3 s2.0 B9780323359559000052

S ECTION I I I Benign and Premalignant Lesions
5
Etiology and Management of Benign
Breast Disease
JENNIFER SASAKI, a ABBY GELETZKE, a RENA B. KASS, V. SUZANNE KLIMBERG,
EDWARD M. COPELAND III, AND KIRBY I. BLAND
T
he aberrations of normal development and involution chart that uses a visual analog scale. This chart should be kept
(ANDI) classification of benign breast disorder (BBD) during at least two menstrual cycles. Mild breast pain (<3 on the
provides an overall framework for benign conditions of the scale) that lasts fewer than 5 days before a menstrual cycle is
breast that encompasses both pathogenesis and the degree of considered normal. The extent to which mastalgia disrupts the
abnormality.1 It is a bidirectional framework based on the fact that patient’s normal lifestyle in terms of sleep, work, and intimacy
most BBDs arise from normal physiologic processes (Table 5.1). provides a useful assessment of severity. A thorough history that
The horizontal component defines BBD along a spectrum from includes diet, methylxanthine intake, and use of new medications
normal to mild abnormality (“disorder”) to severe abnormality (especially hormones, antidepressants such as serotonin reuptake
(“disease”). The vertical component defines the pathogenesis of inhibitors, cardiac medications such as digoxin and cimetidine)
the condition. Together these two components provide a compre- or illicit drugs such as marijuana should be taken,7 and a history
hensive framework into which most BBDs can be fit. This scheme of recent stress should be recorded. Other conditions should be
was recommended by an international multidisciplinary working excluded, such as possible referred pain, such as shoulder bursitis,
group in 1992.2 cervical radiculopathy, costochondritis, myocardial ischemia, lung
disease, hiatal hernia, and cholelithiasis.
Breast Pain Patients are reassured that they do not have breast cancer only
after clinical examination and mammography are performed and
Although mastalgia is one of the most commonly reported symp- reveal no malignancy.5 Fortunately, isolated breast pain is an
toms in women with breast complaints at dedicated breast clinics uncommon symptom of malignancy. In a study by Noroozian and
or general practice,3 it is still underreported and poorly character- colleagues of 1386 women with mammograms performed for
ized. In a 2014 general population survey of 1659 women, more breast pain, only 1.8% were found to have breast cancer.8 Ultra-
than half (51.5%) experienced breast pain, with 17% reporting a sonography can be a useful adjunct to evaluate focal pain, espe-
severity of pain greater than 7 out of 10.4 Maddox and Mansel cially in young dense breasts because 23% of breast pain patients
reported that only 50% of women with breast pain had consulted have cysts or benign masses as the root cause.9
a family physician,5 and fewer still had visited a dedicated breast No study to date has reported an increased risk of breast cancer
clinic. Because of the increasing awareness of breast cancer and with cyclic mastalgia. Initial evaluation should exclude breast pain
the possibility that mastalgia may indicate disease, as well as the from localized benign lesions of the breast that may require needle
effect mastalgia has on the quality of life, more women than ever aspiration or surgical therapy, such as painful cysts, fibroadeno-
are seeking help for breast pain. Treatment usually balances man- mas, subareolar duct ectasia, lipomas, and fibrocystic changes.
agement of relatively minor complaints with the side effects of
treatment. More than 90% of patients with cyclic mastalgia and Classification
64% of patients with noncyclic mastalgia can obtain relief by Classification of mastalgia provides a baseline measurement of
using a combination of nonprescription and prescription drugs.6 pain and severity, dividing symptoms into the categories of cyclic
mastalgia, noncyclic mastalgia, and chest wall pain. This distinc-
tion is important because presentation, occurrence of spontaneous
Clinical Assessment remission, and likelihood of a response to treatment differs for
The degree, severity, and relationship of breast pain to the men- these three conditions. A useful response is obtained in 92% of
strual cycle are best assessed with the use of a daily breast pain patients with cyclic mastalgia, 64% of those with noncyclic mas-
talgia,5 and 97% of those with chest wall pain.10
Cyclic mastalgia accounts for approximately 67% of cases and
a
Jennifer Sasaki and Abby Geletzke share first authorship of this chapter. usually is first seen during the third decade of life as dull, burning,
79
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80 S E C T I O N I I I Benign and Premalignant Lesions
TABLE
5.1 Aberrations of Normal Development and Involution Classification of Benign Breast Disease
Normal Disorder Disease

Early reproductive years (age 15–25) Lobular development Fibroadenoma Giant fibroadenoma
Stromal development Adolescent hypertrophy Gigantomastia
Nipple eversion Nipple inversion Subareolar abscess/mammary duct fistula
Mature reproductive years (age 25–40) Cyclical changes of menstruation Cyclical mastalgia Incapacitating mastalgia
Epithelial hyperplasia of pregnancy Nodularity
Bloody nipple discharge
Involution (age 35–55) Lobular involution Macrocysts
Sclerosing lesions
Duct involution/dilation sclerosis Duct ectasia Periductal mastitis/abscess
Epithelial turnover Nipple retraction Epithelial hyperplasia with atypia
Epithelial hyperplasia
or aching pain.10 However, one breast is usually involved to a and treat. If pain of neurogenic origin is suspected, an empirical
greater extent than the other, and the pain may be sharp and trial of amitriptyline or carbamazepine may be beneficial for diag-
shooting, with radiation to the axilla or arm because of glandular nosis and treatment.
