20.2 Benign breast conditions209
20.3 Breast cancer209
20.4 Diagnosis of breast lesions209
20.5 The male breast209
Self-assessment: questions209
Self-assessment: answers209
20.1. The normal female breast
Structure and function
The function of the female breast is to produce and express milk. The functional unit of the breast is called a lobule (Figure 56) and there are numerous lobules within each breast. A lobule consists of a variable number of acini (glands) lined by secretory epithelium. The acini connect to, and drain into, a terminal duct. Each terminal duct and its acini are together referred to as the terminal duct lobular unit. The terminal ducts drain via a series of larger ducts into the lactiferous ducts and sinuses. The lactiferous ducts open onto the skin surface at the nipple. The nipple and areola are covered by stratified squamous epithelium, and the areolar skin is pigmented. Areolar glands of Montgomery produce secretions to lubricate the nipple during lactation.
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| Figure 56 |
The ducts and acini are lined by two cell types – an inner layer of secretory epithelium and an outer layer of myoepithelial cells. Surrounding and supporting the ducts and acini is breast stroma, which consists of loose connective tissue.
Hormonal influences on the breast
Breast tissue is sensitive to many different hormones. The breast undergoes minor changes with the menstrual cycle, more significant changes during pregnancy and lactation, and undergoes involution when hormone stimulation is withdrawn (menopausal and postmenopausal period).
Changes with the menstrual cycle
After ovulation, there is epithelial proliferation and an increase in the number of acini, and the breast stroma becomes oedematous. These changes occur under the influence of oestrogen and rising levels of progesterone. With menstruation, there is a drop in the levels of these sex steroids with consequent apoptosis of epithelial cells and disappearance of the stromal oedema. The breast becomes quiescent again until the next ovulation.
Pregnancy and lactation
A number of hormones, including oestrogen, progesterone, prolactin and growth hormone, are important in the development of the breast during pregnancy. During pregnancy, there is a marked increase in the number of acini and lobules within the breast at the expense of the stroma. The epithelial cells begin to synthesise milk, which is stored in secretory vacuoles in the cell cytoplasm. With delivery of the baby, the levels of oestrogen and progesterone fall, and the activity of prolactin causes the secretion of milk (lactation).
When breastfeeding ceases, the breast tissue regresses back towards the pre-pregnancy state.
Involution
With increasing age and the reduction in the levels of circulating sex steroids, the ducts and acini begin to atrophy and the amount of breast stroma decreases. In the very elderly, the acini may be completely lost, leaving only breast ducts in a little stroma.
20.2. Benign breast conditions
Inflammation
Acute mastitis
Acute mastitis is the most common inflammatory disorder of the breast, and is usually confined to the lactation period. During breastfeeding, the nipple can develop fissures and cracks. Via these cracks, bacteria (usually Staphylococcus aureus) gain access to the breast tissue. The infection is usually confined to one segment of the breast, and is manifest by oedema and erythema of the overlying skin.
If severe and untreated, the acute inflammation may progress to abscess formation.
Mammary duct ectasia
This term is used to refer to dilatation of the breast ducts. The ducts become filled with inspissated breast secretions and there is associated inflammation and fibrosis. If there is an unusually heavy infiltrate of plasma cells, the term ‘plasma cell mastitis’ is sometimes applied. The aetiology of mammary duct ectasia is unknown. Affected women can present with a palpable mass, skin retraction or nipple discharge, which can occasionally be blood-stained. The lesion is of clinical importance because it can be mistaken for carcinoma clinically, grossly and mammographically.
Fat necrosis
This lesion is usually related to previous trauma to the breast, although a history of trauma may not always be obtained. Histologically, there is an initial focus of necrotic fat cells and acute inflammation, which then becomes heavily infiltrated by macrophages that engulf the debris and hence develop a lipid-laden ‘foamy’ appearance. With healing, the focus often becomes replaced by fibrous tissue and there may be (dystrophic) calcification. Affected women present with a palpable breast lump or nipple retraction, raising the suspicion of carcinoma. If there is calcium deposition, lesions may also mimic carcinoma mammographically.
