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 (– – – –>).

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.

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.

Terminology

The old term for proliferative conditions of the breast was ‘chronic mastitis’; this is incorrect, as these are not inflammatory conditions, but the name may have arisen because of the tenderness that can occur in some cases. Other names include fibroadenosis, epithelial hyperplasia, fibrocystic disease, cystic hyperplasia and mammary dysplasia. Since some of the features are similar to physiological changes the term ‘fibrocystic change’, rather than ‘disease’, is now used.

The terms fibroadenosis and epithelial hyperplasia describe the proliferative changes that occur in the condition (see below), and are appropriate terms for the changes that occur in the 30–45-year age group. Fibrocystic change and cystic hyperplasia are descriptive of the changes that occur from 40–45 years to the menopause, when cysts are more prominent. The term ‘mammary dysplasia’ is not really correct, as true dysplasia occurs only in a few cases.

Incidence

Estimates indicate that at least 10% of women develop clinically apparent benign proliferative breast disease, although breast tissue from women at postmortem shows such changes to be present in 50% or more, suggesting that lesser degrees of change are much more common.

Aetiology and pathogenesis

Although benign proliferative breast disease is not uncommon, the aetiology is poorly understood. There is no doubt that ovarian hormones participate in its causation but the means by which the changes are produced are still obscure.

The fact that the incidence of benign proliferative changes increases as the menopause gets nearer, and that failure of ovulation also increases in this time period, suggests that the relative imbalance between oestrogen and progesterone in each menstrual cycle could be an important aetiological factor. The disturbance may involve interaction of the pituitary and the ovaries. Alternatively, the fault may lie in the responsiveness of the breast tissue to the hormonal influences. Not all parts of the breast are equally affected by the hormonal changes occurring in each menstrual cycle, and this may account for the focal nature of the changes.

Cystic change is considered to be due to an imbalance between epithelial hyperplasia, together with ductal and lobular dilatation, that occurs with each menstrual cycle, and subsequent regressive changes. The cystic dilatation thus occurs because of a distortion of cyclical changes rather than as a consequence of obstruction, which is the usual cause in other organs.

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.

Histological features

A variety of histological changes can occur (Fig. 18.8). These are:

Fig. 18.8 Fibrocystic change. There is adenosis (1), papilloma formation (2), epithelial hyperplasia (3) and small cysts (4).

An individual woman may show one, some or all of these changes. However, the types of change do tend to vary with the age of the patient.

Sclerosing adenosis

In sclerosing adenosis there is lobular proliferation but the acini become distorted. The proliferation involves both epithelium and myoepithelium, but the latter tends to predominate. Large amounts of collagen can intervene between the glandular components, although the extent of this varies both within the same breast and between patients (Fig. 18.9). Due to the collagen component these lesions can mimic carcinomas clinically, and on mammograms where the associated calcification can be seen.

Fig. 18.9 Sclerosing adenosis. There are glandular structures with intervening cords of cells in a fibrous stroma. Areas of calcification (arrowed) are also present; these would render the lesion visible on mammography.

Epithelial hyperplasia

Epithelial hyperplasia, previously called epitheliosis, is the proliferation of epithelial cells that occurs in the small interlobular ducts, the intralobular ducts and the acini, resulting in a solid or almost solid mass obliterating the lumens (Fig. 18.10).

Fig. 18.10 Epithelial hyperplasia. The duct lumen is filled by hyperplastic epithelium.

Atypical hyperplasia

The epithelial hyperplasia that can result in total or partial occlusion of the acini and small ducts may sometimes show abnormalities of cellular growth, with disordered orientation of cells, nuclear pleomorphism and occasional mitotic figures. This is termed either atypical ductal or atypical lobular hyperplasia, depending on its situation. It is important for the pathologist to identify these cellular changes (see below).

