BREAST

Embryology

At the 5th or 6th week of fetal development, two ventral bands of thickened ectoderm (mammary
ridges, milk lines) are evident in the embryo. In most mammals, paired breasts develop along
these ridges, which extend from the base of the forelimb (future axilla) to the region of the hind
limb (inguinal area). These ridges are not prominent in the human embryo and disappear after a
short time, except for small portions that may persist in the pectoral region. Accessory breasts
(polymastia) or accessory nipples (polythelia) may occur along the milk line when normal
regression fails.

Each breast develops when an ingrowth of ectoderm forms a primary tissue bud in the
mesenchyme. The primary bud, in turn, initiates the development of 15 to 20 secondary buds.
Epithelial cords develop from the secondary buds and extend into the surrounding mesenchyme.
Major (lactiferous) ducts develop, which open into a shallow mammary pit. During infancy, a
proliferation of mesenchyme transforms the mammary pit into a nipple. If there is failure of a pit
to elevate above skin level, an inverted nipple results. This congenital malformation occurs in
4% of infants. At birth, the breasts are identical in males and females, demonstrating only the
presence of major ducts. Enlargement of the breast may be evident and a secretion, referred to as
witch's milk, may be produced. These transitory events occur in response to maternal hormones
that cross the placenta.

The breast remains undeveloped in the female until puberty, when it enlarges in response to
ovarian estrogen and progesterone, which initiate proliferation of the epithelial and connective
tissue elements. However, the breasts remain incompletely developed until pregnancy occurs.
Absence of the breast (amastia) is rare and results from an arrest in mammary ridge development
that occurs during the 6th fetal week. Breast hypoplasia also may be iatrogenically induced prior
to puberty by trauma, infection, or radiation therapy. Symmastia is a rare anomaly recognized as
webbing between the breasts across the midline. Accessory nipples (polythelia) occur in less
than 1% of infants. Supernumerary breasts may occur in any configuration along the
mammary milk line, but most frequently occur between the normal nipple location and the
symphysis pubis. Accessory axillary breast tissue is uncommon and usually is bilateral.

Functional Anatomy

The breast is composed of 15 to 20 lobes, which are each composed of several lobules. Fibrous
bands of connective tissue travel through the breast (suspensory ligaments of Cooper), insert
perpendicularly into the dermis, and provide structural support. The mature female breast
extends from the level of the 2nd/3rd rib to the inframammary fold at the 6th/7th rib. It extends
transversely from the lateral border of the sternum to the anterior axillary line. The deep or
posterior surface of the breast rests on the fascia of the pectoralis major, serratus anterior, and
external oblique abdominal muscles, and the upper extent of the rectus sheath. The
retromammary bursa may be identified on the posterior aspect of the breast between the
investing fascia of the breast and the fascia of the pectoralis major muscles. The axillary tail of
Spence extends laterally across the anterior axillary fold. The upper outer quadrant of the breast
contains a greater volume of tissue than do the other quadrants. Considerable variations in the
size, contour, and density of the breast are evident between individuals.

Nipple–areola Complex

The epidermis of the nipple–areola complex is pigmented and is variably corrugated. During
puberty, the pigment becomes darker and the nipple assumes an elevated configuration. During
pregnancy, the areola enlarges and pigmentation is further enhanced. The areola contains
sebaceous glands, sweat glands, and accessory glands, which produce small elevations on the
surface of the areola (Montgomery tubercles). Smooth-muscle bundle fibers, which lie
circumferentially in the dense connective tissue and longitudinally along the major ducts, extend
upward into the nipple where they are responsible for the nipple erection that occurs with various
sensory stimuli. The dermal papilla at the tip of the nipple contains numerous sensory nerve
endings and Meissner's corpuscles. This rich sensory innervation is of functional importance as
the sucking infant initiates a chain of neurohumoral events that results in milk letdown.

Inactive and Active Breast

Each lobe of the breast terminates in a major (lactiferous) duct (2 to 4 mm in dm), which opens
through a constricted orifice (0.4 to 0.7 mm in dm) into the ampulla of the nipple. Immediately
below the nipple–areola complex, each major duct has a dilated portion (lactiferous sinus),
which is lined with stratified squamous epithelium. Major ducts are lined with two layers of
cuboidal cells, while minor ducts are lined with a single layer of columnar or cuboidal cells.
Myoepithelial cells of ectodermal origin reside between the epithelial cells in the basal lamina
and contain myofibrils.

