The Breast

Six to ten major ductal systems

originate at the nipple.
The keratinizing squamous epithelium
of the overlying skin continues into the
ducts and then abruptly changes to a
double-layered cuboidal epithelium.
The surrounding areolar skin is
pigmented and supported by smooth
muscle.

 Successive branching of the large

ducts eventually leads to the
terminal duct lobular unit (TDLU).
In the adult woman, the terminal
duct branches into a grapelike
cluster of small acini to form a lobule.

Inflammation
Inflammatory diseases of the breast are rare;
they often present as an erythematous swollen
painful breast.
Most important is acute mastitis, which is
virtually confined to the lactating period.
Inflammatory breast cancer mimics
inflammation by obstructing dermal
vasculature with tumor emboli, resulting in an
enlarged erythematous breast, and should
always be suspected in a non lactating woman
with the clinical appearance of mastitis.

ACUTE MASTITIS
Almost all cases of acute mastitis occur
during lactation; most of these arise during
the first month of nursing.
During the early weeks of nursing, the
breast is vulnerable to bacterial infection
because of the development of cracks and
fissures in the nipples.
From this portal of entry, usually
Staphylococcus aureus or, less commonly,
streptococci invade the breast tissue.

 Women
present
with
an
erythematous painful breast, usually
accompanied by fever.
At the outset, only one duct system
or sector of the breast is involved.
If not treated, the infection may
spread to the entire breast.

Microscopy
Staphylococcal
infections
tend
to
produce a localized area of acute
inflammation that may progress to the
formation
of
single
or
multiple
abscesses.
Streptococcal infections tend to cause a
diffuse
spreading
infection
that
eventually involves the entire breast.
The involved breast tissue may be
necrotic and is infiltrated by neutrophils.

 Most cases of lactational mastitis are

easily treated with appropriate
antibiotics and complete drainage of
milk from the breast. Rarely, surgical
drainage may be required.

PERIDUCTAL MASTITIS

Also known as Recurrent subareolar abscess,

squamous metaplasia of lactiferous ducts and
Zuska disease.
Women as well as men, present with a painful
erythematous subareolar mass, which is usually
clinically thought to be an infectious process.
More than 90% are smokers.
In recurrent cases, a fistula tract formation

Pathogenesis
Inversion of the nipple is seen secondary to fibrosis and scarring,
which might contribute to the squamous
metaplasia of the duct
Vitamin A deficiency associated with
smoking or toxic substances in tobacco
smoke alter the differentiation of the
ductal epithelium.

Recurrent subareolar abscess. When squamous metaplasia

extends deep into a duct, keratin becomes trapped and
accumulates. If the duct ruptures, the ensuing intense
inflammatory response to keratin results in an erythematous
painful mass. A fistula tract may burrow beneath the smooth
muscle of the nipple to open at the edge of the areola.

Morphology
The main histologic feature is
keratinizing squamous epithelium
extending to an abnormal depth
into the orifices of the nipple ducts.
Keratin is trapped within the
ductal system and causes dilation
and eventually rupture of the duct.

 An
intense
chronic
and
granulomatous inflammatory
response develops to keratin
spilled into periductal tissue.
If secondary infections with
skin bacteria or with mixed
anaerobes
occur,
acute
inflammation is also present.

Treatment
Appropriate clinical management requires
removing the involved duct and fistula tract in
continuity, which, in most cases, is curative.
Incision drains the abscess cavity, but the
offending keratinizing epithelium remains and
recurrences are common.
If a superimposed infection is present,
antibiotic therapy must be directed toward the
bacteria present, as standard staphylococcal
therapy is usually ineffective.

Benign epithelial lesions

These changes have been divided
into three groups, according to the
subsequent risk of developing breast
cancer:
(1) non-proliferative breast changes
(2) proliferative breast disease
(3) atypical hyperplasia.

NONPROLIFERATIVE BREAST
CHANGES (FIBROCYSTIC CHANGES)
To the clinician, the term might mean
"lumpy bumpy" breasts on palpation;
to the radiologist, a dense breast
with cysts; and to the pathologist,
benign morphologic changes.

These
changes
are
termed
"nonproliferative" to distinguish them
from the "proliferative" changes
associated with an increased risk of
breast cancer.

