lymph node and some subclavicular lymph node groups) are behind the pectoralis minor; and level 3

nodes (subclavicular lymph node group) are medial to the pectoralis minor. The interpectoral nodes

(Rotter nodes) are located between the pectoralis major and minor muscles along the lateral pectoral

nerve. The supraclavicular nodes are contiguous with the apex of the axilla. The internal mammary

nodes are located in the first six intercostal spaces within 3 cm of the edge of the sternum, with the

highest concentration of nodes found in the first three intercostal spaces.7,8

Figure 74-4. Tanner stages of breast development.

BREAST PHYSIOLOGY

Breast Development

As epidermal appendages, mammary glands likely evolved from ancient apocrine glands that were

associated with hair follicles.9 The mammary gland is a complex secretory organ consisting of multiple

different cell types. Epithelial cells form the ductal network of the gland, which is embedded within a

fat pad composed of adipocytes. In addition, there are vascular endothelial cells that make up the blood

vessels, stromal cells including fibroblasts, and immune cells. During the three stages of mammary

development (embryonic, pubertal, and pregnancy/lactation), these cells undergo an intricate series of

changes under the regulation of hormones and regulatory factors, resulting in permanent changes to the

mammary gland that both modify its architecture and biologic characteristics.10 Understanding breast

development and morphology is extremely important to the study of both premalignant and malignant

conditions.

In humans, mammary gland development starts in the sixth week of fetal life with the formation of

bilateral milk lines or ectodermal thickenings that extend from the axilla to the groin. These ridges

rapidly regress except for those of the thorax, where invagination of ectoderm cells into the

mesenchyme results in mammary bud formation. In the human embryo, at about 5 months, the deep

layer of the mammary bud epithelium starts to proliferate and produces about 10 to 25 secondary buds,

which will later correspond to lactiferous ducts. Canalization, or the formation of lumens within the

solid core of these epithelial structures, occurs later in development. By birth, six to eight of these ducts

are patent and empty into the nipple.11–15 A parallel bundle of an additional 25 smaller ducts also

appear and are the precursors to the milk-producing units of the breast.16 The subareolar lymphatic

plexus also develops from the ectoderm in a similar fashion,17 while the nipple forms from the

proliferation of the mesenchyme under the areola.14

In infants, only small ductal structures are seen within the stroma and during childhood, these

structures continue to grow isometrically at a rate similar to the rest of the body until puberty.18 These

initial stages of breast development are not dependent on sex steroids but are likely governed by

numerous growth factors that regulate the epithelial-mesenchymal interaction, including Lef-1,19

parathyroid hormone-related protein, and the type 1 parathyroid hormone/parathyroid hormone-related

protein receptor.20

During puberty, the female glands enlarge rapidly secondary to maturation of the ductal system into a

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lobuloalveolar system. This is characterized by thickening of the ductal epithelium, elongating ducts,

and an increasing amount of periductal connective tissue. In addition, stem cells at the tips of the ductal

tree form terminal end buds, which are highly proliferative and give rise to alveolar buds. In early

puberty, these alveolar buds empty into a terminal ductal lobular unit and are referred to as lobules

type 1. Under the influence of ovarian hormones (estrogen and progesterone), lobules type 1 will

differentiate into lobules type 2, which are characterized by smaller but more numerous buds that are

noted as ductules or alveoli. It has been postulated that each menstrual cycle fosters new budding that

never fully returns to the baseline of the prior cycle.21,22 In addition to estrogen and progesterone,

pubertal breast development is also dependent on other hormones and regulatory factors including

prolactin, growth hormone, glucocorticoids, growth factors (hepatocyte growth factor, IGF-1, IGF-2,

FGF, neuregulins especially heregulin), vitamin D receptor, metalloproteinases, and PTEN.23–28

As these developmental events are occurring, physical changes in the breast contour and the

appearance of the nipple become evident and are illustrated as the five Tanner stages of breast

development (Fig. 74-4).29

Menstrual Cycle

During a 28-day menstrual cycle, the mammary gland undergoes five histologic phases described by

