Malignant Diseases of Breast
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Transcript of Malignant Diseases of Breast
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Dr. Anju Pradhan.
Assistant Professor
Department of Pathology
BPKIHS, Dharan
MALIGNANT
DISEASESOF
BREAST
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Objectives
Risk factors of breast carcinoma.
Etiopathogenesis.
Types: In situ / Invasive.
Histomorphology of different types of breastcarcinoma.
Prognostic factors.
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Breast Cancer Risk Factors
Factors Relative Risk
Well-Established Influences
1. Geographic factors Varies in different areas
2. Age Increases after age 30yr
3. Family history
i. First-degree relative with breastcancer
1.2-3.0
ii. Premenopausal 3.1
iii. Premenopausal and bilateral 8.5-9.0
iv. Postmenopausal 1.5
v. Postmenopausal and bilateral 4.0-5.4
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Breast Cancer Risk FactorsFactors Relative Risk
Well-Established Influences
4. Menstrual history
i. Age at menarche 55yr 1.5-2.0
5. Pregnancy
i. First live birth from ages 25 to 29yr 1.5
ii. First live birth after age 30yr 1.9
iii. First live birth after age 35yr 2.0-3.0
iv. Nulliparous 3.0
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Breast Cancer Risk FactorsFactors Relative Risk
Well-Established Influences
6. Benign breast disease
Proliferative disease without atypia 1.6
Proliferative disease with atypicalhyperplasia
>2.0
Lobular carcinoma in situ 6.9-12.0
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Breast Cancer Risk FactorsFactors
Less Well-Established Influences
Exogenous estrogens
Oral contraceptives
Obesity
Alcohol consumption
Cigarette smoking
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Pathogenesis
(1) Genetic changes,
(2) Hormonal influences, and
(3) Environmental variables.
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Pathogenesis1. Genetic Changes
i. Hereditary Breast Cancers:
Mutation in tumor supressor genes BRCA1
(about 50% of hereditary breast cancers) &
BRCA2(1/3rd).
Germ-line mutations in p53(Li-Fraumenisyndrome);
Germ-line mutations in PTEN(Cowdendisease);
ATM gene, carriers of the ataxia-telangiectasia
gene.
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Pathogenesis1. Genetic Changes
ii. Sporadic Breast Cancers:
Overexpression of the HER2/NEUproto-oncogene, which has been found to be
amplified in up to 30% of invasive breastcancers.
Mutations of the tumor suppressor genes RB
and p53.
A large number of genes including theestrogen receptormay be inactivated by
promoter hypermethylation.
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Multiple acquired genetic alterationsare involved in thesequential transformationof a normal epithelial cellinto a
CANCEROUS CELL.
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Genetics
Gene expression profiling can stratify breast cancerinto five subtypes:
1. Luminal A (estrogen receptor positive),
2. Luminal B (estrogen receptor positive),
3. HER2/NEUoverexpressing (estrogen receptor negative),
4. Basal-like (estrogen receptor and HER2/NEUnegative),
and5. Normal breast like.
These subtypes are reproducibleand are associated withdifferent outcomes.
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Pathogenesis2. Hormonal Influences
Endogenous estrogen / hormonal imbalance:
Increased exposure to estrogen peaks duringthe menstrual cycle (long duration ofreproductive life, nulliparity, and late age at
birth of first child),
Functioning ovarian tumors that elaborateestrogens,
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Pathogenesis2. Hormonal Influences
Estrogens stimulate the production of growthfactors by normal breast epithelial cells and bycancer cells.
The ER & PR normally present in breastepithelium, and often present in breast cancercells, may interact with growth promoters, suchas TGF-, PDGF, and FGF elaborated by
human breast cancer cells, to create anautocrine mechanism of tumor development.
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Pathogenesis3. Environmental Variables
The variable incidence of breast cancer ingenetically homogeneous groups and thegeographic differences in prevalence,
Irradiation and
Exogenous estrogens.
