Overview

The breast is an appendage of skin and is a modified sweat gland. It is composed of glandular tissue, fibrous or supporting tissue, and fat. The functional unit of the breast is the terminal duct lobular unit, and any secretions produced in the terminal duct lobular unit drain towards the nipple into 12–15 major subareolar ducts. Although often described as being segmental, the glandular and ductal structures of the breast interweave to form a composite mass. In the resting state, the terminal duct lobular unit secretes watery fluid that is reabsorbed as it passes through the ductules and ducts. This rarely reaches the surface of the nipple because the nipple ducts are blocked or plugged by keratin. If the keratin becomes dislodged, then this physiological secretion can be seen on the surface of the nipple. It varies in colour from white to yellow to green to blue/black, and can be produced in up to two-thirds of non-pregnant women by gentle cleaning of the nipple and massage of the breast.

Anatomy

The breast lies between the skin and the pectoral fascia, to which it is loosely attached. It extends from the clavicle superiorly down on to the abdominal wall, where it extends over the rectus abdominis, external oblique and serratus anterior muscles. The axillary tail of the breast runs between the pectoral muscles and latissimus dorsi to blend with the axillary fat. The breast is supplied by the lateral thoracic artery or the lateral thoracic branch of the axillary artery superolaterally, and by perforating branches of the internal mammary artery superomedially. The functioning unit of the breast, the terminal duct lobular unit, is lined, as are the draining ducts, by a single layer of columnar epithelial cells surrounded by myoepithelial cells. The major subareolar ducts in their terminal portion are lined by stratified squamous epithelium.

The main route of lymphatic spread of breast cancer is to the axillary nodes, which are situated below the axillary vein. On average, there are 20 nodes in the axilla below the axillary vein (Fig. 19.1). These are separated into three levels by their relation to the pectoralis minor muscle. Nodes lateral to the pectoralis minor are considered level I, those beneath are classified as level II, and the nodes medial to pectoralis minor are level III. Level I nodes, which are nearest the breast, are usually affected first by breast cancer. In less than 5% of patients, levels II or III nodes are involved without level I nodes being affected. Lymph also drains to the internal mammary nodes. Occasionally, the main route of lymph drainage of a cancer is to the interpectoral nodes situated between the pectoralis major and minor muscles.

Fig. 19.1 Lymph node drainage of the breast.

Congenital abnormalities

These are most commonly the result of persistent extra-mammary portions of the breast ridge. In the sixth week of embryonal development, a bilateral ridge called the ‘milk line’ develops and extends from the axilla to the groin. Segments coalesce into nests of cells and, in humans, all but one of these nests opposite the fifth intercostal space disappear. In 1–5% of people, one or more of the other nests persists as supernumerary or accessory nipples or, less frequently, as breasts. The most common site for an accessory nipple is in the milk line between the normal breast and the umbilicus; the most common site for an accessory breast is the lower axilla. Supernumerary nipples or breasts rarely require treatment unless they are unsightly. Accessory breast tissue is subject to the same diseases found in normally placed breasts.

Some degree of breast asymmetry is normal, the left usually being the larger of the two. One breast can be absent or hypoplastic, and this is often associated with pectoral muscle defects. Some patients have abnormalities of the pectoralis muscle and absence or hypoplasia of the breast, associated with a characteristic deformity of the upper limb; this cluster of anomalies is called Poland’s syndrome. Abnormalities of the chest wall, such as pectus excavatum and scoliosis of the thoracic spine, can make normal breasts look asymmetric. True asymmetry can be treated by augmentation of the smaller breast, reduction or elevation of the larger breast, or a combination of the two.

Hormonal control of breast development and function

Enlargement of the breast bud in the first week or two of life occurs in approximately 60% of newborn babies; the gland may reach several centimetres in size before regressing. This is because circulating maternal oestrogens cause one or both breasts to enlarge and secrete a colostrum-like fluid (witch’s milk) from the nipple. The swelling usually subsides within a few weeks and the breasts then normally remain dormant until puberty, when the onset of cyclical hormonal activity stimulates growth.

The life cycle of the breast consists of three main periods: development (and early reproductive life), mature reproductive life and involution. Development occurs at puberty and involves proliferation of ducts and ductules associated with very rudimentary lobule formation. The breast then undergoes regular changes in relation to the menstrual cycle. During pregnancy, the breast approximately doubles in weight, and lobules and ducts proliferate in preparation for milk production. Lobular development only becomes marked during pregnancy. Milk production during pregnancy is inhibited by ovarian and placental steroids. Delivery reduces the amount of circulating oestrogen and increases the sensitivity of the breast epithelium to prolactin. Suckling stimulates the release of prolactin and oxytocin, with oxytocin stimulating the myoepithelial cells to eject milk into the terminal ducts. By the age of 30, ageing or involution is evident and continues to the menopause and beyond. During involution, glandular tissue and fibrous tissue atrophy and the shape of the breasts changes and they become more ptotic or droopy. Microscopic changes in the glandular tissue that occur during involution include fibrosis, the formation of small cysts (microcysts) and a focal increase in the number of glandular elements (adenosis). These changes were previously considered abnormal and were called fibrocystic disease or fibroadenosis. However, they occur as part of normal breast ageing or involution and should not be considered as disease.

Clinical features

Approximately 25% of all surgical referrals relate to breast problems. In the UK, 1 in 4 women will attend a breast clinic, and 1 in 9 will develop breast cancer at some point in their lives. The most common symptoms are a breast lump, which may or may not be painful; an area of lumpiness; pain alone; nipple discharge; nipple retraction; a strong family history of breast cancer; breast distortion; swelling or inflammation; or a scaling nipple or eczema. The most important pointer to the diagnosis is the age of the patient. Although malignant disease can occur in young women, benign conditions are much more common. The duration of any symptom is important; breast cancers usually grow slowly, but cysts may appear overnight. Details of risk factors, including family history and current medication, should be obtained and recorded.

Clinical examination

The patient is asked to undress to the waist and sit facing the examiner. Inspection should take place in good light with the patient’s arms by her side, above her head, and then pressing on her hips (Fig. 19.2). Skin dimpling or a change of contour is present in a high percentage of patients with breast cancer (Fig. 19.3). Breast palpation is performed with the patient lying flat with her arms above or under her head. All the breast tissue is examined, using the fingertips to detect any abnormality (Fig. 19.4). Any abnormal area is then examined in more detail, to determine the texture and outline of the mass. Deep fixation is assessed by asking the patient to tense the pectoralis major muscle; this is accomplished by asking her to press her hands on her hips. All palpable lesions should be measured with callipers and the size and site (using the clock) recorded in the hospital notes.

