THE FEMALE BREAST

Pd manusia, sepasang mammary glands terletak di pectoralis muscle on the

upper chest wall.
breasts erdiri dari specialized epithelium dan stroma yg dapat menyebabkan
both benign dan malignant lesions
The human breast terdiri dari 6 hingga 10 major ductal systems.
The keratinizing squamous epithelium of the overlying skin dips into the
orifices at the nipple and kemudian scr mendadak berubah menjadi doublelayered cuboidal epithelium lining the ducts.
Successive branching of the large ducts eventually leads to the terminal duct
lobular unit.
Pada wanita dewasa, the terminal duct rcabang menjadi a grapelike cluster dr
small acini untuk membentuk sebuah lobul .
Setiap system duktus, biasanya mengisi lebih dari 1 kuadran dari breast.
In some women, ducts extend into the subcutaneous tissue of the chest wall
and into the axilla.

Ada 2 Tipe sel yg membatasi duktus dan lobulus.

Contractile myoepithelial cells terdiri dari myofilaments yg terletak di dalam
meshlike pattern on the basement membrane. These cells assist in milk
ejection during lactation and provide structural support to the lobules.
Luminal epithelial cells menutupi permukaan dari myoepithelial cells. Only the
lobular luminal cells are capable of producing milk.
There are also two types of breast stroma.
Inter dan Intralobular stroma.
The interlobular stroma terdiri dari dense
fibrous connective tissue yg bercampur
dengan adipose tissue.
The intralobular stroma membungkus asinus
dari lobulus dan terdiri dari breast-specific
hormonally responsive fibroblast-like cells
bercampur dengan scattered lymphocytes.

The terminal
duct lobular units (TDLUs) are the functional
units of the breast. The TDLU consists of the
extralobular terminal ducts and intralobular
terminal ducts.
The intralobular terminal ducts form the central
space of the lobule and have multiple
outpouchings called acini or ductules.
The ductules differentiate into the secretory
units during lactation.
Intralobular stroma surround the lobules.
Adenosis involves the epithelial and myoepithelial cells of
the ductules.
Solitary (central) papillomas originate in the large ducts (segmental or subsegmental),
but do not involve the TDLU. On the other hand multiple (peripheral) papillomas have
a root in the TDLU and spread into the large ducts.
Cysts arise in the lobule, where the acini dilate, unfold, and then enlarge as fluid-filled
cysts.

There is important cross-talk between breast epithelium and stroma that

promotes the normal structure and function of the breast.
Pda payudara pubertal males dan females, system ductus terbesar, berakhir
di terminal ducts dngn minimal lobule formation.
Perubahan pada payudara adlah perubahan paling dynamic dan ditemukan
pada masa reproductive years (Fig. 23-2).
Sama seperti halnya pada pertumbuhan endometrium setiap kali menstrual

cycle, begitu pula dngn payudara.

Pada stngh tahun pertama dari menstrual cycle the lobules relative diam.
Setelah ovulasi, ibawah pengaruh dari estrogen dan kenaikan leel
progesterone, proliferasi sel meningkat, egitu pula jumlah dr asinus per
lobule.
The intralobular stroma jg tampak menjadi edematous.
Seusai menstruation, jatuhnya level estrogen dan progesterone menginduksi
egresi dari lobules dan the disappearance of the stromal edema.
Hanya dengan onset dr pregnancy payudara menjadi completely mature dan
functional.
Lobules meningkat dengan progresif baik dalam umlah dan ukuran. Sebagai
konsekuensinya, pada akhir dari kehamilan, payudara diisi hampir seluruhnya
dengan lobules-lobulus yg dipisahkan oleh relatively scant stroma
Secepatnya setelah melahirkan, the luminal cells dr lobulus memproduksi
colostrum (high in protein), yg mana dapat berubah menjadi susu (higher in
fat and calories) dalam 10 hari kedepan seiring dngn drop-nya level
progesterone. Tentu saja bukan hal yang mengagetkan, hal ini memberikan
perubahan morphologic, the terminally differentiated breast has a specific
pattern of gene expression.
Breast milk not only provides complete nourishment from birth until several
years of age, but it also provides protection against infection, allergies, and
some autoimmune diseases. Maternal antibodies (chiefly secretory IgA),
vitamins, enzymes, and numerous other mediators (e.g., cytokines,
antioxidants, fibronectin, and lysozyme) augment the infant's own developing
immune defenses. However, certain drugs, radioactive compounds given
during diagnostic procedures, and viruses can also be passed to the infant
through breast milk.
Pada akhir dari laktasi, epithelium payudara dan stroma mengalami extensive
remodeling.
Epithelial cells mengalami apoptosis, lobules regress dan atrophy, dan total
breast size is berkurang. Meskipun begitu, tidak ada full regression, dan hasil
akhir dr pregnancy mnyebabkan a permanent increase in the size and
number of lobules.
Setelah 3 dekade, jauh-jauh hari sblm menopause, lobulus dan their
specialized stroma mulai untuk mengkriut.
Lobular atrophy may be almost complete in elderly . The interlobular stroma
also changes, since the radiodense fibrous stroma of the young female is
progressively replaced by radiolucent adipose tissue.

