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
Incidence increases with age Peaks at
Age 75 80 yrs.

Only 1 % incidence men.

Gender

Age at menarche & Early menarche, Late menopause

menopause increased risk.

Nulliparous women /Late pregnancy

Age at first live birth - proliferation of cells with pre neoplastic
changes.

First-Degree Relatives Mother,sister increased risk.

with Breast Cancer -
BREAST CARCINOMA RISK FACTORS
In previous biopsies => increased risk.
Atypical Hyperplasia Proliferative breast changes without
atypia smaller risk.

Non-Hispanic white women highest rates

Race / Ethnicity of breast cancer.

Postmenopausal hormone Increases the risk of breast cancer.

replacement therapy

High breast density --d/t less complete involution

of lobules at the end of each menstrual cycle
Breast Density increases no. of cells potentially susceptible to
neoplastic transformation.

To chest - d/t cancer therapy, atomic

Radiation Exposure
bomb exposure, or nuclear accidents.
BREAST CARCINOMA RISK FACTORS
1% of women with breast cancer second contralateral
Carcinoma of the Contralateral breast carcinoma / year. Risk - higher for women with
Breast or Endometrium. germline mutations in BRCA1 and BRCA2

Geographic Influence
United States and Europe higher
incidence.

Alcohol consumption higher estrogen levels

Diet
and lower folate levels.

Postmenopausal obese women increased synthesis of

Obesity estrogens in fat depots.

The longer women breastfeed, the greater the reduction

Breastfeeding in risk

Environmental Toxins
Organochlorine pesticides estrogenic

Tobacco & cigarette smoking

Increased risk.
HORMONAL
EXPOSURE
(SPORADIC)
Major risk
factors of
Breast
Carcinoma
GENETIC
FACTORS
(HEREDITARY)
PATHOGNESIS GENETIC FACTORS

Most common
genes implicated BRCA1 BRCA2
in Breast
carcinoma
p53 CHEK2
 BRCA -1Breast BRCA-2, Breast p53( Chr.17) CHEK2( Chr. 22)
Cancer 1,Early Cancer 2,Early
onset ( Chr.17) onset( Chr.13)

FUNCTIONS: FUNCTIONS: FUNCTIONS FUNCTIONS

1. Transcription 1. Stability of 1. Cell cycle 1. Cell cycle
2. DNA Repair of the human control checkpoint
double genome 2. DNA replication kinase,
stranded breaks 2. DNA double 3. DNA repair recognition and
3. Ubiquitination strand break 4. Apoptosis. repair of DNA
4. Transcriptional repair. damage.
regulation. 2. Activates BRCA1
and p53 by
phosphorylation
Germline point Mutations 20% Mutations Mutations - rare
mutations/Deletions Hereditary breast Sporadic breast (<5%).
of BRCA1 gene cancer, ovarian cancer, cancers. Li fraumeni variant
Hereditary breast & increased cancer risk Li fraumeni Increase breast
ovarian cancers. in male carriers. syndrome cancer risk after
radiation exposure
 HER2/neu
Human 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 FACTORS
Excess 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.
 BREAST CARCINOMA - CLASSIFICATION
> 95 % breast malignancies ADENOCARCINOMAS

BREAST
CARCINOMA

IN SITU INVASIVE
Neoplastic cells
limited within the Penetrated
ducts,lobules by through the BM
BM. into the stroma.
CLASSIFICATION BREAST CARCINOMA
NON-INVASIVE/IN Colloid (mucinous)
SITU CARCINOMA carcinoma
Intraductal carcinoma
Papillary carcinoma
Lobular carcinoma in
Tubular carcinoma
situ
Adenoid cystic carcinoma
Secretory carcinoma
INVASIVE CARCINOMA
Inflammatory carcinoma
Infiltrating ( invasive )
duct carcinoma NOS Carcinoma with metaplasia
Infiltrating ( invasive )
lobular carcinoma PAGETS DISEASE OF THE
Medullary carcinoma NIPPLE
Malignant clonal population of cells limited to ducts &
lobules by the basement membrane.
 DUCTAL CARCINOMA IN SITU
Most 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.
DCIS 5 Architectural subtypes
COMEDO
CARCINOMA

SOLID CRIBRIFORM PAPILLARY

MICRO
PAPILLARY
 Comedocarcinoma
Solid 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 DCIS
Monomorphic cell
population nuclear
grades low to high.
CRIBRIFORM DCIS
Intra-epithelial spaces
evenly distributed, regular
in shape.

