Oncology - Breast cancer

Question 1

What causes acute inflammation of the breast?

Answer 1

Mastitis is an occasional complication of lactation. Fissures or abrasions in the nipple predispose to the condition. Infection is transmitted by the suckling neonate who is carrying hospital staphylococci. Abscesses may form in the lobules of the breast leading to scarring.

The patients presents with a red, hot tender lump and systemic upset.

Question 2

How is mastitis managed?

Answer 2

If an abscess is present then it should be aspirated (this may need to be repeated) and sent for MC&S. The mother should not stop breast feeding and oral antibiotics (e.g. flucloxacillin) should be given. It is also worth arranging an ultrasound (young women/ dense breast tissue) or mammogram (older woman, small breasts).

Non lactational abscesses are usually recurrent, associated with smoking and underlying ductal ectasia (plasma cell mastitis). Treatment is outpatient aspiration, oral antibiotics, smoking cessation and prophylactic metronidazole for sepsis, and repeat aspiration if necessary.

Question 3

What causes chronic mastitis?

Answer 3

Chronic infection is uncommon, but can be associated with tuberculosis.

Question 4

What is duct ectasia? How do women present?

Answer 4

This is a chronic inflammatory reaction associated with ectasia of the ducts (cystic dilatation). Infection of the dilated ducts allows escape of contents into the tissues resulting in a granulomatous reaction. Clinically, it may raise suspicion of duct carcinoma. Patients often present with nipple discharge, which may be from single or multiple ducts. The discharge is usually thick and green.

Macroscopically, there is thickening of the fibrous tissue around cystic ducts which are themselves filled with lipid laden fluid and fatty macrophages. Lymphocytes and plasma cells are located in the tissue around the dilated ducts.

Question 5

What is traumatic fat necrosis?

Answer 5

This occurs in obese pendulous breasts and results in an irregular granulomatous fibrous reaction which may mimic carcinoma. It is uncommon, and most women report some history of trauma to the breast.

Question 6

What non breast diseases can cause mastalgia?

Answer 6

• Tietze’s condition (chostochondritis) = tenderness over the medial ends of the ribs (typically 2nd/3rd/4th), not limited to the breast area of the chest, typically unilateral, relieved by NSAIDs
• Bornholm’s disease (epidemic pleurodynia caused by coxsackie A virus) = marked pain with no physical signs in the breast, worse with inspiration, no underlying respiratory disease, relieved with NSAIDs
• Pleurisy = associated respiratory infection, pleural rub
• Angina = usually atypical angina, may be hard to diagnose, previous history of associated vascular disease

Question 7

How should mastalgia of non breast origin be investigated?

Answer 7

ECG
CXR
Stress test

Question 8

What is fibrocystic change? What are its key features?

Answer 8

In this condition there are four characteristic features, and the form which the disease takes varies according to the relative proportions of these features:

1) Fibrosis - there is progressive hyalinization of the stroma
2) Cyst formation - obstruction of ducts leads to dilatation of the ducts and acini. The lining epithelium may show apocrine metaplasia

3) (a) Adenosis - this is an increase in the number of lobules and in the size of existing lobules
(b) Sclerosing adenosis - this is a localised condition which may simulate carcinoma. There is proliferation of acini and stroma and mitotic activity can be marked but there is NO danger of malignancy

4) Epithelial hyperplasia - is the most important component because it forms a link between simple proliferation and malignancy change

Question 9

How can fibrocystic change be classified?

Answer 9

Fibrocystic change can be classified as nonproliferative (cystic) or proliferative.

Proliferative lesions include epithelial proliferations of ducts and lobules (with or without features of atypia) and adenosis, sometimes associated with fibrosis.

These changes are further divided into usual type and atypical. In “usual type hyperplasia”, there is proliferation of uniform “benign” epithelium with “streaming” pattern.

Atypical hyperplasia can be ductal (ADH) or lobular (ALH). In ADH here is proliferation of ductal epithelium forming an irregular network: epithelial cells show mild atypia. There is still retention of the myoepithelial layer however. In ALH there is uniform proliferation of acinar epithelium without acinar expansion but the myoepithelial layer is lost.

Question 10

What is the relationship between fibrocystic change and breast carcinoma?

Answer 10

Fibrocystic change is very common, and the various changes are ascribed to abnormal and exaggerated responses of the breast tissue to cyclical changes in female hormones, they are essentially benign. But a link with carcinoma has been established when there is hyperplasia with cytological atypia (i.e. ADH, ALH). Atypical hyperplasia is associated with a five fold increase in the risk of developing carcinoma.