Clinical Presentations of Breast Disease

 Gejala yg paling umum yg dilaporkan oleh wanita adalah pain, a

palpable mass, "lumpiness" (without a discrete mass), atau nipple
discharge. Asymptomatic women dngn abnormal findings di
mammographic screening also require further evaluation.
Pain (mastalgia atau mastodynia) adalh gejala umum that may be
cyclic with menses or noncyclic.
Diffuse cyclic pain has no pathologic correlate, and most effective
treatments target hormone levels.
Noncyclic pain biasanya terlokalisasi di satu area di breast.
Penyebabnya termasuk ruptured cysts, physical injury, dan infections,
but most often no specific lesion is identified. Meskipun scr gambaran
kasarnya 95% dr painful masses adalh benign, rus tetap diingat
bahwa sekitar 10% dr breast cancers are painful.
Discrete palpable masses juga umum dan harus dibedakan dari
normal nodularity (or "lumpiness") of the breast.
palpable lesions yg paling umum adalh invasive carcinomas,
fibroadenomas, dan cysts.
A breast mass secara umum menjadi dapat di palpasi ketika
ukurannya kurang lbh 2 cm in size.
Palpable masses are most common in premenopausal women ,
tetapi kemungkianan palpable mass menjadi malignant meningkat
seiring usia.
Nipple discharge adlah penemuan yg kurang umum yg cukup
menghawatirkan ketiak dia terjadi secara spontaneous dan unilateral,
Semenjak dia bias terjadi karena carcinoma.
A small discharge is often produced by the manipulation of normal breasts.
Milky discharges (galactorrhea) dihubungkan dengan meningkatnya
level prolactin (e.g., by a pituitary adenoma), hypothyroidism, atau
endocrine anovulatory syndromes, dan dapat jg terjadi pada patients
yg mengkonsumsi oral contraceptives, tricyclic antidepressants,
methyldopa, or phenothiazines.
Repeated nipple stimulation jg dapat menginduksi lactation (a method
sometimes used by women who wish to breastfeed adopted infants).
Galactorrhea is not associated with malignancy.
Bloody or serous discharges are also most commonly associated with
benign conditions, tetapi di beberapa kasus (minoritas) pt menjadi
tanda dr malignancy.
Penyebab tersering adalah solitary large duct papillomas dan cysts.
Benign bloody discharges ga dapat terjadi saat kehamilan,

kemungkinan terjadi sbg hasil dari cepatnya growth dan remodeling

dr breast.
Mammographic screening digunakan untuk mendetect small,
nonpalpable, asymptomatic breast carcinomas.
Sensitivitas dan spesifikasi dr mammography meningkat seiring usia,
sbg hasil dari replacement of the fibrous, radiodense tissue of youth
dengan fatty, radiolucent tissue of the elderly .
At age 40, the probability that a mammographic lesion is cancer is
only 10%, but this rises to greater than 25% in women over 50 .
The principal mammographic signs of breast carcinoma are densities
and calcifications:
Densities.
Mammographic densities are produced most commonly by
invasive carcinomas, fibroadenomas, or cysts.
Most neoplasms are radiologically denser than the intermingled
normal breast tissue.
Nilai keuntungan dari mammography terletak dikemampuannya
untuk mengidentify small, nonpalpable cancers.
For example, rata-rata ukuran dari invasive carcinoma dideteksi
oleh mammography (1.1 cm) yg mana ukuran ini ukurannya kurang
dari stngh ukuran yg mampu di deteksi dngn palpasi (2.4 cm).
Calcifications.
Calcifications form on secretions, necrotic debris, or hyalinized stroma.
Benign calcifications biasanya sering dihubungkan dengan
clusters dr apocrine cysts, hyalinized fibroadenomas, dan
sclerosing adenosis.
Calcifications yg dihubungkan dengan malignancy biasanya
small, irregular, numerous, dan clustered.
Ductal carcinoma in situ (DCIS) paling sering di deteksi sbg
mammographic calcifications, yg mana sering terdeposit di dlm
linear, branching pattern sebagaimana si carcinoma mengisi
ductal system.
Mammographic screening has increased the number of breast
cancers diagnosed as DCIS.
Invasive carcinomas presenting as calcifications without an
accompanying radiodensity are uncommon, generally small in
size, and rarely associated with lymph node metastases.
In about 10% of cases, carcinomas are missed by mammography.
Penyebab kegagalan utama ini adlah adanya surrounding radiodense
tissue (especially in younger women) yg menyamarkan tumor, the
absence of calcifications, small size, a diffuse infiltrative pattern with