Fig. 19.2 Clinical inspection of the breast.

Fig. 19.3 Skin dimpling in the lower inner quadrant of the left breast associated with breast cancer.

Fig. 19.4 Clinical examination of the breast.

If the patient complains of nipple discharge, an attempt should be made to reproduce the discharge and to determine whether it arises from a single or multiple ducts. Any discharge should be tested for haemoglobin. Only marked or moderate amounts of haemoglobin in a nipple discharge are significant.

Assessment of regional nodes

Once the breast has been palpated, the nodal areas are checked (Fig. 19.5). Clinical assessment of axillary nodes is not always accurate. Palpable nodes can be identified in up to 30% of patients with no clinically significant breast disease, while up to 25% of patients with breast cancer who have no palpable nodes on examination will be found histologically to have metastatic disease in the axillary nodes. Ultrasound is better at assessing axillary nodes than clinical examination. The supraclavicular nodes are best examined from behind.

Fig. 19.5 Examination of the regional nodes.

Imaging

Ultrasonography

High-frequency waves are beamed through the breast and reflections are detected and turned into images. Cysts show up as transparent objects (Fig. 19.6) and other benign lesions tend to have well-demarcated edges (Fig. 19.7), whereas cancers usually have an indistinct outline and absorb sound, resulting in a posterior acoustic shadow (Fig. 19.8). Ultrasound is also used to assess axillary nodes in patients with breast cancer. Where nodes are enlarged or the cortex of the node thickened, fine needle aspiration cytology or core biopsy should be performed to establish whether nodal metastases are present.

Fig. 19.6 Ultrasound of a cyst.

Fig. 19.7 Ultrasound of a fibroadenoma.

Fig. 19.8 Ultrasound of a cancer.

Fine needle cytology and biopsy

Core biopsy

Several cores are removed from a mass or an area of microcalcification by means of a cutting needle technique after injection of local anaesthetic (Fig. 19.9). A 14-gauge needle combined with a mechanical gun produces satisfactory samples and allows the procedure to be performed single-handed. Core biopsy can be performed using palpation to guide biopsy but is most successful when image guidance is employed (ultrasound for mass lesions, stereotactic biopsy for calcifications which are usually impalpable). Vacuum-assisted core biopsy devices allow several large cores to be removed without withdrawing the needle from the breast, and have some advantages when biopsying areas of indeterminate microcalcification detected on screening.

Fig. 19.9 Core biopsy being performed.

One-stop clinics

The combination of clinical examination, imaging (mammography with or without ultrasonography for women over 35 years, and ultrasonography for women under 35 years) and core biopsy with or without cytology is known as triple assessment. Patients presenting with a breast lump or suspicious lesion on imaging should have triple assessment performed during a single clinic visit. This allows the majority of patients seen at a breast clinic who have normal breasts to be reassured and discharged after one visit.

Accuracy of investigations

False-positive results occur with all diagnostic techniques. The sensitivity of clinical examination and mammography varies with age, and only two-thirds of cancers in women under 50 years of age are considered suspicious or definitely malignant on clinical examination or mammography (Table 19.1). Image-guided core biopsy is the most accurate and efficient of the various techniques used to diagnose breast masses.

Juvenile hypertrophy

Uncontrolled overgrowth of breast tissue occurs occasionally in adolescent girls, whose breast development initially begins normally at puberty and is followed by rapid breast growth. These changes are usually bilateral, but may be limited to one breast or part of one breast. This process is often referred to as virginal or juvenile hypertrophy (Fig. 19.10). However, it is not hypertrophy, as there is an increase in the amount of stromal tissue rather than in the number of lobules or ducts. This excessive growth is an aberration rather than a true disease, and presenting symptoms are large breasts and pain in the shoulders, neck and back or under the bra straps. Treatment is by reduction mammaplasty.

Fig. 19.10 Juvenile hypertrophy.

Fibroadenoma

Fibroadenomas are classified in most texts as benign tumours, but are best considered as aberrations of development rather than true neoplasms. The reasons are that fibroadenomas develop from a whole lobule rather than from a single cell, and show hormonal dependence similar to that of normal breast tissue, lactating during pregnancy and involuting in the perimenopausal period. Fibroadenomas are most commonly seen immediately following the period of breast development and growth in the 15–25-year age group (Fig. 19.11). They are usually well-circumscribed, firm, smooth, mobile lumps, and may be multiple or bilateral. Although a small number of fibroadenomas increase in size, most do not and over one-third become smaller or disappear within 2 years. Fibroadenomas have a characteristic appearance with easily visualized margins on ultrasound (Fig. 19.7). Large or giant fibroadenomas (> 5 cm) are infrequent but are more commonly seen in women from certain African countries. Occasionally, a fibroadenoma in an adolescent girl undergoes rapid growth, a condition called juvenile fibroadenoma (Fig. 19.12). Once a diagnosis of fibroadenoma has been established on core biopsy, options for management in lesions measuring less than 4 cm include reassurance with no follow up needed or excision; fibroadenomas over 4 cm in diameter should be excised to ensure that phyllodes tumours are not missed (see below). A carcinoma arising in a fibroadenoma is extremely rare. Patients with simple fibroadenomas are not at significantly increased risk of developing breast cancer.

Fig. 19.11 Percentage of patients in 10-year age groups with a discrete breast lump who have common benign conditions and breast cancer.

Fig. 19.12 Juvenile fibroadenoma.

Cyclical mastalgia

Most patients require no specific treatment. Evening primrose oil was previously used for breast pain but recent studies have failed to show any benefit and it is no longer used. Effective agents include danazol (100 mg/day) and tamoxifen (10 mg/day). Tamoxifen does not have a product licence for this condition but it improves pain in 80% of patients. Agnus castis, a fruit extract, has been shown in randomized studies to be somewhat effective in reducing breast pain.