Granulomatous mastitis
This condition is rare. Causes include infections (e.g. tuberculosis, deep-seated fungal infections) and systemic disorders (e.g. Wegener’s granulomatosis, sarcoid).
Fibrocystic changes
This term is used to refer to a wide range of morphological changes to the breast. Fibrocystic change is the commonest disorder of the breast. The exact pathogenesis remains obscure but hormonal imbalances are thought to be important. Affected women are usually aged between 30 and 55 with a marked decrease in incidence after the menopause. The clinical features vary depending on the underlying morphological changes but, in general, fibrocystic change can mimic carcinoma clinically by producing palpable lumps, nipple discharge and mammographic densities. Evidence indicates that some of these conditions are associated with an increased risk of developing carcinoma of the breast (see later).
The morphological subtypes of fibrocystic disease are listed below:
• adenosis
• cysts
• apocrine metaplasia
• fibrosis
• epithelial hyperplasia
• sclerosing adenosis
• radial scars and complex sclerosing lesions.
An individual may show one, or some, or a combination of all of these changes.
Adenosis
This term denotes an increase in the number of acini within a lobule. The gland lumina in adenosis occasionally contain calcium deposits.
Cysts
This term refers to cystic dilatation of acini or terminal ducts. Some cysts may reach a very large size (up to 2–3cm across). The secretions within cysts may calcify.
Apocrine metaplasia
Fibrosis
This is probably a secondary event to rupture of cysts and it may proceed to hyalinisation.
Sclerosing adenosis
In this condition, there is an increased number of acini and increased intralobular fibrosis. The fibrosis causes marked distortion of the acini. The lesion can present as a mammographic density or a palpable mass, therefore mimicking carcinoma. Sclerosing adenosis may be mistaken for carcinoma histologically also. Radial scars and complex sclerosing lesions are morphological variants of sclerosing adenosis, and are characterised by:
• a stellate shape
• a central area of fibrosis and elastosis
• a variable degree of adenosis and distortion of acini.
Radial scar is the term reserved for lesions less than 10mm in diameter, whereas larger lesions are called complex sclerosing lesions. They can mimic carcinoma clinically, mammographically and histologically.
Epithelial hyperplasia
Epithelial hyperplasia is defined as an increase in the number of layers of cells lining the acini or ducts, often resulting in the obliteration of their lumen. Epithelial hyperplasia is classified as being either of usual type or atypical.
Usual-type epithelial hyperplasia (mild, moderate, florid)
In this type, the proliferating epithelial cells show no atypical features. Epithelial hyperplasia is considered mild if the epithelium is three to four cell layers thick, moderate if the epithelium is more than five layers thick, and florid if the lumina are nearly or completely filled by epithelium.
Atypical hyperplasia
In this type, the epithelial proliferations display various degrees of cellular and architectural atypia. There are two subtypes:
• atypical ductal hyperplasia
• atypical lobular hyperplasia.
Benign breast tumours
Fibroadenomas
Fibroadenomas are the most common benign tumour of the breast. The tumours are composed of both glandular and stromal tissue. These benign neoplasms can occur at any age, but they are most commonly seen in women under 35years of age. Fibroadenomas are usually solitary, although in some women they may be multiple and bilateral. In younger women they present as palpable lumps (often freely mobile), and in older women they may present as mammographic densities. They can therefore mimic carcinoma clinically.
Pathology
Fibroadenomas grow within the breast as sharply circumscribed soft to firm nodules, and are usually easily enucleated at surgery. They vary in size from less than 1cm to around 4cm in diameter, although rarely they can reach up to 15cm in diameter (juvenile fibroadenoma/giant fibroadenoma – see below). The cut surface is grey-white and sometimes glistening, and contains slit-like spaces. In older women, fibroadenomas can become calcified. Histologically, these tumours are well-circumscribed nodules consisting of loose cellular stroma associated with breast ducts that, in longitudinal section, appear as compressed and elongated clefts.