In the inactive breast, the epithelium is sparse and consists primarily of ductal epithelium. In
the early phase of the menstrual cycle, minor ducts are cord-like with small lumina. With
estrogen stimulation at the time of ovulation, alveolar epithelium increase, in height, duct lumina
become more prominent, and some secretions accumulate. When the hormonal stimulation
decreases, the alveolar epithelium regresses.
With pregnancy, the breast undergoes proliferative and developmental maturation. As the breast
enlarges in response to hormonal stimulation, lymphocytes, plasma cells, and eosinophils
accumulate within the connective tissues. The minor ducts branch and alveoli develop.With
parturition, enlargement of the breasts occurs via hypertrophy of alveolar epithelium and
accumulation of secretory products in the lumina of the minor ducts.

Alveolar epithelium contains abundant endoplasmic reticulum, large mitochondria, Golgi

complexes, and dense lysosomes. Two distinct substances are produced by the alveolar
epithelium: (1) the protein component of milk, which is synthesized in the endoplasmic
reticulum (merocrine secretion), and (2) the lipid component of milk (apocrine secretion),
which forms as free lipid droplets in the cytoplasm. Milk released in the first few days following
parturition is called colostrum and has low lipid content but contains considerable quantities of
antibodies.
The lymphocytes and plasma cells that accumulate within the connective tissues of the breast are
the source of the antibody component. With subsequent reduction in the number of these cells,
the production of colostrum decreases and lipid-rich milk is released.

Blood Supply, Innervation, and Lymphatics

The breast receives its principal blood supply from:

• perforating branches of the internal mammary artery

• lateral branches of the posterior intercostal arteries
• branches from the axillary artery(highest thoracic, lateral thoracic, and pectoral branches of the
thoracoacromial artery)

 The 2nd , 3rd , and 4th anterior intercostal perforators and branches of the internal
mammary artery arborize in the breast as the medial mammary arteries.
 The lateral thoracic artery gives off branches to the serratus anterior, pectoralis
major and minor, and subscapularis muscles. It also gives rise to lateral mammary
branches.

The three principal groups of veins are:

• perforating branches of the internal thoracic vein

• perforating branches of the posterior intercostal veins
• tributaries of the axillary vein.
The vertebral venous plexus of Batson, which invests the vertebrae and extends from the base of
the skull to the sacrum, may provide a route for breast cancer metastases to the vertebrae, skull,
pelvic bones, and central nervous system.

Lateral cutaneous branches of the 3rd to 6th intercostal nerves provide sensory innervation of the
breast (lateral mammary branches) and of the anterolateral chest wall. These branches exit the
intercostal spaces between slips of the serratus anterior muscle. Cutaneous branches that arise
from the cervical plexus, specifically the anterior branches of the supraclavicular nerve, supply a
limited area of skin over the upper portion of the breast. The intercostobrachial nerve is the
lateral cutaneous branch of the 2nd intercostal nerve and may be visualized during surgical
dissection of the axilla. Resection of the intercostobrachial nerve causes loss of sensation over
the medial aspect of the upper arm.

The boundaries for lymph drainage of the axilla are not well demarcated, and there is
considerable variation in the position of the axillary lymph nodes. The 6 axillary lymph node
groups recognized by surgeons are:

 Axillary vein group (lateral)

• consists of 4 to 6 lymph nodes

• lie medial or posterior to the vein
• receive most of the lymph drainage from the upper extremity

 External mammary group (anterior or pectoral group)

• consists of 5 or 6 lymph nodes

• lie along the lower border of the pectoralis minor muscle contiguous with the lateral
thoracic vessels
• receive most of the lymph drainage from the lateral aspect of the breast
 Scapular group (posterior or subscapular)

• consists of 5 to 7 lymph nodes

• lie along the posterior wall of the axilla at the lateral border of the scapula contiguous
with the subscapular vessels
• receive lymph drainage principally from the lower posterior neck, the posterior trunk, and
the posterior shoulder