Gross appearance

Fibroadenomas are well circumscribed with a lobulated appearance (Fig. 18.12), and range in size from 10 to 40 mm in diameter, although larger tumours can occur in juvenile fibroadenoma (see below). The surrounding breast tissue can become compressed, but the tumour is not tethered; this lack of fixation accounts for its mobility on clinical examination, and the nickname of ‘breast mouse’. In young women, the tumours are soft and have a slightly gelatinous cut surface due to the loose connective tissue component; however, in older women they tend to be firmer as the connective tissue becomes more fibrous and sometimes calcified.

Fig. 18.12 Fibroadenoma. The outer surface is smooth, well circumscribed, and has a lobulated appearance.

Histology

Fibroadenomas show duct-like structures or elongated and thinned ductular structures associated with overgrown connective tissue masses (Fig. 18.13). Fibroadenoma does not progress to malignancy, although very occasionally a tumour, such as lobular carcinoma, will involve a fibroadenoma.

Fig. 18.13 Fibroadenoma. Elongated duct-like structures are surrounded by loose connective tissue.

Juvenile fibroadenoma

Large (50–100 mm in diameter) fibroadenomas can occur in the breast of girls, the tumours growing quite rapidly. They are more frequent in Africans and West Indians than in Caucasians. The tumours are benign and should not be confused with phyllodes tumour.

Female sex and age

Around 1% of all breast cancers occur in men, so being female is an important risk factor. As with all carcinomas, increasing age is another significant factor. Up to the age of 50 years, the rate of increase is steep; it then slows down, although the incidence of breast cancer continues to increase into old age (Fig. 18.16).

Fig. 18.16 The incidence of breast cancer in the UK related to age. There is a marked increase between the ages of 40 and 50, but the highest incidence is in those aged 60–70 years.

Age at menarche and menopause

There is a significantly higher risk of developing breast cancer among women with an early age at menarche. At the other end of the reproductive life, women whose natural menopause occurs before 45 years have only half the breast cancer risk of those whose menopause occurs after 55 years. Therefore women with 40 or more years of active menstruation have twice the breast cancer risk of those with fewer than 30 years of menstrual activity.

Age at first full-term pregnancy

Nulliparous women have an increased risk of developing breast cancer. However, among parous women protection is related to early age for the first full-term pregnancy. If the first birth is delayed to the mid or late thirties, the woman is at a greater risk of developing breast cancer than is a nulliparous woman.

Weight and diet

For women of above average weight but below 50 years of age there is little or no increased risk of developing breast cancer. However, women aged 60 or over whose weight is increased have a higher cancer risk. Diet, obviously, can be a determinant for weight. In rodents, a high-fat diet increases the incidence of breast tumours, and international breast cancer incidence rates correlate with the consumption of fat. Although these observations suggest that a high-fat diet may be a risk factor, the evidence is not as clear as it is for weight.

Radiation

Women treated for Hodgkin’s disease by mantle radiation are at an increased risk of developing breast cancer and now undergo surviellance.

Family history and genetic factors

Breast cancer is common, thus a history of a relative having breast cancer can be found in at least 10% of new cases. However, a proportion of these will be sporadic cancers and not due to familial (inherited genetic) factors. The risk of developing breast cancer is increased in first-degree relatives (e.g. sister, daughter) of breast cancer cases, particularly if that person is pre-menopausal. For example, the risk increases to nine-fold for first-degree relatives of pre-menopausal women with bilateral breast cancer. Up to five-fold increases in risk have been found for women with multiple first-degree relatives with breast cancer.

There are rare familial syndromes such as Li–Fraumeni, in which there is an association between sarcomas, brain tumours and breast cancer at a young age. This is linked in some families to abnormalities of the p53 gene. Approximately 4–6% of breast cancers are associated with a very strong family history and in certain families there is breast and ovarian cancer. Inherited mutations of a gene on the long arm of chromosome 17 (BRCA1) are responsible for families with susceptibility to female breast and ovarian cancer. Another susceptibility gene, BRCA2, located on chromosome 13q12–13, is linked to families with early-onset breast cancer, including male breast cancer. Products of both genes are involved in DNA repair mechanisms. An inherited deletion in CHEK2 increases breast cancer risk.

