The mammary glands develop from mammary ridges (so-called milk lines). The latter are thickenings of the epidermis that appear on the ventral surface of the 5-week fetus. The bilateral mammary ridges extend from the axilla to the vulva. In humans of either gender, the ridges largely disappear during normal fetal development, except for a pair of thickenings, one on either side of the pectoral region. Persistence of other segments of the milk line results in the development of ectopic mammary glandular tissue, which occurs most often at the extreme ends of the mammary ridge, that is, in the axilla and vulva.

The aforementioned thickening is caused by an epithelial bud that forms around condensed mesenchymal tissue. Columns of epithelial cords grow downward, branch, canalize, and transform into ducts and, ultimately, lobules. Each column eventually forms a lobe of the breast. Obviously, stem cells and molecular mechanisms have roles in mammary development; however, these roles are presently unclear (1,2,3).

In most girls, functional breast development does not begin until puberty. Premature thelarche is the unilateral or bilateral appearance of a discoid subareolar thickening before puberty (4). The incidence in white female infants and children up to 7 years of age in the United States in 1980 was 20.8 per 100,000 (5). Its prevalence, as reported in 2010, among 318 female children aged between 1 and 4 years in a midwestern American hospital, was calculated to be 4.7% (6). The nodular breast tissue formed in premature thelarche can measure up to 6.5 cm, and tends to slowly regress over a period of 6 months to 6 years. Premature thelarche has been associated with precocious puberty (7), but not with a predisposition to develop breast carcinoma (8). Histologically, the breast glandular tissue in premature thelarche resembles gynecomastia. Both lesions are characterized by ductal epithelial hyperplasia with solid and micropapillary configurations. Branching of proliferating ducts results in an increased number of ducts. The latter are surrounded by moderately cellular stroma. Excisional biopsy, or overzealous sampling via needle core biopsy, of prematurely developed breast tissue is inappropriate, because it could result in impairment of subsequent physical development of the breast or complete failure of the breast to develop.

With the onset of the cyclical production of estrogen and progesterone at puberty, adolescent female breast development begins (Fig. 1.1). Growth of ducts and periductal stroma is estrogen dependent (9). As stated above, mammary lobules are derived from solid masses of cells that form at the ends of terminal ducts. Breast glandular differentiation occurs mostly during puberty, but this process can continue into the third decade of life and is enhanced by pregnancy (3). The bulk of lobules in the mature breast are embedded in fibrous tissue; however, normal lobules may also be located amid mammary adipose tissue—usually in postmenopausal women (Fig. 1.2).

The functional lobular and ductal elements of the breast are embedded in fibroadipose tissue that forms the bulk of the mammary gland. The relative proportions of fibrous and fatty stroma vary greatly among individuals and with age. The combination of stromal and epithelial components is responsible for the radiologic appearance of breast structure in normal and pathologic states. Magnetic resonance imaging (MRI) provides a relatively precise method for discriminating between fatty and fibroglandular tissue in the breast. By comparing images obtained with mammography and MRI, Lee et al. (10) found a mean fat content of 42.5% (SD ± 30.3%) in mammograms and 66.5% (SD ± 18%) in MRI images. The ranges of fat content obtained by mammography and MRI imaging were 7.5% to 90% and 17% to 89%, respectively. The correlation coefficient for estimates of fat content obtained by both methods was 0.63, with the strongest correlation (r = 0.81) in postmenopausal women.

Breast “density” refers to the proportion of more dense (fibroconnective and glandular) to less dense (adipose) tissues as evidenced on mammography. There has been considerable interest in the genetic and hormonal basis of such density and its relationship to the detection, incidence (and even prognosis) of breast carcinoma (11,12). Greater breast density has been associated with advanced tumor stage at diagnosis and increased risk of both local recurrence and second primary
cancers. The biologic and genetic pathways that modulate mammographic density and its variability during various phases of the menstrual cycle phase remain unresolved (13).

Approximately 20 lactiferous (collecting) ducts terminate in, and exit from, the breast at the nipple. Each lactiferous duct drains a mammary lobe (Fig. 1.3). These lobes vary in extent, and are arranged in a spoke-like manner radiating from the nipple. The individual lobes do not constitute grossly discrete structures, and may overlap with adjacent ones around the edges. The structure of each lobe is simple: the lactiferous duct extends distally from the nipple through a series of branches that diminish in caliber from the nipple to the terminal ductal-lobular units.