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Histologic types of breast cancer
In situ carcinoma
Ductal carcinoma in situ(DCIS; intraductal)
Lobular carcinoma in situ(LCIS)
Invasive carcinoma
Ductal carcinoma (NoSpecial Type)
Lobular carcinoma
Tubular carcinoma
Mucinous carcinoma
Medullary carcinoma
Papillary carcinoma
Metaplastic carcinoma
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CARCINOMA IN SITU
1. DCIS (INTRADUCTAL CARCINOMA insitu):
Neoplastic population of cells limited to ducts and lobules
by the basement membrane.15%-30% in well-screened population.
Mammographic calcification.
Vague palpable mass / nipple discharge / incidental.
Involves a single ductal system.
Spread entire sector of the breast.
Initially atypical hyperplasia of ductal epithelium.
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DCIS - MICROSCOPY
Architectural subtypes
A. Comedocarcinoma
B. Noncomedocarcinoma
1. Solid
2. Cribriform
3. Papillary
4. Micropapillary
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A. COMEDOCARCINOMA
Solid sheets ofpleomorphic cellswith high gradenuclei and central
necrosis.Periductal
fibrosis, chronicinflammation.
Necrotic cellmembranes calcifymicrocalcifications(mammography).
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Comedo DCIS fills several adjacent ducts and ischaracterized by large central zones of necrosis with
calcified debris.
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B.NONCOMEDO DCIS
Monomorphic population of cells.
Nuclear grade low to high.
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B.1. SOLID DCIS
Filling & pluggingof ductal lumina bytumor cells.
Not usuallyassociated withcalcification.
Maybe clinicallyoccult.
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B.1. SOLID DCIS
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B.2.CRIBRIFORM DCIS
Intraepithelialspaces:
- even distribution.
- regular in shape,size.
- (Cookie cutter-like)
Lumens: often filledwith calcifyingsecretory material.
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B.2.CRIBRIFORM DCIS
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B.3.PAPILLARY DCIS
Papillary growthsinto spaces, lined by amonomorphicpopulation of tall
columnar cells.
Lined byfibrovascular core.
Lack myoepitheliallayer.
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B.3.PAPILLARY DCIS
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B.4. MICROPAPILLARY
Papillae - narrowbase, solid, nofibrovascular core.
Bulbousprotrusions.
Calcifications.
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PAGET DISEASE OF NIPPLE
Rare manifestation (1%-2% of breast cancers).
Unilateral, erythematous eruption with a scalecrust.
Pruritus common, mistaken for eczema.
Paget cells : extend from DCIS within the ductalsystem into nipple skin without crossing basement
membrane.Disrupt normal epithelial barrier extracellular fluidto seep out into the nipple surface.
50 to 60% of Paget disease have palpable mass withunderlying invasive carcinoma.
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PAGET DISEASE OF NIPPLE
Paget disease of the nipple DCIS arising within the ductal
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Paget disease of the nipple. DCIS arising within the ductalsystem of the breast can extend up the lactiferous ducts into
nipple skin without crossing the basementmembrane.
ET DISEASE OF NIPPLE
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DCIS WITH MICROINVASION
Foci of tumor cells < 0.1cm d invading thestroma.
In association with comedocarcinoma.
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TREATMENT
Mastectomy DCIS curative in over 95%.
Currently surgical excision usually followedby radiation largely curative.
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LOBULAR CARCINOMA IN SITU
Always an incidental finding.
Not associated with calcification and stromal reaction.
1%-6% of all carcinomas with or withoutmammographic screening.
Bilateral: 20%-40%
Frequently multicentric.
Common in young, 80 to 90% prior to menopause.
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LOBULAR CARCINOMA IN SITU
Microscopy:
Cells : round oroval nuclei with
small nucleoli thatdo not adhere toone another.
Solid nests,expands the lobule.
Signet ring cellspresent commonly.
L b l i i i A hi
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Lobular carcinoma in situ. A monomorphicpopulation of small, rounded, loosely cohesive cells
fills and expands the acini of a lobule.
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LOBULAR CARCINOMA IN SITU
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LOBULAR CARCINOMA IN SITU
Treatment : bilateralprophylactic mastectomy,tamoxifen.