Vogel: proliferative (days 3 to 7), follicular phase of differentiation (days 8 to 14), luteal phase of

differentiation (days 15 to 20), secretory (days 21 to 27), and then menstrual (days 28 to 2). The first

phase starts with the proliferation of the mammary epithelium and is characterized by mitotic figures, a

predominant eosinophilic cell type, dense stroma, and tight lumen. During the follicular phase, the

epithelial cells start to differentiate with the appearance of multiple cellular types (luminal columnar

basophilic, intermediate pale cells, and basal clear cells with hyperchromatic nucleus or myoepithelial

cells). In the luteal phase, the prior dense stroma starts to loosen and the lumen starts to open with

secretions. Also, the basal clear cells have prominent vacuolization, consistent with the known effects of

progesterone on the glycogen content of cultured endometrial epithelium.30 The secretory phase is

notable for active apocrine secretion from luminal cells and an edematous stroma. During the menstrual

phase, the stroma returns to a dense and cellular form, the lumen distends with secretions, and the basal

cells have extensive vacuolization.31 These five phases depict the morphologic changes that occur in the

breast from normal ovarian hormone cycling during menses, further supporting the notion that the

mammary gland is not a resting gland but one that is dynamic.

Pregnancy and Lactation

Although the pubertal phase is marked by significant lobular development, the mammary gland does

not achieve full differentiation until after pregnancy and lactation. In early pregnancy, the distal ducts

continue to proliferate, resulting in more lobules and more alveoli within each lobule. However, by

midpregnancy, proliferation of the lobules ceases and instead alveolar cells begin to differentiate into

acini by hypertrophy and the ability to secrete colostrum into the lumina of the ductules. By the third

trimester, the acini become distended with colostrum and the breast’s connective tissue and fat become

largely replaced by glandular proliferation. In addition, the connective tissue becomes infiltrated with

plasma cells, lymphocytes, and eosinophils. There is also a marked increase in vascularity. The stage of

lactogenesis or the ability to synthesize and secrete milk marks the final stage of maturation of the

mammary gland (lobule type 4).32,33 Following lactation or during weaning, the mammary gland

involutes with lobules type 4 returning to the prepregnancy state as lobules type 2 and 3.34,35

The hormones and regulatory factors that govern mammary development during pregnancy and

lactation overlap with those previously discussed for pubertal breast development, with estrogen,

progesterone, and prolactin playing chief roles. Other hormones and regulatory factors include

intracellular signaling molecules (c-erbB, hox genes, cell–cell adhesion molecules such as E-cadherin,

cell cycle protein cyclin D1, RANK-L, slug transcription factor), activins and inhibins including STAT5,

hypothalamic peptides, thyrotropic-releasing hormone, and lactogenic hormones.36–43

Menopause

By menopause, the mammary gland is mainly replaced by fat as the glandular epithelium undergoes

apoptosis. As such, the postmenopausal phase is characterized by a decrease in lobules and ducts.44,45

In summary, human breast development is a progressive process that is initiated during embryonic

life, with glandular maturation starting at puberty, and attainment of full breast differentiation only

with subsequent pregnancy and lactation.

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CLINICAL EVALUATION OF THE PATIENT WITH BREAST DISEASE

Breast disease is an extremely common clinical problem. Most women who present to a breast health

specialist will have benign breast disease. One of the primary goals of the evaluation is to determine

whether the breast problem represents benign or malignant breast disease. With benign conditions, the

goals are to reassure the patient and if indicated, provide symptomatic treatment. With a malignant

condition, prompt evaluation and treatment should be undertaken, typically involving a

multidisciplinary team including a breast surgeon, medical oncologist, and radiation oncologist. In this

section, the tools that a clinician uses to evaluate patients with breast disease are discussed including the

history, clinical breast examination (CBE), diagnostic imaging studies, and biopsy procedures.

