Carcinoma of the breast

• Beast cancer is the most common non-skin malignancy in women
• If a woman lives to 90, she has a 1 in 8 chance of developing breast cancer
• As the population ages, the umbers with breast cancer will increase

 

Incidence/Epidemiology

 

• There has been an increase in the number of women (particularly older) who have been diagnosed with breast cancer but this seems to be primarily due to screening program
• 20% of women with breast cancer are expected to die of the disease

 

Risk factors

 

• Age – average age of diagnosis is 64
• Age at menarche – increased risk of those who reach menarche younger than 11. Late menopause also increases risk
• First live birth – those who have their first pregnancy before 20 have half the risk of those who are still nulliparous by the age of 35
• First degree relatives with breast cancer
• Race – highest rates in Caucasian women
• Oestrogen exposure – HRT
• Radiation exposure
• Carcinoma of the contra lateral breast or endometrium
• Geographic influence – women in USA and Europe have a higher incidence, risk increases with immigration to the US
• Diet
• Obesity – decreased risk for young obese women due to the association with anovulatory cycles. There is an increase risk for older obese women due to oestrogen in body fat
• Exercise
• Breast-feeding – the longer a women breast feeds, the lower her risk

 

Treatment of women at high risk of developing breast cancer

 

• Bilateral prophylactic mastectomy
• Chemoprevention – tamoxifen (increases risk of thromboembolic disease and endometrial carcinoma)

 

Etiology/Pathogenesis

 

• Breast carcinoma can be divided into hereditary and sporadic

 

 

Hereditary Breast cancer

 

• A history of a first degree relative with breast cancer is reported by 13% of women with the disease
• Around 25% of familial cancers can be attributed to BCRA1 and BCRA2, autosomal dominant genes
• Lifetime risk for female carriers is 60-85% with a median age 20 years earlier than women without this mutation
• BRCA1 also increases the risk of developing ovarian cancer
• BRCA2 is associated with male breast cancer
• Both genes are tumour suppressors
• Appear to play a role in halting the cell cycle and promoting DNA repair
• BRCA1 is phosphorylated in response to damage and may play a role in transducing DNA damage signals from checkpoint kinases to effector proteins
• BRCA1 and 2 along with RAD51 also form a nuclear complex, presumably involved in DNA repair
• BCRA2 can bind to DNA directly and is involved in homologous recombination for the repair of double strand breaks
• In hereditary carcinomas, one mutated BRCA gene is inherited and the second is inactivated by somatic recombination

 

• BCRA1 associated tumours;
• More commonly poorly differentiated
• Have a syncytial growth pattern with pushing margins
• Have a lymphocytic response
• Do not express hormone receptors or overexpress HER2/neu

 

• BCRA2 associated cancers;
• Do not have a distinct morphological appearance

 

• Other genes involved in susceptibility
• Cell cycle checkpoint  kinase gene (CHEK2) – activates BCRA1. Risk for a mutation carrier is 20%
• p53 mutation in individuals with Li-Fraumeni syndrome have an 18 fold increased risk
• PTEN mutation in individuals with Cowden syndrome confers a 25-50% lifetime risk

 

 

Sporadic breast cancer

 

• Risk factors are mentioned above
• Majority of cancers occur in postmenopausal women
• Most express the oestrogen receptor

·        Role of oestrogen in the development of breast cancer;

·        Metabolites of oestrogen can cause mutations or lead to the production of free radicals

·        Promoting proliferation of premalignant cells

 

 

Classification of breast carcinoma

 

·        Almost all breast carcinomas are adenocarcinomas -95%

·        They can be divided into in situ carcinomas and invasive carcinomas

·        Carcinoma in situ refers to a neoplastic population of cells which hasn’t traversed the basement membrane

·        Sometimes the cells can extend to the skin without crossing the basement membrane therefore appearing clinically as Paget disease

·        Invasive carcinoma has invaded past the basement membrane into the stroma

·        Each type can be described as being ‘ductal’ or ‘lobular’. This refers to their resemblance of the involved spaces to ducts or lobules NOT to their cell of origin

·        All carcinomas are thought to arise from the terminal duct lobular unit

 

Carcinoma in situ

 

Ductal carcinoma in situ (DCIS)

 

·        Accounts for 15-30% of carcinomas in well screened population

·        Most frequently presents as a mammographic calcification

·        Can also present as a vaguely palpable mass or nipple discharge

·        Clonal proliferation usually involving only a single duct system – not breaching basement membrane

·        DCIS whether high grade or low grade seem to progress to invasive carcinoma

