Breast Disease – Carcinoma, Gynaecomastia – Disorders of the Male Breast

Breast Disease – Carcinoma, Gynaecomastia – Disorders of the Male Breast In Ebonyi State Universtiy Teaching Hospital

Breast Disease – Carcinoma, Gynaecomastia – Disorders of the Male Breast

The male breast is rudimentary and diseases affecting it are uncommon. Before puberty, the breast development is identical in both male and female.

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The breast develops from an ectodermal mammary ridge, which extends on each side from the base of the forelimb to the region of the hind limb.

Some previous studies in some centers in Nigeria and other parts of the world attest to the rarity of male breast diseases. Such studies have documented gynaecomastia and carcinoma as the two dorminant diseases. The incidence of carcinoma is said to be higher in Africans than in Caucasians but much studies needed to be carried out to authenticate such claims to establish the aetiopathogenetic factors responsible.

Although clinical attention and research are rightly focused on carcinoma of the female breast as the most important disease of the breast, it is important to study and establish the patterns of the male breast diseases.Such studies will also serve to elucidate relationship in aetiopathogenesis, clinical behaviour and histopathological patterns between male and female breast diseases. Of recent, several factors appear to be altering the patterns and clinical behaviour of many diseases and this may also be true of the diseases of male breast. These form the basis of the present review undertaken in the Department of pathology of Ebonyi State University teaching hospital, Nigeria.

AIMS AND OBJECTIVES OF THE STUDY

1. To enumerate the various diseases of male breast and their possible causes.

2. To describe the pattern of presentation of male breast diseases.

3. To study the outcome of male breast diseases attending the Ebonyi State University Teaching Hospital (EBSUTH).

 

LITERATURE REVIEW

GYNAECOMASTIA

Gynaecomastia is the development of breast tissue in the male. It needs to be differentiated from pseudogynaecomastia, which is due to excess subcutaneous fat in the obese. Gynaecomastia may be secondary to a well defined extra-mammary stimulus, or primary due to normal physiological changes. Presentation is with a concentric, often tender, subareolar swelling, which has a clear demarcation from the softer surrounding fat. Histology reveals two patterns: florid, which represents the early proliferative phase; and fibrous, representing an involuted phase as seen in senile gynaecomastia. The florid pattern shows a proliferation of the loose periductal connective tissue infiltrated by plasma cells, lymphocytes and mononuclear cells. There is irregular branching ductal development with variable epithelial hyperplasia which may be extreme, forming delicate papillary projections. Lobule formation is rare and only seen after long-term oestrogen therapy or in Klinefelter’s syndrome.

The incidence of primary gynaecomastia varies with age. Neonatal gynaecomastia occurs in a proportion of male neonates due to circulating maternal hormones which had crossed the placenta. It usually resolves by the age of 4 months. Pubertal gynaecomastia is reported in 38% of boys aged between 10 and 16 years, reaching a peak of 65% in 14-year-olds. At puberty, a surge of gonadotrophins induces testicular activity. Oestrogen production by the Leydig cells of the testicle reaches adult levels before that of testosterone. Along with the peripheral aromatization of weak testicular and adrenal androgens to oestrone and oestradiol, this leads to a relatively low androgen to oestrogen ratio, and the development of gynaecomastia. Pubertal gynaecomastia resolves in 73% of boys after 2 years and 92% after 3 years. At least 25% of pubertal gynaecomastia are unilateral, and where bilateral, are normally of different degrees. This suggests a variation in local factors, possibly related to hormone receptors or local hormone conversion. Senile gynaecomastia increases in frequency with age and persists unless a reversible underlying cause (secondary gynaecomastia) is removed. Around 30% of middle-aged men will have variable degrees of gynaecomastia, increasing to 60% by the seventh decade of life.This is due to a progressive fall in testicular function with age, leading to a fall in testosterone levels and the androgen to oestrogen ratio. Increased weight and body fat with age also lead to an increase in the peripheral aromatization of adrenal and testicular androgens to oestrogens. Secondary gynaecomastia is seen in a disparate group of conditions, and can be due to a wide group of drugs, all of which are, however, associated with a relative fall in the circulating androgen to oestrogen ratio. Decreased androgens: Testicular failure due to congenital anorchia, bilateral cryptorchidism, maldescended testes or congenital enzyme defects, or acquired causes such as viral orchitis, granulomatous disease or bilateral torsion or orchidectomy. These lead to a fall in circulating testosterone, causing a rise in gonadotrophins which stimulates the flagging testes toincrease oestrogen production, Peripheral aromatization further increases circulating oestrogens. Forty per cent of patients with Klinefelter’s syndrome develop gynaecomastia. Non-disjunction leads to the chromosome abnormality of a XXY male. An affected male has an eunuchoid habitus, female hair distribution and testicular atrophy. Unusually in these patients, gynaecomastia with histological lobule formation develops and there is an increased risk of male breast cancer. Where androgen receptor function is lost, as in testicular feminization, or where there is a deficiency in 5-alpha-reductase, which is responsible for the conversion of testosterone to its active form, dihydrotestosterone, androgen resistance leads to various degrees of pseudohermaphroditism, including gynaecomastia.

