BREAST PATHOLOGY

Edna May Go, MD

The Female Breast

Life Cycle Changes

Prepubertal breast
Consists

of duct
system ending in
terminal ducts with
minimal lobule

Beginning of
Menarche
Terminal

ducts give
rise to lobules
Interlobular stroma
increases in volume
Paucity of adipose
tissue

Life Cycle Changes

Follicular phase
Lobules

are
quiescent

After ovulation
Estrogen

and
progesterone
Cell proliferation
increases
Vacuolization of
epithelial cells
Intralobular stroma
becomes markedly
edematous

Life Cycle Chnages

Pregnancy

Lobules increase
number and size
Reversal of stromalepithelial relationship
End of pregnancy

Breast is composed
almost entirely of
lobules separated by a
relatively scant amount
of stroma
By third trimester,
secretory vacuoles of
lipid material found
within epithelial cells of
TDLU

After Birth

Breast produces
colostrum

Changes to milk (higher

fat calories) within first
10 days as progesterone
drops

After cessation of
lactation

Lobules regress and

atrophy

Life Cycle Changes

Third decade
Lobules

and stroma
start to involute

Old Age

Lobules may totally

disappear, leaving only
ducts to create a
morphologic pattern
similar to male breast

Normal breast

extreme

Terminal duct lobular unit

SMA

p63

Normal postpubertal female breast, non-lactating. Arrow heads

delineate the lobule. The terminal ductule (short arrow) leads
from the lobule to the duct system (larger arrows). Note how the
pink fibrillar extracellular matrix material (mostly collagen) tends
to wrap concentrically around the ducts and lobules. r Figure 2.

Diagnostic methods

ine needle aspiration

F
cytology
True-Cut biopsy
Examination of frozen section
Mammography

Fine needle aspiration cytology

woman presents at a clinic with a breast lump, a
needle can be inserted into the area and cells
aspirated without the need for even a local
anaesthetic.

After smearing and staining, the cells are

examined by a pathologist, and if the specimen
is adequate a diagnosis can be made.

Figure 13 Quick-core cutting needle (Cook Medical Inc, Bloomington, IN, USA)
used to obtain core biopsies of soft tissue. (a) Photograph shows the needle set
that has a handle, which enables one-handed control and a spring-loaded
trigger with a rapid-firing mechanism. (b) Close-up photograph of the needle tip
shows the bevelled-point stylet that enables easy penetration into the lesion with
minimal trauma to the surrounding tissue. Firing of the sharp cutting edge of the
cannula facilitates obtaining an intact core tissue sample within the slotted
stylet.

Mammography
X-raying of the breasts is used to help in the
diagnosis of both palpable and impalpable
lesions.
the basis of screening programmes, which try to
detect impalpable small breast cancers. i.e.
early tumours.

It is important that the pathologist carefully

examines the tissue to ensure that the lesion
has been removed.

Tru-Cut biopsy
Another approach which can be used in the clinic is Tru-Cut biopsy, in which a
core of tissue is removed using a biopsy needle.

Examination of frozen section

A further approach is that of examining the breast lesion
very rapidly by frozen section at the time of surgery.

A small sample is frozen, and sections are cut, stained

and interpreted by a pathologist within a few minutes.

Disorder of Development

Milkline remnants
Accessory axillary bresat tissue
Congenital nipple inversion
Spontaneously

