304 North Cardinal St.
Dorchester Center, MA 02124
304 North Cardinal St.
Dorchester Center, MA 02124
The female breast ( E-Fig. 18.1 H ) is dependent for its normal activity on oestrogen and progestogens and thus exhibits considerable structural and functional variation throughout life. Apart from the overt changes occurring during puberty, pregnancy, lactation ( E-Fig. 18.2 H ) and menopause, subtler changes also occur within the normal menstrual cycle. As a corollary, hormonal disturbances probably underlie various benign breast disorders and probably also play some part in the pathogenesis of more serious conditions such as breast cancer . Likewise, the male breast normally remains rudimentary unless breast enlargement, gynaecomastia ( Fig. 18.5 ), is induced by exogenous or endogenous hormone imbalance; it may also result from the use of certain drugs, for example spironolactone.
Most clinically significant breast disorders present as a lump and the major imperative is to identify those that are malignant tumours so that the patient may be treated promptly. Breast cancer screening programmes use radiological techniques ( mammography and/or ultrasound ) to identify clinically undetectable, suspicious breast lesions, including abnormal calcifications. A tissue diagnosis is then made by fine needle aspiration (FNA) and/or core biopsy before definitive treatment is undertaken. It is expected that early removal of very small tumours will be curative.
Infections of the breast are uncommon and mainly occur during lactation; bacteria (usually Staphylococcus aureus ) gain access through cracks and fissures in the nipple and areola. Without early antibiotic therapy, the resulting bacterial mastitis may be followed by the development of a breast abscess that may require surgical drainage. More commonly, localised areas of inflammation of the breast follow trauma, which may be of sufficient severity to produce a condition known as fat necrosis ( Fig. 18.1 ).
A adipose tissue Ap apocrine metaplasia C cyst F fibrosis In inflammatory infiltrate L lipophages
Non-neoplastic breast disease includes a number of disorders that may give rise to a palpable mass or a mammographic abnormality. These conditions may include alterations to the stroma, to the glandular architecture or to the glandular epithelium; usually more than one element is involved. Calcification is not uncommon in these benign lesions and must be differentiated from calcification seen in malignant breast disease. This is not always possible using imaging techniques and biopsy may be required to determine the nature of the lesion.
Simple fibrocystic change ( E-Fig. 18.4 G ) involves cystic dilatation of ducts, apocrine metaplasia of the epithelium and fibrosis of stroma ( Fig. 18.2 ). Adenosis refers to a benign proliferation of glands that may be combined with fibrosis (sclerosis) of the stroma to give rise to sclerosing adenosis ( Fig. 18.3 ), which can be difficult to differentiate from invasive carcinoma both clinically and pathologically. Similar changes with proliferation and distortion of benign breast ducts and lobules along with fibrosis of the stroma may be seen in radial scars and complex sclerosing lesions . A third type of benign lesion is usual ductal hyperplasia (UDH) where there is an increase in the number of layers of cells lining the ducts, i.e. more than the normal two layers. This is generally graded as mild, moderate or florid ductal hyperplasia. Atypical ductal hyperplasia (ADH) ( Fig. 18.4 ) is a condition intermediate between hyperplasia and carcinoma in situ and carries with it a small, but significantly increased, risk of developing carcinoma. Columnar cell change or hyperplasia is another benign lesion often associated with micro-calcifications and, when there is associated epithelial atypia, it may confer a slight increase in the risk of developing cancer.
With the exception of ADH, sclerosing adenosis and atypical columnar cell lesions, the above conditions carry little or no increased risk of malignancy. Benign breast disorders may be difficult to differentiate clinically from carcinoma. Furthermore, these conditions are common and thus may occur concurrently with, but independently of, invasive carcinoma.
A acinar structures D duct F fibrosis
The most common benign neoplasm of the breast is the fibroadenoma ( Fig. 18.6 ), a localised proliferation of breast ducts and stroma. Such lesions occur most frequently in isolated form in women aged 25–35 years. The phyllodes tumour ( Fig. 18.7 ) is related to the fibroadenoma except that it has a tendency to recur and some are frankly malignant. The only other benign tumour of much clinical significance is the benign intraductal papilloma ( Fig. 18.8 ), usually occurring as a solitary lesion in one of the larger mammary ducts. Histologically similar papillary lesions may also be multifocal, a condition known as intraductal papillomatosis . These lesions tend to occur in the smaller ducts and are associated with a small but definite increase in the risk of carcinoma.