Nodularity

Lumpiness and nodularity in the breast can be diffuse or focal. Diffuse nodularity is normal, particularly premenstrually. In the past, women with lumpy breasts were regarded as having fibroadenosis or fibrocystic disease, but this diffuse nodularity is not associated with any underlying pathological abnormality and so these terms are inappropriate. Focal nodularity is a common cause for women seeking medical advice and is seen in women of all ages (Fig. 19.11). Patients with benign focal nodularity often report that the lump fluctuates in size in relation to the menstrual cycle. Breast cancer should be excluded by imaging +/- core biopsy in women with persistent localized asymmetric areas of nodularity, as breast cancer in younger women often presents as nodularity rather than a discrete mass.

Non-cyclical breast pain

Localized pain in the chest wall is a common reason for patients to be referred for advice. The pain may appear to be in the breast but examining a patient on her side to move the breast away from the chest wall demonstrates that the ribs or chest wall muscle are the site of origin of the pain. Oral nonsteroidal anti-inflammatory agents (NSAIDs) are usually effective in improving chest-wall pain. Up to 60% of patients with a persistent localized painful area in the chest wall can be effectively treated by infiltration of local anaesthetic and steroid (2-5 ml 0.5% bupivacaine added to 40 mg of methylprednisolone).

Palpable breast cysts

Approximately 7% of women in developed countries develop a palpable breast cyst at some time in their life. Cysts constitute 15% of all discrete breast masses. They are distended, involuted lobules and are most frequently seen in the perimenopausal period (Fig. 19.11). Clinically, they are smooth discrete lumps that can be painful and are sometimes visible. Mammographically, they have characteristic haloes and are easily diagnosed by ultrasonography (see Fig. 19.6). Symptomatic palpable cysts are treated by aspiration and, provided the fluid is not blood-stained, it is discarded. Cysts that contain blood-stained fluid require excision to exclude an associated intracystic cancer. Such cancers are rare and are usually evident on ultrasound. Most cysts are asymptomatic and, following ultrasound assessment, do not need aspiration. All patients with cysts should have mammography, preferably before cyst aspiration, as between 1 and 3% will have a cancer, usually remote from the cyst, visible on mammography (Fig. 19.13). Patients with cysts have a slightly increased risk of developing breast cancer, but the magnitude of this risk is not considered of clinical significance.

Fig. 19.13 Mammogram of a cyst and a cancer.

Sclerosis

Areas of excessive fibrosis or sclerosis can occur as part of stromal involution. Sclerosing lesions include radial scars, complex sclerosing lesions and sclerosing adenosis and can produce stellate lesions or localized calcification that mimic breast cancer mammographically, and so can cause diagnostic problems during screening. Radial scars are difficult to differentiate on imaging from small cancers and sometimes have small areas of pre cancer (DCIS see page 312) down one of the legs of the scar so most are removed.

Duct ectasia

The major subareolar ducts dilate and shorten with age; when symptomatic, this is known as duct ectasia. By the age of 70, 40% of women have dilated ducts, some of whom present with nipple discharge or retraction. The discharge is usually cheesy and the retraction is classically slit-like (Fig. 19.14), which contrasts with breast cancer, in which the whole nipple is pulled in (Fig. 19.15). Surgery is indicated if the discharge is troublesome or if the patient wishes the nipple to be everted.

Fig. 19.14 Duct ectasia showing slit-like nipple retraction.

Fig. 19.15 Asymmetric nipple inversion in a patient with breast cancer.

Epithelial hyperplasia

An increase in the number of cells lining the terminal duct lobular unit is known as epithelial hyperplasia, the degree of which is graded as mild, moderate or florid. If the hyperplastic cells show cellular atypia, the condition is called atypical hyperplasia. Women with atypical hyperplasia have a significant increase in their risk of breast cancer. The absolute risk of developing breast cancer for a woman with atypical hyperplasia without a first-degree relative with breast cancer is 8% at 10 years; for women with a first-degree relative with breast cancer the risk is 20–25% at 15 years.

Duct papillomas

These can be single or multiple. They are very common, and should be considered as aberrations rather than true neoplasms as they show minimal malignant potential. They can cause persistent and troublesome nipple discharge, which can be either frankly blood-stained (Fig. 19.16), or serous. Treatment comprises removal of the discharging duct (microdochectomy), which removes the papilloma (if this is the cause) and allows exclusion of an underlying neoplasm, seen in approximately 5% of women who present with a blood-stained nipple discharge.

Fig. 19.16 Blood-stained nipple discharge.

Lipomas

These are soft, lobulated, radiolucent lesions and are common. Interest lies in their confusion with pseudolipoma (a soft mass that can be felt around a cancer, caused by indrawing of surrounding fat).

Phyllodes tumours

These rare fibro-epithelial neoplasms may be malignant in their behaviour, although most are benign. They present as localized discrete masses that clinically feel like fibroadenomas, although they tend to be larger (> 4 cm). Up to 20% of benign phyllodes tumours recur locally following simple excision. In more malignant lesions it is the sarcomatous element that recurs; approximately one-quarter of lesions reported as malignant metastasize. Treatment of phyllodes tumours, whether malignant or benign, is wide excision. If the lesion is large, mastectomy may be needed to ensure complete removal.

Other benign tumours that occur in the breast include granular cell tumours, neurofibromas and leiomyomas.

Lactating infection

Improvements in maternal and infant hygiene have reduced considerably the incidence of infection associated with breastfeeding. When infection does occur, it usually develops within the first 6 weeks of breastfeeding. Presenting features are pain, swelling, tenderness and a cracked nipple or skin abrasion. Staphylococcus aureus is the most common organism, although Staph. epidermidis and streptococci are occasionally implicated. Drainage of milk from the affected segment is reduced, with the resultant stagnant milk becoming infected. Early infection is treated with flucloxacillin or co-amoxiclav. An established abscess should be treated by recurrent aspiration, or by incision and drainage (Fig. 19.17). Women should be encouraged to breastfeed, as this promotes milk drainage from the affected segment. Rarely, milk flow needs to be stopped using cabergoline, a prolactin antagonist.

Fig. 19.17 Lactating breast abscess.

Non-lactating infection

This can be separated into infections that occur centrally in the periareolar region and those affecting the periphery of the breast.

Mammary duct fistula

This is a communication between the skin – usually at the areolar margin – and a major subareolar duct (Fig. 19.18). Treatment is by excision of the fistula and diseased duct(s) under antibiotic cover.

Fig. 19.18 Mammary duct fistula and periductal mastitis.