There are likely to be yet more moderate- or low-risk genes that confer susceptibility. It must be remembered that this explains only a small proportion of breast cancers.

Geographic variation

There is a marked variation in breast cancer rates between different countries. The highest rates are in North America, north-west Europe, Australia and New Zealand, with the lowest in South-East Asia and Africa. Several factors probably contribute to this difference: age at menarche, age at first full-term pregnancy, age at menopause and post-menopausal weight. The length of time between age at menarche and first pregnancy may be quite short in some of these low-incidence countries.

Atypical hyperplasia

Women with benign breast disease whose breast biopsies show atypical epithelial hyperplasia have a definite increased risk of developing breast cancer. Ordinary epithelial hyperplasia is associated with a slightly increased risk. The risk is augmented by a family history of breast cancer.

Hormones

The association of breast cancer risk with menarche, menopause and first full-term pregnancy indicates that hormones must have some role in the development of carcinomas, but they are more likely to be promoters than initiators.

Oestrogen activity appears to be important, with overexposure to oestrogens and underexposure to progesterone being significant. Early menarche and late menopause will result in a higher number of menstrual cycles, with repeated surges of oestrogen having a stimulatory effect on breast epithelium. The beneficial effect of early full-term pregnancy could be due to the high concentrations of progesterone and/or prolactin protecting the breast cells against oestrogens in the long term. The risks associated with obesity may be partly due to the ability of fat cells to synthesise oestrogens, or to altered levels of sex hormone-binding protein levels.

Oral contraceptives/hormone replacement therapy

There is a slightly increased risk for current and recent users of oral contraceptives but no long-term increase. Combined oestrogen and progesterone hormone replacement therapy increases the relative risk of developing breast cancer for current users by two-fold, and is greater the longer the duration of treatment. The risk decreases with cessation. Oestrogen-only preparations have a lower risk.

Hormone receptors

Hormones have an effect on cells only after interacting with specific receptors present on or in their target cells. The sex steroid, oestrogen, interacts with a nuclear receptor. Subsequent interaction with DNA results in the formation of differentiation- and proliferation-associated factors. Prolactin and other polypeptides interact with receptors on the cell surface (Fig. 18.17).

Fig. 18.17 Hormone-responsive breast epithelium.

Oestrogen receptors can be detected in varying amounts in about 75% of breast cancers. The progesterone receptor, which can normally be formed only when the oestrogen receptor is present and active, is present in about 50% of tumours, and women whose tumours contain both types of receptor are more likely to respond to some form of hormone manipulation therapy. This suggests that hormones are important in the growth and maintenance of these carcinomas.

Viruses

In mice a tumorigenic virus is transmitted via milk (the Bittner factor). However, no similar agent has been found for human breast cancer.

Ductal carcinoma in situ

Ductal carcinoma in situ can occur in both pre- and post-menopausal women, usually in the 40–60-year age group. It can present as a palpable mass, especially if extensive and associated with fibrosis. If the larger ducts are involved, presentation can be as a nipple discharge, or as Paget’s disease of the nipple. The disease can be found incidentally in surgical biopsies or be detected by mammography screening due to the presence of calcification. Pure ductal carcinoma in situ accounts for about 5% of breast carcinomas that present clinically.

The size of the area involved in the breast can range from 10 to 100 mm in length. It is usually unifocal, being confined within one quadrant of the breast, although multicentricity can occur with larger lesions. Bilateral disease is uncommon. The macroscopic appearances depend on the architecture of the ductal carcinoma in situ. Creamy necrotic material can exude from the cut surface of the breast, rather similar in appearance to comedones.

Histologically, the changes are to be found in the small and medium-sized ducts, although, in older women, the larger ducts can be involved. The ducts contain cells that show cytoplasmic and nuclear pleomorphism to varying degrees. Mitotic figures may be frequent and can be abnormal. These features are used to classify ductal carcinoma in situ into high grade (more aggressive features) and non-high grade lesions. The ducts may be completely filled with cells (solid pattern), or have central necrosis (comedo pattern; Fig. 18.18) which may calcify, rendering the lesion mammographically detectable. The cribriform pattern of ductal carcinoma in situ has numerous gland-like structures within the sheets of cells. Ductal carcinoma in situ can spread along the duct system or into the lobules.

