STRUCTURE AND FUNCTIONS

Mammogenesis—the growth and differentiation of the mammary gland—begins early in embryogenesis. By the sixth week of embryonic development, the primitive milk streak can be identified as an ectodermal thickening along the ventrolateral aspect on each side of the embryo. This milk streak regresses in the ensuing weeks, normally leaving only one pair of mammary glands in the thoracic region; however, multiple nipples and breast tissue may occasionally develop anywhere along the milk line, extending from the armpit to the groin.

During the second trimester, projections of the ectoderm from the primary sprouts—usually between fifteen and twenty—will eventually elongate and arborize (branch out) to form the lactiferous ducts. Canalization of the ducts occurs late in fetal life and requires placental hormones for stimulation. Once the ducts canalize, two layers of epithelial cells are identified: the inner layer of cells, which forms the secretory component, and the outer layer of cells, which forms the myoepithelium, constituting the contractile elements for the expulsion of milk.

Between approximately four and seven days after birth, 80 to 90 percent of newborns have breast secretions (so-called witches’ milk). Such secretions have been noted with equal frequency in male and female infants, and they usually last for three or four weeks. After the first neonatal month, the breast tissue reverts to an undifferentiated state and remains quiescent until puberty. Minimal ductal growth occurs during childhood, and there is no lobuloalveolar development.

At puberty, the surge of female hormones initiates lactiferous duct proliferation and the deposition of fat and connective tissue. These changes produce a rapid increase in the size and density of the breast. They are coordinated by the action of multiple hormones (prolactin, cortisol, growth hormone, insulin, and thyroxin) and estrogen and progesterone. Estrogen encourages ductal proliferation and maturation, while progesterone stimulates lobuloalveolar growth. Ovarian steroids appear necessary for mammary development, as breast enlargement fails to occur at puberty in girls with gonadal dysgenesis. By the time of breast enlargement, the areola becomes more pigmented, and the nipple enlarges.

In adult women, the size, density, and nodularity of the breast are dependent on the build of the individual because much of the breast tissue consists of fat. During the menstrual cycle, the breasts undergo a cyclic change. The rising estrogen and progesterone levels cause an increase in blood flow and interlobular edema. The engorgement, increased density, and nodularity are particularly noticeable late in the menstrual cycle. In the week preceding menstruation, hormonal changes can bring about breast discomfort, tenderness, and a sensation of fullness. This increased sensitivity, often accompanied by marked nodularity, makes the clinical breast examination difficult. Therefore, it is important to examine the breasts seven to ten days after menstruation. Only during this time can tumors be differentiated from physiological nodularity. The breast decreases in size at menses due to a reduction in the number and size of glandular cells with loss of edema.

During pregnancy, the breast undergoes final maturation in preparation for lactation. The breast begins to enlarge in the early weeks, and marked histological changes occur. There is concurrent enlargement, pigmentation, and increased vascularity of the nipple. The earliest histological change within the acinar epithelial cells is cytoplasmic vacuolation. Lymphocytes, plasma cells, and eosinophils collect in the interstitial spaces. During the second trimester, the lobules enlarge. There is an increase in the number and size of the constituent acini. The mammary blood supply is enhanced by increasing vascular luminal diameters and by the formation of new capillaries around the lobules. During the last trimester, the secretory cells fill with fat droplets. The alveoli are distended with a proteinaceous secretion termed colostrum.

Within three to four days postpartum, estrogen and progesterone levels rapidly decline. Prolactin can now, unrepressed by estrogen and progesterone, activate lactation, which is maintained by the infant’s suckling. This stimulates the further release of prolactin and oxytocin, which activate the myoepithelial cells, leading to the expulsion of the alveolar secretion. During the first few days of lactation, only colostrum is produced. Once the colostrum has been expelled, the normal production of milk ensues. Prolactin sustains milk production. Each nursing episode makes prolactin increase fivefold to tenfold. Still, as weeks go by, prolactin levels gradually return to normal until even the nursing-induced rise is negligible. For unknown reasons, however, successful lactation can be maintained for months.

