The mammary gland, as the breast is medically termed, received its name from mamma , the Latin word for breast. The human mammary gland is the only organ that is not fully developed at birth. It experiences dramatic changes in size, shape, and function from birth through pregnancy, lactation, and ultimately involution. Mediated by large changes in gene expression, there are drastic changes in composition, architecture, and function during the life cycle of the human mammary gland. The gland only reaches full maturity when pregnancy occurs. This is the most significant stage of the breast because of the very high metabolic demand that utilizes 25% of the maternal energy intake. Pregnancy and lactation create permanent breast changes that provide a protective, yet not well understood, effect against breast malignancy. The gland undergoes three major phases of growth and development before pregnancy and lactation: in utero, during the first 2 years of life, and at puberty.
The milk streak appears in the fourth week, when the embryo is 2.5 mm long. It becomes the milk line, or ridge, during the fifth week (2.5 to 5.5 mm). Mammary glands begin to develop in the 6-week-old embryo, continuing their proliferation until milk ducts are developed by the time of birth ( Tables 2-1 and 2-2 ). Embryologically, the mammary glands develop as ingrowths of the ectoderm into the underlying mesodermal tissue. In the human embryo, a thickened, raised area of the ectoderm can be recognized in the region of the future gland at the end of the fourth week of pregnancy. The thickened ectoderm becomes depressed into the underlying mesoderm, the surface of the mammary area soon becomes flat, and it finally sinks below the level of the surrounding epidermis. The mesoderm in contact with the ingrowth of the ectoderm is compressed, and its elements become arranged in concentric layers, which at a later stage give rise to the gland’s stroma. The ingrowing mass of ectodermal cells soon becomes pouch or pear shaped and then grows out into the surrounding mesoderm as a number of solid processes that represent the gland’s future ducts. These processes, by dividing and branching, give rise to the future lobes and lobules and, much later, to the alveoli.
|Age of Embryo (wk)||Crown-Rump Length of Embryo (mean)||Developmental Stage|
|4||2.5 mm||Mammary streak|
|5||2.5-5.5 mm||Milk line, or milk ridge|
|6||5.5-11 mm||Parenchymal cells proliferate|
|7-8||11-25 mm||Mammary disk progresses to globular stage|
|9||25-30 mm||Cone stage: Inward growth of parenchyma|
|10-12||30-68 mm||Epithelial buds sprout from invading parenchyma|
|12-13||68 mm to 5 cm||Indentation buds become lobular with notching at epithelial-stromal border|
|15||10 cm||Buds branch into 15-25 epithelial strips|
|20-24||20 cm||Solid cords canalize by desquamation and lysis|
|24-32||30 cm||Further canalization|
|32-40||35-50 cm||Lobular-alveolar development|
|Developmental Stage||Hormonal Regulation||Local Factors||Description|
|Embryogenesis||???||Fat pad necessary for ductal extension||Epithelial bud develops in 18- to 19-week fetus, extending a short distance into mammary fat pad with blind ducts that become canalized; some milk secretion may be present at birth|
|Pubertal development before onset of menses||Estrogen, GH||IGF-1, HGF, TGF-β, ???||Ductal extension into the mammary fat pad; branching morphogenesis|
|After onset of menses||Estrogen, progesterone, PRL?||Lobular development with formation of terminal duct lobular unit|
|Development in pregnancy||Progesterone, PRL, placental lactogen||HER, ???||Alveolus formation; partial cellular differentiation|
|Transition: lactogenesis||Progesterone withdrawal, PRL, glucocorticoid||Unknown||Onset of milk secretion: stage I, midpregnancy; stage II, parturition|
|Lactation||PRL, oxytocin||FIL, stretch||Ongoing milk secretion, milk ejection|
|Involution||Withdrawal of prolactin||Milk stasis (FIL??)||Alveolar epithelium undergoes apoptosis and remodeling and gland reverts to prepregnant state|
By 16 weeks’ gestation, the branching stage has produced 15 to 25 epithelial strips or solid cords in the subcutaneous tissue that represent future secretory alveoli. The smooth musculature of nipple and areola are developed. By apoptosis of the central epithelial cells, branching and canalization continue. By 32 weeks’ gestation the primary milk ducts appear and the mammary vascular system is completely developed. At this time, the secondary mammary anlage (primordium) develops. The secondary mammary anlage then develops with elements of hair follicles, sebaceous glands, and sweat glands, along with the Montgomery glands, around the alveoli. Mesenchymal cells differentiate into the smooth muscle of the nipple and areola between 12 and 16 weeks’ gestation. Thus far, development is independent of hormone stimulation. By 28 weeks’ gestation, placental sex hormones enter the fetal circulation and induce canalization in the fetus.
