CHAPTER 19
Benign Breast Disease
KEY POINTS
1 Breast complaints are common, and the first priority in evaluation is to rule out
malignancy and ensure concordance between physical examination, imaging, and
1055pathology after a diagnosis has been reached.
2 Workup of a breast complaint includes a thorough history and physical, often
accompanied by ultrasound, mammography in women over age 35 and, in some
cases, biopsy and pathologic evaluation.
3 The most common benign breast problems include fibrocystic changes and mastalgia.
These problems are usually best treated by reassurance. Pharmacologic agents are
available but have side effects that usually are not well tolerated.
4 Histologic differences exist between fibroadenomas and phyllodes tumors; phyllodes
tumors require excision, whereas small asymptomatic fibroadenomas can be
observed if the diagnosis is confirmed by classic imaging findings or histologic
assessment and there is no evidence of growth.
5 Breast abscesses are managed with aspiration and antibiotics; the use of incision and
drainage is reserved for recurrence.
6 Spontaneous, unilateral, bloody discharge requires histologic evaluation to exclude
malignancy, but symptoms usually are caused by a benign process such as
intraductal papilloma or duct ectasia.
7 Proliferative lesions such as ductal and lobular neoplasia represent an increased risk
to the patient of subsequent diagnosis of breast cancer in either breast. Atypical
lobular hyperplasia and lobular carcinoma in situ (LCIS) may be followed closely
with repeat mammography and clinical examination, while atypical ductal
hyperplasia (ADH) requires surgical excision because of the risk for concomitant
cancer.
Benign breast diseases are among the most common diagnoses that the busy
obstetrician-gynecologist will see in practice. An ability to accurately and
promptly diagnose benign and malignant breast diseases is within the purview of
the practicing gynecologist (1,2). Benign breast disease is a complex entity
associated with a range of physiologic changes and clinical manifestations that
have an impact on a woman’s health independent of breast cancer risk (3).
Patients may present with complaints ranging from pain to a palpable mass, skin
or nipple changes, or, with increasing frequency, a mammographically-detected
abnormality. Patients are often distressed regarding the possibility of cancer.
Ultimately, the majority of breast complaints are benign conditions, and it is the
practitioner’s role to guide the patient through the process of excluding a
malignancy, reaching a diagnosis, treating her symptoms, and managing future
risk (4).
EVALUATION
History
Evaluation of a new breast symptom begins with a thorough clinical history. The
1056history should include questions regarding current symptoms, duration of the
condition, fluctuation of the signs and symptoms, and factors that aggravate or
relieve the symptom. [1] Assessment of breast problems should focus on the
following points:
Nipple discharge
Characteristics of discharge (spontaneous or elicited, appearance,
unilateral or bilateral, single or multiple duct involvement)
Breast mass (size and change in size, density, or texture)
Breast pain (cyclic versus continuous)
Association of symptoms with menstrual cycle
Change in breast shape, size, or texture
Previous breast biopsies
History of breast trauma
The patient should be questioned about the following risk factors for breast
cancer (see Chapter 42 for more details):
Increasing age (approximately 50% of breast cancers occur after age
65)
Age of menarche less than 12 years of age
Nulliparity or first pregnancy at greater than 30 years of age
Late menopause (older than 55 years of age)
Personal history of breast or other malignancies (ovary, colon, and
prostate)
Family history of breast cancer (especially in first-degree relatives who
were premenopausal or had bilateral disease)
Number of first-degree relatives with breast cancer and their ages
when diagnosed
Family history of male breast cancer
Inherited conditions associated with a high risk for developing breast
cancer, including BRCA1 and BRCA2 genes, Li-Fraumeni syndrome,
PTEN hamartoma tumor syndrome (Cowden), hereditary diffuse
gastric cancer syndrome, and Peutz–Jeghers syndrome
Pathology of previous breast biopsy showing atypia or lobular
carcinoma in situ (LCIS)
Hormone replacement therapy
Alcohol consumption
Postmenopausal weight gain
Several clinical risk prediction models are readily available online. The most
1057commonly used of these is the Breast Cancer Risk Assessment Tool or Gail Risk
Assessment model from the National Cancer Institute (5). The Gail Risk
Assessment model calculates the risk based on the patient’s race, age, age of
menarche, age of first live birth, number of first-degree relatives with breast
cancer, number of previous breast biopsies, and presence of atypia on the biopsy.
The Gail model likely underestimates the genetic contribution to risk and should
not be used for patients with family members with breast, ovarian, tubal, or
peritoneal cancer. Instead, the United States Preventative Services Task Force
(USPSTF) recommends the use of either the Ontario Family History Assessment
Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment
Tool, or the Family History Screen 7 (6). Other useful risk calculators include
BRCAPro and Tyrer–Cuzick (7,8).
While taking the clinical history, it is important to obtain a current list of
medications used, including hormone replacement therapy and herbal medications
such as phytoestrogens. The gestational history should take into consideration the
possibility that the patient may be pregnant or has a prior history of miscarriage or
abortion. A personal history of exposure to radiation, especially in the treatment
of childhood malignancies, is associated with a higher incidence of developing
breast cancer (9). The goal of breast evaluation is to determine clearly whether the
symptom represents a benign breast condition or may be indicative of a neoplastic
process.
Physical Examination
[2] Breast tumors, particularly malignant tumors, usually are asymptomatic
and are discovered by the patient, physical examination, or screening
mammography. Typically, the breast changes slightly during the menstrual
cycle. During the premenstrual phase, most women have increased innocuous
nodularity and mild engorgement of the breast. Rarely these characteristics can
obscure an underlying lesion and make examination difficult. Findings should be
carefully documented in the medical record to serve as a baseline for future
reference.
Inspection
Inspection is performed initially while the patient is seated comfortably with
her arms relaxed at her sides. The breasts are compared for symmetry,
contour, and skin appearance. Edema or erythema is identified easily, and skin
dimpling or nipple retraction is shown by having the patient raise her arms above
her head and then press her hands on her hips, thereby contracting the pectoralis
muscles (Fig. 19-1). Palpable and even nonpalpable tumors that distort the
1058Cooper ligaments may lead to skin dimpling with these maneuvers.
Palpation
[2] While the patient is seated, each breast should be palpated methodically.
Some physicians recommend palpating the breast in long strips, but the exact
palpation technique used is probably not as important as the thoroughness of its
application over the entire breast. One very effective method is to palpate the
breast in enlarging concentric circles until the entire breast is covered. A
pendulous breast can be palpated by placing one hand beneath the breast and
gently palpating the breast between both examining hands with the patient still
seated. The axillary and supraclavicular areas should be palpated for enlarged
lymph nodes. The entire axilla, the upper outer quadrant of the breast, and the
axillary tail of Spence are palpated for possible masses. [2] While the patient is
supine with one arm over her head, the ipsilateral breast is again
methodically palpated from the clavicle to the costal margin and from the
sternum to the latissimus dorsi laterally. If the breast is large, a pillow or towel
may be placed beneath the scapula to elevate the side being examined; otherwise,
the breast tends to fall to the side, making palpation of the lateral hemisphere
more difficult. The major features to be identified on palpation of the breast are
temperature, texture and thickness of skin, generalized or focal tenderness,
nodularity, density, asymmetry, dominant masses, and nipple discharge. Most
premenopausal patients have normally nodular breast parenchyma. The nodularity
is diffuse but predominantly in the upper outer quadrants, where there is more
breast tissue. These benign parenchymal nodules are small, similar in size, and
indistinct. By comparison, breast cancer usually occurs in the form of a
nontender, firm mass with irregular margins. A cancerous mass feels distinctly
different from the surrounding nodularity. A malignant mass may be fixed to the
skin or to the underlying fascia. A suspicious mass is usually unilateral. Similar
findings in both breasts are unlikely to represent malignant disease (3).
1059FIGURE 19-1 Raising the arm reveals retraction of the skin of the lower outer quadrant
caused by a small palpable carcinoma. (From Giuliano AE, Dang CM. Breast disease. In:
Berek JS, Hacker NF, eds. Berek & Hacker’s Gynecologic Oncology. 6th ed. Philadelphia:
Lippincott Williams & Wilkins; 2014:650.)
Breast Self-Examination
1060Breast self-examination (BSE) may help some women but is no longer
recommended for the average-risk patient. BSE is associated with no
improvement in breast cancer survival and increases biopsies for ultimately
benign lesions (10). In patients wishing to do BSE, they should be educated
regarding the natural cyclic changes of the breast and instructed to examine their
breasts at the same time during each menstrual cycle. Premenopausal women who
wish to perform BSE should examine their breasts monthly 7 to 10 days after the
onset of the menstrual cycle. For postmenopausal women, selection of a specific
calendar date is a helpful way to remember to perform a monthly BSE. Women
should be instructed to report any abnormalities or changes to their physicians. If
the physician cannot confirm the patient’s findings, the examination should be
repeated in 1 month or after her next menstrual period (11).