INVASIVE
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INVASIVE(INFILTRATING )CARCINOMA
Age: Young / older not undergoing mammographicscreening.
Palpable mass, often with axillary lymph node metastasisat presentation.
Lymphedema and thickening / dimpling of the skin -peau d orange.
Retraction of nipple.
Inflammatory carcinoma - carcinoma involving dermallymphatics enlarged & erythematous breast.
INVASIVE DUCTAL CARCINOMA
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INVASIVE DUCTAL CARCINOMANST (No Special Type)
Gross:
Firm to hard
irregular borders,foci ofcalcification.
INVASIVE DUCTAL CARCINOMA
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INVASIVE DUCTAL CARCINOMANST
Microscopy:
Well differentiatedtubules withminimally atypical
cells oranastomosingsheets ofpleomorphic cells.
Desmoplasticstroma.
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Poorly differentiated invasive
carcinoma of no special type.Ragged sheets of pleomorphiccells without tubule formation
infiltrate into the adjacentstroma.
Well-differentiated invasive
carcinoma of no special type.Well-formed tubules and nests
of cells with small monomorphicnuclei invade into the stroma witha surrounding desmoplastic
response.
2 INVASIVE LOBULAR
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2.INVASIVE LOBULARCARCINOMA
Presents as palpable mass or mammographicdensity.
One fourth of cases: Diffuse pattern ofinvolvement, may produce vaguely thickenedbreast.
Increasing among postmenopausal HRT.
Gross:
Firm to hard, irregular margin.
Microscopy:
Single file pattern.
2 INVASIVE LOBULAR
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2.INVASIVE LOBULARCARCINOMA
Cellular morphology similar to LCIS.
Metastasis:Peritoneum, retroperitoneum, leptomeninges(carcinomatous meningitis), GIT , ovaries,
uterus.
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3.MEDULLARY CARCINOMA
Well circumscribed mass.
Mistaken clinically and radiographically for afibroadenoma.
H/o rapid growth.
Better prognosis than NST.
Lymph node metastasis are infrequent.
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3.MEDULLARY CARCINOMA
Gross:
Well-circumscribed.
Soft fleshyconsistency.
MEDULLA =
MARROW(Latin)
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3.MEDULLARY CARCINOMA
Microscopy:Solid sheets, large cells
with vesicular nuclei,prominent nucleoli,
frequent mitosis.
Lymphoplasmacyticinfiltrate.
Pushing borders.
All Med. Ca.: poorlydifferentiated.
No lymphatic / vascularinvasion.
Medullary carcinoma.
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yThe cells are highly pleomorphic with frequentmitoses and grow as sheets of cohesive cells.A lymphoplasmacytic infiltrate is prominent.
4 MUCINOUS ( COLLOID)
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4.MUCINOUS ( COLLOID)CARCINOMA
Unusual type (1-6%)
Circumscribed mass.
Older patients.
Slow growth.
4 MUCINOUS ( COLLOID)
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4.MUCINOUS ( COLLOID)CARCINOMA
Gross
Extremely soft.
Sharplycircumscribed
Pale grey bluegelatinousappearance.
4 MUCINOUS ( COLLOID)
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4.MUCINOUS ( COLLOID)CARCINOMA
Microscopy
Clusters of well-differentiatedtumor cells areseen floating in a
sea of mucin.
Mucinous (colloid) carcinoma. The tumor cells are present as
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( ) psmall clusters within large pools of mucin. The borders aretypically well circumscribed, and these cancers often mimic
benign masses.
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5. TUBULAR CARCINOMA
2% - before, now 10%.
Irregular mammographic densities.
Excellent prognosis.
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5. TUBULAR CARCINOMA
Microscopy:
Well formedtubules, no
myoepithelialcells.
Tumor cells indirect contactwith the stroma.
6 INVASIVE PAPILLARY
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6. INVASIVE PAPILLARYCARCINOMA
Rare, 1% or fewer.
MicroscopyStromal invasion - papillary architecture.
Overall prognosis- better.