Skin-associated infection

Primary infection of the skin most commonly affects the lower half of the breast and can be recurrent in women who either are overweight or have large breasts. It is more common after previous surgery or radiotherapy. Treatment is with antibiotics (Table 19.3) and drainage or aspiration of abscesses. Women with recurrent infection should be advised about weight reduction and keeping the area as clean and dry as possible.

Sebaceous cysts are common in the skin of the breast and may become infected. Some recurrent infections in the skin of the lower part of the breast are due to hidradenitis suppurativa, which is more common in smokers. This condition, which affects the apocrine glands of the breast, is difficult to treat. Excision of the affected skin is effective at stopping further infection in about half of patients.

Epidemiology

Over 1 million new cases of breast cancer are diagnosed each year world-wide. It is the most common malignancy in women comprising 18% of all female cancers. In the UK, approximately 1 in 9 women will develop breast cancer. Known risk factors are shown in Table 19.4.

Table 19.4 Established and probable risk factors for breast cancer

The incidence of breast cancer increases with age, doubling every 10 years until the menopause, when the rate of increase slows dramatically (Fig. 19.19). Compared with lung cancer, the incidence of breast cancer is higher at young ages. There is a variation in incidence by up to a factor of 5 between different countries. Studies of migrants from Japan, a low-risk area, to Hawaii show that the rate of breast cancer in migrants becomes the same as the rate in the host country within one or two generations. This suggests that environmental rather than genetic factors are important in the aetiology. Women who start menstruating early in life, or who have a late menopause, have a slightly increased risk of developing breast cancer. Young age at first delivery protects against breast cancer. The risk of breast cancer in women who have their first child after the age of 30 is twice that of women who have their first child before the age of 20. Breast cancer is also increased in nulliparous women, who have a risk approximately 2.4 times that of women having their first child before the age of 20. The highest risk is in women who have a first pregnancy over the age of 40 years. Breastfeeding has a small protective effect and women who have breastfed have a slightly reduced incidence of breast cancer.

Fig. 19.19 Percentage of all deaths in women attributable to breast cancer.

Severe atypical hyperplasia carries a four- to five-fold higher risk of breast cancer than when no proliferative changes are evident. A doubling of breast cancer was observed among teenage girls exposed to radiation during the Second World War. Women treated by radiation therapy for lymphoma during adolescence and teenage years are also at significant risk of developing early-onset breast cancer. Although there is a close correlation between the incidence of breast cancer and dietary fat intake in populations, the relationship is neither particularly strong or consistent. A high alcohol intake does appear to increase breast cancer risk. Patients taking the oral contraceptive pill have a 1.24 times increased relative risk of breast cancer compared to that of the general population. This rapidly falls to normal after stopping the pill. Hormone replacement therapy (HRT) increases breast cancer risk. Combined oestrogen and progestogen HRT is associated with a greater risk than preparations containing oestrogen alone (Table 19.5).

Table 19.5 Relationship of HRT to breast cancer development: relative risk of breast cancer related to type and recency of HRT use*

* Lancet 2003; 362:419–427.

+ Data from WH1 study suggest risk is lower from oestrogen only than combined HRT and may not exceed 1.

Up to 10% of breast cancers in developed countries are due to genetic predisposition. This is mainly through single genes inherited as autosomal dominants but with limited penetrance. Not all gene carriers develop breast cancer. Human breast cancer genes that have been identified and that affect different families include BRCA1 on chromosome 17, BRCA2 on chromosome 13, p53 on chromosome 17 and PTEN on chromosome 10. Throughout the USA and most of Europe, germline mutations in BRCA1 and BRCA2 are believed to occur in just over 1 in 1000 of the population.

In some populations, e.g. Ashkenazi Jews and Icelanders, particular mutations in BRCA1 and BRCA2 may be relatively common. In ‘breast cancer families’, there is also an increased risk of other tumours, notably ovarian cancer. Most BRCA1 and BRCA2 mutations confer a 50–60% lifetime risk of breast cancer. Environmental factors probably modify inherited breast cancer risk, and other genes probably interact with BRCA1 and BRCA2 to modify risk. Pointers to an inherited disposition are a first-degree relative who developed breast cancer, particularly bilateral cancer, under the age of 40 years, numerous female relatives with breast cancer on the same side of the family, or a close female relative who has had ovarian cancer. Options for high-risk women include regular screening, prevention using hormonal agents such as tamoxifen, raloxifene and aromatase inhibitors, or prophylactic bilateral mastectomy. Tamoxifen and raloxifene appear to reduce the risk of developing breast cancer by 40–50%, whereas surgery reduces the risk by over 90%.

Types of breast cancer

Breast cancers are derived from the epithelial cells that line the terminal duct lobular unit. Cancer cells that remain within the basement membrane of the lobule and the draining ducts are classified as in situ or non-invasive. An invasive cancer is one in which cells have moved outside the basement membrane of the ducts and lobules into the surrounding adjacent normal tissue. Both in situ and invasive cancers have characteristic patterns by which they are classified.

Non-invasive

Two main types of non-invasive cancer can be recognized on the basis of cell type. Ductal carcinoma in situ (DCIS) is the most common form (Fig. 19.20), making up to 3–4% of symptomatic and 17–25% of screen-detected cancers. Screen-detected DCIS is most commonly associated with microcalcifications on mammograms (Fig. 19.21), which can be either localized or widespread. Lobular carcinoma in situ (LCIS) (Fig. 19.22) and atypical lobular hyperplasia (ALH) have been combined into a single diagnostic condition called lobular intraepithelial neoplasia (LIN). This is usually an incidental finding and is generally treated by regular follow-up, as these women are at significant risk of developing invasive cancer in either breast.

Fig. 19.20 Ductal carcinoma in situ.

This is characterized by cells with irregularly shaped and often angular nuclei with variable amounts of chromatin. The cells themselves are variable in size and the necrosis seen in the lumen is a frequent finding.

Fig. 19.21 Diffuse microcalcification in the breast affected by ductal carcinoma in situ.

Fig. 19.22 Lobular carcinoma in situ (now called LIN).

This is characterized by regular cells with regular round or oval nuclei. (Compare this with DCIS.)

