Breast

Pathology
Dr. Yaniv Zohar

The Female Breast

Mammary gland modified sweat
gland
Complete source of
nutrition and
immune protection
for the offspring

ascita di Venere, Botticelli 1486, Galleria degli Uffizi, Firenze

Breast Pathology

Normal structure
Developmental disorders
Inflammatory disorders
Non-proliferative disorders
Proliferative disorders (with/without
atypia)
Carcinoma of breast
Stromal tumors
The male breast
4

The Female Breast - Normal

Structure
6-10 major ductal systems
Squamous epithelium of the skin dips into
the orifices in the duct
Abruptly changes into double-layered
cuboidal epithelium of the duct
Branching of the duct leads to the
formation of the terminal duct lobular unit
Each terminal duct branches into a cluster
of small acini to form a lobule
5

The Female Breast - Normal

Structure

The Female Breast - Normal

Histology
Lobule

Terminal duct

The Female Breast - Normal

Histology
Two cell types line the
ducts and lobules of the
breast:
Myoepithelial cells lie
on the basement
membrane, contain
contractile elements
Luminal epithelial cells
overlay the myoepithelial
cells. Only lobular luminal
cells secrete milk

The Female Breast - Normal

Histology

IHC staining of myoepithelial cells with p63

9

The Female Breast - Normal

Histology
Two types of breast
stroma:
Interlobular
stroma dense
fibrous tissue
Intralobular
stroma envelopes
acini, consists of
hormoneresponsive
fibroblast-like cells

10

Disorders of
Development
Milkline remnants
Supernumerary
nipples or breasts
along the milkline
(axilla to perineum)
Painful
premenstural
enlargement
11

Disorders of
Development
Accessory axillary breast tissue
breast tissue extending into the axilla, can
undergo lactational changes or develop
carcinoma
Congenital nipple inversion
usually corrects spontaneously during
pregnancy
acquired nipple retraction may indicate
underlying cancer
12

Clinical Presentation of Breast

Disease
Pain (mastalgia)
Cyclic (with menses) no significance
Noncyclic ruptured cyst, infection, injury, breast
feeding, fat necrosis
95% of painful masses are benign

Palpable mass
Must be distinguished from lumpiness of breast
Becomes palpable when at least 2cm
Likelihood for malignancy increases with age (10%
under 40yo, 60% over 50yo)
13

Clinical Presentation of Breast

Disease
Nipple discharge
Galactorrhea milky discharge, elevated prolactin levels
(pituitary adenoma, hypothyroidism, endocrine anovulatory
syndromes, drugs).
Not associated with malignancy
Bloody/serous discharge benign conditions (large duct
papilloma, cyst)
risk of malignancy increases with age 7% under 60yo, 30%
over 60yo

Mammographic screening
Densities invasive carcinomas (~1cm) , fibroadenomas, cysts
Calcifications form on secretions, necrotic debris or sclerosed
stroma
14

Mammography Stellate lesion

15

16

Inflammatory Disorders of the

Breast
Acute mastitis
Almost all cases within 1
month of breastfeeding
Cracks and fissures in
the nipple port of entry
Staph. aureus or
streptococci
At onset only one duct
system is involved
Treatment antibiotic
and continued
expression of milk

17

Inflammatory Disorders of the

Breast
Periductal mastitis
Not associated with
lactation, history or age
More than 90% of
cases are smokers
Keratinizing squamous
metaplasia of the nipple
ducts, resulting in
keratin plugs, dilation
and rupture of ducts
Chronic granulomatous
inflammation in
response to keratin

Abrupt change
into ductal
epithel

18

Inflammatory Disorders of the

Breast
Mammary duct ectasia
(distension)
Fifth-sixth decade
Multiparous women
Not associated with
smoking
Palpable periareolar mass,
thick white nipple discharge
Dilation of ducts, periductal
and interstitial
granulomatous
inflammation, lipid-laden
macrophages within the
lumen

19

Inflammatory Disorders of the

Breast
Fat necrosis
Painless mass
History of trauma or
breast surgery
Acute lesions
hemorrhagic and
show liquefactive fat
necrosis
Older lesions - giant
cells, calcifications,
hemosiderin
Replaced by scar
20

