BREAST

Embryology

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

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

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

Functional Anatomy

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

contains a greater volume of tissue than do the other quadrants. Considerable variations in the size, contour, and density of the breast are evident between individuals.

Nipple–areola Complex

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

Inactive and Active Breast

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

In the inactive breast, the epithelium is sparse and consists primarily of ductal epithelium. In the early phase of the menstrual cycle, minor ducts are cord-like with small lumina. With estrogen stimulation at the time of ovulation, alveolar epithelium increase, in height, duct lumina become more prominent, and some secretions accumulate. When the hormonal stimulation decreases, the alveolar epithelium regresses.

With pregnancy, the breast undergoes proliferative and developmental maturation. As the breast enlarges in response to hormonal stimulation, lymphocytes, plasma cells, and eosinophils accumulate within the connective tissues. The minor ducts branch and alveoli develop.With parturition, enlargement of the breasts occurs via hypertrophy of alveolar epithelium and accumulation of secretory products in the lumina of the minor ducts.

Alveolar epithelium contains abundant endoplasmic reticulum, large mitochondria, Golgi complexes, and dense lysosomes. Two distinct substances are produced by the alveolar epithelium: (1) the protein component of milk, which is synthesized in the endoplasmic reticulum (merocrine secretion), and (2) the lipid component of milk (apocrine secretion), which forms as free lipid droplets in the cytoplasm. Milk released in the first few days following parturition is called colostrum and has low lipid content but contains considerable quantities of antibodies.

The lymphocytes and plasma cells that accumulate within the connective tissues of the breast are the source of the antibody component. With subsequent reduction in the number of these cells, the production of colostrum decreases and lipid-rich milk is released.

Blood Supply, Innervation, and Lymphatics

The breast receives its principal blood supply from:

perforating branches of the internal mammary arterylateral branches of the posterior intercostal arteries

branches from the axillary artery(highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery)

The 2nd , 3rd , and 4th anterior intercostal perforators and branches of the internal mammary artery arborize in the breast as the medial mammary arteries.

The lateral thoracic artery gives off branches to the serratus anterior, pectoralis major and minor, and subscapularis muscles. It also gives rise to lateral mammary branches.

The three principal groups of veins are:

perforating branches of the internal thoracic vein perforating branches of the posterior intercostal veins

tributaries of the axillary vein.

The vertebral venous plexus of Batson, which invests the vertebrae and extends from the base of the skull to the sacrum, may provide a route for breast cancer metastases to the vertebrae, skull, pelvic bones, and central nervous system.

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

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

Axillary vein group (lateral)

consists of 4 to 6 lymph nodes

lie medial or posterior to the vein

receive most of the lymph drainage from the upper extremity

External mammary group (anterior or pectoral group)

consists of 5 or 6 lymph nodes

lie along the lower border of the pectoralis minor muscle contiguous with the lateral thoracic vessels

receive most of the lymph drainage from the lateral aspect of the breast

Scapular group (posterior or subscapular)

consists of 5 to 7 lymph nodes

lie along the posterior wall of the axilla at the lateral border of the scapula contiguous with the subscapular vessels

receive lymph drainage principally from the lower posterior neck, the posterior trunk, and the posterior shoulder

Central group

consists of 3 or 4 sets of lymph nodes, which are embedded in the fat of the axilla

lie immediately posterior to the pectoralis minor muscle

receive lymph drainage both from the axillary vein, external mammary, and scapular groups of lymph nodes and directly from the breast

Subclavicular group (apical)

consists of 6 to 12 sets of lymph nodes

lie posterior and superior to the upper border of the pectoralis minor muscle

receive lymph drainage from all of the other groups of axillary lymph nodes

Interpectoral group (Rotter's)

consists of 1 to 4 lymph nodes

interposed between the pectoralis major and pectoralis minor muscles

receive lymph drainage directly from the breast.