Hormone and growth factors receptors

The hormones oestrogen and progesterone play important roles in breast cancer. Oestrogen receptors, called ERs after the American spelling (estrogen) are present in approximately 75% of breast. ER is expressed in much greater amounts in cancer cells than in normal breast tissue. ER is thus an important target for treatment, and depriving cancer cells of oestrogen causes the cancer cells to stop growing and the tumour to eventually shrink. The majority of cancers that express ER also have receptors for progesterone and these are called PgRs. The presence of ER and PgR indicates the cancer is likely to benefit from removing oestrogen compared to a cancer which has no ER or PgR (ER and PgR negative) where there is no benefit from hormone treatment.

Growth factors in cancer cells control the rate of growth of the cancer. The most important group of growth factors are the human epidermal growth factor receptors, also known as the HER group. There are four HER receptors, the most important of which is HER2. Around 15–20% of all cancers are HER2 receptor rich and rely on HER2 which can be blocked with a new type of drug called trastuzumab, also known as herceptin^®. This reduces growth and leads to cancers shrinking, and in some patients results in eradication of the cancer. Treatments that block HER1 have been developed. A new oral drug, lapatanib, blocks both HER1 and HER2 and pertuzumab (see p. 319) blocks HER1, HER2 and HER3.

Currently all breast cancers are checked for ER and HER2. Some units check routinely for PgR but others only check PgR in ER negative cancers to make sure they are not likely to benefit from hormone treatment. The amount of ER is reported as ER positive (+ve) or ER negative (−ve) and a commonly used scale classifies the amount of ER and PgR between 0 and 8. Zero is negative. There is no score of 1, and score 2 indicates a very low level of receptors. Most cancers have high levels of ER or PgR with scores of 6, 7 or 8 (ER rich).

HER2 is reported as positive or negative but sometimes two tests are needed in borderline cases and it may take 10–14 days to get a HER2 result.

Cancers may be classified as hormone sensitive, (ER+, PgR+); there are few if any ER-, PgR+. About 20–25% of cancers are hormone resistant (ER− PgR−). Cancers are considered triple negative (ER−, PgR−, HER2−) if all three markers are negative on testing. Triple negative cancers, which are often seen in women carrying an abnormal BRCA1 gene (see p. 312), tend to have a worse outcome, although about half do respond very well to chemotherapy. HER2 positive cancers used to have a worse outlook to HER2 negative cancers before the widespread use of trastuzumab. This drug dramatically improves outcome in HER2 positive disease so that the prognosis for patients with HER2+ and HER2− cancers is similar.

Screening for breast cancer

Randomized controlled trials have shown that screening by mammography can significantly reduce mortality from breast cancer (EBM 19.2). Mortality is reduced by up to 40% in women who attend for screening, with the greatest benefit being seen in women aged over 50. To be effective, attendance at screening programmes has to be greater than 70%. The UK programme screens the 50–70-year age group but may extend from 47–73 over the next decade.

The most appropriate interval between mammographic screens is yet to be determined. In the UK, screening takes place every 3 years but the rate of cancers diagnosed between the second and third years after the initial screen climbs rapidly, suggesting that this interval may be too long, at least for women aged 50–60. Patients are currently screened by two-view mammography.

About two-thirds of screen-detected abnormalities are shown to be benign or normal on further mammographic or ultrasound imaging. Among women aged 50–70, approximately 75 cancers (invasive and non-invasive) are detected for every 10 000 attending for their initial screen. At subsequent screens, approximately 50 cancers should be identified for every 10 000 attenders. Up to 70% of important abnormalities are impalpable, and for these, image-guided (ultrasound or stereotactic radiography) core biopsy is necessary to establish a diagnosis. Compared with symptomatic cancers, screen-detected cancers are smaller and more likely to be non-invasive. The ability of screening to influence mortality from breast cancer (EBM 19.3) indicates that early diagnosis identifies cancers at an earlier stage of evolution, when metastasis is less likely to have occurred.

Mammographic features of breast cancer

Mammographically, a cancer most commonly appears as a dense opacity with an irregular outline from which spicules pass into the surrounding tissue (Fig. 19.23). Associated features include microcalcifications, which can occur within or outside the lesion, skin tethering or thickening, distortion of the shape of the breast or overlying skin, and tenting or direct involvement of underlying muscle. Involved lymph nodes can also sometimes be seen (Fig. 19.24). Microcalcification alone is a feature of DCIS.

Fig. 19.23 Mammogram of a cancer detected at breast screening.

A small lesion at the back of the left breast (arrow).

Fig. 19.24 Mammogram of a cancer (irregular dense mass) and involved axillary nodes (localized density in the axillary tail).

Staging

When invasive cancer is diagnosed, the extent of the disease should be assessed. The currently used TNM (tumour, nodes and metastases) system depends on clinical measurements and clinical assessment of lymph node status, both of which are inaccurate (Table 19.6). To improve the TNM system, a separate pathological classification has been added. Patients with small breast cancers (< 4 cm) have a low incidence of detectable metastatic disease and, unless they have specific symptoms, should not undergo investigations to search for metastases other than in the axilla which can be assessed by ultrasound and/or FNAC or core biopsy. Patients with larger or more locally advanced breast cancers are more likely to have metastases and should be considered for bone scan and liver ultrasound. A simpler classification of breast cancer separates patients into three groups: operable, locally advanced and metastatic.

Table 19.6 TNM Staging for breast cancer

Note: Chest wall includes ribs, intercostal muscles and serratus anterior muscle, but not pectoral muscle.

1 Paget’s disease associated with tumour mass is classified according to the size of the tumour.

2 Dimpling of the skin, nipple retraction or other skin changes may occur in T₁, T₂ or T₃ without changing the classification.

The curability of breast cancer

Almost half the women with operable breast cancer treated by the local treatments of surgery, with or without radiotherapy, die from metastatic disease. This indicates that in most cases the cancer has already spread at the time of presentation. Invasive breast cancers spread via lymphatics and the bloodstream. The first lymph node that drains the tumour is called the sentinel node and is most commonly a level I axillary node. However, in 5% of women the sentinel node is in the internal mammary chain. In most patients with internal mammary node metastases, axillary nodes are also involved. Rarely (usually in medial tumours), the internal mammary nodes are the only regional nodes involved. It was believed that haematogenous spread took place after lymph node involvement, but it is now appreciated that lymph nodes do not act as a filter and that the presence of nodal metastases usually means that the cancer has spread systemically. Metastasis can occur at any site, but the most commonly affected organs are the bony skeleton, lungs, liver, brain, ovaries and peritoneal cavity.

