Sign or symptom	Pathological basis
Lump
• Diffuse	Fibrosis, epithelial hyperplasia and cysts in fibrocystic change
• Discrete	Neoplasm or solitary cyst
• Mobile	Benign neoplasm (usually fibroadenoma)
• Tethered	Invasive neoplasm (carcinoma)
Skin features
• Oedema (peau d’orange)	Impaired lymphatic drainage due to carcinoma
• Puckering and tethering	Invasion of skin by carcinoma
• Erythema	Increased blood flow due to inflammation or tumour
Nipple
• Discharge	Milky—pregnancy or prolactinoma White/green—duct ectasia Bloody—duct papilloma or carcinoma
• Retraction	Tethering by invasive carcinoma
• Erythema and scaling	Paget’s disease of nipple or eczema
Breast pain
• Cyclical	Benign breast changes
• On palpation	Inflammatory lesion (e.g. mastitis)
Microcalcification (on mammography)	Dystrophic calcification associated with benign changes, e.g. cysts, sclerosing adenosis, or in situ or invasive carcinoma
Axillary node enlargement	Often due to metastatic breast carcinoma
Bone pain or fracture	Possibly due to metastatic breast carcinoma or associated with hypercalcaemia

NORMAL STRUCTURE AND FUNCTION

The physiological and pathological changes in a woman’s breasts vary during different phases of her life. This is due to the variations in hormone levels that occur before, during and after the period of reproductive life; hormones are important in the regulation of growth, development and function of the breast.

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.

Developmental abnormalities

Failure of breast development in the female is very rare; in some cases it is due to ovarian agenesis (Turner’s syndrome). Accessory nipples are the commonest abnormality; these can occur anywhere along the ‘milk line’, from axilla to groin. Juvenile hypertrophy is characterised by rapid and disproportionate breast growth during puberty; it can cause psychological distress and may warrant surgical reduction.

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.

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.

Ducts

The extralobular ducts within the same area link together to form subsegmental ducts, which link in turn to form segmental ducts. These drain into the lactiferous ducts and sinuses (Fig. 18.2) which empty on to the surface of the nipple through separate orifices. There are 15 to 20 lactiferous ducts, each draining a segment of breast. The ducts are lined by epithelial cells surrounded by myoepithelial cells. The connective tissue in which they lie is denser than that of the lobules, and they are surrounded by elastic tissue which helps in the drainage function of the ducts.

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.

CLINICAL FEATURES OF BREAST LESIONS

Most pathological lesions of the breast present as a lump or lumps. These can vary in their nature depending on their cause: well-circumscribed or ill-defined; single or multiple small nodules; soft or firm; mobile or attached to skin or underlying muscle. These features assist in the clinical distinction between benign breast lesions and breast carcinomas, but they are relatively weak discriminators on their own. Below the age of about 35, benign breast lumps are much more common than carcinomas. Most women with breast cancer are peri- or post-menopausal. The most likely type of lesion will vary with the age of the patient, although overlaps occur (Table 18.1). However, there can be exceptions and histological examination is mandatory for a definite diagnosis.

Table 18.1 The probable pathological causes of presenting clinical lesions at different ages in women

Physiological conditions can be confused with, or mimic, pathological conditions. A degree of tenderness and swelling of the breast in the premenstrual phase is common. Some women have naturally ‘lumpy’ breasts and this may become exaggerated in this phase of the menstrual cycle. Uneven proliferation of the glandular substance during pregnancy, and irregular involution after pregnancy and during and after the menopause, can result in lumps that are the outcome of physiological and not pathological events. Other manifestations of a pathological lesion within the breast are discharge from the nipple, eczema and ulceration of the skin of the nipple.

DIAGNOSTIC METHODS

Several methods are used to investigate breast lesions. The aim is to get a diagnosis and either negate surgery or be able to discuss management with the patient (i.e. pre-operative diagnosis). They include:

• imaging—mammography and ultrasonography

• fine-needle aspiration cytology

• core biopsy.

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.

INFLAMMATORY CONDITIONS

Infections of the breast are uncommon, usually complications of lactation

Duct ectasia can cause nipple discharge, uncommon in younger women

Fat necrosis is due to trauma, more frequent in the obese

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.

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.