Inflammatory Disorders of the

Breast
Lymphocytic
mastopathy
(sclerosing lymphocytic
lobulitis)

Single or multiple
palpable masses
Most common in
women with type I
DM
Stone-hard lesions
Collagenized stroma
surrounding atrophic
ducts and lobules
21

Benign Epithelial Lesions

Non-proliferative breast changes
(fibrocystic changes)
A very common change
lumpy bumpy breast
Mammography dense breast with cysts
Morphology:
Cystic changes with apocrine metaplasia
Fibrosis
Adenosis
22

Fibrocystic Changes
Cystic changes
Dilation and unfolding of
lobules
May coalesce to form
large cysts
Cysts contain turbid fluid
Lined by flat, atrophic
epithelium, or by
metaplastic apocrine
cells
Calcifications are
common (coarse, at the
bottom of the cyst)
23

Fibrocystic Changes
Fibrosis
Following cyst rupture,
inflammation and
fibrosis

Adenosis
Increase in number of
acini in a lobule
Acini are lined by
columnar cells, may
show atypia (flat
epithelial atypia)
24

Proliferative Breast Disease

Without Atypia
Proliferation of ductal epithelium and/or stroma
without atypia
Often detected as mammographic densities,
calcifications or incidental finding
Epithelial hyperplasia the presence of more than
two layers of luminal cells in a duct or lobule
The additional cells consist of both luminal and
myoepithelial cells (see both types)
25

Proliferative Breast Disease

Without Atypia

26

Proliferative Breast Disease

Without Atypia
Sclerosing adenosis
The number of acini per
lobule is increased
Normal lobular
arrangement
Acini are compressed
and distorted in the
center and dilated in
the periphery
Stromal fibrosis may
compress the lobules
completely, mimicking
invasive carcinoma
27

28

29

Proliferative Breast Disease

Without Atypia
Complex Sclerosing
Lesion
Lesions with components
of sclerosing adenosis,
papilloma and
hyperplasia
Radial scar a central
area of entrapped acini
in a hyalinized stroma
with long radiating
projections
30

Proliferative Breast Disease

Without Atypia
Papilloma
Multiple branching
fibrovascular cores,
covered by luminal
cells and
myoepithelial cells.
Growth within a
dilated duct
Hyperplasia and
apocrine metaplasia
are common
31

Proliferative Breast Disease

With Atypia
Atypical hyperplasia may be ductal or lobular
Cellular proliferation resembling carcinoma in
situ, but lacking sufficient features of carcinoma
The same genetic changes seen in carcinoma in
situ
~20% of women with atypical hyperplasia will
develop breast cancer
32

Proliferative Breast Disease

With Atypia
Atypical ductal
hyperplasia
Monomorphic
proliferation of
regularly spaced cells
Sometimes with
cribriform spaces
Distinguished from
DCIS by being limited
in extent and filling
part of the duct
33

Atypical Ductal Hyperplasia

34

Proliferative Breast Disease

With Atypia
Atypical lobular
hyperplasia
Proliferation of cells
identical to LCIS
Involving less than
50% of the acini
Can also involve ducts
atypical cells lie
between basement
membrane and
normal ductal cells
35

Atypical Lobular Hyperplasia

36

Carcinoma of the Breast

The most common non-skin cancer in
women
Second most lethal cancer in women
(after lung cancer)
For women who live until age 90 1
in 8 risk

37

Cases per 100,000 women (age-adjusted)

Carcinoma of the Breast

38

Cases per 100,000 women (age-adjusted)

Carcinoma of the Breast

39

Carcinoma of the Breast

Risk Factors

40

Carcinoma of the Breast

Risk Factors
1. Female gender
2. Age peak incidence at 7580, mean age changes with
race (US: White 61,
Hispanic 56, AA 46)
3. Age at menarche before
11 20% increased risk
4. Age at first live birth fullterm pregnancy at age 20
50% decreased risk
5. First-degree relative risk
increases with number of
first-degree relatives with
breast cancer. Most cases
have no family history
41

Carcinoma of the Breast

Risk Factors
6. Race/Ethnicity - (p53,
BRCA mutations) *
7. Hormone exposure:

HRT increased risk by 1.2-1.7,

progesterone addition increased
risk.
Oral contraceptives - no
convincing data

8. Breast density high

density strong risk factor

Young age and hormone

exposure, less complete
involution of cells at end of each
cycle, and thus these cells still
respond to est and can
transform into malignant cells

More
difficult to detect
in
* Differences
in pathological
and clinical
features of breast cancer in Arab as
compared tomammography
Jewish women in
Northern
Israel. Zidan J,Sikorsky N,Basher
MRI
instead
W,Sharabi A,Friedman E,Steiner M., Int J Cancer.2012 Aug 15;131(4):924-9.

