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Carcinoma of the Breast

 

·         2nd leading cause of cancer deaths in women

·         1/9 women will develop breast cancer in US during her life time

·         > 1.2 million women world wide will be diagnosed with breast cancer

·         Mortality rate had declined in this country because of

1.       earlier and more accurate detection (aka netter mammography)

2.       more aggressive treatment 

3.       more complete treatment.

·         Most breast cancers are now detected at the In Situ or Stage 1 stages. However, 20% of women with breast cancer will still die of the disease.

Genetic predisposition

1.       Only 5-10% of breast cancers are inherited by the A. Dominant BRCA 1 & 2 genes

2.       Multiple affected family members and younger age of onset (<40 years) both increase the probability of genetic inheritance

3.       Less than 20% of women with a positive family history will carry the BRCA genes

4.       Other associated diseases that can cause breast cancers:

1.       Li- Fraumeni Syndrome (p53 mutation)- commonly develop breast cancers and sarcomas

2.       Cowden’s Syndrome (ch10q) – suppressor genes that are knocked out

3.       Ataxia Telangiectasia (ATM gene) – mismatch repair gene that is knocked out so there is no control of DNA

4.       CHEK2 (cell cycle check-point kinase gene)

 

BRAC1

BRAC 2

Chromosome 17q 21

13q12.3

81 kb/1863 aa

84 kb/ 3418 aa

Tumor suppressor that regulated transcriptional factors and DNA repair

> 500 mutations

> 300 mutations

60-80% risk of carcinoma because of inheritance

Younger age of onset 40-50

50 years

Frequency of mutation .1-.2%

Risk of breast/ovarian cancer 20-40%

10-20%

Male and female breast cancer < 20%

76% = MALE Breast cancer associated

Prostate, colon, pancreas

Prostate and pancreas

Mts  found in sporadic breast cancer very rare <5%


 
 

Risk Factors of Breast Carcinoma

  1. Age (uncommon before 25 years and there is a steady rise after menopause)
  2. Proliferative Breast Disease
  3. Carcinoma of contralateral breast
  4. Carcinoma of endometrium
  5. Radiation exposure
  6. Early Menarche and late menopause
  7. Nulliparity
  8. Age at first child (>30 )
  9. Post menopausal obesity and exogenous estrogens
 


Biology of Breast Carcinoma

The theory in atypical epithelial hyperplasia is that there is genetic instability in the small clonal populations. So the next cellular injury will lead to carcinoma because of the instability.  Also an untreated carcinoma in situ can lead to invasive carcinoma. In carcinoma there are the following changes:

  1. Increased expression of oncogenes – Her2/neu, INT-2, c-myc
  2. Decreased expression of suppressor genes – p53, Rb, NM23
  3. Alteration of cell structure- increased expression of vimentin, a marker of epithelial cells
  4. Loss of cells adhesion- Loss of E-cahderin, integrins
  5. Increased cell cycle proteins- cyclins, KI-67
  6. Increased angiogensis- VEGF, FGF

 

Classification of Breast Carcinomas

In Situ Carcinoma – limited in the duct or lobule (DCIS or LCIS)

 

DCIS- ductal carcinoma in situ

 

LCIS- lobular carcinoma in situ

 
 

 

Proliferation in ductal cells

Proliferation in TDLU of a monomoprhic population of cells

Presentation

·  palpable mass is rarely present

 

Bilateral in 50-70% of cases when both breasts examined

Mammogram

·  50% of mammographically detected lesions

·  Large duct is calcified so is seen on mammograms

·      Usually an incidental finding on biopsy and is

·      NOT found in mammography (no calcifications)

Progression

·  malignant population and NO capacity to invade through the basement membraneà non metastatic

 

· Most incidental lesions do NOT progress

· Progression to invasive cancer is very slow (25-35% over 20 years

Grading

·  Non comedo-

·  nuclear grades low to high without central necrosis.

·  Comedo DCIS  -

·   High nuclear grade (large pleomorphic cells) à more likely to become malignant.  

·  Central necrosis

·  Microvinvasion-

·  foci of tumor cells less than 1mm invading stroma.

·  Seen in high grade DCIS

·  Little metastatic potential

 

Treatment

 

Anti-estrogens (Tamoxifen)

Subtype

 

 

 

Paget’s Disease

-          A from of DCIS that extend from ducts into the skin of the nipple

-          Unilateral ulcerated nipple/areola

-          Usually there is an underlying carcinoma if there is a mass felt

-          Treated by mastectomy

-          Involvement of epidermis by malignant cells
 

 

Invasive Carcinoma - Diagnosed by lump or mammogram. Grossly. A puckered white tumor. 

