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Gynaecomastia and Male Breast Cancer (Review)

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Gynaecomastia and Male Breast Cancer (Review) MOLECULAR MEDICINE REPORTS 3: 21-26, 2010 21 Conditions of the male breast: Gynaecomastia and male breast cancer (Review) LAILA ALALI1, HELEN HONARPISHEH2, ABEER SHAABAN3 and VALERIE SPEIRS1,2 1Leeds Medical School, 2Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS2 9JT; 3St James's Institute of Oncology, St James's University Hospital, Leeds LS9 7TF, UK Received March 27, 2009; Accepted July 6, 2009 DOI: 10.3892/mmr_00000213 Abstract. Breast disease most commonly affects females; 2. Diagnosis and pathology however, a small percentage of men are also affected. Understandably given its low incidence, awareness of male Male breast cancer. Breast cancer in men may be uncommon, breast disease is low, particularly among the general population. but it does occur (3). Male breast cancer (MBC) is responsible We searched the Medline database from 1950 onwards using for less than 1% of all breast cancers, though there is some the search terms male, breast, neoplasms and gynaecomastia, variation in the literature as to the exact figure (3-5). This is and reviewed the conditions associated with male breast dis- in contrast to female breast cancer (FBC), which is the most ease, examining some of the risk factors and discussing how common female cancer worldwide. According to figures from these conditions are diagnosed and treated, and finally putting Cancer Research UK, approximately 300 men are diagnosed forward some suggestions for their future management. with MBC in the UK per year (6). This small number of cases has has made it impossible to set up randomised prospective international trials to determine the most effective way of Contents managing MBC, and it is currently approached in the same way as FBC (7,8). 1. Introduction The incidence of MBC is rising, as reported in an age- 2. Diagnosis and pathology corrected study conducted in the US, where increases of up to 3. Risk factors 26% were been noted between 1973 and 1998 (5). Unpublished 4. Treatment data obtained from UK Cancer Registries suggest that the 5. Conclusions incidence in the UK is also increasing; this is reflected in figures obtained from Cancer Research UK (Fig. 1). There is, moreover, little evidence to suggest a positive change in 1. Introduction the male mortality rate, while in females the mortality rate is decreasing. This may be due to the lack of a thorough under- Breast disease most commonly affects females; however, standing of MBC (9). a small percentage of men are also affected. Awareness of In the majority (75%) of cases, MBC patients present to male breast disease, particularly among the general public, their GP with a painless lump in the subareolar region of the is low. Men do, however, possess a small amount of breast breast, eccentric to the nipple (3,4,7,8). In some instances, tissue, which makes them susceptible to breast disease, in patients may present with other symptoms, such as pain and particular male breast cancer (MBC) and the benign condition nipple involvement. Pain is uncommon, occurring in only 5% gynaecomastia (1,2). This review highlights some of the risk of cases (1,4). Changes in the nipple can include nipple retrac- factors associated with the two conditions, and describes their tion, nipple discharge, and even ulceration (4). Although rare diagnosis and treatment. and occurring in only 1% of MBC cases, it is crucial to consider Paget's disease when relying on clinical features for diagnosis. Paget's disease is a type of breast cancer which originates in the ducts of the breast but spreads to the nipple, causing changes to the nipple skin. Its presentation is often similar to Correspondence to: Dr Valerie Speirs, Leeds Institute of Molecular that of other skin conditions, such as eczema; reddening of the Medicine, Wellcome Trust Brenner Building, St James's University skin and itchiness is often observed, and bleeding and crusting Hospital, Leeds LS9 7TF, UK is common (1,4). E-mail: [email protected] The most frequently occurring type of MBC in terms of histology is invasive ductal carcinoma of no special type, Key words: male breast cancer, gynaecomastia, males which accounts for 90% of MBCs (4,10). Papillary carcinoma is the second most common type, with a 2-fold increased incidence in males compared to females (11). Most histopathological 22 ALALI et al: MALE BREAst DISEASE cancer (2,8,18,20). Gynaecomastia is more common than breast cancer in the male population, with an estimated 40-65% of healthy males affected by the disease (18,20). Variations in numbers may be due to the interchangeable use of clinical and histological definitions, and due to controversy over what actu- ally qualifies as clinical gynaecomastia. For example, Cakan and Kamat defined gynaecomastia as breast glandular tissue enlarged by ≥0.5 cm in diameter (19), while Daniels and Layer required patients to have breast tissue enlarged by ≥2 cm in diameter for a diagnosis of gynaecomastia to be made (22). 