Prognostic factors

Factors related to prognosis include:

• the stage of the tumour at diagnosis: principally, its size and the involvement of the axillary lymph nodes or the presence of clinically evident metastases

• biological factors that relate to tumour aggressiveness: these include histological grade, histological type, the presence of lymphatic or vascular invasion, hormone receptor content and HER2 status (see above).

The single most important prognostic factor is the number of axillary lymph nodes involved (Fig. 19.25). It is possible to combine prognostic factors to form an index that allows the identification of groups with different prognoses. The Nottingham Prognostic Index (Table 19.7) is the most widely used and incorporates three factors: tumour size, node status and histological grade.

• Tumour size (pathological size of lesion in centimeters)

• Node status (scored 1 if no nodes involved, 2 if 1–3 nodes positive, 3 if ≥ 4 nodes involved)

• Grade I tumours (scored as 1) grade II (scored as 2) grade III (scored as 3).

Fig. 19.25 Relation between number of involved axillary lymph nodes (numbered 0-10) and survival after breast cancer.

Table 19.7 Nottingham prognostic index (NPI) and survival

NPI = (0.2 × size in cm) + lymph node stage (score 1 for no nodes, 2 for 1-3 nodes, 3 for ± 4 nodes) + grade (score 1 for grade I, 2 for grade II, 3 for grade III) Originally, the NPI was used to divide women into good, intermediate or poor prognostic groups; several confirmatory studies have led to a refined NPI with five categories

Group	Index value	10-year survival (%)
Excellent (EPG)	≤ 2.4	98
Good (GPG)	≤ 3.4	90
Moderate I (MPGI)	≤ 4.4	83
Moderate II (MPGII)	< 5.4	75
Poor (PPG)	> 5.4	47

Adjuvant! Online^® provides an online tool for evaluating prognosis and the potential benefits from hormonal and chemotherapy and incorporates the tumour size, node status, grade, patient age, their general health status and the hormonal receptor status of the cancer.

Presentation of breast cancer

The most common presentation is with a breast lump or lumpiness, which is usually painless. Any discrete lump, no matter how small or mobile, can be a cancer. The investigation of a breast lump is shown in Figure 19.26. Malignant lesions may be firm and irregular and produce visible signs of breast asymmetry, such as flattening, dimpling or puckering of the overlying skin, or retraction or alteration in nipple contour. Approximately 50% of breast cancers are located in the upper outer quadrant of the breast. Diagnosis of breast lumps is a particular problem in young women, in whom the breasts are dense and lumpier and cancer is rare. Some patients present with features of locally advanced breast cancer such as skin ulceration, with direct infiltration of the skin by tumour or with oedema (Fig. 19.27) of the overlying skin.

Fig. 19.27 Peau d’orange of the skin around the nipple in a patient with inflammatory carcinoma.

Fig. 19.26 Investigation of a breast mass.

*A minimum of three cores is required, preferably image-guided, to be certain the lesion has been adequately sampled.

Breast pain alone is a rare presenting feature of breast cancer; 2.7% of patients with breast pain have cancer, whereas 4.6% of patients presenting with breast cancer have pain as their only symptom. Nipple discharge, which is either blood-stained or contains moderate or large amounts of blood on testing, can be a presenting feature of breast cancer. However, only 5–10% of patients with this symptom will have underlying malignancy. Investigation of patients who present with nipple discharge is shown in Figure 19.28. Patients with breast cancer occasionally present with a dry scaling or red weeping appearance of the nipple known as Paget’s disease; this signifies an underlying invasive or non-invasive cancer (Fig. 19.29) and should be differentiated from eczema (Fig. 19.30). Paget’s disease always affects the nipple and only involves the areola as a secondary event, whereas eczema primarily involves the areola and only secondarily affects the nipple. Approximately 1–2% of patients with breast cancer present with Paget’s disease. In half of these, it is associated with an underlying mass lesion, and 90% of such patients will have an invasive cancer. Of the patients without a mass lesion, 30% have an invasive cancer and the rest have in situ disease alone.

Fig. 19.28 Investigation of nipple discharge.

*Some surgeons prefer total duct excision in women > 45 to reduce the incidence of further discharge from ducts – microdochectomy: removal of diseased duct.

Fig. 19.29 Paget’s disease.

Fig. 19.30 Eczema of the nipple.

Patients can also present initially with palpable axillary nodes or signs and symptoms of distant metastatic disease: for example, palpable supraclavicular nodes, bone pain, a cough or breathlessness, lethargy and tiredness, jaundice and headaches, or a sudden onset of grand mal seizures. Fewer than 1 in 300 patients with breast cancer present with nodal metastases and an occult primary cancer. Up to 70% of women shown histologically to have metastatic adenocarcinoma in the axillary nodes without an obvious breast cancer will have an occult breast cancer. Most of these cancers will be visible on mammography or, if not, can be visualized by MRI of the breast.

Management of operable breast cancer

Local therapy

There are currently two accepted methods of local therapy for operable breast cancer.

Breast-conserving treatment (wide local excision and radiotherapy)

This involves excising the tumour with a 1 cm margin of macroscopically normal tissue. Breast conservation is usually only suitable for single cancers measuring less than 4 cm in diameter. Complete excision of all invasive and non-invasive cancer is necessary. Wide excision should be combined with an axillary node staging procedure. This involves either removing the first node or nodes draining the tumour (sentinel node biopsy), or axillary clearance (removing all nodes at levels I, II and III). To identify the sentinel node(s), blue dye usually combined with radioisotope is injected either under the nipple into the skin over the cancer or around the cancer. Sentinel nodes can be seen on scintigraphy or can be identified with a hand-held probe, or are stained blue. There is rarely a single sentinel node and the average number of sentinel nodes removed at surgery is 3. When blue dye and radioactively labelled sulphur colloid or albumin techniques are combined, one or more sentinel nodes will be identified in approximately 97% of patients, and this sentinel node is accurate in determining the presence of any involved nodes in the axilla in approximately 98% of patients.

The cosmetic outcome following breast conservation relates to psychological well-being. Patients who have a good cosmetic result have low levels of anxiety and depression and improved body image and self-esteem. The larger the volume of tissue excised, the poorer the cosmetic result. The aim of breast-conserving surgery is to remove the cancer completely in as small a volume of tissue as possible.