The lymph fluid that passes through the interpectoral group of lymph nodes passes directly into the central and subclavicular groups.

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

level I lymph nodes

Lymph nodes located lateral to or below the lower border of the pectoralis minor muscle

axillary vein, external mammary, and scapular groups

level II lymph nodes

Lymph nodes located superficial or deep to the pectoralis minor muscle

central and interpectoral groups

level III lymph nodes

Lymph nodes located medial to or above the upper border of the pectoralis minor muscle

subclavicular group.

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

Physiology of the Breast

Breast Development and Function

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

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

Pregnancy, Lactation, and Senescence

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

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

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

Infectious and Inflammatory Disorders of the Breast

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

Bacterial Infection

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

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

Mycotic Infections

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

Fibrocystic Changes

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

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

Pathology of Nonproliferative Disorders

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

Cysts

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

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

Bloodstained- 2 mL of fluid are taken for cytology

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

The 2 cardinal rules of safe cyst aspiration are:

1. the mass must disappear completely after aspiration

2. the fluid must not be bloodstained.

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

Fibroadenomas

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

Periductal Mastitis

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

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

Treatment of Recurrent Subareolar Sepsis

Suitable for Fistulectomy Suitable for Total Duct Excision

Small abscess localized to one segment

Large abscess affecting more than 50% of the areolar circumference

Recurrence involving the same segment

Recurrence involving a different segment

Mild or no nipple inversion Marked nipple inversion

Patient unconcerned about nipple inversion

Patient requests correction of nipple inversion

Younger patient Older patient

No discharge from other ducts Purulent discharge from other ducts

No prior fistulectomy Recurrence after fistulectomy

Pathology of Proliferative Disorders Without Atypia

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

Sclerosing adenosis

prevalent during the childbearing and perimenopausal years

marked intralobular fibrosis and proliferation of small ductules and acini

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

Benign calcifications are often associated with this disorder

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

Radial scars and complex sclerosing lesions

Central sclerosis and varying degrees of epithelial proliferation, apocrine metaplasia, and papilloma formation characterize radial scars and complex sclerosing lesions of the breast

Lesions up to 1 cm in dm are called radial scars, while larger lesions are called complex sclerosing lesions

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

Ductal hyperplasia

mild- 3/4 cell layers above the basement membrane

Moderate- ≥5 cell layers above the basement membrane

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

either solid or papillary

carries an increased cancer risk

Intraductal papillomas

arise in the major ducts, usually in premenopausal women

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

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

rarely undergo malignant transformation

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

Pathology of Atypical Proliferative Diseases

Atypical lobular hyperplasia (ALH) Atypical ductal hyperplasia (ADH)

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

Risk Factors for Breast Cancer

Hormonal and Nonhormonal Risk Factors

Increased exposure to estrogen is associated with an increased risk for developing breast cancer, whereas reducing exposure is thought to be protective.

early menarche, nulliparity, and late menopause

older age at first live birth

obesity , alcohol consumption

radiation exposure

BRCA Mutations

BRCA-1

located on chromosome 17q contains 22 coding exons

functions as tumor-suppressor gene, and for each gene, loss of both alleles is required for the initiation of cancer

a role in transcription, cell-cycle control, and DNA damage repair pathways

germline mutations in BRCA-1 represent a predisposing genetic factor in as many as 45% of hereditary breast cancers and in at least 80% of hereditary ovarian cancers

Female mutation carriers have up to a 90% lifetime risk for developing breast cancer and up to a 40% lifetime risk for developing ovarian cancer

Breast cancer in these families appears as an autosomal dominant trait with high penetrance

BRCA-1–associated breast cancers are invasive ductal carcinomas, are poorly differentiated, and are hormone receptor–negative

BRCA-1 associated breast cancers have a number of distinguishing clinical features, such as an early age of onset when compared with sporadic cases; a higher prevalence of bilateral breast cancer; and the presence of associated cancers in some affected individuals, specifically ovarian cancer and possibly colon and prostate cancers