Changes of involution occur in the breast with increasing age and after lactation. The glandular tissue disappears between thirty-five and forty-five, and alveoli and lobules shrink. These changes are not uniform throughout the breast; some lobules remain prominent, while others become more atrophic. During menopause, the breasts decrease in size and become less dense. There is an increase in the elastic tissue component of the breast.

Anatomically, the extent of the normal female breast is approximately from the second to the sixth rib. The medial border touches the sternum, and the lateral border extends to the mid-portion of the armpit (axilla). The majority of the glandular tissue is in the upper outer quadrant and often extends deep into the axilla. The most important factor controlling breast size, shape, and density variation is obesity. The mammary gland is enclosed between the superficial and deep layers of the superficial fascia. The superficial layer is a thin and delicate structure that is thicker at the inferior portion of the breast and becomes thinner as it approaches the clavicle. The deeper layer splits off the superficial fascia and extends deep into the mammary gland. Between this deep layer and the pectoral fascia, a well-defined, retromammary space contains loose tissue, allowing the breast to glide freely over the chest wall. Portions of the deep layer of the superficial fascia form connective tissue extensions that pass through the retromammary space and join with the pectoral fascia. These extensions help support the breast. The breast is firmly fixed to the skin in the area of the nipple, and the remainder of the lobules are attached to the skin by dense fibrous bands termed Cooper’s ligaments. Involvement of these ligaments with cancer gives rise to the physical sign of skin dimpling.

The breast is composed of glandular tissue, blood vessels, nerves, lymphatics, and varying amounts of fat. The glandular tissue comprises between fifteen and twenty lactiferous ducts radially arranged around the nipple, each separated by fibrous septa. The terminal portion of the lactiferous duct dilates, forming the lactiferous sinus before it empties into the nipple. The functional unit of the breast is the terminal duct lobular unit, which consists of between ten and one hundred alveoli with the intralobular terminal duct and extralobular terminal duct. The arteries supplying the breast are derived from the thoracic branches of the internal mammary artery, the axillary artery, and the intercostal arteries. The chief blood supply to the breast is from perforating branches of the internal mammary artery. The venous drainage of the breast is through the superficial subcutaneous veins, which drain either through the superficial veins into the lower neck or via medial connections into the internal mammary veins. There are also three groups of deep venous drainage. Although there appears to be some cross-drainage from one breast to the other, it is highly unlikely that this is a significant route for metastatic spread of carcinoma to the opposite breast.

Innervation of the breast skin is separated by quadrants. The upper quadrants receive their innervation from the third and fourth branches of the cervical plexus. In contrast, the lower quadrants are supplied by the thoracic intercostal nerves. The nipple’s sensitivity is derived from the lateral cutaneous branch of the fourth intercostal nerve.

Lymphatic drainage of the breast can be divided into a superficial system draining the skin and a deeper system draining the lobules. The breast’s lymphatic drainage is primarily to the axilla, with lesser drainage occurring along the internal mammary chain. The drainage from the upper quadrants passes to the axilla, as does drainage from the lower medial quadrant and adjacent abdominal wall.

DISORDERS AND DISEASES

Congenital anomalies of the breast are relatively rare. The most common are accessory breast tissue (polymastia) and accessory nipples (polythelia) along the milk line. A complete lack of one or both breasts (amastia) or nipples (athelia) is very rare; however, underdeveloped rudimentary breasts are not uncommon. Accessory breasts or nipples occur in approximately 2 percent of the population. Their most frequent location is just below the normal breast. This accessory breast tissue is of little clinical significance. However, it is subject to the same disease processes that occur in normal breasts. Hypertrophy, or overgrowth, of the breast, is another development variation that affects young women, especially adolescents. The most frequent type of true hypertrophy of the breast occurs in adolescence following normal puberty. Excessive growth is the result of increased deposition of fibrous and adipose tissue. The breasts fail to cease enlargement as they reach their normal limits. Little abnormality is to be found in the glandular elements of the breast. The breasts may gain massive size and require surgical reduction.