 Central group

• consists of 3 or 4 sets of lymph nodes, which are embedded in the fat of the axilla
• lie immediately posterior to the pectoralis minor muscle
• receive lymph drainage both from the axillary vein, external mammary, and scapular
groups of lymph nodes and directly from the breast

 Subclavicular group (apical)

• consists of 6 to 12 sets of lymph nodes

• lie posterior and superior to the upper border of the pectoralis minor muscle
• receive lymph drainage from all of the other groups of axillary lymph nodes

 Interpectoral group (Rotter's)

• consists of 1 to 4 lymph nodes

• interposed between the pectoralis major and pectoralis minor muscles
• receive lymph drainage directly from the breast.
• The lymph fluid that passes through the interpectoral group of lymph nodes passes
directly into the central and subclavicular groups.

The lymph node groups are assigned levels according to their relationship to the pectoralis
minor muscle.

 level I lymph nodes

• Lymph nodes located lateral to or below the lower border of the pectoralis minor muscle
• axillary vein, external mammary, and scapular groups

 level II lymph nodes

• Lymph nodes located superficial or deep to the pectoralis minor muscle

• central and interpectoral groups
 level III lymph nodes

• Lymph nodes located medial to or above the upper border of the pectoralis minor muscle
• subclavicular group.

The plexus of lymph vessels in the breast arises in the interlobular connective tissue and in the
walls of the lactiferous ducts and communicates with the subareolar plexus of lymph vessels.
Efferent lymph vessels from the breast pass around the lateral edge of the pectoralis major
muscle and pierce the clavipectoral fascia ending in the external mammary (anterior, pectoral)
group of lymph nodes. Some lymph vessels may travel directly to the subscapular (posterior,
scapular) group of lymph nodes. From the upper part of the breast, a few lymph vessels pass
directly to the subclavicular (apical) group of lymph nodes. The axillary lymph nodes usually
receive more than 75% of the lymph drainage from the breast. The rest is derived primarily from
the medial aspect of the breast, flows through the lymph vessels that accompany the perforating
branches of the internal mammary artery, and enters the parasternal (internal mammary) group of
lymph nodes.

Physiology of the Breast

Breast Development and Function

Breast development and function are initiated by a variety of hormonal stimuli, including
estrogen, progesterone, prolactin, oxytocin, thyroid hormone, cortisol, and growth hormone.
Estrogen, progesterone, and prolactin especially have profound trophic effects that are essential
to normal breast development and function. Estrogen initiates ductal development, while
progesterone is responsible for differentiation of epithelium and for lobular development.
Prolactin is the primary hormonal stimulus for lactogenesis in late pregnancy and the postpartum
period. It upregulates hormone receptors and stimulates epithelial development.

In the female neonate, circulating estrogen and progesterone levels decrease after birth and
remain low throughout childhood because of the sensitivity of the hypothalamic pituitary axis to
negative feedback by these hormones. With the onset of puberty, there is a decrease in the
sensitivity of the hypothalamic pituitary axis to negative feedback and an increase in its
sensitivity to positive feedback by estrogen. These physiologic events initiate an increase in
GnRH, FSH, and LH secretion, and ultimately an increase in estrogen and progesterone secretion
by the ovaries, leading to establishment of the menstrual cycle.

Pregnancy, Lactation, and Senescence

A dramatic increase in circulating ovarian and placental estrogens and progestins is evident
during pregnancy, which initiates striking alterations in the form and substance of the breast. The
breast enlarges as the ductal and lobular epithelium proliferates, the areolar skin darkens, and the
accessory areolar glands of Montgomery become prominent. In the 1st and 2nd trimesters, the
minor ducts branch and develop. During the 3rd trimester, fat droplets accumulate in the alveolar
epithelium and colostrum fills the alveolar and ductal spaces. In late pregnancy, prolactin
stimulates the synthesis of milk fats and proteins.

Following delivery of the placenta, circulating progesterone and estrogen levels decrease, which
permits full expression of the lactogenic action of prolactin. Milk production and release are
controlled by neural reflex arcs that originate in nerve endings of the nipple–areola complex.
Maintenance of lactation requires regular stimulation of these neural reflexes resulting in
prolactin secretion and milk letdown. Oxytocin release results from the auditory, visual, and
olfactory stimuli associated with nursing. Oxytocin initiates contraction of the myoepithelial
cells resulting in compression of alveoli and expulsion of milk into the lactiferous sinuses. After
weaning of the infant, prolactin and oxytocin release decrease. Dormant milk causes increased
pressure within the ducts and alveoli resulting in atrophy of the epithelium.