 These lesions might come to clinical

attention
when
they
mimic
carcinoma by producing palpable
lumps, mammographic densities or
calcifications, or nipple discharge.
Cysts are the most common cause of
a palpable mass

Morphology
There are three principal patterns of
morphologic change:
(1) cyst formation, often with
apocrine metaplasia
(2) fibrosis
(3) adenosis.

 Cysts - Small cysts form by the

dilation and unfolding of lobules.
When cystic lobules coalesce, larger
cysts are formed. Unopened cysts
are brown to blue (blue-dome cysts)
owing
to
the
contained
semitranslucent, turbid fluid.

 Cysts are lined either by a flattened

atrophic epithelium or by cells
altered by apocrine metaplasia.
Papillary projections may be present
in cysts and calcifications are
common.

Apocrine cysts. Cells with round nuclei and

abundant
granular
eosinophilic
cytoplasm,
resembling the cells of normal apocrine sweat
glands, line the walls of a cluster of small cysts.
Secretory debris, frequently with calcifications, is
often present.

 Fibrosis.
Cysts
frequently
rupture,
with
release
of
secretory material into the
adjacent stroma. The resulting
chronic inflammation and fibrous
scarring
contribute
to
the
palpable firmness of the breast.

 Adenosis. Adenosis is defined

as an increase in the number of
acini per lobule. A normal
physiologic
adenosis
occurs
during pregnancy throughout the
breast. In nonpregnant women,
adenosis can occur as a focal
change.

PROLIFERATIVE BREAST DISEASE

WITHOUT ATYPIA
This group of disorders is characterized by
proliferation of ductal epithelium and/or
stroma without cellular abnormalities
suggestive of malignancy.
The following entities are included in this
category: (1) moderate or florid epithelial
hyperplasia, (2) sclerosing adenosis, (3)
complex sclerosing lesions, (4) papillomas,
and (5) fibroadenoma with complex
features.

 They are detected as mammographic

densities
or calcifications (e.g,
sclerosing adenosis), or as incidental
findings in biopsies performed for
other reasons (e.g., hyperplasia).

More than 80% of large duct

papillomas
present
as
nipple
discharge, the remainder as small
palpable masses or mammographic
densities.

 A large papilloma can spontaneously

infarct, possibly because of torsion
on the stalk, resulting in a bloody
discharge.

Non-bloody discharge probably

results from intermittent blockage
and release of normal breast
secretions or irritation of the duct by
the papilloma.

Epithelial Hyperplasia
In the normal breast, only
myoepithelial cells and a single
layer of luminal cells are present
above the basement membrane.
Epithelial hyperplasia is defined
by the presence of more than
two cell layers.

 Hyperplasia is moderate to florid

when there are more than four cell
layers. The proliferating epithelium,
often including both luminal and
myoepithelial cells, fills and distends
the ducts and lobules. Irregular
lumens (fenestrations) can usually be
discerned at the periphery of the
cellular masses.

A, Normal. A normal duct or acinus has a single basally

located myoepithelial cell layer (cells with dark, compact
nuclei and scant cytoplasm) and a single luminal cell layer
(cells with larger open nuclei, small nucleoli, and more
abundant cytoplasm).
B, Epithelial hyperplasia. The lumen is filled with a
heterogeneous population of cells of different morphologies,
often including both luminal and myoepithelial cell types.
Irregular slitlike fenestrations are prominent at the

Sclerosing Adenosis
The number of acini per terminal duct is
increased to at least twice the number
found in uninvolved lobules.
The normal lobular arrangement is
maintained.
The acini are compressed and distorted in
the central portions of the lesion but
characteristically dilated at the periphery.
Myoepithelial cells are usually prominent.

Sclerosing adenosis. The involved terminal duct

lobular unit is enlarged, and the acini are
compressed and distorted by the surrounding
dense stroma. Calcifications are often present
within the lumens.

Complex Sclerosing Lesion (Radial

Scar)
Radial scars are stellate lesions
characterized by a central nidus of
entrapped glands in a hyalinized stroma.
These lesions can resemble irregular
invasive carcinomas mammographically or
on gross examination.
The term "scar" refers to the morphologic
appearance, as these lesions are not
associated with prior trauma or surgery.

Complex sclerosing lesion (radial scar). There is a

central nidus consisting of small tubules entrapped
in a densely fibrotic stroma surrounded by
radiating arms of epithelium with varying degrees
of cyst formation and hyperplasia.