entrapment of the intercostobrachial nerve. Cyclic mastalgia
usually starts in the upper outer quadrant of the breast 5 days or Nomenclature
more before the menstrual cycle, although severe pain can persist
throughout the cycle. Exacerbation of symptoms just before The term fibrocystic disease, of which mastalgia is the most common
menopause can occur. Resolution of symptoms at menopause symptom, is unhelpful because it fails to delineate the full spec-
occurs in 42% of women; however, spontaneous resolution before trum of disease. Postmortem studies of “normal” breast specimens
menopause occurs in 14% of patients.11 indicate that fibrocystic changes occur in 50% to 100% of
Noncyclic mastalgia tends to occur much less frequently, in individuals.19–21 The ANDI classification is used to classify BBDs,
26% of patients, and peaks during the fourth decade of life.9 The such as mastalgia, into those arising secondary to abnormalities
duration of noncyclic mastalgia tends to be shorter, with sponta- of breast development, cyclic changes, or involution rather than
neous resolution occurring in nearly 50% of patients.11 In contrast as disease (see Table 5.1).1
to cyclic mastalgia, noncyclic mastalgia is almost always unilateral.
Exacerbations of pain occur for no apparent reason and are dif- Pathophysiology of Mastalgia
ficult to treat.
A careful clinical breast examination should also rule out Pathogenesis and Etiology
a small thrombosed vein that can present as persistent breast Epithelial and stromal activity, as well as regression, constantly
pain. Mondor disease, superficial thrombophlebitis of the breast, occur within the breast. Fibrosis, adenosis, and lymphoid infiltra-
typically presents as a painful, tender, palpable cord. Although tion, commonly used to characterize mastalgia, cannot be corre-
the exact etiology is unknown, risk factors include trauma, lated with clinical episodes.1 Watt-Boolsen and colleagues found
surgery, local intravenous access, and smoking.12 Ultrasound no histologic differences between women with cyclic and noncyc-
is the recommended mode of diagnostic imaging, with sono- lic mastalgia and asymptomatic patients.22 Jorgensen and Watt-
gram revealing an anechoic, noncompressible, tubular struc- Boolsen reported fibrocystic changes in 100% of 41 women with
ture with areas of narrowing and absence of flow on Doppler,13 breast pain who underwent breast biopsy.23 Although a higher
however, diagnosis can often be made by clinical findings alone. incidence of fibrocystic changes was seen in this cohort than in
Rates of associated malignancy are low, but underlying cancer asymptomatic controls, the total incidence of breast abnormalities
should be excluded by imaging and clinical findings. It is gener- did not differ between groups. Attempts to demonstrate edema as
ally self-limited with resolution in 2 to 8 weeks, though sup- the main cause of cyclic pain and nodularity have been unsuccess-
portive treatment may include antiinflammatories and warm ful. Cysts that commonly occur with ANDI and mastalgia are
compresses.14 secondary to changes of involution, periductal inflammation, and
Mastalgia from other origins includes scapular bursitis,10 cos- fibrosis, which may narrow the ducts distally and cause proximal
tochondritis,15 lateral extramammary pain syndrome,16 cervical dilation.1
radiculopathy,17 or other nonbreast causes. Chest wall pain from
these etiologies is almost always felt either on the lateral chest wall Endocrine Influences
or at the costochondral junction.16 Tietze syndrome, which com- The natural history of mastalgia is clearly linked to the reproduc-
monly affects the second and third costochondral junctions, can tive cycle, with onset at the age of menarche, a linear increase in
manifest as focal medial breast pain.18 Musculoskeletal inflamma- prevalence up to age 50 (prevalence 68%), and cessation of symp-
tion, especially scapular bursitis, can present as referred pain to toms at menopause. In a prospective study of reproductive factors
the breast and is often diagnosed by improvement with a scapular associated with mastalgia, Gateley and colleagues reported that