little or no desmoplastic response, or a location close to the chest

wall or in the periphery of the breast.
all palpable masses require further investigation.
Other imaging modalities are useful adjuncts.
Ultrasonography dpt membedakan antara lesi-lesi solid dan cystic dan
dan dapat membedakan lebih tepat batas-batas dr solid lesions.
Kebanyakan massa yg dpaat dipalpasi tp ga bisaditangkap oleh
mammography dpt didetaksi oleh ultrasound.
Magnetic resonance imaging (MRI) mendeteksi kanker dengan rapid
uptake of contrast agents due to increased tumor vascularity and
blood flow.
Hal ini berguna until screening cancer pada wanita dngn dense
breasts or at very high risk for cancer, in determining the extent of
chest wall invasion by locally advanced cancers, and in the evaluation
of breast implant rupture.

Inflammatory Disorders
Inflammatory diseases dr payudara sangat jarang, accounting for
less than 1% of women with breast symptoms.
Wanita biasanya datang dngn erythematous swollen painful breast.
"Inflammatory breast cancer" adalah gambaran inflamasi oleh
obstructing dermal vasculature dengan tumor emboli, yg tampak
dan harus selalu dicurigai pada nonlactating woman dengan
clinical appearance of mastitis.
Epithelial Breast Lesions
nonproliferative breast changes (Fibrocystic changes)
Duct ectasia
Cysts
Apocrine change
Mild hyperplasia
Adenosis
Fibroadenoma w/o complex features
proliferative disease without atypia
Moderate or florid hyperplasia
Sclerosing adenosis
Papilloma
Complex sclerosing lesion (radial scar)
Fibroadenoma with complex features
proliferative disease with atypia
Atypical ductal hyperplasia (ADH)
Atypical lobular hyperplasia (ALH)
carcinoma in situ
Lobular carcinoma in situ (LCIS)
Ductal carcinoma in situ (DCIS)

ACUTE MASTITIS
Hampir seluruh kasus acute mastitis terjadi ketika bulan pertama
dr breastfeeding.
Ini adalah masa-masa dimana payudara rapuh trhdp bacterial infection
karena perkembangan dr cracks dan fissures di dalam nipples.
From this portal of entry, Staphylococcus aureus or, less
commonly, streptococci invade the breast tissue.
Payudara mnjd erythematous dan painful, dan fever biasanya muncul.
At the outset only one duct system or sector of the breast is involved.
Jk tidak ditangani, infection bs menyebar ke seluruh payudara.
Kebanyakan kasus dr lactational mastitis angat mudah diobti
dengn appropriate antibiotics dan continued expression of milk
from the breast. Rarely, surgical drainage is required.
PERIDUCTAL MASTITIS
Kondisi ini diketahui dengan berbagai istilah, termsuk recurrent
subareolar abscess, squamous metaplasia of lactiferous ducts,
dan Zuska disease.
Women, and sometimes men, muncul dengn painful erythematous
subareolar mass yg scr klinis muncul sbg infectious process.
Lbh dari 90% of the afflicted are smokers. The strong association with
cigarette smoking is intriguing. It has been suggested that the vitamin
A deficiency associated with smoking or toxic substances in tobacco
smoke alter the differentiation of the ductal epithelium.
Kondisi ini tdk berhubungn dngn lactation, a specific reproductive
history, or age.
In recurrent cases, a fistula tract biasanya membentuk tunnels
dibawah smooth muscle dr nipple dan membuka hingga ke kulit
di tepi-tepi areola.
Many women with this condition have an inverted nipple, most
likely as a secondary effect of the underlying inflammation
Morphology. Kunci dr histologic feature adalah keratinizing squamous
metaplasia dr the nipple ducts.
Keratin yg bergerigi2 dari sel sel ini menempel di ductal system,
menyebabkan dilation dan pada akhirnya uktusnya rupture. An intense
chronic and granulomatous inflammatory response develops once
keratin spills into the surrounding periductal tissue. Sometimes a
secondary bacterial infection supervenes and causes acute
inflammation.

Simple incision drains the abscess cavity, but the offending keratinizing
epithelium remains and recurrences are common. When bacterial
infection is present, antibiotics also have a therapeutic role.

Figure 23-5 Recurrent subareolar abscess. When squamous metaplasia extends

deep into a nipple 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.