Papillomas
Papillomas are composed of multiple
branching fibrovascular cores, each
having a connective tissue axis lined
by luminal and myoepithelial cells.
Growth occurs within a dilated duct.
Epithelial hyperplasia and apocrine
metaplasia are frequently present.

 Large duct papillomas are

usually solitary and situated in
the lactiferous sinuses of the
nipple.
Small duct papillomas are
commonly multiple and located
deeper within the ductal system.

Intraductal
papilloma.
A
central
fibrovascular core extends from the wall of
a duct. The papillae arborize within the
lumen and are lined by myoepithelial and
luminal cells.

Gynaecomastia
Gynaecomastia (enlargement of the
male breast) presents as a buttonlike subareolar enlargement
Gynecomastia is chiefly of
importance as an indicator of
hyperestrinism, suggesting cirrhosis
of the liver or the possible existence
of a functioning testicular tumor

 Drugs such as alcohol, marijuana,

heroin, antiretroviral therapy and
anabolic steroids
Klinefelter syndrome

Morphology
proliferation of a dense collagenous
connective tissue, but more striking
are the changes in the epithelium of
the ducts. Marked micropapillary
hyperplasia of the ductal linings
occurs

Carcinoma of the Breast

Breast cancer is the most common
non-skin malignancy in women.
A woman who lives to age 90 has a
one in eight chance of developing
breast cancer.

Risk Factors
Age - Breast cancer is rarely found
before the age of 25 years except in
certain familial cases.
Age at Menarche - early
menarche and late menopause

 First Live Birth - Women with a

first full-term pregnancy at younger
than 20 years of age have half the
risk than nulliparous women or
women over the age of 35 at their
first birth.

 First-Degree Relatives with

Breast Cancer - The risk of breast
cancer increases, only 13% of women
with breast cancer have one affected
first-degree relative, and only 1%
have two or more.
In turn, over 87% of women with a
family history will not develop breast
cancer.

 Breast Biopsies - Increased risk is

associated with prior breast biopsies
showing atypical hyperplasia.
Race - Although the overall
incidence of breast cancer is lower in
women of African-American ancestry

 Estrogen Exposure - Postmenopausal

hormone replacement therapy increases
the risk of breast cancer slightly. Estrogen
and progesterone together increase the
risk more than does estrogen alone.
Radiation Exposure - Women who have
been exposed to therapeutic radiation or
radiation after atom bomb exposure have a
higher rate of breast cancer.

 Carcinoma of the Contralateral Breast

or Endometrium - Increased risk is
associated with carcinoma of the
contralateral breast or endometrium,
probably owing to the share hormonal risk
factors for these tumors.
Geographic Influence - Breast cancer
incidence rates in the United States and
Europe are four to seven times higher
than those in other countries.

 Diet - Various items in diet, in particular dietary

fat, have been suggested to increase risk.
Obesity - There is decreased risk in obese
women younger than 40 years owing to the
association with anovulatory cycles and lower
progesterone levels late in the cycle. There is
increased risk in postmenopausal obese women,
which is attributed to synthesis of estrogens in fat
depots.
Exercise - Studies have been inconsistent, but
some have shown a 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.

ETIOLOGY AND
PATHOGENESIS
The major risk factors for the
development of breast cancer are
hormonal and genetic (family
history).
Breast carcinomas can, therefore, be
divided into sporadic cases, possibly
related to hormonal exposure, and
hereditary cases, associated with
family history or germ-line
mutations.

Hereditary Breast Cancer

About 25% of familial cancers (or
around 3% of all breast cancers) can
be attributed to two highly penetrant
autosomal dominant genes: BRCA1
and BRCA2 .

Sporadic Breast Cancer

The 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.
The majority of these cancers occur
in postmenopausal women and
overexpress ER.

CLASSIFICATION OF BREAST
CARCINOMA
Almost all breast malignancies are
adenocarcinomas, all other types
(i.e., squamous cell carcinomas,
phyllodes tumors, sarcomas, and
lymphomas) make up for fewer than
5% of the total.

 Carcinomas are divided into

in situ carcinomas
invasive carcinomas.

