CH 17: THE BREAST o Extends from the level of the 2nd or 3rd rib to the inframmary fold at the

o Extends from the level of the 2nd or 3rd rib to the inframmary fold at the 6th or 7th rib
EMBRYOLOGY o Extends transversely from the lateral border of the sternum to the anterior axillary line
- 5th or 6th week of fetal development à 2 ventral bands of thickened ectoderm (mammary ridges, milk - Deep or posterior surface of the breast
lines) o Rests on the:
- In mammals: paired breasts develop along these ridges § Fascia of the pectoralis major muscles
o Extend from the base of the forelimb (future axilla) to the region of the hind limb (inguinal § Serratus anterior
area) § External oblique abdominal muscles
- Accessory breasts (polymastia) or accessory nipples (polythelia) may occur along the milk line when § Upper extent of the rectus sheath
normal regression fails - Retromammary bursa
o May be identified on the posterior aspect of the breast between the investing fascia of
Development of each breast the breast and the fascia of the pectoralis major muscles
- When an ingrowth of ectoderm forms a primary tissue bud in the mesenchyme - Axillary tail of Spence
- Primary bud à initiates the development of 15-20 secondary buds o Extends laterally across the anterior axillary fold
- Secondary buds à epithelial cords à extend into the surrounding mesenchyme - Upper quadrant of the breast
- Major/ lactiferous ducts develop à open into a shallow mammary pit o Contains a greater volume of tissue than other quadrants
- During infancy: - Breast has a conical form
o Proliferation of mesenchyme à mammary pit into a nipple o Base of the cone à circular à 10-12 cm in diameter
o If there is a failure of a pit to elevate above skin level à inverted nipple - Nulliparous breast
- At birth: o Hemispheric configuration with distinct flattening above the nipple
o Breasts are identical in males and females à demonstrate only the presence of major - With hormonal stimulation that accompanies pregnancy and lactation à breast becomes larger à
ducts increases in volume and density
o Transitory events that occur in response to maternal hormones that cross the placenta: - With senescence à flattened, flaccid, more pendulous configuration with decreased volume

§ Enlargement of the breast Nipple-Areola complex

§ Witch’s milk ß secretion produced - Epidermis of the nipple- areola complex is pigmented and is variably corrugated
- Female breast - During puberty à pigment becomes darker; nipple assumes an elevated configuration
o Remains undeveloped until puberty à enlarges in response to ovarian estrogen and - Throughout pregnancy:
progesterone à initiate proliferation of the epithelial and connective tissue elements o Areola enlarges and pigmentation is further enhanced
- Breasts remain incompletely developed until pregnancy - Areola contains sebaceous glands, sweat glands, and accessory glands à which produce small
- Amastia à absence of the breast elevations on the surface of the areola (Montgomery’s tubercles)
o Results from an arrest in mammary ridge development that occurs during the sixth fetal - Smooth muscle bundle fibers
week o Lie circumferentially in the dense connective tissue and longitudinally along the major
- Poland’s syndrome ducts
o Hypoplasia or complete absence of the breast o Extend upward into the nipple
o Costal cartilage and rib defects o Responsible for the nipple erection that occurs with various sensory stimuli.
o Hypoplasia of the subcutaneous tissues of the chest wall - The dermal papilla at the tip of the nipple
o Brachysyndactyly o Contains numerous sensory nerve endings and Meissner’s corpuscles.
- Breast hypoplasia may be iatrogenically induced before puberty o This rich sensory innervation is of functional importance, because the sucking of the
o Trauma, infection, or radiation therapy infant initiates a chain of neurohumoral events that results in milk letdown.
- Symmastia
o Rare anomaly recognized as webbing between the breasts across the midline Inactive and Active Breast
- Accessory nipples à polythelia - Each lobe of the breast terminates in a major (lactiferous) duct
o Occur in <1% of infants o 2–4 mm in diameter
o May be associated with abnormalities of the urinary trac (renal agenesis and cancer), o Opens through a constricted orifice (0.4–0.7 mm in diameter) into the ampulla of the
abnormalities of the cardiovascular system (conduction disturbances, hypertension, nipple
congenital heart anomalies), and other conditions (pyloric stenosis, epilepsy, ear - Immediately below the nipple-areola complex, each major duct has a dilated portion (lactiferous
abnormalities, arthrogryposis). sinus) à which is lined with stratified squamous epithelium.
- Supernumerary breasts - Major ducts: lined with two layers of cuboidal cells
o May occur in any configuration along the mammary milk line but most frequently occur - Minor ducts are lined with a single layer of columnar or cuboidal cells.
between the normal nipple location and the symphysis pubis. - Myoepithelial cells of ectodermal origin reside between the epithelial cells in the basal lamina and
- Turner’s syndrome (ovarian agenesis and dysgenesis) and Fleischer’s syndrome (displacement of contain myofibrils.
the nipples and bilateral renal hypoplasia) - In the inactive breast:
o May have polymastia as a component. o The epithelium is sparse and consists primarily of ductal epithelium
- Accessory axillary breast tissue is uncommon and usually is bilateral. - In the early phase of the menstrual cycle:
o Minor ducts are cordlike with small lumina.
FUNCTIONAL ANATOMY - With estrogen stimulation at the time of ovulation:
- 15 to 20 lobes o Alveolar epithelium increases in height
o Each composed of several lobules o Duct lumina become more prominent
- Cooper’s suspensory ligaments o Some secretions accumulate
o Fibrous bands of connective tissue that travel through the breast - When the hormonal stimulation decreases, the alveolar epithelium regresses.
o Insert perpendicularly into the dermis - With pregnancy
o Provide structural support o Breast undergoes proliferative and developmental maturation.
- Mature female breast
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 1
 o As the breast enlarges in response to hormonal stimulation, lymphocytes, plasma cells,
and eosinophils accumulate within the connective tissues.
o The minor ducts branch and alveoli develop.
o Development of the alveoli is asymmetric, and variations in the degree of development
may occur within a single lobule
- With parturition
o Enlargement of the breasts occurs via hypertrophy of alveolar epithelium and
accumulation of secretory products in the lumina of the minor ducts.
o Alveolar epithelium contains abundant endoplasmic reticulum, large mitochondria, Golgi
complexes, and dense lysosomes.
o Two distinct substances are produced by the alveolar epithelium:
§ (a) the protein component of milk, which is synthesized in the endoplasmic
reticulum (merocrine secretion)
§ (b) the lipid component of milk (apocrine secretion), which forms as free
lipid droplets in the cytoplasm.
o Colostrum
§ Milk released in the first few days after parturition
§ 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:
o (a) perforating branches of the internal mammary artery;
o (b) lateral branches of the posterior intercostal arteries; and
o (c) branches from the axillary artery, including the highest thoracic, lateral thoracic, and
pectoral branches of the thoracoacromial artery
- Second, third, and fourth anterior intercostal perforators and branches of the internal mammary
artery
o Arborize in the breast as the medial mammary arteries
- The lateral thoracic artery
o Gives off branches to the serratus anterior, pectoralis major and pectoralis minor, and
subscapularis muscles.
o It also gives rise to lateral mammary branches
- The veins of the breast and chest wall
o Follow the course of the arteries, with venous drainage being toward the axilla.
- The three principal groups of veins are:
o (a) perforating branches of the internal thoracic vein
o (b) perforating branches of the posterior intercostal veins
o (c) tributaries of the axillary vein.
- Batson’s vertebral venous plexus
o Invests the vertebrae and extends from the base of the skull to the sacrum
o May provide a route for breast cancer metastases to the vertebrae, skull, pelvic bones,
and central nervous system.
- Lymph vessels generally parallel the course of blood vessels
- Lateral cutaneous branches of the third through sixth intercostal nerves
o Provide sensory innervation of the breast (lateral mammary branches) and of the
anterolateral chest wall.
o 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
o Supply a limited area of skin over the upper portion of the breast.
- The intercostobrachial nerve is the lateral cutaneous branch of the second intercostal nerve
o May be visualized during surgical dissection of the axilla.
o 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 six axillary lymph node groups recognized by surgeons (Figs. 17-6 and 17-7) are:
o (a) the axillary vein group (lateral)
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
§ Consists of four to six lymph nodes that lie medial or posterior to the vein and
receive most of the lymph drainage from the upper extremity
o (b) the external mammary group (anterior or pectoral group)
§ Consists of five to six lymph nodes that lie along the lower border of the
pectoralis minor muscle contiguous with the lateral thoracic vessels and
receive most of the lymph drainage from the lateral aspect of the breast
o (c) the scapular group (posterior or subscapular)
§ Consists of five to seven lymph nodes that lie along the posterior wall of the
axilla at the lateral border of the scapula contiguous with the subscapular
vessels and receive lymph drainage principally from the lower posterior
neck, the posterior trunk, and the posterior shoulder
o (d) the central group
§ Consists of three or four sets of lymph nodes that are embedded in the fat of
the axilla lying immediately posterior to the pectoralis minor muscle and
receive lymph drainage both from the axillary vein, external mammary, and
scapular groups of lymph nodes, and directly from the breast
o (e) the subclavicular group (apical)
§ Consists of six to twelve sets of lymph nodes that lie posterior and superior
to the upper border of the pectoralis minor muscle and receive lymph
drainage from all of the other groups of axillary lymph nodes
o (f) the interpectoral group (Rotter’s lymph nodes)
§ Consists of one to four lymph nodes that are interposed between the
pectoralis major and pectoralis minor muscles and 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.
Lymph node groups are assigned levels according to their anatomic relationship to the pectoralis minor
muscle.
- Level I lymph nodes
o Lymph nodes located lateral to or below the lower border of the pectoralis minor
muscle
o Include the axillary vein, external mammary, and scapular groups.
- Level II lymph nodes
o Lymph nodes located superficial or deep to the pectoralis minor muscle
o Include the central and interpectoral groups
- Level III lymph nodes
o Lymph nodes located medial to or above the upper border of the pectoralis minor
muscle
o Consist of the 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.
2
 - Efferent lymph vessels from the breast pass around the lateral edge of the pectoralis major muscle o There is an increase in the size and density of the breasts à followed by engorgement
and pierce the clavipectoral fascia, ending in the external mammary (anterior, pectoral) group of of the breast tissues and epithelial proliferation.
lymph nodes. - With the onset of menstruation:
- Some lymph vessels may travel directly to the subscapular (posterior, scapular) group of lymph o The breast engorgement subsides and epithelial proliferation decreases.
nodes.
- From the upper part of the breast, a few lymph vessels pass directly to the subclavicular (apical) Pregnancy, Lactation and Senescence
group of lymph nodes. - A dramatic increase in circulating ovarian and placental estrogens and progestins is evident
- The axillary lymph nodes usually receive >75% of the lymph drainage from the breast. during pregnancy
o The rest is derived primarily from the medial aspect of the breast, flows through the o Initiates striking alterations in the form and substance of the breast
lymph vessels that accompany the perforating branches of the internal mammary - The breast enlarges as the ductal and lobular epithelium proliferates
artery, and enters the parasternal (internal mammary) group of lymph nodes. - The areolar skin darkens
- The accessory areolar glands (Montgomery’s glands) become prominent
PHYSIOLOGY OF THE BREAST - In the first and second trimesters:
Breast Development and Function o The minor ducts branch and develop
- Initiated by a variety of hormonal stimuli: - During the third trimester:
o Estrogen, progesterone, prolactin, oxytocin, thyroid hormone, cortisol, and growth o Fat droplets accumulate in the alveolar epithelium
hormone. o Colostrum fills the alveolar and ductal spaces
- Estrogen, progesterone, and prolactin - In late pregnancy:
o Have profound trophic effects that are essential to normal breast development and o Prolactin stimulates the synthesis of milk fats and proteins.
function. - After delivery of the placenta:
o Estrogen à initiates ductal development o Circulating progesterone and estrogen levels decrease
o Progesterone à responsible for differentiation of epithelium and for lobular § Permitting full expression of the lactogenic action of prolactin.
development - Milk production and release
o Prolactin à primary hormonal stimulus for lactogenesis in late pregnancy and the o Controlled by neural reflex arcs that originate in nerve endings of the nipple-areola
postpartum period. complex
§ It upregulates hormone receptors and stimulates epithelial development. o Maintenance of lactation requires regular stimulation of these neural reflexes, which
- Fig. 17-8 depicts the secretion of neurotrophic hormones from the hypothalamus, which is results in prolactin secretion and milk letdown
responsible for regulation of the secretion of the hormones that affect the breast tissues. - Oxytocin
o Release results from the auditory, visual, and olfactory stimuli associated with nursing.
o Initiates contraction of the myoepithelial cells
§ Results in compression of alveoli and expulsion of milk into the lactiferous
sinuses
- After weaning of the infant:
o Prolactin and oxytocin release decreases
o Dormant milk causes increased pressure within the ducts and alveoli, which results in
atrophy of the epithelium
- With menopause:
o There is a decrease in the secretion of estrogen and progesterone by the ovaries and
involution of the ducts and alveoli of the breast
o The surrounding fibrous connective tissue increases in density, and breast tissues are
replaced by adipose tissues

Gynecomastia
- Refers to an enlarged breast in the male
- The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) - Physiologic gynecomastia
o Regulate the release of estrogen and progesterone from the ovaries. o Occurs during three phases of life: neonatal period, adolescence, and senescence
- Secretion of the gonadotropin- releasing hormone (GnRH) from the hypothalamus § Common to each of these phases = excess of circulating estrogens in
o Regulate the release of LH and FSH from the basophilic cells of the anterior pituitary relation to circulating testosterone.
- Positive and negative feedback effects of circulating estrogen and progesterone o Neonatal gynecomastia
o Regulate the secretion of LH, FSH, and GnRH. § Caused by the action of placental estrogens on neonatal breas tissues
§ These hormones are responsible for the development, function, and o Adolescence
maintenance of breast tissues. § Excess of estradiol relative to testosterone
- In the female neonate: o Senescence
o Circulating estrogen and progesterone levels decrease after birth and remain low § The circulating testosterone level falls, which results in relative
throughout childhood because of the sensitivity of the hypothalamic-pituitary axis to hyperestrinism
negative feedback from these hormones. - Ductal structures of the male breast:
- With the onset of puberty: o Enlarge
o There is a decrease in the sensitivity of the hypothalamic-pituitary axis to negative o Elongate
feedback and an increase in its sensitivity to positive feedback from estrogen. o Branch with a concomitant increase in epithelium.
o These physiologic events initiate an increase in GnRH, FSH, and LH secretion and - During puberty:
ultimately an increase in estrogen and progesterone secretion by the ovaries, leading o The condition often is unilateral
to establishment of the menstrual cycle. o Typically occurs between ages 12 and 15 years.
- At the beginning of the menstrual cycle: - In senescent gynecomastia
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 3
 o Usually bilateral
- In the nonobese male:
o Breast tissue measuring at least 2 cm in diameter must be present before a diagnosis
of gynecomastia may be made.
- Mammography and ultrasonography
o Used to differentiate breast tissues
- Dominant masses or areas of firmness, irregularity, and asymmetry
o Suggest the possibility of a breast cancer, particularly in the older male
- Gynecomastia generally does not predispose the male breast to cancer
o However, the hypoandrogenic state of Klinefelter’s syndrome (XXY), in which
gynecomastia is usually evident, is associated with an increased risk of breast cancer
- Gynecomastia is graded based on the degree of breast enlargement, the position of the nipple with
reference to the inframammary fold, and the degree of breast ptosis and skin redundancy:
o Grade I—mild breast enlargement without skin redundancy
o Grade IIa—moderate breast enlargement without skin redundancy
o Grade IIb—moderate breast enlargement with skin redundancy
o Grade III—marked breast enlargement with skin redundancy and ptosis.
INFECTIOUS AND INFLAMMATORY DISORDERS OF THE BREAST
- Infections in the postpartum period
- Infections of the breast unrelated to lactation
Bacterial Infection
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
- Pathophysiologic mechanisms that may initiate gynecomastia: estrogen excess states; androgen
deficiency states; pharmacologic causes; and idiopathic causes.
- Estrogen excess
o Results from an increase in the secretion of estradiol by the testicles or by nontesticular
tumors, nutritional alterations such as protein and fat deprivation, endocrine disorders
(hyperthyroidism, hypothyroidism), and hepatic disease (nonalcoholic and alcoholic
cirrhosis)
- Refeeding gynecomastia
o Is related to the resumption of pituitary gonadotropin secretion after pituitary shutdown.
- Androgen deficiency may initiate gynecomastia.
- Concurrently occurring with decreased circulating testosterone levels is an elevated level of
circulating testosterone-binding globulin
o Results in a reduction of free testosterone.
o This senescent gynecomastia usually occurs in men age 50 to 70 years.
- Hypoandrogenic states
o Can be from primary testicular failure or secondary testicular failure
o Klinefelter’s syndrome (XXY) is an example of primary testicular failure that is manifested
by gynecomastia, hypergonadotropic hypogonadism, and azoospermia.
o Secondary testicular failure may result from trauma, orchitis, and cryptorchidism.
- Renal failure, regardless of cause, also may initiate gynecomastia.
- Pharmacologic causes of gynecomastia
o Drugs with estrogenic activity (digitalis, estrogens, anabolic steroids, marijuana)
o Drugs that enhance estrogen synthesis (human chorionic gonadotropin)
o Drugs that inhibit the action or synthesis of testosterone (cimetidine, ketoconazole,
phenytoin, spironolactone, antineoplastic agents, diazepam)
o Drugs such as reserpine, theophylline, verapamil, tricyclic antidepressants, and
furosemide
§ Induce gynecomastia through idiopathic mechanisms.
- When gynecomastia is caused by androgen deficiency à then testosterone administration may
cause regression.
- When it is caused by medications à discontinued if possible.
- When endocrine defects are responsible à receive specific therapy
- Gynecomastia is progressive and does not respond to other treatments à surgical therapy
o Local excision, liposuction or subcutaneous mastectomy
- Attempts to reverse gynecomastia with danazol have been successful, but the androgenic side
effects of the drug are considerable
o Remain proportionately the most common time for breast infections to occur
o Proportionately less common, however, are still a relatively common presentation to
breast specialists.
o The latter are classified as intrinsic (secondary to abnormalities in the breast) or
extrinsic (secondary to an infection in an adjacent structure, e.g., skin, thoracic cavity)
à the most common being probably periductal mastitis and infected sebaceous cysts,
respectively
- Staphylococcus aureus and Streptococcus species
o Organisms most frequently recovered from nipple discharge from an infected breast.
- Typically breast abscesses are seen in staphylococcal infections:
o Present with point tenderness, erythema, and hyperthermia
- When these abscesses are related to lactation
o They usually occur within the first few weeks of breastfeeding
- If there is progression of a staphylococcal infection:
o This may result in subcutaneous, subareolar, interlobular (periductal), and
retromammary abscesses (unicentric or multicentric).
- Previously almost all breast abscesses were treated by operative incision and drainage, but now the
initial approach is antibiotics and repeated aspiration of the abscess, usually ultrasound- guided
aspiration
4
 - Operative drainage à reserved for those cases that do not resolve with repeated aspiration and
antibiotic therapy or cases in which there is some other indication for incision and drainage (e.g.,
thinning or necrosis of the overlying skin).
- Preoperative ultrasonography ß effective in delineating the required extent of the drainage
procedure.
- Staphylococcal infections
o Tend to be more localized
o May be situated deep in the breast tissues
- Streptococcal infections
o Present with diffuse superficial involvement.
- They are treated with local wound care, including application of warm compresses, and the
administration of IV antibiotics (penicillins or cephalosporins).
- Breast infections may be chronic, possibly with recurrent abscess formation.
o In this situation, cultures are performed to identify acid-fast bacilli, anaerobic and aerobic
bacteria, and fungi.
o Uncommon organisms may be encountered, and long-term antibiotic therapy may be
required Mondor’s Disease
- Biopsy of the abscess cavity wall should be considered at the time of incision and drainage to rule
out underlying breast cancer in patients where antibiotics and drainage have been ineffective
- Nowadays hospital-acquired puerperal infections of the breast are much less common
o But nursing women who present with milk stasis or noninfectious inflammation may still
develop this problem.
- Epidemic puerperal mastitis
o Initiated by highly virulent strains of methicillin-resistant S aureus that are transmitted via
the suckling neonate
o May result in substantial morbidity and occasional mortality.
o Purulent fluid may be expressed from the nipple.
§ In this circumstance, breastfeeding is stopped, antibiotics are started, and
surgical therapy is initiated
- Nonepidemic (sporadic) puerperal mastitis
o Refers to involvement of the interlobular connective tissue of the breast by an infectious
process.
o The patient develops nipple fissuring and milk stasis à initiates a retrograde bacterial
infection.
- Emptying of the breast using breast suction pumps
o Shortens the duration of symptoms and reduces the incidence of recurrences.
- The addition of antibiotic therapy results in a satisfactory outcome in >95% of cases
- Zuska’s disease/ recurrent periductal mastitis
o A condition of recurrent retroareolar infections and abscesses COMMON BENIGN DISORDERS AND DISEASES OF THE BREAST
o Smoking has been implicated as a risk factor for this condition Aberrations of Normal Development and Involution
o This syndrome is managed symptomatically by antibiotics coupled with incision and
drainage as necessary.
o Attempts to obtain durable long-term control by wide debridement of chronically infected
tissue and/or terminal duct resection have been reported and can be curative, but they
can also be frustrated by postoperative infections
Hidradenitis Suppurativa
- Hidradenitis suppurativa of the nipple-areola complex or axilla is a chronic inflammatory condition
that originates within the accessory areolar glands of Montgomery or within the axillary sebaceous
glands
- Women with chronic acne
o Predisposed to developing hidradenitis
- When located in and about the nipple-areola complex:
o May mimic other chronic inflammatory states, Paget’s disease of the nipple, or invasive
breast cancer.
- Involvement of the axillary skin
o Often multifocal and contiguous.
- Antibiotic therapy with incision and drainage of fluctuant areas is appropriate treatment.
- Excision of the involved areas may be required.
- Large areas of skin loss may necessitate coverage with advancement flaps or split-thickness skin
grafts.
- A variant of thrombophlebitis that involves the superficial veins of the anterior chest wall and breast.
- In 1939, Mondor described the condition as “string phlebitis,” a thrombosed vein presenting as a
tender, cord-like structure.
- Frequently involved veins include:
o Lateral thoracic vein
o Thoracoepigastric vein
- Less commonly involved: superficial epigastric vein.
- Typically, a woman presents with acute pain in the lateral aspect of the breast or the anterior chest
wall.
- A tender, firm cord is found to follow the distribution of one of the major superficial veins.
- Rarely, the presentation is bilateral, and most women have no evidence of thrombophlebitis in other
anatomic sites.
- This benign, self-limited disorder is not indicative of a cancer.
o When the diagnosis is uncertain, or when a mass is present near the tender cord, biopsy
is indicated.
- Therapy for Mondor’s disease includes the liberal use of anti-inflammatory medications and
application of warm compresses along the symptomatic vein.
- The process usually resolves within 4 to 6 weeks.
- When symptoms persist or are refractory to therapy, excision of the involved vein segment may be
considered.

Mycotic Infections
- Rare and usually involve blastomycosis or sporotrichosis
- Intraoral fungi that are inoculated into the breast tissue by the suckling infant
o Initiate these infections
o Present as mammary abscesses in close proximity to the nipple-areola complex
- Pus mixed with blood may be expressed from sinus tracts
- Antifungal agents can be administered for the treatment of systemic (noncutaneous) infections.
o 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
o Presents as erythematous, scaly lesions of the inframammary or axillary folds.
o Scrapings from the lesions demonstrate fungal elements (filaments and binding cells).
o Therapy involves the removal of predisposing factors such as maceration and the topical
application of nystatin.

BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 5

 - The basic principles underlying the aberrations of normal development and involution (ANDI)
classification of benign breast conditions are the following:
o (a) benign breast disorders and diseases are related to the normal processes of
reproductive life and to involution
o (b) there is a spectrum of breast conditions that ranges from normal to disorder to
disease
o (c) the ANDI classification encompasses all aspects of the breast condition, including
pathogenesis and the degree of abnormality.
- The horizontal component of Table 17-2 defines ANDI along a spectrum from normal, to mild
abnormality (disorder), to severe abnormality (disease).
- The vertical component indicates the period during which the condition develops.