The inflammatory conditions of the breast may be acute or chronic. They can becaused by various factors, including infectious agents, foreign bodies, or trauma. Acute mastitis is usually the result of the spread of microorganisms from the nipple, particularly during lactation. The breast shows acute inflammation with swelling, warmness, and redness. An abscess or collection of pus may form in the subareolar or deep glandular tissue. Diffuse cellulitis occasionally develops as the infection spreads into the adjacent soft tissue. Acute mastitis usually resolves following appropriate antibiotic treatment. Chronic mastitis may follow acute mastitis, or its onset may be insidious. The causative organisms are similar to those responsible for acute mastitis.

Fat necrosis within the breast tissue may follow trauma or a breast augmentation procedure using silicone or other materials. It may also be associated with necrosis developing in a malignant tumor. A history of trauma with surrounding bruises and pain is found in only about half the cases. Fat necrosis often manifests itself as a small, firm, nodular mass of insidious onset. The consistency, adhesion to the skin, lack of pain, and presence of calcifications on mammography add to the confusion with carcinoma. In chronic cases, extensive fibrosis is seen. Careful microscopic sampling of different areas of the lesion is necessary since malignant tumors could be associated with the foci of fat necrosis.

Almost all women are affected by a benign condition called fibrocystic breast change during their lives. Many other terms have been used for fibrocystic change in the medical literature, such as mammary dysplasia, fibrocystic disease, and chronic cystic mastitis. Still, these terms are no longer considered appropriate. This condition primarily affects women between twenty and forty-five years of age. Symptoms include nodularity in the breasts associated with pain and tenderness, particularly around menses. Although the pathogenesis is not clear, fibrocystic changes appear to result from a hormonal imbalance of estrogen and progesterone. Genetic makeup, age, parity, and lactational history may also play a role. The majority of fibrocystic changes are not premalignant. Oral contraceptives reduce the incidence of some types of fibrocystic changes.

The most common benign neoplasm of the breast is a fibroadenoma, with most cases occurring between fifteen and thirty years of age. Thought to be of lobular origin, these neoplasms are estrogen-dependent, are often associated with menstrual irregularities, and can enlarge significantly during pregnancy. Clinically, fibroadenomas are usually well-defined, rounded lesions with a firm or rubbery consistency. They are freely mobile since there are no attachments between the tumor and the adjacent tissue. Fibroadenomas vary in size, with the majority being between one and three centimeters in diameter. Some tumors, however, can be as large as ten to twelve centimeters and are termed giant fibroadenoma; these are more common in adolescents, particularly people of African descent in their second decade of life. The large size of these tumors may be intimidating, but they have no malignant potential. Local excision with nipple preservation is adequate and allows subsequent normal breast development.

Breast cancer is a major cause of death among women worldwide. The World Health Organization estimates that in 2011, breast cancer was responsible for more than 508,000 deaths in women (Global Health Estimates, WHO, 2013). The initial physical signs and symptoms of breast carcinoma are varied. The most common clinical manifestation is a discrete lump. Swelling, nipple retraction, skin dimpling, axillary lumps, and occasionally bloody nipple discharge make up the remainder of the local physical signs. In general, nipple discharge is not often associated with cancer. When it is, it is usually a persistent, spontaneous bloody discharge. In women younger than fifty years of age, the presence of a bloody discharge is usually associated with an intraductal papilloma, which is not a malignant breast lesion. The shortening of Cooper’s ligaments causes skin retraction; its presence classically raises strong suspicion of breast carcinoma. Other benign breast lesions can produce similar changes. However, plasma cell mastitis, fat necrosis, and Mondor’s disease are most common. Women with distant metastasis may experience general malaise, weight loss, bone pain, and headaches.