Alcoholism suppresses the pituitary-testicular axis which leads to a reduced production of testosterone when compared to oestrogen, superimposed on which may be the effects of hepatic failure. Increased oestrogens:

(i) Up to 10% of malignant testicular tumours, most commonly tumours which secrete chorionic gonadotrophin (HCG), are associated with gynaecomastia. Gynaecomastia is related to tumour type, being associated with IO-20% of chorionic carcinomas, 4% of embryonal tumours and 1% of seminomas. HCG stimulates the Leydig cells of the testes to produce oestrogen and testosterone.

Testosterone is aromatized by the tumour and peripherally to oestrogens, leading to a relative excess of oestrogen. The rare benign Leydig tumour secretes relatively larger amounts of oestrogen than testosterone and is associated with gynaecomastia in 30% of cases. Testicular tumours producing gynaecomastia may be impalpable, and testicular ultrasound should be considered.

ii. Other tumours may lead to the development of gynaecomastia: hypothalamic and pituitary tumours mediated by HCG via the testes; adrenal tumours by conversion of excess adrenal androgens to oestrogens; hepatic tumours by increased aromatase activity within the tumour; ectopic hormone production, oestrogen, HCG or luteinizing hormone by tumours of the bronchus, stomach, pancreas and liver.

Increased peripheral aromatization

Hepatic failure leads to a reduced clearance of the weak adrenal androgen, androstenedione, which is available for peripheral conversion to oestrogens. Hyperthyroidism is associated with gynaecomastia in up to 40% of affected males, due to increased production of adrenal androgens the peripheral conversion to oestrogens.

Starvation produces an initial suppression of testicular function, followed by recovery with refeeding, leading to gynaecomastia by mechanisms similar those at puberty. Gynaecomastia develops in 30% of males with renal failure who begin dialysis, and usually resolves within a year. Mechanisms are thought to be due to suppression and restimulation of the pituitary-adrenal and testicular axis, similar to starvation and refeeding.

Drugs

Many drugs are associated with the development of gynaecomastia. Some effects may be expected due to the drug action, while other effects are unexpected and unwanted. Effects may be due to the drug or metabolites. ii. Female sex hormones such as stilboestrol, previously used for carcinoma of the prostate, and oestrogens absorbed from hair cream or from vaginal cream from a sexual partner have all been associated with gynaecomastia.

(ii) Testosterone and anabolic steroids used by body builders are associated with gynaecomastia, due to peripheral aromatization to oestrogens. Some body builders have found that the concomitant taking of tamoxifen prevents gynaecomastia. Other drugs with oestrogenic activity include digoxin, marijuana, heroin and clomiphene.

Many drugs have anti-androgenic effects, either by an inhibition of synthesis or blockage of its action. These include cyproterone acetate, cimetidine, ranitidine, penicillamine, diazepam, ketoconazole, spironolactone, phenytoin and medroxyprogesterone acetate. When spironolactone is used to treat hepatic ascites, gynaecomastia is universal.