DIAGNOSIS

Table 74-1 Medical History of a Breast Problem

As the first step in the evaluation of a breast problem, it is important to elicit a relevant history. This

includes the specific history related to the presenting breast problem, as well as a more general history

focused on assessing breast cancer risk. This includes age at menarche, number of pregnancies, number

of live births, and age at first live birth. Family history and history of breast biopsy should also be

elicited. Menopausal status (for premenopausal patients, the time in their menstrual cycle) and the use

of any hormonal therapies should be assessed (Table 74-1).

Clinical Breast Examination

CBE is performed in both the sitting and supine positions (Fig. 74-5). The patient is disrobed from the

waist up and then provided a front-opening gown. Visual inspection is first accomplished with the

patient sitting upright with the arms relaxed to her side. The bilateral breasts are compared for size and

shape. It is normal to find slight differences in breast size, with the left breast often slightly bigger than

the right. Breast shape is also contrasted. Recent changes to breast size or alterations in breast shape can

be concerning signs and need to be evaluated by the provider, as tumors located superficially can cause

changes to the breast contour. The skin of the breasts is inspected for dimpling, edema (peau d’orange),

and/or erythema. In cases of significant erythema and peau d’orange, the provider needs to consider the

diagnosis of an inflammatory breast cancer (IBC) versus an infectious etiology. This is followed by close

inspection of the nipples for symmetry. Although some women have a lifelong history of nipple

inversion, any new history of nipple inversion needs to be regarded with a high index of suspicion.

Next, the nipple–areola complex is evaluated for any eczematous changes or ulcerations (to suggest

conditions such as Paget disease of the breast [PDB]). The patient is then asked to raise her arms to

2036

allow for a more complete visual inspection of the lower aspect of the breasts bilaterally. The visual

examination is completed when the patient is asked to place her hands on the hips and then to contract

the pectoral muscles. This allows for a final visual assessment of breast symmetry. Furthermore, tumors

deep within the substance of the breast involving Cooper’s ligaments can result in skin retraction and

can sometimes be seen best with contraction of the pectoral muscles.

Figure 74-5. Breast examination. A: The patient’s ipsilateral arm is supported by the examiner to relax the pectoral muscle while

the axillary nodes are examined. B: Bimanual examination of the breast in the upright position. C: Bimanual examination in the

supine position with the arm raised over the head.

With the patient remaining in the sitting position but now with the pectoral muscles relaxed,

palpation of the regional lymph nodes of the neck, clavicles (infraclavicular and supraclavicular), and

axilla is then performed. To best delineate the axillary lymph nodes, the patient should be examined

with the ipsilateral arm supported. Attention is paid to evaluate the size, consistency (soft or firm), and

characteristics (mobile or matted, tender or nontender) of the lymph nodes. Bimanual palpation of the

breasts for masses and asymmetry completes the sitting examination.

The patient is then placed in the supine position with the ipsilateral arm raised above the head and

the contralateral breast covered with the gown. The breast tissue is carefully palpated to evaluate for

masses and asymmetry. It must be noted that generalized lumpiness is not a pathologic finding, with

most normal breasts having more nodularity in the upper outer quadrants, at the inframammary ridge,

and in the subareolar region. Comparing the breasts for symmetry by palpation may help discriminate

benign findings from those that require additional evaluation. The area examined extends from the

clavicle to the lower rib cage and medially from the sternal border to the midaxillary line. In addition,

the axillary tail of the breast should be carefully palpated. The three search patterns that have been

described are concentric circles, radial spoke method, and the vertical strip pattern (Fig. 74-6). As the

first two methods can result in a less than thorough examination of the nipple–areola complex, we

prefer the vertical strip pattern as it incorporates this area. Otherwise, with the other two search

patterns, a separate examination of the nipple–areola complex needs to be performed.