Malignant tumours of the female breast are extremely common, with a peak incidence in the decade before the menopause. Most are adenocarcinomas arising from the epithelium of the terminal duct–lobular unit. Traditionally, these tumours were thought to resemble ductal or lobular breast structures and were named accordingly. The most recent edition of the World Health Organization (WHO) Classification of breast tumours recommends the term invasive carcinoma of no special type for those tumours that would previously have been called ductal carcinomas, recognising that this is essentially a default diagnostic group, used only after excluding all of the other ‘special’ types of breast carcinoma, including lobular carcinoma . These ‘special’ subtypes of invasive carcinoma are associated with distinct clinical and pathological features, often with a good prognosis; examples are tubular carcinoma and mucinous carcinoma of the breast ( Fig. 18.10 ). Medullary carcinoma (not illustrated) is a rare variant characterised by high grade histological features and a prominent inflammatory infiltrate. A range of histological appearances of breast carcinoma is illustrated in Figs 18.9 to 18.12 .
In many cases, the development of invasive breast cancer is preceded by carcinoma in situ, in which the malignant cells proliferate within the mammary ducts or lobules but do not breach the basement membrane ( ductal or lobular carcinoma in situ ( DCIS or LCIS )). Risk factors for breast carcinoma include younger age at menarche, later first live birth, family history of breast cancer and previous biopsy with ADH.
In some cases of breast carcinoma, both in situ and invasive, malignant cells may spread along mammary and lactiferous ducts onto the surface of the nipple resulting in Paget’s disease of the nipple ( Fig. 18.13 ).
Sarcomas also occur in the breast, the most common being angiosarcoma (see Fig. 11.12). This may follow previous radiotherapy for treatment of breast carcinoma. Carcinoma of the breast does occur in males but is extremely uncommon.
B rigid cell bridges D ductal structures F fibrous tissue In intra-canalicular pattern L leaf-like pattern P peri-canalicular pattern N solid cell nests Ne necrosis S glandular space St stroma
F fibrous tissue L lobular carcinoma in situ M malignant cells Mu mucin N malignant cell nests T tubular structures
The ideal aim is to give each patient exactly the right type and amount of treatment for their particular cancer. Breast cancer is not a single disease, but a group of conditions that progress at different rates and respond differently to treatments. The difficulty is to identify those cancers that need extra treatment (in addition to surgery and radiotherapy) and those that will respond to hormonal therapies.
Treatment is primarily dependent on the type, grade and clinical and pathological stage of the tumour. Patient factors such as age, other health problems and patient preferences are also important. However, in addition, the presence of oestrogen and progestogen receptors (ER and PR) in breast cancer cells has been shown to confer an improved prognosis and to render the cancer susceptible to hormonal treatment. Testing cancers for ER and PR has been standard practice for many years. More recently, the presence of human epidermal growth factor 2 ( HER-2 or erbB2 ) has been shown to confer a worse prognosis. HER-2 is a normal component of normal cells but it is overexpressed in about 20% of breast cancers, usually high grade, high stage, poor prognosis tumours. Tumours that overexpress her-2 (usually because of gene amplification) are likely to respond to treatment with drugs such as trastuzumab. These are monoclonal antibodies, specifically targeting the her-2 protein and able to switch it off.
More recently, genomic testing has offered the hope of even better risk stratification, determining which patients are at highest risk of disease recurrence and which will benefit most from chemotherapy and radiotherapy. Tumour gene expression is analysed and a score is assigned to estimate likely patient risk and benefit from therapy.
Combinations of surgery, hormonal therapy, chemotherapy and radiotherapy are typically used in managing breast carcinoma, depending upon patient fitness, tumour stage at presentation and other features such as tumour hormone receptor status and HER-2 status. Where feasible, most tumours are treated by initial surgical excision, often with sampling of axillary lymph nodes to look for nodal metastases (see box ‘Sentinel node biopsy’ in Ch. 7). If the resected tumour demonstrates high risk features, the patient is then more likely to be offered additional or adjuvant chemoradiotherapy post-operatively.