corrected during pregnancy

Macromastia
Reconstruction or augmentation
Most

common complication is formation of thick

fibrous capsule causing cosmetic deformity

Site for fibroadenoma and carcinoma

Clinical Presentations of Breast

Disease

Mastalgia or mastodynia
Most

Palpable mass
Not

common symptom

become palpable until 2cm in diameter

Nipple discharge
Galactorrhea

is seen in increased production of

prolactin (pituitary adenoma), hypothyroidism,
endocrine anovulatory syndromes

Mammography

Screening recommended at age 40

Principal mammographic signs of breast
cancer
Densities
Invasive

carcinoma, fibroadenoma, cysts

Calcifications
Associated

with secretory material, necrotic debris,

hyalinized stroma
DCIS is most common malignancy associated with
calcifications

Inflammations

Acute mastitis
During

early weeks of nursing

Vulnerable

to bacterial infection because of

development of cracks and fissures in the nipple
Staphylococcus aureus

Most common
Single or multiple abscesses

Streptococci

Less common
Diffuse spreading infection

INFLAMMATIONS

ACUTE MASTITIS
+ BREAST FEEDING
+ CRACKS FISSURES IN NIPPLES,
+ STAPH, STREP
+ LOCALIZED ACUTE
INFLAMMATION

Inflammations

Periductal mastitis
Recurrent subareolar abscess, squamous metaplasia
of lactiferous ducts, Zuska disease
Seen in smokers (90%)

Vitamin A deficiency
Toxic substances alter differentation of ductal epithelium

Recurrent disease
Fistula tract
Inverted nipple secondary to fibrosis and scarring

Keratin is trapped within ductal system causing

dilation and rupture

PERIDUCTAL MASTITIS
+ SQUAMOUS METAPLASIA OF
LACTIFEROUS DUCTS
+ RECURRENT SUBAREOLAR
ABSCESS
+ MORE THAN 90% ARE SMOKERS
+ KERATINIZING SQUAMOUS

EPITHELIUM INTO THE ORIFICES

OF THE LACTIFEROUS DUCTS/
GRANULOMATOUS REACTIONS

Inflammations

Mammary duct
ectasia
Fifth-sixth decade
Multiparous women
Dilation of ducts,
inspissation of breast
secretions, marked
periductal and
interstitial chronic
granulomatous
inflammation reaction

Duct ectasia

Mamfoamy histiocytes and the periductal tissue

is infiltrated mary duct ectasia. The dilated duct
contains by lymphocytes

Inflammations

Fat necrosis
History

of trauma
Hemorrhage (early stage), central liquefactive
necrosis of fat (later), pregressive fibroblastic
proliferation and increase vascularization and
lymphocytic inflitration
Foreign body giant cells, calcification,
hemosiderin

This is fat necrosis of the breast. The most common

etiology is trauma. It can be a localized, firm area with
scarring that can mimic a breast carcinoma.
Microscopically, however, fat necrosis consists of irregular
steatocytes with no peripheral nuclei and intervening pink
amorphous necrotic material and inflammatory cells,
including foreign body giant cells responding to the
necrotic fat cells.

Inflammations

Lymphocytic mastopathy
Sclerosing

lymphocytic lobulitis
Collagenized stroma surrounding atrophic ducts
and lobules
Epithelial basement membrane is thickened
Prominent lymphocytic infiltrate surrounds
epithelium and blood vessels
Most common in women with type 1 diabetes or
autoimmune thyroid disease

Lymphocytic mastitis/diabetic
mastopathy characterized by keloid-like fibrosis and
prominent lymphocytic infiltrate surrounding breast ducts and
lobules.

Inflammations

Granulomatous mastitis
Systemic
Wegener

granulomatosis, sarcoidosis

Infections
Mycobacterial,

Granulomatous
Uncommon

fungal

lobular mastitis

breast-limited disease distinguished by

grnulomas involving lobular epithelium
Only affects parous women
Hypersensitivity reaction mediated by alterations in
lobular epithelium during lactation

Benign Epithelial Lesions

Nonproliferative breast changes (Fibrocystic

changes)
Benign morphologic changes
Cysts are most common cause of palpable mass and
alarming if solitary, firm and unyielding
Patterns

Cysts

Fibrosis

May have apocrine metaplasia

Caused by cyst rupture

Adenosis

Increase in number of acini per lobule

Benign Epithelial Lesions

Lactational adenoma
Palpable

masses in pregnant or lactating women

Normal-appearing breast tissue with physiologic
adenosis and epithelial lactational changes
Exaggerated focal response to hormonal
influences