Diagnostic Mammography and Breast Ultrasound

1A woman who has an indeterminate or abnormal CBE will typically benefit from a diagnostic imaging

evaluation, which can include targeted ultrasound, mammography, and/or MRI. It is important to note

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that any clinically suspicious mass, even in the absence of an imaging abnormality, needs to be biopsied

as up to 15% of breast cancers are mammographically occult.46

Soft tissue densities and clustered microcalcifications are two common mammographic findings

suggestive of breast cancer. Soft tissue densities can appear as well-defined round/oval/lobulated

masses, spiculated masses, irregular masses, or as areas of architectural distortion without an obvious

mass (Fig. 74-7). Nearly 90% of spiculated soft tissue masses are associated with invasive cancer

whereas well-defined solid masses are rarely predictive of malignancy. Microcalcifications can have

benign or malignant features, with benign calcifications often appearing rim-like, large, coarse, smooth,

round, and/or oval in appearance. Calcifications that are associated with malignancy tend to be smaller

in size, ranging between 0.1 and 1 mm in diameter. They are typically clustered, numbering 4 to 5/

cm3. Histologically, these represent intraductal calcifications in areas of necrotic tumor or calcifications

within mucin-secreting tumors. In addition, malignant microcalcifications can often appear in a granular

or linear branching pattern, with the linear branching pattern being highly associated with malignancy

(Fig. 74-8).

Figure 74-6. Clinical breast examination search patterns: vertical strip, radial spoke, and concentric circles.

Figure 74-7. Mammographic masses. A: Spiculated mass with calcifications. B: Lobulated mass with indistinct posterior margin. C:

Well-circumscribed mass.

Breast ultrasound is another important diagnostic imaging modality for the evaluation of breast

masses and/or mammographic abnormalities. Breast ultrasound is complementary to mammography

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and is particularly valuable for the evaluation of breast masses. Breast ultrasound can increase the

sensitivity and specificity of mammography for detection of breast cancer.47 Ultrasound can

differentiate a cystic mass from a solid one, characterize a palpable lesion that is not seen on

mammography, and can assist with determining the actual size of a lesion. Ultrasonographic features

that are used to characterize a lesion include shape (oval, round, lobular, irregular); margin

(circumscribed, obscured, microlobulated, ill-defined, speculated); orientation (parallel or not parallel to

skin); matrix echogenicity (anechoic, hypoechoic, hyperechoic); homogeneity (homogeneous,

heterogeneous); and attenuation (indifferent, shadowing, enhancement).

Figure 74-8. Microcalcifications. The branching, irregular appearance is classic for ductal carcinoma in situ.

Figure 74-9. Comparison of core needle biopsy specimen (A) and fineneedle aspiration specimen (B). Only the core specimen can

demonstrate the architectural detail.

Diagnostic MRI

Gadolinium contrast-enhanced MRI is complementary to mammography and breast ultrasound. It is not

typically used for the evaluation of benign breast masses but does have a high sensitivity for detection

of breast cancer. As such, MRI is most commonly used to evaluate extent of disease and exclude occult

breast cancers in patients with newly diagnosed breast cancer. In a meta-analysis of 44 studies, the

sensitivity and specificity of diagnostic breast MRI was determined to be 90% and 72%, respectively.48

The role of MRI in the evaluation of patients with newly diagnosed breast cancer is discussed in the

section on Evaluation of the Patient with Breast Cancer.

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Biopsy Procedures

Breast biopsy is one of the most common general surgery procedures performed in the United States.

There are multiple different types of breast biopsy ranging from fine needle aspiration (FNA) biopsy to

excisional biopsy. The different types of breast biopsy are discussed later.

