Carcinoma of the breast

Breast cancer is the commonest cause of death in middle-aged women in Western countries. In 1985, 719 000 new cases were diagnosed world-wide. In England and Wales one in 12 women will develop the disease during their lifetime.

Aetiological factors

I.       Geographical. It occurs commonly in the Western world accounting for 3—5 per cent of deaths, yet is a rare tumour in Japan. In developing countries it accounts for 1—3 per cent of deaths.

2.       Age. Carcinoma of the breast is extremely rare below the age of 20, but thereafter the incidence steadily rises so that by the age of 90 nearly 20 per cent of women are affected (Fig. 46.27).

  By age 25      1 in 19608      By age  60      1 in 24
  By age 30      1 in 2525        By age  65      1 in 17
  By age 35      1 in 622          By age  70      1 in 14
  By age 40      1 in 217          By age  75      1 in 11
  By age 45      1 in 93            By age  80      l  in 10
  By age 50      l  in 50            By age  85      l  in 9
  By age 55      1 in 33 
            Ever               1in 8
  1987—1988 Cancer incidence rates, NCI, USA.

3.       Gender. Less than I per cent of patients with breast cancer are male.

4.       Genetic. It occurs more commonly in women with a family history of breast cancer than in the general population. Breast cancer related to a specific mutation accounts for about 5 per cent of breast cancers, yet has far-reaching repercussions in terms of counselling and attempted prevention in these women. This will be discussed more fully in a subsequent section.

5.       Diet. Because breast cancer so commonly affects women in the ‘developed’ world, dietary factors may play a part in its causation. There is some evidence that there is a link between diets low in phyto-oestrogens. A high intake of alcohol is associated with an increased risk of developing breast cancer.

6.       Endocrine. Breast cancer is commoner in nulliparous women and breastfeeding in particular appears to be protective. Also protective is having a first child at an early age, especially if associated with late menarche and early menopause. It is known that in postmenopausal women, breast cancer is more common in the obese. This is thought to he because of an increased conversion of steroid hormones to oestradiol in the body fat. The role of exogenous hormones, in particular the oral contraceptive pill and hormone replacement therapy, in the development of breast cancer is more controversial, but it can be said with some authority that for most women the benefits of these treatments will far outweigh the small putative risk.

The increase in the likelihood of developing breast cancer associated with the above risk factors is usually quantified in terms of the relative risk (RR). Thus a RR of 2.0 means that the individual has twice the chance of developing breast cancer as the average for the population, whilst a RR of 0.5 indicates a risk reduction of 50 per cent.

Pathology

Breast cancer may arise from the epithelium of the duct system anywhere from the nipple end of major lactiferous ducts to the terminal duct unit which is in the breast lobule. It may be entirely in situ — an increasingly common phenom­enon with the advent of breast cancer screening — or may be invasive cancer. The degree of differentiation of the tumour is usually described by three grades — well differentiated, moderately or poorly differentiated. Ductal carcinoma is the most common variant, but lobular carcinoma occurs in up to 10 per cent of cases, although this may be mixed. Rarer histo­logical variants, usually carrying a better prognosis, include colloid carcinoma whose cells produce abundant mucin, medullary carcinoma with solid sheets of large cells often associated with a marked lymphocytic reaction and tubular carcinoma. Invasive lobular carcinoma is commonly multi-focal and/or bilateral.

Inflammatory carcinoma is a fortunately rare, highly aggressive cancer which presents as a painful, swollen breast, which is warm with cutaneous oedema. This is due to blockage of the subdermal lymphatics with carcinoma cells. Inflammatory cancer usually involves at least one-third of the breast and may mimic a breast abscess. A biopsy will confirm the diagnosis and show undifferentiated carcinoma cells.

In situ carcinoma is preinvasive cancer which has not breached the epithelial basement membrane. This was

previously a rare, usually asymptomatic finding in breast biopsy specimens but is becoming increasingly common owing to the advent of mammographic screening — it accounts for 20 per cent of cancers detected by screening. In situ carcinoma may be ductal (DCIS) or lobular (LCIS), the latter often multifocal and bilateral. Both are markers for the later development of invasive cancer which will go on to develop in at least 20 pet cent of cases. Although mastectomy is curative, this is overtreatment in many cases and the best treatment for in situ carcinoma is the subject of a number of clinical trials.

Paget’s disease of the nipple

Pager’s disease of the nipple (Fig. 46.28a and b) is a superficial manifestation of an underlying breast carcinoma. It presents as an eczema-like condition of the nipple and areola which persists in spite of local treatment. The nipple is eroded slowly and eventually disappears. If left, the underlying carcinoma will sooner or later become clinically evident. Thus nipple eczema should be biopsied if there is any doubt about its cause. Microscopically Pager’s disease is characterised by the presence of large, ovoid cells with abundant, clear, pale-staining cytoplasm in the Malpighian layer of the epidermis.

The spread of mammary carcinoma

1. Local spread. The tumour increases in size and invades other portions of the breast. It tends to involve the skin and to penetrate the pectoral muscles, and even the chest wall.

2. Lymphatic metastasis occurs primarily to the axillary lymph nodes and to the internal mammary chain of lymph nodes. The site of the tumour within the breast does not dictate which nodes will be involved, e.g. medial tumours spread just as readily to the axillary nodes as do lateral tumours. The involvement of lymph nodes is not necessarily a chronological event in the evolution of the carcinoma, but rather a marker for the metastatic potential of that tumour. In advanced disease there may be involvement of supraclavicular nodes and of any contralateral lymph nodes.

3. Spread by the bloodstream. It is by this route that skeletal metastases occur (in order of frequency) in the lumbar vertebrae, femur, thoracic vertebrae, rib and skull; they are generally osteolytic. Metastases may also occur in the liver, lung and brain, and occasionally the adrenal glands and ovaries.