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7.METAPLASTIC CARCINOMA
Rare (
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MAJOR PROGNOSTICFACTORS
1. Tumor size
Carcinomas < 1 cm have an excellentprognosis in the absence of lymph node
metastases.
90% survival without treatment.
MAJOR PROGNOSTIC
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MAJOR PROGNOSTICFACTORS
2. Distant metastasis
Cure unlikely.
Disease palliation hormone responsive tumors.
Sites: lungs, bones, liver, adrenals, brain andmeninges.
3. Lymph node metastasis
In the absence of distant metastasis; axillarylymph node statusmost important prognostic
factor.
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MAJOR PROGNOSTIC FACTORS
No: of nodes affectedNo node involved
1 to 3 positive nodes
>10 positive nodes
Sentinel nodes:
Predictor of status ofremaining nodes.
Spare complete axillary
node dissection if negative.
10yr survival rateo 70 to80%
o 35 to 40%
o 10 to 15%
MAJOR PROGNOSTIC
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MAJOR PROGNOSTICFACTORS
4. Locally advanced disease
Skin / skeletal metastasis: frequentlyassociated with distant metastasis.
5. Inflammatory carcinoma
Poor prognosis: three yr. survival rate is 3-10%.
MINOR PROGNOSTIC
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MINOR PROGNOSTICFACTORS
Used to decide chemotherapy / hormonaltherapies those who might not need anyadditional treatment
a. Estrogen receptors (50 - 85% tumors,postmenopausal)
Positive better prognosis
Valuable to predict response to therapy
b. Progesterone receptors
c. HER2/neu
MINOR PROGNOSTIC
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MINOR PROGNOSTICFACTORS
1.Histologic subtypes
Tubular, mucinous, medullary, lobular &papillary better as compared to NST.
2. Tumor Grade
Bloom Richardson Grading System 10 yrsurvival
Gr1 60%, Gr2 15%, Gr 3 10%
MINOR PROGNOSTIC
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MINOR PROGNOSTICFACTORS
3. ERPR
80% positive for ERPR respond to hormonaltherapy.
40% positive for one type respond totherapy.
Negative -
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MINOR PROGNOSTICFACTORS
4.HER2/neu ( human epidermal growth factorreceptor 2)
Evaluation determine response to therapy
targeted to this protein ("Herceptin") .
5. Lymphovascular invasion:poor prognosis.
6. Proliferative rate:High proliferative rates areassociated with a poorer prognosis.
7. DNA content :Aneuploid tumors worse
prognosis
THERAPEUTIC APPRAOACHES
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THERAPEUTIC APPRAOACHES
Current:
Combination of surgery & postoperativeradiation & systemic control hormonal or
chemotherapy or both.
Newer strategies:Inhibition of HER2 / neuHerceptin.
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Summary
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Carcinoma of breast: In situ / Invasive.In situ: limited by basement membrane.
Invasive: Invasion into the stroma.
The normal breast is maintained by a complex set ofinteractions among luminal cells, myoeithelial cells, thebasement membrane, and the stromal cells.
Multiple acquired genetic alterations are involved in the
sequential transformation of a normal epithelial cell into acancerous cell.
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Risk factors:delayed child bearing,
long duration between menarche and menopause,
atypical proliferative lesions, and
family history of breast cancer in a first-degree relative,particularly if the disease was multifocal orpremenopausal.
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Only 5% to 10% of all breast cancers are related toinherited mutations;
The majority are in the BRCA1 and BRCA2genes, lesscommonly in p53, PTENor ATMgenes.
Prognosis is dependent on:
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Prognosisis dependent on:
tumor size,lymph node involvement,
distant metastasis at presentation,
tumor grade and histologic type,
proliferation rate,
estrogen receptor status,
aneuploidy, and
overexpression of HER2/NEU.
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"When you make a mistake,
don't look back at it long.Take the reason into your mind,
and then look forward.
Mistakes are lessons of wisdom.
The past cannot be changed.
The future is yet in your power."Phyllis Bottome
1884-1963, Novelist and Lecturer