Fine Needle Aspiration

FNA of the breast is the least invasive breast biopsy procedure. FNA can be used for both diagnosis and

treatment and can be performed using palpation or image guidance. During FNA cells or fluids are

removed from the breast using a small gauge needle (20 to 25 gauge). FNA is commonly used to sample

suspicious breast and axillary lesions especially those that are palpable. Other indications include

drainage of simple cysts and small abscesses. The patient is placed in the supine position on the

examination table at a 30-degree angle with the arm of the involved side above the head. When lesions

are lateral or in the axilla, the patient is positioned in the lateral decubitus position. Inframammary

lesions may require an assistant to help retract the breast. For ultrasound guidance, the probe is

positioned directly over the area of interest. As an example, for a breast cyst, the probe would be placed

directly over the cyst with the cyst located at the side of the probe; this way the shortest distance to the

cyst is shown. Prior to aspiration, the cyst is thoroughly scanned in all planes for septa or loculations to

facilitate complete aspiration. The skin is then prepped with an antiseptic solution and further scanning

is performed in a sterile fashion. With the nondominant hand steadying the cyst, 1 to 2 mL of 1%

lidocaine is injected into the skin. A 20-gauge needle with a 5 or 10 mL syringe is inserted in a plane

parallel to the chest wall directly toward the center of the cyst. The plunger is then slowly retracted to

create a vacuum to aspirate the cyst contents. For palpable lesions not requiring ultrasound guidance,

aspiration can be performed in a similar fashion. The aspiration site can be dressed with an adhesive

bandage. If there is bleeding, pressure is applied for 15 minutes. Other potential complications include

infection and failure to adequately sample the area of concern. In institutions with experienced

cytopathologists, diagnostic FNA has a reported sensitivity of 98% and a specificity of 97%.49 However,

as the tissue architecture cannot be evaluated by FNA, the diagnosis of invasive cancer cannot be made.

In the past, FNA was commonly used to sample palpable breast masses as part of the Triple Test for

evaluation of palpable masses. Currently, ultrasound can more accurately assess these lesions and low

suspicion lesions are followed with serial imaging. High suspicion lesions are best sampled by core

needle biopsy to allow assessment of tissue architecture (Fig. 74-9).

Core Needle Biopsy

2 Core needle biopsy is also a minimally invasive strategy for breast biopsy. Given the limitations of

FNA, core needle biopsy allows for more tissue to be sampled, permitting a histologic diagnosis, and

offering the ability to discriminate between invasive and noninvasive breast cancer. Core needle biopsy

can be performed by palpation, but ultrasound-guided core needle biopsy typically offers superior

results. Ultrasound imaging and patient preparation are similar to that described for patients undergoing

FNA. The skin and planned needle tract are anesthetized with lidocaine, and a small stab incision is

made with a No. 11 blade prior to needle entry. A common core biopsy device consists of a hollow 14-

gauge needle (range: 18-gauge to 11-gauge) with a spring firing mechanism. More advanced devices

have vacuum assistance and an automated firing mechanism. Under ultrasound guidance, the tip of the

needle is guided toward the lesion, often to its edge as the needle excursion is typically approximately 2

cm. Advancing the needle beyond the abnormality can result in sampling error and/or injury to the

chest wall. The device is then fired and the needle is withdrawn, with the resultant “tissue core” placed

into formalin. Three tissue cores are obtained to ensure adequate sampling of the abnormality. A clip is

then deployed under ultrasound guidance to mark the biopsy site for future reference. For palpable

masses, the procedure can be performed without ultrasound guidance. The nondominant hand is used to

steady the mass and is positioned perpendicular to the entry point of the needle device to avoid

inadvertent needle stick injury.

For nonpalpable lesions that cannot be imaged by ultrasound but are present on mammography (most

commonly microcalcifications), stereotactic core biopsy can be performed. Stereotactic techniques use

the principle of triangulation, which allows the precise location of a breast lesion to be determined in

three dimensions.50 The patient can be upright or prone depending on the machine. More commonly,

the patient is placed in the prone position on the stereotactic table, which has an opening for the breast.

A mammography unit is attached beneath the table and compresses the dependent breast. An initial

scout image is obtained perpendicular to the compressed breast and evaluated. The skin overlying the

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