The lumina develop in the outgrowths, forming the lactiferous ducts and their branches. The lactiferous ducts open into a shallow epithelial depression known as the mammary pit. The pit becomes elevated as a result of the mesenchymal proliferation forming the nipple and areola. An inverted nipple is a result of the failure of the pit to elevate. A lumen is formed in each part of the branching system of cellular processes after 32 weeks’ gestation. Near term, about 15 to 25 mammary ducts form the fetal mammary gland ( Figure 2-1 ). Duct and sebaceous glands coalesce near the epidermis. Parenchymal differentiation occurs with the development of lobular-alveolar structures that contain colostrum. This change occurs at 32 to 40 weeks and is called the end-vesicle stage.
Fetal and Prepubertal Development
The mammary glands of male and female fetuses of 13 to 40 weeks’ gestation were studied ultrastructurally by Tobon and Salazar. This work confirms morphologic developments in the fetal breast tissue in response to hormonal stimuli that are similar to those in the maternal breast. The Golgi system and abundant reticula with dilated cisternae filled with fine granular material are present in the cellular structure. Abundant mitochondria and lipid droplets are observed. Proliferation and conditioning of the epithelial cells are evident, and, in the last trimester, microvilli along the ductal lumen are accompanied by large cytoplasmic protrusions (see Table 2-2 ).
Study of the ultrastructure of the fetal breast may help in understanding the functional lactating breast. The secretion of a fluid resembling milk may take place at birth as a result of maternal hormones that have passed across the placenta into the fetal circulation. The lactiferous sinuses appear before birth as swellings of the developing ducts.
An extensive anatomic and histologic study of the human infant breast revealed an epithelial differentiation that followed a chronologic pattern, starting with secretory changes and apparently going through a period of apocrine metaplasia before the postsecretory changes and involution. The embryonic fat probably plays a role in growth and morphogenesis of the ductal system. No distinguishing features were found between the breasts of female and male infants, however.
The terminal end buds, lateral buds, and lobules of three to five alveolar buds predominate in prepubertal tissue. Lobules of alveolar buds and lobules of up to 60 ductules predominate in pubertal females. In prepuberty, these epithelium-lined ducts will bud out to form alveoli when stimulated by hormones of menarche (see Figure 2-1 ).
The breast is made up of glandular tissue, supporting connective tissue, and protective fatty tissue. Immediately after birth, the newborn’s breast may even be swollen and secreting a small amount of milk, often termed witch’s milk. This phenomenon, common among both male and female infants, is caused by the stimulation of the infant’s mammary glands by the same hormones produced by the placenta to prepare the mother’s breast for lactation. This secretory activity subsides within 3 to 4 weeks, and then the mammary glands are inactive until shortly before the onset of puberty, when hormones begin to stimulate growth again. During childhood (prepuberty), the gland merely keeps pace with physical growth ( Figures 2-2 and 2-3 ).
The molecular biology of mammary gland development depends on a combination of systemic mammotropic hormones plus local cell-to-cell interactions. A variety of growth factors mediate the local cell interactions. These factors include the epidermal growth factor (EGF), transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), and the Wnt gene families. In the developing breast these factors are thought to act in concert with systemic hormones.