42

Carcinoma of the Breast

Risk Factors
9. Radiation exposure
risk is greatest with
exposure at young
age and high doses
10.Carcinoma of
contralateral
breast or
endometrium
11.Geography US and
Europe higher rates
(4-7 fold)
43

Carcinoma of the Breast

Risk Factors

Diet no influence
Alcohol consumption
higher risk
Obesity lower risk in
young women, higher in
postmenopausal women, bc
of prodn of est by fat tissue
Exercise small protective
effect
Long breastfeeding
lower risk
Environmental toxins
organochlorine pesticides?
Tobacco no effect
44

Carcinoma of the Breast

Etiology and Pathogenesis
Hereditary breast cancer
~12% of cases are hereditary
BRCA-1 and BRCA-2 mutations - ~3%
BRCA-1 increased risk for ovarian
carcinoma
BRCA-2 smaller risk for ovarian carcinoma,
higher risk for male breast carcinoma
Higher risk for prostate and pancreatic
carcinoma

Other genes p53 (Li-Fraumeni syn),

PTEN (Cowden syn), LKBI/STK11 (PeutzJeghers syn), ATM (Ataxia-Telangiectasia
syn)
BRCA-1 associated tumors are usually
poorly differentiated, have medullary
features and do not express hormone
receptors (triple negative)
45

GENE
% of "Single
(location)
Gene"
Syndrome
Hereditary
(Incidence)*
Cancers
BRCA1(17q21) 52%(2%ofall
Familialbreast breastcancers)
andovarian
cancer(1in
860)

Breast Cancer
Risk by Age Changes in Sporadic
70
Breast Cancer
40%to90%
Mutationsrare;
inactivatedin50%of
somesubtypes(e.g.
medullaryand
metaplastic)by
methylation

Other
Associated
Cancers
Ovarian,male
breastcancer
(butlowerthan
BRCA2),
prostate,
pancreas,
fallopiantube

BRCA2(13q12- 32%(1%ofall 30%to90%

13)Familial
breastcancers)
breastand
ovariancancer
(1in740)

Mutationsandlossof
expressionrare

Ovarian,male
breastcancer,
prostate,
pancreas,
stomach,
melanoma,
gallbladder,bile
duct,pharynx

p53(17p13.1) 3%(<1%ofall
Li-Fraumeni(1 breastcancers)
in5,000)

>90%

CHEK2(22q12. 5%(1%ofall
1)Li-Fraumeni breastcancers)
variant(1in
100)

10%to20%

Mutationsin20%,LOHinSarcoma,
30%to42%;most
leukemia,brain
frequentintriplenegative tumors,
cancers
adrenocortical
carcinoma,
others
Mutationsrare(<5%);
Prostate,thyroid,
lossofproteinexpressionkidney,colon
inatleastonethirdby
unknownmechanism(s)

Functions
Tumorsuppressor,
transcriptionalregulation,
repairofdouble-stranded
DNAbreaks

Comments
Breastcarcinomasare
commonlypoorly
differentiatedandtriple
negative(basal-like),and
haveP53mutations.

Tumorsuppressor,
transcriptionalregulation,
repairofdouble-stranded
DNAbreaks

Biallelicgermline
mutationscausearare
formofFanconianemia(
Chapter7)

Tumorsuppressorwith
p53isthemost
criticalrolesincellcycle
commonlymutatedgene
control,DNAreplication,DNAinsporadicbreast
repair,andapoptosis
cancers

Cellcyclecheckpointkinase, Mayincreaseriskfor
recognitionandrepairofDNAbreastcancerafter
damage,activatesBRCA1 radiationexposure
andp53byphosphorylation