MAMMARY DUCT ECTASIA

Penyakit ini cendrung untuk muncul pada usia 50-60an, biasanya
trjd pd multiparous women.
Tidak seperti periductal mastitis, dia tidak berhubungan dngn
cigarette smoking.
Patients muncul dngn poorly defined palpable periareolar mass
yg biasanya sering diasosiasikan dng thick, white nipple
secretions dan terkadang ada skin retraction.
Pain dan erythema kurang umum.
Morphology. Hasil ini dikarakteristikkan terutama dngn dilation dr ducts,
inspissation dr breast secretions, dan a marked periductal dan interstitial
chronic granulomatous inflammatory reaction.
Ilatasi dari duktus diisi oleh granular yg mengandung banyak lipid-laden
macrophages. The periductal dan interductal tissue megandung dense
infiltrates of lymphocytes dan macrophages, dan variable numbers of
plasma cells. Terkadang, granulomatous inflammation terbentuk
disekitar cholesterol deposits. Proses Fibrosis pada akhirnya dapat
menghasilkan skin dan menyebabkan nipple retraction. Squamous
metaplasia of nipple ducts is absent.

The principal significance of this disorder is that it produces an irregular

palpable mass that mimics the mammographic appearance of
carcinoma.
FAT NECROSIS
Fat necrosis dpt muncul sbg painless palpable mass, skin thickening
atau retraction, a mammographic density, or mammographic
calcifications.
The majority of affected women have a history of breast trauma or prior
surgery

 Morphology. Acute lesions may be hemorrhagic dan

mengandung central areas dari liquefactive fat necrosis.
In subacute lesions the areas of fat necrosis memberikan
gambaran ill-defined, firm, gray-white nodules containing small
chalky-white foci atau dark hemorrhagic debris.
The central region of necrotic fat cells is ada awalnya
dihubungkan dngn intense neutrophilic infiltrate mixed with
macrophages. Dalam bbrp hari kedepan, proliferating fibroblasts
berhubungan dngn new vessels dan chronic inflammatory cells
disekeliling area yg injury. Subsequently, giant cells, calcifications,
and hemosiderin make their appearance, dan pada akhirnya the
focus digantikan dngn scar tissue atau is encircled and walled off
by fibrous tissue.
As with other inflammatory breast disorders, the major clinical
significance of the condition is its possible confusion with breast cancer.

Benign Epithelial Lesions

These lesions dibagi ke dalam 3 groups, according to the subsequent
risk of developing breast cancer:
(1) nonproliferative breast changes
(2) proliferative breast disease
(3) atypical hyperplasia.
NONPROLIFERATIVE BREAST CHANGES (FIBROCYSTIC CHANGES)
This group includes a number of very common morphologic alterations
that are often grouped under the term 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 histologic findings.
These lesions are termed nonproliferative to distinguish them from
"proliferative" changes, which are associated with an increased risk of
breast cancer.
Morphology. Ada 3 principal morphologic changes:
(1) cystic change, often with apocrine metaplasia;
(2) fibrosis;
(3) adenosis.
Cysts. Kista kecil dibentuk oleh dilatasi dan unfolding of lobules, and
in turn may coalesce to form larger cysts. Unopened cysts
contain turbid, semi-translucent fluid that produces a brown or
blue color (blue-dome cysts) (Fig. 23-7B). Cysts are lined either
by a flattened atrophic epithelium or by metaplastic apocrine
cells. The latter cells, which have an abundant granular,
eosinophilic cytoplasm and round nuclei, closely resemble the

normal apocrine epithelium of sweat glands (Fig. 23-7C).

Calcifications are common and may be detected by
mammography (see Fig. 23-7A). "Milk of calcium" is a term
mammographers use to describe calcifications that line the
bottom of a rounded cyst. Cysts are alarming when they are
solitary and firm to palpation. The diagnosis is confirmed by the
disappearance of the cyst after fine-needle aspiration of its
contents.
Fibrosis. Cysts frequently rupture, releasing secretory material into
the adjacent stroma. The resulting chronic inflammation and
fibrosis contribute to the palpable firmness of the breast.
Adenosis. Adenosis didefinisikan sebagai meningkatnya sejumlah
acini per lobule. A normal physiologic adenosis terjaid saat
pregnancy.
In nonpregnant women, adenosis apat muncul sbgai focal
change. Asinus biasanya membesar (blunt-duct adenosis), tetapi
jangan bingung dngn seperti yg tampak pada sclerosing
adenosis. Calcifications kadnag-kadang muncul di dalam lumens.
Asinus dibatasi oleh columnar cells, which may appear benign or
show atypical features ("flat epithelial atypia"). These lesions may
be the earliest recognizable precursor of epithelial neoplasia.
Lactational adenomas present as palpable masses in pregnant or
lactating women. They are formed by normal-appearing breast tissue
with physiologic adenosis and lactational changes. These lesions are
probably not true neoplasms but an exaggerated focal response to
hormonal influences.
PROLIFERATIVE BREAST DISEASE WITHOUT ATYPIA
These changes are commonly detected as mammographic densities,
calcifications, or as incidental findings in specimens from biopsies
performed for other reasons. Although each can be found in isolation,
typically more than one lesion is present, frequently in association with
nonproliferative breast changes.
hese lesions are characterized by proliferation of ductal epithelium
and/or stroma without cytologic or architectural features suggestive of
carcinoma in situ.
Morphology
Epithelial Hyperplasia. Normal breast ducts and lobules are lined by a
double layer of myoepithelial cells and luminal cells .Epithelial
hyperplasia is defined by the presence of more than two cell layers. The
additional cells consist of both luminal and myoepithelial cell types that
fill and distend ducts and lobules. Irregular lumens can often be
discerned at the periphery of the cellular masses .Epithelial hyperplasia
is usually an incidental finding.