Early reproductive years

- Fibroadenomas
o Seen and present symptomatically predominantly in younger women age 15 to 25
o Usually grow to 1 or 2 cm in diameter and then are stable but may grow to a larger size.
- Small fibroadenomas (≤1 cm in size) à considered normal
- Larger fibroadenomas (≤3 cm) à disorders
- Giant fibroadenomas (>3 cm) à disease PATHOLOGY OF NONPROLIFERATIVE DISORDERS
- Multiple fibroadenomas (more than five lesions in one breast) à very uncommon and are # Determining the clinical significance of benign, atypical, and malignant changes is a problem that
considered disease. is compounded by inconsistent nomenclature
- It is noted that with the introduction of mammographic screening, asymptomatic fibroadenomas are ○ three clinically relevant groups:

-
sometimes found in an older screened population.
The precise etiology of adolescent breast hypertrophy is unknown. 1. Nonproliferative disorders
- A spectrum of changes from limited to massive stromal hyperplasia (gigantomastia) is seen. ■ Account for 70% of benign breast conditions and carry no
- Nipple inversion increased risk for the development of breast cancer
o A disorder of development of the major ducts, which prevents normal protrusion of the
nipple.
2. Proliferative disorders without atypia
o Mammary duct fistulas arise when nipple inversion predisposes to major duct 3. Proliferative disorders with atypia
obstruction, leading to recurrent subareolar abscess and mammary duct fistula.

Later reproductive years

- Cyclical mastalgia and nodularity
o Usually are associated with premenstrual enlargement of the breast and are regarded
as normal.
- Cyclical pronounced mastalgia and severe painful nodularity are viewed differently than are
physiologic discomfort and lumpiness.
- Painful nodularity that persists for >1 week of the menstrual cycle à disorder.
- In epithelial hyperplasia of pregnancy, papillary projections sometimes give rise to bilateral bloody
nipple discharge.

Involution of lobular epithelium

- Dependent on the specialized stroma around it.
- However, an integrated involution of breast stroma and epithelium is not always seen, and disorders
of the process are common.
- When the stroma involutes too quickly:
o Alveoli remain and form microcysts, which are precursors of macrocysts.
o The macrocysts are common, often subclinical, and do not require specific treatment.
- Sclerosing adenosis 1. Breast macrocysts
o Considered a disorder of both the proliferative and the involutional phases of the breast ○ an involutional disorder, have a high frequency of occurrence, and are often multiple
cycle. 2. Duct ectasia
- Duct ectasia (dilated ducts) and periductal mastitis are other important components of the ANDI ○ a clinical syndrome characterized by dilated subareolar ducts that are palpable and
classification. often associated with thick nipple discharge
- Periductal fibrosis ○ 2 theories:
o A sequela of periductal mastitis and may result in nipple retraction. ■ a primary event that led to stagnation of secretions --> epithelial
- About 60% of women ≥70 years of age exhibit some degree of epithelial hyperplasia ulceration --> leakage of duct secretions (containing chemically irritating
- Atypical proliferative diseases: fatty acids) into periductal tissue
o Include ductal and lobular hyperplasia, both of which display some features of carcinoma ■ this sequence was thought to produce a local inflammatory
in situ. process with periductal fibrosis and subsequent nipple
o Women with atypical ductal or lobular hyperplasia have a fourfold increase in breast retraction
cancer risk ■ alternative theory: periductal mastitis to be the primary process -->
weakening of the ducts and secondary dilatation

BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 6

 ○ It is possible that both processes occur and together explain the wide spectrum of ■ complex sclerosing lesions
problems seen: ■ larger lesions
■ nipple discharge ■ all of the histologic features of a radial scar are seen in the
■ nipple retraction larger complex sclerosing lesions, but there is a greater
■ inflammatory masses disturbance of structure with papilloma formation, apocrine
■ abscesses metaplasia, and occasionally sclerosing adenosis.
3. Calcium deposits ○ core-needle biopsy sampling
○ frequently encountered in the breast ■ Distinguishing between a radial scar and invasive breast carcinoma can be
○ most are benign and are caused by cellular secretions and debris or by trauma and challenging based on this
inflammation ○ Often the imaging features of a radial scar (which can be quite similar to an invasive
○ Calcifications that are associated with cancer include microcalcifications cancer) will dictate the need for either a vacuum assisted biopsy or surgical excision
■ vary in shape and density and are <0.5 mm in size, and fine, linear in order to exclude the possibility of carcinoma
calcifications, which may show branching
4. Fibroadenomas 2. Ductal Hyperplasia
○ Have abundant stroma with histologically normal cellular elements ○ Mild ductal hyperplasia
○ show hormonal dependence similar to that of normal breast lobules in that they lactate ■ three or four cell layers above the basement membrane
during pregnancy and involute in the postmenopausal period ○ Moderate ductal hyperplasia
5. Adenomas of the breast ■ five or more cell layers above the basement membrane
○ well circumscribed and are composed of benign epithelium with sparse stroma, which ○ Florid ductal epithelial hyperplasia
is the histologic feature that differentiates them from fibroadenomas ■ occupies at least 70% of a minor duct lumen
○ may be divided into ■ found in >20% of breast tissue specimens, is either solid or papillary, and is
■ tubular adenomas associated with an increased cancer risk
■ Seen in young nonpregnant women
■ lactating adenomas
■ seen during pregnancy or during the postpartum period
6. Hamartomas
○ discrete breast tumors that are usually 2 to 4 cm in diameter, firm, and sharply
circumscribed
7. Adenolipomas
○ Consist of sharply circumscribed nodules of fatty tissue that contain normal breast
lobules and ducts.

Fibrocystic Disease
# Nonspecific term
# used as a diagnostic term to describe symptoms, to rationalize the need for breast biopsy, and to
explain biopsy results
# Synonyms include fibrocystic changes, cystic mastopathy, chronic cystic disease, chronic cystic
mastitis, Schimmelbusch’s disease, mazoplasia, Cooper’s disease, Reclus’ disease, and
fibroadenomatosis
# refers to a spectrum of histopathologic changes that are best diagnosed and treated specifically.

PATHOLOGY OF PROLIFERATIVE DISORDERS WITHOUT ATYPIA

# include sclerosing adenosis, radial scars, complex sclerosing lesions, ductal epithelial hyperplasia,
and intraductal papillomas

1. Sclerosing Adenosis 3. Intraductal Papillomas

○ prevalent during the childbearing and perimenopausal years and has no malignant
potential
○ Histologic changes are both proliferative (ductal proliferation) and involutional
(stromal fibrosis, epithelial regression)
○ Characterized by 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
○ can be managed by observation as long as the imaging features and pathologic
findings are concordant
○ Central sclerosis and various degrees of epithelial proliferation, apocrine metaplasia,
and papilloma formation characterize radial scars and complex sclerosing lesions of
the breast
■ radial scars
■ Lesions up to 1 cm in diameter
■ originate at sites of terminal duct branching where the
characteristic histologic changes radiate from a central area of
fibrosis
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
○ arise in the major ducts, usually in premenopausal women
○ generally are <0.5 cm in diameter but may be as large as 5 cm
○ Common presenting symptom: nipple discharge
■ serous or bloody
○ Grossly, intraductal papillomas are pinkish tan, friable, and usually attached to the wall
of the involved duct by a stalk
○ rarely undergo malignant transformation, and their presence does not increase a
woman’s risk of developing breast cancer (unless accompanied by atypia)
○ However, multiple intraductal papillomas, which occur in younger women and are less
frequently associated with nipple discharge, are susceptible to malignant
transformation.
7
PATHOLOGY OF ATYPICAL PROLIFERATIVE DISEASES
# The atypical proliferative diseases have some of the features of carcinoma in situ but either lack a
major defining feature of carcinoma in situ or have the features in less than fully developed form
1. Atypical ductal hyperplasia (ADH)
○ appears similar to low grade ductal carcinoma in situ (DCIS) histologically and is
composed of monotonous round, cuboidal, or polygonal cells enclosed by basement
membrane with rare mitoses.
○ A lesion will be considered:
■ ADH if it is up to 2 or 3 mm
■ DCIS if it is >3 mm
○ The diagnosis can be difficult to establish with core-needle biopsy specimen alone and
many cases will require excisional biopsy specimen for classification
○ at increased risk for development of breast cancer and should be counseled
appropriately regarding risk reduction strategies
2. Lobular neoplasia
○ spectrum of disorders ranging from atypical lobular hyperplasia to lobular carcinoma in
situ
a. Atypical lobular hyperplasia (ALH)
○ results in minimal distention of lobular units with cells that are similar to those seen in
LCIS
b. Lobular carcinoma in situ (LCIS)
○ The diagnosis of LCIS is made when small monomorphic cells that distend the terminal
ductal lobular unit are noted
○ acini are full and distended while the overall lobular architecture is maintained
○ Classic LCIS
■ not associated with a specific mammographic or palpable abnormality but is
an incidental finding noted on breast biopsy
■ not treated with excision as the patient is at risk for developing invasive
breast cancer in either breast and therefore the patient is counseled
regarding appropriate risk reduction strategies
○ Pleomorphic LCIS - variant of LCIS
■ there can be calcifications or other suspicious mammographic changes that
dictate the need for biopsy
■ can be difficult to distinguish from high-grade DCIS
■ managed similar to those with DCIS with attention to margins and
consideration for radiation therapy in the setting of breast conserving
treatment
■ immunohistochemical staining for E-cadherin can help to discriminate
between LCIS and DCIS
■ In lobular neoplasias, such as ALH and LCIS, there is a lack of
E-cadherin expression, whereas the majority of ductal lesions
will demonstrate E-cadherin reactivity.
TREATMENT OF SELECTED BENIGN BREAST DISORDERS AND DISEASES
Cysts
# Because needle biopsy of breast masses may produce artifacts that make mammography
assessment more difficult, many multidisciplinary teams prefer to image breast masses before
performing either fine-needle aspiration or core-needle biopsy
# In practice, however, the first investigation of palpable breast masses may be a needle biopsy,
which allows for the early diagnosis of 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, then the cyst is aspirated to dryness,
the needle is removed, and the fluid is discarded because cytologic examination of
such fluid is not cost effective.
○ After aspiration, the breast is carefully palpated to exclude a residual mass
# In most cases, however, imaging has been performed prior to a needle being introduced into the
breast; majority of cysts are now aspirated under ultrasound guidance.
# If a mass was noted on initial ultrasound or there is a residual mass post aspiration, then a tissue
specimen is obtained, usually by core biopsy.
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
# When cystic fluid is bloodstained, fluid can be sent for cytologic examination
# A simple cyst is rarely of concern, but a complex cyst may be the result of an underlying
malignancy
# pneumocystogram
○ can be obtained by injecting air into the cyst and then obtaining a repeat mammogram.
○ wall of the cyst cavity can be more carefully assessed for any irregularities
Fibroadenomas
# Most 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
# Ultrasonography may reveal specific features that are pathognomonic for fibroadenoma, and in a
young woman (e.g., under 25 years) where the risk of breast cancer is already very low a core-
needle biopsy may not be necessary.
# In patients where biopsy is performed, the patient is counseled concerning the ultrasound and
biopsy results, and surgical excision of the fibroadenoma may be avoided.
# Cryoablation and ultrasound-guided vacuum-assisted biopsy are approved treatments,
especially lesions <3 cm
# Larger lesions are often still best treated by excision
# With short-term follow-up, a significant percentage of fibroadenomas will decrease in size and will
no longer be palpable.
○ many will remain palpable, especially those larger than 2 cm
# should be counseled that the options for treatment include surgical removal, cryoablation, vacuum
assisted biopsy, or observation.
Sclerosing Disorders
# Sclerosing adenosis
○ clinical significance lies in its imitation of cancer
○ On physical examination, it may be confused with cancer, by mammography, and at
gross pathologic examination.
○ Excisional biopsy and histologic examination are frequently necessary to exclude
the diagnosis of cancer.
# Radial scars
○ The diagnostic work-up frequently involves stereotactic biopsy
# usually is not possible to differentiate these lesions with certainty from cancer by mammographic
features, so a larger tissue biopsy is recommended either by way of vacuum-assisted biopsy or
an open surgical excisional biopsy
# The mammographic appearance of a radial scar or sclerosing adenosis (mass density with
spiculated margins) will usually lead to an assessment that the results of a core-needle biopsy
specimen showing benign disease are discordant with the radiographic findings.
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 culture using a transport medium appropriate for the
detection of anaerobic organisms.
# absence of pus
○ women are started on a combination of antibiotics to cover polymicrobial infections
while awaiting the results of culture.
○ Antibiotics are then continued based on sensitivity tests.
○ Many cases respond satisfactorily to antibiotics alone
# considerable purulent material is present
○ repeated ultrasound guided aspiration is performed
○ ultimately in a proportion of cases surgical treatment is required
# subareolar abscess
○ Unlike puerperal abscesses, it is usually unilocular and often is associated with a single
duct system.
○ Ultrasound will accurately delineate its extent.
○ In those cases that come to surgery, the surgeon may either undertake simple
drainage with a view toward formal surgery, should the problem recur, or proceed with
definitive surgery
■ childbearing age- simple drainage is preferred
■ but if there is an anaerobic infection, recurrent infection
frequently develops.
8
 # Recurrent abscess with fistula
○ a difficult problem # Obesity - Because the major source of # The terminal differentiation of breast
○ Treatment was previously recommended to be opening up of the fistulous track and estrogen in postmenopausal women is the epithelium associated with a full-
allowing it to granulate conversion of androstenedione to estrone term pregnancy
■ this approach may still be used, especially if the fistula is recurrent after by adipose tissue
previous attempts at fistulectomy
Nonhormonal Risk Factors
○ Nowadays the preferred initial surgical treatment is by fistulectomy and primary
# Radiation exposure
closure with antibiotic coverage
○ Young women who receive mantle radiation therapy for Hodgkin’s lymphoma- risk
○ Excision of all the major ducts is an alternative option depending on the
that is 75 times greater than that of age-matched control subjects
circumstances
○ Survivors of the atomic bomb blasts in Japan during World War II have a very high
incidence of breast cancer, likely because of somatic mutations induced by the
radiation exposure.
○ radiation exposure during adolescence, a period of active breast development,
magnifies the deleterious effect.
# Alcohol consumption
○ risk of breast cancer increases as the amount of alcohol a woman consumes increase
○ increase serum levels of estradiol
# long-term consumption of foods with a high fat content
○ contributes to an increased risk of breast cancer by increasing serum estrogen levels

Risk Assessment Models

# The longer a woman lives without cancer, the lower her risk of developing breast cancer.
○ a woman age 50 years has an 11% lifetime risk of developing breast cancer, and a
woman age 70 years has a 7% lifetime risk of developing breast cancer
# Because risk factors for breast cancer interact, evaluating the risk conferred by combinations of
risk factors is difficult.

○ When a localized periareolar abscess recurs at the previous site and a fistula is
present, the preferred operation is fistulectomy
○ However, when subareolar sepsis is diffused rather than localized to one segment or
when more than one fistula is present, total duct excision is the most expeditious
approach.
■ The first circumstance is seen in young women with squamous
metaplasia of a single duct, whereas the latter circumstance is seen in
older women with multiple ectatic ducts.
○ Age is not always a reliable guide, however, and fistula excision is the preferred initial
procedure for localized sepsis irrespective of age
○ Antibiotic therapy
■ useful for recurrent infection after fistula excision,
■ 2- to 4-week course is recommended before total duct excision.
Nipple Inversion
# More women request correction of congenital nipple inversion than request correction for the
nipple inversion that occurs secondary to duct ectasia.
# Although the results are usually satisfactory, women seeking correction for cosmetic reasons
should always be made aware of the surgical complications of altered nipple sensation, nipple
necrosis, and postoperative fibrosis with nipple retraction.
# Because nipple inversion is a result of shortening of the subareolar ducts, a complete division of
these ducts is necessary for permanent correction of the disorder.
RISK FACTORS FOR BREAST CANCER
Hormonal Risk Factors
# Increased exposure to estrogen is associated with an increased risk for developing breast cancer,
whereas reducing exposure is thought to be protective.
Increased Risk Protective
# factors that increase the number of # Moderate levels of exercise and a
menstrual cycles, such as early menarche, longer lactation period, factors that
nulliparity, and late menopause decrease the total number of
# older age at first live birth menstrual cycles
Gail Model
# most frequently used in the United States
# incorporates age, age at menarche, age at first live birth, the number of breast biopsy
specimens, any history of atypical hyperplasia, and number of first-degree relatives with
breast cancer
# predicts the cumulative risk of breast cancer according to decade of life.
# To calculate breast cancer risk, a woman’s risk factors are translated into an overall risk score by
multiplying her relative risks from several categories (Table 17-6)
○ risk score is then compared to an adjusted population risk of breast cancer to
determine a woman’s individual or absolute risk.
○ The output is a 5-year risk and a lifetime risk of developing breast cancer.
# recently modified to more accurately assess risk in African American women
# There have also been modifications that project individualized absolute invasive breast cancer risk
for Asian and Pacific Island American women.
# the most widely used model in the United States.
Claus Model
# the other frequently used risk assessment model, which is based on assumptions about the
prevalence of high-penetrance breast cancer susceptibility genes
# Compared with the Gail model, the Claus model incorporates more information about family history
but excludes other risk factors
○ provides individual estimates of breast cancer risk according to decade of life based on
presence of first- and second-degree relatives with breast cancer and their age at
diagnosis
---------------------
# Risk factors that are less consistently associated with breast cancer (diet, use of oral
contraceptives, lactation) or are rare in the general population (radiation exposure) are not
included in either the Gail or Claus risk assessment model.
# Neither the Gail model nor the Claus model accounts for the risk associated with mutations in the
breast cancer susceptibility genes BRCA1 and BRCA2 (described in detail in the following section)
---------------------
BRCAPRO model
# a Mendelian model that calculates the probability that an individual is a carrier of a mutation in
one of the breast cancer susceptibility genes based on their family history of breast and ovarian
cancer

BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 9

 # The probability that an individual will develop breast or ovarian cancer is derived from this mutation
probability based on age-specific incidence curves for both mutation carriers and noncarriers.
# Use in the clinic is challenging since it requires input of all family history information regarding
breast and ovarian cancer
Tyrer-Cuzick model
# attempts to utilize both family history information and individual risk information
# uses the family history to calculate the probability that an individual carries a mutation in one of the
breast cancer susceptibility genes, and then the risk is adjusted based on personal risk factors,
including age at menarche, parity, age at first live birth, age at menopause, history of atypical
hyperplasia or LCIS, height, and body mass index
---------------------
# Once a risk model has been utilized to assess breast cancer risk, this must be communicated to
the individual and put into context with competing risk and medical comorbidities
Breast Cancer Screening
Risk Management
# Several important medical decisions may be affected by a woman’s underlying risk of developing
breast cancer:
○ when to use postmenopausal hormone replacement therapy
○ at what age to begin mammography screening or incorporate magnetic resonance
imaging (MRI) screening
○ when to use tamoxifen to prevent breast cancer
○ when to perform prophylactic mastectomy to prevent breast cancer
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
Postmenopausal hormone replacement therapy
# widely prescribed in the 1980s and 1990s because of its effectiveness in controlling the symptoms
of estrogen deficiency, namely vasomotor symptoms such as hot flashes, night sweats and their
associated sleep deprivation, osteoporosis, and cognitive changes
# thought to reduce coronary artery disease
# Use of combined estrogen and progesterone became standard for women who had not
undergone hysterectomy because unopposed estrogen increases the risk of uterine cancer.
# Women’s Health Initiative (WHI)
○ designed by the National Institutes of Health as a series of clinical trials to study the
effects of diet, nutritional supplements, and hormones on the risk of cancer,
cardiovascular disease, and bone health in postmenopausal women.
○ Findings: breast cancer risk is threefold to fourfold higher after >4 years of use and
there is no significant reduction in coronary artery or cerebrovascular risks
○ estrogen + progesterone increased the incidence of breast cancer
■ confirmed by the Million Women study, which also showed that the
increased risk was substantially greater for the combined estrogen +
progesterone replacement therapy than other types of hormone
replacement therapy.
# The Collaborative Group on Hormonal Factors in Breast Cancer
○ found an increased risk of breast cancer with every use of estrogen replacement
therapy
○ also reported increased risk among current users but not past users and risk increased
with increasing duration of use of hormone replacement therapy
# Routine use of screening mammography in women ≥50 years of age has been reported to reduce
mortality from breast cancer by 25%
# there has been debate over the potential harms associated with breast screening
# Controversy over the age to initiate screening mammography is evident in the current
recommendations
# The U.S. Preventive Services Task Force (USPSTF), the American Cancer Society (ACS), and the
National Comprehensive Cancer Network (NCCN) are three organizations with differing
recommendations for screening mammography in average risk women
○ guidelines, however, similarly define high-risk women as those with:
■ personal history of breast cancer
■ history of chest radiation at young age
■ confirmed or suspected genetic mutation known to increase risk for
developing breast cancer
# USPSTF recommends biennial screening mammography for women age 50 - 74 years.
○ USPSTF applies these guidelines to asymptomatic women age >40 years who do not
have a preexisting breast cancer or who were not previously diagnosed with a high-risk
breast lesion, and who are not at high risk for breast cancer because of a known
underlying genetic mutation or history of chest radiation at a young age
# ACS released updated guidelines stating average-risk women should start annual screening
mammography at 45 years of age
○ Women age 45 - 54 years should be screened annually
○ > 55 years - should transition to biennial screening or have the opportunity to continue
annual screening
○ Women should have the opportunity to begin annual screening between the ages of 40
and 44 years and should continue screening as long as their overall health is good and
have a life expectancy of 10 years or longer.
○ The ACS does NOT recommend clinical breast examination for breast cancer
screening among average-risk women at any age
# NCCN recommends that average-risk women begin annual screening mammograms at ≥40 years
of age, along with annual clinical breast exams and breast awareness
# The United Kingdom expert panel estimated that an invitation to breast screening delivers about a
20% reduction in breast cancer mortality
○ At the same time, however, the panel estimated that in women invited to the screening,
about 11% of the cancers diagnosed in their lifetime constitute overdiagnosis.
○ Despite the overdiagnosis, the panel concluded that breast screening confers
significant benefit and should continue.
# The use of screening mammography in women <50 years of age is more controversial for several
reasons:
10
 a. breast density is greater, and screening mammography is less likely to detect early
breast cancer (i.e., reduced sensitivity)
b. screening mammography results in more false-positive test findings (i.e., reduced
specificity), which results in unnecessary biopsy specimens
c. younger women are less likely to have breast cancer (i.e., lower incidence), so fewer
young women will benefit from screening
# In the United States, on a population basis, however, the benefits of screening mammography in
women between the ages of 40 and 49 years is still felt to outweigh the risks; although targeting
mammography to women at higher risk of breast cancer improves the balance of risks and benefits
and is the approach some health care systems have taken.
○ an abnormal mammography finding was three times more likely to be cancer in a
woman with a family history of breast cancer than in a woman without such a history.
# mounting data regarding mammographic breast density demonstrate an independent correlation
with breast cancer risk
○ Incorporation of breast density measurements into breast cancer risk assessment
models appears to be a promising strategy for increasing the accuracy of these tools
○ hampered by inconsistencies in the reporting of mammographic density
# Ultrasonography
○ can also be used for breast cancer screening in women with dense breasts, but there
is no data available that the additional cancers detected with this modality reduce
mortality from breast cancer.
# Current recommendations by the United States Preventive Services Task Force are that women
undergo biennial mammographic screening between the ages of 50 - 74 years
# MRI for breast cancer screening
○ recommended by the ACS for women with a 20% to 25% or greater lifetime risk using
risk assessment tools based mainly on
■ family history
■ BRCA mutation carriers
■ those individuals who have a family member with a BRCA mutation who
have not been tested themselves
■ individuals who received radiation to the chest between the ages of 10 and
30 years
■ history of Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley
Ruvalcaba syndrome or w/ first-degree relative with one of these
syndromes
# an extremely sensitive screening tool that is not limited by the density of the breast
tissue as mammography is; however, its specificity is moderate, leading to more false-
positive events and the increased need for biopsy
Chemoprevention
# Tamoxifen
○ a selective estrogen receptor modulator
○ first drug shown to reduce the incidence of breast cancer in healthy women
○ Breast Cancer Prevention Trial (NSABP P-01)
■ incidence of breast cancer was reduced by 49% in the group receiving
tamoxifen
■ decrease was evident only in ER-positive breast cancers with no significant
change in ER-negative tumors
○ Royal Marsden Hospital Tamoxifen Chemoprevention Trial, the Italian Tamoxifen
Prevention Trial, and the International Breast Cancer Intervention Study I (IBIS-I) trial
■ showed a reduction in ER-positive breast cancers with the use of tamoxifen
compared with placebo
■ no effect on mortality
■ however, the trials were not powered to assess either breast cancer
mortality or all-cause mortality events.
# adverse events: increased risk of endometrial cancer, thromboembolic events, cataract
formation, and vasomotor disturbances in individuals receiving tamoxifen.
# Tamoxifen therapy
○ currently is recommended only for the ff women:
■ Gail relative risk of 1.66% or higher, who are age 35 to 59
■ age > 60
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
■ diagnosis of LCIS or atypical ductal or lobular hyperplasia
■ deep vein thrombosis occurs 1.6 times as often, pulmonary emboli 3.0
times as often, and endometrial cancer 2.5 times as often in women taking
tamoxifen
○ increased risk for endometrial cancer is restricted to early stage cancers in
postmenopausal women
○ Cataract surgery is required almost twice as often among women taking tamoxifen.
# P-2 trial, the Study of Tamoxifen and Raloxifene- STAR trial
○ Raloxifene, another selective estrogen receptor modulator, was selected for the
experimental arm in this follow-up prevention trial because its use in managing
postmenopausal osteoporosis suggested that it might be even more effective at breast
cancer risk reduction, but without the adverse effects of tamoxifen on the uterus.
○ the two agents were nearly identical in their ability to reduce breast cancer risk, but
raloxifene was associated with a more favorable adverse event profile
○ An updated analysis revealed that raloxifene maintained 76% of the efficacy of
tamoxifen in prevention of invasive breast cancer with a more favorable side effect
profile
○ Although tamoxifen has been shown to reduce the incidence of LCIS and DCIS,
raloxifene did not have an effect on the frequency of these diagnoses.
# MAP.3 trial
○ Aromatase inhibitors (AIs) have been shown to be more effective than tamoxifen in
reducing the incidence of contralateral breast cancers in postmenopausal women
receiving AIs for adjuvant treatment of invasive breast cancer.
○ first study to evaluate an AI as a chemopreventive agent in postmenopausal women at
high risk for breast cancer.
○ Exemestane was shown to reduce invasive breast cancer incidence by 65%
○ Side effect profiles demonstrated more grade II or higher arthritis and hot flashes in
patients taking exemestane
# IBIS II trial
○ randomized 3864 postmenopausal women to either anastrozole, a nonsteroidal
aromatase inhibitor, vs. placebo with a further randomization to bisphosphonate or not
based on bone density
○ anastrozole reduced the incidence of invasive breast cancer by about 50%
○ also looked at the effect of the aromatase inhibitor on cognitive function and reported
no adverse effects
# American Society of Clinical Oncology
○ recommends tamoxifen for chemoprevention in premenopausal or postmenopausal
women
○ consideration for raloxifene or exemestane in postmenopausal women who are noted
to be at increased risk of breast cancer
Risk-Reducing Surgery
# prophylactic mastectomy
○ reduced risk by >90%
○ effects of prophylactic mastectomy on the long-term quality of life are poorly quantified
○ A study involving women who were carriers of a breast cancer susceptibility gene
(BRCA) mutation found that the benefit of prophylactic mastectomy differed
substantially according to the breast cancer risk conferred by the mutations.
■ estimated lifetime risk of 40% --> prophylactic mastectomy added almost 3
years of life
■ estimated lifetime risk of 85% --> prophylactic mastectomy added >5 years
of life
○ risk-reducing mastectomy was highly effective at preventing breast cancer in both
BRCA1 and 2 mutation carriers.
# Risk-reducing salpingo-oophorectomy
○ highly effective at reducing the incidence of ovarian cancer and breast cancer in BRCA
mutation carriers
○ associated with a reduction in breast cancer-specific mortality, ovarian cancer-specific
mortality, and all-cause mortality
# While studies of bilateral prophylactic or risk-reducing mastectomy have reported dramatic
reductions in breast cancer incidence among those without known BRCA mutations, there is little
data to support a survival benefit.
# some are dissatisfied with the cosmetic outcomes mostly due to reconstructive issues
11
BRCA Mutations
# Up to 5% of breast cancers are caused by inheritance of germline mutations such as BRCA1 and
BRCA2, which are inherited in an autosomal dominant fashion with varying degrees of
penetrance
BRCA1
# located on chromosome arm 17q, spans a genomic region of approximately 100 kilobases (kb) of
DNA, and contains 22 coding exons for 1863 amino acids.
# Both BRCA1 and BRCA2 function as tumor suppressor genes, and for each gene, loss of both
alleles is required for the initiation of cancer.
# Data accumulated since the isolation of the BRCA1 gene suggest a role in transcription, cell-cycle
control, and DNA damage repair pathways.
# More than 500 sequence variations in BRCA1 have been identified
# germline mutations in BRCA1 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 been reported to have up to an 85% lifetime risk (for some
families) for developing breast cancer and up to a 40% lifetime risk for developing ovarian cancer
# average lifetime risk has been reported to lie between 60% - 70%
# Breast cancer susceptibility in these families appears as an autosomal dominant trait with high
penetrance
# Approximately 50% of children of carriers inherit the trait
# BRCA1-associated breast cancers are invasive ductal carcinomas which are:
○ poorly differentiated
○ in the majority hormone receptor negative
○ have a triple receptor negative (immunohistochemical profile: ER-negative, PR-
negative, and HER2-negative) or basal phenotype (based on gene expression
profiling)
# BRCA1-associated breast cancers' distinguishing clinical features:
○ early age of onset compared with sporadic cases
○ a higher prevalence of bilateral breast cancer
○ presence of associated cancers in some affected individuals
■ specifically ovarian cancer and possibly colon and prostate cancers
# 185delAG and 5382insC
○ two most common founder mutations
○ account for 10% of all the mutations seen in BRCA1
○ occur at a 10-fold higher frequency in the Ashkenazi Jewish population than in non-
Jewish Caucasians
○ The carrier frequency of the 185delAG mutation in the Ashkenazi Jewish population is
1% and, along with the 5382insC mutation, accounts for almost all BRCA1 mutations in
this population.
○ Analysis of germline mutations in Jewish and non-Jewish women with early-onset
breast cancer indicates that 20% of Jewish women who develop breast cancer before
age 40 years carry the 185delAG mutation.
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
# There are founder BRCA1 mutations in other populations including, among others, Dutch, Polish,
Finnish, and Russian populations.
BRCA2
# located on chromosome arm 13q and spans a genomic region of approximately 70 kb of DNA
# The 11.2-kb coding region contains 26 coding exons
○ It encodes a protein of 3418 amino acids
# bears no homology to any previously described gene, and the protein contains no previously
defined functional domains
# The biologic function of BRCA2 is not well defined, but like BRCA1, it is postulated to play a role in
DNA damage response pathways
○ BRCA2 messenger RNA also is expressed at high levels in the late G1 and S phases
of the cell cycle.
# The kinetics of BRCA2 protein regulation in the cell cycle is similar to that of BRCA1 protein, which
suggests that these genes are coregulated.
# The mutational spectrum of BRCA2 is not as well established as that of BRCA1
# >250 mutations have been found
# breast cancer risk for BRCA2 mutation carriers is close to 85%
# lifetime ovarian cancer risk, while lower than for BRCA1, is still estimated to be close to 20%
# Breast cancer susceptibility in BRCA2 families is an autosomal dominant trait and has a high
penetrance
# Approximately 50% of children of carriers inherit the trait
# Unlike male carriers of BRCA1 mutations, men with germline mutations in BRCA2 have an
estimated breast cancer risk of 6%, which represents a 100-fold increase over the risk in the
general male population
# BRCA2-associated breast cancers are invasive ductal carcinomas which are:
○ more likely to be well differentiated
○ express hormone receptors than are BRCA1-associated breast cancers
# BRCA2-associated breast cancer's distinguishing clinical features:
○ early age of onset compared with sporadic cases
○ higher prevalence of bilateral breast cancer
○ presence of associated cancers in some affected individuals
■ specifically ovarian, colon, prostate, pancreatic, gallbladder, bile duct, and
stomach cancers, as well as melanoma
# A number of founder mutations have been identified in BRCA2
○ 6174delT mutation
■ found in Ashkenazi Jews with a prevalence of 1.2% and accounts for 60%
of ovarian cancer and 30% of early-onset breast cancer patients among
Ashkenazi women
○ 999del5
■ observed in Icelandic and Finnish populations
○ 3036delACAA
■ observed in a number of Spanish families
Identification of BRCA Mutation Carriers
# Identifying hereditary risk for breast cancer is a four-step process that includes:
○ obtaining a complete, multigenerational family history
○ assessing the appropriateness of genetic testing for a particular patient
○ counseling the patient
○ interpreting the results of testing
# Genetic testing
○ should not be offered in isolation, but only in conjunction with patient education and
counseling, including referral to a genetic counselor
○ Initial determinations include whether the individual is an appropriate candidate for
genetic testing and whether genetic testing will be informative for personal and clinical
decision-making
○ A thorough and accurate family history is essential to this process, and the maternal
and paternal sides of the family are both assessed because 50% of the women with a
BRCA mutation have inherited the mutation from their fathers
○ To help clinicians advise women about genetic testing, statistically based models that
determine the probability that an individual carries a BRCA mutation have been
developed
12
 ○ A method for calculating carrier probability that has been demonstrated to have
acceptable performance (i.e., both in terms of calibration and discrimination) such as
the Manchester scoring system and BODICEA should be used to offer referral to a
specialist genetic clinic
○ A hereditary risk of breast cancer is considered if a family includes:
■ Ashkenazi Jewish heritage
■ a first-degree relative with breast cancer before age 50
■ a history of ovarian cancer at any age in the patient or first- or second-
degree relative with ovarian cancer
■ breast and ovarian cancer in the same individual
■ two or more first- or second-degree relatives with breast cancer at any age
■ patient or relative with bilateral breast cancer
■ male breast cancer in a relative at any age
○ The threshold for genetic testing is lower in individuals who are members of ethnic
groups in whom the mutation prevalence is increased.
BRCA Mutation Testing
# Appropriate counseling for the individual being tested for a BRCA mutation is strongly
recommended, and documentation of informed consent is required
# gene sequence analysis
○ the test that is clinically available for analyzing BRCA mutations
# In a family with a history suggestive of hereditary breast cancer and no previously tested member,
the most informative strategy is first to test an affected family member
○ This person undergoes complete sequence analysis of both the BRCA1 and BRCA2
genes
○ If a mutation is identified, relatives are usually tested only for that specific mutation
# An individual of Ashkenazi Jewish ancestry is tested initially for the three specific mutations that
account for hereditary breast and ovarian cancer in that population
○ If results of that test are negative, it may then be appropriate to fully analyze the
BRCA1 and BRCA2 genes
○ A positive test result is one that discloses the presence of a BRCA mutation that
interferes with translation or function of the BRCA protein
# A woman who carries a deleterious mutation has a breast cancer risk of up to 85% (in some
families) as well as a greatly increased risk of ovarian cancer
# A negative test result is interpreted according to the individual’s personal and family history,
especially whether a mutation has been previously identified in the family, in which case the
woman is generally tested only for that specific mutation
# If the mutation is not present, the woman’s risk of breast or ovarian cancer may be no greater than
that of the general population
# no BRCA mutation can be passed on to the woman’s children
# In the absence of a previously identified mutation, a negative test result in an affected individual
generally indicates that a BRCA mutation is not responsible for the familial cancer
○ the possibility remains of an unusual abnormality in one of these genes that cannot yet
be identified through clinical testing
# Phenocopy
○ the familial cancer is indeed caused by an identifiable BRCA mutation but that the
individual tested had sporadic cancer
○ especially possible if the individual tested developed breast cancer close to the age of
onset of the general population (age 60 years or older) rather than before age 50
years, as is characteristic of BRCA mutation carriers
# Overall, the false-negative rate for BRCA mutation testing is <5%
# Some test results, especially when a single base-pair change (missense mutation) is identified,
may be difficult to interpret
○ This is because single base-pair changes do not always result in a nonfunctional
protein
○ Thus, missense mutations not located within critical functional domains, or those that
cause only minimal changes in protein structure, may not be disease associated and
are usually reported as indeterminate results.
# testing other family members with breast cancer to determine if a genetic variant tracks with their
breast cancer may provide clarification as to its significance.
# Indeterminate genetic variance currently accounts for 12% of the test results
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
# The Health Insurance Portability and Accountability Act of 1996 (HIPAA) made it illegal in the
United States for group health plans to consider genetic information as a preexisting condition or to
use it to deny or limit coverage
# individuals applying for health insurance are not required to report whether relatives have
undergone genetic testing for cancer risk, only whether those relatives have actually been
diagnosed with cancer
Cancer Prevention for BRCA Mutation Carriers.
# Risk management strategies for BRCA1 and BRCA2 mutation carriers include the following:
Risk-reducing mastectomy and reconstruction
# Although removal of breast tissue reduces the likelihood that BRCA1 and BRCA2 mutation carriers
will develop breast cancer, mastectomy does not remove all breast tissue, and women continue to
be at risk because a germline mutation is present in any remaining breast tissue.
# For postmenopausal BRCA1 and BRCA2 mutation carriers who have not had a mastectomy, it
may be advisable to avoid hormone replacement therapy because no data exist regarding the
effect of the therapy on the penetrance of breast cancer susceptibility genes.
# Because breast cancers in BRCA mutation carriers have the same mammographic appearance as
breast cancers in noncarriers, a screening mammogram is likely to be effective in BRCA mutation
carriers, provided it is performed and interpreted by an experienced radiologist with a high level of
suspicion.
Risk-reducing salpingo-oophorectomy
# The risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers ranges from 20% to 40%,
which is 10 times higher than that in the general population.
# a reasonable prevention option in mutation carriers
# In women with a documented BRCA1 or BRCA2 mutation, consideration for bilateral risk-reducing
salpingooophorectomy should be between the ages of 35 and 40 years at the completion of
childbearing
# Removing the ovaries reduces the risk of ovarian cancer and breast cancer when performed in
premenopausal BRCA mutation carriers
# Hormone replacement therapy is discussed with the patient at the time of oophorectomy
# For those who have opted to defer risk-reducing surgery:
○ The Cancer Genetics Studies Consortium recommends yearly transvaginal
ultrasound timed to avoid ovulation and annual measurement of serum cancer
antigen 125 levels beginning at age 25 years as the best screening modalities for
ovarian carcinoma in BRCA mutation carriers
Intensive surveillance for breast and ovarian cancer
# Present screening recommendations for BRCA mutation carriers who do not undergo risk-reducing
mastectomy include
○ clinical breast examination every 6 months and mammography every 12 months
beginning at age 25 years because the risk of breast cancer in BRCA mutation carriers
increases after age 30 years
# Recent attention has been focused on the use of MRI for breast cancer screening in high-risk
individuals and known BRCA mutation carriers.
○ MRI appears to be more sensitive at detecting breast cancer in younger women with
dense breasts
○ However, as noted previously, MRI does lead to the detection of benign breast lesions
that cannot easily be distinguished from malignancy, and these false-positive events
can result in more interventions, including biopsy specimens.
○ The current recommendations from the American Cancer Society are for annual MRI in
women with
■ a 20% to 25% or greater lifetime risk of developing breast cancer (mainly
based on family history)
■ women with a known BRCA1 or BRCA2 mutation
■ have a first-degree relative with a BRCA1 or BRCA2 mutation and have
not had genetic testing themselves
■ treated with radiation therapy to the chest between the ages of 10 and 30
years
■ Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-
Ruvalcaba syndrome, or a first-degree relative with one of these
syndromes
13

Chemoprevention
# Despite a 49% reduction in the overall incidence of breast cancer and a 69% reduction in the
incidence of estrogen receptor positive tumors in high-risk women taking tamoxifen reported in the
NSABP P1 trial, there is insufficient evidence to recommend the use of tamoxifen uniformly for
BRCA1 mutation carriers
○ Cancers arising in BRCA1 mutation carriers are usually high grade and are most often
hormone receptor negative.
○ Approximately 66% of BRCA1-associated DCIS lesions are estrogen receptor
negative, which suggests early acquisition of the hormone-independent phenotype.
# In the NSABP P1 trial there was a 62% reduction in the incidence of breast cancer in BRCA2
carriers, similar to the overall reduction seen in the P1 trial. In contrast, there was no reduction
seen in breast cancer incidence in BRCA1 carriers who started tamoxifen in P1 age 35 years or
older
----------------------
# PALB2 (partner and localizer of BRCA2)
○ recently been characterized as a potential high-risk gene for breast cancer.
○ allows nuclear localization of BRCA2 and provides a scaffold for the BRCA1–PALB2–
BRCA2 complex
○ the risk of breast cancer for PALB2 mutation carriers is as high as that of BRCA2
mutation carriers
○ The absolute risk of breast cancer for PALB2 female mutation carriers by 70 years of
age ranged from 33% (95% CI, 25–44) for those with no family history of breast cancer
to 58% (95% CI, 50–66) for those with two or more first-degree relatives with breast
cancer at 50 years of age
○ The risk of breast cancer for female PALB2 mutation carriers, depending on the age,
was about five to nine times as high compared with the general population
○ While screening with mammogram along with MRI has been suggested for PALB2
mutation carriers starting at age 30 with consideration of risk-reducing mastectomy,
there is currently insufficient evidence regarding the risk of ovarian cancer and its
management
# Other hereditary syndromes associated with an increased risk of breast cancer include
○ Cowden disease
■ PTEN mutations, in which cancers of the thyroid, GI tract, and benign skin
and subcutaneous nodules are also seen
○ Li-Fraumeni syndrome
■ TP53 mutations, also associated with sarcomas, lymphomas, and
adrenocortical tumors)
○ hereditary diffuse gastric cancer syndrome
■ CDH1 mutations, associated with diffuse gastric cancer and lobular breast
cancers)
○ syndromes of breast and melanoma
# With the discovery of additional genes related to breast cancer susceptibility, panel testing is
available for a number of genes in addition to BRCA1 and BRCA2
# The interpretation of results is complex and is best done with a genetic counselor.
EPIDEMIOLOGY
# Breast cancer is the most common site-specific cancer in women and is the leading cause of death
from cancer for women age 20 to 59 years
# It accounts for 30% of all newly diagnosed cancers in women and is responsible for 14% of the
cancer-related deaths 561 in women.
# Breast cancer was the leading cause of cancer-related mortality in women until 1987, when it was
surpassed by lung cancer.
○ From 1960 to 1963, 5-year overall survival rates for breast cancer were 63% and 46%
in white and African American women, respectively, whereas the rates for 1981 to
1983 were 78% and 64%, respectively. For 2002 to 2008 rates were 92% and 78%,
respectively.
# There is a 10-fold variation in breast cancer incidence among different countries worldwide.
○ Cyprus and Malta have the highest age-adjusted mortality for breast cancer (29.6 per
100,000 population), whereas Haiti has the lowest (2.0 deaths per 100,000 population).
○ Women living in less industrialized nations tend to have a lower incidence of breast
cancer than women living in industrialized countries, although Japan is an exception.
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
○ In the United States, Mormons, Seventh Day Adventists, American Indians, Alaska
natives, Hispanic/Latina Americans, and Japanese and Filipino women living in Hawaii
have a below-average incidence of breast cancer
○ Nuns (due to nulliparity) and Ashkenazi Jewish women have an above-average
incidence.
# Breast cancer burden has well-defined variations by geog- raphy, regional lifestyle, and racial or
ethnic background
○ In general, both breast cancer incidence and mortality are relatively lower among the
female populations of Asia and Africa, relatively underdeveloped nations, and nations
that have not adopted Westernized reproductive and dietary patterns.
○ European and North American women and women from heavily industrialized or
Westernized countries have a substantially higher breast cancer burden.
# Factors that influence breast cancer incidence may differ from those that affect mortality
○ Incidence rates are lower among populations that are heavily 100 weighted with
women who begin childbearing at young ages and who have multiple full-term
pregnancies followed by prolonged lactation.
○ Breast cancer incidence and mortality rates rise among second- and third-generation
Asian Americans as they adopt Western lifestyles
# Disparities in breast cancer survival among subsets of the American population are generating
increased publicity because they are closely linked to disparities in socioeconomic status
○ These socioeconomic disadvantages create barriers to effective breast cancer
screening and result in delayed breast cancer diagnosis, advanced stage distribution,
inadequacies in comprehensive treatment, and, ultimately, increased mortality rates.
○ Some of the treatment delivery disparities are related to inadequately con- trolled
comorbidities (such as hypertension and diabetes), which are more prevalent in
minority populations.
# Advances in the ability to characterize breast cancer sub- types and the genetics of the disease
are now provoking speculation regarding possible hereditary influences on breast cancer risk that
are related to racial or ethnic ancestry.
○ Lifetime risk of breast cancer is lower for African Americans, yet a paradoxically
increased breast cancer mortality risk also is seen.
○ African Americans also have a younger age distribution for breast cancer; among
women <45 years of age, breast cancer incidence is highest among African Americans
compared to other subsets of the American population.
○ African American women of all ages have notably higher incidence rates for estrogen
receptor- negative tumors
○ Male breast cancer also is seen with increased frequency among both African
Americans and Africans
NATURAL HISTORY
# 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 Cooper’s suspensory
ligaments 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.
○ The size of the primary breast cancer correlates with disease-free and overall survival,
but there is a close association between cancer size and axillary lymph node
involvement.
○ In general, up to 20% of breast cancer recurrences are local-regional, >60% are
distant, and 20% are both local- regional 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
14
 ○ Cancer cells may grow through the lymph node capsule and fix to contiguous # Multifocality
structures in the axilla, including the chest wall. ○ refers to the occurrence of a second cancer within the same breast quadrant as the
○ Typically, axillary lymph nodes are involved sequentially from the low (level I) to the primary cancer (or within 4 cm of it)
central (level II) to the apical (level III) lymph node groups. # LCIS occurs bilaterally in 50% to 70% of cases, whereas DCIS occurs bilaterally in 10% to 20% of
○ Approximately 95% of the women who die of breast cancer have distant metastases, cases
and traditionally the most important prognostic correlate of disease-free and over- all
survival was axillary lymph node status.
○ Women with node-negative disease had less than a 30% risk of recurrence, compared
with as much as a 75% risk for women with node-positive disease.