46

Carcinoma of the Breast

Etiology and Pathogenesis
Sporadic breast cancer
~90% of the cases
Major risk factors are
related to hormone (est)
exposure
Majority of cases in
postmenopausal women
(bc were exposed
previously)
Most cases are ER
positive (high
expression)

47

Carcinoma of the Breast

Etiology and Pathogenesis
Carcinogenesis and tumor progression
Early lesions show some of the genetic changes
found in frank carcinoma
Most early lesions are the atypical hyperplasias,
show increased expression of estrogen receptor
LOH rare in typical hyperplasia, more common in
atypical hyperplasia and universally present in
DCIS
48

Carcinoma of the Breast

Etiology and Pathogenesis
Carcinogenesis and tumor
progression
DNA instability (aneuploidy) is
found only in high-grade DCIS
Nuclear enlargement
Irregularity
Hyperchromasia

Most carcinomas arise from

ER-positive luminal cells
ER-negative carcinomas arise
from ER-negative
myoepithelial cells
Transition from carcinoma in situ
into invasive carcinoma is less
understood

LG-DCIS

IG-DCIS

HG-DCIS
49

Carcinoma of the Breast

Etiology and Pathogenesis

50

Carcinoma in Situ
Ductal carcinoma in situ - DCIS
50% of cancers detected by
mammography (linear calcifications)
Rarely (micropapillary - sometimes)
produce nipple discharge
Malignant clonal population restricted
to the ducts and lobules by the
basement membrane not in stroma
Myoepithelial cells are preserved
51

Carcinoma in Situ
Ductal carcinoma in situ - DCIS
Morphology
Five architectural
subtypes:

Comedocarcinoma
Solid
Cribrifirm
Papillary
Micropapillary

Majority of cases
show a mixture of
patterns
52

Linear calcific

Carcinoma in Situ
Ductal carcinoma in situ - DCIS
Comedocarcinoma
Solid sheets of
pleomorphic cells
High-grade nuclei
Central areas of
necrosis, often
calcified (detected by
mammography)
Periductal fibrosis is
common (sometimes
palpable)
53

Carcinoma in Situ
Ductal carcinoma in situ - DCIS
Non-comedo DCIS
Monomorphic population of cells
Nuclei range from low grade to high grade
Patterns:
Solid: cells fill the involved space
Cribrifirm: cookie-cutter pattern
Papillary: growth along fibrovascular cores
Micropapillary: protrusions without
fibrovascular core
54

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56

57

58

59

Carcinoma in Situ
Ductal carcinoma in situ - DCIS
Paget Disease of the nipple
Rare manifestation of breast
cancer
Erythematous eruption, crust
and pruritus
DCIS cells from the duct
extend into the nipple skin
without crossing the
basement membrane
Often mistaken for eczema
and delay diagnosis of BC
Prognosis is determined by
the underlying disease
(DCIS/IDC)
60

61

62

63

Carcinoma in Situ
Lobular carcinoma in situ - LCIS
No mammographic signs always
incidental finding (when do biopsy for sth
else)
Bilateral in 20-40% of cases (DCIS 10-20%)
More common in young women
LCIS cells are identical to invasive lobular
carcinoma
Loss of expression of E-cadherin = hallmark

64

Carcinoma in Situ
Lobular carcinoma in situ - LCIS
Dyscohesive cells,
oval to round nucleus
and small nucleoli
(like ALH and ILC)
Mucin-positive,
signet-ring cells are
common
ER PR positive,
Her2/neu negative
65

66

E-CAD

E-CAD

67

Invasive Carcinoma
Palpable tumors are associated with axillary
LN metastases in >50% of cases
With screening tumors are half the size and
LN metastases in less than 20% of cases
Lymphatic obstruction can result in
lymphedema and thickening of the skin
peau dorange
Inflammatory carcinoma tumors with
extensive invasion and obstruction of dermal
lymphatics
68

Invasive Carcinoma

69

Invasive Carcinoma

70

71

Invasive Ductal Carcinoma

Most tumors are hard and have irregular borders
Dense stroma, foci of calcifications and necrosis
are often seen
Well-differentiated: tubule formation, small round
nuclei, rare mitotic figures
Moderately-differentiated: partial tubule formation,
solid clusters or single cells, nuclear pleomorphism
and mitotic figures
Poorly-differentiated: nests or solid sheets of cells
with large pleomorphic nuclei, abundent mitotic
figures and necrosis