With menopause there is a decrease in the secretion of estrogen and progesterone by the ovaries
and involution of the ducts and alveoli of the breast. The surrounding fibrous connective tissue
increases in density, and breast tissues are replaced by adipose tissues.

Infectious and Inflammatory Disorders of the Breast

Excluding the postpartum period, infections of the breast are rare and are classified as intrinsic
(2nd to abnormalities in the breast) or extrinsic (2nd to an infection in an adjacent structure, e.g.,
skin, thoracic cavity).

Bacterial Infection

Staphylococcus aureus and Streptococcus species are the organisms most frequently recovered
from nipple discharge from an infected breast. Breast abscesses are typically seen in
staphylococcal infections and present with point tenderness, erythema, and hyperthermia. These
abscesses are related to lactation and occur within the first few weeks of breast-feeding.
progression of a staphylococcal infection may result in subcutaneous, subareolar, interlobular
(periductal), and retromammary abscesses (unicentric or multicentric), necessitating operative
drainage of fluctuant areas. Preoperative ultrasonography is effective in delineating the extent of
the drainage procedure, which is best accomplished via circumareolar incisions or incisions
paralleling Langer's lines. While staphylococcal infections tend to be more localized and may be
located deep in the breast tissues, streptococcal infections usually present with diffuse superficial
involvement. They are treated with local wound care, including warm compresses, and the
administration of intravenous antibiotics (penicillins or cephalosporins). Breast infections may
be chronic, possibly with recurrent abscess formation. In this situation, cultures are taken to
identify acid-fast bacilli, anaerobic and aerobic bacteria, and fungi. Uncommon organisms may
be encountered and long-term antibiotic therapy may be required.

Hospital-acquired puerperal infections of the breast are much less common now, but nursing
women who present with milk stasis or noninfectious inflammation may still develop this
problem. Epidemic puerperal mastitis is initiated by highly virulent strains of methicillin-
resistant S. aureus that are transmitted via the suckling neonate and may result in substantial
morbidity and occasional mortality. Pus frequently may be expressed from the nipple. In this
circumstance, breast-feeding is stopped, antibiotics are started, and surgical therapy is initiated.
Nonepidemic (sporadic) puerperal mastitis refers to involvement of the interlobular connective
tissue of the breast by an infectious process. The patient develops nipple fissuring and milk
stasis, which initiate a retrograde bacterial infection. Emptying of the breast by using breast
suction pumps shortens the duration of symptoms and reduces the incidence of recurrences. The
addition of antibiotics results in a satisfactory outcome in more than 95% of cases.

Mycotic Infections

Fungal infestations of the breast are rare and usually involve blastomycosis or sporotrichosis.
Intraoral fungi that are inoculated into the breast tissue by the suckling infant initiate these
infections, which present as mammary abscesses in close proximity to the nipple–areola
complex. Pus mixed with blood may be expressed from sinus tracts. Amphotericin B is the most
effective antifungal agent for the treatment of systemic (noncutaneous) infections. This therapy
generally eliminates the necessity of surgical intervention, but occasionally drainage of an
abscess, or even partial mastectomy, may be necessary to eradicate a persistent fungal infection.
Candida albicans affecting the skin of the breast presents as erythematous, scaly lesions of the
inframammary or axillary folds. Scrapings from the lesions demonstrate fungal elements
(filaments and binding cells). Therapy involves the removal of predisposing factors such as
maceration and the topical application of nystatin.

Fibrocystic Changes

This designation is applied to a miscellany of changes in the female breast that range from those
that are innocuous to patterns associated with an increased risk of breast carcinoma. It is widely
accepted that this range of changes is the consequence of an exaggeration and distortion of the
cyclic breast changes that occur normally in the menstrual cycle.