Question 11

How does fibrocystic change present?

Answer 11

Women present with breast discomfort, dull heavy pain that is worse premenstrually. The breasts have a cobblestone appearance on palpation.

Question 12

How is fibrocystic change managed?

Answer 12

Women over 45 should be referred for mammogram to rule out occult carcinoma. General advice involves restricting dietary fat, and avoiding caffeine.

Treatment for cyclical mastalgia should be with paracetamol, danzol, tamoxifen, and bromocriptine.

Treatment for non cyclical mastalgia is with paracetamol and NSAIDs.

Question 13

What lesions are related to fibrocystic change?

Answer 13

1) Fibroadenoma = benign, nodular proliferation now considered to be a component of fibrocystic change and NOT a true neoplasm. It is usually single, occurring in young women. It presents clinically as a small, firm, mobile lump. Radiologically is appears as a well demarcated mass. Microscopically, the proliferation of intralobular stroma compresses the entrapped glands, creating a “pushing” border that sharply separates it from the surrounding normal tissue
2) Radial scar = this small, firm lesions shows a central dense fibrous core with radiating fingers of fibrosis entrapping and distorting glandular elements. It is benign, but can be confused with a carcinoma even on histological examination. Similar but larger lesions, also detected by mammography, are known as complex sclerosing lesions

Question 14

What is Phyllodes tumour?

Answer 14

This tumour is a large, bulky mass of variable malignancy with ulceration of overlying skin. Cystic spaces contain leaf like projections from the cyst wall and myxoid contents are characteristic.

Question 15

What is a ductal papilloma?

Answer 15

Ductal papilloma is local areas of epithelial proliferation in large mammary ducts. This proliferation is hyperplastic rather than malignant or premalignant. Can present with blood stained discharge.

Question 16

What are the 2 types of ductal papilloma?

Answer 16

1) Solitary papilloma - lesions found almost always near the nipple. Macroscopically, the tumour is a complex, branching pedunculated tumour filling the lacteal sinus.
Microscopically, the branches have a connective tissue core covered by columnar epithelium with underlying myoepithelium - this gives a double layer of cells covering the fronds

2) Multiple papillomata - these may be distributed throughout the duct system. In this form multicentric carcinoma can develop

These are the only important benign breast tumours, other types are rare.

Question 17

What is DCIS?

Answer 17

This is one of the two forms of non invasive carcinoma, and affects the ducts. It may be visible as a greyish white material filling the dilated ducts, and central necrotic debris may be squeezed out of the ducts. DCIS tends to fill and distort ductal spaces.

Solid or cribriform cylinders of cells show the usual features of malignancy. It is important to differentiate the condition from atypical ductal hyperplasia. DCIS is graded into high and low grade, the former having a higher risk of invasive carcinoma. DCIS is a precursor of invasive carcinoma and can often be seen as calcifications on mammography.

Question 18

How is Paget’s disease of the nipple related to DCIS?

Answer 18

Paget’s disease of the nipple is caused by the extension of DCIS up the lactiferous ducts and into the overlying skin of the nipple. It produces a crusty exudate over the nipple and areolar skin. In almost ALL cases an underlying carcinoma is present, and approximately 50% of the time the carcinoma is invasive.

Question 19

What is LCIS?

Answer 19

This lesion is usually multifocal and bilateral. The breast acini of affected lobules are distended by fairly uniform carcinoma cells which grow into the duct system or break through the basement membrane to become infiltrating carcinoma.

Question 20

Why is LCIS an important lesion?

Answer 20

Approximately 1/3 of women with LCIS will develop invasive carcinoma. Unlike DCIS, subsequent invasive carcinomas may arise in either breast. Most of these cancers are invasive lobular carcinomas, but invasive ductal carcinomas can also arise in LCIS. LCIS is therefore both a marker of increased risk of carcinoma in BOTH breasts and a direct precursor to some cancers.

Question 21

What is the most common type of breast carcinoma?

Answer 21

Infiltrating (or invasive) ductal carcinoma is the commonest form of breast cancer. It presents as a firm lump. Pathological features are:

• surface shows a coarse texture (peau d’orange)
• strands of fibrous tissue extend in all directions
• nipple often retracted in late stages
• localised hard, craggy mass, greyish white in colour with yellow flecks (“unripe pear appearance”)
• often fixed to the underlying muscle

Question 22

What are the microscopic features of invasive ductal carcinoma?