3. Risk factors Figure 1. Age-standardised breast cancer incidence rates for the UK showing Male breast cancer. The rarity of MBC makes it difficult to a gradual rise in incidence over the last ten years. determine the true causes of the disease; few studies have had a sufficiently large sample size to ensure significant findings (9). Fortunately, researchers can use information gathered from studies on FBC to design their studies and to determine subtypes of breast cancer observed in females have also been whether the results are the same for MBC. There are many fac- reported in males; however, most men do not have well-developed tors potentially linked to MBC (Table I), but these relationships lobules, making lobular carcinoma exceedingly rare (3,4,10). need further investigation for significance to be determined. Ductal carcinoma in situ, often of a low grade, has been A positive family history of breast cancer is found in reported in 5-15% of cases (12). Hormone receptor expression approximately 20% of MBC patients, and increases the risk is extremely common in MBC, with figures of up to 90% by as much as 3-fold (9,10,23). There are certain genetic muta- reported, compared to only 60-70% in FBC (3,13). Previous tions that show a clear association with MBC, and others that studies report that the rate of HER2 in MBC is similar to that are in the early stages of investigation. Breast cancer in men found in FBC (14,15). However, due to the improved stan- is common in families that carry the BRCA2 mutation. Most dardisation of HER2 testing, recent data indicate that HER2 inherited MBCs are thought to be associated with a mutation amplification is infrequent in male breast tumours, accounting in the BRCA2 gene, which is reported to increase the risk for only 5% of cases (16,17). of MBC by 80- to 100-fold compared with the general male population (24). This gene is located on chromosome 13q12-13 Gynaecomastia. Gynaecomastia is a condition involving and is thought to be involved in DNA repair, as it is respon- benign proliferation of the glandular tissue in the male breast, sible for the regulation of the activity of the DNA repair gene resulting in non-cancerous breast enlargement (2,18). It is often RAD51 (9,10,23,25). Despite this strong link, the percentage associated with life stages characterised by significant hormonal of individuals with a BRCA2 mutation varies significantly imbalances, e.g., the neonatal period, puberty and old age (18). among different populations. A study on Icelandic men found Neonates are at risk of gynaecomastia since they are exposed the BRCA2 mutation in 40% of male cancer patients, whereas to high levels of estrogen from the mother's placenta. This type a study in California discovered the mutation in only 4% of of gynaecomastia is known as transient, and is estimated to be patients. These figures could be influenced by small sample present in 60-90% of neonates (18-20). Pubertal gynaecomastia size, or could be indicative of genetic differences in individuals affects 48-64% of boys. The cause is not fully understood, but of different ethnic backgrounds (9,10,23). is presumed to be due to an imbalance in estrogen and androgen. Cowden syndrome is an autosomal dominant condition Gynaecomastia in late life is typically observed in men over caused by a germline mutation in the PTEN gene that makes 50 years of age. Traces of gynaecomastia reported in as many individuals susceptible to benign or malignant neoplasms. As as 55% of autopsies suggest that it often goes undiagnosed PTEN is a tumour suppressor gene, any mutations of this gene (18-20). prevent the suppression of tumours growing in the breast. It The above-mentioned types of gynaecomastia associated has been suggested that PTEN only plays a role in cancer in with hormone imbalances are examples of true gynaecomastia. individuals affected by Cowden syndrome (2,23,25). Another class of gynaecomastia is pseudo-gynaecomastia. CHEK2 is another gene that is potentially associated Physical examination is required to differentiate between the with MBC. It is a cell-cycle checkpoint kinase and, like two types (21). Pseudo-gynaecomastia is a condition where BRCA2, has a role in DNA repair. It has been proposed that the male breast is enlarged due to the deposition of adipose CHEK2*1100delC, a variant identified by a CHEK2 Breast tissue, and is often associated with obesity (2,21). In contrast, Cancer Consortium study, is responsible for up to 9% of MBCs true gynaecomastia is an increase in the hyperplasia of the and increases the risk of MBC by approximately 10-fold. breast tissue. It often presents as a firm rubbery mass of tissue However, other related studies that looked for the mutation in the subareolar area.
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