Chemotherapeutic agents and radiotherapy cause testicular damage, and are often associated with gynaecomastia, especially following orchidectomy for testicular carcinoma. Drugs associated with gynaecomastia where the action is unclear include methyldopa, verapamil, clonidine, captopril, nifedipine, frusemide, amiloride, tricyclic antidepressants, phenothiazines, domperidone, metoclopramide, ibuprofen, theophylline, metronidazole, ethionamide and isoniazid. These actions may be mediated via alterations in hepatic function or gonadotrophin control, and long-term use is often required to produce gynaecomastia. ?* Clinical assessment, particularly with respect to age, underlying ill health and medication, along with examination, will usually differentiate physiological from pathological gynaecomastia and pseudogynaecomastia. (Hands and Greenall, 1991) Examination of the chest, abdomen and testes is also required. Where gynaecomastia is clearly neonatal or pubertal, no investigation is required. A history of recent progressive10 breast enlargement without pain or tenderness and without an easily identifiable cause is an indication for investigation. In the older patient, it is prudent to perform chest radiography and liver function tests. Endocrinological •* assessment is only required where there is suspicion of an abnormality. Testicular ultrasound should be considered where there is no other clear cause, and gynaecomastia develops at ages other than that expected. Exclusion of breast cancer is usually possible on clinical grounds although mammography is useful and has the same sensitivity in men as it does in women. In the older patient, the presence of asymmetry, eccentricity, firmness, fixation or ulceration should raise the suspicion of breast cancer. In this situation, fine needle aspiration is diagnostic. Mammography produces characteristic appearance in gynaecomastia, pseudogynaecomastia and male breast cancer.” Having excluded significant secondary causes and malignancy, the majority of patients are happy with simple reassurance. Secondary gynaecomastia may be improved by treatment of the underlying cause or withdrawal of the offending drug, if this is possible.

Excision of the gynaecomastia is indicated for tenderness and cosmetic reasons. Variable results are reported for the drug treatment of gynaecomastia. Danazol and tamoxifen have both been shown to lead to a reduction in the size of the gynaecomastia, but surgical excision is still required in many patients. Danazol leads to a rapid reduction in tenderness, which is the major symptom in many patients. For minor degrees, subareolar excision of the gynaecomastia using a circumareolar incision providing not all the breast tissue is excised (tissue is left attached to the nipple) and only breast tissue but not the surrounding fat is excised produces an acceptable cosmetic result. Complications include haematoma, reduction in nipple sensation and, rarely, nipple loss. This method produces a poor result in obese patients where liposuction may be useful, particularly in pseudogynaecomastia. For gynaecomastia with skin redundancy, mastoplexy is required, along with repositioning of the nipple on de-epitbelialized pedicles. With the exception of Klinefelter’s syndrome, gynaecomastia is not associated with an increased risk of male breast cancer.

MALE BREAST CANCER

Male breast cancer is in many ways similar to the female disease, and accounts for around 0.7% of all breast cancers and 0.2% of malignant disease in males, in the UK.” Other populations report higher incidences. In Nigeria, male disease accounts for 3% of breast cancers, 16 and increased incidence is also reported in US blacks compared to whites, and also •3HBHHSB£F US Jews.” The mean age at presentation with male breast cancer in the UK is 64 years, a decade later than in the female.15 There is an exponential rise in incidence with age, from 0.1 per 100 000 at age 35 to 9 per 100 000 at age 90, with no mid-life change in slope as seen in women due to the menopause. Unlike in women, there has been no increase in risk over the last 40 years. The left breast is affected more often than the right, and bilateral male breast cancer develops in 1.4%. No consistent endocrine abnormality has been identified, but testicular failure and increased endogenous production of oestrogens have consistently been associated with the development of male breast cancer. No causative link has been identified between gynaecomastia and male breast cancer.