Wide excision should be followed by radical radiotherapy using megavoltage equipment to deliver 45–50 Gy to the whole breast. An additional boost of 10–15 Gy by electrons of appropriate energy, or an iridium-192 (¹⁹²Ir) implant, is given to the tumour bed in women under 50 years of age or those with close margins. For patients with involved nodes identified by a sentinel node biopsy or an axillary node sampling procedure, the remaining axillary nodes should be removed or treated by radiotherapy to the axilla and/or the medial supraclavicular fossa. Studies of local radiotherapy to the tumour bed given intraoperatively or after operation using external beam or an intracavity balloon device have been reported and seem to show satisfactory rates of local control in patients at low risk of local recurrence after breast conserving surgery.

Summary Box 19.4 Breast conservation

• Suitable for localized, operable breast cancers in which there is no evidence of metastatic disease beyond regional nodes; excision must leave a reasonable cosmetic result to produce benefits compared with mastectomy

• Includes wide local excision of the cancer to clear histological margins, axillary surgery (sentinel node biopsy, or clearance of the axillary nodes) and whole-breast radiotherapy consisting of a 45–50 Gy dose of radiotherapy applied to the whole breast, with an optional 10–15 Gy boost to the tumour bed.

Mastectomy

This is an alternative method of local treatment. It is indicated in patients:

• for whom radiotherapy is not available or when there is a wish to avoid radiotherapy

• who elect to have a mastectomy

• who have more than one focus of cancer in their breast and where removal of all the cancers would produce an unacceptable cosmetic result

• who have a localized invasive cancer but a large area of surrounding non-invasive disease

• when breast conservation would produce an unacceptable cosmetic result. (This includes some central lesions directly underneath the nipple, and most cancers measuring more than 4 cm in diameter.) Breast-conserving surgery is possible in these women if they have shrinkage following initial systemic therapy, or if the breast defect is filled with a latissimus dorsi flap (Fig. 19.31).

Fig. 19.31 A patient who had a left mastectomy and breast reconstruction with a latissimus dorsi reconstruction.

The patient also had a nipple reconstruction with tattooing.

Mastectomy removes all breast tissue with some overlying skin (usually including the nipple), but leaves the chest wall muscles intact. If reconstruction is being performed, minimal skin around the tumour can be excised. Mastectomy should be combined with some form of axillary surgery. Radiotherapy is given after mastectomy to patients who are at high risk of local recurrence. Risk factors for local recurrence after mastectomy include axillary lymph node involvement, lymphatic or vascular invasion by tumour, a grade III cancer, a cancer more than 4 cm in diameter (pathological measurement), or a tumour that involves the pectoral fascia or pectoral muscle.

Summary Box 19.5 Mastectomy

• Is appropriate for large operable breast cancers or in patients with extensive non-invasive disease, an incomplete excision after attempted breast-conserving surgery or some women with central tumour

• Consists of total removal of the breast together with sentinel node biopsy, axillary node sampling or axillary clearance

• Should be followed by chest-wall radiotherapy in those women identified to be at significantly increased risk of local recurrence.

Complications of treatment

Haematoma and infection are uncommon (less than 5%) after breast surgery. Removal of all the axillary nodes often damages the intercostobrachial nerve, which results in numbness and paraesthesia down the upper inner aspect of the arm. Other nerves that can potentially be damaged during axillary surgery are the long thoracic nerve, damage to which causes winging of the scapula, and the thoracodorsal nerve, which can lead to atrophy of the latissimus dorsi muscle and prominence of the scapula. Axillary surgery is associated with some short-term reduction in shoulder movement and about 5% of women develop a frozen shoulder. Approximately 5–10% of patients treated by a full axillary dissection develop lymphoedema. The treatment of lymphoedema is unsatisfactory and is best managed by bandaging and a supportive elastic arm stocking.

Psychological aspects

Most women who present with breast lumps are emotionally distressed. When breaking bad news, the first step should be to check the patient’s perception of what is wrong. Almost two-thirds of patients with breast cancer already suspect that their lump is malignant. In patients with proven malignancy, the doctor’s role is to confirm that their diagnosis is correct, pause to let this sink in, acknowledge their distress and establish what concerns are contributing to this distress. When a patient is unaware that she has cancer, the doctor should break the news more slowly. Most specialist units employ nurse counsellors who ensure that the patient is fully informed about the nature of the disease and its treatment. They provide advice on prostheses after surgery, and help recognize and support patients with significant psychiatric problems.

Up to 30% of women with breast cancer develop an anxiety state or depressive illness within a year of diagnosis, 3–4 times the expected rate. After mastectomy, 20–30% of patients develop persisting problems with body image and sexual difficulties. Breast-conserving surgery reduces problems with body image. Psychiatric morbidity is increased when radiotherapy or chemotherapy is used. Few patients mention psychological problems to their doctor because they think it is unacceptable to do so. Doctors can promote the disclosure of such problems by being empathetic, making educated guesses about how patients are feeling, and summarizing what they have disclosed.

There is evidence that patients benefit psychologically from immediate breast reconstruction. Options for reconstruction include the placement of an implant behind the chest wall muscles at the time of mastectomy. The problem with this approach is that the size of implant that can be inserted is limited and symmetry is difficult to obtain. Another option is to place a tissue expander behind the pectoral muscles. The use of implants has increased because larger pockets can now be created by the use of decellularized human or pig skin sutured from the pectoralis major to the chest wall to create a larger pocket into which an implant or expander can be placed. Small amounts of fluid are injected regularly into an expander over a period of months before replacing it, at a second operation, with a permanent prosthesis. Alternative options include using myocutaneous flaps; the most commonly used are the latissimus dorsi myocutaneous flap with or without an implant (Fig. 19.31), and the rectus abdominis myocutaneous flap alone.

Follow-up

Patients treated by wide local excision and radiotherapy have between a 0.4 and 1% per year rate of local recurrence in the treated breast. Those with cancer in one breast are also at risk of cancer in the other breast (0.4–0.6% per year). The majority of local recurrences after mastectomy occur within the first few years. The aim of follow-up is to detect local recurrence at a stage when it is treatable, to support the patient psychologically and to discuss problems associated with adjuvant therapy. Patients should have an annual mammogram of one or both breasts every 1–2 years for life. No investigations should be performed to detect asymptomatic metastases, as there is no evidence that this influences survival.