In some patients, primary surgical excision of the tumour may not be feasible. This may be due to the tumour being locally advanced or even known to be metastatic at the time of diagnosis. Some of these patients with advanced disease may benefit from neoadjuvant chemoradiotherapy , which aims to reduce the extent of disease, and may facilitate subsequent surgical removal. Use of neoadjuvant treatment in breast cancer has increased greatly in recent years. From a pathological perspective, this often necessitates more detailed assessment of diagnostic biopsies than would traditionally have been required. For example, small biopsy specimens of tumour should be provisionally graded and also tested for hormone receptors and HER-2 . These features may guide selection of patients for neoadjuvant therapy.
Familial breast cancer constitutes about 5%–10% of all breast cancers and up to 40% in women less than 35 years of age. Of familial breast cancers, up to 20% occur in women with mutations in the breast cancer susceptibility genes BRCA1 and 2. Mutations in these two genes are also found in almost all women with hereditary ovarian carcinomas. These discoveries offer the hope of genetic testing for members of affected families and the possibility of prophylactic treatment. In addition, although the histopathological appearances of these tumours are somewhat different from non-hereditary types of breast cancer, the discovery of these genes offers new insights into the mechanisms of carcinogenesis.
P Paget’s cells
|Fat necrosis ( E-Fig. 18.3 G )||Fat cells with loss of nuclei, inflammatory infiltrate rich in foamy histiocytes||18.1|
|Fibrocystic change ( E-Fig. 18.4 G )||Dilated ducts with apocrine metaplasia of the epithelium, fibrosis of the stroma||18.2|
|Sclerosing adenosis||Proliferation and distortion of small benign ducts in a fibrotic stroma||18.3|
|Ductal hyperplasia||Increase in thickness of epithelial cell layers lining ducts||18.4|
|Atypical ductal hyperplasia (ADH)||Increased epithelial cells within a duct with many of the features of low grade ductal carcinoma in situ but more limited in extent|
|Gynaecomastia||Enlargement of ducts, increased thickness of epithelial layers, increased periductal fibrous tissue in the male breast||18.5|
|Fibroadenoma ( E-Fig. 18.5 G )||Mixture of benign epithelial and stromal components forming a discrete, usually mobile mass||18.6|
|Phyllodes tumour||Mixture of epithelial and stromal elements with overgrowth of the stromal component giving a ‘leaf-like’ pattern, increased cellularity and cytological atypia of the stroma: a few are malignant||18.7|
|Intraductal papilloma||Branching stromal structures covered by cuboidal or low columnar epithelial cells||18.8|
|Ductal carcinoma in situ (DCIS)||Atypical cells filling and expanding breast ducts (various patterns) may be high or low grade||18.9A and B|
| Invasive breast carcinoma (NST)
( E-Fig. 18.6 G )
|Invasive atypical cells forming duct-like structures or solid nests – graded as 1–3 depending on architecture, cytological atypia and mitotic activity||18.9C|
|Tubular carcinoma||Invasive carcinoma consisting of well-formed small ductal structures||18.10A|
|Mucinous carcinoma ( E-Fig. 18.7 G )||Invasive carcinoma with plentiful mucin production, often with nests of malignant cells floating in pools of mucin||18.10B|
|Lobular carcinoma in situ (LCIS)||Expanded lobular structures filled with small atypical cells showing no gland formation||18.11|
|Invasive lobular carcinoma||Invasive carcinoma consisting of small cells, resembling lobular cells, invades as single cells or as lines of cells known as ‘Indian files’||18.11|
|Paget’s disease of the nipple ( E-Fig. 18.9 G )||Invasion of malignant cells into the epidermis of the nipple, usually an underlying invasive carcinoma or DCIS||18.13|
A 27-year-old lady presents with her 10-week-old infant, complaining of a painful lump in the left breast. She is breastfeeding her child and has been feeling generally unwell. On examination, she is febrile and there is a soft, fluctuant lump close to the nipple, accompanied by tenderness and redness of the overlying skin. On gentle pressure, some green fluid exudes from the nipple. Cytological examination reveals numerous neutrophil polymorphs. Which ONE of the following statements is correct?
She has a prolactinoma.
She has a breast abscess.
She has duct ectasia.
She has a fibroadenoma.
She has breast carcinoma.
A 43-year-old lady complains of a lumpy area in her left breast. Mammography is normal and there is only vague lumpiness on examination, without a discrete mass. She undergoes a needle core biopsy (above) . Which of the following processes is illustrated?