PROLIFERATIVE BREAST DISEASE WITHOUT

ATYPIA

+ PROLIFERATION OF DUCTAL EPITHELIUM

AND / OR STROMA
WITHOUT EPITHELIAL ABNORMALITY

+ MODERATE OR FLORID EPITHELIAL

HYPERPLASIA
+ SCLEROSING ADENOSIS
+ COMPLEX SCLEROSING LESIONS
+ PAPILLOMAS
+ FIBROADENOMAS WITH COMPLEX FEATURES

Benign Epithelial Lesions

Epithelial
Hyperplasia
Defined

as more
than two cell layers
Moderate to florid
More

then four cell

layers

Benign Epithelial Lesions

Sclerosing adenosis
Number of acini per
terminal duct is
ingreased to at least
twice the number
found in uninvolved
lobules
Normal lobular
arrangement is
maintained
Myoepithelial cells
are prominent

Benign Epithelial Lesions

Complex Sclerosing
Lesion (Radial Scar)
Stellate

lesions
characterized by a
central nidus of
entrapped glands in
a hyalinized stroma
Not associated with
prior trauma or
surgery

Benign Epithelial Lesions

Papillomas

Composed of multiple
branching fibrovascular
cores, each having a
connective tissue axis
lined by luminal and
myoepithelial cells
Epithelial hyperplasia
and apocrine
metaplasia may be
present
Small duct papillomas
showincreased risk of
subsequent carcinoma

Proliferative Breast Disease with

Atypia

Atypical ductal
hyperplasia
Histologically
resemble DCIS
Characteristically
limited in extent,
cells are not
completely
monomorphic, fail to
completely fill ductal
spaces

Atypical lobular
hyperplasia
Cells identical to LCIS
Cells do not fill or
distend more than
50% of the acini
within a lobule
May extend into ducts

Increased risk of
developing invasive
carcinoma

Breast Lesions and Relative Risk of Developing Invasive

Carcinoma

Pathologic lesion

Relative risk (Absolute

lifetime risk)

Breast at risk

Modifiers of risk

Nonproliferative breast changes

1.0 (3%)

neither

Proliferative disease without

atypia

1.5 to 2.0
(5-7%)

both

Increased risk if there is

family history
Decreased risk 10 years
after biopsy

Proliferative disease with atypia

(ADH, ALH)

4.0 to 5.0
(13-17%)

both

Increased risk if there is

familty history
Increase risk if
premenopausal
Decreased risk 10 years
after biopsy for ALH

LCIS

8.0 to 10.0
(25-30%)

both

Treatment

DCIS

8.0 to 10.0
(25-30%)

ipsilateral

Treatment

Risk Factors in Carcinoma of the Breast

Age
Rarely

found before

25y/o
77% occur in
women50 y/o up
Average age is 64

Age at menarche
Women

who reach
menarche
whenyounger than
11 y/o have 20%
increased risk

Risk Factors in Carcinoma of the Breast

First live birth

First

full term
pregnancy at
younger than 20 y/o
have half the risk of
nulliparous women
or women over the
age of 35 at their
first birth

First-degree
relatives with
breast cancer
Risk

of breast
cancer increase
with the number of
affected first
degree relatives
(mother, sister,
daughter)

Risk Factors in Carcinoma of the

Breast

Breast biopsies
Increased

risk
associated with
prior breast biopsies
showing atypical
hyperplasia

Race
Lower

in black
women but presents
at more advanced
stage and increased
mortality compared
to white women
Caucasian women
generally have the
highest rate of
breast cancer

Risk Factors in Carcinoma of the

Breast

Estrogen exposure
Postmenopausal

hormone
replacement
therapy slightly
increases the risk of
breast cancer
Estrogen with
progesterone
increases the risk
more than estrogen
alone

Radiation exposure
Threapeutic

radiation or
radiation after atom
bomb exposure
increases risk

Risk Factors in Carcinoma of the

Breast

Carcinoma of the
contralateral breast
or endometrium
Increases

risk

Geographic
influence
US

and EU are 4x to
7x higher than other
countries

Risk Factors in Carcinoma of the Breast

Diet

Moderate or heavy
alcohol consumption
increases risk

Obesity

Due to higher estrogen

levels and lower folate
levels?