In a longitudinal cohort of 6 to 8 years of age, girls were followed from 2004 to 2011 in three geographic areas in the United States. Using Tanner staging, the age at onset of breast maturation was documented. Stage 2 onset varied by race/ethnicity, BMI at baseline, and site. Mean onset was 8.8, 9.3, 9.7, and 9.7 years for black, Hispanic, white and non-Hispanic, and Asian, respectively. The greater the BMI, the younger the age of maturation. This study confirmed earlier maturation in girls in the last decade.
Puberty stimulates rapid breast growth activated by ovulation and establishment of menses. The development of the human breast involves two distinct processes: organogenesis and milk production. Organogenesis involves ductal and lobular growth and begins before and continues through puberty, resulting in growth of the breast parenchyma with its surrounding fat pad. When a girl is between 10 and 12 years of age, just before puberty, the ductal tree extends and generates its branching pattern, lengthening the existing ducts, dichotomously branching the growing ductal tips, and monopodially branching, with the growth of the lateral buds at the sides of the ducts ( Tables 2-2 and 2-3 ). During this period of rapid growth, the ducts can develop bulbous terminal end buds. The formation of alveolar buds begins within a year or two of the onset of menses. During the menstrual cycle, the breast changes, beginning with the follicular phase of days 3 to 14. The stroma becomes less dense. Lumina expansion takes place in the ducts. Occasionally mitosis occurs, but no secretion has been seen. In days 15 to 28, or the luteal phase, the density of the stroma progresses, and the ducts have a lumen and some secretion. From days 26 to 28 epithelial cells are reduced as apoptosis occurs, and blood flow is greatest in midcycle. The sprouting of new alveolar buds continues for several years, producing alveolar lobes. Mammary stem cell (MaSC) populations from the basal ductal layer are driven by the ovarian hormonal circuit, and changes in epitheal and stromal development result. The mammary mini-remodeling with each cycle does not fully regress at the end of the cycle.
|Phase||Age (yr)||Developmental Characteristics|
|I||Puberty||Preadolescent elevation of nipple with no palpable glandular tissue or areolar pigmentation|
|II||11.1 ± 1.1||Presence of glandular tissue in subareolar region; nipple and breast project as single mound from chest wall|
|III||12.2 ± 1.09||Increase in amount of readily palpable glandular tissue, with enlargement of breast and increased diameter and pigmentation of areola; contour of breast and nipple remains in single plane|
|IV||13.1 ± 1.15||Enlargement of areola and increased areolar pigmentation; nipple and areola form secondary mound above breast level|
|V||15.3 ± 1.7||Final adolescent development of smooth contour with no projection of areola and nipple|
The breast is located in the superficial fascia between the second rib and sixth intercostal cartilage and upon the deep pectoral fascia that is superficial to the pectoralis major muscle. It tends to overlap this muscle inferiorly to become superficial to the external oblique and serratus anterior muscles. The loose connective tissue between the breast and deep fascia forms the “submammary space,” which allows some movement. It measures 10 to 12 cm in diameter. It is located horizontally from the parasternal to midaxillary line. The central thickness of the breast is 5 to 7 cm ( Figure 2-4 ).
At puberty, the breasts of a girl enlarge to their adult size, with the left frequently slightly larger than the right. In a nonpregnant woman the mature breast weighs approximately 200 g. During pregnancy, breast size and weight increase; thus when a pregnant woman is near term, the breast weighs 400 to 600 g. During lactation the breast weighs 600 to 800 g (see Figure 2-3 ).
The shape of breasts varies from woman to woman, just as body build and facial characteristics do. Genetic, racial, and dietary variations may be associated with discoidal, hemispheric, pear-shaped, or conical forms. Typically, the breast is dome-shaped or conic in adolescence, becoming more hemispheric and finally pendulous in a parous woman. Mammary glandular tissue projects somewhat into the axillary region. This is known as the tail of Spence ( Figure 2-5 ). Mammary tissue in the axilla, which is connected to the central duct system, becomes more obvious during pregnancy and produces milk during lactation, when it may cause various symptoms (see Chapter 8 ). The tail of Spence is distinguished from a supernumerary gland because it connects to the normal duct system. Occasionally, in normal women, small masses of breast tissue may grow through the deep fascia to the muscle below. This may explain some pain distribution when the breast is engorged.