The following seven “P’s” represent the essential components of breast
examination:
Positions
Palpation
Pads of fingers for palpation
Pressure
Perimeter
Pattern of search
Patient education
The woman should inspect her breasts while standing or sitting before a mirror,
looking for any asymmetry, skin dimpling, or nipple retraction. Elevating her
arms over her head or pressing her hands against her hips to contract the
pectoralis muscles will highlight any skin dimpling. Finally, the woman should
examine her breasts while bending over and leaning forward. While standing or
sitting, she should carefully palpate her breasts with the fingers of the opposite
hand. She should lie down and again palpate each quadrant of the breast as well
as the axilla using the pads of the three middle fingers with three pressures—light,
medium, and deep—covering the entire breast from the clavicle to the
inframammary fold, from the sternum to the latissimus dorsi laterally. The area
within the perimeter of the breast should be palpated, preferably using an up-anddown method called the vertical stripe, rather than the concentric circular or radial
methods, in which the edges of the breast tissue often are omitted. Many women
feel anxious about performing breast examination (12). The examination may be
performed while showering; soap and water may increase the sensitivity of
palpation, and the privacy of the shower may provide a less anxiety-provoking
environment.
1061Breast Imaging
Mammography
[2] Mammography remains the gold standard for screening for breast
cancer. It is an excellent screening test and its sensitivity usually increases
with age as does cancer incidence (13). Full-field digital mammography
(FFDM), which records mammographic images on a computer, is a modification
of the older screen-film mammography and has become standard in many centers.
This technology has allowed many conveniences including the ability to
manipulate a computerized image for optimal viewing and access to distant
consultations through telemammography. Radiation exposure is less with digital
than with conventional film mammography. Digital mammography has
demonstrated superior sensitivity, but lower specificity for women with dense
breasts and those aged 40 to 49 years at the expense of increased costs and more
false-positive results (14).
Tomosynthesis, or three-dimensional (3D) mammography, is another
breast imaging technique used in conjunction with standard mammography
to improve the sensitivity of screening. This technique uses a moving x-ray
source to collect 3D volumetric data and reconstruct thin sections of the breast. In
tomosynthesis, increased lesion detection comes at the expense of increased
radiation exposure (15). In prospective trials, tomosynthesis plus mammography
resulted in a cancer detection rate of 8.0 to 8.8 per 1,000 screens versus 6.1 to 6.3
per 1,000 for mammography alone (15–17). Tomosynthesis has the theoretical
advantage of eliminating false positives that occur as a result of superimposition
of compressed breast tissue in standard mammography. This was supported by
retrospective data, but thus far has failed to be consistently supported in
prospective trials. Tomosynthesis does decrease the need to call patients back for
additional views (18).
[2] Compression of the breast is necessary to obtain good mammographic
images, and patients should be forewarned that breast compression is
uncomfortable. With good technique and well-maintained modern equipment,
exposure to radiation can be limited. FFDM has a 22% lower mean glandular
radiation dose than film-screen mammography per acquired view. FFDM delivers
1.86 mGy average breast radiation dose per view compared to 2.37 mGy for film
screen, while tomosynthesis delivers twice the dose of digital mammography on
average (19,20).
[2] Slow-growing breast cancers can be identified by mammography at least
2 years before the mass reaches a size detectable by palpation. These tumors
have a less aggressive biologic behavior than interval breast cancers (19–21).
Mammography is the only reproducible method of detecting nonpalpable breast
1062cancer, but its use depends on the availability of state-of-the-art equipment and a
dedicated breast radiologist.
This desire for supplemental screening modalities coupled with concerns about
radiation exposure have prompted some centers to adopt whole-breast ultrasound
screening programs using either handheld probes or automated systems wherein
an automated transducer is used to acquire standardized images (22). These
adjuncts can detect mammographically occult breast cancers, again at the risk of
increased false-positive findings, leading to unnecessary core needle biopsy
(CNB) (22,23).
Indications for Mammography
[2] The indications for mammography are as follows:
1. To establish a baseline breast mammogram and reevaluate patients at
regular intervals to diagnose a potentially curable breast cancer before it
has been diagnosed clinically.
2. To screen women who are at high risk for developing breast cancer.
3. To evaluate a questionable or ill-defined breast mass or other suspicious
change in the breast that is detected by clinical breast examination.
4. To search for occult breast cancer in a patient with metastatic disease in
axillary nodes or elsewhere from an unknown primary origin.
5. To screen for unsuspected cancer before cosmetic operations or biopsy of
a mass.
6. To monitor breast cancer patients who were treated with a breastconserving surgery and radiation.
Mammographic Abnormalities
A mammographic abnormality includes a mass (solid or cystic),
microcalcifications (benign, indeterminate, or suspicious), asymmetric density,
architectural distortion, and appearance of a new density. [2] There are eight
morphologic categories of mammographic abnormalities (24):
1. Calcification distribution
2. Number of calcifications
3. Description of calcifications
4. Mass margin
5. Shape of mass
6. Density of mass
7. Associated findings
8. Special cases
1063Mammographic abnormalities should be visible on two views, usually
craniocaudal (CC) and mediolateral oblique (MLO). The lesion should triangulate
to the same location on those two views. Calcifications can be
macrocalcifications, which are coarse and usually represent benign degenerative
breast conditions. Calcifications associated with breast cancer are clustered,
pleomorphic microcalcifications; typically, five to eight or more calcifications are
aggregated in one part of the breast (25). These calcifications may be associated
with a mammographic mass density. A mass density may appear without
evidence of calcifications. It can represent a cyst, benign tumor, or a malignancy.
A malignant density usually has irregular or ill-defined borders and may lead to
architectural distortion, which may be subtle and difficult to detect in a dense
breast. Other mammographic findings suggesting breast cancer are architectural
distortion, asymmetric density, skin thickening or retraction, or nipple retraction.
Examples of mammographic abnormalities can be found in several electronic
sources (26).
Mammographic Reports
The American College of Radiology recommended the [2] Breast Imaging
Reporting and Data System (BI-RADS) as a standardized scheme for
describing mammographic lesions. In the BI-RADS system, there are six
categories for mammographic findings (other than incomplete) (24).
1. Incomplete, needs further imaging
2. Negative
3. Benign finding
4. Probably benign, short-interval follow-up recommended
5. Suspicious finding and biopsy should be performed
6. Highly suggestive of malignancy and appropriate action should be
undertaken
7. Known malignancy
The patient should be referred for tissue diagnosis if the report identifies a
lesion as a category 4 or 5 (20). A category 0 indicates incomplete evaluation,
and further diagnostic studies are required. Category 3 connotes a finding that
is most likely benign; a short-interval follow-up is recommended, and breast
examination by an expert should be considered.
Correlation of Findings
[2] Biopsy must be performed on patients with a dominant or suspicious
mass despite absence of mammographic findings (23). Mammography should
1064be performed before biopsy so other suspicious areas can be noted and the
contralateral breast can be checked (Fig. 19-2). Mammography is never a
substitute for biopsy because it may not reveal clinical cancer, especially
when it occurs in the dense breast tissue of young women with fibrocystic
changes. The sensitivity of mammography is approximately 80%, with a
specificity of 80% to 95% depending on the expertise of the radiologist
interpreting the study and patient factors including breast density, patient age, use
of hormone therapy, and the size, location, and mammographic appearance of the
tumor (27). Mammography is less sensitive in young women with dense breast
tissue than in older women, who tend to have fatty breasts (28). Small tumors,
particularly those without calcifications, are more difficult to detect, especially in
women with dense breasts.
FIGURE 19-2 Bilateral mammography shows the extent of breast carcinoma, illustrating
the importance of bilateral mammography in the workup of a clinically apparent mass.
(From Giuliano AE, Dang CM. Breast disease. In: Berek JS, Hacker NF, eds. Berek &
1065Hacker’s Gynecologic Oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins;
2014:652.)
Ultrasonography
Breast ultrasonography is frequently used for focused scanning of a palpable
lesion or mammographic finding (29). Reliable, portable, computer-enhanced
ultrasonography with high-frequency transducers and improved imaging is
available to evaluate and treat problems of the breast. It is a sensitive, minimally
invasive technique that is used frequently to evaluate some breast symptoms,
especially in younger women with dense breast tissue, but is dependent on the
availability of a skilled ultrasonographer (29). Some lesions can be detected only
with ultrasonography (23). It is the preferred modality to distinguish a solid from
a cystic mass (29). Breast ultrasonography may be used as an adjunct for
screening in women with dense breasts (30). Ultrasonography has a higher falsepositive rate than mammography (22,30).
