Breast

Embryology and prenatal development

Our understanding of prenatal breast development has been largely drawn from mammalian studies, particularly in mice. There is variation in stages of human fetal breast development at particular gestational ages between individuals. Prenatal breast development is identical in males and females, and usually begins around the fifth to sixth weeks in utero . Firstly, two ventral ectodermal ridges, around 2–4 cell layers thick – the ‘mammary bands’ or ‘milk streaks’ – develop from the axillae to the inguinal regions bilaterally. Next, in the sixth to seventh weeks, the ‘mammary crest’ develops. This is a disc-shaped thickening, 4–6 cells wide, on the mammary band, at the fourth intercostal space on the anterior thorax, indicating the future nipple position. The third stage involves proliferation and invagination of the mammary crests, penetrating downwards as diverticuli into the underlying mesenchyme, forming the primary breast buds ( Fig. 43.1A ). Around the same time, the remaining mammary bands start to involute.

From weeks 12–20, secondary epithelial outgrowths from the deep surface of the primary breast buds arise, penetrating further into the mesenchyme ( Fig. 43.1B ). These mammary sprouts, or primitive ducts, have a slender stalk with a bulbous end. They undergo progressive elongation, branching and canalization until term, when around 15–20 lobes of glandular breast tissue, each connected to a lactiferous duct, have formed ( Fig. 43.1C ). The epithelial cells lining them are arranged in two layers of cuboidal cells: the innermost luminal layer is secretory in function, and the basal layer differentiates into myo­epithelial cells.

Formation of the primary breast bud and subsequent secondary epithelial outgrowths are regulated by hormonal and growth factor signalling from the lipid-rich extracellular matrix of the surrounding adipose tissue in the mesoderm in the first and second trimesters. In the third trimester, canalization of the ducts occurs under the influence of placental oestrogens entering the fetal circulation. Throughout the second and third trimesters, the mesenchyme differentiates into the supporting breast stroma, containing adipocytes, collagens, fibroblasts, smooth muscle and nerve cells. The stroma is also rich in immune cells such as macrophages and eosinophils.

The nipple is formed in the third trimester, at the site of initial epidermal downgrowth: the mammary pit ( Fig. 43.1D ). The overlying epidermal cells differentiate into nipple skin, with associated Montgomery's tubercle apocrine glands on the areola. The mesenchyme proliferates and differentiates to circular smooth muscle fibres arranged both longitudinally and circularly, and the nipple and areola become pigmented.

Infancy

In most infants born at term there are palpable breast nodules. Following the withdrawal of maternal oestrogens at parturition, fetal prolactin is produced from the pituitary gland, causing transient production of colostrum, which can continue for 3–4 weeks. From around 3–4 months after birth, the breasts undergo involution, similar to changes seen in the postmenopausal breast, and remain quiescent until puberty.

Puberty

In females, pubertal breast development begins between the ages of 9 and 13 years, at an average of 11 years, and takes between 3 and 5 years to complete. At a histological level, changes occur in both the breast parenchyma and the stroma. In the parenchyma, ductal elongation and branching morphogenesis occur. Cells are arranged in an outer myoepithelial layer and an inner luminal layer, which is further divided into ductal luminal epithelial cells lining the ducts, and alveolar luminal cells, capable of secretory function. More alveoli arise with each menstrual cycle but the number only increases significantly with pregnancy. In the stroma, there is an increase in size and elasticity of the connective tissues, with enhanced vascularity and adiposity.

Pubertal mammary branching is dependent on increased levels of circulating oestradiol, exerting its effect through oestrogen receptors, predominantly ERα and, to a lesser extent, ERβ, in both the parenchyma and the stroma. Breast development is also dependent on growth hormone, insulin-like growth factor-1 and prolactin.

At a macroscopic level, the changes seen in the breast at puberty have been described in five stages, originally by Tanner ( Fig. 43.2 ; Table 43.1 ).

Developmental Anomalies

Hyperplastic and accessory breast abnormalities

Polythelia is the presence of an accessory nipple and occurs in up to 5% of the adult population. Polythelia may be found at any site along the line of the embryological mammary band, most commonly in the thoracic, axillary or abdominal regions ( Fig. 43.3 ).

Polymastia is the presence of accessory or ectopic breast tissue, occurring in 2–6% of adults. The axilla is the site of accessory breast tissue in 60–70% and may be bilateral. Other reported sites include the thoraco-abdominal wall, down to the level of the groin, the vulva and subscapular regions. Ectopic tissue can undergo physiological fluctuation with the menstrual cycle and often enlarges in pregnancy, with patients often only first realising its presence during a pregnancy. If the accessory breast has an associated nipple, it may function during lactation post-partum.

Adolescent macromastia and juvenile breast hypertrophy occur when the breasts become excessively large, the former at a steady rate throughout puberty, and the latter at a dramatic rate over 6–12 months. Both can result in marked asymmetry and psychological upset. The aetiology is idiopathic, although one theory proposes breast hypersensitivity to normal levels of circulating oestrogens. Breast development is complete by the age of 20, and at this stage reduction mammoplasty may be considered in some patients with macromastia.

Pregnancy

After puberty, the breast undergoes a degree of involution until pregnancy, when massive remodelling occurs. At pregnancy, there is further duct and lobule formation, with secondary and tertiary ductal branching, and increased numbers of secretory acini. Alveoli increase dramatically in number and individually increase in size, with reduction in the stromal adipose tissue ( Fig. 43.4 ). Macroscopically, there is significant breast enlargement, dilation of superficial veins and increased pigmentation of the nipple/areolar complex. Pregnant breast development relies primarily on progesterone and prolactin, both crucial for ductal side branching and development of alveoli, in addition to oestrogens, lactogen and chorionic gonadotrophin.

Lactation

At parturition there is a sudden drop in placental lactogen and ovarian sex steroids, which, throughout pregnancy, have inhibited the lactogenic effect of prolactin on breast epithelium. Lactation usually begins at 1–4 days post-partum and can continue for 3 years or so, dependent on prolactin and oxytocin secretions from the anterior and posterior pituitary, respectively, in response to infant suckling. When the breast is no longer lactating, involution of the glandular tissue occurs due to apoptosis of epithelial cells. Atrophy of the breast parenchyma is accompanied by increased deposition of adipocytes, returning the breast to a pre-pregnant state, ready for subsequent pregnancies.

Menopause

At the menopause, there is a decrease in overall volume of the breast, with involution of the glandular breast tissue. There is increased deposition of fatty tissue and regression of connective tissues in the stroma.

Male breast

The male breast remains rudimentary from infancy and does not form lobules or alveoli. However, it can hypertrophy, resulting in gynaecomastia. This occurs most often at puberty, when boys will often notice a small amount of breast tissue behind the nipple. Occasionally, this will develop further either unilaterally or bilaterally. In later life, typically between the ages of 50 and 80 years, gynaecomastia may also occur. Often the aetiology is obscure but commonly recognized causes include drugs such as histamine H2-receptor antagonists, spironolactone, and antiandrogens used in prostatic carcinoma. Recreational drugs, including marijuana, alcohol and anabolic steroids, are also identified as causes.