The vast majority of fibroadenomas are benign. However, those containing cysts, sclerosing adenosis, epithelial calcification or papillary apocrine change (so-called complex fibroadenomas) are associated with an increased risk of developing breast cancer.
Juvenile fibroadenoma / giant fibroadenoma
These terms are interchangeable and are used to refer to a reasonably distinct type of fibroadenoma that tends to occur in adolescents (often black girls) and reaches a large size (over 10cm in diameter). Histologically, they also tend to be rather hypercellular, but cellular atypia is not a feature.
Duct papillomas
Duct papillomas are uncommon and are usually seen in middle-aged women. They appear as outgrowths projecting into the duct lumen and consist of a fibrovascular core covered by benign breast duct epithelium. There are two types of duct papilloma:
• Large duct papillomas – these arise within the large central breast ducts and are usually solitary. Presentation is usually with a bloodstained nipple discharge, although some present as palpable lumps or mammographic densities. They are associated with an increased risk of developing carcinoma.
• Small duct papillomas – these arise in the smaller peripheral ducts, are often asymptomatic, and may be multiple. Multiple small duct papillomas are seen in younger patients, and are associated with an increased risk of developing breast cancer.
Adenomas
Adenomas of the breast are rare. There are three main subtypes:
• Tubular adenomas – these are sharply circumscribed nodules composed of closely packed ductal structures with little intervening stroma.
• Lactating adenomas – these are adenomas that arise during pregnancy and lactation.
• Nipple adenomas – these present as nodules just under the nipple. Microscopically, they consist of proliferating ductal structures and show a variety of growth patterns. The overlying skin may become ulcerated, mimicking Paget’s disease of the nipple (see below).
Benign connective tissue tumours
Risk of invasive breast carcinoma in women with benign breast disease
Several large case–control studies have now clarified the association between benign breast abnormalities and breast cancer risk.
There is no increased risk in the presence of:
• mastitis
• duct ectasia
• ordinary cysts
• apocrine metaplasia
• adenosis
• fibrosis
• mild usual-type epithelial hyperplasia without atypia
• fibroadenoma without complex features.
There is slightly increased risk (1.5–3 times) in the presence of:
• moderate or florid usual-type epithelial hyperplasia without atypia
• radial scars/complex sclerosing lesions
• fibroadenoma with complex features
• duct papilloma.
There is moderately increased risk (4–5 times) in the presence of:
• atypical ductal hyperplasia
• atypical lobular hyperplasia.
A family history of breast cancer increases the risk in all categories.
Some researchers have advocated a new classification system for benign breast disease that reflects the above observations. Three main categories of disease are defined in this system:
• non-proliferative diseases – this category includes the entities that are associated with no increased risk of developing breast cancer
• proliferative diseases without atypia – this category includes entities that are associated with a slightly increased risk of developing breast cancer
• proliferative diseases with atypia – this category includes atypical hyperplasia.
20.3. Breast cancer
Breast cancer is a major cause of cancer morbidity. One woman in eight will develop breast cancer in her lifetime and, of these, a third will die from the disease.
Risk factors
The cause of breast cancer is still uncertain, but a number of factors that increase the risk of developing breast cancer have been identified.
Genetic predisposition
It has long been known that there is a familial aggregation of breast cancer, and at least four genes that convey increasing susceptibility to breast cancer have been identified. These are:
• BRCA1
• BRCA2
• p53
• ATM gene (responsible for ataxia telangiectasia).
Genetic predisposition is responsible for only 5–10% of breast cancer cases.
Age
Breast cancer is uncommon before the age of 25years, but the incidence increases steeply with age, doubling about every 10years until the menopause. The rise slows in the postmenopausal period.
Factors related to menses
Early age at menarche and late age at menopause are associated with an increased risk of breast cancer. These findings indicate that hormones may have an important role in the development of carcinoma of the breast.
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