Download - Breast carcinoma pathology
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.