Management of locally advanced breast cancer

Locally advanced breast cancer (LABC) is characterized by features suggesting infiltration of the skin or chest wall by tumour or matted involved axillary nodes (Table 19.11). It has a variable natural history, with reported 5-year survivals of between 1 and 30%. The median survival was previously about 2–2.5 years but this has improved with better systemic therapy. LABC can arise because of its position in the breast (for example, peripheral), neglect (some patients do not present to hospital for months or years after they notice a mass) or biological aggressiveness. The latter includes inflammatory cancers that present with erythema and/or widespread peau d’orange affecting the breast skin. The peau d’orange is because of lymphatic obstruction by cancer cells in lymphatics or in lymph nodes (see Fig. 19.27). Inflammatory carcinomas are uncommon and are characterized by brawny, oedematous, indurated and erythematous skin changes (Fig. 19.32). They have the worst prognosis of all LABCs.

Table 19.11 Clinical features of locally advanced breast cancer

Pregnancy after treatment for breast cancer

There is only limited information on the effect of pregnancy on the outcome of patients with breast cancer, but the available data show no detrimental effect.

Chemotherapy

With chemotherapy, a balance must be achieved between a high response rate and limiting side effects. The best palliation is obtained with regimens that produce the highest response rates. The most frequently used drugs in metastatic breast cancer are the anthracyclines, adriamycin and epirubicin. Taxanes (taxol and taxotere) are also commonly used. Overall rates of response to chemotherapy are approximately 40–60%, with a median time to relapse of 6–10 months. Subsequent courses have response rates of less than 25%.

Hormonal treatment

A variety of hormonal interventions are available for use in metastatic breast cancer (Table 19.12). In premenopausal women these include oophorectomy (surgical, radiation- or drug-induced by GnRh analogues) combined with tamoxifen. Options in postmenopausal women include the new aromatase inhibitors (anastrozole, letrozole and exemestane) and the progestogens (such as medroxyprogesterone acetate or megestrol acetate). First-line treatment is with letrozole or anastrozole. Objective responses to hormonal treatments are seen in 30% of all patients and in 50–60% of those with oestrogen receptor-positive tumours. Response rates of 25% are seen when using second-line hormonal agents, although fewer than 15% of patients who show no response to first-line treatment will have a response to second-line agents. Approximately 10–15% of patients respond to third-line endocrine agents.

Table 19.12 Hormonal treatment of metastatic breast cancer

⁴

Note These agents can be used in any order.

1 There is evidence that combined ovarian suppression plus an anti-oestrogen is superior to single-agent treatment in premenopausal women.

2 Letrozole or anastrozole are first-line agents in postmenopausal women. Data for letrozole is more impressive than for anastrozole.

3 A steroidal aromatase inhibitor (e.g. exemestane) can have efficacy even if a tumour is resistant to the non-steroidal aromatase inhibitors letrozole and anastrozole.

4 Licensed in England, Wales and Northern Ireland, but not Scotland; continues to be evaluated in trials.

Anti-HER2 therapy

The humanized monoclonal antibody trastuzumab, raised against HER2, increases both the rate and duration of response of patients with metastatic disease when combined with chemotherapy in patients with tumours over-expressing HER2. The oral agent lapatanib which targets HER1 and HER2 is in clinical trials.

Specific problems

Lymphoma

This is rare in the breast. Staging investigations are necessary because patients will usually have disease elsewhere. Characteristically, lymphoma presents as a discrete smooth rubbery mass.

Sarcomas

Sarcomas can develop in breast tissue and can affect the skin overlying the breast. Rarely, they are induced by radiotherapy to the chest wall. Sarcomas are treated by excision. These tumours are usually large at diagnosis, so mastectomy is generally necessary. Radiotherapy should be given to the chest wall after excisional surgery, but there is no evidence that adjuvant chemotherapy is of benefit.

Malignant phyllodes tumours

Previously called cystosarcoma phyllodes, these present as large lobulated lesions that can involve the overlying skin. Initial treatment is by wide excision or mastectomy. The roles of radiotherapy and chemotherapy in these lesions are unclear.

Secondary tumours

Metastases from tumours elsewhere, e.g. bronchus, thyroid, melanoma or the opposite breast, produce a well-defined mass both clinically and mammographically.

Gynaecomastia

Gynaecomastia (the growth of breast tissue in males to any extent in all ages) is entirely benign and usually reversible. It commonly occurs at puberty and in old age and is seen in 30–60% of boys aged 10–16. In this age group it usually requires no treatment, as 80% resolve spontaneously within 2 years (Fig. 19.33). Embarrassment or persistent enlargement is an indication for surgery. Senescent gynaecomastia usually affects men between 50 and 80, and in most cases does not appear to be associated with any endocrine abnormality. Causes include excess alcohol intake and drugs including cannabis, cirrhosis, hypogonadism and, rarely, testicular tumours. Rapidly progressive gynaecomastia is an indication for an assessment of hormonal profile. A history of recent progressive breast enlargement without pain and tenderness, or an easily identifiable cause, should raise the suspicion of breast cancer. If there is a localized mass, then further investigations should be performed. Surgery consists of excision of glandular tissue combined with liposuction or liposuction alone and is reserved for patients with significant social embarrassment.

Fig. 19.33 Gynaecomastia in a male.

Male breast cancer

Fewer than 0.5% of all breast cancers occur in men, and breast cancer comprises 0.7% of all male cancers. The peak incidence in males is 5–10 years later than in women. Klinefelter’s syndrome and a strong family history are the only known risk factors. Male breast cancers can be associated with BRCA2 gene mutations. Cancer usually presents with an eccentric breast mass or retraction of the overlying skin. Direct involvement of the skin occurs more often in male breast cancer because of the smaller breast volume compared to the female breast, and so the disease is more likely to be advanced at diagnosis. Mammography and core biopsy will confirm the diagnosis. Treatment for localized breast cancer is by breast conserving surgery or total mastectomy and the removal of the sentinel or all the axillary nodes, usually followed by postoperative radiotherapy to the chest wall. Adjuvant tamoxifen is effective at reducing recurrence. Adjuvant chemotherapy should be considered for fit patients with tumours that have nodal involvement or are oestrogen receptor-negative.