The normal and abnormal breast

The normal course of breast development 

Breast development begins in the embryo at about 6 weeks, when precursors of the mammary glands are formed in ectodermal ridges of the ventral surface of the embryo. The multiple pairs of buds normally disappear during the third month except for two breast buds in the pectoral region that eventually develop into the mammary glands.

At birth, the human breast is undeveloped and identical in males and females. The mammary gland in many respects is an embryonic organ because it undergoes its major differentiation after birth.

Palpable breast tissue in newborn infants is considered to be physiologic and related mainly to exposure to maternal hormones in utero or through breast-feeding.1 It is significantly more frequent and pronounced in girls than in boys, which may indicate that the breast tissue is sensitive to sex steroids. Other factors like nutrition or external hormones may also affect the size of postnatal breast tissue.2, 3

There is a gender difference in serum estradiol levels, breast tissue sensitivity to sex steroids, and breast size. The histology of breast tissue in children under 2 years of age is similar to that of the puerperal gland of the adult female, and at 2 years of age the adult pattern of human breast and estrogen receptor is already established.4

Sex hormone levels in early life may influence the development of breast pathology. For example, females exposed to elevated levels of maternal serum estradiol during fetal life have an increased risk of developing breast cancer in adulthood.5 On the other hand, maternal preeclampsia, characterized by low estrogen levels, has a protective effect against breast cancer in adulthood.6

During puberty, which begins at the age of 10–12 years, the pituitary gland releases follicle-stimulating hormone (FSH) and luteinizing hormone (LH), resulting in the maturation of ovary follicles, which secrete estrogens. These hormones induce the growth and maturation of the breast and genital organs. Estrogen promotes the growth of ductal epithelium in the breast. Terminal ductals also form buds that precede further breast lobules. The role of progesterone in the developing gland is not clear, but it is understood that both estrogen and progesterone are necessary for full development of a ductal, lobular, alveolar mammary tissue.7

The adult breast 

The breast consists of three major structures: skin, subcutaneous tissue, and breast tissue comprising both parenchyma and stroma. The parenchyma is divided into 15–20 segments that converge at the nipple, where 5–10 collecting milk ducts drain each segment. The ducts themselves are subdivided into lobes, lobules, and alveoli. The secretory epithelium in the alveoli synthesizes the milk. Subcutaneous breast tissue contains fat, connective tissue, blood vessels, nerves, and lymphatics. The skin of the breast is thin and contains hair follicles, sebaceous glands, and eccrine sweat glands.

The nipple has abundant sensory nerve endings including Ruffini-like bodies and end bulbs of Krause. There are also sebaceous and apocrine sweat glands but not hair follicles. The areola is circular and pigmented, measuring 15–60 mm in diameter. At the periphery there are Morgagni's tubercles formed by openings of the Montgomery's glands, which are sebaceous glands capable of secreting milk.8

Breast changes during pregnancy 

During pregnancy, marked ductal, lobular, and alveolar growth occurs as the result of the influence of the luteal and placental sex steroids. In the first 3–4 weeks of pregnancy, marked ductal sprouting occurs under estrogen influence. At 5–8 weeks, breast enlargement is significant with dilatation of the superficial veins and increasing pigmentation of the nipple-areolar complex.

In the second trimester, progesterone stimulates lobular formation. From the second half of pregnancy, increasing breast size is due to increasing dilatation of the alveoli with colostrum, as well as hypertrophy of myoepithelial cells, connective tissue, and fat.9, 10

Breast changes during lactation 

After parturition, immediate withdrawal of placental lactogens and sex hormones occurs. Prolactin in the presence of growth hormone, insulin, and cortisol converts the mammary epithelial cells from a presecretory to a secretory state. The initial secretion is of colostrum, a thin, serous, sticky, yellow fluid that contains lactoglobulin, decadienoic acid, phospholipids, fat-soluble vitamins, and lactoalbumin. After colostrum secretions, transitional milk and then mature milk appears.9, 10

Breast changes during menopause 

Decline in ovarian function leads to regression of epithelial structures and stroma. The duct system remains, but the lobules shrink and collapse.