# 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 after initial treatment, distant metastases are the most common cause of
death in breast cancer patients.
○ For this reason, conclusive results cannot be derived from breast cancer trials until at
least 5 to 10 years have elapsed.
○ Although 60% of the women who develop distant metastases will do so within 60
months of treatment, metastases may become evident as late as 20 to 30 years after
treatment of the primary cancer.
○ Patients with estrogen receptor negative breast cancers are proportionately more likely
to develop recurrence in the first 3 to 5 years, whereas those with estrogen receptor
positive tumors have a risk of developing recurrence, which drops off more slowly
beyond 5 years than is seen with ER-negative tumors
○ Recently, a report showed that tumor size and nodal status remain powerful predictors
of late recurrences compared to more recently developed tools such as the
immunohistochemical score (IHC4) and two gene expression profile tests (Recurrence
Score and PAM50).
○ Common sites of involvement, in order of frequency, are bone, lung, pleura, soft
tissues, and liver. Lobular Carcinoma In Situ
○ Brain metastases are less frequent over- all, although with the advent of adjuvant # LCIS originates from the terminal duct lobular units and develops only in the female breast.
systemic therapies it has been reported that CNS disease may be seen earlier. # It is characterized by distention and distortion of the terminal duct lobular units by cells that are
○ There are also reports of factors that are associated with the risk of developing brain large but maintain a normal nuclear to cytoplasmic ratio.
metastases. # Cytoplasmic mucoid globules are a distinctive cellular feature.
○ For example, they are more likely to be seen in patients with triple receptor negative # LCIS may be observed in breast tissues that contain microcalcifications, but the calcifications
breast cancer (ER-negative, PR-negative, and HER2-negative) or patients with HER2- associated with LCIS typically occur in adjacent tissues.
positive breast cancer who have received chemotherapy and HER2-directed therapies. # This neighborhood calcification is a feature that is unique to LCIS and contributes to its diagnosis.
# The frequency of LCIS in the general population cannot be reliably determined because it usually
HISTOPATHOLOGY OF BREAST CANCER presents as an incidental finding.
Carcinoma In Situ # The average age at diagnosis is 45 years, which is approximately 15 to 25 years younger than
# Cancer cells are in situ or invasive depending on whether or not they invade through the basement the age at diagnosis for invasive breast cancer.
membrane. # LCIS has a distinct racial predilection, occurring 12 times more frequently in white women than in
# Broders’s original description of in situ breast cancer stressed the absence of invasion of cells into African-American women.
the surrounding stroma and their confinement within natural ductal and alveolar boundaries. # Invasive breast cancer develops in 25% to 35% of women with LCIS.
# Because areas of invasion may be minute, the accurate diagnosis of in situ cancer necessitates # Invasive cancer may develop in either breast, regardless of which breast harbored the initial focus
the analysis of multiple microscopic sections to exclude invasion. of LCIS, and is detected synchronously with LCIS in 5% of cases.
# Before the widespread use of mammography, diagnosis of breast cancer was by physical # In women with a history of LCIS, up to 65% of subsequent invasive cancers are ductal, not lobular,
examination. in origin.
# When screening mammography became popular, a 14-fold increase in the incidence of in situ # For these reasons, LCIS is regarded as a marker of increased risk for invasive breast cancer
cancer (45%) was demonstrated, and DCIS was more frequently diagnosed than LCIS by a ratio of rather than as an anatomic precursor.
>2:1. # Individuals should be counseled regarding their risk of developing breast cancer and appropriate
# Multicentricity risk reduction strategies, including observation with screening, chemoprevention, and risk-reducing
○ refers to the occurrence of a second breast cancer outside the breast quadrant of the bilateral mastectomy.
primary cancer (or at least 4 cm away)
○ occurs in 60% to 90% of women with LCIS, whereas the rate of multicentricity for DCIS
is reported to be 40% to 80%
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 15
Ductal Carcinoma In Situ
# Although DCIS is predominantly seen in the female breast, it accounts for 5% of male breast
cancers.
# Published series suggest a detection frequency of 7% in all biopsy tissue specimens.
# Intraductal carcinoma
○ Frequently applied to DCIS, which carries a high risk for progression to an invasive
cancer
# Histologically, DCIS is characterized by a proliferation of the epithelium that lines the minor ducts,
resulting in papillary growths within the duct lumina.
# Early in their development, the cancer cells do not show pleomorphism, mitoses, or atypia, which
leads to difficulty in distinguishing early DCIS from benign hyperplasia.
# The papillary growths (papillary growth pattern) eventually coalesce and fill the duct lumina so that
only scattered, rounded spaces remain between the clumps of atypical cancer cells, which show
hyperchromasia and loss of polarity (cribriform growth pattern).
# Eventually pleomorphic cancer cells with frequent mitotic figures obliterate the lumina and distend
the ducts (solid growth pattern).
# With continued growth, these cells outstrip their blood supply and become necrotic (comedo
growth pattern).
# Calcium deposition occurs in the areas of necrosis and is a common feature seen on
mammography.
# DCIS is now frequently classified based on nuclear grade and the presence of necrosis (Table 17-
9).
# Based on multiple consensus meetings, grading of DCIS has been recommended.
# Although there is no universal agreement on clas- sification, most systems endorse the use of
cytologic grade and presence or absence of necrosis.
# The risk for invasive breast cancer is increased nearly fivefold in women with DCIS.
# The invasive cancers are observed in the ipsilateral breast, usually in the same quadrant as the
DCIS that was originally detected, which suggests that DCIS is an anatomic precursor of invasive
ductal carcinoma
Invasive Breast Carcinoma
# Invasive breast cancers have been described as lobular or ductal in origin.
# Early classifications used the term lobular to describe invasive cancers that were associated with
LCIS, whereas all other invasive cancers were referred to as ductal.
# Current histologic classifications recognize special types of 565 breast cancers (10% of total
cases), which are defined by specific histologic features.
# To qualify as a special-type cancer, at least 90% of the cancer must contain the defining histologic
features.
# About 80% of invasive breast cancers are described as invasive ductal carcinoma of no special
type (NST).
# These cancers generally have a worse prognosis than special-type cancers. Foote and Stewart
originally proposed the following classification for invasive breast cancer:
○ Paget’s disease of the nipple
■ Frequently presents as a chronic, eczematous eruption of the nipple, which
may be subtle but may progress to an ulcerated, weeping lesion
■ Usually is associated with extensive DCIS and may be associated with an
invasive cancer
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
■ A palpable mass may or may not be present.
■ A nipple biopsy specimen will show a 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 cells) in the rete pegs of the epithelium.
■ May be confused with superficial spreading melanoma
■ Differentiation from pagetoid intraepithelial melanoma is based on the
presence of S-100 antigen immunostaining in melanoma and
carcinoembryonic antigen immunostaining in Paget’s disease
■ Surgical therapy for Paget’s disease may involve lumpectomy or
mastectomy, depending on the extent of involvement of the nipple-areolar
complex and the presence of DCIS or invasive cancer in the underlying
breast parenchyma.
○ Invasive ductal carcinoma—Adenocarcinoma with productive fibrosis (scirrhous,
simplex, NST), 80%
■ Presents with macroscopic or microscopic axillary lymph node metastases
in up to 25% of screen-detected cases and up to 60% of symptomatic
cases
■ This cancer occurs most frequently in perimenopausal or postmenopausal
women in the fifth to sixth decades of life as a solitary, firm mass.
■ It has 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 often are arranged in small clusters, and there is a broad
spectrum of histologic types with variable cellular and nuclear grades
■ In a large patient series from the SEER database, 75% of ductal cancers
showed estrogen receptor expression
○ Medullary carcinoma, 4%
■ Special-type breast cancer
■ It accounts for 4% of all invasive breast cancers and is a frequent
phenotype of BRCA1 hereditary breast cancer
■ Grossly, the cancer is soft and hemorrhagic
■ A rapid increase in size may occur secondary to necrosis and hemorrhage.
■ On physical examination, it is bulky and often positioned deep within the
breast.
■ Bilaterality is reported in 20% of cases.
■ Medullary carcinoma is characterized microscopically by:
# (a) a dense lymphoreticular infiltrate composed predominantly
of lymphocytes and plasma cells
# (b) large pleomorphic nuclei that are poorly differentiated and
show active mitosis
# (c) a sheet-like growth pattern with minimal or absent ductal or
alveolar differentiation.
■ Approximately 50% of these cancers are associated with DCIS, which
characteristically is present at the periphery of the cancer, and <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.
○ Mucinous (colloid) carcinoma, 2%
■ Another special-type breast cancer,
■ Accounts for 2% of all invasive breast cancers and typically presents in the
older 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.
■ Over 90% of mucinous carcinomas display hormone receptors.
16
 ■ Lymph node metastases occur in 33% of cases, and 5- and 10-year
survival rates are 73% and 59%, respectively.
■ Because of the mucinous component, cancer cells may not be evident in all
microscopic sections, and analysis of multiple sections is essential to
confirm the diagnosis of a mucinous carcinoma.
○ Papillary carcinoma, 2%
■ Special-type cancer of the breast that accounts for 2% of all invasive breast
cancers
■ It generally presents in the seventh decade of life and occurs in a
dispropor- tionate number of nonwhite women.
■ Typically, papillary carcinomas are small and rarely attain a size of 3 cm in
diameter
■ These cancers are defined by papillae with fibrovascular stalks and
multilayered epithelium.
■ In a large series from the SEER database 87% of papillary cancers have
been reported to express estrogen receptor.
■ McDivitt and colleagues noted that these tumors showed a low frequency of
axillary lymph node metastases and had 5- and 10-year survival rates
similar to those for mucinous and tubular carcinoma
○ Tubular carcinoma, 2%
■ Another special-type breast cancer
■ Accounts for 2% of all invasive breast cancers
■ It is reported in as many as 20% of women whose cancers are diagnosed
by mammographic screening and usually is diagnosed in the
perimenopausal or early menopausal periods.
■ Under low-power magnification, a haphazard array of small, randomly
arranged tubular elements is seen.
■ In a large SEER database 94% of tubular cancers were reported to express
estrogen receptor.
■ 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.
■ 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%.
○ Invasive lobular carcinoma, 10%
■ Accounts for 10% of breast cancers
■ The histopathologic features of this cancer include small cells with rounded
nuclei, inconspicuous nucleoli, and scant cytoplasm
■ Special stains may confirm the presence of intracytoplasmic mucin, which
may displace the nucleus (signet-ring cell carcinoma)
■ At presentation, invasive lobular carcinoma varies from clinically inapparent
carcinomas to those that replace the entire breast with a poorly defined
mass
■ It is frequently multifocal, multicentric, and bilateral
■ Because of its insidious growth pattern and subtle mammographic features,
invasive lobular carcinoma may be difficult to detect
■ Over 90% of lobular cancers express estrogen receptor
○ Rare cancers (adenoid cystic, squamous cell, apocrine)
DIAGNOSIS OF BREAST CANCER
# In ∼30% of cases, the woman discovers a lump in her breast.
# Other less frequent presenting signs and symptoms of breast cancer include:
○ (a) breast enlargement or asymmetry
○ (b) nipple changes, retraction, or discharge
○ (c) ulceration or erythema of the skin of the breast
○ (d) an axillary mass
○ (e) musculoskeletal discomfort
# However, up to 50% of women presenting with breast complaints have no physical signs of breast
pathology
# Breast pain usually is associated with benign disease.
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
# Misdiagnosed breast cancer accounts for the greatest number of malpractice claims for errors in
diagnosis and for the largest number of paid claims.
# Litigation often involves younger women, whose physical examination and mammogram may be
misleading.
# If a young woman (≤45 years) presents with a palpable breast mass and equivocal mammographic
findings, ultrasound examination and biopsy are used to avoid a delay in diagnosis
Examination
Inspection
# The clinician inspects the woman’s breast with her arms by her side with her arms straight up in
the air, and with her hands on her hips (with and without pectoral muscle contraction).
# Symmetry, size, and shape of the breast are recorded, as well as any evidence of edema (peau
d’orange), nipple or skin retraction, or erythema.
# With the arms extended forward and in a sitting position, the woman leans forward to accentuate
any skin retraction.
Palpation
# As part of the physical examination, the breast is carefully palpated.
# With the patient in the supine position, the clinician gently palpates the breasts, making certain to
examine all quadrants of the breast from the sternum laterally to the latissimus dorsi muscle and
from the clavicle inferiorly to the upper rectus sheath.
# The examination is performed with the palmar aspects of the fingers, avoiding a grasping or
pinching motion.
# The breast may be cupped or molded in the examiner’s hands to check for retraction.
# A systematic search for lymphadenopathy then is performed.
# By supporting the upper arm and elbow, the examiner stabilizes the shoulder girdle.
# Using gentle palpation, the clinician assesses all three levels of possible axillary lymphadenopathy.
# Careful palpation of supraclavicular and parasternal sites also is performed.
# A diagram of the chest and contiguous lymph node sites is useful for recording location, size,
consistency, shape, mobility, fixation, and other characteristics of any palpable breast mass or
lymphadenopathy.
IMAGING TECHNIQUES
Mammography
# Mammography has been used in North America since the 1960s, and the techniques used
continue to be mod- ified and improved to enhance image quality.
# Conventional mammography delivers a radiation dose of 0.1 cGy per study.
# By comparison, chest radiography delivers 25% of this dose.
# However, there is no increased breast cancer risk associated with the radiation dose delivered with
screening mammography.
# Screening mammography is used to detect unexpected breast cancer in asymptomatic women. In
this regard, it supplements history taking and physical examination.
# With screening mammography, two views of the breast are obtained: the craniocaudal (CC) view
and the mediolateral oblique (MLO) view
○ The MLO view images the greatest volume of breast tissue, including the upper outer
quadrant and the axillary tail of Spence.
○ Compared with the MLO view, the CC view provides better visualization of the medial
aspect of the breast and permits greater breast compression.
# Diagnostic mammography is used to evaluate women with abnormal findings such as a breast
mass or nipple discharge.
○ In addition to the MLO and CC views, a diagnostic examination may use views that
better define the nature of any abnormalities, such as the 90° lateral and spot
compression views.
○ The 90° lateral view is used along with the CC view to triangulate the exact location of
an abnormality.
○ Spot compression may be done in any projection by using a small compression device,
which is placed directly over a mammographic abnormality that is obscured by
overlying tissues.
○ The compression device minimizes motion artifact, improves definition, separates
overlying tissues, and decreases the radiation dose needed to penetrate the breast.
○ Magnification techniques (×1.5) often are combined with spot compression to better
resolve calcifications and the margins of masses.
○ Mammography also is used to guide interventional procedures, including needle
localization and needle biopsy.
# Specific mammographic features that suggest a diagnosis of breast cancer include:
17
 ○ a solid mass with or without stellate features
○ asymmetric thickening of breast tissues
○ clustered microcalcifications
# The presence of fine, stippled calcium in and around a suspicious lesion is suggestive of breast
cancer and occurs in as many as 50% of nonpalpable cancers
# These microcalcifications are an especially important sign of cancer in younger women, in whom it
may be the only mammographic abnormality.
# Only 20% of women with nonpalpable cancers had axillary lymph node metastases, compared with
50% of women with palpable cancers
# Normal-risk women ≥20 years of age should have a breast examination at least every 3 years
# Starting at age 40 years, breast examinations should be performed yearly, and a yearly
mammogram should be taken.
# Screen film mammography has replaced xeromam- mography because it requires a lower dose of
radiation and provides similar image quality
# Digital mammography was developed to allow the observer to manipulate the degree of contrast in
the image.
○ This is especially useful in women with dense breasts and women <50 years of age
# The use of digital breast tomosynthesis with 3D images has been introduced as an alternative to
standard 2D mammography imaging that is limited by superimposition of breast parenchyma and
breast density
○ In digital breast tomosynthesis, multiple projection images are reconstructed to allow
visual review of thin breast sections, each reconstructed slice as thin as 0.5 mm, which
provides better characterization of noncalcified lesions.
○ These multiple projection exposures are obtained by a digital detector from a
mammography X-ray source that moves through a limited arc angle while the breast is
compressed.
○ Then these projection image data sets are reconstructed using specific algorithms,
which provide the clinical reader a series of images through the entire breast.
○ In 2011, tomosynthesis was approved by the U.S. Food and Drug Administration (FDA)
to be used in combination with standard digital mammography for breast cancer
screening.
# Contrast-enhanced digital mammography (CEDM) was also approved by the FDA in 2001, which
utilizes an iodinated contrast material and modified digital mammography units for imaging.
○ CEDM has been shown to be feasible and detects breast cancers at a rate similar to
MRI, which has potential to offer an alternative to MRI.
○ The advantages of CEDM over MRI are that
■ Use of compression limits motion
■ There is decrease in cost
■ Decrease in exam time
■ There is an option for patients who are unable to tolerate MRI or who due
to various reasons cannot have MRI due to incompatibility, such as the
presence of a pacemaker or tissue expanders
Ductography
# The primary indication for ductography is nipple discharge, particularly when the fluid contains
blood.
# Radiopaque contrast media is injected into one or more of the major ducts, and mammography is
performed.
# A duct is gently enlarged with a dilator, and then a small, blunt cannula is inserted under sterile
conditions into the nipple ampulla.
# With the patient in a supine position, 0.1 to 0.2 mL of dilute contrast media is injected, and CC and
MLO mammographic views are obtained without compression.
# Intraductal papillomas are seen as small filling defects surrounded by contrast media
# Cancers may appear as irregular masses or as mul- tiple intraluminal filling defects.
Ultrasonography
# Second only to mammography in frequency of use for breast imaging, ultrasonography is an
important method of resolving equivocal mammographic findings, defining cystic masses, and
demonstrating the echogenic qualities of specific solid abnormalities.
# On ultrasound examination, breast cysts are well circumscribed, with smooth margins and an
echo-free center.
# Benign breast masses usually show smooth contours, round or oval shapes, weak internal echoes,
and well-defined anterior and posterior margins.
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
# Breast cancer characteristically has irregular walls but may have smooth margins with acoustic
enhancement.
# Ultrasonography is used to guide fine-needle aspiration biopsy, core-needle biopsy, and needle
localization of breast lesions.
# Its findings are highly reproducible, and it has a high patient acceptance rate, but it does not
reliably detect lesions that are ≤1 cm in diameter.
# Ultrasonography can also be utilized to image the regional lymph nodes in patients with breast
cancer
# The sensitivity of examination for the status of axillary nodes ranges from 35% to 82% and
specificity ranges from 73% to 97%.
# The features of a lymph node involved with cancer include cortical thickening, change in shape of
the node to more circular appearance, size larger than 10 mm, absence of a fatty hilum and
hypoechoic internal echoes.
Magnetic Resonance Imaging
- In the process of evaluating MRI as a means of characterizing mammographic abnormalities,
additional breast lesions have been detected
- in the circumstance of negative findings on both mammography and physical examination, the
o probability of a breast cancer being diagnosed by MRI is extremely low
- current interest in the use of MRI to screen the breasts of high-risk women and of women with a
newly diagnosed breast cancer
- Two cases
o women who have a strong family history of breast cancer or who carry known genetic
mutations require screening at an early age because mammographic evaluation is
limited due to the increased breast density in younger women
o study of the contralateral breast in women with a known breast cancer has shown a
contralateral breast cancer in 5.7% of these women
- can also detect additional tumors in the index breast (multifocal or multicentric disease) that may
be missed on routine breast imaging and this may alter surgical decision making
- has been advocated by some for routine use in surgical treatment planning based on the fact that
additional disease can be identified with this advanced imaging modality and the extent of disease
may be more accurately assessed
- A randomized trial performed in the United Kingdom (COMICE trial) that enrolled 1623 women did
not show a decrease in rates of reoperation in those women randomized to undergo MRI in
addition to mammography and ultrasonography (19%) com- pared to those undergoing standard
breast imaging without MRI (19%)
- Houssami and colleagues performed a meta- analysis including two randomized trials and seven
comparative cohort studies to examine the effect of preoperative MRI compared to standard
preoperative evaluation on surgical out- comes
o reported that the use of MRI was associated with increased mastectomy rates.
o problematic because there is no evidence that the additional disease detected by MRI
is of clinical or biologic significance, particularly in light of the low local-regional failure
rates currently reported in patients undergoing breast conserving surgery who receive
whole breast irradiation and systemic therapies
- There is an ongoing trial in the Alliance for Clinical Trials in Oncology that is randomizing patients
to preoperative MRI vs. standard imaging to assess the impact of MRI on local regional recurrence
rates in patients with triple receptor negative and HER2 positive breast cancers.
- use of dedicated breast coils
o mandatory in the MRI imaging of the breast
- A BIRADS lexicon is assigned to each examination and an abnormality noted on MRI that is not
seen on mammography requires a focused ultrasound examination for further assessment
- If the abnormality is not seen on corresponding mammogram or ultrasound, then MRI-guided
biopsy is necessary
- Some clinical scenarios where MRI may be useful
o the evaluation of a patient who presents with nodal metastasis from breast cancer
without an identifiable primary tumor
o assess response to therapy in the setting of neoadjuvant systemic treatment
o select patients for partial breast irradiation techniques
o evaluation of the treated breast for tumor recurrence
18
BREAST BIOPSY
Nonpalpable Lesions
- Image-guided breast biopsy specimens
o frequently required to diagnose nonpalpable lesions
- Ultrasound localization techniques
o used when a mass is present,
- stereotactic techniques
o used when no mass is present (microcalcifications or architectural distortion only)
- combination of diagnostic mammography, ultrasound or stereotactic localization, and fine-needle
aspiration (FNA) biopsy
o achieves almost 100% accuracy in the preoperative diagnosis of breast cancer
- FNA biopsy
o permits cytologic evaluation
- core-needle
o permits the analysis of breast tissue architecture and allows the pathologist to
determine whether invasive cancer is present
o permits the surgeon and patient to discuss the specific management of a breast cancer
before therapy begins
o preferred over open biopsy for nonpalpable breast lesions because a single
surgical procedure can be planned based on the results of the core biopsy
- advantages of core-needle biopsy
o low complication rate
o minimal scarring
o lower cost compared with excisional breast biopsy.
Palpable Lesions
- FNA or core biopsy of a palpable breast mass can usually be performed in an outpatient setting
- 1.5-in, 22-gauge needle attached to a 10-mL syringe or a 14-gauge core biopsy needle is used
- FNA
o use of a syringe holder enables the surgeon performing the FNA biopsy to control the
syringe and needle with one hand while positioning the breast mass with the opposite
hand
- After the needle is placed in the mass, suction is applied while the needle is moved back and forth
within the mass
- Once cellular material is seen at the hub of the needle, the suction is released and the needle is
with- drawn
- cellular material is then expressed onto microscope slides
- Both air-dried and 95% ethanol–fixed microscopic sections are prepared for analysis
- When a breast mass is clinically and mammographically suspicious, the sensitivity and specificity
of FNA biopsy approaches
- Core-needle biopsy of palpable breast masses
o performed using a 14-gauge needle, such as the Tru-Cut needle
- Automated devices also are available
- Vacuum-assisted core biopsy devices (with 8–10 gauge needles)
o commonly utilized with image guidance where between 4 and 12 samples can be
acquired at different positions within a mass, area of architectural distortion or micro-
calcifications
- If the target lesion was microcalcifications, the specimen should be radiographed to confirm
appropriate sampling
- radiopaque marker
o should be placed at the site of the biopsy to mark the area for future intervention
- In some cases the entire lesion is removed with the biopsy technique and clip placement allows
for accurate targeting of the site for surgical resection
- Tissue specimens are placed in formalin and then processed to paraffin blocks
- Although the false-negative rate for core-needle biopsy specimens is very low, a tissue specimen
that does not show breast cancer cannot conclusively rule out that diagnosis because a sampling
error may have occurred
- The clinical, radiographic, and pathologic findings should be in concordance. If the biopsy findings
do not concur with the clinical and radiographic findings, the multidisciplinary team (including
clinician, radiologist, and pathologist) should review the findings and decide whether or not to
recommend an image-guided or open biopsy to be certain that the target lesion has been
adequately sampled for diagnosis
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
BREAST CANCER STAGING AND BIOMARKERS
Breast Cancer Staging
- determined primarily through physical examination of the skin, breast tissue, and regional lymph
nodes (axillary, supraclavicular, and internal mammary)
- clinical determination of axillary lymph node metastases has an accuracy of only 33%
- Ultrasound (US)
o more sensitive than physical examination alone in determining axillary lymph node
involvement during preliminary staging of breast carcinoma
- FNA or core biopsy of sonographically indeterminate or suspicious lymph nodes
o can provide a more definitive diagnosis than US alone
- Pathologic stage
o Combines the findings from pathologic examination of the resected primary breast
cancer and axillary or other regional lymph nodes
- Fisher and colleagues found that accurate predictions regarding the occurrence of distant
metastases were possible after resection and pathologic analysis of 10 or more levels I and II
axillary lymph nodes
- A frequently used staging system is the TNM (tumor, nodes, and metastasis) system
- The American Joint Committee on Cancer (AJCC) has recently modified the TNM system for
breast cancer to include both anatomic and biologic factors
- Koscielny and colleagues demonstrated that tumor size correlates with the presence of axillary
lymph node metastases
- Others have shown an association between tumor size, axillary lymph node metastases, and
disease-free survival
- One of the most important predictors of 10- and 20-year survival rates in breast cancer
o number of axillary lymph nodes involved with metastatic disease
- Routine biopsy of internal mammary lymph nodes is not generally performed
- however, it has been reported that in the context of a “triple node” biopsy approach either the
internal mammary node or a low axillary node when positive alone carried the same prognostic
weight
- When both nodes were positive
o the prognosis declined to the level associated with apical node positivity
- A double node biopsy of the low axillary node and either the apical or the internal mammary node
gave the same maximum prognostic information as a triple node biopsy
- With the advent of sentinel lymph node dissection and the use of preoperative lymphoscintigraphy
for localization of the sentinel nodes, surgeons have again begun to biopsy the internal mammary
nodes but in a more targeted manner
- The 8th edition of the AJCC staging system does allow for staging based on findings from the
internal mammary sentinel nodes
- Drainage to the internal mammary nodes
o more frequent with central and medial quadrant cancers
- Clinical or pathologic evidence of metastatic spread to supraclavicular lymph nodes is no longer
considered stage IV disease
- routine scalene or supraclavicular lymph node biopsy is not indicated.
BIOMARKERS
- Risk factor biomarkers
o associated with increased cancer risk
§ familial clustering and inherited germline abnormalities
§ proliferative breast disease with atypia
§ mammographic density
- Exposure biomarkers
o a subset of risk factors that include measures of carcinogen exposure such as DNA
adducts
- Surrogate endpoint biomarkers
o biologic alterations in tissue that occur between cancer initiation and development.
o used as endpoints in short- term chemoprevention trials and include histologic
changes, indices of proliferation, and genetic alterations leading to cancer
- Prognostic biomarkers
o provide information regarding cancer outcome irrespective of therapy, whereas
predictive biomarkers provide information regarding response to therapy
- Candidate prognostic and predictive biomarkers and biologic targets for breast cancer
o the steroid hormone receptor pathway
o growth factors and growth factor receptors
19
 § human epidermal growth factor receptor 2 (HER2)/ neu, epidermal growth
factor receptor (EGFR), transforming growth factor, platelet-derived growth
factor, and the insulin- like growth factor family
o indices of proliferation
§ proliferating cell nuclear antigen (PCNA) and Ki-67
o indices of angiogenesis
§ vascular endothelial growth factor (VEGF) and the angiogenesis index
o the mammalian target of rapamycin (mTOR) signaling pathway
o tumor-suppressor genes such as p53
o cell cycle, cyclins, and cyclin-dependent kinases
o proteasome
o COX-2 enzyme
o peroxisome proliferator-activated receptors (PPARs)
o indices of apoptosis and apoptosis modulators such as bcl-2 and the bax:bcl-2 ratio.
Steroid Hormone Receptor Pathway
- Hormones play an important role in the development and progression of breast cancer
- Estrogens, estrogen metabolites, and other steroid hormones such as progesterone
o all have been shown to have an effect
- Breast cancer risk
o related to estrogen exposure over time
- postmenopausal women
o hormone replacement therapy consisting of estrogen plus progesterone increases the
risk of breast cancer by 26% compared to placebo
- Patients with hormone receptor-positive tumors
o survive two to three times longer after a diagnosis of metastatic disease than do
patients with hormone receptor-negative tumors
- Patients with tumors negative for both estrogen receptors and progesterone receptors
o not considered candidates for hormonal therapy
- Tumors positive for estrogen or progesterone receptors
o higher response rate to endocrine therapy than tumors that do not express estro- gen
or progesterone receptors
- determination of estrogen and progesterone receptor status
o used to require biochemical evaluation of fresh tumor tissue
- estrogen and progesterone receptor status
o can be measured in archived tissue using immunohistochemical techniques
- Hormone receptor status
o can be measured in specimens obtained with fine-needle aspiration biopsy or core-
needle biopsy, and this can help guide treatment planning
- Testing for estrogen and progesterone receptors
o should be performed on all primary invasive breast cancer specimens
- Tumor hormone receptor status should be ascertained for both premenopausal and
postmenopausal patients to identify patients who are most likely to benefit from endocrine therapy.
- HER2/ neu
o both an important prognostic factor and a predictive factor in breast cancer
o When overexpressed in breast cancer, it promotes enhanced growth and proliferation,
and increases invasive and metastatic capabilities
- Clinical studies have shown that patients with HER2/neu–overexpressing breast cancer have
poorly differentiated tumors with high prolifera- tion rates, positive lymph nodes, decreased
hormone receptor expression, and an increased risk of recurrence and death due to breast cancer
- Routine testing of the primary tumor specimen for HER2/neu expression should be performed on
all invasive breast cancers
o can be done with immunohis- tochemical analysis to evaluate for overexpression of the
cell- surface receptor at the protein level or by using fluorescence in situ hybridization
to evaluate for gene amplification
- While HER2/ERBB2 activation can also be assessed based on mRNA expression and reverse
transcription polymerase chain reaction (RT-PCR) (Oncotype Dx, Genomic Health), this approach
is not recommended for clinical decision-making because of the high false negative rate
- Patients whose tumors show HER2 amplification or HER2/neu protein overexpression are
candidates for anti-HER2/neu therapy
- Trastuzumab (Herceptin)
o recombinant humanized monoclonal antibody directed against HER2
- Randomized clinical trials have demonstrated that single-agent trastuzumab therapy is well
tolerated and active in the treatment of women with HER2/neu–overexpressing metastatic breast
cancer
- Subsequent adjuvant trials demonstrated that trastuzumab also was highly effective in the
treatment of women with early-stage breast cancer when used in combination with che-
motherapy
- Patients who received trastuzumab in combina- tion with chemotherapy had between a 40% and
50% reduction in the risk of breast cancer recurrence and approximately a one- third reduction in
breast cancer mortality compared with those who received chemotherapy alone

