breast pathology 2
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RISK FACTORS
“Common denominator for most of these factors is strong and or prolonged estrogen stimulation operating on a genetically susceptible background”.
1. Age
2. Age at menarche
3. First live birth
4. First degree relatives with breast cancer
5. Breast biopsies
6. Race
RISK FACTORS
Age at menarche
Attaining menarche before 11yrs increases the risk of breast cancer by 20%.
(comparing women who reached menarche >14yrs)
RISK FACTORS
Age at first child birth:
Full term pregnancy before 20yrs of age reduces the risk by 50%.
(in comparison to nulliparous women or women over the age of 35yrs at their first child birth)
RISK FACTORS
Age at first child birth:
“Pregnancy results in terminal differentiation of epithelial cells, removing them from the potential pool of cancer precursors”
RISK FACTORS
First degree relatives with breast cancer:
Majority of breast cancers occur in women without any such family history.
Only 13% have family history of affected 1°
relative.
RISK FACTORS
Breast biopsies:
There is increased risk of developing breast cancer in those with previous biopsies showing atypical hyperplasia.
RISK FACTORS
Race: risk of developing breast cancer after 50yrs of age in different races…..
CAUCASIANS 1:15AFRICAN AMERICAN 1:20ASIAN 1:26
HISPANIC 1:27 (Figures show the risk of developing an invasive
carcinoma within the next 20yrs at age of 50.)
RISK FACTORS
• Estrogen exposure• Radiation exposure• Ca of endometrium / Ca of contralateral breast• Geographic influence• Diet• Obesity• Exercise• Breast feeding• Environmental toxins
Additional RISK FACTORS
Estrogen exposure:
• HRT may increase the risk slightly• ER+PR increases the risk more than ER alone• OCs are unlikely to increase the risk• Oophorectomy decreases the risk of developing
breast carcinoma by 75%.
Additional RISK FACTORS
Radiation exposure:
• Therapeutic radiation• Exposure to atomic energy radiation
The following factors increases the risk 1-younger age 2-higher radiation dose
Additional RISK FACTORS
Carcinoma of contralateral breast / EM:
Increases the risk due to shared estrogen effect.
Additional RISK FACTORS
Geographical influence:
Incidence of breast cancer in US & Europe is 4-7x higher than other countries.
Risk of breast cancer increases in immigrants over several generations.
No specific factor have been identified, but diet, physical activity have been implicated.
Additional RISK FACTORS
Breast feeding: decreases the risk of breast Ca.
Environmental toxins: organochloride pesticides
(they may have estrogen effect)
Tobacco: no relation to breast carcinoma
but, associated with periductal mastitis.
Additional RISK FACTORS
Risk factors for Breast Cancer
Major MinorGender (Female > Male) Early menarche
Age Late menopause
Family history (1° relative with premenopausal or bilateral breast cancers)
Obesity
Personal h/o contralateral breast cancer
Low dose radiation
Noninvasive carcinoma (Ductal or Lobular carcinoma in situ)
Benign proliferative changes with atypia
Source: Sabiston – Text book of Surgery, 15th Ed, Vol-1
Etiology and Pathogenesis
“The major risk factors for the development of breast cancer are hormonal and genetic (family history)”
Etiology can be better understood by dividing them into:
Hereditary breast cancers &
Sporadic breast cancers.
Hereditary breast carcinoma
• 13% of women with familial br.ca. have one affected relative.
• 1% have multiple affected relatives.
• ~3-5% of all breast carcinomas are familialy occuring.
• Two genes are well characterized:
• BRCA-1 located on Chr# 17q
• BRCA-2 located on Chr# 13q
These two genes are highly penetrant autosomal dominant genes.
Hereditary breast carcinoma
• Action of BRCA-1 & 2:
1-they act as tumor suppressor genes
2-they are involved in DNA repair mechanisms
They are identical in size (81 & 84kb)
They are functionally identical
Hundreds of mutations have been reported involving these two genes.
Hereditary breast carcinoma
Hereditary breast carcinoma
• BRCA-1 mechanism -1DNA damage
Phosphorylation of BRCA-1
Activation of check point kinases and effector proteins
Initiation of DNA repair mechanisms
Hereditary breast carcinoma
• BRCA-1 mechanism -2
DNA damage
Binding of BRCA-1, 2 & RAD51 to nuclear –dot-complex
Initiation of DNA repair
• BRCA-2 mechanism of action:
Product from BRCA-2 can bind directly to DNA and initiate the repair of double stranded DNA.
Hereditary breast carcinoma
• Why the loss of these functions of BRCA-1 and or 2 specifically affects the breast?
---it’s not exactly clear.
---probably other cell types have additional mechanisms for DNA repair, that the breast tissue lacks.
Hereditary breast carcinoma
• Other genes involved in familial breast carcinoma: this accounts for <10% of familial breast carcinomas.
1-CHEK-2 (cell cycle check point kinase gene) - 5%2-p53 mutations in Li-Fraumeni syndrome - 18x3-PTEN mutation in Cowden’s syndrome – 25-50%4-LKB-1 gene mutation in Peutz-Jegher syndrome5-ATM gene mutaion in ataxia-telangiectasia – 7%
After all these genes 2/3rds of familial breast carcinomas remain unexplained.
Hereditary breast carcinoma
Sporadic breast carcinomas
• Major risk factor is exposure to hormones(Gender, age at menarche and menopause, reproductive
history, breast feeding, and exogenous estrogens).
They occur more commonly in post menopausal women
They over express ER.
• Action of estrogens:
-Metabolites of estrogens can generate DNA damaging free radicals.
-ER drive the premalignant cells to malignancy.
Sporadic breast carcinomas
Nature of BRCA-1 induced tumors
• Poorly differentiated
• Syncytial growth pattern
• They have pushing margins
• They show lymphocytic infiltration
• Do not express hormone receptors
• They do not over express HER2/neu
Mechanism of estrogen action on cancer cells having estrogen receptor.
Source: Sabiston – Text book of Surgery, 15th Ed, Vol-1
Source: Sabiston – Text book of Surgery, 15th Ed, Vol-1
Significance of negative surgical margins in Invasive (A) compared with intraductal (B) carcinoma.
Schirrhous carcinoma of the breast.
Note the shrinkning and elevation of the breast with nipple retraction.
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