Abnormal breast development 

The most frequently observed abnormality in both sexes is an accessory nipple (polythelia). It may appear at any point along the milk streak, from the axilla to the groin. True mammary glands rarely develop from accessory nipples, most often located in the axilla, though during pregnancy they may function. Complete lack of development of the breast is called amastia, and when only a nipple is present it is called amazia.

Acquired abnormalities of the breast, such as amastia, are mostly iatrogenic, due to biopsies or radiation therapy. Traumatic injuries or burns can cause contraction and deformity.7

Gynecomastia 

Gynecomastia is male breast enlargement, unilateral or bilateral. It can be due to hormonal imbalance or secondary causes such as liver failure or drugs (e.g., cimetidine, or HIV protease inhibitors). In male pubertal gynecomastia, there is an abnormal ratio between androstenedione and estrone or estradiol. Gynecomastia has been successfully treated with antiestrogens, as evidence of involvement of estrogens in the pathology.11

Breast cancer 

The clinical manifestations of breast cancer are similar in men and women. It is characterized by inverted nipple and peau d'orange, and to a lesser degree by dilated subcutaneous veins, red skin, erosions, ulcers, and nodules.

Breast cancer in males is a rare condition, affecting only 1,000 men each year in the United States. Only 1% of breast cancers occur in men. The male/female ratio is higher in the black than in the white population. Hormonal, genetic, and environmental factors appear to be important in the development of the disease. Tumors in men are more likely to be estrogen-receptor positive.12

Histologically, breast carcinomas of both sexes are indistinguishable, but histologic types of ductal origin occur relatively more frequently in men than in women, whereas those of lobular origin are uncommon in men, reflecting the absence of lobular structures.

The risk of breast cancer in men increases with age and is associated with testicular pathology. High fertility is associated with a decreased risk of breast cancer, as is a history of prostate cancer and exogenous androgens. Hyperestrogenism and related conditions (rapid weight gain, gallbladder stones, diabetes, Klinefelter syndrome, chronic liver diseases) increase the risk of breast cancer. In women, the risk of breast cancer increases over time and becomes pronounced after menopause.

History of breast cancer in first-degree relatives doubles the risk of breast cancer in both men and women. From mammography readings, male breast cancer is usually subcapsular and eccentric to the nipple. Margins of the lesions are well-defined and calcifications are rarer and coarser than those occurring in female breast cancer.

Several immunohistochemical studies have been done in search of differences in the pathogenesis of breast cancer. In a comparative analysis of carcinoma matched for stage in men and women, male carcinoma was more frequently estrogen receptor-positive, less likely to overexpress proteins p53 and Erb-B2, and not different from women in either progesterone receptor or the Bcl2 gene.13 The c-kit gene codes for the transmembrane tyrosine kinase receptor protein playing a role in normal and neoplastic tissue.14 It seems that c-kit is lost in the malignant transformation of females but not in that of males, suggesting a different pathway of oncogenesis in males and females.

Treatment of breast cancer includes lumpectomy, mastectomy (Figure 1), radiation therapy (Figure 2), chemotherapy, and hormone therapy.(Continued on page 34)

View Large Image Download to PowerPoint

Figure 1. Woman following total mastectomy.

View Large Image Download to PowerPoint

Figure 2. Radiation dermatitis following radiotherapy of the left breast.

Paget disease of the breast 

Of all breast carcinomas, 0.5–4.3% are characterized by unilateral eczematous changes mimicking nipple dermatitis.15 The pathologic mechanism involves the production of Paget cells, which are large, atypical cells distributed throughout the epidermis. The exact type of cell is unknown, but is believed to originate from sweat ducts. Histologic findings reveal large pale cells with vesicular nuclear chromatin invading the nipple epithelium.

Immunohistochemical studies consistently show that the majority of Paget cells in mammary disease and extramammary variants are negative for estrogen or progesterone receptors.16 Interestingly, the same studies demonstrate strong androgen receptor activity in more than 10% of Paget cells and the invasive carcinoma arising from it, suggesting a possibly pathogenic role and a therapeutic option, both depending on the androgen receptor status.

Androgens are believed to be strong promoters of carcinogenesis via a multifactorial complex mechanism in various malignancies.17 Paget mammary carcinoma might well be one of them, as in vitro data show growth stimulation of mammary cell lines by androgens.18

Breast infections 

Breast infection affects women between 18–50 years of age. It can be considered non-lactational or lactational. Infection can also affect the skin overlying the breast and occurs either as a primary event or secondary to a lesion within the skin such as sebaceous cyst or hydradenitis suppurativa.