The three major structures of the breast are skin, subcutaneous tissue, and corpus mammae. The corpus mammae is the breast mass that remains after freeing the breast from the deep attachments and removing the skin, subcutaneous connective tissue, and adipose tissue.
The breasts of an adult woman are always paired and develop from a line of glandular tissue found in the fetus and known as the milk line. This milk streak, or galactic band, develops from the axilla to the groin during the fifth week of embryonic life. In the thoracic region, the band develops into a ridge, and the rest of the band regresses ( Figure 2-6 ).
In some women, additional residual tissue of the galactic band remains as mammary tissue, which can develop anywhere along this line. Hypermastia is the presence of accessory mammary glands, which are phylogenic remnants of the embryonic mammary ridge resulting from incomplete regression or dispersion of the primitive galactic band (see Figure 2-6 ). Because of this origin, accessory nipples and glandular tissue may be found along these lines, which extend from the clavicular to the inguinal regions. Occasionally, supernumerary glands are found in the urogenital region, on the buttocks, or on the back. The glands are derived from the ectoderm, whereas the connective tissue stroma is mesodermal in origin.
The accessory tissue may involve the corpus mammae, the areola, and the nipple. Hypermastia occurs in 2% to 6% of women. The response of hypermastia to pregnancy and lactation depends on the tissue present.
Box 2-1 defines other selected breast abnormalities. Symmastia is a webbing across the midline between the breasts, which are usually symmetric. A more common variation is the presternal confluence representing blending of breast tissue associated with large breasts. These abnormalities are ectodermal in origin and have many variations, from an empty skin web to the presence of significant glandular tissue. Little is known about their function, but several procedures exist for their surgical amelioration.
Accessory breast: Any tissue outside the two major glands
Amastia: Congenital absence of breast and nipple
Amazia: Nipple without breast tissue
Hyperadenia: Mammary tissue without nipple
Hypoplasia: Underdevelopment of breast
Polythelia: Supernumerary nipple(s) (also hyperthelia)
Symmastia: Webbing between breasts
Congenital absence of the breast is called amastia, which is rare. When a nipple is present but no breast tissue, the condition is called amazia. Another term for this condition when it occurs in addition to a normal breast is hyperthelia.
Some have suggested a relationship between polythelia (supernumerary nipple) and renal defect. Polythelia has also been associated with renal agenesis, renal cell carcinoma, obstructive disease, and supernumerary kidneys. Others have described associations with congenital cardiac anomalies, pyloric stenosis, ear abnormalities, and arthrogryposis multiplex congenita. After careful study of 65 patients with a supernumerary nipple, Hersh et al. found 7 individuals (11%) who had significant renal lesions, somewhat less than the incidence reported originally. Apparently no association exists in black patients.
Poland syndrome, first described in 1841 ( Box 2-2 ), includes absence of the pectoral muscle, chest wall deformity, and breast anomalies. It is now known also to include symbrachydactyly, with hypoplasia of the middle phalanges and central skin webbing. Breast hypoplasia is underdevelopment of the breast. Although 90% of cases of breast hypoplasia are associated with hypoplasia of the pectoral muscles, 92% of women with pectoral muscle abnormalities have normal breasts. Box 2-2 lists types of breast hypoplasia, hyperplasia (overdevelopment), and acquired breast abnormalities.