The alterations are here subdivided into nonproliferative and proliferative patterns. The
nonproliferative lesions include cysts and/or fibrosis without epithelial cell hyperplasia, known
as simple fibrocystic change. The proliferative lesions include a range of banal to atypical duct
or ductular epithelial cell hyperplasias and sclerosing adenosis. All tend to arise during
reproductive life but may persist after the menopause.

Pathology of Nonproliferative Disorders

Nonproliferative disorders of the breast account for 70% of benign breast conditions and carry no
increased risk for the development of breast cancer. It is characterized by an increase in fibrous
stroma associated with dilation of ducts and formation of cysts of various sizes. The stroma
surrounding all forms of cysts is usually compressed fibrous tissue, having lost its normal
delicate, myxomatous appearance. A stromal lymphocytic infiltrate is common in this and all
other variants of fibrocystic change. This category includes cysts and apocrine metaplasia, duct
ectasia, periductal mastitis, calcifications, fibroadenomas, and related lesions

• Cysts
 A 21-gauge needle attached to a 10-mL syringe is placed directly into the mass, which is
fixed by fingers of the nondominant hand. The volume of a typical cyst is 5 to 10 mL, but
it may be 75 mL or more. If the fluid that is aspirated is:

not bloodstained- cyst is aspirated to dryness, and the fluid is discarded

Bloodstained- 2 mL of fluid are taken for cytology

mass is then imaged with ultrasound and any solid area on the cyst wall is
biopsied by needle

The 2 cardinal rules of safe cyst aspiration are:

1. the mass must disappear completely after aspiration

2. the fluid must not be bloodstained.

If either of these conditions is not met, then ultrasound, needle biopsy, and perhaps
excisional biopsy are recommended.

• Fibroadenomas

Removal of all fibroadenomas has been advocated irrespective of patient age or other
considerations, and solitary fibroadenomas in young women are frequently removed to
alleviate patient concern. Yet most fibroadenomas are self-limiting and many go
undiagnosed, so a more conservative approach is reasonable. Careful ultrasound
examination with core-needle biopsy will provide for an accurate diagnosis.
Subsequently, the patient is counseled concerning the biopsy results, and excision of the
fibroadenoma may be avoided.

• Periductal Mastitis

Painful and tender masses behind the nipple–areola complex are aspirated with a 21-
gauge needle attached to a 10-mL syringe. Any fluid obtained is submitted for cytology
and for culture using a transport medium appropriate for the detection of anaerobic
organisms. In the absence of pus, women are started on a combination of metronidazole
and dicloxacillin while awaiting the results of culture. Antibiotics are then continued
based on sensitivity tests. when there is considerable pus present, surgical treatment is
recommended.

Unlike puerperal abscesses, a subareolar abscess is usually unilocular and often is

associated with a single duct system. Preoperative ultrasound will accurately delineate its
extent. The surgeon may either undertake simple drainage with a view toward formal
surgery, should the problem recur, or proceed with definitive surgery. In a woman of
childbearing age, simple drainage is preferred, but if there is an anaerobic infection,
recurrent infection frequently develops. Recurrent abscess with fistula is a difficult
 problem and may be treated by fistulectomy or by major duct excision, depending on the
circumstances.

Treatment of Recurrent Subareolar Sepsis

Suitable for Fistulectomy
Small abscess localized to one
segment
Recurrence involving the same
segment
Mild or no nipple inversion
Patient unconcerned about nipple
inversion
Younger patient
No discharge from other ducts
No prior fistulectomy
Suitable for Total Duct Excision
Large abscess affecting more than 50% of the areolar
circumference
Recurrence involving a different segment
Marked nipple inversion
Patient requests correction of nipple inversion
Older patient
Purulent discharge from other ducts
Recurrence after fistulectomy

Pathology of Proliferative Disorders Without Atypia

Proliferative breast disorders without atypia include sclerosing adenosis, radial scars, complex
sclerosing lesions, ductal epithelial hyperplasia, and intraductal papillomas.