Growth Factor Receptors and Growth Factors

- Overexpression of EGFR in breast cancer
o correlates with estrogen receptor negative status and with p53 overexpression
- increased immunohistochemical membrane staining for the HER2 growth factor receptor in breast
cancer
o associated with mutated TP53, Ki67 overexpression, and estrogen receptor–
negative status
- HER2
o member of the ErbB family of growth factor receptors in which ligand binding results in
receptor homodimerization and tyrosine phosphorylation by tyrosine kinase domains
Indices of Proliferation
within the receptor
- PCNA
- Tyrosine phosphorylation
o a nuclear protein associated with a DNA polymerase whose expression increases in
o followed by signal transduction, which results in changes in cell behavior
phase G1 of the cell cycle, reaches its maximum at the G1/S interface, and then
- important property of this family of receptors is that ligand binding to one receptor type also may
decreases through G2
result in heterodimerization between two different receptor types that are coexpressed
o Immunohistochemical staining outlines the proliferating compartments in breast tissue
o leads to transphosphorylation and transactivation of both receptors in the complex
- Good correlation is noted between PCNA expression and
(transmodulation)
o cell-cycle distributions seen on flow cytometry based on DNA content
- In this context, the lack of a specific ligand for the HER2/neu receptor suggests that HER2/neu
o uptake of bromodeoxyuridine and the proliferation-associated Ki67 antigen
may function solely as a co-receptor, modulating signaling by other EGFR family members
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 20
 - Individual proliferation markers are associated with slightly different phases of the cell cycle and
are not equivalent
- PCNA and Ki67 expression are positively correlated with p53 overexpression, high S-phase
fraction, aneuploidy, high mitotic index, and high histologic grade in human breast cancer
specimens, and are negatively correlated with estrogen receptor content
- Ki67
o was included with three other widely measured breast cancer markers (ER, PR, and
HER2) into a panel of four immunohistochemical makers (IHC4), which together
provided similar prognostic information to that in the 21 Gene Recurrence Score
- While there has been significant interest in using Ki67 as biomarker and while IHC4 panel would
be much less expensive than the 21 Gene Recurrence Score, there remain issues regarding
reproducibility across laboratories.
Indices of Angiogenesis
Angiogenesis
- necessary for the growth and invasiveness of breast cancer and promotes cancer progression
through several different mechanisms, including delivery of oxygen and nutrients and the secretion
of growth- promoting cytokines by endothelial cells
- VEGF
o induces its effect by binding to transmembrane tyrosine kinase receptors
- Overexpression of VEGF in invasive breast cancer
o correlated with increased microvessel density and recurrence in node-negative breast
cancer
- An angiogenesis index has been developed in which microvessel density (CD31 expression) is
combined with expression of thrombospondin (a negative modulator of angiogenesis) and
p53 expression
- Both VEGF expression and the angiogenesis index
o may have prognostic and predictive significance in breast cancer
- Bevacizumab (a monoclonal antibody to VEGF)
o approved by the FDA for use in metastatic breast cancer in combination with pacli-
taxel chemotherapy
o This approval was based on results from a phase 3 trial by the Eastern Cooperative
Oncology Group. The group’s E2100 trial showed that when bevacizumab was added
to paclitaxel chemotherapy, median progression-free survival increased to 11.3 months
from the 5.8 months seen in patients who received paclitaxel alone
o The results were not repro- duced in other trials, and the indication for the drug was
revoked by the FDA in 2011.
Indices of Apoptosis
- Alterations in programmed cell death (apoptosis)
o may be triggered by p53-dependent or p53-independent factors
o may be important prognostic and predictive biomarkers in breast cancer
- Bcl-2 family proteins
o appear to regulate a step in the evolutionarily conserved pathway for apoptosis, with
some members functioning as inhibitors of apoptosis and others as promoters of
apoptosi
- Bcl-2
o only oncogene that acts by inhibiting apoptosis rather than by directly increasing
cellular proliferation
- bax
o death-signal protein
o induced by genotoxic stress and growth factor deprivation in the presence of wild-type
(normal) p53 and/or AP-1/fos
- The bax to bcl-2 ratio and the resulting formation of either bax- baxhomodimers, which stimulate
apoptosis, or bax–bcl-2 het- erodimers, which inhibit apoptosis
o represent an intracellular regulatory mechanism with prognostic and predictive implica-
tions
- In breast cancer, overexpression of bcl-2 and a decrease in the bax to bcl-2 ratio
o correlate with high histologic grade, the presence of axillary lymph node metastases,
and reduced disease-free and overall survival rates
- decreased bax expression
o correlates with axillary lymph node metastases
o poor response to chemotherapy
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
o decreased overall survival.
- The remaining biomarkers and biologic targets listed earlier are still in preclinical testing, and
clinical trials are evaluating their importance in breast cancer for both prognostic and predictive
purposes
Coexpression of Biomarkers
- Selection of optimal therapy for breast cancer requires both an accurate assessment of prog- nosis
and an accurate prediction of response to therapy
- breast cancer markers that are most important in determining therapy
o estrogen receptor
o progesterone receptor
o HER2/ neu
- Clinicians evaluate clinical and pathologic staging and the expression of estrogen receptor,
progesterone receptor, and HER2/neu in the primary tumor to assess prognosis and assign
therapy
- Adjuvant! Online (http://www.adjuvantonline.com) is one of a number of programs available to
clinicians that incor- porates clinical and pathologic factors for an individual patient and calculates
risk of recurrence and death due to breast cancer and then provides an assessment of the
reduction in risk of recurrence that would be expected with the use of combination chemotherapy,
endocrine therapy, or both of these
- Adjuvant! Online was developed using information from the SEER data- base, the EBCTCG
overview analyses, and results from other individual published trials.198 The website is updated
and modi- fied as new information becomes available. Clinicopathologic factors are used to
separate breast cancer patients into broad prognostic groups, and treatment decisions are made
on this basis (Table 17-12)
- Other indices and programs that are validated and used include the Nottingham Prognostic Index,
and PREDICT.199-201 When an approach, which combines prognostic factors is used, up to 70%
of early breast cancer patients receive adjuvant chemotherapy that is either unnecessary or
ineffective.
- a wide variety of biomarkers have been shown to individually predict prognosis and response to
therapy, but they do not improve the accuracy of either the assessment of prognosis or the
prediction of response to therapy.
- As knowledge regarding cellular, biochemical, and molec- ular biomarkers for breast cancer have
improved, prognostic indices have been developed that combine the predictive power of several
individual biomarkers with the relevant clinicopatho- logic factors.
- Recent technological advances have enabled implemen- tation of high throughput gene expression
assays in clinical practice
- These assays enable detailed stratification of breast cancer patients for assessment of prognosis
and for prediction of response to therapy
- Oncotype DX
o a 21-gene RT-PCR–based assay that has been approved for use in newly diagnosed
patients with node-negative, ER-positive breast cancer
- A recurrence score is generated, and those patients with high recurrence scores are likely to
benefit from chemotherapy, whereas those with low recurrence scores benefit most from endocrine
therapy and may not require chemotherapy
- Results from the Trial Assessing Individualized Options for Treatment for breast cancer
(TAILORx), designed to prospectively validate the use of 21-gene expression assay, have shown
that patients with low recurrence score (0 to 10) have a low rate of local-regional and distant
recurrence (98.7%) and very good overall survival at 5 years (98%) with endocrine therapy alone
without chemotherapy
- This study has randomly assigned patients with an intermediate recurrence score (11 to 25) to
endocrine therapy alone or to chemotherapy followed by endocrine therapy.
- retrospective analysis has shown
o the 21-gene recurrence score can be used in postmenopausal patients with ER-
positive tumors and 1 to 3 involved axillary lymph nodes to predict the benefit of
chemotherapy in addition to endocrine therapy
- Knowledge of the recurrence score
o has been shown to alter treatment recommendations by oncologists, and patients
likewise change their decision to undergo treatment based on the risk of recurrence
- The MammaPrint assay uses a 70-gene expression profile to assess the risk of distant metas-
tasis. Mammaprint is FDA approved for use in stage-1 or stage- 2, node negative, ER-positive or
ER-negative breast cancers to identify patients with high or low risk of recurrence. Although fresh
21
 tissue was initially required to perform the assay, it has since been adapted for use in paraffin-
embedded tissue samples
- The prospective RASTER study reported that patients classified as low risk based on MammaPrint
had a 97% distant recurrence-free interval at five years
- Results of the prospective MINDACT (MicroarrayInNode negative and 1–3 positive lymph node
Disease may Avoid ChemoTherapy) trial were recently reported
- The study was designed to assess whether the 70-gene expression assay would help avoid
chemotherapy in patients who are considered clinically high risk but categorized as low genomic
risk based on the assay
- A 5-year rate of distant metastasis-free survival of more than 92% was identified as the cutoff for
the benefit of chemotherapy
- At 5 years, the rate of survival without distant metastasis in patients with high clinical risk and low
genomic risk was 94.7%, meeting the criteria for noninferiority
- However, the rate of disease-free survival and overall survival was higher with chemotherapy in
the intention to treat population.
OVERVIEW OF BREAST CANCER THERAPY
- Before diagnostic biopsy, the surgeon must consider the possibility that a suspicious mass or
mammographic finding may be a breast cancer
- Once a diagnosis of breast cancer is made
o the type of therapy offered to a breast cancer patient is determined by the stage of the
disease, the biologic subtype, and the general health status of the individual.
Laboratory tests and imaging studies are performed based on the initial stage (table
17-13)
- Before therapy is initiated, the patient and the surgeon must share a clear perspective on the
planned course of treatment. Before initiating local therapy, the surgeon should determine the
clinical stage, histologic characteristics, and appropriate biomarker levels.
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
In Situ Breast Cancer (Stage 0)
- Both LCIS and DCIS may be difficult to distinguish from atypical hyperplasia or from cancers with
early invasion
- Expert pathologic review
o required in all cases.
- Bilateral mammography
o performed to determine the extent of the in situ cancer and to exclude a second cancer
- LCIS
o considered a marker for increased risk rather than an inevitable precursor of invasive
disease
o current treatment options
§ observation
§ chemoprevention
§ bilateral total mastectomy
- The goal of treatment
o prevent or detect at an early stage the invasive cancer that subsequently develops in
25% to 35% of these women
- There is no benefit to excising LCIS because the disease diffusely involves both breasts in many
cases and the risk of developing invasive cancer is equal for both breasts
- use of tamoxifen as a risk-reduction strategy
o should be considered in women with a diagnosis of LCIS.
- Women with DCIS and evidence of extensive disease (>4 cm of disease or disease in more
than one quadrant)
o usually require mastectomy
- women with limited disease
o lumpectomy and radiation therapy are generally recommended
- nonpalpable DCIS
o needle localization or other image-guided techniques are used to guide the surgical
resection
- Specimen mammography
o performed to ensure that all visible evidence of cancer is excised
- Adjuvant tamoxifen therapy
o considered for DCIS patients with ER-positive disease
- gold standard against which breast conservation therapy for DCIS iis mastectomy
- Women treated with mastectomy have local recurrence and mortality rates of <2%
- There is no randomized trial comparing mastectomy vs. breast conserving surgery, and none of
the randomized trials of breast-conserving surgery with or without radiotherapy for DCIS were
powered to show a difference in mortality
- Women treated with lumpectomy and adjuvant radiation therapy in the initial clinical trials
o were noted to have a local recurrence rate that is increased compared to mastectomy.
o About 45% of these recurrences will be invasive cancer when radiation therapy is not
used
- The B-17 trial was conducted by the NSABP to assess the need for radiation in patients treated
with breast conserving surgery for DCIS. Patients were randomly assigned to lumpectomy with
radiation or lumpectomy alone, and after a mean follow-up time of 90 months rates of both
ipsilateral noninvasive and invasive recurrences were significantly lower in patients who received
radiation. However, in the B-17 trial the margins were not prospectively assessed, and it is
estimated that up to half of the patients may have had tumor at the margin of resection
- The benefit of the addition of radiation over breast-conserving surgery alone for DCIS has also
been demonstrated in several other randomized trials where margins were prospectively assessed
including the European Organization for Research and Treatment of Cancer (EORTC) protocol
10853; the United Kingdom, Australia, New Zealand DCIS Trial; and the Swedish Trial
- In 2016, the Society of Surgical Oncology (SSO), American Society for Radiation Oncol- ogy
(ASTRO), and the American Society of Clinical Oncology (ASCO) established consensus
guidelines on margins for patients with DCIS undergoing breast-conserving surgery
- Based on a multidisciplinary consensus panel using a meta-analysis of margin width and ipsilateral
breast tumor recurrence, a 2-mm margin was determined as adequate width for DCIS for patients
undergoing breast-conserving surgery with whole-breast radiation therapy
- Despite the data from randomized trials showing a benefit in all patient subgroups with the addition
of radiation in DCIS, there has been an interest in trying to define a subset where radiation could
be avoided in order to minimize the cost and inconvenience associated with radiation
- In addition, there have been several studies published where patients were treated with excision
alone and never developed invasive breast cancer even at 25 years of follow-up
22
 - Silverstein and colleagues were proponents of avoiding radiation therapy in selected patients - For these patients, tamoxifen could be viewed as treating what, by the current standard, would be
with DCIS who have widely negative margins after surgery They reported that when greater than viewed as inadequate local excision of the primary tumor.
10-mm margins were achieved, there was no additional benefit from radiation therapy. When
margins were between 1 and 10 mm, there was a relative risk of local recurrence of 1.49,
compared to 2.54 for those with margins less than 1 mm. These data suggested that appropriately
selected patients with DCIS might not require postoperative radiation therapy.
- The Eastern Cooperative Oncology Group (ECOG) initiated a prospective registry trial (ECOG
5194) to identify those patients who could safely undergo breast-conserving surgery without
radiation
- Eligible patients
o those with low or intermediate grade DCIS measuring 2.5 cm or less who had negative
margins of at least 3 mm and those with high-grade DCIS who had tumors measuring 1
cm or less with a negative margin of at least 3 mm
- At a median follow-up of 6.2 years, patients with low or intermediate grade DCIS had an in-breast
recurrence rate of 6.1% while those with high-grade DCIS had a recurrence rate of 15.3%.
Approximately 4% of patients developed a contralateral breast cancer during follow-up in both the
low/intermediate and high-grade groups. This study identi- fied an acceptable recurrence rate for
those patients with low or intermediate grade DCIS treated with excision alone with a margin of at
least 3 mm. In contrast, patients with high-grade DCIS had an unacceptably high local recurrence
rate.
- The Radiation Therapy Oncology Group (RTOG) initiated the 9804 trial for patients with “good
risk” DCIS and randomized them to lumpectomy vs. lumpectomy with whole breast irradiation
- Eligible patients
o were those with unicentric, low or intermediate grade DCIS measuring 2.5 cm or less
with a margin of 3 mm or greater
- The trial was closed early due to slow accrual; however, the results for 585 patients were recently
reported with a median follow-up of 6.46 years.223,224 The local recurrence rate at 5 years was
0.4% for patients ran- domized to receive radiation and 3.2% for those who did not receive
radiation.
- Solin et al utilized samples from the ECOG 5194 trial to develop a quantitative multigene RT-PCR
assay for predict- ing recurrence risk in patients with DCIS treated with surgery alone\
- They were able to define low, intermediate, and high risk groups using a DCIS Score
- The DCIS Score was able to quantify the risk of recurrence in the breast for both DCIS and
invasive events. This tool has recently been evaluated in another dataset and appears to be a
promising tool for clinical use
- When selecting therapy for patients with DCIS, one must consider clinical and pathologic factors,
including tumor size, grade, mammographic appearance, and patient preference
- There is no single correct surgical treatment, and many patients will require extensive
counseling in order to make a decision regarding surgical therapy
- role of axillary staging in patients with DCIS is limited
o One consideration is for patients undergoing mastectomy
o Since most lesions are currently diagnosed with needle core biopsy, there is about a
20% incidence of invasive breast cancer on final pathologic assessment of the primary
tumor. Since it is not feasible to perform sentinel node dissection after mastectomy,
most surgeons will recommend the use of sentinel node dissection at the time of
mastectomy for DCIS.
- Results from the NSABP B-24 trial reported a significant reduction in local recurrence after 5
years of tamoxifen in women with ER-positive DCIS. Based on this finding, some guidelines have
advocated that all patients (women with ER- positive DCIS without contraindications to tamoxifen
therapy) should be offered tamoxifen following surgery and radiation therapy for a duration of 5
years
o revealed a significant reduction in recurrence with adjuvant tamoxifen therapy for
patients with DCIS; however, the results were not initially assessed based on ER
status.226 There were 1804 women with DCIS randomized to lumpectomy and
radiation with or without tamoxifen. The rate of breast cancer events was significantly
lower in those who received tamoxifen at a median follow-up of 74 months (8.2% vs.
13.4%, P = 0.0009)
- Subsequently, Allred and colleagues evaluated 41% of patients with DCIS in the NSABP B-24
trial to determine the effect of tamoxifen based on ER status measured in the primary tumor.203
They found that 76% of women had DCIS that was ER-positive and these women had a greater
reduction in ipsilateral breast tumor recurrence with tamoxifen than did patients with ER-negative
DCIS (11% vs. 5.2%, P <0.001). However, it should be noted that 15% of patients in B-24 had
tumor at the resection margins
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 23
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 24
Early invasive breast cancer (stage I, IIA, or IIB)
- There have been six prospective randomized trials comparing breast-conserving surgery to
mastectomy in early stage breast cancer, and all have shown equivalent survival rates regardless of
the surgical treatment type.
- NSABP B-06, which is the largest of all the breast conservation trials, compared total mastectomy
to lumpectomy with or without radiation therapy in the treatment of women with stages I and II breast
cancer.
o the disease-free (DFS), distant disease-free, and overall survival (OS) rates for
lumpectomy with or without radiation therapy were similar to those observed after total
mastectomy.
o However, the incidence of ipsilateral breast cancer recurrence was higher in the group
not receiving radiation therapy.
- These findings supported the use of lumpectomy and radiation therapy in the treatment of stages
I and II breast cancer and this has since become the preferred method of treatment for women
with early stage breast cancer who have uni-focal disease and who are not known BRCA
mutation carriers.
- The in-breast recurrence rate was substantially higher in the lumpectomy alone group (39.2%)
compared with the lumpectomy plus adjuvant radiation therapy group (14.3%)
o confirming the importance of radiation therapy in the management of patients with
invasive disease.
- At 15 years of follow-up, the absolute reduction in mortality with the use of radiation therapy after
lumpectomy was 5.1% in node-negative patients and 7.1% in node-positive patients. These data
support the concept that radiation has an impact on survival.
- Accelerated partial breast irradiation (APBI) is also an option for carefully selected patients with
DCIS and early-stage breast cancer.
o Since the majority of recurrences after breast conservation occur in or adjacent to the
tumor bed, there has been interest in limiting the radiation to the area of the primary
tumor bed with a margin of normal tissue.
o APBI is delivered in an abbreviated fashion (twice daily for 5 days) and at a lower total
dose compared with the standard course of 5 to 6 weeks of radiation (50 Gy with or
without a boost) in the case of whole breast irradiation.
o Proponents have suggested that this shortened course of treatment may increase the
feasibility of breast conservation for some women and may improve radiation therapy
compliance.
- Currently, mastectomy with axillary staging and breast conserving surgery with axillary
staging and radiation therapy are considered equivalent treatments for patients with stages
I and II breast cancer.
- Breast conservation is considered for all patients because of the important cosmetic advantages
and equivalent survival outcomes
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
o however, this approach is not advised in women who are known BRCA mutation
carriers due to the high lifetime risk for development of additional breast cancers.
- Relative contraindications to breast conservation therapy include
o (a) prior radiation therapy to the breast or chest wall
o (b) persistently positive surgical margins after reexcision
o (c) multicentric disease
o (d) scleroderma or lupus erythematosus.
- For most patients with early-stage disease, reconstruction can be performed immediately at the
time of mastectomy.
o Immediate reconstruction allows for skin-sparing, thus optimizing cosmetic outcomes.
o Skin-sparing mastectomy with immediate reconstruction has been popularized over
the past decade as reports of low local-regional failure rates have been reported and
reconstructive techniques have advanced.
o There is a growing interest in the use of nipple-areolar sparing mastectomy with
reports suggesting the oncologic safety of this approach in early stage breast cancer.
§ Patients who are planned for postmastectomy radiation therapy may not be
ideal candidates for nipple-sparing mastectomy because of the effects of
radiation on the preserved nipple.
o reconstruction allows patients to wake up with a breast mound, which provides some
psychological benefit for the patient.
o It is also more economical as both the extirpative and reconstructive surgery are
combined in one operation.
- Immediate reconstruction can be performed using implants or autologous tissue
o flaps commonly used include the transverse rectus abdominis myocutaneous flap, deep
inferior epigastric perforator flap, and latissimus dorsi flap (with or without an implant).
- If postmastectomy radiation therapy is needed, a tissue expander can be placed at the time of
mastectomy to save the shape of the breast and reduce the amount of skin replacement needed at
the time of definitive reconstruction.
o The expander can be deflated at the initiation of radiation therapy to allow for irradiation
of the chest wall and regional nodal basins.
o Removal of the tissue expander and definitive reconstruction, usually with autologous
tissue, can proceed 6 months to 1 year after completion of radiation therapy.
- Axillary lymph node status has traditionally been an important determinant in staging and
prognosis for women with early stage breast cancer.
o Historically, axillary lymph node dissection (ALND) was utilized for axillary staging and
regional control by removing involved lymph nodes.
o Randomized trials evaluating immediate ALND over ALND performed in a delayed
fashion once clinically palpable axillary disease became evident have not shown any
detriment in survival.
o it became clear that routine use of ALND for axillary staging was not necessary in up to
75% percent of women with operable breast cancer presenting with a negative axilla at
the time of screening.
- Lymphatic mapping and sentinel lymph node (SLN) dissection were initially developed for
assessment of patients with clinically node-negative melanoma.
o Given the changing landscape of newly diagnosed breast cancer patients with a clinically
node-negative axilla, surgeons quickly began to explore the utility of SLN dissection as
a replacement for ALND in axillary staging.
o In the early 1990s, David Krag at the University of Vermont began performing SLN
dissection with injection of a radioisotope in the primary tumor site and localizing the SLN
node with a handheld gamma probe.
o These studies along with initial work by Doug Reintgen and Charles Cox at the Moffitt
Cancer Center and Umberto Veronesi and his colleagues at the European Institute of
Oncology in Milan led the way toward validation of the technique in large single institution
and multicenter studies.
o The incidence of lymphedema and sensory loss for the SLN group was significantly lower
than with the standard axillary treatment.
o At 12 months, drain usage, length of hospital stay, and time to resumption of normal day-
to-day activities after surgery were also statistically significantly lower in the SLN group.
o NSABP B-32 trial - patients who had SLN dissection alone were found to have decreased
morbidity (arm swelling and range of motion) and improved quality of life vs. patients who
underwent ALND.
- Z0010 and Z0011 trials by the American College of Surgeons Oncology Group (ACOSOG)
25
 o To evaluate the incidence and prognostic significance of occult metastases identified in
the bone marrow and SLNs (Z0010) of early-stage clinically node-negative patients and
to evaluate the utility of ALND in patients with clinical T1-2, N0 breast cancer with 1 or 2
positive SLNs for patients treated with breast-conserving surgery and whole breast
irradiation (WBI)
o Although the presence of disease in the bone marrow identified a population at high risk
for recurrence, neither immunohistochemical detection of disease in the SLNs or the
bone marrow was statistically significant on multivariable analysis with clinicopathologic
and treatment factors included.
o The investigators concluded that routine use of immunohistochemistry to detect occult
disease in SLNs is not warranted.
- The morbidity of SLN dissection alone vs. SLN dissection with completion ALND has been reported
by the ACOSOG investigators.
o Immediate effects of SLN dissection in the Z0010 trial included:
§ wound infection in 1%
§ axillary seroma in 7.1%
§ axillary hematoma in 1.4%.
o At 6 months following surgery,
§ axillary paresthesias were noted in 8.6% of patients
§ decreased range of motion in the upper extremity was reported in 3.8%
§ 6.9% of patients had a change in the arm circumference of >2 cm on the
ipsilateral side, which was reported as lymphedema.
o Younger patients were more likely to report paresthesias, whereas increasing age and
body mass index were more predictive of lymphedema.
o When adverse surgical effects were examined in the Z0011 trial, patients undergoing
SLN dissection with ALND had more wound infections, seromas, and paresthesias than
those women undergoing SLN dissection alone.
o Lymphedema at 1 year after surgery was reported by 13% in the SLN plus ALND group
but only 2% in the SLN dissection alone group.
o Arm circumference measurements were greater at 1 year in patients undergoing SLN
dissection plus ALND, but the difference between study groups was not statistically
significant. 252 This supports the results published from the ALMANAC trial.
- Prior to the publication of ACOSOG Z0011, completion ALND was standard of care for patients with
positive SLNs.
o Since the reporting of ACOSOG Z0011, the National Comprehensive Cancer Network
(NCCN) guidelines now state that there was no OS difference for patients with 1 or 2
positive SLNs treated with breast-conserving surgery who underwent completion ALND
vs. those who had no further axillary surgery.
o In addition, the American Society of Breast Surgeons issued a consensus statement
supporting omission of ALND for patients who meet Z0011 criteria
o The results of ACOSOG Z0011 have revolutionized management of the axilla and
changed practice such that selected patients with axillary metastasis can now avoid
ALND if they have clinical and pathologic features similar to those patients enrolled on
Z0011.
- The International Breast Cancer Study Group (IBCSG) 23-01 trial was similar in design to Z0011
but enrolled only patients with micrometastases in the SLNs.
o The investigators published the primary and secondary endpoints of the trial showing no
differences in OS or local-regional recurrencet between the study arms.
- Most pathology laboratories perform a more detailed analysis of the SLN than is routinely done for
axillary nodes recovered from a levels I and II dissection.
o This can include examining thin sections of the node with step sectioning at multiple
levels through the paraffin blocks or performing immunohistochemical staining of the
SLN for cytokeratin or a combination of these techniques.
o The results of ACOSOG Z0010 and NSABP B-32 showed no clinically meaningful
difference in survival based on detection of occult metastases in the SLNs using
immunohistochemical staining and do not support the routine use in SLN processing.
- The GeneSearch Breast Lymph Node Assay
o is a real-time reverse-transcriptase polymerase chain reaction assay that detects breast
tumor cell metastasis in lymph nodes through the identification of the gene expression
markers mammaglobin and cytokeratin 19.
o These markers are present in higher levels in breast tissue and not in nodal tissue (cell
type-specific messenger RNA).
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
o The GeneSearch breast lymph node assay generates expression data for genes of
interest, which are then evaluated against predetermined criteria to provide a qualitative
(positive/negative) result.
o The assay is designed to detect foci that correspond to metastases that are seen with
examination by standard hematoxylin and eosin staining and measure >0.2 mm.
o With the findings of ACOSOG Z0011 that there is not a survival benefit to the use of
ALND in selected patients, many surgeons have abandoned the intraoperative
evaluation of SLNs.
- There are a number of nomograms and predictive models designed to determine which patients with
a positive SLN are at risk for harboring additional positive non-SLNs in the axilla. These tools can
be helpful in determining the likelihood of additional disease in the axilla and may be used clinically
to counsel patients.
- In patients who present with axillary lymphadenopathy that is confirmed to be metastatic disease on
FNA or core biopsy, SLN dissection is not necessary, and patients can proceed directly to ALND or
be considered for preoperative systemic therapy
o The American Society of Clinical Oncology has included SLN dissection is its guidelines
as appropriate for axillary staging in these patients.
- If an SLN cannot be identified, then ALND is generally performed for appropriate staging.
o However, this is not universally accepted, and there are as yet no randomized studies
yet.
- The ASCO guidelines suggest that adjuvant chemotherapy should be considered for patients with:
o positive lymph nodes, ER-negative disease, HER2-positive disease, Adjuvant! Online
mortality greater than 10%, grade 3 node-negative tumors >5 mm, triple-negative
tumors, lymphovascular invasion, or estimated distant relapse risk of greater than 15%
at 10 years based on the 21 gene recurrence score assay.
- Adjuvant endocrine therapy is considered for women with hormone receptor-positive cancers, and
an aromatase inhibitor is recommended if the patient is postmenopausal.
o HER2/ neu status is determined for all patients with newly diagnosed invasive breast
cancer and when positive, should be used to guide systemic therapy recommendations.
o The FDA approved trastuzumab in November 2006 for use as part of a treatment
regimen containing doxorubicin, cyclophosphamide, and paclitaxel for treatment of
HER2/neu-positive, node-positive breast cancer.
o Subsequently, the BCIRG 006 study reported that giving trastuzumab concurrently with
docetaxel and carboplatin appeared as effective as giving trastuzumab following an
anthracycline containing regimen.
o In addition to trastuzumab, pertuzumab has also recently been FDA approved for
adjuvant use in patients with HER2 amplified breast cancers with high risk of recurrence.
Advanced Local-Regional Breast Cancer (Stage IIIA or IIIB)
- Women with stage IIIA and IIIB breast cancer have advanced local-regional breast cancer but
have no clinically detected distant metastases
- In an effort to provide optimal local-regional disease-free survival as well as distant disease-free
survival for these women, surgery is integrated with radiation therapy and chemotherapy.
