Breast pathology 2

Breast Pathology

Breast Carcinoma

Dr.CSBR.Prasad, M.D.

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

• Rare < 20years

• 70% of breast cancers occur in women >50yrs

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%.


Radiation exposure:

• Therapeutic radiation• Exposure to atomic energy radiation

The following factors increases the risk 1-younger age 2-higher radiation dose


Carcinoma of contralateral breast / EM:

Increases the risk due to shared estrogen effect.


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.


Diet:

High fat

Low ß-carotene

High alcohol


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.


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.


• 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.



• BRCA-1 mechanism -1DNA damage

Phosphorylation of BRCA-1

Activation of check point kinases and effector proteins

Initiation of DNA repair mechanisms


• 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.


• 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.


• 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.


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

They don not have distinct morphological appearances.

Nature of BRCA-2 induced tumors


Mechanism of estrogen action on cancer cells having estrogen receptor.



Significance of negative surgical margins in Invasive (A) compared with intraductal (B) carcinoma.




Gynecomastia in Chief Chengwayo


-Phyllode’s tumor in a women of 18years.

-Weight 18kgs.-Ulceration

(arrow) due to pressure.

Paget’s disease of the nipple.

Mandor’s disease

Bilateral ductectasia with fistula formation and nipple retraction.

Polythelia with congenital inversion of the nipple.

Schirrhous carcinoma of the breast.

Note the shrinkning and elevation of the breast with nipple retraction.

Peau d’ orange of the breast

Large fungating carcinoma of the right breast with

enlarged axillary lymphnodes.

Lymphangiosarcoma developed after 3years after radical mastectomy.

Carcinma of the male breast.

Carcinoma of the male breast – advanced.

Health & Medicine

Breast pathology 2