Fig. 18.18 Ductal carcinoma in situ. Both ducts are expanded. One has (A) a central necrotic area which has calcified and would show on a mammogram. The basement membrane (B) is intact.

The previous management of ductal carcinoma in situ was generally mastectomy, so it is difficult to know the fate of these lesions if left. Estimates of residual carcinoma changing from non-invasive to invasive range from one-third to one-half, based on studies where there was local incomplete excision. If the tumour is completely removed the woman’s prognosis is excellent.

Lobular carcinoma in situ

Lobular carcinoma in situ occurs more frequently in pre-menopausal women, but can be found in biopsies taken to investigate mammographic (screening) abnormalities. A major problem is that it does not present as a palpable lump and is usually found in biopsies removed for other reasons. A further important clinical feature is that it is often multifocal within the one breast and is frequently bilateral. Not surprisingly, there are no specific radiological or macroscopic features.

Histologically, the changes are found in the acini—hence the term ‘lobular’—although they may extend into extralobular ducts and replace ductal epithelium (Fig. 18.19). Within the acini, the normal cells are replaced by relatively uniform cells with clear cytoplasm that appear loose and non-cohesive. The overall size of the acini increases, but the lobular shape is retained. Unlike the situation in ductal carcinoma in situ, necrosis is unusual.

Fig. 18.19 Lobular carcinoma in situ. A breast lobule in which the acini are expanded. There is complete loss of the lumen and of the two-cell layer.

About one-quarter to one-third of all patients with lobular carcinoma in situ who are treated by biopsy alone will go on to develop an invasive carcinoma. This may occur in either or both breasts and there may be a long time interval.

Gross features

The macroscopic appearance of the tumours tends to depend on the amount or type of stroma within the carcinoma. It is this that gave rise to the terms previously applied to tumours: scirrhous, medullary (or encephaloid) and mucinous (or colloid).

The term scirrhous implies that there is a prominent fibrous tissue reaction, usually in the central part of the tumour. This results in the carcinoma having a dense white appearance, which grates when cut. Yellow streaks may be seen; these are due to the presence of elastic tissue within the tumour. Carcinomas with a prominent stromal reaction usually have irregular edges, extending into the adjacent fat or other structures (Fig. 18.20).

Medullary (brain-like) tumours are very cellular with little stroma. The edges of the carcinoma are often more rounded and discrete than those of the scirrhous tumours (Fig. 18.21). Necrosis is common. When palpated the tumours feel much softer.

Fig. 18.21 Medullary carcinoma. Breast tissue containing a 60 mm diameter carcinoma with a rounded edge, and no evidence of a fibrous reaction.

Mucinous carcinomas have a predominance of mucin, or jelly-like, material within them. They usually have a well-defined edge.

Some of the changes that occur within carcinomas explain their clinical features, for example skin and nipple retraction due to the fibrous reaction.

Infiltrating ductal carcinomas

Infiltrating duct or ductal carcinomas of no special type comprise the majority (up to 75%) of infiltrating breast carcinomas. Macroscopically, they usually have a scirrhous consistency. The size of the tumours varies between patients. They can occur in both pre- and post-menopausal women.

Histologically, the tumour cells are arranged in groups, cords and gland-like structures. Quite marked variations can be seen between different carcinomas even though they are of the same type (Fig. 18.22). For example, the size of the solid groups of cells can be variable, and ductal carcinoma in situ is often present. The amount of stroma between the tumour cells can also vary, but in those carcinomas in which it is prominent it is most marked at the centre, with the periphery being more cellular. Collections of elastic tissue (elastosis) around ducts or within the stroma are common in tumours with a scirrhous reaction.

Fig. 18.22 Infiltrating ductal carcinoma. The lesion is composed of irregular solid groups of cells in a dense fibrous stroma, with an associated lymphocytic infiltrate.