[2] Following are indications for breast ultrasonography:
Palpable abnormality
Ambiguous mammographic findings
Silicone leak
Mass in woman younger than 30 years, lactating, or pregnant
Guidance for interventional procedures
Possible role for additional imaging in high-risk individuals
Ultrasonography is useful in distinguishing benign from malignant lesions
identified by mammography (29). Ultrasonography may be especially useful if
the patient feels a mass, but the physician cannot detect an abnormality and the
mammogram does not disclose one. It may identify cancers in the dense breast
tissue of premenopausal women, but it is usually used to distinguish a benign cyst
from a solid tumor. Ultrasonography cannot reliably detect
microcalcifications, and it is not as useful as mammography in assessing
women with fatty breasts.
[2] Handheld or real-time ultrasonography is very accurate in
differentiating solid masses from cysts (31). If a lesion proves to be a simple
cyst, no further evaluation is necessary. If the simple cyst is symptomatic,
aspiration may be performed. Rarely ultrasonography may identify a small cancer
within a cyst, an intracystic carcinoma. These complex cysts warrant surgical
biopsy.
Magnetic Resonance Imaging
1066Magnetic resonance imaging (MRI) is an appealing technique for imaging the
breast because it is highly sensitive and does not utilize ionizing radiation. Several
roles have been proposed for the use of breast MRI, but relatively few of these are
clearly supported by the literature (32).
It has been suggested that MRI may be useful for further workup of
inconclusive findings on mammography and ultrasonography (33). Gadolinium
enhancement on breast MRI is associated with breast cancer, but has varying
degrees of specificity (32). Enhancement patterns are known to vary with the
menstrual cycle and some noncancerous masses enhance with gadolinium (33).
[2] The National Comprehensive Cancer Network has recommended the
addition of annual MRI screening for patients with >20% lifetime risk of
breast cancer to routine mammographic screening (34). Screening MRI is not
recommended for women with average risk of breast cancer. In retrospective
studies of the high-risk population, 10 cancers are identified per 1,000 women
screened, 70% of which are seen on MRI only (35). MRI screening has a
sensitivity of greater than 90%, but a specificity of 60%, resulting in fivefold the
number of biopsies and 10-fold the callback rate for a 6-month follow-up study
(BI-RADS category 3 assessment) of mammographic screening alone (35,36). In
prospective studies, 10-year survival is not improved, but fewer cancers detected
on MRI are lymph node–positive compared to mammography with no additional
screening (36). This finding has led to the hypothesis that earlier diagnosis in this
population leads to improved quality of life by allowing less radical therapy.
Routine preoperative evaluation of patients diagnosed with breast cancer is a
common practice that is not evidence based (37). Several large meta-analyses
have demonstrated no oncologic benefit to routine preoperative MRI (38–40).
These studies demonstrate no difference in disease-free survival, or local or
distant recurrence, but do show increased rates of biopsy, mastectomy, overall
number of surgical procedures, and cost (38–40). [2] Routine preoperative
breast MRI in patients diagnosed with breast cancer is not necessary.
Breast MRI is commonly used to evaluate the in-breast response to
neoadjuvant chemotherapy (NAC) (41). MRI enhancement does correlate with
the extent of disease found at evaluation of the surgical specimen, but less
frequently influences clinical decision making. In a study of 60 patients who
received NAC in an attempt to allow breast conservation, mammographic
findings and patient preference determined the decision for or against breast
conserving surgery despite a favorable post-NAC MRI (41). No patient initially
felt to require downstaging was denied breast conserving treatment on the basis of
post-NAC MRI, and of those electing to undergo lumpectomy, 91% were
successful (41).
One case in which pre-operative MRI clearly benefits patients is that of a
1067woman presenting with breast cancer with axillary metastasis and no identifiable
primary tumor. [2] Breast MRI identifies a mammographically occult primary
breast cancer in patients presenting with axillary metastasis in two-thirds of
patients, thus allowing breast conserving surgery (42).
MRI is extremely useful in identifying silicone released by ruptured breast
implants in patients with augmented breasts (Fig. 19-3). One interesting trial in
which 208 asymptomatic women underwent breast MRI prior to scheduled
explantation of recalled silicone breast implants, showed a sensitivity and
specificity of 93% and a negative predictive value of 98% (43). In practice,
breast MRI may be used reliably to rule out implant rupture.
BREAST TISSUE EVALUATION: HISTOLOGY AND
CYTOLOGY
The safest course is tissue biopsy evaluation of all dominant masses found on
physical examination and, in the absence of a mass, evaluation of suspicious
lesions shown by breast imaging. Over 1 million women have breast biopsies
each year in the United States. Between 70% and 80% of these biopsies yield a
benign lesion (44). The diagnosis of a benign breast lesion versus breast
cancer is often difficult to determine based on clinical examination and
requires evaluation of tissue by core CNB. The sensitivity of CNB performed
using either stereotactic or ultrasound guidance is greater than 95% (45). Fineneedle aspiration cytology is an alternative to CNB, which allows cytologic
evaluation at about one-tenth the cost of CNB and remains useful in health
systems where the cost of CNB and pathologic analysis is prohibitive. The main
limitations of FNA are high rate of insufficient sampling, inability to distinguish
invasive from noninvasive cancers and insufficient tissue for
immunohistochemistry staining to determine hormone receptor and HER2 status
(46). CNB has replaced FNA and surgical biopsy as the diagnostic procedure of
choice for evaluation of a breast mass (47,48). CNBs can be performed with
mammographic or stereotactic, ultrasound or MRI guidance.
1068FIGURE 19-3 Mammography shows implant and extracapsular free silicone (arrow).
[2] About 30% of lesions suspected to be cancer prove to be benign on
biopsy, and about 15% of lesions believed to be benign prove to be malignant
(19). Dominant masses or suspicious nonpalpable breast lesions require
1069pathologic examination. In most cases, pathologic diagnosis should be obtained
before the decision is made to monitor a breast mass (49). An exception may be a
premenopausal woman with a nonsuspicious mass presumed to be fibrocystic
disease or a fibroadenoma with classical imaging findings. An apparently
fibrocystic lesion that does not completely resolve within several menstrual
cycles may be sampled for biopsy. Any mass in a postmenopausal woman
who is not taking estrogen therapy should be presumed to be malignant.
When the results of the clinical diagnosis, breast imaging studies, and pathology
are all in agreement, the workup is complete and treatment and follow-up
planning may be initiated. Figures 19-4 and 19-5 present algorithms for
management of breast masses in premenopausal and postmenopausal
patients. Simultaneous evaluation of a breast mass using clinical breast
examination, radiography, and needle biopsy can lower the risk of missing cancer
to only 1%, effectively reducing the rate of diagnostic failure and increasing the
quality of patient care (48).
[2] If the presence of breast cancer is strongly suggested by physical
examination, the diagnosis can be confirmed by CNB, and the patient may be
counseled regarding treatment. Treatment should not be determined based
on results of physical examination and mammography alone, in the absence
of biopsy results. The most reasonable approach to the diagnosis and
treatment of breast cancer is outpatient CNB, followed by definitive
operation at a later date if needed. Routine operative surgical biopsies are of
historical interest only and should not be performed. The pathologic data
obtained by CNB contributes to appropriate consideration of neoadjuvant
therapies and allows patients to adjust to the diagnosis of cancer, carefully
consider therapeutic options, and seek a second opinion (46,47). In cases of
indeterminate diagnoses on CNB, surgical excision remains useful to clarify
diagnosis and rule out coexistent malignancy.
Core Needle Biopsy
[2] The interpretation of results from CNB is classified by categories B1 to
B5 (50):
B1: Normal tissue
B2: Benign lesions: fibroadenomas, fibrocystic change, sclerosing adenosis,
duct ectasia, fat necrosis, abscess
B3: Uncertain malignant potential: atypical epithelial hyperplasia, lobular
neoplasia, phyllodes tumor, papillary lesions, radial scar, complex
sclerosing lesions
B4: Suspicious
1070B5: Malignant
Histologic Analysis
Histologic evaluation with hematoxylin and eosin (H&E) staining confirms
benign or malignant disease. Images of benign and malignant breast lesions can
be viewed through the Internet Pathology Laboratory for Medical Education (51).
BENIGN BREAST CONDITIONS
Benign breast disorders account for most breast problems. These conditions are
frequently considered in the context of excluding breast cancer and often are
unrecognized for their own associated morbidity (3). To provide appropriate
management, it is important to consider benign breast disorders from four aspects:
(i) clinical picture, (ii) medical significance, (iii) treatment intervention, and (iv)
pathologic etiology (3). A framework for understanding benign breast problems is
called Aberrations of Normal Development and Involution (ANDI) (52,53). It
includes symptoms, histology, endocrine state, and pathogenesis in a progression
from a normal to a disease state. Most benign breast conditions arise from normal
changes in breast development, hormone cycling, and reproductive evolution
(52).