- However, it should be noted that these patients have an increased risk of distant metastasis that
is often highlighted by radiological evidence when staging PET or CT and bone scans are performed.
o Thus, local treatment alone is not appropriate for patients with locally advanced
disease.
- Preoperative (also known as neoadjuvant) chemotherapy should be considered in the initial
management of patients with locally advanced stage III breast cancer,
o especially those with estrogen receptor negative tumors.
o Chenitherapy is used to maximize distant disease-free survival,
o whereas radiation therapy is used to maximize local-regional control and disease-free
survival.
o In selected patients with stage IIIA cancer, preoperative chemotherapy can reduce the
size of the primary cancer and permit breast-conserving surgery.
- Investigators from the MD Anderson Cancer Center
o They noted that the ipsilateral breast tumor recurrence rates increased when patients
had clinical N2 or N3 disease, >2 cm of residual disease in the breast at surgery, a
pattern of multifocal residual disease in the breast at surgery, and lymphovascular space
invasion in the primary tumor.
o This study demonstrated that breast-conserving surgery can be used for appropriately
selected patients with locally advanced breast cancer who achieve a good response with
preoperative chemotherapy.
26
 o However, the Oxford overview of all randomized studies of neoadjuvant therapy (vs.
adjuvant therapy) reported a hazard ratio of 1.5 (i.e., 50% increase) in local recurrence
rates.
- In both stages IIIA and IIIB disease, surgery is followed by adjuvant radiation therapy. However
there is a small percentage of patients who experience progression of disease during neoadjuvant
therapy, and therefore the surgeon should review patients with the oncologist at regular points during
the neoadjuvant regimen.
- For selected clinically indolent, ER-positive, locally advanced tumors, primary endocrine therapy
may be considered, especially if the patient has other comorbid conditions.
o Results from the ACOSOG Z1031 trial suggest that neoadjuvant endocrine therapy is a
good option for tumor downstaging in patients with strongly ER-positive tumors.
- The preoperative endocrine prognostic index (PEPI score) can be calculated based on
pathologic findings from surgery following neoadjuvant endocrine therapy.
o This can help guide decision-making regarding the need for systemic chemotherapy in
this patient population.
o from 18 SEER geographic areas was 89.2%.
Internal mammary lymph nodes
- Metastatic disease to internal mammary lymph nodes may be occult, may be evident on chest
radiograph or CT scan, or may present as a painless parasternal mass with or without skin
involvement.
- There is no consensus regarding the need for internal mammary lymph node radiation therapy in
women who are at increased risk for occult involvement (cancers involving the medial aspect of the
breast, axillary lymph node involvement) but who show no signs of internal mammary lymph node
involvement.
- Systemic chemotherapy and radiation therapy are indicated in the treatment of grossly involved
internal mammary lymph nodes.
Distant Metastases (Stage IV)
- Treatment for stage IV breast cancer is not curative but may prolong survival and enhance a
woman’s quality of life.
- Endocrine therapies that are associated with minimal toxicity are preferred to cytotoxic
chemotherapy in ER-positive disease.
o Appropriate candidates for initial endocrine therapy include women with hormone
receptor-positive cancers who do not have immediately life threatening disease
(or “visceral crisis”).
o This includes not only women with bone or soft tissue metastases but also women with
limited visceral metastases.
- Symptoms per se (e.g., breathlessness) are not in themselves an indication for chemotherapy.
o For example, breathlessness due to a pleural effusion can be treated with percutaneous
drainage, and if the breathlessness is relieved, the patient should be commenced on
endocrine therapy
o if the breathlessness is due to lymphangitic spread, then chemotherapy would be the
treatment of choice.
- Systemic chemotherapy is indicated for women with hormone receptor-negative cancers, “visceral
crisis,” and hormone-refractory metastases.
- Women with stage IV breast cancer may develop anatomically localized problems that will benefit
from individualized surgical or radiation treatment, such as brain metastases, pleural effusion,
pericardial effusion, biliary obstruction, ureteral obstruction, impending or existing pathologic fracture
of a long bone, spinal cord compression, and painful bone or soft tissue metastases.
- Bisphosphonates or antiRANKL (receptor activator of nuclear factor kappa-B ligand) agent,
denosumab, which may be given in addition to chemotherapy or endocrine therapy, should be
considered in women with bone metastases.
- Whether to perform surgical resection of the local-regional disease in women with stage IV breast
cancer has been debated after several reports have suggested that women who undergo resection
of the primary tumor have improved survival over those who do not.
o The surgical management of patients with stage IV disease should be addressed by
obtaining multidisciplinary input and by considering the treatment goals of each individual
patient and the patient’s treating physicians.
Local-Regional Recurrence
- Women with local-regional recurrence of breast cancer may be separated into two groups:
o those who have had mastectomy and
o those who have had lumpectomy.
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
- Women treated previously with mastectomy undergo surgical resection of the local-regional
recurrence and appropriate reconstruction.
- Chemotherapy and antiestrogen therapy are considered, and adjuvant radiation therapy is given
if the chest wall has not previously received radiation therapy or if the radiation oncologist feels that
given the time from previous treatment there is scope for further radiation therapy, particularly if this
is palliative.
- Women treated previously with a breast-conservation procedure undergo a mastectomy and
appropriate reconstruction.
- Chemotherapy and antiestrogen therapy are considered depending of the hormone receptor status
and HER2 status of the tumor.
Breast Cancer prognosis
- Survival rates for women diagnosed with breast cancer in the United States can be obtained from
the SEER Program of the National Cancer Institute.
- The overall 5-year relative survival for breast cancer patients from the time period of 2003 to 2009
- The 5-year relative survival by race was reported to be 90.4% for white women and 78.7% for black
women.
- The 5-year survival rate for patients with localized disease (61% of patients) is 98.6%; for patients
with regional disease (32% of patients), 84.4%; and for patients with distant metastatic disease (5%
of patients), 24.3%.
- Breast cancer survival has significantly increased over the past two decades due to improvements
in screening and local and systemic therapies.
SURGICAL TECHNIQUES IN BREAST CANCER THERAPY
1. Excisional Biopsy With Needle Localization
- Excisional biopsy implies complete removal of a breast lesion with a margin of normal-appearing
breast tissue.
- In the past, surgeons would obtain prior consent from the patient, allowing mastectomy if the initial
biopsy results confirmed cancer.
- Today it is important to consider the options for local therapy (lumpectomy vs. mastectomy with or
without reconstruction) and the need for nodal assessment with SLN dissection.
- Needle-core biopsy is the preferred diagnostic method
o excisional biopsy should be reserved for those cases in which the needle biopsy
results are discordant with the imaging findings or clinical examination.
- In general, circumareolar incisions can be used to access lesions that are subareolar or within a
short distance of the nipple-areolar complex.
- Elsewhere in the breast, incisions can be placed along the lines of tension in the skin that are
generally concentric with the nipple-areola complex.
- In the lower half of the breast, the use of radial incisions typically the best outcome.
- When the tumor is quite distant from the central breast, the biopsy incision can be excised
separately from the primary mastectomy incision, should a mastectomy be required.
- Radial incisions in the upper half of the breast are not recommended because of possible scar
contracture resulting in displacement of the ipsilateral nipple-areola complex.
o Similarly, curvilinear incisions in the lower half of the breast may displace the nipple-
areolar complex downward.
- After excision of a suspicious breast lesion, the specimen should be X-rayed to confirm that the
lesion has been excised with appropriate margins.
- The biopsy tissue specimen is orientated for the pathologist using sutures, clips, or dyes. Additional
margins (superior, inferior, medial, lateral, superficial, and deep) may be taken from the surgical bed
if the specimen X-ray shows the lesion is close to one or more margins.
- Some surgeons also take additional shavings from the margins as one approach to confirm complete
excision of the suspicious lesion.
- Electrocautery or absorbable ligatures are used to achieve wound hemostasis. Cosmesis may be
facilitated by approximation of the surgical defect using 3-0 absorbable sutures. A running
subcuticular closure of the skin using 4-0 or 5-0 absorbable monofilament sutures is performed.
Wound drainage is usually not required.
- Excisional biopsy with needle or seed localization requires a preoperative visit to the mammography
suite for placement of a localization wire or a radioactive or magnetic seed that can be detected
intraoperatively with a handheld probe.
- The lesion can also be targeted by sonography in the imaging suite or in the operating room. The
lesion to be excised is accurately localized by mammography, and the tip of a thin wire hook or a
seed is positioned close to the lesion.
27
 o Using the wire hook as a guide, or detection of the seed with a handheld probe, the
surgeon subsequently excises the suspicious breast lesion while removing a margin of
normal-appearing breast tissue. Before the patient leaves the operating room, specimen
radiography is performed to confirm complete excision of the suspicious lesion
2. Sentinel lymph node dissection
- Sentinel lymph node (SLN) dissection is primarily used to assess the regional lymph nodes in
women with early breast cancers who are clinically node-negative by physical examination and
imaging studies.
- This method also is accurate in women with larger tumors, but nearly 75% of these women will prove
to have axillary lymph node metastases on histologic examination, and wherever possible it is better
to identify them preoperatively as this will allow a definitive procedure for known axillary disease.
- SLN dissection has also been reported to be accurate for staging of the axilla after chemotherapy in
women with clinically node-negative disease at initial presentation.
- Clinical situations where SLN dissection is not recommended include patients with:
o inflammatory breast cancers
o those with biopsy proven metastasis
o DCIS without mastectomy
o prior axillary surgery.
- Although limited data are available, SLN dissection appears to be safe in pregnancy when
performed with radioisotope alone.
- Evidence from large prospective studies suggests that the combination of intraoperative gamma
probe detection of radioactive colloid and intraoperative visualization of blue dye (isosulfan blue dye
or methylene blue) is more accurate for identification of SLNs than the use of either agent alone.
o Some surgeons use preoperative lymphoscintigraphy, although it is not required for
identification of the SLNs.
- On the day before surgery, or the day of surgery, the radioactive colloid is injected either in the
breast parenchyma around the primary tumor or prior biopsy site, into the subareolar region, or
subdermally in proximity to the primary tumor site.
o With a 25-gauge needle, 0.5 mCi of 0.2-μm technetium 99m–labeled sulfur colloid is
injected for same-day surgery, or a higher dose of 2.5 mCi of technetium-labeled sulfur
colloid is administered when the isotope is to be injected on the day before surgery.
Subdermal injections are given in proximity to the cancer site or in the subareolar
location. Later, in the operating room, 3 to 5 mL of blue dye is injected either in the breast
parenchyma or in the subareolar location.
o It is not recommended that the blue dye be used in a subdermal injection because
this can result in tattooing of the skin (isosulfan blue dye) or skin necrosis (methylene
blue).
o For nonpalpable cancers, the injection of the technetium-labeled sulfur colloid solution
can be guided by ultrasound or by mammographic guidance.
o In women who have undergone previous excisional biopsy, the injections are made in
the breast parenchyma around the biopsy cavity but not into the cavity itself.
o Women are told preoperatively that the isosulfan blue dye injection will cause a change
in the color of their urine and that there is a very small risk of allergic reaction to the
dye (1 in 10,000).
o Anaphylactic reactions have been documented, and some groups administer a
regimen of antihistamine, steroids, and a histamine H-2 receptor antagonist
preoperatively as a prophylactic regimen to prevent allergic reactions.
o The use of radioactive colloid is safe, and radiation exposure is very low.
- Sentinel node dissection can be performed in pregnancy with the radioactive colloid without the use
of blue dye.
- A hand-held gamma counter is used to transcutaneously identify the location of the SLN. This
can help to guide placement of the incision.
o A 3- to 4-cm incision is made in line with that used for an axillary dissection, which is a
curved transverse incision in the lower axilla just below the hairline.
o After dissecting through the subcutaneous tissue, the surgeon dissects through the
axillary fascia, being mindful to identify blue lymphatic channels.
o Following these channels can lead directly to the SLN and limit the amount of dissection
through the axillary tissues.
o The gamma probe is used to facilitate the dissection and to pinpoint the location of the
SLN.
o As the dissection continues, the signal from the probe increases in intensity as the
SLN is approached.
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
o The SLN also is identified by visualization of blue dye in the afferent lymph vessel and
in the lymph node itself.
o Before the SLN is removed, a 10-second in vivo radioactivity count is obtained. After
removal of the SLN, a 10-second ex vivo radioactive count is obtained, and the node is
then sent to the pathology laboratory for either permanent- or frozen-section analysis.
o The lowest false-negative rates for SLN dissection have been obtained when all blue
lymph nodes and all lymph nodes with counts >10% of the 10-second ex vivo count of
the SLN are harvested (“10% rule”).
o Based on this, the gamma counter is used before closing the axillary wound to measure
residual radioactivity in the surgical bed.
o A search is made for additional SLNs if the counts remain high.
o This procedure is repeated until residual radioactivity in the surgical bed is less than 10%
of the 10-second ex vivo count of the most radioactive SLN and all blue nodes have been
removed.
o Studies have demonstrated that 98% of all positive SLNs will be recovered with the
removal of four SLNs; therefore, it is not necessary to remove greater than four SLNs for
accurate staging of the axilla.
- Results from the NSABP B-32 trial showed that the false negative rate for SLN dissection is
influenced by tumor location, type of diagnostic biopsy, and number of SLNs removed at surgery.
o The authors reported that tumors located in the lateral breast were more likely to have a
false-negative SLN. This may be explained by difficulty in discriminating the hot spot in
the axilla when the radioisotope has been injected at the primary tumor site in the lateral
breast.
o Those patients who had undergone an excisional biopsy before the SLN procedure were
significantly more likely to have a false-negative SLN.
o This report further confirms that surgeons should use needle biopsy for diagnosis
whenever possible and reserve excisional biopsy for the rare situations in which needle
biopsy findings are non-diagnostic or discordant.
o Finally, removal of a larger number of SLNs at surgery appears to reduce the false-
negative rate.
o Yi and associates reported that the number of SLNs that need to be removed for accurate
staging is influenced by individual patient and primary tumor factors.
- In the B-32 trial, SLNs were identified outside the levels I and II axillary nodes in 1.4% of cases. This
was significantly influenced by the site of radioisotope injection.
o When a subareolar or periareolar injection site was used, there were no instances of
SLNs identified outside the level I or II axilla, compared with a rate of 20% when a
peritumoral injection was used.
o This supports the overall concept that the SLN is the first site of drainage from the
lymphatic vessels of the primary tumor.
- Although many patients will have similar drainage patterns from injections given at the primary tumor
site and at the subareolar plexus, some patients will have extra-axillary drainage, either alone or in
combination with axillary node drainage, and this is best assessed with a peritumoral injection of the
radioisotope.
- Kong et al reported that internal mammary node drainage on preoperative lymphoscintigraphy
was associated with worse distant disease-free survival in early-stage breast cancer patients.
3. Breast conservation
- Breast conservation involves resection of the primary breast cancer with a margin of normal-
appearing breast tissue, adjuvant radiation therapy, and assessment of regional lymph node
status.
- Resection of the primary breast cancer is alternatively called segmental mastectomy,
lumpectomy, partial mastectomy, wide local excision, and tylectomy.
- For many women with stage I or II breast cancer, breast-conserving therapy (BCT) is preferable to
total mastectomy because BCT produces survival rates equivalent to those after total mastectomy
while preserving the breast.
- Data from the EBCTCG meta-analysis revealed that the addition of radiation reduces recurrence
by half and improves survival at year 15 by about a sixth.
- When all of this information is taken together, BCT is considered to be oncologically equivalent
to mastectomy.
- BCT appears to offer advantages over mastectomy with regard to quality of life and aesthetic
outcomes.
28
 o BCT allows for preservation of breast shape and skin as well as preservation of
sensation, and it provides an overall psychologic advantage associated with breast
preservation.
- Breast conservation surgery is currently the standard treatment for women with stage 0, I, or
II invasive breast cancer.
- Women with DCIS require only resection of the primary cancer and adjuvant radiation therapy
without assessment of regional lymph nodes.
- When a lumpectomy is performed, a curvilinear incision lying concentric to the nipple-areola complex
is made in the skin overlying the breast cancer when the tumor is in the upper aspect of the breast.
Radial incisions are preferred when the tumor is in the lower aspect of the breast.
- Skin excision is not necessary unless there is direct involvement of the overlying skin by the primary
tumor.
- The breast cancer is removed with an envelope of normal-appearing breast tissue that is adequate
to achieve a cancer-free margin.
- Recently the SSO and ASTRO developed a consensus statement, encouraging “no tumor on ink”
to be the standard definition of a negative margin for invasive stages I and II breast cancer in
patients who undergo breast conserving surgery with whole-breast irradiation.
o The meta-analysis found that increasing the margin width does not affect local
recurrence rates as long as the inked or transected margin is microscopically negative.
- Specimen X-ray should routinely be performed to confirm the lesion has been excised. Specimen
orientation is performed by the surgeon.
- Additional margins from the surgical bed are taken as needed to provide a histologically negative
margin. Requests for determination of ER, PR, and HER2 status are conveyed to the pathologist.
- It is the surgeon’s responsibility to ensure complete removal of cancer in the breast.
o Ensuring surgical margins that are free of breast cancer will minimize the chances of
local recurrence and will enhance cure rates.
o If negative margins are not obtainable with reexcision, mastectomy is required. SLN
is performed before removal of the primary breast tumor. When indicated, intraoperative
assessment of the sentinel node can proceed while the segmental mastectomy is being
performed.
- The use of oncoplastic surgery can be entertained at the time of segmental mastectomy or at a
later time to improve the overall aesthetic outcome.
o The use of oncoplastic techniques range from a simple reshaping of breast tissue to local
tissue rearrangement to the use of pedicled flaps or breast reduction techniques.
o The overall goal is to achieve the best possible aesthetic result.
o In determining which patients are candidates for oncoplastic breast surgery, several
factors should be considered, including:
§ the extent of the resection of breast tissue necessary to achieve negative
margins
§ the location of the primary tumor within the breast
§ the size of the patient’s breast and body habitus.
o Oncoplastic techniques are of prime consideration when
§ (a) a significant area of breast skin will need to be resected with the specimen
to achieve negative margins;
§ (b) a large volume of breast parenchyma will be resected resulting in a
significant defect;
§ (c) the tumor is located between the nipple and the inframammary fold, an
area often associated with unfavorable cosmetic outcomes;
§ d) excision of the tumor and closure of the breast may result in malpositioning
of the nipple.
4. Mastectomy and axillary dissection
- A skin-sparing mastectomy
o removes all breast tissue, the nipple-areola complex, and scars from any prior biopsy
procedures.
o There is a recurrence rate of less than 6% to 8%, comparable to the long-term recurrence
rates reported with standard mastectomy, when skin-sparing mastectomy is used for
patients with Tis to T3 cancers.
- A total (simple) mastectomy without skin sparing
o removes all breast tissue, the nipple-areola complex, and skin.
- An extended simple mastectomy
o removes all breast tissue, the nipple-areola complex, skin, and the level I axillary lymph
nodes.
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
- A modified radical (“Patey”) mastectomy
o removes all breast tissue, the nipple-areola complex, skin, and the levels I, II, and III
axillary lymph nodes; the pectoralis minor that was divided and removed by Patey may
be simply divided, giving improved access to level III nodes, and then left in situ, or
occasionally the axillary clearance can be performed without dividing pectoralis minor.
- The Halsted radical mastectomy
o removes all breast tissue and skin, the nipple-areola complex, the pectoralis major and
pectoralis minor muscles, and the levels I, II, and III axillary lymph nodes. The use of
systemic chemotherapy and hormonal therapy as well as adjuvant radiation therapy for
breast cancer have nearly eliminated the need for the radical mastectomy.
- Nipple-areolar sparing mastectomy
o has been popularized over the last decade especially for risk-reducing mastectomy in
high risk women.
o For those patients with a cancer diagnosis, many consider the following factors for
eligibility:
§ tumor located more than 2 to 3 cm from the border of the areola,
§ smaller breast size,
§ minimal ptosis,
§ no prior breast surgeries with periareolar incisions,
§ body mass index less than 40 kg/m2 ,
§ no active tobacco use,
§ no prior breast irradiation,
§ no evidence of collagen vascular disease.
- Some reasons for considering mastectomy:
o For a variety of biologic, economic, and psychosocial reasons
o For Women who are less concerned about cosmesis, it cost less and avoids
inconvenience of radiation therapy.
o Tumors that cannot be excised with a reasonable cosmetic result or have extensive
microcalcifications
o large cancers that occupy the subareolar and central portions of the breast
o women with multicentric primary cancers
5. Modified radical mastectomy
- A modified radical mastectomy preserves the pectoralis major muscle with removal of levels I,
II, and III (apical) axillary lymph nodes.
- A modified radical mastectomy permits preservation of the medial (anterior thoracic) pectoral
nerve, which courses in the lateral neurovascular bundle of the axilla and usually penetrates the
pectoralis minor to supply the lateral border of the pectoralis major.
- Anatomic boundaries of the modified radical mastectomy are:
o the anterior margin of the latissimus dorsi muscle laterally,
o the midline of the sternum medially,
o the subclavius muscle superiorly,
o and the caudal extension of the breast 2 to 3 cm inferior to the inframammary fold
inferiorly.
- Skin-flap thickness varies with body habitus but ideally is 7 to 8 mm inclusive of skin and
telasubcutanea.
- Once the skin flaps are fully developed, the fascia of the pectoralis major muscle and the overlying
breast tissue are elevated off the underlying musculature, which allows for the complete removal of
the breast.
- Subsequently, an axillary lymph node dissection is performed.
o The most lateral extent of the axillary vein is identified, and the areolar tissue of the
lateral axillary space is elevated as the vein is cleared on its anterior and inferior
surfaces.
o The areolar tissues at the junction of the axillary vein and the anterior edge of the
latissimus dorsi muscle, which include the lateral and subscapular lymph node groups
(level I), are cleared.
o Care is taken to preserve the thoracodorsal neurovascular bundle.
o The dissection then continues medially with clearance of the central axillary lymph node
group (level II).
o The long thoracic nerve of Bell is identified and preserved as it travels in the investing
fascia of the serratus anterior muscle.
29
 § Every effort is made to preserve this nerve because permanent disability with
a winged scapula and shoulder weakness will follow denervation of the
serratus anterior muscle.
o Patey divided the pectoralis minor and removed it to allow access right up to the apex of
the axilla. The pectoralis minor muscle is usually divided at the tendinous portion near
its insertion onto the coracoid process, which allows dissection of the axillary vein
medially to the costoclavicular (Halsted’s) ligament.
o Finally, the breast and axillary contents are removed from the surgical bed and are sent
for pathologic assessment.
o In his modified radical mastectomy, Patey removed the pectoralis minor muscle. Many
surgeons now divide only the tendon of the pectoralis minor muscle at its insertion onto
the coracoid process while leaving the rest of the muscle intact, which still provides good
access to the apex of the axilla.
- Seromas beneath the skin flaps or in the axilla represent the most frequent complication of
mastectomy and axillary lymph node dissection, reportedly occurring in as many as 30% of cases.
o The use of closed-system suction drainage reduces the incidence of this complication.
Catheters are retained in the wound until drainage diminishes to <30 mL per day.
- Wound infections occur infrequently after a mastectomy, and the majority are a result of skin-flap
necrosis.
o Cultures of specimens taken from the infected wound for aerobic and anaerobic
organisms, debridement, and antibiotic therapy are effective management.
- Moderate or severe hemorrhage in the postoperative period is rare and is best managed with early
wound exploration for control of hemorrhage and reestablishment of closed-system suction
drainage.
- The incidence of functionally significant lymphedema after a modified radical mastectomy is
approximately 20% but can be as high as 50% to 60% when postoperative radiation is employed.
o Extensive axillary lymph node dissection, the delivery of radiation therapy, the presence
of pathologic lymph nodes, and obesity are predisposing factors.
o Patients should be referred to physical therapy at the earliest signs of lymphedema to
prevent progression to the later stages.
o The use of individually fitted compressive sleeves and complex decongestive therapy
may be necessary.
Reconstruction of the Breast and Chest Wall
# The goals of reconstructive surgery after a mastectomy for breast cancer are:
○ Wound closure
○ Breast reconstruction, which is either immediate or delayed
# Wound closure after mastectomy
○ Is usually accomplished with simple approximation of the wound edges
○ If a more radical removal of skin and subcutaneous tissue is done, a pedicled
myocutaneous flap from the latissimus dorsi is the best approach
○ A skin graft provides functional coverage to tolerate adjuvant radiation therapy, but this
is not preferred because poor graft adherence may delay delivery of radiation therapy
# Breast reconstruction after risk-reducing mastectomy or after mastectomy for early-stage
breast cancer, it may be performed at the same time as the mastectomy
○ This allows for a skin-sparing mastectomy to be performed → offers the best overall
cosmetic outcomes
○ Reconstruction can proceed with an expander/implant reconstruction or with
autologous tissue (ex. a pedicled myocutaneous flap or a free flap using microvascular
techniques)
# With locally advanced breast cancer, reconstruction is delayed until after completion of adjuvant
radiation therapy to ensure that local-regional control of disease is obtained
# The use of postmastectomy radiotherapy should also be considered as a reason for delayed
reconstruction
○ Because radiotherapy to a reconstructed breast has been reported to result in inferior
cosmetic outcomes
# Consideration can be made for placement of a tissue expander to allow for skin-sparing, but this
should be discussed with the radiation oncologist
# If chest wall coverage is needed to replace a large skin or soft tissue defect, the latissimus dorsi
and the rectus abdominis myocutaneous flaps are most frequently used
○ The latissimus dorsi myocutaneous flap
■ Consists of a skin paddle based on the underlying latissimus dorsi muscle
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
■ Muscle is supplied by the thoracodorsal artery with contributions from the
posterior intercostal arteries
○ A transverse rectus abdominis myocutaneous (TRAM) flap
■ Consists of a skin paddle based on the underlying rectus abdominis muscle
■ Muscle is supplied by vessels from the deep inferior epigastric artery
■ The free TRAM flap uses microvascular anastomoses to establish blood
supply to the flap
# When the bony chest wall is involved with cancer, resection of a portion of the bony chest wall is
indicated
○ If only one or two ribs are resected and soft tissue coverage is provided, reconstruction
of the bony defect is usually not necessary because scar tissue will stabilize the chest
wall
○ If more than two ribs are sacrificed, it is advisable to stabilize the chest wall with
prosthetic material, which is then covered with soft tissue by using a latissimus dorsi or
TRAM flap
NONSURGICAL BREAST CANCER THERAPIES
Radiation Therapy
# Radiation therapy is used for all stages of breast cancer depending on whether the patient is
undergoing BCT or mastectomy
# Those women treated with mastectomy who have cancer at the surgical margins are at sufficiently
high risk for local recurrence to warrant the use of adjuvant radiation therapy to the chest wall
postoperatively
# Are at increased risk for recurrence and are candidates for the use of chest wall and
supraclavicular lymph node radiation therapy:
○ Women with metastatic disease involving four or more axillary lymph nodes
○ Premenopausal women with metastatic disease involving one to three lymph nodes
# In advanced local-regional breast cancer (stage IIIA or IIIB)
○ Women are at high risk for recurrent disease after surgical therapy
○ Adjuvant radiation therapy is used to reduce the risk of recurrence
# Current recommendations for stages IIIA and IIIB breast cancer are
○ (a) adjuvant radiation therapy to the breast and supraclavicular lymph nodes after
neoadjuvant chemotherapy and segmental mastectomy with or without axillary lymph
node dissection
○ (b) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after
neoadjuvant chemotherapy and mastectomy with or without axillary lymph node
dissection
○ (c) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after
segmental mastectomy or mastectomy with axillary lymph node dissection and
adjuvant chemotherapy
# It is important to include all multidisciplinary team members (medical oncology, plastic surgery,
radiation oncology, and surgical oncology) regarding the risks and benefits of postmastectomy
radiation therapy in patients with one to three positive nodes
# APBI (partial breast irradiation) for breast-conserving surgey
○ Can be delivered via brachytherapy, external beam radiation therapy using 3D
conformal radiation, or intensity-modulated radiation therapy
○ Use of APBI should be based on current guidelines or offered in the setting of a
prospective trial
Chemotherapy Adjuvant
Chemotherapy
# The Early Breast Cancer Trialists’ Collaborative Group analysis of adjuvant chemotherapy
demonstrated reductions recurrence and death in women ≤70 years of age with stage I, IIA, or IIB
breast cancer
○ For those ≥70 years of age, the lack of definitive clinical trial data prevented definitive
recommendations
# Adjuvant chemotherapy is of minimal benefit to women with negative nodes and cancers ≤0.5
cm in size and is not recommended
# Women with negative nodes and cancers 0.6 to 1.0 cm are divided into:
○ Low risk of recurrence
○ Those with unfavorable prognostic features that portend a higher risk of recurrence and
a need for adjuvant chemotherapy
# Adverse prognostic factors include:
30
 ○ Blood vessel or lymph vessel invasion
○ High nuclear grade
○ High histologic grade
○ HER2/ neu overexpression
○ Negative hormone receptor status
# American Society of Clinical Oncology guidelines suggest that adjuvant chemotherapy should
be considered for patients with:
○ Positive lymph nodes
○ HER2-positive disease
○ Adjuvant! Online mortality greater than 10%
○ Grade 3 lymph node negative tumors >5 mm
○ Triple-negative tumors
○ Lympho-vascular invasion, or
○ Estimated distant relapse risk of greater than 15% at 10 years based on 21 gene
recurrence score
# Adjuvant chemotherapy is recommended by the NCCN guidelines for women with these
unfavorable prognostic features