~50% ER positive, Her2/neu negative

72

73

74

75

Invasive Lobular Carcinoma

Usually presents as a
palpable mass
25% of cases - infiltrative
tumor without palpable mass
Dyscohesive infiltrating cells,
often arranged in single files
(Indian files) or loose
clusters
No tubule formation
Signet-ring cells may be
present
Loss of E-Cadherin
ER positive, Her2/neu negative

76

77

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Invasive Lobular Carcinoma

Different pattern of
metastasis peritoneum,
leptomeninges, GIT,
ovaries and uterus
May be mistaken for
signet-ring cell
carcinoma arising from
GIT
Same prognosis as
ductal carcinoma
79

Invasive Carcinoma Other

Subtypes
Medullary carcinoma
Women in 6th decade
Poorly differentiated

Syncitial pattern
Pleomorphic nuclei
Mitotic figures
Lymphoplasmacytic
infiltrate
pushing border
ER,PR,Her2/neu negative

Slightly better prognosis

More common in BRCA1
carriers
80

Invasive Carcinoma Other

Subtypes
Mucinous carcinoma
Older women
Slowly growing
Islands of tumor cells
within lakes of mucos
pushing border
ER positive, Her2/neu
negative

Slightly better
prognosis
81

Invasive Carcinoma Other

Subtypes
Tubular carcinoma
Women in late 40s
Relatively rare
Well-formed tubules
May be mistaken for
sclerosing adenosis
No myoepithelial cells
ER positive, Her2/neu
negative

Excellent prognosis
82

83

Invasive Breast Carcinoma

Prognostic Factors
Major factors
1. Invasive vs. in situ
2. Distant metastases
3. Axillary LN involvement
(>0.2cm)

0 LN - 75% 10-year DFS

1-3 LN - 35%
>10LN - 10%

4. Tumor size - <1cm 90% 10year survival

5. Locally advanced disease (e.g
skin)
6. Inflammatory carcinoma 310% 3-year survival
84

Invasive Breast Carcinoma

Prognostic Factors
Minor factors
. Histologic subtype
(tubular, mucinous, lobular,
medullary, papillary)

. Histologic grade
. Hormone receptor
expression
. Her2/neu overexpression
. Lymphovascular invasion
. Proliferation rate
. Response to neo-adjuvant
therapy
85

Stromal Tumors of the Breast

Different types of
stroma in the breast
give rise to different
neoplasms
Intralobular stroma:
Fibroadenoma
Phyllodes tumor

Interlobular stroma
Connective tissue
tumors (lipoma,
angiosarcoma, etc)
86

Fibroadenoma
Most common benign
tumor of breast
Young women (20s30s)
Bi-phasic
Epithelial component is
hormonally responsive
increase in size with
pregnancy
May be clonal or
polyclonal (cyclosporin
A)
87

Fibroadenoma
Spherical nodules,
sharply circumscribed
Vary in size
Delicate cellular,
often myxoid stroma
surrounding epithelial
components
In older women
stroma becomes
hyalinized and the
epithelium atrophic
88

89

90

Phyllodes Tumor
Most present at 6th decade
Vary in size
Nodules of proliferating
stroma covered by
epithelium
Distinguished from
fibroadenoma by:

Cellularity
Mitotic rate
Nuclear pleomorphism
Infiltrative borders

Most are low-grade

High-grade lesions can
metastasize (only stromal
component)

91

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The Male Breast

Gynecomastia
Estrogenic stimulus
Liver cirrhosis (conversion of
androgens to est)
Elderly
Drugs: Alcohol, marijuana,
heroin, HAART, anabolic
steroids (anti-androgenic)
Klinefelter syn. (XXY)
Functioning testicular
neoplasms (Leydig cell
tumor)

Increase in connective
tissue and micropapillary
hyperplasia of duct lining

93

The Male Breast

Carcinoma
1% of the incidence in
women (lifetime risk
0.11%)
Risk factors first-degree
relatives, decreased
testicular function,
exogenous estrogens,
obesity, age
4-14% of cases BRCA2
mutation
Histology and management
similar to females
94

QUESTION
S?
95

Lab slides

96

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THANKS

109