Sclerosing Adenosis. The number of acini per terminal duct is

increased to at least double 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. On occasion, stromal fibrosis may completely compress the
lumens to create the appearance of solid cords or double strands of
cells lying within dense stroma, a histologic pattern that at times closely
mimics the appearance of invasive carcinoma . Sclerosing adenosis can
come to attention as a palpable mass, a radiologic density, or
calcifications.
Complex Sclerosing Lesion. Complex sclerosing lesions have
components of sclerosing adenosis, papillomas, and epithelial
hyperplasia. One member of this group, the radial sclerosing lesion
("radial scar"), is the only commonly occurring benign lesion that forms
irregular masses and can closely mimic invasive carcinoma
mammographically, grossly, and histologically. There is a central nidus
of entrapped glands in a hyalinized stroma with long radiating
projections into stroma. The term radial scar is a misnomer, as these
lesions are not associated with prior trauma or surgery.
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.
more than 80% of large duct papillomas produce a nipple discharge.
Large papillomas may undergo infarction, possibly because of torsion
on the stalk, resulting in a bloody discharge. Nonbloody discharge
probably results from intermittent blockage and release of normal breast
secretions or irritation of the duct by the papilloma. The remaining large
duct papillomas and most small duct papillomas come to clinical
attention as small palpable masses, or as densities or calcifications
seen on mammograms.
PROLIFERATIVE BREAST DISEASE WITH ATYPIA
Proliferative disease with atypia includes atypical ductal hyperplasia and
atypical lobular hyperplasia. Atypical ductal hyperplasia is present in 5%
to 17% of specimens from biopsies performed for calcifications and is
found less frequently in specimens from biopsies for mammographic

densities or palpable masses. Occasionally, atypical ductal hyperplasia

is associated with radiologic calcifications; more commonly it is adjacent
to another calcifying lesion. Atypical lobular hyperplasia is an incidental
finding and is found in fewer than 5% of specimens from biopsies
performed for any reason.
Morphology. Atypical hyperplasia is a cellular proliferation resembling
carcinoma in situ but lacking sufficient qualitative or quantitative
features for diagnosis as carcinoma. Unlike other benign changes,
atypical hyperplasias harbor some of the same acquired genetic losses
and gains that are present in carcinoma in situ.
Atypical ductal hyperplasia is recognized by its histologic
resemblance to ductal carcinoma in situ (DCIS). It consists of a
relatively monomorphic proliferation of regularly spaced cells,
sometimes with cribriform spaces. It is distinguished from DCIS by
being limited in extent and only partially filling ducts
Atypical lobular hyperplasia is defined as a proliferation of cells
identical to those of lobular carcinoma in situ (LCIS, described later), but
the cells do not fill or distend more than 50% of the acini within a
lobule . Atypical lobular hyperplasia can also involve contiguous ducts
through pagetoid spread, in which atypical lobular cells lie between the
ductal basement membrane and overlying normal ductal epithelial cells.
CLINICAL SIGNIFICANCE OF BENIGN EPITHELIAL CHANGES
Multiple epidemiologic studies have classified benign histologic changes
in the breast and determined their association with the later
development of invasive cancer. Nonproliferative changes do not
increase the risk of cancer. Proliferative disease is associated with a
mild increase in risk, while proliferative disease with atypia confers a
moderate increase in risk. Both breasts are at increased risk, although a
few more subsequent carcinomas occur in the same breast.14 Risk
reduction can be achieved by bilateral prophylactic mastectomy or
treatment with estrogen antagonists, such as tamoxifen.15 However,
more than 80% of women with atypical hyperplasia will not develop
breast cancer, and many choose careful clinical and radiologic
surveillance over intervention.

Carcinoma of the Breast

Carcinoma of the breast 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. In 2007 an estimated 178,480 women were
diagnosed with invasive breast cancer, 62,030 with carcinoma in situ,
and over 40,000 women died of the disease .As the demographic bulge
of the "baby boomers" continues to grow older, the number of women
with breast cancer is expected to increase by about a third over the next
20 years. It is both ironic and tragic that a neoplasm arising in an
exposed organ, readily accessible to self-examination and clinical
diagnosis, continues to exact such a heavy toll. Only lung cancer
causes more cancer deaths in women living in the United States.
t has long been appreciated that breast cancer is a heterogeneous
disease with a wide array of histologic appearances. Recent gene
profiling studies have confirmed that there are many types of cancers
but also show that most carcinomas cluster into several major groups
with important biologic and clinical differences. The majority of
carcinomas are estrogen receptor (ER) positive and are characterized
by a gene signature dominated by the dozens of genes under the
control of estrogen. Among the ER-negative tumors, many fall into a
distinctive "basal-like" group that is discussed later.
ER-positive and ER-negative carcinomas show striking differences with
regard to patient characteristics, pathologic features, treatment
response, and outcome. In the past, most studies grouped all breast
cancers together, but it is now widely recognized that the diagnosis of
breast cancer encompasses multiple molecular subclasses of disease,
as discussed later.
ETIOLOGY AND PATHOGENESIS
The major risk factors for the development of breast cancer are
hormonal and genetic. Breast carcinomas can therefore be divided into
sporadic cases, probably related to hormonal exposure, and hereditary
cases, associated with germline mutations. Hereditary carcinoma has
received intense scrutiny in the hopes that the specific genetic
mutations can be identified and that these alterations will illuminate the
causes of nonfamilial breast cancers as well. Recent studies have
borne out these hopes. We begin our discussion with hereditary breast
cancer and follow with sporadic breast cancer.
Hereditary Breast Cancer

PROGNOSTIC AND PREDICTIVE FACTORS

The outcome for women with breast cancer varies widely. Many women
have a normal life expectancy, whereas others have only a 10% chance
of being alive in 5 years. Except in women who present with distant
metastasis (<10%) or with inflammatory carcinoma (<5%) (in whom the
prognosis is poor regardless of other findings), prognosis is determined
by the pathologic examination of the primary carcinoma and the axillary
lymph nodes. Prognostic information is important in counseling patients
about the likely outcome of their disease, choosing appropriate
treatment, and the design of clinical trials.
Major prognostic factors that are the strongest predictors of death from
breast cancer are incorporated into the American Joint Committee on
Cancer (AJCC) staging system,57 which is used to divide patients into
five stages (0 to IV) that are correlated with survival.The major
prognostic factors are as follows:
Invasive carcinoma versus in situ disease. By definition, in situ
carcinoma is confined to the ductal system and cannot
metastasize. Breast cancer deaths associated with DCIS are due
to the subsequent development of invasive carcinoma or areas of
invasion that were not detected at the time of diagnosis. The
great majority of women with adequately treated DICS are cured.
In contrast, at least half of invasive carcinomas have
metastasized locally or distantly at the time of diagnosis.
Distant metastases. Once distant metastases are present, cure is
unlikely, although long-term remissions and palliation can be
achieved, especially in women with hormonally responsive
tumors. As mentioned earlier, the tumor type influences the timing
and location of metastases.58,59
Lymph node metastases. Axillary lymph node status is the most
important prognostic factor for invasive carcinoma in the absence
of distant metastases. The clinical assessment of lymph node
status is unreliable due to both false positives (e.g., palpable
reactive nodes) and false negatives (e.g., lymph nodes with small
metastatic deposits). Therefore, biopsy is necessary for accurate
assessment. With no nodal 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 to 10% to 15% when more
than 10 nodes are positive.Lymphatic vessels in most breast
carcinomas drain first to one or two sentinel nodes, which can be
identified with radiotracer or colored dyes. If a biopsy restricted to
the sentinel nodes is negative for metastasis, it is unlikely that
other more distant nodes will be involved and the patient can be

spared the morbidity of a complete axillary dissection. For these

reasons, sentinel node biopsy has been adopted in many centers
as part of the assessment of lymph node status. In some tumors
of the medial breast, the sentinel node is an intrathoracic internal
mammary node. These nodes are generally not biopsied owing to
the morbidity associated with the procedure.Macrometastases
(greater than 0.2 cm) are of proven prognostic importance.
Through more sensitive approaches, including serial sectioning of
lymph nodes, immunohistochemistry for keratins, and RT-PCRbased detection of tumor-specific mRNA, increased numbers of
women with micrometastases (0.2 cm or less) are being
identified. The clinical significance of these small metastases is
unclear and is being addressed by current clinical trials.
Approximately 10% to 20% of women without axillary lymph node
metastases have a recurrence outside of the breast and about
the same number die from breast cancer. In these patients,
metastasis may occur via the internal mammary lymph nodes or
hematogenously.
Tumor size. The size of an invasive carcinoma is the second most
important prognostic factor. The risk of axillary lymph node
metastases increases with the size of the primary tumor, but both
are independent prognostic factors. Women with node-negative
carcinomas <1 cm in size have a 10-year survival rate of over
90%, whereas survival drops to 77% for cancers >2 cm.
Unfortunately, breast self-examination does not lower breast
cancer mortality,60 suggesting that by the time breast cancers
become palpable (typically when at least 2 to 3 cm), tumors
capable of metastasizing have already done so.
Mammographically detected cancers are smaller and less likely to
have metastasized.
Locally advanced disease. Carcinomas invading into skin or skeletal
muscle are usually large and may be difficult to treat surgically.
With increased awareness of breast cancer detection, such cases
have fortunately decreased in frequency and are now rare at
initial presentation.
Inflammatory carcinoma. Breast cancers presenting with breast
swelling and skin thickening due to dermal lymphatic involvement
have a particularly poor prognosis. The 3-year survival rate is only
3% to 10%. Less than 3% of cancers are in this group, but the
incidence is higher in African American women and younger
women.
Minor Prognostic and Predictive Factors
In addition to the six factors used by the AJCC, a number of other
factors are predictive of outcome; some of these also direct therapies
against particular molecular targets.