Carcinoma in situ refers to a

neoplastic population of cells limited
to ducts and lobules by the
basement membrane. It does not
invade into lymphatics and blood
vessels and cannot metastasize.

 Invasive carcinoma (synonymous with

"infiltrating" carcinoma) has invaded
beyond the basement membrane into
stroma.
The cells might also invade into the
vasculature and thereby reach regional
lymph nodes and distant sites.
Even the smallest invasive breast
carcinomas have capacity to metastasize.

Distribution of Histologic Types

of Breast Cancer
Total Cancers
In Situ Carcinoma
Invasive Carcinoma
No special type carcinoma
("ductal")
Lobular carcinoma
Tubular/cribriform carcinoma
Mucinous (colloid) carcinoma
Medullary carcinoma
Papillary carcinoma
Metaplastic carcinoma

Per Cent
1530
7085
79
10
6
2
2
1
<1

Invasive (Infiltrating)
Carcinoma
By the time a cancer becomes palpable, over half the
patients will have axillary lymph node metastases.
Larger carcinomas may be fixed to the chest wall or
cause dimpling of the skin.
Lymphatics may become so involved as to block the
local area of skin drainage and cause lymphedema
and thickening of the skin, a change referred to as
peau d'orange.
Tethering of the skin to the breast by Cooper
ligaments mimics the appearance of an orange peel.
When the tumor involves the central portion of the
breast, retraction of the nipple may develop.

Mammogram shows a density with an

irregular border. There is a small,
superimposed, incidental calcification.

An irregular dense white mass

is present within yellow
adipose tissue.

Invasive Carcinoma, No Special Type

(NST; Invasive Ductal Carcinoma)

majority of carcinomas (70% to 80%)

that cannot be classified as any other
subtype.
On gross examination, most
carcinomas are firm to hard and have
an irregular border. Within the center
of the carcinoma, there are small
pinpoint foci or streaks of chalky
white elastotic stroma and
occasionally small foci of

 Well-differentiated tumors consist of

tubules lined by minimally atypical cells
and can occasionally be difficult to
distinguish from benign sclerosing lesions.
Others are composed of anastomosing
sheets of pleomorphic cells.
Most carcinomas induce a marked
increase in dense, fibrous desmoplastic
stroma, giving the tumor a hard
consistency on palpation and replace fat,
resulting in a mammographic density
(scirrhous carcinoma).

A, Well-differentiated invasive carcinoma of no special type.

Well-formed tubules and nests of cells with small
monomorphic nuclei invade into the stroma with a
surrounding desmoplastic response. B, Poorly differentiated
invasive carcinoma of no special type. Ragged sheets of
pleomorphic cells without tubule formation infiltrate into the
adjacent stroma.

 Carcinomas of NST are accompanied

by varying amounts of DCIS.
The grade of the DCIS usually
correlates with the grade of the
invasive carcinoma.
Comedo DCIS is usually associated
with
poorly
differentiated
carcinomas, and low-grade DCIS is
usually
associated
with
welldifferentiated carcinomas.
Carcinomas associated with a large
amount of DCIS require large

Medullary carcinoma
Well circumscribed mass
Medullary carcinomas have a slightly
better prognosis than do carcinomas
of no special type,

 The tumor has a soft, fleshy

consistency (medulla is Latin for
"marrow") and is well circumscribed.
The carcinoma is characterized by (1)
solid, syncytium-like sheets (occupying
more than 75% of the tumor) of large
cells with vesicular, pleomorphic
nuclei, containing prominent nucleoli
and frequent mitoses;

 (2) a moderate to marked

lymphoplasmacytic infiltrate
surrounding and within the tumor;
and (3) a pushing (noninfiltrative)
border.
All medullary carcinomas are poorly
differentiated. DCIS is minimal or
absent. Lymphatic or vascular
invasion is never seen.

PROGNOSTIC AND PREDICTIVE

FACTORS
Prognosis is determined by the pathologic
examination of the primary carcinoma and the
axillary lymph nodes.
The major prognostic factors are as follows:
Invasive carcinoma or in situ disease.
Breast cancer deaths associated with DCIS are
due to the subsequent development of invasive
carcinoma or areas of invasion undetected at
the time of diagnosis. In contrast, at least half of
invasive carcinomas will have metastasized
locally or distantly at the time of diagnosis.