1071FIGURE 19-4 Algorithm for management of breast masses in premenopausal women.
1072FIGURE 19-5 Algorithm for management of breast masses in postmenopausal women.
[3] Three life cycles reflect different reproductive phases in a woman’s life
and are associated with unique breast manifestations.
1. During the early reproductive period (15 to 25 years), lobule and stromal
formation occurs. The ANDI conditions associated with this period are
fibroadenoma (mass) and juvenile hypertrophy (excessive breast
development). In this first stage, the progression from ANDI to a disease state
results in the formation of giant fibroadenomas and multiple fibroadenomas.
2. During the mature reproductive period (25 to 40 years), cyclic hormonal
changes affect glandular tissue and stroma. In this second period, the ANDI
1073is an exaggeration of these cyclic effects, such as cyclic mastalgia and
generalized nodularity.
3. The third phase is involution of lobules and ducts or turnover of epithelia,
which occurs during ages 35 to 55 years. The ANDI associated with lobular
involution are macrocysts (lumps) and sclerosing lesions (mammographic
abnormalities). Those associated with ductal involution are duct dilation
(nipple discharge) and periductal fibrosis (nipple retraction), and those with
epithelial turnover are mild hyperplasia (pathologic description).
Disease conditions with increased epithelial turnover are epithelial hyperplasias
with atypia. Breasts are under endocrine control and show a wide range of
appearances during reproductive life. ANDI classification allows the clinician to
understand the pathogenesis of these conditions and to understand that these
disorders are aberrations of a normal process that does not usually require any
specific treatment (53).
BREAST MASS
Fibrocystic Change
[3] Fibrocystic change, the most common lesion of the breast, is an imprecise
term that covers a spectrum of clinical signs, symptoms, and histologic
changes (52). The term refers to a histologic picture of fibrosis, cyst formation,
and epithelial hyperplasia. Cysts arise from the breast lobules and are an
aberration of normal breast involution (53). Macroscopic cysts occur in
approximately 7% of women, and microscopic, nonpalpable cysts occur in about
40% of women (54). It is common in women 35 to 55 years of age, but rare in
postmenopausal women not taking hormone therapy. The presence of estrogen
seems necessary for the clinical symptoms to occur. This finding is supported by
the observation that it is present bilaterally, increased in the perimenopausal age
group, and responsive to endocrine therapy (55). In essence, a diagnosis of
fibrocystic change can lead to significant patient anxiety but is of little clinical
significance as long as malignancy is excluded (3). These lesions are associated
with benign changes in the breast epithelium and patients with this entity should
be reassured.
Clinical Findings in Fibrocystic Disease
[3] Fibrocystic changes may produce an asymptomatic mass that is smooth,
mobile, and potentially compressible. Fibrocystic change is more often
accompanied by pain or tenderness and sometimes nipple discharge. In
many cases, discomfort coincides with the premenstrual phase of the cycle,
1074when the cysts tend to enlarge. Fluctuations in size and rapid appearance or
disappearance of a breast mass are common. Multiple or bilateral masses
appear frequently, and many patients have a history of a transient mass in
the breast or cyclic breast pain. Cyclic breast pain is the most commonly
associated symptom of fibrocystic changes.
Differential Diagnosis
Pain, fluctuation in size, multiplicity of lesions, and bilaterality are the features
most helpful to differentiate fibrocystic disease from carcinoma. If a dominant
mass is present, the diagnosis of cancer should be suspected until it is disproved
by complete aspiration of a cyst, or pathologic analysis by CNB if a mass is
present after aspiration. Microscopic findings associated with fibrocystic disease
include cysts (gross and microscopic), papillomatosis, adenosis, fibrosis, and
ductal epithelial hyperplasia (3).
Diagnostic Tests
[3] Patients with cystic disease may have a discrete fibrocystic mass that is
frequently indistinguishable from carcinoma, based on clinical findings.
Mammography may be helpful, but there are no mammographic signs diagnostic
of fibrocystic change. Ultrasonography is useful in differentiating a cystic from a
solid mass. Characteristic findings on ultrasonography that confirm a simple
cyst include the following:
Mass with thin walls
Smooth round shape
Absence of internal echoes
Posterior acoustic enhancement
If these imaging criteria are not met, a tissue diagnosis of the mass, by CNB, is
required. The finding of a simple cyst by ultrasonography rules out carcinoma.
Any lesion that is suspicious by mammography or ultrasonography should be
biopsied. When the diagnosis of fibrocystic change is established by
ultrasonography, aspiration of a cyst is indicated only if the patient is
symptomatic or the cyst obscures visualization of breast tissue on mammography
and prevents adequate imaging. Aspiration may be performed with
ultrasonographic guidance, but image guidance may not be absolutely necessary
when the cyst is palpable (56). Aspiration of a cyst is a minimally invasive
procedure performed with a 21- or 22-gauge needle without local anesthesia and
is not associated with significant risks or complications. There is minimal pain
and little risk for infection or bleeding. Benign cyst fluid is straw colored to dark
1075green to brownish and does not need to be submitted for cytologic evaluation
(57). The patient should be reexamined at a short interval thereafter for cyst
recurrence. Cysts will reoccur in one-third of patients, cause anxiety, and require
repeated evaluations. [3] Tissue biopsy should be performed in the presence of
the following findings (54–59):
No cyst fluid is obtained.
The fluid is bloody.
The fluid is thick.
The cyst is complex.
There is an intracystic mass.
A mass persists after aspiration.
A persistent mass is noted at any time during follow-up.
If a needle biopsy is performed and results are negative for malignancy, a
suspicious mass that does not resolve at short-interval follow-up imaging
should be excised (56). Surgery should be conservative, because the primary
objective is to exclude cancer. Simple mastectomy or extensive removal of breast
tissue is not indicated for fibrocystic disease. Most patients do not require
treatment for fibrocystic changes, just reassurance that fibrocystic change is a
transient phenomenon of aging that is associated with hormonal effects on the
breast glandular tissue that eventually subsides.
Cyst Fluid Analysis
Investigators have examined the electrolyte and protein content of cyst fluid, but
this is of little significance in the clinical management of fibrocystic disease. The
potassium-to-sodium ratio is a marker that may be used to distinguish cyst
subtypes (60). Cysts are either secretive, lined by an apocrine epithelium with a
high potassium-to-sodium ratio and a higher hormone or steroid concentration
(type I); or transudative, lined by flattened lobule epithelium with a low
potassium-to-sodium ratio and a higher concentration of albumin,
carcinoembryonic antigen, CA125, and steroid hormone–binding globulin (type
II) (60). Apocrine cysts produce and secrete large amounts of prostate-specific
antigen (PSA) (61). The role of this serine protease in proliferative breast disease
is not fully understood.
Fibrocystic Change and Risk for Breast Cancer
[3] Fibrocystic change is not associated with an increased risk of breast
cancer unless there is histologic evidence of epithelial proliferative changes,
with or without atypia (62). The common coincidence of fibrocystic disease and
1076malignancy in the same breast reflects the fact that both processes are common
events. Approximately 80% of biopsies show fibrocystic changes. In an
evaluation of the relationship between fibrocystic change and breast cancer in
10,366 women who underwent biopsy between 1950 and 1968 and were followed
for a median of 17 years, approximately 70% of the biopsies showed
nonproliferative breast disease, whereas 30% showed proliferative breast disease
(62). Cytologic atypia were present in 3.6% of cases. Women with
nonproliferative disease had no increased risk of breast cancer, whereas women
with proliferative breast disease and no atypical hyperplasia had a twofold higher
risk of breast cancer. [6] Patients whose biopsy results showed atypical ductal
or lobular hyperplasia had an approximately fivefold higher risk than
women with nonproliferative disease to develop invasive breast cancer in
either breast. Patients with carcinoma in situ have an 8- to 10-fold risk of
developing breast cancer. This risk is bilateral for lobular lesions and ipsilateral
for ductal lesions. A family history of breast cancer added little risk for women
with nonproliferative disease, but family history plus atypia increased breast
cancer risk by 11-fold. The presence of cysts alone did not increase the risk of
breast cancer, but cysts combined with a family history of breast cancer increased
the risk about threefold (62). Women with these risk factors (family history of
breast cancer and proliferative breast disease) should be followed carefully with
physical examination and mammography. For such women, age-specific
probability of developing invasive breast carcinoma in the next 10 years is 1 in
2,000 (age 20), 1 in 256 (age 30), 1 in 67 (age 40), 1 in 39 (age 50), and 1 in 29
(age 60) (62). The relative risk for developing breast cancer depends on the type
of proliferative lesion diagnosed.