Non-lactational infection occurs centrally in the periareolar region or in the peripheral breast tissue. Lactational infection is usually caused by staphylococci and may also be due to streptococci. The patient with lactational infection generally has a history of cracked nipple or a skin abrasion. Infection most commonly occurs after six weeks of breast-feeding or during weaning. Typical symptoms are pain, erythema, swelling, tenderness, or systemic signs of infection.

Pyoderma gangrenosum 

A non-infective breast disorder, pyoderma gangrenosum is a destructive ulceration of the skin. The etiology is unknown but is believed to be cause by an altered immune system. Approximately 50% of cases are idiopathic and the rest associated with systemic illness such as inflammatory bowl disease, arthritis, collagen diseases, biliary cirrhosis, and hematopoietic neoplasm, e.g., leukemia. Though rare, cases of pyoderma gangrenosum have been reported following breast biopsy and plastic surgery.19, 20, 21 Treatment includes topical wound care and systemic treatment with steroids and cyclosporine.

Nipple dermatitis 

Eczema of the nipple and areola is generally bilateral and symmetric, uncommonly appearing on one side.22 Most of the time the underlying cause remains obscure. Pruritus, the dominant symptom, may be paroxysmal or continuous and may be severe at night. Patients frequently have a personal or family history of atopic dermatitis.

Contact dermatitis often arises from the application of perfumes to the breast or from rubber- or nickel-containing brassiere cup wires.23 Topical medication for inflamed or sore nipples can cause allergic contact dermatitis.

Seborrheic dermatitis manifests as unilateral, oily, scaly erythematous patches. Treatment with mild topical steroids results in prompt temporary resolution.

Frictional irritation, for example jogger's nipple, results from an unprotected moist nipple rubbing against poorly fitting clothing.

Dermatitis artefacta is chronic and recurrent (Figure 3).24 It takes time before the diagnosis is confirmed by bizarre-shaped lesions that lead to scars. Patient reaction may be extreme, alerting the clinician to the nature of the disease. Though psychotherapy has been recommended, it has not always had the desired results.

View Large Image Download to PowerPoint

Figure 3. Dermatitis artefacta, a chronic and recurrent condition in which bizarre-shaped lesions lead to scars.

Fungal infections (tinea corporis or tinea versicolor) may present as solitary erythematous scaly patches on the nipple and areola, with or without lesions elsewhere on the body.

Hyperkeratosis of the nipple and areola is a rare benign condition of unknown etiology. It presents as a thickening and hyperpigmentation. Unilateral involvement is associated with the presence of epidermal nevi or ichthyosis elsewhere.

All of the preceding conditions are epidermal lesions. The differential diagnosis of nipple and areola disorders should also include two subepidermal unilateral conditions. One is Paget's disease, described earlier. The other is erosive papillomatosis, a condition that is rare, idiopathic, and benign. It may present with scaling, erythema, and induration, with later ulceration, discharge, and crusting. Symptoms include pruritus, burning, and pain.

Nipple piercing 

Nipple piercing, commonly done today, may damage one or more milk ducts, depending on the size and orientation of the cutting edge of the needle. Most nipple jewelry is made of niobium, platinum, nickel-free gold, titanium, and other inert metals in order to avoid allergic reaction. When the jewelry is removed, the holes normally shrink and close after a few weeks, and usually during lactation. Healing takes six months to a year.

Complications of nipple piercing include infection with hepatitis B or C, tuberculosis, syphilis, HIV, verruca vulgaris, mastitis, breast abscess, and endocarditis. A foreign metal body in breast tissue can cause granuloma.25, 26, 27

Micropigmentation 

Micropigmentation (nipple tattooing) is the enhancement of the skin or repigmentation of hypopigmented lesions after scarring or after surgical removal of the areola. Micropigmentation has been used with some success in nipple areola reconstruction, the final stage of breast reconstruction. It produces a three-dimensional effect of a projecting nipple and at the same time resolves the embarrassment of persistent nipple projection problems encountered in conventional reconstruction procedures.

Side effects include: