Dr. P. Karpagam Kiruba Rajeswari, M.B.B.S.,D.C.P.,

Tutor in Pathology,MAPIMS

Most common non-skin malignancy in women!!!

BREAST CARCINOMA – RISK FACTORS

PATHOGNESIS – GENETIC FACTORS

Most common genes

implicated in Breast

carcinoma

BRCA -1Breast

Cancer 1,Early onset ( Chr.17)

BRCA-2, Breast Cancer 2,Early onset( Chr.13)

p53( Chr.17) CHEK2( Chr. 22)

FUNCTIONS:1. Transcription2. DNA Repair of

double stranded breaks

3. Ubiquitination4. Transcriptional

regulation.

FUNCTIONS:1.Stability of the human genome2.DNA double strand break repair.

FUNCTIONS1. Cell cycle

control2. DNA

replication3. DNA repair4. Apoptosis.

FUNCTIONS1. Cell cycle

checkpoint kinase, recognition and repair of DNA damage.

2. Activates BRCA1 and p53 by phosphorylation

Germline point mutations/Deletions of BRCA1 gene Hereditary breast & ovarian cancers.

Mutations 20% Hereditary breast cancer, ovarian cancer, increased cancer risk in male carriers.

Mutations Sporadic breast cancers. Li fraumeni syndrome

Mutations - rare (<5%). Li fraumeni variantIncrease breast cancer risk after radiation exposure

HER2/neuHuman Epidermal growth factor Receptor2

Member of ErbB protein family.

HER2 is a cell membrane surface-bound receptor tyrosine kinase - normally involved in signal transduction pathways cell growth and differentiation.

Approximately 30 % of breast cancers amplification of the HER2/neu gene/ overexpression of its protein product.

 Overexpression of this receptor in breast cancer increased disease recurrence and worse prognosis.

PATHOGENESIS – HORMONAL FACTORSExcess Hormonal exposure

Sporadic cancers.

Post menopausal women sporadic cancers ER positive.

Hormones breast growth during puberty, menstrual cycles, pregnancy cycles of proliferation cells at risk for DNA damage.

If premalignant or malignant cells are present, hormones - stimulate their growth + growth of normal epithelial and stromal cells tumour development.

Metabolites of estrogen mutations / generate DNA-damaging free radicals.

> 95 % breast malignancies ADENOCARCINOMAS

CLASSIFICATION – BREAST CARCINOMA

NON-INVASIVE/IN SITU CARCINOMA

Intraductal carcinoma Lobular carcinoma in

situ

INVASIVE CARCINOMA

Infiltrating ( invasive ) duct carcinoma – NOS

Infiltrating ( invasive ) lobular carcinoma

Medullary carcinoma

Colloid (mucinous) carcinoma Papillary carcinoma Tubular carcinoma Adenoid cystic

carcinoma Secretory carcinoma Inflammatory carcinoma Carcinoma with

metaplasia

PAGET’S DISEASE OF THE NIPPLE

Malignant clonal population of cells limited to ducts & lobules by the basement membrane.

DUCTAL CARCINOMA IN SITUMost DCIS detected by

calcifications on mammography/mammographic density - periductal fibrosis surrounding a DCIS/rarely palpable mass/ nipple discharge/incidental finding on a biopsy for another lesion.

Spreads through ducts & lobules extensive lesions entire sector of a breast.

DCIS – involves lobules – acini distorted, unfolded appear as small ducts.

ComedocarcinomaSolid sheets of pleomorphic

cells with high grade hyperchromatic nuclei.

Areas of central necrosis +nt.

Necrotic cell membranes – calcify clusters/linear & branching microcalcifications on mammography.

Periductal concentric fibrosis & chronic inflammation.

Extensive lesions – palpable as vague nodularity.

Noncomedo DCISMonomorphic cell

population – nuclear grades low to high.

CRIBRIFORM DCIS Intra-epithelial spaces

–evenly distributed, regular in shape.

COOKIE CUTTER – LIKE

• SOLID DCISCompletely fills the

involved spaces.

Noncomedo DCISPAPILLARY DCIS Grows into spaces along

fibrovascular cores lack myoepithelial cell layer.

• MICROPAPILLARY DCIS

Bulbous protrusions without a fibrovascular core arranged in complex intraductal patterns.

Calcifications – assoc.with necrosis/form on intraluminal secretions.

PAGET’S DISEASE OF NIPPLE Rare manifestation of breast CA. U/l erythematous eruption, Pruritus. Malignant cells/PAGET CELLS

Extend from DCIS within ductal system – via lactiferous sinuses nipple skin without crossing the BM.

Tumour cells – disrupt tight squamous epithelial barrier – ECF seeps out onto nipple surface oozing scaly crust.

Paget’s cells – detected by nipple Bx/cytological preparation of the exudate.

Palpable mass 50 – 60 % of women => invasive CA.

No palpable mass => DCIS Poorly differentiated, ER Negative,

HER2/neu overexp. Prognosis – depends on features of

underlying Ca.

PAGET’S DISEASE OF NIPPLE

DCIS WITH MICROINVASION Area of invasion

through BM stroma - > 0.1 cm.

Assoc. with comedocarcinoma.

Few microinvasion foci prognosis similar to DCIS.

MANAGEMENT AND PROGNOSIS OF DCIS

MASTECTOMY for DCIS – curative > 95 % pts.

Recurrence – rare – d/t residual DCIS in ducts in subcutaneous tissue – not removed during surgery/ d/t occult foci of invasion not detected at diagnosis.

Breast conservation – can be done but slightly higher risk of recurrence.

Major risk factors for recurrence:

1.Grade2.Size3.Margins

In ER + ve DCIS Post-op. radiation + Tamoxifen recurrence risk – low.

Death < 2 % DCIS.

LOBULAR CARCINOMA IN SITUIncidental biopsy finding

-no calcifications /stromal reactions mammographic densities.

Bilateral - 20% to 40% .

Young women.

Loss of expression of E-cadherin(transmembrane cell adhesion protein cohesion of normal breast epithelial cells).

LOBULAR CARCINOMA IN SITU - MORPHOLOGY Dyscohesive round cells

with oval or round nuclei and small nucleoli. Absence of atypia, pleomorphism, mitoti activity, necrosis.

Involved acini – recognizable as lobules.

Mucin-positive signet-ring cells.

ER and PR +ve.

LOBULAR CARCINOMA IN SITUInvasive carcinoma 1%

per year.

Both breasts - increased risk.

Risk - slightly higher in the

ipsilateral breast.

Invasive carcinomas - lobular type.

Treatment: 1.Bilateral prophylactic

mastectomy. 2.Tamoxifen.3.Close clinical follow-up. 4.Mammographic screening.

INVASIVE CARCINOMA – CLINICALFEATURESPalpable mass.

Axillary lymph node metastases

Fixity to the chest wall / skin dimpling.

Nipple retraction

Lymphatics - involved - block the local area of skin drainage lymphedema, skin thickening.

Tethering of the skin to the breast by Cooper ligaments peau d'orange.

Mammography Radiodense mass

Invasive Carcinoma, No Special Type (NST; Invasive Ductal Carcinoma)

Majority (70% to 80%).

Gross appearance: Most tumors - firm to hard ,irregular border . Less frequently - well-circumscribed border , softer consistency.

When cut / scraped characteristic grating sound d/t small, central pinpoint foci or streaks of chalky-white elastotic stroma and occasional small foci of calcification.

Invasive Carcinoma – NST- HPEFeatures Well diff. Ca Mod. diff.Ca Poorly diff. Ca.

Tubule formation

Prominent Less,solid clusters/single

infiltrating cells

Ragged nests/solid

sheets of cellsNuclei Small,round,mo

nomorphicGreater nuclear pleomorphism

Nuclei – enlarged,irregul

ar.Mitotic figures Rare Present NumerousProliferation

rate- - High

Tumour necrosis - - Present

INVASIVE LOBULAR CARCINOMAPalpable mass/

mammographic density with irregular borders. Sometimes - tumor infiltrates the tissue diffusely – little desmoplasia, not palpable, no mammographic density. Metastases – difficult to detect.

Bilateral - 5 – 10 %.

Biallelic loss of expression of (CDH1, encodes E-cadherin) d/t mutations.

INVASIVE LOBULAR CARCINOMAMorphology: Histologic

hallmark dyscohesive infiltrating tumor cells, often arranged in single file or in loose clusters or sheets INDIAN FILE APPEARANCE.

Tubule formation - absent.

Signet-ring cells containing an intracytoplasmic mucin droplet are common.

Desmoplasia - minimal or absent

INVASIVE LOBULAR CARCINOMAWell-differentiated and

moderately differentiated carcinomas diploid, ER positive, HER2/neu overexpression - rare

Poorly differentiated carcinomas aneuploid, lack hormone receptors, may overexpress HER2/neu.

Different pattern of metastasis than other breast cancers. Metastasis peritoneum ,retroperitoneum, the leptomeninges (carcinoma meningitis), the gastrointestinal tract, ovaries and uterus.

MEDULLARY CARCINOMAMC - 6th decade.

May closely mimic a benign lesion clinically and radiologically/ present as a rapidly growing mass.

MORPHOLOGY : Well – circumscribed,soft,fleshy mass - little desmoplasia more yielding on palpation and cutting. (medulla =>“marrow”).

MEDULLARY CARCINOMA - HPE1. Solid, syncytium-like

sheets of large cells with vesicular, pleomorphic nuclei, prominent nucleoli > 75% of the tumor

2. Frequent mitotic figures; 3. Moderate to marked

lymphoplasmacytic infiltrate surrounding and within the tumor.

4. Pushing (noninfiltrative) border.

Poorly differentiated.

MEDULLARY CARCINOMAHigh nuclear grade,

aneuploidy, hormone receptors - nt, HER2/neu overexpression –nt.

Lymph node metastases -

infrequent.

Syncytial growth pattern and pushing borders - d/t overexpression of adhesion molecules intercellular cell adhesion molecule and E-cadherin limit metastatic potential.

MUCINOUS/COLLOID CARCINOMAOlder women (median

age 71) grow slowly - many years.

Morphology: Tumor – soft/rubbery . Consistency & appearance of pale gray-blue gelatin. Borders - pushing / circumscribed.

MUCINOUS CARCINOMA - HPETumor cells - arranged in

clusters and small islands within large lakes of mucin.

Mucinous carcinomas diploid, well to moderately differentiated, and ER positive.

Lymph node metastases - uncommon.

Overall prognosis is slightly better.

TUBULAR CARCINOMASmall irregular mammographic

densities - late 40s.

Uncommon.

Morphology: Well-formed tubules + nt, myoepithelial cell layer, BM - nt tumor cells in direct contact with the stroma. Apocrine snouts - typical.Calcifications - within the lumens.

> 95% of all tubular carcinomas - diploid, ER + ve,HER2/neu –ve .

Well differentiated. Excellent prognosis.

INVASIVE PAPILLARY & MICROPAPILLARY CARCINOMA

Rare - 1% or fewer of all invasive cancers.

More commonly seen in DCIS.

INVASIVE PAPILLARY CA.

ER positive.Favorable prognosis. INVASIVE

MICROPAPILLARY CA.ER negative,HER2

positive. Lymph node metastases -

very commonPrognosis is poor.

INFLAMMATORY CARCINOMATumors swollen,

erythematous breast - caused by extensive invasion and obstruction of dermal lymphatics by tumor cells.

Underlying carcinoma - diffusely infiltrative - does not form a discrete palpable mass confusion with true inflammatory conditions a delay in diagnosis.

Many patients metastases at diagnosis / recur rapidly.

Overall prognosis poor.

METAPLASTIC CARCINOMA Includes a variety of rare

types of breast cancer (<1% of all cases) matrix-producing carcinomas, squamous cell carcinomas, and carcinomas with a prominent spindle cell component.

ER-PR-HER2/neu “triple negative”.

Lymph node metastases - infrequent.

Prognosis - poor.

PROGNOSTIC FACTORS - MAJOROutcome in breast CA –

varies widely.

Prognosis – determined by pathologic examination of primary carcinoma & axillary lymph nodes.

American Joint Committee on Cancer (AJCC) staging system divides patients into five stages (O to IV) correlated with survival.

Major prognostic factors strongest predictors of death.

1)Invasive vs insitu CA.2)Distant metastasis3)Lymph node metastasis4)Tumour size5)Locally advanced ds.6)Inflammatory CA.

StageT: Primary

CancerLymph Nodes

(LNs)M: Distant Metastasis

5-Year Survival (%)

0 DCIS or LCIS No metastases Absent 92I Invasive

carcinoma ≤2 cm

No metastases Absent 87

II Invasive carcinoma >2

cm

No metastases Absent 75

Invasive carcinoma <5

cm

1 to 3 positive LNs

Absent

III Invasive carcinoma >5

cm

1 to 3 positive LNs

Absent 46

Any size invasive

carcinoma

≥4 positive LNs

Absent

Invasive carcinoma

with skin or chest wall

involvement or inflammatory

carcinoma

0 to >10 positive LNs.

Absent

IV Any size invasive

carcinoma

Negative or positive lymph

nodes

Present 13

PROGNOSTIC FACTORS - MINOR

FIBROADENOMAMC benign tumor - 2 nd & 3 rd

decade.Multiple, bilateral. Young women palpable mass.

Older women mammographic density / calcifications.

Epithelium – hormonally reponsive increase in size during lactation complicated by inflammation, infarction mimics CA.

Stroma - densely hyalinized after menopause -may calcify. Large lobulated (“popcorn”) calcifications characteristic mammographic appearance.

Small calcifications - clustered -require biopsy to exclude carcinoma.

GROSS: Spherical, sharply circumscribed, rubbery, grayish white, freely movable nodules -bulge above the surrounding tissue and contain slitlike spaces.< 1 cm – large tumors.

FIBROADENOMA - HPEStroma – delicate,

cellular,myxoid-resembles normal intralobular stroma.

Epithelium - surrounded by stroma - compressed & distorted by it.

Risk of malignancy assoc. with Complex fibroadenomas cysts > 0.3 cm. in size, sclerosing adenosis, epithelial calcifications, papillary apocrine change.

FIBROADENOMA - TYPES INTRACANALICULAR PERICANALICULAR

In pericanalicular histologic pattern, the glands maintain their round or oval profiles. There is no prognostic or clinical significance attached to the pericanalicular and intracanalicular patterns. Both may be seen within the same lesion. 

PHYLLODES TUMOUR Phyllodes – leaf-likeArise from intralobular

stroma.

Any age, most – 6th decade.

Majority palpable masses, few found by mammography.

Cystosarcoma phyllodes – Misnomer.

MORPHOLOGY : Few cms. to massive lesions involving the entire breast Larger lesions bulbous protrusions d/t the presence of nodules of proliferating stroma covered by epithelium . Some tumors - protrusions extend into a cystic space.

PHYLLODES TUMOURHPE: Greater cellularity,

mitotic rate, nuclear pleomorphism, stromal overgrowth, and infiltrative borders.

Recur locally, rare metastases.

Majority Low-grade lesions

Rare High-grade lesions.

Phyllodes tumors - excised with wide margins / mastectomy to avoid local recurrences.

NORMAL MALE BREAST

Consists of the nipple and a rudimentary duct system ending in terminal buds without lobule formation.

GYNAECOMASTIA Enlargement of male breast.

Puberty/very aged/hyperestrinism.

Cirrhosis of liver, Increased adrenal estrogens as androgenic functions of testis fail in very aged, Drugs – alcohol, marijuana, heroin, ART, anabolic steroids used by atheletes & body builders, Klinefelter syndrome.

D/t imbalance between estrogens, stimulate breast tissue and androgens which counteract these effects

Unilateral or bilateral

Button-like subareolar enlargement.

Morphology : Increase in dense collagenous connective tissue, marked micropapillary epithelial hyperplasia of the duct lining. Individual epithelial cells fairly regular, columnar to cuboidal cells with regular nuclei. Lobule formation is rare.