood [15, 16]. The causes of gynaecomastia development range from benign physiologic processes to rare neoplasms. Proper identification of the aetiology of the gynaecomastia is important for clinical management [17, 18]. Based on its aetiology, gynaecomastia is classified into three categories: physiologic, secondary, and pharmacologic.
Physiologic gynaecomastia can occur in neonatal, pubertal, and elderly males. Neonatal gynaecomastia, which is the enlargement of breast tissue in newborns due to maternal hormones, usually resolves within several weeks of birth. Pubertal gynaecomastia is common and has a peak incidence at age 13–15 years. It is usually bilateral and is associated with breast tenderness (Fig. 14.2). It is due to hormonal surges during this period and in most cases resolves in a couple of years without any intervention. The incidence of gynaecomastia increases with age, and enlargement of breast tissue is usually due to a hormonal imbalance.
Secondary gynaecomastia can be due to hypogonadism (either congenital or acquired), endocrine disorders such as hyperthyroidism, metabolic disorders such as alcohol-induced liver disease, and chronic renal disease. It can also arise from neoplasms such as testicular tumours associated with increased levels of oestrogen, human chorionic gonadotropin, and prolactin; adrenal cortical tumours; and rarely other solid tumours such as bronchogenic carcinoma and squamous cell carcinoma of the skin [17, 19].
Pharmacologic gynaecomastia appears to be the result of the ingestion of a variety of implicated medications. Exogenous oestrogens, anabolic steroids, digitalis, marijuana, chlorpromazine, and some chemotherapeutic agents and antituberculosis drugs are reported to cause gynaecomastia [9, 19].
Gynaecomastia presents as a soft, mobile breast enlargement behind the nipple. The lesion can vary in size; most commonly it is 2–5 cm. Breast tenderness and pain can occur, but other symptoms such as nipple discharge, bleeding, and skin retraction are usually indicative of an additional pathology such as malignancy [12, 17].
Bilateral gynaecomastia (Courtesy of Dr. Veronique Tan)
The imaging features of gynaecomastia depend on the duration of the lesion. In the early development phase, a discrete subareolar mass, corresponding to increased fibroglandular tissue, can be identified on mammography or ultrasound evaluation. Long-standing lesions (usually more than 1 year) are characterised by a dendritic pattern with linear bands of fibroglandular tissue radiating to the periphery. Mammography can show an asymmetric or central subareolar density, and ultrasound evaluation reveals hyperechoic fibroglandular tissue surrounding a central, subareolar hypoechoic area (Fig. 14.3). Microcalcifications are rarely present. Both ultrasound and mammography can be used to identify carcinomas arising in the background of gynaecomastia in males as effectively as they are used in females.
Mammographic image of gynaecomastia. A flame-shaped density containing interspersed fat and ill-defined borders is seen in the subareolar region
The macroscopic features of gynaecomastia are nonspecific. Usually, it appears as ill-defined fibrous tissue with no identifiable discrete nodules (Fig. 14.4).
Gross appearance of gynaecomastia. (a) Gynaecomastia shows adipose tissue with an ill-defined, grey-white fibrous density. (b) The edge of the fibrous density is imperceptible
Histologic features vary with the age of the lesion, regardless of its aetiology. In the early phase (also referred to as the florid phase), gynaecomastia is characterised by an increased number of ducts embedded within the oedematous myxoid stroma (Figs. 14.5 and 14.6). Varying degrees of intraductal epithelial proliferation are present. Most of the ducts show a branching configuration and are lined by an epithelium of three to four cells thick, without significant cytologic atypia (Fig. 14.7). The epithelial proliferation has a characteristic appearance, with tapering tufts protruding into the lumen, resembling a micropapillary architectural pattern (Figs. 14.8 and 14.9). The proliferating epithelial cells forming the luminal protrusions of gynaecomastia are not monomorphic (Figs. 14.10, 14.11, and 14.12). Epithelial hyperplasia may be florid (Fig. 14.13). The stroma around the ducts is usually hypervascular and may contain inflammatory cells (Figs. 14.14 and 14.15). Metaplastic changes such as apocrine and squamous metaplasia can occur in gynaecomastia (Fig. 14.16). Pseudoangiomatous stromal hyperplasia (PASH) can also be present (Fig. 14.17). In the later phase of gynaecomastia (also called the fibrous phase), fibrotic stroma predominates, ductal proliferation is diminished, and the epithelium undergoes atrophy (Fig. 14.18). The ducts are usually lined by flattened epithelium. The periductal stroma is hyalinised.