 

Duct Carcinoma nos

Lobular carcinoma

Histology

·       Associated with DCIS

·       tumor cells arranged in tubules, cords, solid nests, invading stroma

E cadherin present

·   Associated with LCIS

·   Only affects single cells

·   Diffuse invasive pattern -“Indian file”

·   Loss of E- Cadherin (adhesion molecule)

Presentation

·       tumor mass with irregular border

·       Gross- packed white tumor with no well defined borders

·         Bilateral and multi-centric

·         Poorly circumscribed

 

Mammogram

·       Found in mammography

 

Grading

·       Grade 1- Well formed tubules, mild nuclear pleomorphism, mitoses <5/10 HPF

·       Grade III- no tubules, severe nuclear pleomorphism, mitoses > 5/10 HPF

·       As grade increase, the number of tubules decreases and the architecture decreases, and mitoses increases

 

 

Metastasis

·       Lungs, lymph nodes, bones

CSF, meninges, serosa, bone marrow, and solid organs

 

Other Types of Invasive Carcinoma

 

Medullary Carcinoma

Colloid Carcinoma

 

Tubular Carcinoma

 

Incidence

· 1-5% of cancers

Unusual variant

10% of all cancers

 

· Type of Ductal carcinoma with no tubule involvement

 

infiltration of ducts

Epidemiology

· younger than the average age

· High proportion of patients have BRCA1 mutation

older women

Younger than average

 

Presentation

· circumscribed mass, fleshy and soft feeling

· pushing (non infiltrative boarder)

·   soft gelatinous consistency

 

Mutlifocal and bilaterally common

 

Histo

· Lymphoplasmsacytic infiltrate surround and within tumor

· Solid synctium-like sheets of large cells with vesicular and pleomorphic nuclei and frequent mitoses

·   large intakes of mucin with tumor cells floating in it

·   tumor cells are in nests or isolated

 

Well formed tubules

 

Prognosis

· Prognosis slightly better than other carcinomas

·   better survival

 

Low grade= good prognosis

 

Metastasis

·  

·   lymph node metastasis 20%

Lymph node metastasis < 10%


Mammography

  • Radiographic Changes in Non-palpable Lesions
  •  Densities - Spiculated, Well-circumscribed smooth borders
  •  Architectural distortion- Rare- diffuse cancers
  •  Calcifications 
  •  Benign 
  •  Malignant - small, irregular, clustered, linear or branching
  •  Changes over time - densities, distortions, calcifications
  •  Palpable masses may not be detectable by mammography

Common features of all types of invasive carcinomas.

  •  Large tumors can extend into the skin (“clinical peau d’orange”)
  •  Involvement of dermal lymphatics - Inflammatory carcinoma
  •  Lymphatic Spread - axillary and Internal mammary
  • 1/3 of patients will present with lymphatic involvement
  •  Distant metastases to virtually any site (lungs, bone, liver, adrenals, meninges are favored sites).

Breast Cancer staging – she didn’t talk about it but she said it will be covered in the next hour.

  • Stage 0- DCIS or LCIS (5 year survival rate 92%).
  • Stage I - Invasive carcinoma 2cm or less without nodal mets (5 year survival 87%)
  • Stage II - Invasive carcinoma 5 cm or less in size with nodal + (mobile) or more than 5 cm without nodes or distant mets (5 year survival 75%)
  • Stage III - Invasive carcinoma more than 5 cm with nodal involvement without distant mets (5 year survival 46%)
  • Stage IV - Any form of breast cancer with distant mets   (5 year survival 13%)

Prognostic factors

  1. Axillary lymph nodes mets – MOST Important
    1. Number
    2. Size
    3. Capsular invasion
  2. locally advanced disease – invasion of skin
  3. tumor size- the smaller the size (<1-2 cm) the better
  4. tumor grade based on nuclear pleomorphism and mitoses
  5. estrogen/progesterone receptor presence is better – can be treated with anti-estrogen drugs like Tamoxifen
  6. lymphovascular invasions- associated with nodal mets
  7. proliferation rate- high rate= poor prognosis
  8. Expression of oncogenes -HER2/neu associated with poor prognosis but also an Ab is available
  9. DNA Ploidy- aneuploid tumors have abnormal DNA indices and slightly worse prognosis
  10. Angiogenesis- micro vessel density increased metastatic risk
  11. stromal proteases- involved in matrix degeneration à poor prognosis

Sentinel node biopsy is performed in patients with a breast carcinoma and clinically negative nodes. 

Sentinel Node- is the first draining lymph node for the tumor. 

  1. Radioactive material/dye injected into tumor and it will drain to the sentinel node. (Because it is radioactive, you can trace it to the most dense location, the sentinel node, with a cool transducer that makes a beep when it detects the radioactivity)
  2. Biopsy of first draining lymph node
  3. If the sentinel node is negative, an axillary node dissection is not performed. This is to prevent an unnecessary total lymphectomy, which has many risks and complications like lymph edema.


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