There is, however, a definite association that varies in frequency with the methods used. Clinically coexisting gynaecomastia is reported in around 4-7% of male breast cancer patients, but histologic gynaecomastia is present in 28% of invasive male breast cancer specimens and 60% of ductal carcinoma in situ, with the more proliferative florid form of gynaecomastia being present in half of the in situ cases but only 7% of the invasive cases. Klinefelter’s Syndrome increases risk of male breast cancer by a factor of 20, imparting a 3% lifetime risk. In patients with Klinefelter’s syndrome, a transition from atypical hyperplasia to carcinoma is seen. An increased risk of male breast cancer is seen in males with a family history of female breast cancer. The magnitude of the risk is similar to that of female family members.

Reported lifetime risk for a male with a mother and sister who developed breast cancer is around 2.3% and family associated risk is more important where young men develop breast cancer. Female relatives of men with breast cancer also have an increased risk, the degree of which is greater where the men developed the disease before the age of 55 years. The BRCA2 gene mutation seems to increase the risk in both male and female family members, whereas no such association seems to exist in males of families possessing the BRCA1 mutation. Ionizing radiation, occupational factors and electromagnetic fields have also been implicated in increasing risk. Presentation is with a painless mass in 90% of cases, nipple change occurs in 20% with inversion, fixation, encrustation, oedema and ulceration. Nipple discharge occurs in 14% and is often blood-stained, unlike benign tumours of the male breast, where a serous discharge is reported in 2%. Examination reveals a firm, often eccentric, mass adjacent to the nipple-areolar complex; adherences to the underlying pectoralis fascia and nipple changes are also common. Palpable axillary lymphadenopathy may be present and is reported in the absence of an overt breast primary.

Fine needle aspiration cytology or core cut biopsies are the mainstays of diagnosis. Mammography produces characteristic appearances and ultrasound may be of use. The treatment of male breast cancer is multidisciplinary, combining surgery and radiotherapy to obtain local control.

Adjuvant endocrine or chemotherapy is used with an aim of improving survival. Over the last 40 years, radical mastectomy has given way to modified radical mastectomy combined with radiotherapy to the chest wall, which reduces local recurrence but has not been shown to improve the survival rate. Wide local excision of male breast carcinoma is rarely appropriate because of the central position of the tumour in relation to the nipple and the close proximity of the skin and pectoralis major. The axilla should be cleared surgically to control the disease locally and for staging.

All histological types are seen, including Paget’s disease, although invasive lobular carcinomas are less common. Hormone receptors are more common, oestrogen receptors being expressed in 87% and progesterone receptors in 69% of male breast cancers. Adjuvant systemic therapy should be considered despite the lack of prospective controlled trials. Both tamoxifen and poly-chemotherapy seem to improve survival, but with chemotherapy reserved for those who have ER-ve tumours and who are at high risk of systemic relapse.

In locally advanced or metastatic male breast cancer, tamoxifen produces a response in 48%, and in up to 71% of oestrogen receptor-positive tumours. Due to its lack of side-effects, tamoxifen is the treatment of choice, as polychemotherapy seems to be no more effective, producing response rates of 44%. Radiotherapy has a role in local Control and also in palliation of bone metastasis, with Prophylatfic fixation of long bones or decompression for spinal cord compression. The most important prognostic factor is axillary node involvement, with reported 5-year survival rates of 78- 94% for node-negative patients and 38-59% for non-depositive patients. Tumour grade and size and lymphatic and vascular invasion are also important. Overall 5-year survival rates are reported to be 58-100% for stage I disease, 38-77% for stage II, 29-47% stage III and 4% for stage IV, which are not dissimilar to those for breast cancer.

OTHER MALE BREAST DISEASES

All forms of breast disease found in women have been reported in the male, whether or not they are associated with gynaecomastia. Conditions originating from the lobule are extremely rare.

Fibrocystic change

Gynaecomastia has specific histological appearances, with lobule formation being uncommon. Cystic hyperplasia histologically identical to that seen in the female, with background fibrosis, apocrine cystic change, duct ectasia, epithelial-hyperplasia and intra-ductal papillary hyperplasia is rarely seen in gynaecomastia specimens. Cystic change is generally considered an involutional disorder of the breast, but it occasionally occurs in young women who have never been pregnant. Similar mechanisms may be involved in the male.