• Sclerosing adenosis

prevalent during the childbearing and perimenopausal years

marked intralobular fibrosis and proliferation of small ductules and acini

distorted breast lobules and usually occurs in the context of multiple microcysts, but
occasionally presents as a palpable mass

Benign calcifications are often associated with this disorder

Excisional biopsy and histologic examination are frequently necessary to exclude the
diagnosis of cancer

• Radial scars and complex sclerosing lesions

Central sclerosis and varying degrees of epithelial proliferation, apocrine metaplasia, and
papilloma formation characterize radial scars and complex sclerosing lesions of the breast
 Lesions up to 1 cm in dm are called radial scars, while larger lesions are called complex
sclerosing lesions

Excisional biopsy and histologic examination are frequently necessary to exclude the
diagnosis of cancer

• Ductal hyperplasia

mild- 3/4 cell layers above the basement membrane

Moderate- ≥5 cell layers above the basement membrane

Severe- occupies at least 70% of a minor duct lumen

either solid or papillary

carries an increased cancer risk

• Intraductal papillomas

arise in the major ducts, usually in premenopausal women

generally ˂ 0.5 cm in dm but may be as large as 5 cm

A common presenting symptom is nipple discharge, which may be serous or bloody

rarely undergo malignant transformation

However, multiple intraductal papillomas, which occur in younger women and are less
frequently associated with nipple discharge, are susceptible to malignant transformation

Pathology of Atypical Proliferative Diseases

Atypical lobular hyperplasia (ALH)

Atypical ductal hyperplasia (ADH)

have some of the features of carcinoma in situ (CIS) but either lack a major defining feature of
CIS or have the features in less than fully developed form

Risk Factors for Breast Cancer

Hormonal and Nonhormonal Risk Factors

 Increased exposure to estrogen is associated with an increased risk for developing

breast cancer, whereas reducing exposure is thought to be protective.
 early menarche, nulliparity, and late menopause
  older age at first live birth
 obesity , alcohol consumption
 radiation exposure

BRCA Mutations

BRCA-1

 located on chromosome 17q

 contains 22 coding exons
 functions as tumor-suppressor gene, and for each gene, loss of both alleles is
required for the initiation of cancer
 a role in transcription, cell-cycle control, and DNA damage repair pathways
 germline mutations in BRCA-1 represent a predisposing genetic factor in as many
as 45% of hereditary breast cancers and in at least 80% of hereditary ovarian
cancers
 Female mutation carriers have up to a 90% lifetime risk for developing breast
cancer and up to a 40% lifetime risk for developing ovarian cancer
 Breast cancer in these families appears as an autosomal dominant trait with high
penetrance
 BRCA-1–associated breast cancers are invasive ductal carcinomas, are poorly
differentiated, and are hormone receptor–negative
 BRCA-1 associated breast cancers have a number of distinguishing clinical
features, such as an early age of onset when compared with sporadic cases; a
higher prevalence of bilateral breast cancer; and the presence of associated
cancers in some affected individuals, specifically ovarian cancer and possibly
colon and prostate cancers

BRCA-2

 located on chromosome 13q

 contains 26 coding exons
 biologic function of BRCA-2 is not well defined, but like BRCA-1, it is
postulated to play a role in DNA damage response pathways
 breast cancer risk for BRCA-2 mutation carriers is close to 85% and the lifetime
ovarian cancer risk, while lower than for BRCA-1, is still estimated to be close to
20%
 Breast cancer in BRCA-2 families is an autosomal dominant trait and has a high
penetrance
 Unlike male carriers of BRCA-1 mutations, men with germline mutations in
BRCA-2 have an estimated breast cancer risk of 6%
 BRCA-2–associated breast cancers are invasive ductal carcinomas, which are
more likely to be well differentiated and to express hormone receptors than
BRCA-1–associated breast cancer.
  BRCA-2–associated breast cancer has a number of distinguishing clinical
features, such as an early age of onset compared with sporadic cases; a higher
prevalence of bilateral breast cancer; and the presence of associated cancers in
some affected individuals, specifically ovarian, colon, prostate, pancreas,
gallbladder, bile duct, and stomach cancers, as well as melanoma

Cancer Prevention for BRCA Mutation Carriers

Risk management strategies for BRCA-1 and BRCA-2 carriers include:

 Prophylactic mastectomy and reconstruction;

 Prophylactic oophorectomy and hormone replacement therapy;
 Intensive surveillance for breast and ovarian cancer; and
 Chemoprevention

