Development

Before puberty, the breast consists of a few ducts which are connected to the nipple and open to the surface, but there are no glandular structures. Shortly before menarche, lengthening and branching of the ducts occurs and the terminal buds appear. There is increased volume of fat and connective tissue. With the onset of menses, further growth takes place and continues until at least the age of 25, unless accelerated by the intervention of pregnancy.

Hormonal regulation

Development of the breast requires the co-ordinated action of many hormones. The precise role of each hormone is difficult to determine because they may have both growth and secretory effects, and may regulate the activity of each other (Fig. 18.1).

Fig. 18.1 The action of hormones in the development of the breast. Some hormones have a definite effect (———>), whereas the role of others is less certain (– – – –>).

Structure

The main function of the breast is the production and expression of milk (Fig. 18.2).

Fig. 18.2 Structure of the adult female breast, showing the major components and their functions.

Lobules

The lobules are the secretory units of the breast. Each lobule consists of a variable number of acini, or glands, embedded within loose connective tissue and connecting to the intralobular duct (Fig. 18.3). Each acinus is composed of two types of cell, epithelial and myoepithelial. The epithelial cells are secretory. Although synthesising milk only during the later stages of pregnancy and post-partum, they continuously secrete a variety of glycoproteins into the glandular lumens. They are surrounded by myoepithelial cells which contact with the basement membrane and may directly or indirectly control luminal cell function. The intralobular duct connects with the extralobular duct and this, together with the lobule, is called the terminal ductal lobular unit.

Fig. 18.3 A breast lobule showing the different components. The acinus is lined by epithelial cells surrounded by myoepithelial cells and the basement membrane.

Cyclical variations

The breast undergoes minor changes during each menstrual cycle but these will vary if there is a failure of ovulation or if pregnancy intervenes. The breast is sensitive to changes in the levels of sex steroids during the different phases (Fig. 18.4). The lobular stroma becomes oedematous during the secretory phase, due to the effects of oestrogens, and this accounts for the breast fullness often felt in the premenstrual phase. An increase in the number of cells in mitosis occurs at days 22–24 of the cycle, coincident with the high peaks of oestrogen and progesterone; however, the numbers are never very high. A loss of cells occurs by apoptosis (Ch. 5) at the end of the cycle, due to a fall in hormone levels, so that an overall balance is maintained. In view of the changes that can occur in the breast in the second half of the menstrual cycle, it is better to examine clinically the breasts of a pre-menopausal woman in the first half of the cycle.

Fig. 18.4 Changes in breast epithelium and stroma in relation to the levels of oestrogen and progesterone during the menstrual cycle. Mitotic activity peaks at 22–24 days and apoptosis at 26 days.

Pregnancy and lactation

During pregnancy, the lobules undergo controlled proliferation and enlargement in preparation for the synthetic and secretory activity of lactation. By the third trimester the number of acini in each lobule and the overall size of the lobules have markedly increased. The epithelial cells have become differentiated and they synthesise and secrete milk (Fig. 18.5). The various components of milk (casein, alpha-lactalbumin and milk fat globule membranes derived from the luminal surface of breast cells) are useful markers of the state of differentiation of breast cells, and because of this they have been extensively studied in breast disease.

Fig. 18.5 Lactation. Breast histology from a woman 30 weeks pregnant, showing the acini lined by cells containing secretory vacuoles, and with secretions in their lumens.

Oestrogens, progesterone and prolactin, together with other hormones shown in Figure 18.1, are important in the development of the breast during pregnancy; however, once delivery occurs, the levels of sex steroids fall and it is prolactin that is necessary for the initiation of lactation. When breast feeding ceases there is a rapid involution of the differentiated lobular structure, and the breast returns to the pre-pregnancy structure.

Involution

Changes occur in the breast with increasing age; these involutional changes relate to the altered sex steroid levels that accompany decreasing ovarian function. The connective tissue of the lobules changes from a loose to a dense structure, the basement membranes around acini become thicker, and the lining cells of the acini are lost. These changes start in the pre-menopausal period and continue past the menopause; they often occur at an uneven rate, producing clinically palpable lumps. In elderly women, the major component of the breast is adipose tissue.

Screening for breast cancer

In several developed countries with a high incidence of breast cancer, such as the UK, screening programmes for the detection of early breast cancer have been introduced. Trials in Sweden and the USA strongly suggest that women whose cancers have been detected by regular mammographic screening have an increased survival rate. This is because the tumours are detected when they are either pre-invasive (in situ carcinoma) or invasive but small, with less risk of metastasis. Unscreened women present when the tumour has grown to a size sufficient to be felt, at which stage there is a higher probability of metastases.