trigger point injection anesthetic and treatment with an injection women with cyclic mastalgia were more likely to be premeno-
of steroid.10 Neurogenic pain is much more difficult to diagnose pausal, to be nulliparous, or to have been at a young age when
CHAPTER 5 Etiology and Management of Benign Breast Disease 81
they had their first child.6 However, theories of the exact hor- could have been overlooked. More important, normal breast func-
monal events, including progesterone deficiency,24 excess estro- tion is a balance between estrogen and progesterone, which is a
gen,25 changes in the progestin/estrogen ratio,26 differences in part of the neuroendocrine control exerted by the hypothalamic-
receptor sensitivity,27 disparate follicle-stimulating hormone pituitary-gonadal axis (see Fig. 5.1). The theory of an inadequate
(FSH) and luteinizing hormone (LH) secretion,28 low androgen luteal phase defect has never been confirmed. Three studies35–37
levels,29 and high prolactin (PRL) levels30 have been difficult to demonstrate a significant decrease in luteal phase progesterone in
prove or have not abated with hormone therapy. women with mastalgia versus pain-free control subjects; however,
Under normal circumstances, PRL exerts structural growth four other comparable studies have not confirmed these results.38–
41
and secretory differentiation, mammary immune system develop- Nevertheless, an estrogen-progesterone imbalance could affect
ment, and initiation and maintenance of milk secretion.31 PRL PRL secretion. An impairment of the normal ability to counteract
secretion is episodic and shows circadian rhythm, with clustering estrogen-induced PRL release by increasing the central dopami-
of more intense episodes after midnight. In addition, PRL secre- nergic tone has been suggested as a cause of mastalgia.45
tion has menstrual and seasonal variations.32 These variations may,
to some extent, account for the discrepancies in available reports.29 Nonendocrine Influences
Mastalgia may be related to an upward shift in the circadian PRL Serum studies in animals demonstrate that caffeine intake can
profile, a possible downward shift in menstrual profiles, and loss increase PRL,46 insulin,47 and corticosterone48 and can decrease
of seasonal variations.32 Patients with mastalgia also show a height- thyroid-stimulating hormone, free triiodothyronine, and thy-
ened PRL secretion in response to thyrotropin-releasing hormone roxine.46 Minton and associates49,50 originally hypothesized that
(TRH) antidopaminergic drugs28 and may actively sequester methylxanthines, either by inhibiting phosphodiesterase and
iodine within their breast tissue as a result of an alteration in PRL breakdown of cyclic adenosine monophosphate (cAMP) or by
control33 (Fig. 5.1). In addition, stress can cause a rise in PRL increasing catecholamine release, increase cAMP, leading to cellu-
response.34 lar proliferation in the breast51 (see Fig. 5.1). Tissue from patients
Disturbances in the pituitary-ovarian steroid axis have long with breast disease showed unchanged phosphodiesterase activ-
been associated with breast pain (see Fig. 5.1). However, numerous ity but appeared to have increased adenylate cyclase levels and
studies have not shown differences in estrogen and progesterone increased responsiveness to the biochemical-stimulating effects
between asymptomatic controls and patients with mastalgia.35–44 of methylxanthines.49,50 Caffeine itself has no direct effect on
Available reports have measured estrogen over various time cAMP, but catecholamines can increase cAMP. Studies in Min-
courses, from single mid-luteal phase samples to daily for an entire ton’s laboratory have shown increased release of circulating cat-
cycle. Clearly, circadian, menstrual, seasonal, or episodic changes echolamines in response to caffeine consumption52 (see Fig. 5.1).
STRESS
Endogenous
Hypothalamus opioids
Inappropriate
dopaminergic tone
Naloxone
Catecholamines
Pituitary ORAL
Hyperprolactinemia
Methylxanthines
ity)
Luteal phase
Nicotine
itiv
insufficiency
Tyramine
ns
(premenopausal)
rse
ovary
pe
Exogenous
y
(H
estrogen
(postmenopausal)
Unopposed
estrogen
End organ
(no feedback)
• Fig. 5.1 Suggested theories of causation of breast pain.