All grades of epithelial hyperplasia, including atypical ductal hyperplasia are seen associated with gynaecomastia, and may lead to a difficulty in cytological assessment. Intraduct papilloma presenting with serous or bloody nipple discharge and subareolar mass may be diagnosed by galactography.

However, management as in the female, with cytological assessment, mammography or ultrasound, is most appropriate. Sclerosis adenosis is considered to be an aberration of lobular involution and has been described in association with pulmonary oat cell carcinoma, presumably related to ectopic hormone production.

Fibroadenoma and phyllodes tumour

In the female, fibroadenoma is considered to be an overdevelopment of the breast lobule. In the male, fibroadenoma has been reported in specimens of excised idiopathic gynaecomastia. Lobule formation was not seen despite extensive sampling. Phyllodes tumour has been reported in gynaecomastia secondary to prolonged oestrogen therapy for prostatic. Carcinoma, which may lead to lobule formation.

Duct ectasia _and Periductal mastitis

As in the female, there is a blurring between the conditions of duct ectasia and periductal mastitis. Duct ectasia is reported as an incidental finding. Nipple retraction, discharge and tender subareolar mass, with periareolar inflammation, complicated by periareolar abscess and marnmillary fistula formation all related, to periductal mastitis have all been reported.

Treatment: Involves incision and fistula excision and closure under antibiotic cover.

BREAST INFECTIONS

Neonatal mastitis and abscesses occur with equal frequency in both sexes in the first 2 weeks of life; beyond this they become less common in boys. Neonatal mastitis is treated with antibiotics where abscess formation occurs; incision and drainage is required; the incision should be placed as peripherally as possible to reduce the risk of damage to the breast bud. The most common causative organism is Staphylococcus aureus, although salmonella and Escherichia coli may also be cultured. Galactocele has also been reported in infants, presumably due to the development of witches’ milk and factors similar to those that cause the condition in the mother. Mondor’s disease of the male breast associated with a Staphylococcus aureus breast abscess has been reported as a palpable inflamed cord running from the areola. This is due to superficial thrombophlebitis and in this case was excised at the time of abscess drainage, but it could ^have been treated conservatively, as in the other non-specific infections of the male breast include tuberculosis, which may be difficult to differentiate from breast cancer (Hamit and Ragsdale, 1982). Periareolar breast abscess due to Pseudomonas aeruginosa, complicated by mammillary fistula and human papilloma virus-associated nipple lesions have been reported in men with acquired immunodeficiency syndrome.

MASTALGIA

In gynaecomastia, pain is common and often the most troublesome symptom. It is well treated with danazol.

Chest wall pain is as common as in the female, but does not present to breast surgeons. Tietze’s syndrome, costochondritis, and painful rib syndrome are reported.

MATERIALS AND METHODS

SAMPLE COLLECTION

Clinical records of all patients that presented with breast diseases between 1996 – 2003 obtained from the histopathology laboratory of the morbid Anatomy Department of Ebonyi State University Teaching Hospital, were obtained (after clearing due ethical requirement) and analyzed. Statistical analysis using age groups, frequency distributions was carried out on the data obtained.

A pair of serial sections of 5m thick was made from each of the pairs of the paraffin embedded tissue blocks.

SECTIONING

The disuse blocks were fixed in the clamp of Rotary microtome after being placed on ice blocks to prevent fibril sections. The microtome knife was inserted and secured firmly with tightening screws. The microtome gauge was set at 5m thickness. The cutting of the blocks was made with regular even strokes to produce sections.

The sections made were transferred to 50% alcohol solution to prevent on warm water at 45%c to spread these sections. A clean frosted-end slide was used to pick the sections from the water bath. The slides were then drained dry and placed on a hot air oven to enhance adhesion of sections to the slide and melting off the wax before staining.

STAINING

The sections were stained using the Haematoxylin and Eosin (H & E) staining technique. Haematoxylin is used as a routine in conjunction with eosin for the demonstration of the general structure of the tissue. The procedure for H & E staining technique is described in the Appendix.