The degree of differentiation or grade of the tumour is based on the extent to which it resembles non-tumorous breast: whether the cells are in a gland-like pattern or as solid sheets; the degree of nuclear pleomorphism; and the number of mitotic figures present. A well-differentiated (grade I) infiltrating duct carcinoma tends to behave less aggressively than a poorly differentiated (grade III) tumour, which is composed of sheets of pleomorphic cells with large numbers of mitotic figures.

Infiltrating lobular carcinomas

While lobular carcinoma in situ usually occurs in pre-menopausal women, the infiltrating lesion can also occur in post-menopausal women. In the UK, infiltrating lobular carcinomas constitute about 10% of invasive breast carcinomas, but the incidence may vary in other parts of the world.

Infiltrating lobular carcinomas have abundant fibrous stroma, so that macroscopically they are always scirrhous. While infiltrating ductal carcinomas usually form at one focus in the breast, infiltrating lobular carcinomas can be multifocal throughout the breast.

Histologically the cells are small and uniform and are dispersed singly, or in columns one cell wide (‘Indian files’; Fig. 18.23), in a dense stroma. Elastosis can be present. The cells infiltrate around pre-existing breast ducts and acini, rather than destroying them as occurs with invasive duct carcinomas. This method of infiltration may account for the occasional multifocal nature of the tumours. The cells in some carcinomas may appear signet-ring in shape due to the accumulation of mucin within an intracytoplasmic acinus, displacing the nucleus to one side. A characteristic feature of these tumours is that the cells lack the cell adhesion molecule E-cadherin, which may account for their pattern of spread. Residual lobular carcinoma in situ can sometimes be found in the invasive tumours.

Fig. 18.23 Infiltrating lobular carcinoma. Strands of single cells (Indian file) invade fibrous stroma.

Mucinous carcinomas

Mucinous carcinomas (also known as colloid, mucoid and gelatinous carcinomas) usually arise in post-menopausal women and comprise 2–3% of invasive carcinomas.

Macroscopically, the tumours are well circumscribed and have a soft, grey, gelatinous cut surface. They vary in size from 10 to 50 mm in diameter. Since there is no dense stroma and the edges are rounded, these tumours do not cause retraction of the nipple or tethering of the skin.

These carcinomas comprise small nests and cords of tumour cells, which show little pleomorphism, embedded in large amounts of mucin (Fig. 18.24). The latter is composed of neutral or weakly acidic glycoproteins, which are secreted by the tumour cells and are different from the proteoglycans of the stroma.

Fig. 18.24 Mucinous carcinoma. Small solid and tubular groups of cells lie in pools of mucin, or jelly-like material.

The survival of women with mucinous carcinomas is better than that of those having invasive duct or lobular carcinomas.

Tubular carcinomas

As the name implies, tubular carcinomas are well-differentiated carcinomas composed of cells arranged as tubules. They are often small lesions, less than 10 mm in diameter, and are firm, gritty tumours with irregular outlines. Tubular carcinomas form 1–2% of invasive carcinomas but constitute a higher proportion of screen-detected tumours.

Histologically, they are composed of well-formed tubular structures, the cells of which show little pleomorphism or mitotic activity. The stroma is dense, often with elastosis (Fig. 18.25).

Fig. 18.25 Tubular carcinoma. Tubular profiles lie in a fibrous stroma.

Patients with tubular carcinomas do extremely well—better than those with well-differentiated invasive duct carcinomas.

Medullary carcinomas

The incidence of medullary carcinomas is difficult to assess because not all of the criteria for diagnosis have been strictly adhered to in some studies; hence figures have ranged from very rare to 5%. These tumours usually occur in post-menopausal women.

Medullary carcinomas are circumscribed and often large. Histologically, they are composed of large tracts of confluent cells with little stroma in between them. The cells show quite marked nuclear pleomorphism, and mitotic figures are frequent. There is never evidence of gland formation. These cytological appearances put them into the ‘poorly differentiated’ category. Around the islands of tumour cells there is a prominent lymphocytic infiltrate, predominantly T-lymphocytes, with macrophages (Fig. 18.26).