Management of Fibrocystic Change
[3] Fibrocystic change is a normal evolutionary change in breast
development and involution and does not require a specific treatment other
than a good clinical breast examination and age-appropriate mammographic
screening or imaging studies directed to signs and symptoms. A number of
nutritional and dietary supplements have been investigated to relieve symptoms.
The role of caffeine consumption in the aggravation of fibrocystic change is
controversial (63,64). Results of some studies suggest that eliminating caffeine
from the diet is associated with improvement of symptoms. Many patients are
aware of these studies and report relief of symptoms after discontinuing intake of
coffee, tea, and chocolate. Vitamin E and B6 supplementation have been
suggested as possible treatments given the biochemical changes observed in
fibrocystic breast tissue with direct administration (65). Observations about the
clinical effects of these vitamins are difficult to confirm and are anecdotal (66).
1077Investigations of nutritional interventions for fibrocystic breast conditions have
had insufficient data to draw clear conclusions about their effectiveness (67).
Exacerbations of pain, tenderness, and cyst formation may occur at any time until
menopause, when symptoms usually subside, unless patients are taking estrogen.
Patients with symptoms of pain that significantly diminish the quality of life may
consider hormonal therapies for mastalgia (68).
Fibroepithelial Lesions
Fibroadenoma
[4] Fibroadenomas are the most common benign tumors of the breast. They
usually occur in young women (age 20 to 35 years) and may occur in teenagers
(69,70). In women younger than 25 years, fibroadenomas are more common than
cysts. They rarely occur after menopause, although occasionally they are found,
often calcified, in postmenopausal women (71). For this reason, it is postulated
that fibroadenomas are responsive to estrogen stimulation. Fibroadenomas may
appear as single masses or as multiple lesions.
Clinically, a young woman usually notices a mass while showering or dressing.
Most masses are 1 to 3 cm in diameter when detected, but they can become
extremely large (i.e., the giant fibroadenoma). On physical examination, they are
firm, smooth, and rubbery. They do not elicit an inflammatory reaction, are freely
mobile, and cause no dimpling of the skin or nipple retraction. They are often
bilobed, and a groove can be palpated on examination. On mammographic and
ultrasonographic imaging, the typical features are of a well-defined, smooth,
oblong, solid mass with clearly defined margins.
[4] Fibroadenoma is not associated with an increased risk for breast cancer
(3). The natural history of fibroadenoma can be regression, growth, or no change
in size. Most fibroadenomas are static or cease growth at approximately 2 to 3
cm, about 15% of tumors regress spontaneously, and only 5% to 10% progress
(72). A fibroadenoma that is classic on imaging need not be biopsied, but should
be followed with short-interval repeat imaging to document stability. Because
cancer occurring in a fibroadenoma is rare and regression is frequent,
management recommendations are conservative unless there is evidence of
growth (34). Rarely will the fibroadenoma increase to more than 2 to 3 cm in size.
Large or growing fibroadenomas must be excised to exclude carcinoma or
phyllodes tumor. Complete excision of a fibroadenoma with local anesthesia can
be performed to treat the lesion and confirm the absence of malignancy. Less
invasive local treatment of a fibroadenoma is advocated by some and can be
performed with either ultrasonographically guided percutaneous vacuum-assisted
biopsy devices or percutaneous cryoablation (73).
1078On gross examination of an excised mass, the fibroadenoma appears
encapsulated and sharply delineated from the surrounding breast parenchyma.
Microscopically, there is proliferation of the epithelial and stromal component. In
longstanding lesions and in postmenopausal patients, calcifications may be
observed within the stroma.
Multiple Fibroadenomas
Multiple fibroadenomas occur in some women and were reported to occur more
frequently in premenopausal women undergoing immunosuppression for organ
transplantation (74).
Phyllodes Tumor
[4] Phyllodes tumors are rare fibroepithelial tumors that display a spectrum
of clinical and pathologic behaviors that may be either benign, borderline, or
malignant (75). The majority of phyllodes tumors are benign (60%), with
fewer being malignant (20%) and borderline lesions (20%) (76). Variation in
histologic interpretation may influence these rates (71). Phyllodes tumors may
occur at any age but tend to be more common in women who are in their late 30s,
40s, and 50s (76). These lesions are rarely bilateral and usually appear as
isolated masses that are difficult to distinguish clinically from a
fibroadenoma. Patients often relate a long history of a previously stable nodule
that suddenly increases in size. Reported sizes range from 1 to 50 cm (77). Size is
not a dependable on the diagnostic criterion, although phyllodes tumors tend to be
larger than fibroadenomas, probably because of their rapid growth. There are no
good clinical criteria by which to distinguish a phyllodes tumor from a
fibroadenoma. Whereas observation of a fibroadenoma is acceptable, excision of
a phyllodes tumor is necessary for local control and for determination of benign
or malignant features. To avoid unnecessary excision of benign fibroadenomas
that are indistinguishable from phyllodes tumors on clinical examination, imaging
criteria were sought to aid in identifying patients who require EB for complete
histopathologic evaluation and local control. Mammography may show a halo
around a phyllodes tumor mass but cannot reliably distinguish a fibroadenoma
from a phyllodes tumor (76). Ultrasonography evaluation has limitations even
when color and pulse Doppler ultrasonography are used in conjunction with it
(76).
[4] Microscopic evaluation of a lesion is important to determine the
diagnosis. The histologic distinction between fibroadenoma, benign,
borderline, and malignant phyllodes tumor can be very difficult on minimal
tissue sampling with CNB (71,78). It may be easier to distinguish benign
phyllodes from malignant phyllodes tumors than benign phyllodes tumors from
1079fibroadenomas (71). Histologic features that stratify lesions include number of
mitoses per high power field, stromal cellularity, pushing or infiltrating tumor
margin, cellular atypia, tumor necrosis, and stromal overgrowth (71).
[4] If a lesion cannot be clearly characterized as a fibroadenoma, excision
may be necessary. Factors that are considered in recommending excision include
older age, new mass in a well-screened individual, rapid growth, size greater than
2.5 to 3 cm, suspicious CNB, and mammographic or ultrasonographic features
that demonstrate lobulation and intramural cysts. If observation is elected, repeat
clinical examination and imaging in a short interval is essential to evaluate the
change in size.
[4] Treatment of core biopsy–proven phyllodes tumor is wide local excision,
attempting to obtain a 1- to 2-cm margin since malignancy may not be
excluded (79). Massive tumors, or large tumors in relatively small breasts, may
require mastectomy; otherwise, mastectomy should be avoided, and axillary
lymph node dissection is not indicated. In most cases a phyllodes tumor is locally
excised because it was felt to be a fibroadenoma. Reexcision is rarely necessary
for benign phyllodes tumor, but is recommended for phyllodes tumors with
borderline or malignant features (79–81).
The prognosis of benign and malignant phyllodes tumors is variable (82,83).
[4] Tumors judged to be benign phyllodes tumors can recur locally in up to
10% of patients (81). Recurrence is associated with margin involvement,
whereas mortality correlates with size and grade (82). In high-grade malignant
phyllodes tumors, size and excision margins are associated with local recurrence
and metastatic spread, and mastectomy may be required to achieve complete
surgical excision in patients with small breasts (83). [4] Malignant phyllodes
tumors tend to recur locally and, although metastasis is unusual, they may
occasionally metastasize to the lung, although brain, pelvic, and bone
metastases may occur (83). The stromal component of the tumor is malignant
and metastasizes, behaving like a sarcoma. Axillary involvement is extremely
unusual. Often, the appearance of metastasis is the first sign that a phyllodes
tumor is malignant. Chemotherapy for metastatic phyllodes tumors should be
based on regimens for sarcoma, not adenocarcinoma (84). Radiation therapy
generally is not used in the treatment of phyllodes tumors, but in the presence of a
bulky tumor, positive margins, recurrence, or malignant histology, it may be of
some benefit (85).
Fat Necrosis
Fat necrosis of the breast is rare but clinically important because it produces
a mass, clinically indistinguishable from carcinoma, often accompanied by
skin or nipple retraction. Fat necrosis often presents as a confusing clinical
1080finding. Trauma is presumed to be the cause, although only about one-half of
patients have a history of injury to the breast. Ecchymosis is occasionally seen
near the mass. Tenderness may or may not be present. If untreated, the mass
associated with fat necrosis gradually disappears. Diagnostic imaging studies are
usually insufficient (86). As a rule, the safest course is needle-core or excisional
biopsy of the entire mass to rule out carcinoma. Fat necrosis is common after
segmental resection and radiation therapy or native tissue reconstruction (87).
PAIN
Mastitis and Breast Abscess
Lactational Mastitis and Abscesses
Infection in the breast is rare unless the patient is lactating or has experienced an
injury. Lactational mastitis must be distinguished from lactational abscess (3).