The Primary Breast Cancer

More than 80% of breast cancers show productive fibrosis that involves the epithelial and
stromal tissues. With growth of the cancer and invasion of the surrounding breast tissues, the
accompanying desmoplastic response entraps and shortens the suspensory ligaments of Cooper
to produce a characteristic skin retraction. Localized edema (peau d'orange) develops when
drainage of lymph fluid from the skin is disrupted. With continued growth, cancer cells invade
the skin and eventually ulceration occurs. As new areas of skin are invaded, small satellite
nodules appear near the primary ulceration

In general, up to 20% of breast cancer recurrences are locoregional, more than 60% are distant,
and 20% are both locoregional and distant

Axillary Lymph Node Metastases

As the size of the primary breast cancer increases, some cancer cells are shed into cellular spaces
and transported via the lymphatic network of the breast to the regional lymph nodes, especially
the axillary lymph nodes. Lymph nodes that contain metastatic cancer are at first ill-defined and
soft, but become firm or hard with continued growth of the metastatic cancer. Eventually the
lymph nodes adhere to each other and form a conglomerate mass. Cancer cells may grow
through the lymph node capsule and fix to contiguous structures in the axilla including the chest
wall. Typically, axillary lymph nodes are involved sequentially from the low (level I) to the
central (level II) to the apical (level III) lymph node groups.

While more than 95% of the women who die of breast cancer have distant metastases, the most
important prognostic correlate for disease-free and overall survival is axillary lymph node status.
Node-negative women have less than a 30% risk of recurrence, compared to as much as a 75%
risk for node-positive women.

Distant Metastases
At approximately the 20th cell doubling, breast cancers acquire their own blood supply
(neovascularization). Thereafter, cancer cells may be shed directly into the systemic venous
blood to seed the pulmonary circulation via the axillary and intercostal veins or the vertebral
column via Batson's plexus of veins, which courses the length of the vertebral column. These
cells are scavenged by natural killer lymphocytes and macrophages. Successful implantation of
metastatic foci from breast cancer predictably occurs after the primary cancer exceeds 0.5 cm in
diameter, which corresponds to the 27th cell doubling. For 10 years following initial treatment,
distant metastases are the most common cause of death in breast cancer patients. While 60% of
the women who develop distant metastases will do so within 24 months of treatment, metastases
may become evident as late as 20 to 30 years after treatment of the primary cancer. Common
sites of involvement, in order of frequency, are bone, lung, pleura, soft tissues, and liver.

Histopathology of Breast Cancer

Carcinoma In Situ

Cancer cells are in situ or invasive depending on whether or not they invade through the
basement membrane.

Salient Characteristics of In Situ Ductal (DCIS) and Lobular (LCIS) Carcinoma of the Breast
LCIS DCIS
Age (years) 44–47 54–58
Incidence a 2–5% 5–10%
Clinical signs None Mass, pain, nipple discharge
Mammographic signs None Microcalcifications
Premenopausal 2/3 1/3
Incidence of synchronous invasive carcinoma 5% 2–46%
Multicentricity 60–90% 40–80%
Bilaterality 50–70% 10–20%
Axillary metastasis 1% 1–2%
Subsequent carcinomas:
Incidence 25–35% 25–70%
Laterality Bilateral Ipsilateral
Interval to diagnosis 15–20 years 5–10 years
Histology Ductal Ductal

a
Among biopsies of mammographically detected breast lesions.

Multicentricity--occurrence of a second breast cancer outside the breast quadrant of the primary
cancer
Multifocality--occurrence of a second cancer within the same breast quadrant as the primary
cancer

Lobular Carcinoma In Situ

 originates from the terminal duct lobular units

 only develops in the female breast
 characterized by distention and distortion of the terminal duct lobular units by cancer
cells, which are large but maintain a normal nuclear:cytoplasmic ratio
 Cytoplasmic mucoid globules are a distinctive cellular feature
 calcifications associated with LCIS typically occur in adjacent tissues
 occurs 12x more frequently in white women than in African American women

Ductal Carcinoma In Situ(intraductal carcinoma)

 predominantly seen in the female breast

 accounts for 5% of male breast cancers.
 Histologically, DCIS is characterized by a proliferation of the epithelium that lines the
minor ducts, resulting in papillary growths within the duct lumina
 four morphologic categories are prototypes of pure lesions: Papillary, cribriform, solid,
and comedo types
 papillary and cribriform types of DCIS probably transform to invasive cancer over a
longer time frame and are of lower grade
 solid and comedo types of DCIS are generally higher-grade lesions and probably invade
over a shortened natural history