Unilateral hypoplasia, contralateral breast normal
Bilateral hypoplasia with asymmetry
Unilateral hyperplasia, contralateral breast normal
Bilateral hyperplasia with asymmetry
Unilateral hypoplasia, contralateral breast hyperplasia
Unilateral hypoplasia of breast, thorax, and pectoral muscles (Poland syndrome)
Acquired abnormalities caused by trauma, burns, radiation treatment for hemangioma or intrathoracic disease, chest tube insertion in infancy, and preadolescent biopsy
Hyperadenia is the presence of mammary tissue without nipples. The swelling and secretion of this tissue may produce pain during lactation. Occasionally, aberrant breast tissue can cause discomfort or embarrassment in adolescence and during menses, especially when located in the axilla. Mammographic features of normal accessory axillary breast tissue were reviewed by Adler et al. in 13 women who were diagnosed on routine mammography. Seven of these women had a mass or fullness on physical examination; one was seen postpartum because of pain; nine were asymptomatic. They ranged in age from 31 to 67 years. On radiographics, the accessory tissue resembled the rest of the normal glandular tissue but was separate from it. It occurred on the right in 11 of the 13 women. The accessory tissue was recognized as a normal developmental variant, distinguishable from the frequent axillary tail of Spence, which represents a direct extension from the outer margin of the main mass of glandular tissue.
On mammography, accessory tissue is best visualized on oblique and exaggerated craniocaudal views and by ultrasound. In rare cases, it may be appropriate to remove the tissue surgically, a treatment well known to experienced plastic surgeons. If treatment is not initiated before pregnancy and lactation in these women, pain and swelling will be intensified and may progress to mastitis or the necessity to terminate lactation.
Apart from physiologic variations, other conditions of abnormal anatomy include hypomastia (abnormally small breasts), hypertrophy, and inequality.
The most common cause of acquired breast abnormality is iatrogenic and is most commonly caused by chest wall trauma in premature infants when chest tubes are inserted. Biopsy in prepubertal girls may remove vital tissues. Cutaneous burns to the chest wall may result in scaring and breast deformity. Such findings do not automatically prevent breastfeeding. The lactation center at the University of Rochester has been consulted about several such women who have been able to breastfeed with assistance and encouragement in spite of scarring and seeming deformity.
The mammary gland is an orderly conglomeration of a variable number of independent glands. It undergoes a series of changes that can be divided into developmental and differentiation phases. Surgical dissection of many postoperative specimens has contributed more precise information about the anatomic structure of the breast. The ramifications of the lactiferous ducts and stroma were carefully studied by Weatherly-White, who reported that in 95% of women the ducts ascend into the axilla, occasionally following the brachial plexus and axillary vessels into the apex of the axilla. Ducts are found in the epigastric region in 15% of women. In rare cases, ducts cross the midline (see Figure 2-6 ).
The morphology of the corpus mammae includes two major divisions, the parenchyma and the stroma. The parenchyma includes the ductular-lobular-alveolar structures. It is composed of the alveolar gland with treelike ductular branching alveoli, which are approximately 0.12 mm in diameter. The ducts are approximately 2 mm in diameter. The lobi, which are arranged like spokes converging on the central nipple, are 15 to 25 in number. Each lobus is divided again into 20 to 40 lobuli, and each lobulus is again subdivided into 10 to 100 alveoli, or tubulosaccular secretory units. The stroma includes the connective tissue, fat tissue, blood vessels, nerves, and lymphatics.
The mass of tissue in the breast consists of the tubuloalveolar glands embedded in fat (the adipose tissue), giving the gland its smooth, rounded contour. The mammary fat pad is essential for the proliferation and differentiation of the mammary epithelium, providing the necessary space, support, and local control for duct elongation and, ultimately, lobuloalveolar proliferation. Each gland forms a lobe of the breast, and the lobes are separated by connective tissue septa. These septa attach to the skin. Each tubuloalveolar gland opens into a lactiferous duct, which leads into a more elastic duct. A slight constriction occurs before the duct opens onto the surface of the nipple ( Figure 2-7 ). Extension of ducts within the fat pad is orderly. The fat pad is critical to the development of the arborization. Fat is distributed throughout the gland buffering the alveolae and ducts. An inhibitory zone into which other ducts cannot penetrate exists around each duct, and development does not normally proceed beyond the duct end-bud stage before puberty.