During lactation, an area of redness, tenderness, and induration frequently
develops in the breast. [5] Lactational mastitis is caused by transmission of
bacteria during nursing and poor hygiene. The organism most commonly
found in lactational mastitis and abscesses is Staphylococcus aureus (88). If
lactational mastitis is diagnosed, manual pressure, antibiotics, and continued
breastfeeding are recommended. In its early stages, the infection often can be
treated while breastfeeding is continued by administering an antibiotic such as
dicloxacillin 250 mg four times daily, or oxacillin 500 mg four times daily, for 7
to 10 days. [5] If the lesion progresses to a localized mass with local and
systemic signs of infection, an abscess is present. It should be drained,
percutaneously, and breastfeeding should again be encouraged to continue
(89).
Nonlactational Abscess
Rarely, infections or abscesses may develop in young or middle-aged women who
are not lactating (90). The approach to nonlactational abscess is conservative
(91,92). A suspected abscess should be evaluated with ultrasonography to detect
the presence of an inflammatory mass, frank pus, solitary cavity, or a
multiloculated abscess (93). Aspiration of pus, if present, and antibiotic therapy is
instituted with reaspiration, if necessary (93). When the fluid collection is large,
percutaneous drain placement is an option (89). A single aspiration is sufficient in
about one-half of patients (94). Recurrent abscess formation is low (10%), in
general, but much higher in smokers (94). Bacteriologic analysis of 190 abscesses
in nonlactating and lactating women showed a preponderance of gram-positive
1081cocci. S. aureus was the most common organism isolated (51.3%). Of these, 8.6%
were methicillin-resistant S. aureus (MRSA), but rates of MRSA are expected to
rise as colonization rates increase in the general population. Other common
organisms included mixed anaerobes (13.7%) and anaerobic cocci (6.3%) (93).
[5] If these infections recur after multiple aspirations, incision and drainage
followed by excision of the involved lactiferous duct or ducts at the base of
the nipple may be necessary during a quiescent interval. In virtually all cases,
mammillary sinus (lactiferous duct fistula) can be confirmed as the cause of
reinfection or persistent infection (95). Inflammatory carcinoma is a consideration
when erythema of the breast is present. Patients should not undergo prolonged
treatment for an apparent infection unless biopsy eliminated the possibility of
inflammatory carcinoma. Patients who smoke should be counselled regarding
smoking cessation.
Subareolar Abscess and Lactiferous Duct Fistula
Subareolar abscess and fistula of the lactiferous ducts secondary to squamous
metaplasia can occur (95). The distal duct can be occluded with inspissated
debris. Several large reviews report a high association of lactiferous duct fistulae
with tobacco smoking (95). The definitive treatment for lactiferous duct sinus is
excision of the lactiferous duct and drainage of the abscess cavity. [5] The
recurrence rate is greater when only incision and drainage is performed
(3,95).
Granulomatous Mastitis
Granulomatous (lobular) mastitis is characterized by an inflammatory phlegmon
of the breast that is often tender, painful, and associated with skin ulceration. It
may be confused with multiple recurrent abscesses or even cancer. It occurs most
frequently in parous women (96). Granulomatous mastitis may be associated with
hyperprolactinemia but is idiopathic. Diagnosis is by CNB, which will
demonstrate noncaseating granulomata surrounding the breast lobule. Culture of
the tissue should be sent to rule out other causes of granulomata such as
tuberculosis. Therapy for granulomatous mastitis is observation alone and the
process usually resolves within 9 months to 1 year (96). A short course of
antimicrobial therapy may be useful in patients with positive cultures.
Mondor Disease
The Mondor disease is superficial thrombophlebitis of the thoracoepigastric vein
presenting as pain and erythema of the breast progressing to a palpable cord.
Therapy is supportive care with warm compresses and nonsteroidal anti-
1082inflammatory medication.
Mastalgia
Mastalgia is a recognized organic condition that is studied less thoroughly than
other breast problems and a challenge to treat (97). The etiology is believed to be
hormonal (63). Approximately 70% to 80% of women experience severe breast
pain at some time in their lives and mastalgia is the most common breast
symptom causing women to consult physicians (63,98). For one in six of these
patients, the mastalgia is so severe that it alters lifestyle and requires repeated
investigations and treatment. Mastalgia interferes with sexual function in 40% of
affected women and sleep in 35% (99). Social relationship, work, and athletic
performance have been reported to suffer (99).
Types of Mastalgia
[3] Breast pain is a distressing constellation of symptoms that is classified as
cyclic, noncyclic, or extramammary (97). Cyclic mastalgia is related to
exaggerated premenstrual symptoms beginning in the luteal phase of the
menstrual cycle, associated with breast engorgement, pain, ache, heaviness, and
tenderness that is bilateral and can last for more than 1 week in some women
(63,97,100). Cyclical mastalgia is more prevalent in women in their third and
fourth decades of life and accounts for two-thirds of all breast pain symptoms
(63). Noncyclic mastalgia is independent of menstrual cycles and is described as
achy, burning soreness. It may be intermittent or constant, is usually unilateral,
occurs in the fourth and fifth decades, and is more difficult to treat than cyclic
mastalgia (63). Extramammary pain is perceived to be located in the breast but
is related to an extramammary site. Chest wall muscular pain, costal cartilage
symptoms, herpes zoster, radiculopathies, and rib fractures are among some of the
more common causes of extramammary pain. Costochondritis (Tietze syndrome)
is a manifestation of chest-wall pain that is frequently interpreted as breast pain.
Management of Mastalgia
[3] Breast pain is an unlikely symptom of malignancy, and when malignancy
is excluded by a clinical breast examination and age-appropriate breast
imaging for focal breast pain, the most important treatment is reassurance
(98,101). Reassurance of the benign nature of mastalgia alone provides an
improvement in complaints (97). For patients with persistent symptoms,
suggested treatments have spanned the gamut of medications, lifestyle
modifications, vitamins and supplements, and local excision. Discontinuation of
hormone therapy may be effective in some women. Maintenance of a pain-
1083score diary is important to understand the relationship of pain to factors
such as the menstrual cycle, activities of daily living, and stress. Failure of
therapy can lead to increased depression and anxiety in patients and treatment of
this syndrome should not be neglected (100).
Effective nonpharmacologic therapy begins with appropriately sized external
support garments (97). The breast has minimal structural support and is at
significant risk for motion-related displacement resulting in mastalgia. The use of
external support to minimize breast motion appears to be effective in reducing
breast pain. An ill-fitting brassiere is associated with a threefold risk of mastalgia
(102). Wearing a brassiere that gives good support and protection, both night and
day, improved symptoms in the majority of women (97). The effect of a sports
bra was greater than that of hormonal modulation with danazol in randomized
trial (103). In a small randomized controlled trial, exercise was associated with an
improvement in the symptoms of mastalgia. Exercising thrice weekly yielded
greater improvement in the quality of life than reassurance and supportive
garments alone (104).
Topical nonsteroidal therapy is another option for women with mastalgia (105).
Gel formulations of NSAIDs often are used for analgesia. In one study, patients
were stratified by cyclic versus noncyclic pain and then randomized to treatment
with NSAIDs versus placebo. There was a significant reduction in cyclic and
noncyclic pain in all groups, but the magnitude of change was greater in the
treatment arms and similar for cyclic and noncyclic pain.
Hormone-modulating drugs, including toremifene, ormeloxifene, danazol,
bromocriptine, tamoxifen, and Depo-Provera, are recognized drug treatments for
mastalgia (97). All of these pharmacologic therapies are associated with
significant side effects that limit their general use and several are not approved by
the FDA. [3] Withdrawal of birth control pills or hormone therapy may be all
that is required to alleviate symptoms (63).
The next line of therapy for patients not responding to supportive garments,
exercise, and analgesic, is selective estrogen receptor modulators (SERM).
Treatment with the SERM tamoxifen demonstrated reduction in breast pain at 10
and 20 mg per day, with equivalent effects compared with danazol and
bromocriptine in most studies (97). Despite this, tamoxifen is not approved for
this use in the United States. Ormeloxifene is a nonsteroidal SERM, most often
prescribed as an oral contraceptive pill that shows equivalent effect to tamoxifen
for noncyclical breast pain (106). Notably, at 12 weeks of therapy 60% of patients
reported relief of symptoms, but this was not durable, and by 24 weeks, the
percentage of women reporting relief had dropped to 30% (106). Ten percent of
women in this trail developed ovarian cysts and other bothersome side effects
included menstrual irregularities and dizziness.