·        Treated by surgical excision, mastectomy curative in 95% of cases and breast conservation reducing this slightly

 

Lobular Carcinoma in situ (LCIS)

 

·        Not associated with any calcification or any stromal reaction that would form a density therefore LCIS is always an incidental finding in a biopsy performed for another reason

·        Accounts for 1-6% of all carcinomas and is bilateral in 20-40% of cases

·        More common in young women

·        Unclear if it is always a precursor or invasive carcinoma

·        Expresses receptor for oestrogen and progesterone

·        Do not overexpress HER2/neu

·        Treatment options include, bilateral mastectomy, tamoxifent or close clinical follow up with mammography

 

 

 

Invasive Carcinoma

 

·        Often presents as a palpable mass

·        By the time it is palpable over half of patients will have axillary node metastases

·        Larger carcinomas maybe fixed to the chest wall and cause dimpling of the skin – pea d’orange, tethering of the breast to the skin by Cooper’s ligaments

·        ‘inflammatory carcinoma’ refers to the clinical presentation of a carcinoma extensively involving the dermal lymphatics resulting in a erythematous enlarged breast. The underlying carcinoma has a diffuse infiltrative pattern and does not generally present as a discrete mass. Diagnosis doesn’t correlate with any histological type of breast cancer

·        The most common histological types are;

o       No special type (NST)

o       Lobular

o       Tubular/cribriform

o       Mucinous (colloid)

o       Medullary

o       Papillary

o       Metaplastic

 

No special type (NST) Invasive carcinoma

·        Make up 70-80% of invasive carcinoma

·        Generally accompanied by varying amounts of DCIS

 

Invasive lobular carcinoma

·        Usually presents as a palpable mass but 25% have a diffuse pattern of invasion and may only produce a vaguely thickened area of breast

·        May have a greater incidence of bilaterality but this may be due to the fact that more women with lobular carcinoma had contralateral surgery

·        Increasing incidence in postmenopausal women – possible due to HRT

·        Well differentiated lobular carcinomas are usually diploid, associated with LCIS and express hormone receptors. They rarely express HER2/neu

·        Poorly differentiated lobular carcinomas are usually aneuploid, lack hormone receptors and may over express HER2/neu

·        If matched by grade and stage lobular carcinomas show the same progression of NST tumours

·        Lobular carcinomas have a different pattern of metastasis, they are less likely to go to the lungs and pleura and are more likely to metastise to the peritoneum, leptomeninges, GI tract, ovaries and uterus

·        Histological pattern is of parallel arrays of small regular cells with scant cytoplasm arranged in linear arrays or small clusters of cells

 

Medullary carcinoma

·        Normally presents as a well circumscribed mass that may be mistaken for a fibroadenoma

·        There may be a history of rapid/explosive growth

·        Generally have a slightly better prognosis than NST carcinomas as they have limited metastatic potential

·        Not associated with a great deal of desmoplasia, therefore tumours may appear softer or palpation

·        Tumour is characterised by;

·        Solid syncytium like sheets of large cells with large, pleomorphic nuclei

·        Lymphoplasmacytic infiltrate

·        A pushing, non infiltrative border

·        All are poorly differentiated and DCIS is generally absent

 

Mucinous (Colloid) carcinoma

·        Unusual (1-6% of breast cancers)

·        Presents as a circumscribed mass

·        Tends to occur in older women and grow slowly over a number of years

·        Mucinous carcinomas are generally diploid and generally express hormone receptors

·        Prognosis is slightly better then NST carcinoma

·        Tumour is very soft and has the appearance of gelatine, with tumour cells appearing as clusters within large pools of mucin                     

 

Tubular Carcinoma

·        Represents 10% of all tumours less than 1 cm in diameter

·        Typically detected as irregular mammographic densities

·        Tumours consist exclusively of well-defined tubules and are sometimes mistaken for benign sclerosing lesions, however myoepithelial cells are absent and the tumour cells are in direct contact with the stroma

·        All are well differentiated, diploid and express hormone receptors

 

Invasive papillary carcinoma

·        Rare – 1% of all invasive carcinomas

·        Commonly seen in DCIS

·        Clinical presentation similar to NST carcinoma

·        Overall better prognosis however

 

Metaplastic carcinoma

·        ‘metaplastic carcinoma’ includes a wide variety of types of breast cancer including adenocarcinoma, squamous cell carcinoma and carcinomas with a prominent spindle cell component that might be mistaken for sarcomas

·        Some of these carcinomas express similar genes to myoepothelial cells and are likely to be derived from them

Given the heterogeneity, clinical features and prognosis is unc