Invasive Breast Carcinoma

Foote and Stewart originally proposed the following classification for invasive breast cancer:

I. Paget's disease of the nipple

 presents as a chronic, eczematous eruption of the nipple, which may be subtle, but
may progress to an ulcerated, weeping lesion
 A palpable mass may or may not be present
 associated with extensive DCIS and may be with an invasive cancer
 Bx of the nipple

• population of cells that are identical to the underlying DCIS cells (pagetoid
features or pagetoid change)
• Pathognomonic of this cancer is the presence of large, pale, vacuolated cells
(Paget's cells) in the rete pegs of the epithelium

 Surgical Tx
 • lumpectomy, mastectomy, or modified radical mastectomy, depending on the
extent of involvement and the presence of invasive cancer

II. Invasive ductal carcinoma

a. Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST) 80%

 presents with macroscopic or microscopic axillary lymph node metastases in

60% of cases
 perimenopausal or postmenopausal women in the 5th to 6th decades of life as
a solitary, firm mass
 poorly defined margins and its cut surfaces show a central stellate
configuration with chalky white or yellow streaks extending into surrounding
breast tissues. The
 cancer cells arranged in small clusters, and there is a broad spectrum of
histologies with variable cellular and nuclear grades

b. Medullary carcinoma 4%

 A frequent phenotype of BRCA-1 hereditary breast cancer

 Grossly, the cancer is soft and hemorrhagic
 A rapid increase in size may occur secondary to necrosis and hemorrhage
 Bilaterality is reported in 20% of cases
 Microscopically characterized by

• a dense lymphoreticular infiltrate composed predominantly of

lymphocytes and plasma cells;
• large pleomorphic nuclei that are poorly differentiated and show active
mitosis; and
• a sheet-like growth pattern with minimal or absent ductal or alveolar
differentiation

 Approximately 50% of these cancers are associated with DCIS, which is

characteristically present at the periphery of the cancer, and fewer than
10% demonstrate hormone receptors
 In rare circumstances, mesenchymal metaplasia or anaplasia is noted
 Because of the intense lymphocyte response associated with the cancer,
benign or hyperplastic enlargement of the lymph nodes of the axilla may
contribute to erroneous clinical staging
 Women with this cancer have a better 5-year survival rate than those with
NST or invasive lobular carcinoma

c. Mucinous (colloid) carcinoma 2%

  Typically presents in the elderly population as a bulky tumor
 This cancer is defined by extracellular pools of mucin, which surround
aggregates of low-grade cancer cells
 The cut surface of this cancer is glistening and gelatinous in quality
 Fibrosis is variable, and when abundant it imparts a firm consistency to the
cancer
 Approximately 66% of mucinous carcinomas display hormone receptors
 Lymph node metastases occur in 33% of cases
d. Papillary carcinoma 2%

 It generally presents in the 7th decade of life and occurs in a disproportionate

number of nonwhite women
 Typically, papillary carcinomas are small and rarely attain a size of 3 cm in
diameter
 Defined by papillae with fibrovascular stalks and multilayered epithelium
 low frequency of axillary lymph node metastases

e. Tubular carcinoma (and ICC) 2%

Tubular carcinoma is another special-type breast cancer and accounts for 2% of

all invasive breast cancers. It is reported in as many as 20% of women whose
cancers are diagnosed by mammography screening and is usually diagnosed in the
perimenopausal or early menopausal periods. Under low-power magnification, a
haphazard array of small, randomly arranged tubular elements is seen.
Approximately 10% of women with tubular carcinoma or with invasive cribriform
carcinoma, a special-type cancer closely related to tubular carcinoma, will
develop axillary lymph node metastases, which are usually confined to the lowest
axillary lymph nodes (level I). However, the presence of metastatic disease in one
or two axillary lymph nodes does not adversely affect survival. Distant metastases
are rare in tubular carcinoma and invasive cribriform carcinoma. Long-term
survival approaches 100%.