 Histologic subtype. The 30-year survival rate of women with special

types of invasive carcinomas (tubular, mucinous, medullary,
lobular, and papillary) is greater than 60%, compared with less
than 20% for women with NST cancers. With the exception of
medullary carcinoma, most of these carcinomas will be well to
moderately differentiated, ER positive, and HER2/neu negative.
This favorable prognosis probably does not apply to unusual
special-type carcinomas without these characteristics.
Histologic grade. The most commonly used grading system, the
Nottingham Histologic Score (also referred to as Scarff-BloomRichardson), combines nuclear grade, tubule formation, and
mitotic rate to classify invasive carcinomas into three groups that
are highly correlated with survival.52 Survival for patients with welldifferentiated grade 1 carcinomas (approximately 20% of the
total) gradually declines to 70% at 24 years. In contrast, most
deaths for poorly differentiated grade 3 carcinomas
(approximately 46% of the total) occur in the first 10 years, and
45% of patients survive long-term. Women with moderately
differentiated grade 2 carcinomas (approximately 35% of the
total) have better survival initially, but their long-term survival is
only slightly better than grade 3 carcinomas.
Estrogen and progesterone receptors. Current assays use
immunohistochemistry to detect nuclear hormone receptors, a
finding that is correlated with a better outcome and is an
important predictor of response to hormonal therapy (see Fig. 2323). Eighty percent of carcinomas that are ER and PR positive
respond to hormonal manipulation, whereas only about 40% of
those with either ER or PR alone respond. ER-positive cancers
are less likely to respond to chemotherapy. Conversely, cancers
that fail to express either ER or PR have a less than 10%
likelihood of responding to hormonal therapy but are more likely
to respond to chemotherapy.
HER2/neu. HER2/neu overexpression is associated with poorer
survival, but its main importance is as a predictor of response to
agents that target this transmembrane protein (e.g., trastuzumab
or lapatinib). Several different assays are used to determine
HER/neu gene amplification and protein overexpression
Lymphovascular invasion. Tumor cells are present within
vascular spaces (either lymphatics or small capillaries) in about
half of all invasive carcinomas. This finding is strongly associated
with the presence of lymph node metastases. It is a poor
prognostic factor for overall survival in women without lymph
node metastases and a risk factor for local recurrence. As already
mentioned, extensive plugging of the lymphovascular spaces of
the dermis with carcinoma cells (inflammatory carcinoma) bodes

a very poor prognosis.

Proliferative rate. Proliferation can be measured by mitotic counts
(e.g., as part of histologic grading), by immunohistochemical
detection of cellular proteins produced during the cell cycle (e.g.,
cyclins, Ki-67), by flow cytometry (as the S-phase fraction), or by
thymidine labeling index. Carcinomas with high proliferation rates
have a poorer prognosis but may respond better to
chemotherapy.
DNA content. The amount of DNA per tumor cell can be determined
by flow-cytometric analysis or by image analysis of tissue
sections. Tumors with a DNA index of 1 have the same total
amount of DNA as normal diploid cells, although marked
karyotypic changes may be present. Aneuploid tumors are those
with abnormal DNA indices and have a slightly worse prognosis.
Response to neoadjuvant therapy. Most patients complete their
surgery and subsequently receive systemic treatment (referred to
as adjuvant therapy). Neoadjuvant therapy is an alternative
approach in which the patient is treated before surgery. Although
this approach does not improve survival, the degree that the
tumor responds to chemotherapy is a strong prognostic factor.
Clinical and radiologic examinations are useful to monitor
changes during treatment, but often underestimate or
overestimate the amount of residual carcinoma. Cancers most
likely to respond well are poorly differentiated, ER negative, and
have areas of necrosis. The subgroup of patients who achieve a
pathologic complete response (i.e., no residual cancer in the
breast or lymph nodes) have a greater than 95% long-term
survival, in contrast to the poor prognosis of this group as a
whole.62 Pathologic response can be used as a short-term end
point for clinical trials (which thus can yield useful information with
fewer patients in shorter periods of time) and is being linked to
research studies investigating the molecular basis of tumor
sensitivity or resistance to therapy.
Gene expression profiling. Expression profiling has been shown to
predict survival and recurrence-free interval, and also identifies
patients who are most likely to benefit from particular types of
chemotherapy. Methods that require rapidly frozen tissue will be
difficult to apply in clinical practice, but alternative approaches
that use formalin-fixed paraffin-embedded tissues are beginning
to enter clinical practice.