Answer 22

Neoplastic cells are spherical and arranged in cords separated by dense collagenous stroma. Cancer cells may form occasional acini. The microscopic appearance can vary, and these carcinomas are often grouped under the heading of “invasive breast carcinomas of no special type”.

Question 23

What is infiltrating lobular carcinoma?

Answer 23

10% of breast cancers are of this type. Based on distribution of the “in situ” precursor, this tumour may be multicentric within the breast and there is a 30% change of a similar tumour arising in the contralateral breast. Microscopically the tumour infiltrates the tissues as single files (Indian file pattern) of malignant cells. Almost all of these carcinomas express hormone receptors.

Question 24

Give some examples of rarer forms of breast cancer

Answer 24

These include tubular carcinoma - showing well differentiated cells often with intratubular calcification - medullary carcinoma - a highly cellular tumour with florid lymphocytic infiltrate - and mucoid carcinoma, where malignancy cells lie in pools of mucin.

Inflammatory carcinoma is another rare breast cancer that is defined by the clinical presentation of an enlarged, swollen, erythematous breast, usually without a palpable mass.

Question 25

What are common sites of metastasis for breast cancer and how does it spread?

Answer 25

Axillary lymph nodes, lung, liver and bone are common sites for metastatic spread.

Spread can be:

(i) direct - local infiltration (e.g. Paget’s disease)
(ii) via lymphatics to axillary lymph nodes and through internal mammary lymphatics to thorax (esp cancers sited medially)
(iii) haematogenous - ?bone marrow where cells can lie dormant

In late stages of the disease there can be local spread via skin lymphatics causing:

• widespread lesion - skin becomes stiff and board like “cancer-en-cuirasse”
• blockage of dermal lymphatics - oedema of skin except at anchorage points, peau d’orange

Question 26

How is breast cancer graded?

Answer 26

Breast adenocarcinomas are graded histologically using the modified Bloom and Richardson scoring system to categorize aggressiveness and probable behaviour. This is done on the basis of tubule formation, nuclear pleomorphism, and mitotic rate. Other important histological findings are:

• receptor status: breast cancer cells may express oestrogen/ progesterone receptors. Their presence or absence affects treatment
• 25% of breast cancers express HER-2/neu and these have a worse prognosis

Question 27

How is breast cancer investigated?

Answer 27

Initial diagnosis of a breast mass or breast abnormality detected by breast screening should involve “triple assessment” approach:

1) Clinical examination
2) Imaging:
- two view mammography (oblique/ craniocaudal); rarely useful in women <40 years old
- breast ultrasonography: useful if there is a palpable mass and can distinguish cystic from solid lesions. Malignant lesions have indistinct edges. Not useful for screening
- MRI
3) Biopsy: core biopsy with or without FNA

Question 28

How is breast cancer staged?

Answer 28

Breast cancer is staged using the modified TNM classification:

• Tis = DCIS or LCIS
• T1 = tumour <2 cm diameter
• T2 = tumour >2 cm but <5 cm
• T3 = tumour >5 cm
• T4 = tumour involving skin or chest wall

Routine haematology and biochemical screening (including LFTs and Ca) should also be performed.

Other tests, including (i) CXR, (ii) liver ultrasound, (iii) CT chest, abdo, pelvis, and (iv) isotope bone scan, which may be indicated for high risk patients.

Question 29

How is breast cancer most commonly treated?

Answer 29

Treatment is typically surgical with either wide local excision (i.e. lumpectomy) or mastectomy. An exception may be frail, elderly ladies with metastatic disease who may be better managed with hormonal therapy.

Around 2/3 of tumours are removed by wide local excision. Several factors determine whether wide local excision is preferred over mastectomy, this includes:

1) Wide local excision:
- solitary lesion
- peripheral tumour
- small lesion in large breast
- DCIS <4 cm

2) Mastectomy:
- multifocal tumour
- central tumour
- large lesions in a small breast
- DCIS >4 cm

Women should also be offered reconstructive therapy.

Question 30

What is the Nottingham Prognostic Index?

Answer 30

This can be used to give an indication of survival. In this system, the tumour size is weighted less heavily than other prognostic parameters.

The NPI is given by: tumour size x 0.2 + lymph nodes involved + grade score

The higher the NPI the worse the prognosis.