BRCA-2

located on chromosome 13q contains 26 coding exons

biologic function of BRCA-2 is not well defined, but like BRCA-1, it is postulated to play a role in DNA damage response pathways

breast cancer risk for BRCA-2 mutation carriers is close to 85% and the lifetime ovarian cancer risk, while lower than for BRCA-1, is still estimated to be close to 20%

Breast cancer in BRCA-2 families is an autosomal dominant trait and has a high penetrance

Unlike male carriers of BRCA-1 mutations, men with germline mutations in BRCA-2 have an estimated breast cancer risk of 6%

BRCA-2–associated breast cancers are invasive ductal carcinomas, which are more likely to be well differentiated and to express hormone receptors than BRCA-1–associated breast cancer.

BRCA-2–associated breast cancer has a number of distinguishing clinical features, such as an early age of onset compared with sporadic cases; a higher prevalence of bilateral breast cancer; and the presence of associated cancers in some affected individuals, specifically ovarian, colon, prostate, pancreas, gallbladder, bile duct, and stomach cancers, as well as melanoma

Cancer Prevention for BRCA Mutation Carriers

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

Prophylactic mastectomy and reconstruction; Prophylactic oophorectomy and hormone replacement therapy;

Intensive surveillance for breast and ovarian cancer; and

Chemoprevention

The Primary Breast Cancer

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

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

Axillary Lymph Node Metastases

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

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

Distant Metastases

At approximately the 20th cell doubling, breast cancers acquire their own blood supply (neovascularization). Thereafter, cancer cells may be shed directly into the systemic venous blood to seed the pulmonary circulation via the axillary and intercostal veins or the vertebral column via Batson's plexus of veins, which courses the length of the vertebral column. These cells are scavenged by natural killer lymphocytes and macrophages. Successful implantation of metastatic foci from breast cancer predictably occurs after the primary cancer exceeds 0.5 cm in diameter, which corresponds to the 27th cell doubling. For 10 years following initial treatment, distant metastases are the most common cause of death in breast cancer patients. While 60% of

the women who develop distant metastases will do so within 24 months of treatment, metastases may become evident as late as 20 to 30 years after treatment of the primary cancer. Common sites of involvement, in order of frequency, are bone, lung, pleura, soft tissues, and liver.

Histopathology of Breast Cancer

Carcinoma In Situ

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

Salient Characteristics of In Situ Ductal (DCIS) and Lobular (LCIS) Carcinoma of the Breast

  LCIS DCIS

Age (years) 44–47 54–58

Incidence a 2–5% 5–10%

Clinical signs None Mass, pain, nipple discharge

Mammographic signs None Microcalcifications

Premenopausal 2/3 1/3

Incidence of synchronous invasive carcinoma 5% 2–46%

Multicentricity 60–90% 40–80%

Bilaterality 50–70% 10–20%

Axillary metastasis 1% 1–2%

Subsequent carcinomas:    

  Incidence 25–35% 25–70%

  Laterality Bilateral Ipsilateral

  Interval to diagnosis 15–20 years 5–10 years

  Histology Ductal Ductal

a Among biopsies of mammographically detected breast lesions.

Multicentricity--occurrence of a second breast cancer outside the breast quadrant of the primary cancer

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

Lobular Carcinoma In Situ

originates from the terminal duct lobular units

only develops in the female breast

characterized by distention and distortion of the terminal duct lobular units by cancer cells, which are large but maintain a normal nuclear:cytoplasmic ratio

Cytoplasmic mucoid globules are a distinctive cellular feature

calcifications associated with LCIS typically occur in adjacent tissues

occurs 12x more frequently in white women than in African American women

Ductal Carcinoma In Situ(intraductal carcinoma)

predominantly seen in the female breast accounts for 5% of male breast cancers.