Although gene expression profiles provide a vast amount of information

about carcinomas, they are not well correlated with tumor size or lymph
node status-two of the strongest prognostic factors.63 This suggests that
while patterns of gene expression likely determine metastatic potential,
time and chance also influence whether and when metastasis occurs. It
is likely that future means of estimating prognosis will involve some
combination of these "old" and "new" factors.
Current therapeutic approaches directed at local and regional control
consist of combinations of surgery (mastectomy or breast conservation)
and postoperative radiation, whereas attempts at systemic control rely
on hormonal treatment, chemotherapy, or both. Axillary node dissection
or sentinel node sampling is performed for prognostic purposes, but the
axilla can also be treated with radiation alone. Newer therapeutic
strategies include inhibitors of membrane-bound growth factor receptors
(e.g., HER2/neu), stromal proteases, and angiogenesis.
Such therapies are based on models of breast cancer dissemination
that have evolved as our understanding of its biology has changed.
Earlier models proposed that breast cancer spreads in a contiguous
fashion by direct extension from breast to nodes and could therefore be
cured by en bloc surgical resection. However, radical surgery, including
mastectomies with removal of pectoralis muscles, internal mammary
nodes, and even supraclavicular nodes, failed to decrease mortality. A
subsequent model, based on studies demonstrating that breastconserving surgery and radiation were equivalent to radical
mastectomy, postulated that all cancers had spread systemically by the
time of diagnosis and that local or regional treatment was unimportant
for overall survival. In the current era of increased detection of earlystage carcinomas by mammography, a third model that combines the
first two is thought to be a more appropriate guide to therapy.
STROMAL TUMORS
The two types of stroma in the breast, intralobular and interlobular (see
the introductory section on the normal female breast), give rise to
distinct types of neoplasms. The breast-specific biphasic tumors
fibroadenoma and phyllodes tumor arise from intralobular stroma. This
specialized stroma may elaborate growth factors for epithelial cells,
resulting in the proliferation of the non-neoplastic epithelial component
of these tumors. Interlobular stroma is the source of the same types of
tumors found in connective tissue in other sites of the body (e.g.,
lipomas and angiosarcomas) as well as tumors arising more commonly
in the breast (e.g., pseudoangiomatous stromal hyperplasia,

myofibroblastomas, and fibrous tumors).

Fibroadenoma
his is the most common benign tumor of the female breast. Most occur
in women in their 20s and 30s, and they are frequently multiple and
bilateral. Young women usually present with a palpable mass and older
women with a mammographic density or mammographic calcifications.
The epithelium of the fibroadenoma is hormonally responsive, and an
increase in size due to lactational changes during pregnancy, which
may be complicated by infarction and inflammation, can mimic
carcinoma. The stroma often becomes densely hyalinized after
menopause and may calcify. Large lobulated ("popcorn") calcifications
have a characteristic mammographic appearance, but small
calcifications may appear clustered and require biopsy to exclude
carcinoma.
Morphology. Fibroadenomas grow as spherical nodules that are
usually sharply circumscribed and freely movable. They vary in size
from less than 1 cm to large tumors that can replace most of the breast.
The tumors are well-circumscribed, rubbery, grayish white nodules that
bulge above the surrounding tissue and often contain slitlike spaces .
The delicate, cellular, and often myxoid stroma resembles normal
intralobular stroma. 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 atrophic.
Some fibroadenomas are polyclonal hyperplasias of lobular stroma due
to some type of stimulus. For example, almost half of women receiving
cyclosporin A after renal transplantation develop fibroadenomas. In this
setting the tumors are frequently multiple and bilateral. Regression may
occur after cessation of cyclosporin treatment. Other fibroadenomas are
benign neoplasms associated with clonal cytogenetic aberrations that
are confined to the stromal component. No consistent cytogenetic
changes have been found.
Fibroadenomas were originally grouped with other "proliferative
changes without atypia" in conferring a mild increase in the risk of
subsequent cancer. However, in one study the increased risk was
limited to fibroadenomas associated with cysts larger than 0.3 cm,
sclerosing adenosis, epithelial calcifications, or papillary apocrine
change ("complex fibroadenomas")