1084For patients with severe symptoms not responding to SERMs, a temporary
course of a hormonal-regimen such as danazol or bromocriptine might then be
considered, always weighing the benefits against the side effects. Danazol is a
synthetic androgen that suppresses release of pituitary gonadotropin, prevents
luteinizing hormone surge, and inhibits ovarian steroid formation (107). It is the
only medication approved by the U.S. Food and Drug Administration (FDA) for
mastalgia. The androgenic effects—acne, edema, change in voice, weight gain,
headaches, depression, and hirsutism—often are intolerable, and many patients
stop taking danazol even when symptoms are improved (108). It can be initiated
at doses of 100 to 200 mg twice daily orally for patients with severe pain and then
tapered to a lower dose of 100 mg per day (108).
Breast pain is increased in some individuals who have elevated prolactin (PRL)
levels induced by thyrotropin-releasing hormone (TRH) (107). Bromocriptine is a
dopamine antagonist that inhibits the release of PRL. Bromocriptine (2.5 mg
twice daily) given for 3 to 6 months is effective in reducing mastalgia in women
who have TRH-induced elevation of PRL with side effects of nausea, vomiting,
and headache (109).
The side-effect profile of hormone modulating treatments has prompted a
search for alternative therapies with vitamins, supplements, and herbal extracts.
None of these has clearly been shown to be more efficacious than placebo, but
they remain popular among patients because they are less likely to be associated
with adverse drug-related side effects (97). Evening primrose oil containing
essential fatty acids (γ-linolenic acid [GLA]) was originally studied because of its
effect on prostaglandin synthesis, but has failed to demonstrate efficacy over
placebo (97). GLA use was found to be safe, without any significant side effects,
and was prescribed as therapy for mastalgia because of its lack of side effects.
Chamomile extract, in very small randomized studies, has been found to lead to
an improvement in symptoms and may represent the safest nonhormonal
supplement option, although the true efficacy of all investigated supplements is
likely negligible (97,110).
Macromastia
Women with very large breasts frequently experience pain in the neck, shoulders,
back, and breasts secondary to the excess weight of their breasts. This pain tends
to worsen throughout the day (111). Macromastia may cause distortions in
anatomy and posture resulting in shoulders that are pulled forward and
compensatory hypertrophy of the trapezius muscle. Many women develop painful
grooves in the shoulders from support garments, which may become permanent
over time.
In patients with obesity, primary therapy should be directed at weight loss with
1085a goal of achieving a normal body mass index. If symptoms persist and fail to
improve with physical therapy, then a referral should be made for consideration of
reduction mammoplasty. In a survey of 400 women who underwent reduction
mammoplasty, 94% reported improvement in shoulder grooving, 93% in shoulder
pain, 81% in back pain, and 88% in self-esteem. Despite postoperative
complications in 53% of patients, 93% reported that they would have the surgery
again (112).
DISORDERS OF THE NIPPLE–AREOLAR COMPLEX
Nipple Discharge
Nipple discharge is a presenting breast symptom in relatively few patients seeking
evaluation of a breast symptom. In one report, 4.5% of patients presenting with a
breast complaint reported nipple discharge, with roughly half being spontaneous
and the remainder provoked (113). Nipple discharge that does not occur
spontaneously has no pathologic significance. Provoked or self-induced nipple
discharge should be managed by reassurance and instruction to discontinue
manipulation. Spontaneous nipple discharge is more likely to be associated with
an underlying pathologic problem than provoked discharge. [6] Although it is a
distressing finding, less than 10% of spontaneous nipple discharge is
associated with carcinoma (114). Nipple discharge can be caused by neoplastic
or nonneoplastic processes (115). Usually discharge caused by malignancy is
bloody, as is that caused by papillomas. Nonneoplastic processes include
galactorrhea, physiologic changes resulting from mechanical manipulation,
parous condition, periductal mastitis, subareolar abscess, fibrocystic change, and
mammary duct ectasia. Neoplastic causes of nipple discharge in nonlactating
women are solitary intraductal papilloma, carcinoma, papillomatosis, squamous
metaplasia, and adenosis (113,115). Extramammary causes are related to
hormones and drugs (115). [6] Following are the important characteristics of
the discharge and other factors to be evaluated by history and physical
examination:
1. Nature of discharge (serous, bloody, or milky)
2. Association with a mass
3. Unilateral or bilateral
4. Single or multiple ducts
5. Discharge that is spontaneous (persistent or intermittent) or expressed by
pressure at a single site or on the entire breast
6. Relation to menses
7. Premenopausal or postmenopausal
10868. Hormonal medication (contraceptive pills or estrogen)
Breast Papilloma
Unilateral, spontaneous, bloody, or serosanguineous discharge from a single
duct is usually caused by an intraductal papilloma or, rarely, by an
intraductal cancer. In either case, a mass may not be palpable. The involved
duct may be identified by pressure at different sites around the nipple and at the
margin of the areola. Bloody discharge is more suggestive of cancer but usually is
caused by a benign papilloma in the duct. In premenopausal women, spontaneous
multiple-duct discharge, unilateral or bilateral, is most marked just before
menstruation. It often is caused by fibrocystic change. Discharge may be green or
brownish. Papillomatosis and ductal ectasia are usually seen on biopsy. If a mass
is present, it should be removed. Milky discharge from multiple ducts in
nonlactating women presumably reflects increased secretion of pituitary PRL;
serum PRL and thyroid-stimulating hormone levels should be evaluated to detect
a pituitary tumor or hypothyroidism. Hypothyroidism may cause galactorrhea.
Alternatively, phenothiazines may cause milky discharge that disappears when
the medication is discontinued. Oral contraceptive agents may cause clear, serous,
or milky discharge from multiple ducts or, less often, from a single duct. The
discharge is more evident just before menstruation and disappears when the
medication is stopped.
[6] Chronic unilateral nipple discharge, especially if it is bloody, is an
indication for resection of the involved ducts. Mammography and
ultrasonography are performed to rule out an associated mass. On occasion,
ductography may be performed to identify a filling defect before excision of the
duct system, but usually this technique is painful and of little value (116).
Ductography is not a substitute for excision because it misses multiple lesions and
cannot visualize the periphery (117).
The role of cytologic examination of nipple discharge is unclear. It may
identify malignant cells and lead to an appropriate oncologic operation (116).
Negative findings do not rule out cancer and a CNB should be performed of any
underlying mass and may prompt further surgical therapy (117). Complete
histopathologic evaluation of the involved ductal system is the preferred method
of diagnosis if no mass is present. Cytologic assessment should not be relied on
for diagnosis.
The usual approach for nipple discharge is surgical excision through a
periareolar incision adjacent to the trigger point, the pressure point that elicits
nipple discharge (115). A microdochectomy of a single duct or a central duct
excision of the major subareolar ducts can be performed under local or general
anesthesia. The putative duct can be cannulated, methylene blue can be injected,
1087or a lacrimal probe can be inserted into the duct for localization. Ultrasound may
assist in localizing a focally dilated duct and allow for needle localization (118).
A resection of breast tissue for 3 to 5 cm, or until no bloody fluid can be
identified in the ductal system, is performed. Complications are rare, but the
patient must be warned of possible skin and nipple loss as a result of
compromised vascularity, change in nipple sensation, deformity, inability to
breastfeed, and recurrence if only a single duct is removed.
When there is a history of unilateral nipple discharge, localization is not
possible, and no mass is palpable, the patient should be reexamined every week
for several months. When unilateral discharge persists, even without definite
localization or tumor, surgical exploration should be considered if the discharge is
copious. The alternative is careful follow-up at intervals of 3 to 6 months.
Mammography should be performed every 6 months. Purulent discharge may
originate in a subareolar abscess and requires excision of the related lactiferous
sinus (119).
Duct Ectasia
Duct ectasia is another common cause of nipple discharge in peri- and
postmenopausal women. It is characterized by corkscrewing and dilation of the
subareolar ducts, which can be demonstrated on ultrasound, and by thick or
cheesy appearing discharge. Nipple retraction may be present due to involution
and foreshortening of the affected ducts (120). This benign condition is best
treated with reassurance, but occasionally may require excision for diagnosis.
Nipple Inversion and Retraction
In cases of nipple retraction, even a single tethered duct results in partial pulling
in of the nipple and a slit-like appearance (121). The term nipple inversion, on the
other hand, is reserved for cases in which the complete nipple is pulled in. This
may be congenital or acquired. Congenital nipple inversion is present in about 5%
of women, usually bilateral, and is a benign condition (122).
[6] Acquired nipple retraction or inversion must be carefully investigated,
including a full clinical evaluation with ultrasound and the addition of
mammography if the patient is more than 35 years old. This finding is most
commonly a result of duct ectasia or periductal mastitis, but may less commonly
be caused by carcinoma in 5% to 20%, or even by tuberculosis (122). If workup is
normal, reassurance, with ongoing clinical surveillance, is the only treatment
required.