Cancer Type Treatment

Hormone receptor-negative Adjuvant chemotherapy is appropriate

Cancers > 1 cm
Neoadjuvant (Preoperative) Chemotherapy
Hormone receptor-positive Candidates for antiestrogen therapy # National Cancer Institute (1970, Milan) study: For women with T3 or T4 breast cancer, best results
Node-negative With or without chemotherapy were achieved when surgery was interposed between chemotherapy courses
T1 tumors # NSABP B-18 trial:
○ Women were assigned to receive either surgery followed by chemotherapy or
neoadjuvant chemotherapy followed by surgery → no difference in the 5-year disease-
ER-positive Assessment of overall risk (using prognostic factors
free survival rates
Node-negative or additional testing such as the 21-gene recurrence
○ After neoadjuvant chemotherapy there was an increase in the number of lumpectomies
score assay) can help to guide decision making
performed and a decreased incidence of node positivity → suggested that neoadjuvant
regarding chemotherapy
chemotherapy be considered for the initial management of breast cancers judged too
large for initial lumpectomy
Special-type cancers (tubular, Adjuvant antiestrogen therapy should # Several prospective clinical trials:
mucinous, medullary, etc.) be advised for cancers >1 cm ○ Neoadjuvant vs. adjuvant chemotherapy are equivalent in terms of OS
# Usually strongly ER-positive ○ Increase in local-regional recurrence (LRR) rates for patients receiving neoadjuvant
chemotherapy when radiation therapy was used alone without surgery after completion
Node-positive tumors, or Use of chemotherapy is appropriate of chemotherapy
Special-type cancer > 3 cm (with antiestrogen therapy, if hormone receptor # Mittendorf and colleagues
positive) ○ Risk of LRR was driven by biologic factors and disease stage and was not impacted by
the timing of chemotherapy delivery
# For stage IIIA breast cancer, the following should be considered, especially for estrogen # Neoadjuvant chemotherapy offers the opportunity to observe the response of the intact primary
receptor negative disease: tumor and any regional nodal metastases to a specific chemotherapy regimen
○ Preoperative chemotherapy with an anthracycline and taxane-containing regimen # For patients whose tumors remain stable in size or even progress with the initial neoadjuvant
followed by… chemotherapy regimen, a new regimen may be considered that uses another class of agents
○ Either a modified radical mastectomy or segmental mastectomy with axillary dissection # After treatment with neoadjuvant chemotherapy, patients are assessed for clinical and pathologic
followed by… response to the regimen
○ Adjuvant radiation therapy # Patients whose tumors achieve a pathologic complete response to neoadjuvant chemotherapy
# While the same regimen may be considered for estrogen receptor positive disease, it is known have been shown to have statistically improved survival outcomes to those of patients whose
that these tumors respond less well to chemotherapy with: tumors demonstrate only a partial response, remain stable, or progress on treatment
○ <10% pCR rate overall # Researchers at MD Anderson Cancer Center:
○ <3% pCR rate for lobular cancers ○ Residual cancer burden (RCB) is predictive of 10-year relapse-free survival with
# Other options such as neoadjuvant endocrine therapy followed by local regional treatment or in neoadjuvant chemotherapy in triple negative, ER-positive, and HER2-positive tumors
some cases primary endocrine therapy may be considered depending on other tumor ○ RCB is divided into 4 classes: RCB-0 or pathologic complete response, RCB-1, RCB-2,
characteristics and the patient’s comorbid conditions and preference and RCB-3
# Patients who experience progression of disease during neoadjuvant chemotherapy have the
poorest survival
○ This means that while patients who achieve a pCR will have a better prognosis based
on their response to neoadjuvant chemotherapy, equally other patients will have a
poorer prognosis compared to when they started neoadjuvant therapy based on the
nonresponse to treatment

BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 31

 # Current NCCN recommendations for treatment of operable advanced local-regional breast
cancer are:
○ Neoadjuvant chemotherapy with an anthracycline-containing or taxane-containing
regimen or both, followed by…
○ Mastectomy or lumpectomy with axillary lymph node dissection if necessary, followed
by…
○ Adjuvant radiation therapy
# For patients with HER2-positive breast cancer, trastuzumab and pertuzumab can be combined
with chemotherapy in the preoperative setting to increase pathologic complete response rates
# For inoperable stage IIIA and for stage IIIB breast cancer, neoadjuvant chemotherapy is used to
decrease the local-regional cancer burden, which may then permit subsequent modified radical or
radical mastectomy, which is followed by adjuvant radiation therapy
Nodal Evaluation in Patients Receiving Neoadjuvant Chemotherapy
# Standard practice for the axilla has been to:
○ Perform an axillary lymph node dissection after chemotherapy; or
○ Perform a sentinel lymph node dissection before chemotherapy for nodal staging
before chemotherapy is initiated
# Regarding the use of SLN dissection at the completion of chemotherapy, studies have
demonstrated the feasibility of SLN dissection in breast cancer patients after neoadjuvant
chemotherapy
# SLN dissection has been accepted for assessment of the axilla in the clinically node-negative axilla
after neoadjuvant chemotherapy
# Clinicians have been slower to adopt this approach for axillary staging after chemotherapy in
patients who started with initial node-positive disease
# Caudle et al at MD Anderson Cancer Center:
○ Performed a study of patients with biopsy-confirmed nodal metastases with a clip
placed in the biopsy-proven lymph node
○ Patients underwent SLN dissection with targeting and removal of the clipped node
(targeted axillary dissection [TAD])
○ TAD includes SLN surgery and selective localization and removal of the clipped node,
with the goal to determine if pathologic changes in the clipped node accurately reflect
the status of the nodal basin
○ SLN surgery and ALND (axillary lymph node dissection), the FNR (false-negative rate)
was 10.1%, and adding evaluation of the clipped node reduced the FNR to 1.4%
○ TAD followed by ALND had an FNR of 2.0%
Neoadjuvant Endocrine Therapy
# Neoadjuvant endocrine therapy is being increasingly evaluated in clinical trials
# ER-positive tumors do not shrink in response to chemotherapy as readily as ER-negative tumors
○ The pCR rate in ER-negative tumors is approximately three times that of ER-positive
tumors
# Fisher et al:
○ As age increases, women obtain less benefit from chemotherapy
○ They recommended that factors including tumor estrogen receptor concentration,
nuclear grade, histologic grade, tumor type, and markers of proliferation should be
considered in these patients before choosing between the use of chemotherapy and
hormonal therapy
○ If the tumor is estrogen-receptor rich, these patients may benefit more from endocrine
therapy in the neoadjuvant setting than they might if they received standard
chemotherapy
# Neoadjuvant endocrine therapy has been shown to shrink tumors, enabling breast-conserving
surgery in women with hormone receptor-positive disease who otherwise would have to be treated
with mastectomy
# The IMPACT trial:
○ Evaluated neoadjuvant use of tamoxifen or anastrozole or both in combination in
postmenopausal women with ER-positive operable or locally advanced breast cancer
○ No significant differences in objective tumor response among tamoxifen, anastrozole,
or a combination of the two
○ Only 31% had breast-conserving surgery with tamoxifen, whereas 44% underwent
breast-conserving surgery with anastrozole
# Invasive lobular cancers in particular have been shown to respond poorly to neoadjuvant
chemotherapy and may have better response to neoadjuvant endocrine therapy
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
# It is suggested that neoadjuvant endocrine therapy is an appropriate alternative in ER-positive
breast cancers
○ Aromatase inhibitors were associated with significantly higher response and breast
conservation rates compared with tamoxifen
# Increasing knowledge of secondary resistance mechanisms to endocrine therapy and cross talk
between ER and the PI3K/Akt/mTOR pathway have led to the evaluation of PI3K pathway
inhibitors in combination with endocrine therapy
# Postmenopausal women with ER-positive early breast cancers were treated with letrozole or
letrozole in combination with everolimus, a mTOR inhibitor, in a randomized trial
○ Clinical response and antiproliferative response, characterized by reduction in Ki67,
was superior in the combination arm
# Clinical trials are evaluating the use of CDK inhibitors in combination with neoadjuvant endocrine
therapy
○ Neoadjuvant anastrozole in combination with palbociclib, a CDK4/6 inhibitor, has been
shown to significantly reduce Ki67, suggesting that CDK4/6 inhibition can increase the
efficacy of neoadjuvant endocrine therapy
# With the use of neoadjuvant chemotherapy or endocrine therapy, observation of the response of
the intact tumor and/or nodal metastases to a specific regimen could ultimately help to define
which patients will benefit from specific therapies in the adjuvant setting
# In adjuvant trials the primary endpoint is typically survival, whereas in neoadjuvant trials the
endpoints have more often been clinical or pathologic response rates
Antiestrogen Therapy
Tamoxifen
# Within the cytosol of breast cancer cells are specific proteins (receptors) that bind and transfer
steroid moieties into the cell nucleus to exert specific hormonal effects
# The most widely studied hormone receptors are the estrogen receptor and progesterone receptor
# Hormone receptors are detectable in >90% of well-differentiated ductal and lobular invasive
cancers
# Receptor status may remain the same between the primary cancer and metastatic disease in the
same patient in the majority of cases
# But there are instances where the status is changed in the metastatic focus → therefore, biopsy
of newly diagnosed metastatic disease should be considered for assessment of hormone
receptor and HER2 status
# After binding to estrogen receptors in the cytosol, tamoxifen blocks the uptake of estrogen by
breast tissue
○ Clinical responses to antiestrogen are evident in >60% of women with hormone
receptor-positive breast cancers
○ Evident response in <10% of women with hormone receptor-negative breast cancers
# Tamoxifen has a mortality benefit that continues to be statistically significant in the second and
third 5-year periods (i.e., years 5–9 and 10–15) when the patients are no longer receiving
endocrine treatment—the so-called carry-over effect
# Also showed a 39% reduction in the risk of cancer in the contralateral breast
# The antiestrogens do have defined toxicity, including bone pain, hot flashes, nausea, vomiting,
and fluid retention
# Thrombotic events occur in <3% of treated women
# Cataract surgery is more frequently performed in patients receiving tamoxifen
# The Stockholm trial:
○ 5 years of tamoxifen was associated with a significant reduction in locoregional
recurrences and distant metastasis in postmenopausal women with ER-positive breast
cancer
○ However, an increase in endometrial cancers was observed with long-term
tamoxifen use
# Extended adjuvant therapy with letrozole after 5 years of tamoxifen was shown to improve
disease-free survival without improvement in overall survival except in node-positive patients
# Tamoxifen therapy is also considered for women with DCIS that is found to be ER-positive
# The goals of such therapy are to decrease the risk of an ipsilateral recurrence after breast
conservation therapy for DCIS and to decrease the risk of a primary invasive breast cancer or a
contralateral breast cancer event
# Tamoxifen is not recommended for patients who have had bilateral mastectomies with ER-
positive DCIS
# With the use of aromatase inhibitors in postmenopausal women, use of adjuvant tamoxifen has
increasingly been limited to premenopausal women.
32
Aromatase Inhibitors
# In postmenopausal women, aromatase inhibitors are now considered first-line therapy in the
adjuvant setting
# Currently, three third-generation aromatase inhibitors are approved for clinical use:
○ The reversible nonsteroidal inhibitors anastrozole and letrozole
○ The irreversible steroidal inhibitor exemestane
# Alll the aromatase inhibitors have been shown to have similar efficacy with a similar spectrum of
adverse effects
# Early breast cancers treated with tamoxifen or aromatase inhibitors demonstrated that 5 years of
aromatase inhibitors reduced the rate of recurrence by 30% and 10-year breast cancer mortality by
about 15% compared to 5 years of tamoxifen
# NSABP B42 and MA-17R studies:
○ Extended letrozole improved disease-free survival without significant improvement in
overall survival
# Patients who are node-positive, have received adjuvant chemotherapy, with prior receipt of
tamoxifen are likely to benefit from long-term use of an aromatase inhibitor
# The aromatase inhibitors are less likely than tamoxifen to cause endometrial cancer but do lead to
changes in bone mineral density that may result in osteoporosis and an increased rate of
fractures in postmenopausal women
○ The risk of osteoporosis can be averted by treatment with bisphosphonates
# Joint pains are a side effect that affects a significant number of patients
# Women with hormone receptor–positive cancers achieve significant reduction in risk of
recurrence of breast cancer and mortality from breast cancer through the use of endocrine
therapies
# For postmenopausal women with ER-positive, HER2- negative, metastatic breast cancer, available
endocrine therapies include:
○ Nonsteroidal aromatase inhibitors (anastrozole and letrozole)
○ Steroidal aromatase inhibitors (exemestane)
○ Serum ER modulators (tamoxifen or toremifene)
○ ER down- regulators (fulvestrant)
○ Progestin (megestrol acetate)
○ Androgens (fluoxymesterone)
○ High-dose estrogen (ethinyl estradiol)
# A third generation nonsteroidal aromatase inhibitor or palbociclib, the CDK 4/6 inhibitor, in
combination with letrozole may be considered as a treatment option for first-line therapy
# Activation of CDK4/CDK6 cell cycle signaling axis has been implicated in mediating endocrine
resistance
# PALOMA-1
○ Median progression-free survival (PFS) was doubled with the combination (palbociclib
+ letrozole) compared to letrozole alone
○ Based on this, the FDA approved palbociclib in combination with letrozole for the
treatment of postmenopausal women with ER-positive, HER2-negative advanced
breast cancer as initial treatment
# Two additional CDK4/6 inhibitors, ribociclib and abemaciclib, have been approved for use in
combination with endocrine therapy for patients with hormone receptor– positive advanced breast
cancer.
# PALOMA-3
○ Fulvestrant with palbociclib is a potential option for women with metastatic breast
cancer who have progressed on prior endocrine therapy
○ Abemaciclib in combination with fulvestrant or as single agent is approved for use in
ER-positive advanced breast cancers previously treated with endocrine therapy
# In premenopausal women with stage IV ER-positive breast cancer without previous exposure to
endocrine therapy, initial treatment with tamoxifen or ovarian suppression/ablation plus aromatase
inhibitor with or without CDK4/6 inhibitors are reasonable options
# Activation of the PI3K/mammalian target of rapamycin (mTOR) signal transduction pathway
has also been implicated in secondary resistance to estrogen targeting
# BOLERO-2
○ An improvement in PFS was observed with combination (everolimus + exemestane)
compared to exemestane alone leading to FDA approval
○ Similar improvement in PFS was observed with a combination of tamoxifen and
everolimus
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
○ A trial of letrozole in combination with temsirolimus, an mTOR inhibitor, did not show
any improvement in PFS in aromatase inhibitor–naive metastatic postmenopausal
women
# Women whose tumors respond to an endocrine therapy with either shrinkage of their breast cancer
(objective response) or long-term stabilization of disease (stable disease) are considered to
represent “clinical benefit” and should receive additional endocrine therapy at the time of
progression because their chances of a further response remain high
# Patients whose tumors progress de novo on an endocrine agent have a low rate of clinical benefit
(<20%) to subsequent endocrine therapy
# The choice of endocrine or chemotherapy should be considered based on the disease site and
extent as well as the patient’s general condition and treatment preference
# The adjuvant use of aromatase inhibitors and recent advances in tumor genome sequencing
technologies have enabled the identification of secondary ESR1 mutations
○ These mutations, typically present in the ligand binding domains, lead to ligand-
independent activation of the receptor, mediate resistance to aromatase inhibitors, and
are associated with shorter survival
○ Reported incidence of these mutations are variable (20%–30%) based on prior
exposure to aromatase inhibitors and are uncommon in primary breast cancers
Ablative Endocrine Therapy
# Today, adrenalectomy and/or hypophysectomy (once primary endocrine modalities used to treat
metastatic breast cancer) are seldom used
# In women who are premenopausal at diagnosis, ovarian ablation can be accomplished by
oophorectomy or ovarian radiation
# Ovarian suppression can be accomplished by the use of gonadotrophin-hormone releasing
hormone agonists, such as goserelin or leuprolide
# Relapse-free and overall survival was superior with endocrine therapy combination
# SOFT and TEXT trials:
○ Exemestane plus ovarian suppression significantly reduces recurrences as compared
with tamoxifen plus ovarian suppression; however, there was no significant differences
in overall survival
○ Tamoxifen plus ovarian suppression was not superior to tamoxifen alone in terms of
disease-free survival, but improved outcomes were observed in ovarian suppression in
women with a high risk of recurrence
# Ovarian suppression in combination with an aromatase inhibitor can be considered in select
premenopausal women with high-risk features (age <40 years, positive lymph nodes) who
warranted adjuvant chemotherapy
Anti-HER2 Therapy
# The determination of tumor HER-2 expression or gene amplification for all newly diagnosed
patients with breast cancer is now recommended
○ It is used to assist in the selection of adjuvant chemotherapy in both node-negative and
node-positive patients
# Trastuzumab was initially approved for the treatment of HER2/neu-positive breast cancer in
patients with metastatic disease
# NSABP and the North Central Cancer Treatment Group trials
○ Evaluated the impact of adjuvant trastuzumab therapy in patients with early stage
breast cancer
○ Demonstrated an improvement in 3-year disease-free survival with a reduction in
mortality in the patients who received trastuzumab
# While anthracycline-based adjuvant chemotherapy was considered preferable in HER2-positive
breast cancer, the BCIRG 006 found no statistical significance in overall survival (in a comparison
of anthracycline + taxane + trastuzumab (AC-TH) vs. taxane, carboplatin, trastuzumab (TCH))
○ While anthracycline chemotherapy was numerically superior, this was accompanied
by an increase in the incidence of leukemia and congestive heart failure
# A year of adjuvant trastuzumab is considered standard of care
○ Two years of adjuvant trastuzumab has been shown to be more effective, but
associated with more toxicity
# PHRAE trial:
○ Study failed to demonstrate that 6 months of trastuzumab was noninferior compared to
the standard therapy
# Patients with HER2-positive tumors benefit if trastuzumab is added to taxane chemotherapy
33
 # Because of overlapping cardiotoxicities, trastuzumab is not usually given concurrently with
anthracyclines
# Buzdar and colleagues:
○ Increased pathologic complete response rates if trastuzumab in combination with
sequential paclitaxel followed by FEC-75 (5-fluorouracil, epirubicin, cyclophosphamide)
vs. the same chemotherapy regimen without trastuzumab
# Currently trastuzumab is the only HER2-targeted agent approved for use in the adjuvant setting
# Lapatinib
○ Is a dual tyrosine kinase inhibitor that targets both HER2 and EGFR that was approved
for use with capecitabine in patients with HER2-positive metastatic disease
○ Adjuvant lapatinib was shown to be inferior to trastuzumab
○ The combination of lapatinib with trastuzumab did yield a significant improvement in
disease-free survival compared to trastuzumab alone
# Ado-trastuzumab emtansine (T-DM1)
○ Approved for HER2-positive metastatic breast cancer patients who have previously
received trastuzumab and a taxane either separately or in combination
○ Is an antibody drug conjugate that incorporates the HER2 targeted activity of
trastuzumab with the cytotoxic activity of DM1, a microtubule inhibitory agent leading to
apoptosis
# Pertuzumab
○ Is a humanized monoclonal antibody that binds at a different epitope of the HER2
extracellular domain (subdomain II) and prevents dimerization of HER2 with other
members of the family, primarily HER3
○ In the metastatic setting, it is approved in combination with trastuzumab and docetaxel
for patients with metastatic HER2- positive breast cancer who have not received prior
HER2-targeted therapy or chemotherapy for metastatic disease.
○ In the neoadjuvant setting, pertuzumab is approved in combination with trastuzumab
and docetaxel in HER2-positive, early stage breast cancers that are greater than 2 cm
or node-positive
○ NeoSphere trial: neoadjuvant use of pertuzumab with trastuzumab and docetaxel led to
nearly a 17% increase in pathologic complete response in the breast
○ TRYPHAENA study: pathologic complete responses ranging from 57% to 66% were
observed with neoadjuvant pertuzumab and trastuzumab combination given with
anthracycline-containing or nonanthracycline-containing chemotherapy
# Currently there is significant interest in identifying patients who can avoid chemotherapy and
potentially be treated with HER2- targeted agents alone
# Pertuzumab was recently FDA approved in combination with trastuzumab and chemotherapy in
the adjuvant setting in HER2 amplified breast cancers with high risk of recurrence
# The ExteNET study
○ Evaluated the use of neratinib, an irreversible inhibitor of EGFR, HER2, and HER4, in
HER2- positive early stage patients who have completed adjuvant trastuzumab
○ A year of neratinib after completion of chemotherapy and trastuzumab-based adjuvant
therapy significantly improved survival
○ Neratinib has FDA approval for HER2 amplified breast cancers following a year of
adjuvant trastuzumab
# HER2 mutations
○ In addition to amplifications or copy number alterations, activating mutations or single
nucleotide variants in HER2 have been described
○ Typically observed in ER-positive breast cancers, and now has a reported higher
prevalence in invasive lobular carcinomas, particularly in the pleomorphic subtype
○ These mutations, usually exclusive with HER2 amplification, are observed in kinase or
extracellular domains and predict for responses or resistance to HER2-targeting
agents.
○ A phase 2 trial of neratinib in HER2-mutated metastatic breast cancers showed a
clinical benefit rate of 36% with one complete response and one partial response in a
heavily pretreated population
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
SPECIAL CLINICAL SITUATIONS
Nipple Discharge
Unilateral Nipple Discharge
# Nipple discharge is a finding that can be seen in a number of clinical situations
# It may be suggestive of cancer if it is:
○ Spontaneous
○ Unilateral
○ Localized to a single duct
○ Present in women ≥40 years of age
○ Bloody
○ Associated with a mass
# A trigger point on the breast may be present so that pressure around the nipple-areolar complex
induces discharge from a single duct
○ In this circumstance, mammography and ultrasound are indicated for further evaluation
○ A ductogram also can be useful and is performed by cannulating a single discharging
duct with a small nylon catheter or needle and injecting 1.0 mL of water-soluble
contrast solution
# Nipple discharge associated with a cancer may be clear, bloody, or serous
# Testing for the presence of hemoglobin is helpful, but hemoglobin may also be detected when
nipple discharge is secondary to an intraductal papilloma or duct ectasia
# Definitive diagnosis depends on excisional biopsy of the offending duct and any associated
mass lesion
○ A 3.0 lacrimal duct probe can be used to identify the duct that requires excision
○ Another approach is to inject methylene blue dye within the duct after ductography
○ The nipple must be sealed with collodion or a similar material so that the blue dye does
not discharge through the nipple but remains within the distended duct facilitating its
localization
○ Localization with a wire or seed is performed when there is an associated mass that
lies >2.0 to 3.0 cm from the nipple.
Bilateral Nipple Discharge
# Nipple discharge is suggestive of a benign condition if it is:
○ Bilateral and multiductal in origin
○ Occurs in women ≤39 years of age
○ Is milky or blue-green
# Prolactin-secreting pituitary adenomas
○ Are responsible for bilateral nipple discharge in <2% of cases
○ If serum prolactin levels are repeatedly elevated, plain radiographs of the sella turcica
are indicated, and thin section CT scan is required
○ Optical nerve compression, visual field loss, and infertility are associated with large
pituitary adenomas
Axillary Lymph Node Metastases in the Setting of an Unknown Primary Cancer
# A woman who presents with an axillary lymph node metastasis that is consistent with a breast
cancer metastasis has a 90% probability of harboring an occult breast cancer
# However, axillary lymphadenopathy is the initial presenting sign in only 1% of breast cancer
patients
# Fine-needle aspiration biopsy or core-needle biopsy can be used to establish the diagnosis
when an enlarged axillary lymph node is identified
# When metastatic cancer is found, immunohistochemical analysis may classify the cancer as
epithelial, melanocytic, or lymphoid in origin
# The presence of hormone receptors (estrogen or progesterone receptors) suggests metastasis
from a breast cancer but is not diagnostic
# The search for a primary cancer includes careful examination of the thyroid, breast, pelvis, and
rectum
# The breast should be examined with diagnostic mammography, ultrasonography, and MRI to
evaluate for an occult primary lesion
# Further radiologic and laboratory studies should include chest radiography and liver function
studies
# Additional imaging of the chest, abdomen, and skeleton may be indicated if the extent of nodal
involvement is consistent with stage III breast cancer
# Suspicious findings on mammography, ultrasonography, or MRI necessitate breast biopsy
34
 # When a breast cancer is found, treatment consists of an axillary lymph node dissection with a
mastectomy or preservation of the breast followed by whole-breast radiation therapy
# Chemotherapy and endocrine therapy should be considered
Breast Cancer During Pregnancy
# Breast cancer occurs in 1 of 3000 pregnant women, and axillary lymph node metastases are
present in up to 75% of these women
# The average age of the pregnant woman with breast cancer is 34 years
# < 25% of the breast nodules developing during pregnancy and lactation will be cancerous
# Ultrasonography and needle biopsy specimens are used in the diagnosis of these nodules
# Mammography is rarely indicated because of its decreased sensitivity during pregnancy and
lactation (however, the fetus can be shielded if mammography is needed)
# Approximately 30% of the benign conditions encountered will be unique to pregnancy and lactation
(galactoceles, lobular hyperplasia, lactating adenoma, and mastitis or abscess)
# Once a breast cancer is diagnosed, complete blood count, chest radiography (with shielding of the
abdomen), and liver function studies are performed
# Because of the potential deleterious effects of radiation therapy on the fetus, radiation cannot be
considered until the fetus is delivered
# A modified radical mastectomy can be performed during the first and second trimesters of
pregnancy, even though there is an increased risk of spontaneous abortion after first-trimester
anesthesia
# During the third trimester, lumpectomy with axillary node dissection can be considered if
adjuvant radiation therapy is deferred until after delivery
# Lactation is suppressed
# Chemotherapy administered during the first trimester carries a risk of spontaneous abortion and
a 12% risk of birth defects
# There is no evidence of teratogenicity resulting from administration of chemotherapeutic agents
in the second and third trimesters → many clinicians now consider the optimal strategy to be
delivery of chemotherapy in the second and third trimesters as a neoadjuvant approach, which
allows local therapy decisions to be made after the delivery of the baby
# Pregnant women with breast cancer often present at a later stage of disease because breast
tissue changes that occur in the hormone-rich environment of pregnancy obscure early cancers
# However, pregnant women with breast cancer have a prognosis, stage by stage, that is similar to
that of nonpregnant women with breast cancer
Male Breast Cancer
# < 1% of all breast cancers occur in men
# Male breast cancer is preceded by gynecomastia in 20% of men
# It is associated with:
○ Radiation exposure
○ Estrogen therapy
○ Testicular feminizing syndromes
○ Klinefelter’s syndrome (XXY)
# Breast cancer is rarely seen in young males and has a peak incidence in the sixth decade of life
# A firm, nontender mass in the male breast requires investigation
# Skin or chest wall fixation is particularly worrisome
# DCIS makes up <15% of male breast cancer
# Infiltrating ductal carcinoma makes up >85%
# Special-type cancers, including infiltrating lobular carcinoma, have occasionally been reported
# Male breast cancer is staged in the same way as female breast cancer, and stage by stage, men
with breast cancer have the same survival rate as women
# Overall, men do worse because of the more advanced stage of their cancer (stage II, III or IV) at
the time of diagnosis
# The treatment of male breast cancer is surgical, with the most common procedure being a
modified radical mastectomy
# SLN dissection has been shown to be feasible and accurate for nodal assessment in men
presenting with a clinically node-negative axilla
# Adjuvant radiation therapy is appropriate in cases in which there is a high risk for local-regional
recurrence
# Approximately 80% of male breast cancers are hormone receptor–positive, and adjuvant
tamoxifen is considered
# Systemic chemotherapy is considered for men with:
○ Hormone receptor-negative cancers
BULLECER D & V, CHY, PRADO, SARENO, TANG 2021
○ Large primary tumors, multiple positive nodes, and locally advanced disease
Phyllodes Tumors
# The nomenclature, presentation, and diagnosis of phyllodes tumors (including cystosarcoma
phyllodes) have posed many problems for surgeons
# These tumors are classified as benign, borderline, or malignant
# Borderline tumors have a greater potential for local recurrence
# Mammographic evidence of calcifications and morphologic evidence of necrosis do not distinguish
between benign, borderline, and malignant phyllodes tumors
# Consequently, it is difficult to differentiate benign phyllodes tumors from the malignant variant and
from fibroadenomas
# Phyllodes tumors are usually sharply demarcated from the surrounding breast tissue, which is
compressed and distorted
○ Connective tissue composes the bulk of these tumors, which have mixed gelatinous,
solid, and cystic areas
○ Cystic areas represent sites of infarction and necrosis
○ These gross alterations give the gross cut tumor surface its classical leaf-like
(phyllodes) appearance
○ The stroma of a phyllodes tumor generally has greater cellular activity than that of a
fibroadenoma
# Molecular biology techniques have shown the stromal cells of fibroadenomas to be either
polyclonal or monoclonal (derived from a single progenitor cell), whereas those of phyllodes
tumors are always monoclonal
# Most malignant phyllodes tumors contain liposarcomatous or rhabdomyosarcomatous
elements rather than fibrosarcomatous elements
# Evaluation of the number of mitoses and the presence or absence of invasive foci at the tumor
margins may help to identify a malignant tumor
# Small phyllodes tumors are excised with a margin of normal-appearing breast tissue
# When the diagnosis of a phyllodes tumor with suspicious malignant elements is made, reexcision
of the biopsy specimen site to ensure complete excision of the tumor with a 1-cm margin of
normal-appearing breast tissue is indicated
# Large phyllodes tumors may require mastectomy
# Axillary dissection is not recommended because axillary lymph node metastases rarely occur.
Inflammatory Breast Carcinoma
# Inflammatory breast carcinoma (stage IIIB) accounts for <3% of breast cancers
# Characterized by the skin changes of:
○ Brawny induration
○ Erythema with a raised edge
○ Edema (peau d’orange)
# Permeation of the dermal lymph vessels by cancer cells is seen in skin biopsy specimens
# There may be an associated breast mass
# The clinical differentiation of inflammatory breast cancer may be extremely difficult, especially
when a locally advanced scirrhous carcinoma invades dermal lymph vessels in the skin to produce
peau d’orange and lymphangitis
# Inflammatory breast cancer also may be mistaken for a bacterial infection of the breast
# > 75% of women who have inflammatory breast cancer present with palpable axillary
lymphadenopathy, and distant metastases also are frequently present
# A PET-CT scan should be considered at the time of diagnosis to rule out concurrent metastatic
disease
# Surgery alone and surgery with adjuvant radiation therapy have produced disappointing results
# Neoadjuvant chemotherapy with an anthracycline-containing regimen may affect dramatic
regressions in up to 75% of cases
# Tumors should be assessed for HER2 and hormone receptors with treatment dictated based on
receptor status
# Modified radical mastectomy is performed after demonstrated response to systemic therapy to
remove residual cancer from the chest wall and axilla
# Adjuvant chemotherapy may be indicated depending on final pathologic assessment of the breast
and regional nodes
# The chest wall and the supraclavicular, internal mammary, and axillary lymph node basins receive
adjuvant radiation therapy → this multimodal approach results in 5-year survival rates that
approach 30%
# Patients with inflammatory breast cancer should be encouraged to participate in clinical trials
35
 # 60% of women developing this cancer have a history of adjuvant radiation therapy
# Forequarter amputation may be necessary to palliate the ulcerative complications and advanced
lymphedema

Lymphomas
# Primary lymphomas of the breast are rare, and there are two distinct clinicopathologic variants
# One type
○ Occurs in women ≤39 years of age
○ Is frequently bilateral
○ Has the histologic features of Burkitt’s lymphoma
# The second type
○ Is seen in women ≥40 years of age
○ Is usually of the B-cell type
# Breast involvement by Hodgkin’s lymphoma has been reported
# An occult breast lymphoma may be diagnosed after detection of palpable axillary
lymphadenopathy
# Treatment depends on the stage of disease
○ Lumpectomy or mastectomy may be required
○ Axillary dissection for clearance of disease may be necessary
○ Recurrent or progressive local-regional disease is best managed by chemotherapy and
radiation therapy
# The prognosis is favorable, with 5- and 10-year survival rates of 74% and 51%, respectively
# Anaplastic large cell lymphoma has been described in association with breast implants for
cosmetic
or reconstructive purposes. This disease is treated with complete
excision of the implant capsule with any associated soft tissue
Rare Breast Cancers mass. More advanced cases may require systemic therapy and
Squamous Cell (Epidermoid) Carcinoma radiation treatment
# Squamous cell (epidermoid) carcinoma is a rare cancer that arises from metaplasia within the duct
system
# Generally is devoid of distinctive clinical or radiographic characteristics
# Regional metastases occur in 25% of patients
# Distant metastases are rare

Adenoid Cystic Carcinoma

# Adenoid cystic carcinoma is very rare, accounting for <0.1% of all breast cancers
# It is typically indistinguishable from adenoid cystic carcinoma arising in salivary tissues
# Generally 1 to 3 cm in diameter at presentation and are well circumscribed
# Axillary lymph node metastases are rare, but deaths from pulmonary metastases have been
reported

Apocrine Carcinomas
# Apocrine carcinomas are well-differentiated cancers that have rounded vesicular nuclei and
prominent nucleoli
# There is a very low mitotic rate and little variation in cellular features, but may display an
aggressive growth pattern.

Sarcomas
# Sarcomas of the breast are histologically similar to soft tissue sarcomas at other anatomic sites
# This diverse group includes fibrosarcoma, malignant fibrous histiocytoma, liposarcoma,
leiomyosarcoma, malignant schwannoma, rhabdomyosarcoma, osteogenic sarcoma, and
chondrosarcoma
# The clinical presentation is typically that of a large, painless breast mass with rapid growth
# Diagnosis is by core-needle biopsy or by open incisional biopsy
# Sarcomas are graded based on cellularity, degree of differentiation, nuclear atypia, and mitotic
activity
# Primary treatment is wide local excision, which may necessitate mastectomy
# Axillary dissection is not indicated unless there is biopsy proven lymph node involvement
# Angiosarcomas are classified as de novo, as postradiation, or as arising in association with
postmastectomy lymphedema (described originally as lymphangiosarcoma of the upper extremity
in women with ipsilateral lymphedema after radical mastectomy)
# The average interval between modified radical or radical mastectomy and the development of an
angiosarcoma is 7 to 10 years

BULLECER D & V, CHY, PRADO, SARENO, TANG 2021 36