Question 31

How is lymph node involvement determined as part of breast cancer treatment?

Answer 31

Axillary management depends on whether there is known lymph node involvement or not. If there is, then axillary lymph node clearance/ dissection is performed. Otherwise, sentinal node biopsy/ axillary node sampling is performed. This more limited procedure limits post operative morbidity. However, if subsequent histology confirms the presence of nodal involvement patients either need to undergo completion clearance or radiotherapy.

Question 32

Which patients receive radiotherapy in breast cancer management?

Answer 32

Whole breast radiotherapy is recommended for patients who have had a wide local excision, as this reduces the risk of recurrence by around 2/3. For women who have had a mastectomy, radiotherapy is recommended for T3-4 tumours and those with four or more positive lymph nodes.

Question 33

When is hormonal therapy used for breast cancer?

Answer 33

Adjuvent hormonal therapy is offered if tumours are positive for hormone receptors. For many years, this was done using tamoxifen (an anti-oestrogen) for 5 years after diagnosis. Tamoxifen is still used in pre and peri menopausal women. In post menopausal women, aromatase inhibitors such as anastrazole are used instead. This is because aromatization of androgens accounts for the vast majority of oestrogen production.

Question 34

What is the mechanism of action of Tamoxifen? What are its adverse side effects?

Answer 34

Tamoxifen is a SERM (selective oestrogen receptor modulator) which acts as an oestrogen receptor antagonist and partial agonist. It is used in the management of oestrogen receptor positive breast cancer.

Adverse side effects include:

• menstrual disturbance: vaginal bleeding, amenorrhoea
• hot flushes - 3% of patients stop taking tamoxifen due to climateric side effects
• venous thromboembolism
• endometrial cancer

Tamoxifen is typically given for 5 years following tumour removal. Raloxifene is a pure oestrogen receptor antagonist and carries a lower risk of endometrial carcinoma.

Question 35

Outline the overall management of breast cancer

Answer 35

Diagnosis: mammogram/ ultrasound scan + biopsy

Surgery: mastectomy or breast conserving surgery + axillary node sampling/ clearance

Chemotherapy: if at high risk (i.e. node positive/ large tumour/ high pathological grade). If Her2 positive add herceptin to chemotherapy.

Radiotherapy: may be used to breast if breast conserving surgery/ to the axilla if supportive

Oestrogen receptor positive: tamoxifen or aromatase inhibitor

Question 36

What women should receive chemotherapy as part of their treatment of breast cancer?

Answer 36

Most patients (not small, low grade, node negative disease) with moderate to high risk disease benefit from adjuvant chemotherapy. Equivalent relative benefit is seen in post and premenopausal women. Combination chemotherapy is used (typically an anthracycline containing regimen, e.g. epirubicin in combination with or followed by a tanxane (docetaxel and paclitaxel)).

Question 37

How should women with breast cancer be followed up?

Answer 37

Follow up is used to detect recurrence of disease, manage treatment related toxicity and screen for new primary lesions. It does NOT improve survival. The cancer risk to the second breast is increased four fold. Mammography should be performed yearly, bilaterally if the patient had breast conserving treatment.

Question 38

What is the definition of locally advanced breast cancer?

Answer 38

This is defined as tumours >5cm in size or showing evidence of skin or chest wall invasion (i.e. “fixed”) or inflammatory breast cancer (erythematous with lymphatic permeation). A response to primary treatment with chemotherapy may facilitate surgery and in some instances may allow breast conserving treatment.

Question 39

How is metastatic breast cancer managed?

Answer 39

Treatment depends on a number of factors. For example, chemotherapy should be considered in a young patient with rapidly progressive, visceral disease, particularly if relapse has occurred early after surgery or in oestrogen receptor negative disease that is unlikely to respond to hormonal therapy. The SAME regimes are used in the adjuvant setting are given. Therefore, the first line treatment includes anthracyclines (but not if already used adjuvantly), with taxanes being used as second line. Third and fourth line agents include capecitabine and vinorelbine. Herceptin for HER2 positive women is given together with chemotherapy (but should not be used with anthracycline chemotherapy because of the increased risk of cardiac toxicity). Lapatinib, a duel action oral tyrosine kinase inhibitor, is a newer agent recently introduced for the treatment of HER2 positive metastatic disease. For limited disease (e.g. bone only) in ER positive patients then endocrine treatment would be appropriate first line.