In most cases, the site of the breast lump is in the upper outer quadrant or the retroareolar area, just beneath the nipple. This is likely attributable to the fact that most mammary glandular tissue occupies the upper outer quadrant of the breast. Approximately 5 percent of breast cancers occur in both breasts.

There are several different histopathological subtypes of breast cancer. Their recognition by the pathologist is crucial since some have different prognostic implications. Most breast malignancies are primarily epithelial in origin, with only a small number of sarcomas and metastatic tumors reported. Although the terminal duct lobular unit is probably the location of origin of almost all cancers, neoplasms are traditionally classified into ductal and lobular carcinomas.

The most common malignant neoplasm of the breast is a nonspecific type of infiltrating ductal carcinoma, reported in 75 percent of breast cancer cases. It is presumed to be ductal in origin, and there may be coexistent areas of intraductal carcinoma. However, this component is not always obvious. There is a poorly defined area of firmness that can often be palpated within the breast. At the time of surgical biopsy, most of these cancers range between one and three centimeters in diameter. Tumors less than one centimeter in diameter are not usually detected, although the increased use of screening mammography has brought some of these early lesions to light. Other tumors may reach a massive size, greater than ten centimeters, before the patient seeks medical advice, often because of the patient’s denial or lack of knowledge. The mass has a hard consistency and gives a gritty resistance when the specimen is cut. The outer margin of the mass is irregular with numerous fibrous bands, which can cause retraction of the nipple and dimpling of the overlying skin. The neoplasm may also be fixed to the underlying chest wall. Ulceration of the nipple or other skin parts is uncommon, except in advanced cases.

Invasive lobular carcinoma is the second most common breast malignancy. These tumors tend to be multifocal and bilateral. When the opposite or uninvolved breast is sampled, about one-third show areas of carcinoma. Nodules of invasive lobular carcinoma are frequently difficult to localize, and occasionally no masses are encountered.

PERSPECTIVE AND PROSPECTS

Breast cancer has been described in many cultures and can even be found recorded in early Egyptian hieroglyphics. In recent years, the investigation of breast diseases has blossomed. The normal physiological conditions of the breast, various benign diseases, and breast cancer have been clearly separated. The significance, prognosis, relation to breast cancer, and treatment of these diseases have been elucidated. Epidemiological studies have shown marked differences in the incidence of breast cancer within populations. These findings have suggested hypotheses about the etiology and natural history of breast cancer. Increased patient awareness and continued advancement of screening mammography have resulted in earlier diagnosis of the disease.

Throughout the nineteenth century and in the early twentieth century, the prognosis for breast cancer was dismal because of the advanced stage of the disease at the usual time of its initial manifestation. In 1894, William Halsted and Willy Meyer each published, independently and for the first time, a description of the radical mastectomy procedure, including the resection of the entire breast, pectoral muscles, axillary lymph nodes, and associated skin and subcutaneous tissue. However, it was not until the late 1930s that the Halsted radical mastectomy began to be questioned by other surgeons. Enthusiasm for a more conservative management-simple mastectomy with adjuvant radiation therapy was ignited. In the early 1950s, newer concepts emerged to manage benign and malignant breast diseases. For example, the concept that breast cancer was a systemic disease and potentially unaffected by local treatment had risen. For the first time, a staging system was devised. Several studies confirmed that the most important prognostic indicator was the presence or absence of axillary nodal metastasis. In the 1960s and 1970s, hormonal therapy and adjuvant chemotherapy gradually gained acceptance.

Developments in understanding breast diseases and the variety of treatments available have provided major roles for the surgeon, medical oncologist, radiation oncologist, diagnostic radiologist, and pathologist. The multidisciplinary approach necessitates a coordinated, multidisciplinary team of experts to achieve the most optimal patient care outcome.