In rare cases, lobular development can occur; its pathogenesis is unclear. Ductal epithelial cells in gynaecomastia are usually strongly positive for oestrogen, progesterone, and androgen receptors [16, 17]. The presence of a dual cell population in the epithelial hyperplasia can be demonstrated by immunohistochemical stains for myoepithelial markers. Gynaecomastia glands occurring secondary to antiandrogen therapy may show positivity for prostate-specific antigen . This finding should not be misinterpreted as showing a prostate origin for these glands.
Microscopic features of gynaecomastia. (a) Scattered ducts associated with hypercellular stroma. (b) The epithelium shows tufting. Inset shows high magnification of the epithelial tufts
Microscopic features of gynaecomastia. The stroma is densely fibrous and lacks an adipose tissue component
Microscopic features of gynaecomastia. (a) Ducts show a branching configuration without marked epithelial thickening. The stroma is hypocellular. (b) Higher magnification of a duct without significant epithelial hyperplasia
Microscopic features of gynaecomastia. (a) Lining epithelium shows marked proliferation. (b) Proliferating epithelial cells are polymorphic in appearance
Microscopic features of gynaecomastia. (a) Slightly dilated ducts are lined by thickened epithelium showing focal tufting, which may mimic a micropapillary pattern. (b) Micropapillary-like tufts are slender and non-rigid and comprise epithelial cells with a heterogeneous appearance (arrow)
Microscopic features of gynaecomastia. (a–d) Lining epithelium shows micropapillary tufts, which are irregularly distributed and tapering near the tips
Microscopic features of gynaecomastia. Lining epithelium shows luminal protrusions. Inset shows high magnification of the epithelial protrusions into the duct lumen
Microscopic features of gynaecomastia. (a, b) Cellular fibrotic stroma associated with small glands, which are lined by epithelium of three to four cells thick
Microscopic features of gynaecomastia. (a, b) Florid usual ductal hyperplasia almost completely fills the lumen. Based on the polymorphous nature of the epithelium, it is not atypical
Microscopic features of gynaecomastia. (a, b) The periductal stroma is oedematous and has myxoid features. (c) The stromal cells have variably dense and irregular nuclei admixed with a proliferation of capillaries
Microscopic features of gynaecomastia. (a) The periductal stroma is hypercellular and contains scattered inflammatory cells. (b) Prominent periductal inflammatory infiltrate
Microscopic features of gynaecomastia. Cystic change with apocrine metaplasia is shown
Microscopic features of gynaecomastia. (a, b) Pseudoangiomatous stromal hyperplasia (PASH) is commonly seen in a background of gynaecomastia
Microscopic features of gynaecomastia. Hypocellular diffuse fibrosis (end stage of gynaecomastia)
Gynaecomastia must be differentiated from pseudogynaecomastia and benign and malignant breast neoplasms. Pseudogynaecomastia (lipomastia) refers to prominence of the breast due to excessive adipose deposition in subcutaneous tissue without breast glandular proliferation; it usually occurs in elderly, obese males. Physical examination and imaging studies reveal diffuse breast enlargement without subareolar nodules.
The epithelial proliferation seen in the early phase of gynaecomastia can be quite prominent and can mimic in situ carcinoma. The characteristic architectural features of gynaecomastia and the lack of cytologic monotony of in situ ductal carcinoma should be helpful in making the distinction. Atypical ductal hyperplasia is rarely diagnosed in a background of gynaecomastia . Its distinction from usual ductal hyperplasia is based on primarily morphological and adjunctive immunohistochemical features, with atypical ductal hyperplasia often disclosing a cribriform pattern of uniform epithelial cells accompanied by high ER and reduced CK5/6 expression.
Benign breast lesions such as nipple duct adenomas, papillomas, and sclerosing adenosis may occur in the male breast. Histologic criteria for these lesions are the same as in a female breast.
Prognosis and Therapy Considerations
Gynaecomastia reflects an underlying imbalance in the hormonal physiology in which there is an increase in oestrogen relative to androgen action at the breast-tissue level. Similar to female breast development, oestrogen, along with growth hormone and insulin growth factor-1 (IGF-1), is required for breast growth in males. Normally a balance exists between oestrogens and androgens in males. Any pathologic condition or medication that can cause an elevation in the ratio of oestrogen to androgen, either by increasing oestrogen levels or decreasing androgen levels, can induce gynaecomastia [13, 17, 18].
Most cases of gynaecomastia are asymptomatic and patients seek clinical attention for cosmetic concerns. The condition may cause local pain and tenderness, however, and could occasionally be the result of a serious underlying illness or sensitivity to a medication; it may even be inherited. In all ages, if a specific cause of the gynaecomastia is identified, treatment of the underlying cause is warranted, but most cases do not require treatment. Treatment should not be initiated during the initial phase, when the breast hypertrophy may regress. If no underlying cause is discovered, then close observation is appropriate. Surgery to remove the enlarged breast tissue may be necessary if gynaecomastia does not resolve spontaneously or with medical therapy.
Male Breast Cancer
Male breast cancer is simply breast carcinoma that occurs in the breast tissue of men.
Clinical and Epidemiological Features
Because of its relative rarity, male breast cancer has not been studied as extensively as female breast cancer. Male breast cancer is an uncommon tumour in Western countries, accounting for less than 1 % of all breast cancers and less than 1 % of all malignancies in males. The ratio of male to female breast cancer is approximately 1:100 in the United States. According to the American Cancer Society, an estimated 2240 new cases of male breast cancers occur annually, and approximately 400 men die from breast cancer [22–24]. The incidence rate of male breast cancer is higher in African Americans than in whites, and it is higher in geographic regions where chronic liver disease due to infectious and neoplastic aetiologies is relatively higher than in Western countries [25–30]. In central Africa, breast cancer constitutes 5–6 % of all malignancies in males.
Risk factors for male breast cancer include family history of breast cancer, inherited gene mutations, Klinefelter syndrome, liver disease, increased sources of endogenous and exogenous oestrogen, obesity, occupational and environmental exposures, and radiation . Breast cancer risk is increased if other members of the family have had breast cancer. About one of five men with breast cancer has a close male or female relative with breast cancer. Men with a mutation in the BRCA2 gene have an increased risk of breast cancer. BRCA1 mutations can also increase the risk of male breast cancer, but the risk appears to be lower. Mutations in CHEK2 and PTEN genes may be responsible for some male breast cancers [29, 31–34]. Klinefelter syndrome is a congenital condition defined by chromosomal abnormality of XXY. Compared with other men, patients with this syndrome have lower levels of androgens and higher levels of oestrogens; for this reason, they often develop gynaecomastia. Men with Klinefelter syndrome have a 50-fold higher risk of developing breast cancer than men in the general population. Ionising radiation is a known risk factor for female breast cancers, and similarly, the risk of male breast cancer increases with exposure to chest radiation. The liver plays an important role in sex hormone metabolism by making binding proteins. These binding proteins affect hormonal activity. Men with severe liver disease such as cirrhosis have relatively low levels of androgens and higher levels of oestrogen, which lead to a higher rate of gynaecomastia as well as an increased risk of developing breast cancer. Men with occupational exposures to electromagnetic fields, gasoline fumes, or polyaromatic hydrocarbons have been reported as having a higher risk of developing breast cancer [22, 35].