Clinical presentation

While any portion of the breast, including the axillary tail, may be involved, breast cancer commences most frequently in the upper, outer quadrant (Figs 46.29 and 46.30). Most breast cancers will present as a hard lump, which may be associated with indrawing of the nipple. As the disease advances locally there may be skin involvement with peau d’orange (Fig. 46.31) or frank ulceration and fixation to the chest wall (Fig. 46.32). This is described as cancer-en­cuirasse. About 5 per cent of breast cancers in the UK will present with either locally advanced disease or symptoms of metastatic disease. This figure is nearer 20 per cent in the developing world. These patients must then undergo a staging evaluation so that the full extent of their disease can be ascertained. This will include a careful clinical examination, chest X-ray, serum alkaline phosphatase and gamma glutamine transaminase (GGT), with liver ultrasound if these are abnormal, and an isotope bone scan (Fig. 46.33). This is important for both prognosis and treatment — a patient with widespread visceral metastases may obtain an increased length and quality of survival from systemic hormone or chemotherapy, but she is not likely to benefit from surgery as she will die from her metastases before local disease becomes a problem. In contrast, patients with relatively small (less than 5 cm in diameter) tumours confined to the breast and ipsilateral lymph nodes rarely need staging beyond a good clinical examination as the pick-up rate for distant metastases is so low.

Phenomena resulting from lymphatic obstruction in Staging of breast cancer

advanced breast cancer

Peau d’orange is due to cutaneous lymphatic oedema. Where the infiltrated skin is tethered by the sweat ducts it cannot swell, leading to an appearance like orange skin. Occasionally the same phenomenon is seen over a chronic abscess.

Late oedema of the arm is a troublesome complication of breast cancer treatment fortunately seen less often now that radical axillary dissection and radiotherapy are rarely combined. It does however occasionally still occur after either modality of treatment alone and appears anytime from months to years after treatment. There is usually no precipitating cause but recurrent tumour should be excluded as neoplastic infiltration of the axilla can cause arm swelling due to both lymphatic and venous blockage. This neoplastic infiltration is often painful due to nerve involvement.

An oedematous limb is susceptible to bacterial infections following quite minor trauma, and these require vigorous antibiotic treatment. Treatment of late oedema is difficult but limb elevation, elastic arm stockings and pneumatic compression devices can be useful.

Cancer-en-cuirasse4. The skin of the chest is infiltrated with carcinoma and has been likened to a coat.

It may be associated with a grossly swollen arm. This usually occurs in cases with local recurrence after mastectomy, and occasionally is seen to follow the distribution of irradiation to the chest wall. The condition may respond to palliative systemic treatment but prognosis in terms of survival is poor.

Lymphangiosarcoma (Fig. 46.34) is a rare complication of lymphoedema with an onset many years following the original treatment. It takes the form of multiple subcutaneous nodules in the upper limb and must be distinguished from recurrent carcinoma of the breast. The prognosis is poor but some cases respond to cytotoxic therapy or irradiation. Interscapulothoracic (forequarter) amputation is sometimes indicated.

There are two traditional systems of classification for breast carcinoma which predominantly rely on clinical staging of the disease. These are the Manchester system and the Inter­national Union Against Cancer TNM (tumour, nodes, metas­tases) staging system. These are illustrated in Table 46.6.

The TNM system was an attempt to allow a common language amongst oncologists world-wide, thus allowing accurate information exchange and evaluation of studies of treatment, as well as providing prognostic information to aid in the planning of treatment for the individual patient. However, this refinement of taxonomy in fact contributes little to any of these activities.

Further subdivisions in the TNM system now mean that there are seven T-stages, four N-stages and three M-stages, allowing for 180 possible combinations. Pathological lymph node staging depends on both the number of lymph nodes removed, thus the extent of surgery, and how assiduous the pathologist is in looking for deposits of tumour within the nodes. ‘M’ staging depends on what investigations have been performed — thus will vary between centres. Consequently staging is observer biased.

Although prognosis broadly correlates with stage, other factors also influence prognosis and should be assessed, for example the Nottingham Prognostic Index includes nor only tumour size and lymph node status but tumour grade.

Conventional staging will indicate broadly which treat­ment is required but again other factors may be equally important. For example, surgical treatment of a small stage I, or II (T1 or T2) breast tumour usually requires only wide local excision rather than mastectomy — but the latter may have to be performed if the breast is very small, the tumour central or multifocal, or for patient preference. Equally the use of adjuvant systemic therapy is decided on not only tumour size and lymph node status but also biological measures such as oestrogen receptor status, patient age and menopausal status, and in the case of tamoxifen this can be recommended irrespective of clinicopathological variables.

Thus as we gain more knowledge of the biological variables which affect prognosis it becomes increasingly clear that it is these factors (discussed in more detail below) rather than anatomical mapping which influence outcome and treatment. Perhaps a more pragmatic approach would be to classify patients according to the treatment that they require. This is shown in Table 46.7.

Prognosis of breast cancer

The best indicators of likely prognosis in breast cancer are still tumours size and lymph node status (Fig. 46.35). However, it is realised that some large tumours will remain confined to the breast for decades whereas some very small tumours are incurable at diagnosis. Hence the prognosis of a cancer depends not on its chronological age but on its invasive and metastatic potential. In an attempt to define which tumours will behave aggressively, and thus require early systemic treatment, a host of prognostic factors has been described. These include histological grade of the tumour, hormone receptor status, measures of tumours proliferation such as 5-phase fraction and thymidine-labelling index, growth factor analysis and oncogene or oncogene product measurements. Many others are under investigation but have proved of little practical value in patient management.