Fig. 18.26 Medullary carcinoma. Large groups of irregularly shaped tumour cells are surrounded by an infiltrate of lymphocytes.

Despite the aggressive cytological features of these tumours, the patients have a significantly better 10-year survival than women with invasive duct carcinomas. It may be that the lymphocytic and macrophage infiltrate has a beneficial effect, and this has stimulated much research into the immunological responses to tumours generally.

Papillary carcinomas

Papillary carcinomas are rare tumours that occur in post-menopausal women. They are usually circumscribed and can be focally necrotic, with little stromal reaction. The tumours are in the form of papillary structures, and areas of intraductal papillary growth are usually found.

The prognosis of patients with these carcinomas is probably better than that of the much more common invasive duct carcinoma.

Other types

Much rarer types of breast carcinoma include: adenoid cystic carcinomas; secretory carcinomas, which occur predominantly in juveniles; apocrine carcinomas, which are composed of cells with abundant eosinophilic cytoplasm; and carcinomas showing metaplasia, e.g. squamous, spindle cell, cartilaginous and osseous features.

Type of carcinoma

Medullary, mucinous, tubular and, possibly, invasive lobular carcinomas generally behave less aggressively than other types, but these constitute the minority of types so that this knowledge is of value to only a few patients.

Histological grade

As described above, tumours can be graded for their degree of differentiation. Patients whose tumours are well differentiated (grade I), showing greater resemblance to non-malignant breast, do better, while those whose tumours are poorly differentiated (grade III) do worse; however, prediction of how the group with moderately differentiated carcinomas will do is more difficult.

Stage

When a woman presents with a breast carcinoma, staging is undertaken so as to assess the absence or presence and extent of spread both locally and distantly. The management of the patient will depend on the stage of the disease. The two main systems used are the International Classification of Staging and the TNM (Tumour, Node, Metastasis) system (Table 18.2).

Table 18.2 The main staging systems used to assess the extent of spread of breast carcinomas

If there is evidence of metastatic spread to axillary lymph nodes when the patient presents with the primary carcinoma, both the 5- and 10-year survival figures are worse than in those with no evidence of metastasis. The outlook for the patient is also worse if there is evidence of more distant spread.

Oestrogen receptors

The presence of oestrogen receptors within a carcinoma indicates that the tumour cells have a higher degree of functional differentiation. It is thus not surprising that women whose tumours are oestrogen receptor-positive have better survival figures than those whose carcinomas are oestrogen receptor-negative. More importantly, they are more likely to benefit from tamoxifen, an oestrogen receptor antagonist.

Growth kinetics

The growth activity of carcinomas can be measured by several methods; that of breast carcinomas may be low, medium or high. Tumours with lower cell growth rates tend to behave better clinically. It must be remembered that tumours with a high rate of division may also have a high cell death rate by apoptosis, and that not all cell divisions result in doubling of the population as the division may be abnormal.

HER-2

The oncogene c-erbB-2/HER-2 is altered in approximately 20% of invasive breast carcinomas. There is amplification of the gene with resultant overexpression of the membrane-related protein. Patients whose carcinomas have this alteration have a poorer prognosis. A humanised monoclonal antibody, trastuzumab (Herceptin) has been developed, which can be used as adjuvant treatment and to treat women with metastatic disease, if the cancers have the molecular alteration.

Examples of the effects some of these prognostic factors may have on survival are shown in Figure 18.29.

Fig. 18.29 Relationship of various prognostic factors with survival for patients with operable breast cancer. Grade or degree of tumour differentiation (grade I = well differentiated; grade II = moderately differentiated; grade III = poorly differentiated). 10-year survival. Presence or absence of lymph node metastasis, and relationship to number of lymph nodes involved. 10-year survival. Presence or absence of oestrogen receptor within the tumours. 5-year survival (less significant after this period).