Histologically, DCIS is characterized by a proliferation of the epithelium that lines the minor ducts, resulting in papillary growths within the duct lumina

four morphologic categories are prototypes of pure lesions: Papillary, cribriform, solid, and comedo types

papillary and cribriform types of DCIS probably transform to invasive cancer over a longer time frame and are of lower grade

solid and comedo types of DCIS are generally higher-grade lesions and probably invade over a shortened natural history

Invasive Breast Carcinoma

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

I. Paget's disease of the nipple

presents as a chronic, eczematous eruption of the nipple, which may be subtle, but may progress to an ulcerated, weeping lesion

A palpable mass may or may not be present

associated with extensive DCIS and may be with an invasive cancer

Bx of the nipple

population of cells that are identical to the underlying DCIS cells (pagetoid features or pagetoid change)

Pathognomonic of this cancer is the presence of large, pale, vacuolated cells (Paget's cells) in the rete pegs of the epithelium

Surgical Tx

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

II. Invasive ductal carcinoma

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

presents with macroscopic or microscopic axillary lymph node metastases in 60% of cases

perimenopausal or postmenopausal women in the 5th to 6th decades of life as a solitary, firm mass

poorly defined margins and its cut surfaces show a central stellate configuration with chalky white or yellow streaks extending into surrounding breast tissues. The

cancer cells arranged in small clusters, and there is a broad spectrum of histologies with variable cellular and nuclear grades

b. Medullary carcinoma 4%

A frequent phenotype of BRCA-1 hereditary breast cancer

Grossly, the cancer is soft and hemorrhagic

A rapid increase in size may occur secondary to necrosis and hemorrhage

Bilaterality is reported in 20% of cases

Microscopically characterized by

a dense lymphoreticular infiltrate composed predominantly of lymphocytes and plasma cells;

large pleomorphic nuclei that are poorly differentiated and show active mitosis; and

a sheet-like growth pattern with minimal or absent ductal or alveolar differentiation

Approximately 50% of these cancers are associated with DCIS, which is characteristically present at the periphery of the cancer, and fewer than 10% demonstrate hormone receptors

In rare circumstances, mesenchymal metaplasia or anaplasia is noted

Because of the intense lymphocyte response associated with the cancer, benign or hyperplastic enlargement of the lymph nodes of the axilla may contribute to erroneous clinical staging

Women with this cancer have a better 5-year survival rate than those with NST or invasive lobular carcinoma

c. Mucinous (colloid) carcinoma 2% Typically presents in the elderly population as a bulky tumor This cancer is defined by extracellular pools of mucin, which surround

aggregates of low-grade cancer cells The cut surface of this cancer is glistening and gelatinous in quality Fibrosis is variable, and when abundant it imparts a firm consistency to the

cancer Approximately 66% of mucinous carcinomas display hormone receptors Lymph node metastases occur in 33% of cases

d. Papillary carcinoma 2%

It generally presents in the 7th decade of life and occurs in a disproportionate number of nonwhite women

Typically, papillary carcinomas are small and rarely attain a size of 3 cm in diameter

Defined by papillae with fibrovascular stalks and multilayered epithelium

low frequency of axillary lymph node metastases

e. Tubular carcinoma (and ICC) 2%

Tubular carcinoma is another special-type breast cancer and accounts for 2% of all invasive breast cancers. It is reported in as many as 20% of women whose cancers are diagnosed by mammography screening and is usually diagnosed in the perimenopausal or early menopausal periods. Under low-power magnification, a haphazard array of small, randomly arranged tubular elements is seen. Approximately 10% of women with tubular carcinoma or with invasive cribriform carcinoma, a special-type cancer closely related to tubular carcinoma, will

develop axillary lymph node metastases, which are usually confined to the lowest axillary lymph nodes (level I). However, the presence of metastatic disease in one or two axillary lymph nodes does not adversely affect survival. Distant metastases are rare in tubular carcinoma and invasive cribriform carcinoma. Long-term survival approaches 100%.