The squamocolumnar junction in the lactiferous ducts, where the squamous epithelium joins the glandular duct epithelium, is normally distal to a dilated segment of the lactiferous duct, the lactiferous sinus, located just beneath the nipple surface. Extension of squamous epithelium into or below the lactiferous sinus represents metaplasia of the lining ductal epithelia. This process, when exuberant, may result in obstruction of the affected duct. Lactiferous ducts in the nipple are surrounded by circular and longitudinal arrays of smooth muscle fibers rooted in dense fibrous stroma.

The branching mammary ductal system is embedded in specialized, hormonally responsive stroma. The extralobular ducts are lined mainly by a single layer of epithelium, with underlying myoepithelial cells and basement membrane. In the nonlactating breast, the major ducts cut in cross section have contours marked by numerous folds or indentations that create a stellate structure, with a serrated contour. The epithelium in the bay-like pouches of the duct lumen can give rise to ductular branches. Fully formed lobules originate directly from these pouches in the more distal segments of the mammary duct system—and more rarely in its more proximal segments, that is, the lactiferous ducts of the nipple (14).

The great majority of epithelial cells that form the lining of the mammary glandular system (ducts and lobules) are cuboidal or columnar cells. Their cytoplasm is endowed with abundant organelles involved in secretory functions. Myoepithelial cells lie between the epithelial layer and the basal lamina (Fig. 1.4). The cytoplasm of myoepithelial cells, distributed in a network of slender processes that invest the overlying epithelial cells, is rich in myofibrils. The histologic appearance and immunoreactivity of myoepithelial cells is variable, especially in pathologic conditions, and depends on the degree to which the myoid or epithelial phenotype is accentuated in a particular situation. Myoepithelial cells are typically spindle shaped (“bipolar”), but they may become cuboidal, or undergo “myoid” or clear cell change in certain proliferative or pathologic conditions (Fig. 1.5). Myoepithelial cells display nuclear reactivity for p63 and p40 (15). Epithelioid (cuboidal) myoepithelial cells can have absent or reduced p63 reactivity. Glands lined by apocrine epithelia (inactive, hyperplastic, or noninvasive malignant) occasionally show complete lack of myoepithelial cells as evidenced by immunohistochemistry (16,17,18).

The normal periductal stroma contains fibroblasts and elastic fibers, as well as scattered sparse lymphocytes, plasma cells, mast cells, and histiocytes. Ochrocytes are histiocytes with a cytoplasmic accumulation of lipofuscin pigment (Fig. 1.6). These pigmented cells become more numerous in the postmenopausal breast and in association with inflammatory or proliferative conditions (19). In addition to being present in the duct lumen, ochrocytes are found in the ductal epithelium, where they have a “pagetoid-like” distribution, and in periductal stroma. They are easily distinguished from pagetoid and periductal carcinoma cells by immunostains that typically yield the following results: CK7 (-), CK20 (-), and CD68 (+). When restricted to an intraepithelial position, ochrocytes may be confused with epithelioid myoepithelial cells, but they are not reactive with myoepithelial markers such as p63, myosin, and calponin.

Secretion of milk originates in lobules—the distal-most portion of the mammary glandular system. Lobules are composed of alveolar glands encased in specialized vascularized stroma. They are drained by terminal lobular ducts, which in turn open into the extralobular duct system. The resting lobular gland is lined by a single layer of cuboidal epithelial cells supported by loosely connected myoepithelial cells and a basement membrane.

The “normal” microscopic anatomy of the lobules is inconstant because the histologic appearance of the lobule in the mature breast is subject to changes associated with the menstrual cycle, pregnancy, lactation, exogenous hormone administration, aging, and menopause. Furthermore, there is variation in the functional state of individual lobules regardless of physiologic circumstances, an observation that suggests that individual lobules or regions of the breast have intrinsic differences in response to hormonal and other stimuli. This is reflected in the substantial variability in labeling indices, indicating different proliferative rates among lobules in a given individual (20). Immunoreactivity for estrogen and progesterone receptors is also variably expressed in the epithelial cells of the lobules and ducts.

Histologic alterations occur in the normal breast during the menstrual cycle (21). According to some authors, the proliferative phase, days 3 through 7, features the highest rate of epithelial mitoses and of apoptosis (22,23). Other investigators who defined this phase as days 0 to 5 reported that “apoptosis and mitosis were by and large absent in this phase” (22). Lobular glands at this time are lined by crowded, poorly oriented epithelial cells with little or no lumen formation and secretion. Myoepithelial cells are inconspicuous and
difficult to distinguish from epithelial cells. The lobular stroma is relatively dense and hypovascular, with plump fibroblasts ringing the glands.