Erosive Adenomatosis of the Nipple
1088Erosive adenomatosis is a rare benign condition of the nipple that mimics the
Paget disease (123). Patients seek treatment for pruritus, burning, and pain. On
clinical examination, the nipple can appear ulcerated, crusting, scaling, indurated,
and erythematous. The nipple can be enlarged and more prominent during
menstrual cycles (124). The differential diagnosis includes squamous cell
carcinoma, psoriasis, contact dermatitis, seborrheic keratosis, adenocarcinoma
metastatic to the skin, and unusual primary tumors of the nipple (123). Excisional
biopsy should be performed to diagnose the lesion. Local excision is curative
(124).
Accessory Breast Tissue
Approximately 1% of the population has accessory breast tissue (125). Most
commonly, this is polythelia, or the presence of a rudimentary nipple areola
complex, but may include varying degrees of breast glandular tissue in which
case it is referred to as polymastia or supernumerary breast. This tissue may be
found anywhere along the milk line running from the axilla to groin. Polythelia
most commonly occurs just below the normal breast and may even be confused,
at times, with a nevus. Polymastia occurs most frequently in the axilla (126). Not
infrequently, the accessory breast tissue may go unrecognized until the hormonal
changes of puberty or even pregnancy cause the tissue to become more
noticeable. Despite this, the majority of polythelia and polymastia remain
asymptomatic (125). It is important to note that normal benign and malignant
diseases of the breast may occur in the accessory tissue and all breasts should be
monitored should the patient elect not to have the tissue removed for cosmetic
reasons. Polythelia is associated with urogenital abnormalities and may be
associated with an increased risk of urogenital malignancy (127).
Identification of the accessory breast tissue should prompt ultrasound
evaluation of the urogenital organs.
BENIGN MAMMOGRAPHIC ABNORMALITIES
Diabetic Mastopathy/Lymphocytic Mastitis
This benign breast lesion often appears as an asymptomatic breast mass found
incidentally on imaging. Its ultrasonographic features can be quite concerning as
it appears as a hypoechoic solid mass with irregular margins, inhomogeneous
echotexture, and marked posterior shadowing (128). Diabetic mastopathy is
strongly associated with diabetes mellitus and felt to be autoimmune in nature. It
is hypothesized that, as a result of the hyperglycemic state, advanced glycosylated
1089end products are formed and act as neoantigens triggering an autoimmune
response (128). A CNB will show dense keloid-like fibrosis and periductal,
lobular, or perivascular lymphocytic infiltration (129). Diabetic mastopathy does
not require excision, but requires CNB to establish the diagnosis.
Pseudoangiomatous Stromal Hyperplasia
Pseudoangiomatous stromal hyperplasia (PASH) is a benign stromal proliferation
that shares some histologic appearance with angiosarcoma (130). PASH may
present as an area of increased density on physical examination or may be
incidentally identified on CNB done for another reason, but it is most commonly
identified on breast imaging as a solid, well-defined, noncalcified mass (131).
After a diagnosis has been clearly reached, it requires no further therapy.
Sclerosing Adenosis
Sclerosing adenosis may present as a palpable mass or mammographic
abnormality (132). This is a benign sclerosing lesion and the risk for subsequent
cancer is low (132). No treatment is needed.
Risk Lesions
[7] When found on CNB, these lesions represent an increased risk to the patient
of subsequent diagnosis of breast cancer in either breast. Historically, these
lesions were surgically excised because of the risk of finding concomitant
invasive cancer at final pathologic review. This suggestion was based on largely
retrospective data, but newer analysis suggests that surgical excision may be
overtreatment in many patients in whom these diagnoses represent only
generalized increased risk (133). Further prospective, multicenter trials are needed
to clarify this problematic issue.
Patients diagnosed with risk lesions should be counseled regarding surveillance
and risk reduction. The risk for development of invasive cancer is approximately
3.5 to 5 times that of the general population (133–136). Patients should continue
with yearly mammography and clinical breast examination. Her risk for
subsequent breast cancer may be decreased by avoidance of exogenous estrogens,
initiation of an exercise program, and a generally healthy lifestyle (108). Patients
with additional contributors to high risk may be considered for chemoprevention
with tamoxifen therapy.
Lobular Neoplasia
Lobular neoplasia is a spectrum of atypia with lobular hyperplasia (ALH) on the
more ordered end to the more distorted LCIS. Patients can be reassured that LCIS
1090is not an obligate precursor to lobular carcinoma. Historically, upgrade rates for
ALH were thought to range from 0% to 67%, with a mean of 9% (133). LCIS
upgrade rates were, on average, higher, with a mean of 18% and range of 0% to
60% (134). When limited to data for which imaging and pathologic concordance
was confirmed, only one invasive cancer was found in 337 cases and upgrade
rates to noninvasive cancer (ductal carcinoma in situ) in these patients was around
1% (133). Similar low rates have been reported in other recent retrospective series
(135–136). The 2017 [7] NCCN guidelines recommend close observation alone
for patients with atypical lobular hyperplasia or classic LCIS found on CNB
and felt to be concordant with imaging (35). These lesions should be followed
with repeat mammography at a 6-month interval to document stability. This
approach does not apply in cases of pleomorphic LCIS, for which little natural
history data is available. This is considered a more aggressive lesion, likely more
closely related to ductal carcinoma in situ than lobular neoplasia, and is managed
with excision to negative margins (138).
Atypical Ductal Hyperplasia
Unlike lobular neoplasia, ADH found with CNB has unacceptably high rates of
upgrade to invasive carcinoma found at surgical excision (133,138). In a recent
meta-analysis, the lowest possible upgrade rate of ADH to invasive carcinoma
was calculated to be 8% (133), and historical averages have been in the range
20% to 25% (139). Consequently, surgical excision is recommended for
patients with ADH (35).
Radial Scars
[7] Radial scars are sclerosing lesions most commonly encountered as incidental
findings in biopsies performed for other indications. When larger in size, they
may present as a mammographic speculated mass (3). Surgical excision is
recommended because the upstaging rate to invasive cancer is approximately 7%
(35,140). Following excision, patients remain at a mildly increased risk for
developing breast cancer relative to the general population. In a study of 880
women with radial scars who followed for an average of 20 years, the relative risk
of developing breast cancer at 10 years was 1.82 (141).
DISORDERS OF BREAST AUGMENTATION
Estimates indicate that greater than 11 million women worldwide have undergone
augmentation mammoplasty. Breast implants are usually placed under the
pectoralis muscle or in the subcutaneous tissue of the breast. Most implants are
made of an outer silicone shell filled with a silicone gel or saline. The
1091complications of breast implantation are significant.
Capsular Contracture
Rates of contracture vary in the literature from less than 10% to over 60%.
Capsular contraction or scarring around the implant, leading to firmness
and distortion of the breast, can be painful and sometimes requires removal
of the implant and capsule.
In a prospective study of nearly 1,000 patients, 6-year contracture rates were
4.6% for augmentation, 6.9% for revision-augmentation, 10.7% for
reconstruction, and 18.3% for revision reconstruction, with the majority of these
occurring within the first 3 years (142). Following the first 6 postoperative years,
contracture rates are estimated to be an additional 1% per year indefinitely (142).
Rupture
Implant rupture may occur in as many as 10% of women, and bleeding of gel
through the capsule is even more common (143). In 2006, the U.S. FDA
reapproved silicone gel–filled implants for use in women 22 years or older for
cosmetic purposes and for reconstruction after breast surgery or in women with
traumatic or congenital breast defects and recommended MRI screening for
implant rupture beginning 3 years after the first implant surgery and then every 2
years (144). The agency advised symptomatic women with ruptured implants to
discuss the need for surgical removal with their physicians. When there is no
evidence of associated symptoms, implant removal is generally not indicated
because the risks of removal are probably greater than the risk of retention.
Noncontrast MRI is very sensitive for detecting implant rupture, but is costly
(43). High-resolution ultrasonography, which is slightly less sensitive has been
suggested as a more cost-efficient alternative for use in asymptomatic individuals
(145–147). Even without rupture, seepage of silicone particles may lead to
palpable adenopathy caused by foreign-body reaction.
Breast Implant–Associated Anaplastic Large Cell Lymphoma
Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a rare
cancer, but has generated a large degree of patient and physician concern (148).
Its true incidence is unknown, but a study from the Netherlands estimates one to
three cases per million women with breast implants per year, while a US study
calculated the lifetime risk to be approximately 1:30,000 in patients with implants
(149,150).
The typical presentation is that of a seroma surrounding an implant more than 1
year after placement of implant without history of recent trauma, but BIA-ALCL
1092may less commonly present as a mass (151). Patients with an unexpected seroma
should be evaluated with aspiration of the fluid followed by
immunohistochemistry for CD30. Diagnosis may be confirmed by a T-cell clonal
population on flow cytometry and large anaplastic cells on cell block cytology.
Treatment includes complete excision of the implant, caps
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