1 The Normal Breast and Benign Diseases of the Breast

• The functional unit of the female breast is the terminal duct lobular unit (TDLU).

• The entire ductal system is lined by two cell layers: inner epithelial cells and outer myoepithelial cells.

• Ectopic breast tissue in the axilla may raise clinical concern for metastasis.

• Inverted nipples may be congenital or may be associated with breast carcinoma.

• Acute mastitis and inflammatory carcinoma may look alike clinically.

• Chronic mastitis and fat necrosis can result in a hard irregular mass and mimic malignancy.

• Fibroadenoma is the most common benign neoplasm of the female breast, composed of benign proliferation of stroma and epithelium.

• Sclerosing adenosis is a proliferation of the stroma and the smallest tubules within the TDLU. It may mimic carcinoma clinically, radiologically, and histologically. The presence of myoepithelial cells confirms the benign nature of the lesion.

• Ductal hyperplasia (proliferation of the ductal epithelial lining cells) may be of the usual type (mild, moderate, or florid) or atypical and may have varying degrees of risk for future cancer.

• Atypical lobular hyperplasia (proliferation of the epithelium lining the lobules) is associated with an increased risk of future carcinoma. There is no such entity as lobular hyperplasia of the usual type.

The Normal Breast

The breast is a modified, specialized apocrine gland located in the superficial fascia of the anterior chest wall (Fig. 1-1). The nipple projects from the anterior surface and is hyperpigmented. It is composed of dense fibrous tissue covered by skin and contains bundles of smooth muscle fibers, which assist with milk expression. The skin adjacent to the nipple is also hyperpigmented and is called the areola.

Figure 1-1 Normal breast. Diagram of breast composition and location. TDLU, terminal ductal lobular unit.

The breast parenchyma consists of 15 to 20 lobules, which drain secretions into a ductal system that converges and opens into the nipple.¹ The functional unit of the breast is the terminal duct lobular unit (TDLU) (Fig. 1-2), which is composed of the terminal (intralobular) duct, and its ductules/acini (also referred to as lobules). The terminal ducts join together to form the larger ducts, which have a dilatation (lactiferous sinus) just before they open into the nipple. The TDLUs are embedded in loose specialized, hormonally responsive connective tissue stroma, the intralobular stroma. The dense fibrous tissue between the breast lobules is called interlobular stroma, which is not responsive to hormones (Fig. 1-3).

Figure 1-2 The terminal ductal lobular unit (TDLU) is the functional unit of the breast. The large arrow indicates the terminal (intralobular) duct. The short arrow identifies the ductules (lobules) (H&E, ×200).

Figure 1-3 Normal female breast. Lobules (2) scattered within interlobular stroma (1). A larger duct is also seen (3) (H&E, ×100).

Lymphatic drainage of the breast is to the axillary, supraclavicular, and mediastinal lymph nodes.

Histology

The entire ductal system, extralobular large and intermediate ducts, as well as the intralobular (terminal ducts and ductules/lobules), is lined by two cell layers: inner epithelial cells and an outer interrupted layer of myoepithelial cells.¹ The latter cells have contractile properties and assist in expelling milk. Special techniques can be used to highlight the myoepithelial cells. Immunohistochemical stains for muscle-specific actin (MSA), S100, p63, and calponin can be used to detect the myoepithelial cell layer (Fig. 1-4).

Figure 1-4 Two-cell lining of the ductal system. The inner layer consists of epithelial cells (long arrow), and the calponin stain highlights the outer myoepithelial cells (short arrow) (Calponin stain, ×200).

The largest ducts change from a columnar epithelial lining to a squamous epithelial lining just distal to the lactiferous sinus, beyond which it becomes stratified squamous epithelium and merges with the surface skin.

Physiologic Changes in Female Breast Histology

During childhood and before puberty, the female breast is composed of a branching ductal system that lacks lobular units. At puberty, female glandular tissue proliferates under stimulation of estrogen and progesterone. Once formed, the lactiferous ducts and interlobular duct system are stable and unaffected by fluctuating hormone levels during the menstrual cycle, pregnancy, and lactation. The TDLUs, however, are dynamic and undergo changes with alterations in hormone levels. These changes involve both the epithelium and the intralobular stroma.

Menstrual Cycle

The following are pre- and postmenstrual phases of the menstrual cycle:

Follicular phase: During the follicular phase of the menstrual cycle, the TDLUs are at rest and do not show any growth. The intralobular stroma is dense and indistinct from the dense interlobular stroma.

Luteal phase: After ovulation, the terminal duct epithelium proliferates, and the number of terminal ducts within a lobule increases and the basal epithelial cells become vacuolated. The intralobular stroma is edematous and loose and becomes distinct from the interlobular stroma. These changes manifest as progressive fullness, heaviness, and tenderness of the breast.