In the UK, women between the ages of 50 and 69 are invited to attend for breast screening by mammography every 3 years. Suspicious features on the mammographic image, such as microcalcification and localised densities, are further investigated by ultrasonography and clinical examination, with histology of biopsy samples, and very occasionally cytology, providing the definitive diagnosis. Impalpable lesions detected in this way require an X-ray-directed guidewire to be inserted into them before surgery to help the surgeon find the right area.

Besides being smaller, the invasive tumours have a higher frequency of being of a more favourable histological type and lower grade. This, along with the lower incidence of lymph node metastasis, will contribute to the improved prognosis. The surgery for these early lesions is more likely to be conservative.

The greater density of the pre-menopausal breast means that mammography may be less reliable for screening women under 50 years.

Acute pyogenic mastitis

Acute pyogenic mastitis is a painful acute inflammatory condition which usually occurs in the first few weeks after delivery, and Staphylococcus aureus is the commonest organism. The usual portal of entry is a crack in the nipple, although persistence of the keratotic plug at the orifice of a duct may be a factor. The organisms spread via the lymphatics, and the infection tends to be confined to one segment of the breast, resulting in localised swelling and erythema. The infection can spread to other segments and, if Streptococcus pyogenes is the causative organism, a more widespread inflammation occurs with systemic symptoms. If antibiotics are given but there is inadequate drainage, a localised breast abscess will result.

Other infections

Mammary duct ectasia

Mammary duct ectasia involves the larger ducts within the breast but, in severe cases, can also extend to the smaller interlobular ducts. It occurs predominantly in women in the second half of reproductive life and after the menopause, and mild degrees of the condition are often an incidental finding in breast tissue excised for other conditions. Severe forms, in which it is the primary presenting condition, are less frequent. Severe cases can be mistaken clinically for a carcinoma as there may be a discharge from the nipple which may be bloodstained. Fibrosis around the ducts may result in nipple retraction, and there may be a firm palpable mass. However, mammary duct ectasia is a purely inflammatory condition with no relationship to malignancy.

The aetiology is unknown but the affected women are usually parous. The ducts are dilated and filled with white–green viscid matter; this material may be discharged from the nipple. The matter can usually be seen with the naked eye in excised tissue. The tissue around the ducts contains lymphocytes, plasma cells and macrophages, with a significant degree of fibrosis. Due to the inflammatory reaction, the condition is sometimes known as periductal mastitis.

Fat necrosis

Trauma, e.g. seat belt injury, is thought to be the cause of fat necrosis, although a history is not always obtained. It is more frequent in obese women and after the menopause, when the breast has a proportionally greater amount of adipose tissue. It usually presents as a discrete lump and can therefore mimic a carcinoma clinically.

Macroscopically, the tissue is yellow and haemorrhagic, with flecks of calcification. Fibrous tissue is also present, the amount depending on the duration of the condition.

Histologically, the appearances are the same as those of any adipose tissue that undergoes necrosis (Ch. 6): collections of macrophages and giant cells containing lipid material may be seen, and there is an associated reaction with lymphocytes, fibroblasts and small vascular channels. The necrotic fat acts as a persistent irritant, resulting in a chronic inflammatory process and hence fibrous tissue formation.

Similar foreign body reactions can occur in the breast around ruptured prosthetic implants, in which silicone fluid is frequently used; a very dense fibrous tissue reaction can result, causing considerable distortion.

Fibrocystic change

The commonest proliferative condition of the breast is fibrocystic change. Although benign and non-neoplastic, it is important because:

Clinical and gross features

Proliferative lesions and their associated tissue responses generally occur between the ages of 30 and 55, with a marked decrease in incidence after the menopause. The incidence reaches a maximum in the years just before the menopause (Fig. 18.6).

Fig. 18.6 Incidence rates of benign proliferative breast changes occurring in women at different ages.

The clinical features tend to vary with the age of the patient and the underlying pathological changes. In younger women, there is usually a diffuse granularity in one or more segments of the breast, with nodules up to 5 mm in diameter. The area may be tender, particularly in the premenstrual period. In women nearer the menopause, there is usually an ill-defined rubbery mass. The finding of discrete swelling indicates the presence of cysts. If fibrosis is a component of the proliferative lesion, the lump will be firm and therefore more difficult to differentiate clinically from carcinoma.

Surgery for benign conditions is now uncommon. If undertaken it is more common to find nodules of soft pink or grey tissue, up to 3 mm in diameter in younger women, whereas in women nearer the menopause cysts are frequently seen. These cysts can vary in size from 2 to 20 mm (Fig. 18.7) and, rarely, a solitary large cyst can be seen. The small cysts are often multiple. They frequently have a dark blue surface and, on opening, contain clear, yellowish or blood-stained fluid. The intervening tissue is usually firm due to the increase in fibrous tissue but the softer foci of epithelial proliferation can be seen and felt.

Fig. 18.7 Fibrocystic change: cysts. Breast tissue from a 48-year-old woman showing one large cyst and multiple smaller ones, with areas of fibrosis.