Decreased risk in
obese women younger
than 40 years

Due to anovulatory
cycles and lower
progesterone levels

Increased risk in
postmenopausal
obese women

Due to synthesis of
estrogen in fat

Risk Factors in Carcinoma of the Breast

Exercise
Decreased

risk of
breast cancer in
premenopausal
women who
exercise

Breast-feeding
The

longer women
breast-feed, the
greater is the
reduction in the risk
of breast cancer

Risk Factors in Carcinoma of the Breast

Environmental
toxins
Organochlorine

pesticides have
estrogenic effects

Tobacco
Not

associated with
breast cancer

Etiology and Pathogenesis

The major risk factors for the development of

breast cancer are hormonal and genetic (family
history)
About 25% of familial cancers (or around 3%of all
breast cancers) can be attributed to 2 highly
penetrant autosomal dominant genes: BRCA1 and
BRCA2
The general lifetime breast cancer risk for
female carriers is 60% to 85%, the median age at
diagnosis is about 20 years earlier compared to
women without these mutations

Etiology and Pathogenesis

Mutated BRCA1 also increases the risk of

developing ovarian carcinoma
Male breast cancers are markedly increased
only in familites carrying BRCA2 mutations
BRCA1-associated breast cancers are more
commonly poorly differentiated, have a
syncitial growth pattern with pushing
margins, have a lymphocytic response, and do
not express hormone receptors or overexpress
HER2/neu epidermal growth factor receptor

Most common Single Gene Mutations Associated

with Hereditary Breast Cancer

BRCA1 (17q21)
Syndrome:

Familial breast and ovarian cancer

Incidence: 1 in 860
~2% of all breast cancers
Function: tumor suppressor, transcriptional
regulation, repair of double-stranded DNA breaks
Breast carcinomas are commonly poorly
differntiated and triple negative (basal-like),
and have p53 mutations

Most common Single Gene Mutations Associated

with Hereditary Breast Cancer

BRCA2 (13q12-13)
Syndrome:

Familial breast and ovarian cancer

Incidence: 1 in 740
~1% of all breast cancers
Function: tumor suppressor, transcriptional
regulation, repair of double-stranded DNA breaks
Biallelic germline mutations cause a rare form of
Fanconi anemia

Most common Single Gene Mutations Associated

with Hereditary Breast Cancer

P53 (17p13.1)
Syndrome: Li-Fraumeni
Incidence: 1 in 5000
<1% of all breast cancers
Function: tumor suppressor with critical roles in cell
cycle control, DNA replication, DNA repair and
apoptosis
P53 is the most commonly mutated gene in sporadic
breast cancers
Also seen in sarcoma, leukemia, brain tumors,
adrenocortical carcinoma, others

Most common Single Gene Mutations Associated

with Hereditary Breast Cancer

CHEK2 (22q12.1)
Syndrome: Li-Fraumeni variant
Incidence: 1 in 100
~1% of all breast cancers
Function: cell cycle checkpoint kinase, recognition
and repair of DNA damage, activates BRCA1 and p53
by phosphorylation
May increase risk for breast cancer after radiation
exposure
Also seen in cancers of prostate, thyroid, kidney,
colon

Etiology and Pathogenesis

In sporadic tumors, about 50% have decreased

or absent expression of BRCA1
Major risk factors for sporadic breast cancer
are related to hormone exposure: gender, age
at menarche and menopause, reproductive
history, breast feeding, and exogenous
estrogens
Majority of sporadic tumors occur in
postmenopausal women and overexpressed
ER

Proposed precursor-carcinoma sequence in breast cancer

Ductal Carcioma in Situ

Intraductal
carcinoma
5 architectural
subtypes
Comedocarcinoma
Solid sheets of
pleomorphic cells
with high-grade
nuclei and central
necrosis
Necrotic cell
membranes commonly
calcify

Ductal Carcinoma in Situ

Noncomedo DCIS
Monomorphic

population of cells
with nuclear grades
ranging from low to
high
Cribriform DCIS
Intraepithelial

spaces are evenly

distributed and
regular in shape
(cookie cutter like)