Menses: As the levels of estrogen and progesterone fall with the onset of menstruation, there is an increase in apoptosis in the TDLU. Lymphocytes infiltrate the intralobular stroma, which becomes dense. The TDLU finally re-gresses to its resting appearance.

Pregnancy: During pregnancy, there is a striking increase in the number of terminal ducts, and the TDLUs are enlarged in response to the rising sex hormone levels.

Lactation: In the lactating breast, the individual terminal ducts form acini, which show epithelial vacuolization as a result of the presence of secretions that also fill their lumina (Fig. 1-5). After lactation, the units involute and return to their old structure.

Figure 1-5 Lactating breast. Increased number of lobules with cytoplasmic vacuoles and intraluminal secretion (H&E, ×200).

Postmenopause: After menopause, the TDLUs atrophy owing to the low hormone levels so that only small residual foci remain. The lactiferous ducts and interlobular duct system remain, but the interlobular stroma is reduced in amount accompanied by a relative increase in fatty tissue.

The normal male breast differs in structure from the female breast in that there are no lobules. The male breast consists of ductal structures surrounded by fibroadipose tissue (Fig. 1-6).

Figure 1-6 Normal male breast consists of a few ductal structures and stroma. There are no lobules (H&E, ×100).

Abnormalities of Breast Development

The following are abnormalities that can occur in breast development:

Mammary heterotopia (accessory breasts or nipples) may occur anywhere along embryonic mammary ridges, the most common sites being the chest wall, axilla, and vulva. It may manifest as polythelia (supernumerary nipples) or polymastia (aberrant breast tissue).² The accessory breast tissue responds to hormonal changes and, if located in the axilla, it may enlarge and raise concern for metastases.

Congenital inverted nipples are clinically significant, since a similar change may be produced by underlying cancer.

Juvenile hypertrophy (virginal hypertrophy) is a rare condition in adolescent girls in which the breasts (usually both; rarely only one) markedly enlarge owing to hormonal stimulation. No endocrine abnormality is detected. Patients present with embarrassment, pain, and discomfort. Reduction mammoplasty improves the quality of life.

Hamartoma is a well–circumscribed, often encapsulated mass composed of varying combinations of benign epithelial and stromal elements including fat.³ Hamartoma is usually asymptomatic. It may manifest as a palpable mass, or it may be detected by mammography. Hamartoma may cause breast deformity if it is very large.

Gynecomastia

Gynecomastia is defined as enlargement of one or both breasts in a male.⁴ Many cases are idiopathic. In some cases, gynecomastia may be caused by excessive estrogen stimulation. Predisposing factors include the following:

Hormonal imbalance, as may occur in puberty or old age

Exogenous hormones

Drugs, including dilantin, digitalis, and marijuana

Klinefelter syndrome (testicular feminization)

Testicular tumors

Liver disease

On palpation, a firm disc-shaped subareolar mass is noted. Microscopic features of gynecomastia include ductal epithelial hyperplasia, stromal edema, and fibrosis around ducts (Fig. 1-7).

Figure 1-7 Gynecomastia. Stromal and ductal proliferation in the male breast (H&E, ×100).

Inflammatory and Reactive Breast Lesions

The following are inflammatory and reactive breast conditions of various causes:

Acute inflammation of the breast (acute mastitis) is associated with redness, swelling, pain, and tenderness and may occur during the early postpartum months as a result of lactation (puerperal mastitis).⁵ Staphylococcus aureus is the most common infecting agent. There are two general categories of predisposing factors:

Cracks in the nipple and stasis of milk due to improper nursing technique

Stress and sleep deprivation, which may lower the immune status and cause engorgement by inhibiting milk flow

At the microscopic level, cellulitis of the interlobular connective tissue is seen. Diagnosis is made on clinical grounds, and antibiotics lead to complete resolution. Delay in treatment may lead to abscess formation and requires drainage of pus.

Inflammatory breast carcinoma should be ruled out when there is no response to antibiotic therapy.

Chronic mastitis may be idiopathic ⁶^–⁸ or in response to infection (tuberculosis), foreign material (silicone), or systemic disease (sarcoidosis). Diagnosis requires microbiologic, immunologic, and histologic evaluation. Idiopathic granulomatous mastitis⁷ is diagnosed after exclusion of specific etiologic agents. Microscopically, chronic mastitis shows granulomas with or without caseation. Surgical excision may be followed by recurrence, abscess formation, or fistula formation.

Mammary duct ectasia is a distinct entity that usually occurs in perimenopausal women as a result of obstruction of the lactiferous ducts by inspissated luminal secretions. Obstruction leads to dilatation of the ducts and periductal chronic inflammation (Fig. 1-8). Grossly, chronic mastitis may produce irregular masses with induration that closely mimic breast carcinoma, and biopsy may be required to exclude carcinoma.