 

RESULTS

HISTOLOGICAL TYPES OF DISEASES OF MALE BREAST

TYPE NUMBER OF CASES

Gynaecomastia 5 %

Carcinoma

Infiltrating ductal

Invasive ductal

Adenocarcinoma

Mucinous Carcinoma

The total biopsies reviewed from the patients’ result forms between 1996 and 2003 is 2053. Out of this total biopsies 914 cases were diseases of the breast. And out of 914 cases of breast diseases, 21 cases were found to be males and 893 cases found to be females.

 

DISCUSSION

Diseases of the male breast are uncommon and many review have reported Gynacomastia and carcinoma as the leading diseases constituted 71% in my study while Fibrocystic disease, Mastitis and Lymphadenitis made up the remaining. Mastitis and lymphadenitis were very rare and one case of each of them was reported in Ebonyi State Teaching Hospital. And four cases of fibrocystic diseases reported.

Carcinoma was the commonest disease and accounted for over 48% of cases. No pubertal and adolescence case reported but occurred within an age range of 40 to 89 years.

Gynaecomastia reported 24% of the cases. It occurred between the age range of 10-89 years. All these studies agree on the puberteal and post-pubertal occurrence of gynaecomastia as also attested to by Black.

However, these studies reveal a gradual rise in the age incidence of gynaecomastia with the present study revealing a starting mean age of 30 years. Earlier studies have documented that development of gynaecomastia may be due to hyperoestrinism, a decrease in adrogenic activity or both. Before the age of 25 years, it is usually related to hormonal pubertal changes where as in later years it may be caused by hormonally active tumors, cirrhosis or medication. Such occurrence in older age groups is presumably owing to a relative increase in adrenal oestrogens as the androgenic function of the testis diminishes. It has been said that gynaecomastia may also occur in chronic marijuana smokers and heroin addicts.

These drugs are profoundly abused and many youths are addicted to them. Such abuse and addiction constitute major public health problems to many nations and governments at present. This may explain, in part why gynaecomastia is common now than before and also why age incidence is rising. The incidence of gynaecomastia is higher in Africans than in Caucasians and also common feature of chronic liver disease in Africans. Countries in which the incidence of gynaecomastia and carcinoma of the male breast is high.

The 48% carcinoma cases of the male breast found in EBSUTH is high compared to 1.9% reported in ile-ife by Adeniji and 3.4% reported in Ibadan by Aghadiuno (Aghadiuno, 1987). This increase may not be unconnected with the rising incidence of gynaecomastia as microscopic changes consistent with gynaecomastia have been found in 40% of breast carcinoma. It is important to note that higher incidence of carcinoma of the male breast have reported in other parts of Africa. In Calabar, Nigeria Otu reported a male: female ratio of 1:7 while Templeton in Uganda reported an incidence of 12%. However in Caucasians Roswit found a male: female ratio of 1:100 while Sasco in united State of America found that 1% of breast cancers occur in males. The high incidence of cirrhosis of the liver and hepatocellular Carcinoma in Africans with elevated levels may be responsible for the higher incidence of gynaecomastia and Carcinoma of the male breast. This is the reverse pattern found in females where in incidence of Carcinoma of the breast is higher in Caucasians compared to Africans. The mean age of Carcinoma of the male breast in Ebonyi was 64.5 years with range of 40 to 89 years.

Infiltrating lobular Carcinoma arises from terminal ductules of the breast and has higher incidence of bilaterality and multicentricity compared to those arising from the ducts. It is quite an uncommon Carcinoma in males and none was found in my study.

Invasive ductal Carcinoma occurred moderately, three cases of it was found in my study.

CONCLUSION

This article concludes that the case of carcinoma in males in Ebonyi State University Teaching Hospital is higher compared to the cases of gynaeconmastia in males and other male breast diseases.

Note that Carcinoma occurred mostly in male adults between 60 – 89 years age range and was predominant in males within 60 to 69 years age group.

 

RECOMMENDATION

Based on the observations made during this study, males between the age unit of 60-89 should endeavour to screen for breast cancer early enough for proper treatment.

Breast Disease – Carcinoma, Gynaecomastia – Disorders of the Male Breast

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