 Distant metastases - Once distant metastases

are present, cure is unlikely. Favored sites for
dissemination are the lungs, bones, liver,
adrenals, brain, and meninges.

Lymph node metastases - Axillary lymph node

status is the most important prognostic factor for
invasive carcinoma in the absence of distant
metastases. With no involvement, the 10-year
disease-free survival rate is close to 70% to 80%;
the rate falls to 35% to 40% with one to three
positive nodes and 10% to 15% in the presence of
more than 10 positive nodes.

Tumor size - The size of the carcinoma is the

second most important prognostic factor and is

 Locally advanced disease - Tumors

invading into skin or skeletal muscle are
frequently associated with concurrent or
subsequent distant disease.
Inflammatory carcinoma - Women
presenting with the clinical appearance of
breast swelling and skin thickening have a
particularly poor prognosis with a 3-year
survival rate of only 3% to 10%.

Minor Prognostic Factors

Histologic subtypes - The 30-year survival rate
of women with special types of invasive
carcinomas (tubular, mucinous, medullary,
lobular, and papillary) is > 60%, compared with <
20% for women with cancers of no special type.
Tumor grade - The most commonly used
grading system to assess the degree of tumor
differentiation (Scarff Bloom Richardson)
combines nuclear grade, tubule formation, and
mitotic rate. 85 % of women with welldifferentiated grade I tumors, 60% of women with
moderately differentiated grade II tumors, and
15% of women with poorly differentiated grade III

 Estrogen and progesterone receptors

- Women with hormone receptor-positive
cancers have a slightly better prognosis
than do women with hormone receptornegative carcinomas.
HER2/neu. HER2 (human epidermal growth
factor receptor 2 or c-erb B2 or neu) is a
transmembrane glycoprotein involved in
cell growth control. Overexpression of
HER2/neu is associated with a poor
prognosis.
Lymphovascular invasion (LVI) - Tumor
cells may be seen within vascular spaces
(either lymphatics or small capillaries)
surrounding tumors.

 Current therapeutic approaches

include
local
and
regional
control, using combinations of
surgery (mastectomy or breast
conservation) and postoperative
radiation, and systemic control,
using hormonal treatment or
chemotherapy or both.

Paget disease of the

nipple
rare manifestation of breast cancer (1% to
2% of cases) and presents as a unilateral
erythematous eruption with a scale crust.
Pruritus is common, and the lesion might
be mistaken for eczema.
Malignant cells, referred to as Paget cells,
extend from DCIS within the ductal system
into nipple skin without crossing the
basement membrane.

 The tumor cells disrupt the normal

epithelial barrier, and this allows
extracellular fluid to seep out onto
the nipple surface.
The Paget cells are easily detected
by nipple biopsy or cytologic
preparations of the exudate.

STROMAL TUMORS
The two types of stroma in the
breast, intralobular and interlobular,
give rise to distinct types of
neoplasms.
The breast-specific biphasic tumors
fibroadenoma and phyllodes tumor
arise in the interlobular stroma.

Fibroadenoma
most common benign tumor of the female
breast.
Occurring at any age within the
reproductive period of life, fibroadenomas
are somewhat more common before age 30.
They are frequently multiple and bilateral.
Young women usually present with a
palpable mass and older women with a
mammographic density or mammographic
calcifications.

Mammogram shows a well-circumscribed mass. B,

Fibroadenoma. A rubbery, white, wellcircumscribed mass is clearly demarcated from
the surrounding yellow adipose tissue.

Morphology
Fibroadenomas grow as spherical nodules that
are usually sharply circumscribed and freely
movable in the surrounding breast substance.
They vary in size from less than 1 cm in
diameter to large tumors that can replace
most of the breast.
Grossly, the tumors are well-circumscribed,
rubbery, grayish white nodules that bulge
above the surrounding tissue and often
contain slitlike spaces.

 The stroma is usually delicate,

cellular, and often myxoid,
resembling intralobular stroma,
enclosing glandular and cystic
spaces lined by epithelium.
The epithelium may be
surrounded by stroma or
compressed and distorted by it.
In older women, the stroma
typically becomes densely
hyalinized and the epithelium

The lesion consists of a proliferation of

intralobular stroma surrounding and often
pushing and distorting the associated
epithelium. The border is sharply delimited
from the surrounding tissue.