Papillary

DCIS

Grows

into spaces and

lines fibrovascular
cores typically lacking
the normal
myoepithelial cell layer

Micropapillary
Bulbous

DCIS

protrusions
without a fibrovascular
core, forming complex
intraductal patterns

Ductal Carcinoma in Situ

Ductal Carcinoma in Situ

Lobular Carcinoma in Situ

Not associated with

calcifications or a stromal
reaction that would form a
density
1-6% of all carcinomas
Bilateral in 20-40%
Cells are identical with
invasive lobular carcinoma
and atypical lobular
hyperplasia
LCIS and ILC lack
expression of e-cadherin
(transmembrane protein
responsible for epithelial
cell adhesion)

Invasive Ductal Carcinoma

Invasive carcinoma, no
special type (NST)

Cannot be classified as
any other type

70-80% of all breast

cancer
Gross: firm to hard,
irregular border, small
pinpoint foci or streaks
of chalky white
elastotic stroma at the
center, calcifaction
may be present

Microscopic: well
differentiated tumors
consists of tubules
lined by minimally
atypical cells (typically
do not overexpress
HER2/neu),
others are composed of
anastomosing sheets of
pleomorphic cells
(typically overexpress
HER2/neu)

Invasive Ductal Carcinoma

Invasive Ductal Carcinoma

Invasive Lobular Carcinoma

Usually present like IDC as

palpable mass or
mammographic density
Reported to have greater
incidence of bilaterality
(biased)
Incidence increasing in
postmenopausal women
probably due to hormone
replacement therapy

Histologic hallmark is the

pattern of single
infiltrating tumor cells ,
often only once cell width
(Indian filing)
Lack hormone receptors,
aneuploid, may
overexpress HER2/neu
Has different metastasis
pattern: peritoneum,
retroperitoneum,
leptomeninges, GIT,
ovaries and uterus

Invasive Lobular Carcinoma

Medullary Carcinoma

Well circumscribed mass

History of rapid growth
Consists of solid synctiumlike sheets (occupying
more than 75% of the
tumor) of large cells with
vesicular, pleomorphic
nuclei, containing
prominent nucleoli and
frequent mitoses
Has moderate to marked
lymphoplasmacytic
infiltrates

Has a pushing (noninfiltrative) border

All medullary carcinoma
are poorly differentiated
Lymphovascular invasion is
never seen
Has slightly better
prognosis than IDC
Aneuploid, absence of
hormone receptors,
HER2/neu overexpression
is not observed
13% carry BRCA1 gene but
most are not associated
with BRCA1 mutation

Medullary Carcinoma

Mucinous Carcinoma

1-6% of all breast

cancers
Presents as
circumscribed mass
Seen in older women
Grow slowly
Tumor cells are seen
as clusters and small
islands of cells within
large lakes of mucin

Prognosis is slightly
better than IDC
Incidence slightly
higher in women with
BRACA1 mutation

Mucinous Carcinoma

Tubular Carcinoma

2% of all breast
cancers
10% of all breast
cancers with less
than 1cm diameter
Women in late forties
Multifocal within one
breast (10-56%),
bilateral in 9-38%
Axillary metastasis
occur in less than 10%

Consists exclusively
of well-formed
tubules with absent
myoeptihelial cell
layer
Apocrine snouts are
typical, calcifications
95% are diploid and
express hormone
receptors
Excellent prognosis

Tubular Carcinoma

Invasive Papillary Carcinoma

~1% of all invasive breast cancers

Invasive carcinoma with papillary
architecture
Overall prognosis is better than IDC
Invasive papillary carcinomas are usually ER
positive and have favorable prognosis
Invasive micropapillary carcinomas are more
likely ER negative and HER2 positive with
lymph node metastates and poorer prognosis

Metaplastic Carcinoma

<1% of all cases

Includes conventional adenocarcinoma with
chondroid stroma, squamous cell carcinomas
and carcinomas with a prominent spindle cell
component
ER-PR and HER2/neu negative
Lymph node metastasis is infrequent but
prognosis is poor

Major Prognostic Factors

Invasive carcinoma or in situ

disease

Lymph node metastases

In situ by definition are confined

to ductal system and cannot
metastasize

Distant metastasis

Once distant metastases are

present, cure is unlikely

Axillary lymph node status is the

most important prognostic factor
for invasive carcinoma in the
absence of distant metastases
Sentinel node is highly predictive
of the status of the remaining
nodes
Macrometastases (>0.2cm) are of
proven prognostic importance
~10-20% without axillary lymph
node metastases have a
recurrence outside of breast