COOKIE CUTTER LIKE

SOLID DCIS
Completely fills the
involved spaces.
 Noncomedo DCIS
PAPILLARY 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.
 PAGETS 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.
Pagets 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.
PAGETS 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
Major risk factors for
MASTECTOMY for DCIS recurrence:
curative > 95 % pts.
1. Grade
Recurrence rare d/t 2. Size
residual DCIS in ducts in 3. Margins
subcutaneous tissue not
removed during surgery/ d/t
occult foci of invasion not In ER + ve DCIS Post-
detected at diagnosis. op. radiation +
Tamoxifen recurrence
Breast conservation can be
risk low.
done but slightly higher risk
of recurrence. Death < 2 % DCIS.
 LOBULAR CARCINOMA IN SITU
Incidental 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 SITU
Invasive 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 CLINICALFEATURES
Palpable 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- HPE
Features Well diff. Ca Mod. diff.Ca Poorly diff. Ca.
Tubule formation Prominent Less,solid Ragged nests/solid
clusters/single sheets of cells
infiltrating cells
Nuclei Small,round,mono Greater nuclear Nuclei
morphic pleomorphism enlarged,irregular.
Mitotic figures Rare Present Numerous
Proliferation rate - - High
Tumour necrosis - - Present
 INVASIVE LOBULAR CARCINOMA
Palpable 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 CARCINOMA
Morphology: 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 CARCINOMA
Well-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 CARCINOMA
MC - 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 - HPE
1. 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 CARCINOMA
High 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 CARCINOMA
Older women (median age
71) grow slowly - many
years.

Morphology: Tumor
soft/rubbery . Consistency
& appearance of pale gray-
blue gelatin. Borders -
pushing / circumscribed.
 MUCINOUS CARCINOMA - HPE
Tumor 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
Small irregular mammographic
CARCINOMA
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 common
Prognosis is poor.
 INFLAMMATORY CARCINOMA
Tumors 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 - MAJOR
Outcome in breast CA
varies widely.
Major prognostic factors
Prognosis determined by strongest predictors of
pathologic examination death.
of primary carcinoma & 1) Invasive vs insitu CA.
axillary lymph nodes. 2) Distant metastasis
3) Lymph node metastasis
4) Tumour size
American Joint 5) Locally advanced ds.
Committee on Cancer 6) Inflammatory CA.
(AJCC) staging system
divides patients into five
stages (O to IV) correlated
with survival.
 T: Primary Lymph Nodes M: Distant 5-Year Survival
Stage Cancer (LNs) Metastasis (%)
0 DCIS or LCIS No metastases Absent 92
I Invasive No metastases Absent 87
carcinoma 2 cm
II Invasive No metastases Absent 75
carcinoma >2 cm
Invasive 1 to 3 positive LNs Absent
carcinoma <5 cm
III Invasive 1 to 3 positive LNs Absent 46
carcinoma >5 cm
Any size invasive 4 positive LNs Absent
carcinoma
Invasive 0 to >10 positive Absent
carcinoma with LNs.
skin or chest wall
involvement or
inflammatory
carcinoma
IV Any size invasive Negative or Present 13
carcinoma positive lymph
nodes
PROGNOSTIC FACTORS - MINOR
Histologic Gene
expression
Type & Grade profiling
 TYPES OF STROMAL TUMORS

INTRALOBULAR FIBROADENOMA
STROMA PHYLLODES TUMOUR

LIPOMAS
ANGIOSARCOMAS
INTERLOBULAR PSEUDOANGIOMATOUS
STROMAL HYPERPLASIA
STROMA FIBROUS TUMOURS
MYOFIBROBLASTOMA
 FIBROADENOMA
MC 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 GROSS: Spherical, sharply
circumscribed, rubbery, grayish
appearance.
white, freely movable nodules -
Small calcifications - clustered - bulge above the surrounding
require biopsy to exclude carcinoma. tissue and contain slitlike spaces.
< 1 cm large tumors.
 FIBROADENOMA - HPE
Stroma 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-like
Arise 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 TUMOUR
HPE: 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.