malignant diseases of breast

8/3/2019 Malignant Diseases of Breast

1/70

Dr. Anju Pradhan.

Assistant Professor

Department of Pathology

BPKIHS, Dharan

MALIGNANT

DISEASESOF

BREAST


2/70

Objectives

Risk factors of breast carcinoma.

Etiopathogenesis.

Types: In situ / Invasive.

Histomorphology of different types of breastcarcinoma.

Prognostic factors.


3/70

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


4/70

Breast Cancer Risk FactorsFactors Relative Risk


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


5/70

Breast Cancer Risk FactorsFactors Relative Risk


6. Benign breast disease

Proliferative disease without atypia 1.6

Proliferative disease with atypicalhyperplasia

>2.0

Lobular carcinoma in situ 6.9-12.0


6/70

Breast Cancer Risk FactorsFactors

Less Well-Established Influences

Exogenous estrogens

Oral contraceptives

Obesity

Alcohol consumption

Cigarette smoking


7/70

Pathogenesis

(1) Genetic changes,

(2) Hormonal influences, and

(3) Environmental variables.


8/70

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.


9/70

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.


10/70

Multiple acquired genetic alterationsare involved in thesequential transformationof a normal epithelial cellinto a

CANCEROUS CELL.


11/70

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.


12/70

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,


13/70

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.


14/70

Pathogenesis3. Environmental Variables

The variable incidence of breast cancer ingenetically homogeneous groups and thegeographic differences in prevalence,

Irradiation and

Exogenous estrogens.


15/70

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


16/70

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.


17/70

DCIS - MICROSCOPY

Architectural subtypes

A. Comedocarcinoma

B. Noncomedocarcinoma

1. Solid

2. Cribriform

3. Papillary

4. Micropapillary


18/70

A. COMEDOCARCINOMA

Solid sheets ofpleomorphic cellswith high gradenuclei and central

necrosis.Periductal

fibrosis, chronicinflammation.

Necrotic cellmembranes calcifymicrocalcifications(mammography).


19/70

Comedo DCIS fills several adjacent ducts and ischaracterized by large central zones of necrosis with

calcified debris.


20/70

B.NONCOMEDO DCIS

Monomorphic population of cells.

Nuclear grade low to high.


21/70

B.1. SOLID DCIS

Filling & pluggingof ductal lumina bytumor cells.

Not usuallyassociated withcalcification.

Maybe clinicallyoccult.


22/70

B.1. SOLID DCIS


23/70

B.2.CRIBRIFORM DCIS

Intraepithelialspaces:

- even distribution.

- regular in shape,size.

- (Cookie cutter-like)

Lumens: often filledwith calcifyingsecretory material.


24/70

B.2.CRIBRIFORM DCIS


25/70

B.3.PAPILLARY DCIS

Papillary growthsinto spaces, lined by amonomorphicpopulation of tall

columnar cells.

Lined byfibrovascular core.

Lack myoepitheliallayer.


26/70

B.3.PAPILLARY DCIS


27/70

B.4. MICROPAPILLARY

Papillae - narrowbase, solid, nofibrovascular core.

Bulbousprotrusions.

Calcifications.


28/70

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.


29/70

PAGET DISEASE OF NIPPLE

Paget disease of the nipple DCIS arising within the ductal


30/70

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


31/70

DCIS WITH MICROINVASION

Foci of tumor cells < 0.1cm d invading thestroma.

In association with comedocarcinoma.


32/70

TREATMENT

Mastectomy DCIS curative in over 95%.

Currently surgical excision usually followedby radiation largely curative.


33/70

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.


34/70


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


35/70

Lobular carcinoma in situ. A monomorphicpopulation of small, rounded, loosely cohesive cells

fills and expands the acini of a lobule.


36/70



37/70


Treatment : bilateralprophylactic mastectomy,tamoxifen.

INVASIVE


38/70

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


39/70

INVASIVE DUCTAL CARCINOMANST (No Special Type)

Gross:

Firm to hard

irregular borders,foci ofcalcification.

INVASIVE DUCTAL CARCINOMA


40/70

INVASIVE DUCTAL CARCINOMANST

Microscopy:

Well differentiatedtubules withminimally atypical

cells oranastomosingsheets ofpleomorphic cells.

Desmoplasticstroma.


41/70

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


42/70

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


43/70

2.INVASIVE LOBULARCARCINOMA

Cellular morphology similar to LCIS.

Metastasis:Peritoneum, retroperitoneum, leptomeninges(carcinomatous meningitis), GIT , ovaries,

uterus.


44/70

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.


45/70


Gross:

Well-circumscribed.

Soft fleshyconsistency.

MEDULLA =

MARROW(Latin)


46/70


Microscopy:Solid sheets, large cells

with vesicular nuclei,prominent nucleoli,

frequent mitosis.

Lymphoplasmacyticinfiltrate.

Pushing borders.

All Med. Ca.: poorlydifferentiated.

No lymphatic / vascularinvasion.

Medullary carcinoma.


47/70

yThe cells are highly pleomorphic with frequentmitoses and grow as sheets of cohesive cells.A lymphoplasmacytic infiltrate is prominent.

4 MUCINOUS ( COLLOID)


48/70

4.MUCINOUS ( COLLOID)CARCINOMA

Unusual type (1-6%)

Circumscribed mass.

Older patients.

Slow growth.



49/70


Gross

Extremely soft.

Sharplycircumscribed

Pale grey bluegelatinousappearance.



50/70


Microscopy

Clusters of well-differentiatedtumor cells areseen floating in a

sea of mucin.

Mucinous (colloid) carcinoma. The tumor cells are present as


51/70

( ) psmall clusters within large pools of mucin. The borders aretypically well circumscribed, and these cancers often mimic

benign masses.


52/70

5. TUBULAR CARCINOMA

2% - before, now 10%.

Irregular mammographic densities.

Excellent prognosis.


53/70

5. TUBULAR CARCINOMA

Microscopy:

Well formedtubules, no

myoepithelialcells.

Tumor cells indirect contactwith the stroma.

6 INVASIVE PAPILLARY


54/70

6. INVASIVE PAPILLARYCARCINOMA

Rare, 1% or fewer.

MicroscopyStromal invasion - papillary architecture.

Overall prognosis- better.


55/70

7.METAPLASTIC CARCINOMA

Rare (


56/70

MAJOR PROGNOSTICFACTORS

1. Tumor size

Carcinomas < 1 cm have an excellentprognosis in the absence of lymph node

metastases.

90% survival without treatment.

MAJOR PROGNOSTIC


57/70


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.


58/70

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


59/70


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


60/70

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


61/70


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


62/70


3. ERPR

80% positive for ERPR respond to hormonaltherapy.

40% positive for one type respond totherapy.

Negative -


63/70


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


64/70

THERAPEUTIC APPRAOACHES

Current:

Combination of surgery & postoperativeradiation & systemic control hormonal or

chemotherapy or both.

Newer strategies:Inhibition of HER2 / neuHerceptin.


65/70

Summary


66/70

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.


67/70

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.


68/70

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:


69/70

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.


70/70

"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

malignant diseases of breast

Documents