Metastasis occur via internal

mammary lymph nodes or
hematogenously

Major Prognostic Factors

Tumor size

Second most important

prognostic factor and is
independent from lymph
node status
Women with nodenegative carcinomas under
1cm in diameter have a
prognosis approaching
that of women without
breast cancer (10 year
survival rate is 90%
without treatment)

Locally advance disease

Tumors invading into skin

or skeletal muscle are
frequently associated with
concurrent or subsequent
distant disease

Inflammatory carcinoma

Breast cancers presenting

with breast swelling and
skin thickening due to
dermal lymphatic
involvement have a
particularly poor prognosis

Minor Prognostic Factors

Histologic subtypes

Tubular, mucinous,
medullary, lobular,
papillary

Tumor grade
Nottingham Histologic
Score (Scarf-BloomRichardson)
Combines nuclear
grade, tubule
formation and mitotic
rate

Estrogen and
Progesterone
receptors
Hormone receptorpositive cancers have
a slightly better
prognosis than
hormone receptornegative cancers
ER-positive cancers
are less likely to
respond to
chemotherapy

Minor Prognostic Factors

HER2/neu

Human epidermal growth

factor receptor 2, c-erb B2,
neu)
Transmembrane glycoprotein
involved in cell growth
control
Overexpression is associated
with amplification of the
gene on 17q21
Overexpression is associated
with poorer survival but its
main importance is as a
predictor of response to
agents that target it [e.g.
Trastuzumab (Herceptin) or
lapatinib]

Lymphovascular invasion

Strongly associated with the

presence of lymph node
metastases
Poor prognostic factor in
women without lymph node
metastases
Risk factor for local
recurrence

Minor Prognostic Factors

Proliferative rate

Tumors with high

proliferation rates have a
worse prognosis
Methods to asses
prolifetation

Mitotic count
Immunohistochemical
detection of cellular
proteins produced during
cell cycle (cyclins, Ki-67)
Flow cytometry as the Sphase fraction
Thymidine labeling index

DNA content

Determined by flow
cytometry or image tissue
analysis
Tumors with a DNA index
of 1 have the same total
amount of DNA as normal
diploid cell
Aneuploid tumors are
those with abnormal DNA
indices and have a slightly
worse prognosis

Minor Prognostic Factors

Response to
neoadjuvant therapy
Alternative approach
wherein patient is
treated before
surgery
Most likely to respond
well are poorly
differentiated, ER
negative tumors with
necrosis

Gene expression
profiling
Can predict survival
and recurrence-free
interval
Identifies patient who
are most likely to
benefit from
particular type of
chemotherapy

Stromal Tumors

Fibroadenoma

Most common benign tumor

of the female breast
Epithelium is hormonally
responsive
Characteristic large lobulated
(popcorn) calcifications on
mammography
Well circumscribed, rubbery
mass
Stroma is usually delicate,
cellular and often myxoid,
enclosing glandular and
cystic spaces lined by
epithelium

Stromal Tumors

Phyllodes Tumor

Arise fromintralobular
stroma like fibroadenoma
Cystosarcoma phllodes
Phyllodes (Greek,
leaflike)
Varies in size, larger
lesions often have bulbous
protrusions
Distinguished
fromfibroadenoma on the
basis of cellularity, mitotic
rate, nuclear
pleomorphism, stromal
overgrowth and
infiltrative borders

Stromal Tumors

Benign stromal lesions

Pseudoangiomatous
stromal hyperplasia
Fibrous tumors
Myofibroblastoma
Lipoma
Hamartoma
Fibromatosis

Clonal proliferation of
fibroblasts and
myofibroblasts
Locally aggressive but
do not metastasize

Sarcomas

Malignant tumors of the

extrinsic connective
tissue of the breast

Angiosarcoma,
rhabdomyosarcoma,
liposarcoma,
leiomyosarcoma,
chondrosarcoma,
osteosarcoma

Sarcomatous
differentiation is seen
in phyllodes tumor and
metaplastic carcinomas

Other malignant tumors

Lymphomas
Mostly

of large cell
type of B-cell origin
Young women with
Burkitt lymphoma
may present with
massive bilateral
breast involvement
and are often
pregnant or
lactating

Metastases
Most

frequent
nonmammary
metastases are
melanomas and lung
cancer

Male Breast

Gynecomastia

Enlargement of male
breast

Proliferation of dense
collagenous connective
tissue
Marked micropapillary
hyperplasia of ductal
linings
Seen in puberty, very
aged, hyperestrinism
(esp. in liver cirrhosis),
Klinefelter syndrome
(XXY), functioning
testicular neoplasms

Male Breast Cancer

Frequency ratio to female

breast cancer is less than
1:100
Risk factors similar to those
in women

First degree relatives with

breast cancer, decreased
testicular function, exposure
to exogenous estrogens,
increasing age, infertility,
obesity, prior benign breast
disease, exposure to ionizing
radiation, residency in
Western countries

Gynecomastia is not a risk

factor

4-14% are attributed to germ

line BRCA2 mutations
ER positivity is more common
in male breast cancer (81%)
Because breast epithelium in
men is limited to large ducts
near the nipple, cancer
usually present as a palpable
subareolar mass, 2-3cm in
diameter
Prognostic factor are similar
in men and women

Molecular classification

Studies of breast cancers using gene

expression profiling have identified several
major breast cancer subtypes

.The best characterized of these have been

designated :
luminal A, luminal B, HER2 and basal-like

basal-like breast cancers as a distinct group.

These tumors are invasive ductal carcinomas
that feature high-histologic grade,
solid architecture,
absence of tubule formation,
high mitotic rate,
a stromal lymphocytic infiltrate,
a pushing border,
geographic zones of necrosis
and/or a central fibrotic focus, and little or
no associated DCIS

-these tumors are typically ER-, PR-, and HER2negative (triple negative)
and show expression of basal cytokeratins,
EGFR, and other basal-related genes
-approximately 80% of BRCA1-associated breast
cancers cluster with the basal-like group

Table 10.6 Major Molecular Categories of Breast Cancer Determined by

Gene Expression Profiling

Luminal

HER2

Basal

Gene Expression Patterns

High expression of hormone receptors

and associated genes (luminal A>
luminal B)

High expression of HER2 and other

genes in amplicon
Low expression of ER and associated
genes

High expression of basal epithelial genes,

basal cytokeratins
Low expression of ER and associated
genes
Low expression of HER2

Clinical Features

~70% of invasive breast cancers

ER/PR positive
Luminal B tend to be higher-histologic
grade than luminal A
Some overexpress com-HER2 (luminal
B)

~15% of invasive breast cancers

ER/PR negative
More likely to be high grade and nodepositive HER2 overexpression and gene
amplification

~15% of invasive breast cancers

ER/PR/HER2 negative
BRCA1-associated cancers
Particularly common in African
American women

Treatment Response and Outcome

Respond to endocrine therapy (response

may be different for luminal A and
luminal B)
Response to chemotherapy variable
(luminal B> luminal A)
Favorable prognosis

Respond to trastuzumab (Herceptin)

Respond to anthracycline-based
chemotherapy
Poor prognosis

No response to endocrine therapy or

trastuzumab (Herceptin)
?Response to platinum-based
chemotherapy
Poor prognosis

At the present time, the clinical value of characterizing invasive breast

cancers beyond routine histopathologic type and ER, PR, and HER2
status has not been established.
Table 10.7 Immunophenotyping as a Surrogate for Molecular
Category Using Estrogen Receptor, Progesterone Receptor
and HER2 Status
Luminal A

Molecular Category
Luminal B
HER2

Basal-like*

ER

PR

HER2

*Additionally performing immunostains for cytokeratin (CK)5/6 and epidermal growth factor receptor (EGFR) helps to
define more precisely tumors in the basal-like group which in addition to being ER-, PR-, and HER2-negative are positive
for CK5/6 and/or EGFR.

Thank you.