Indeed, studies by Minton and colleagues have shown “catechol- TABLE

amine supersensitivity” in patients with ANDI. There were sig- 5.2 Effectiveness of Interventions for Mastalgia
nificantly higher levels of β-adrenergic receptors in symptomatic
patients than in asymptomatic controls.53 The increased activity MASTALGIA
and sensitivity of the β-adrenergic–adenylate cyclase system in Side
symptomatic patients suggest a genetic predisposition for ANDI Drug Cyclical Noncyclical Combined Effects
that is stimulated by the biochemical or hormonal effects of
methylxanthines. Moreover, Butler and colleagues have been able Methylxanthines50 — — 83% None
to categorize patients genetically into fast and slow acetylators Dietary fat 90% 73% 83% None
based on their caffeine metabolism.54 Like the methylxanthines, reduction69
a common biochemical effect of nicotine, tyramine, and physical
and emotional stress is enhancement of catecholamine release and Evening primrose 58% 38% — 4%
an increase of circulating catecholamines53 (see Fig. 5.1). Arsiriy oil6
showed that women with mastalgia and ANDI had significantly Molecular iodine59 — — 65% 11%
higher levels of urinary catecholamines than did asymptomatic 6,7
Danazol 92% 64% — 30%
controls.55 Studies have shown increased serum epinephrine
and norepinephrine and decreased baseline dopamine levels in Gestrinone 91
— — 55% None
patients with cyclic as well as noncyclic mastalgia.53 The increase 9,93
LHRH agonist — — 67% 37%
or stimulation of adenylate cyclase activity in breast tissue appears
to be an important step for triggering the intracellular cAMP- Thyroid
—
— 73% None
mediated events leading to symptomatic ANDI.53 Randomized replacement
studies on smoking, tyramine, or stress reduction have not been Analgesics11,104 — — 92% None
performed. 108
The theory that fat increases endogenous hormone levels, and Tamoxifen 90% 56% — 65%a
thus breast pain, has led to the performance of dietary fat- LHRH, Luteinizing hormone-releasing hormone.
restriction studies.56 In these studies, women with breast pain a
Regimen is 20 mg of tamoxifen. On 10 mg, side effects and efficacy are lower.
show lower levels of plasma essential fatty acid gamma-linolenic
acid than do asymptomatic controls. It has been hypothesized that
essential fatty acid deficiencies may affect the functioning of the
cell membrane receptors of the breast by producing a supersensi- Therefore double-blind, placebo-controlled trials are required to
tive state.57,58 High levels of saturated fats inhibit the rate-limiting prove the effectiveness of drugs in the treatment of mastalgia.61
delta-6 desaturation step between linoleic acid and gamma- Gamma-linolenic acid, bromocriptine, danazol, LH-releasing
linolenic acid. Catecholamines, diabetes, glucocorticoids, viral hormone (LHRH) agonists, molecular iodine, and tamoxifen
infections, and high cholesterol levels likewise limit this step.57,58 have all been shown by such trials to be of use in the treatment
With both estrogen and progesterone receptors, a supersensitive of breast pain. The safety and efficacy of these therapies, as well as
state can be produced with a higher ratio of saturated to unsatu- less proven therapies, are discussed in the next section (Table 5.2).
rated fatty acids. Administration of essential fatty acids in the
form of evening primrose oil (9% gamma-linolenic acid) bypasses Nutritional Therapy
the delta-6 desaturation step, leading to a gradual reduction in Nutritional factors have been less well documented than other
the proportions of the saturated fatty acids57 and diminishing the modalities in the cause and treatment of breast pain. Although
abnormal sensitivity of the breast tissue. Likewise, Ghent and they are the least expensive and least prone to side effects, dietary
colleagues have theorized that the absence of dietary iodine may changes are often the most difficult to institute in the noncompli-
also render terminal intralobular duct epithelium more sensitive ant patient.
to estrogen stimulation.59 Methylxanthines. Chemicals classified as methylxanthines
Anatomic and extrinsic factors may contribute to the develop- include caffeine, theophylline, and theobromine. These substances
ment of breast pain. Scurr and associates found breast pain to be are found in coffee, tea, chocolate, and cola beverages, as well
related to cup size but not underband size. Women reported as in many respiratory medications and stimulants. Minton
increased pain with participation in sports and activities exacer- and colleagues reported complete disappearance of all palpable
bated by ill-fitting and nonsupportive bras; however, overall breast nodules, pain, tenderness, and nipple discharge 1 to 6 months
pain was more common in women with lower activity levels. In after eliminating methylxanthines from the diet of 13 of 20
a survey conducted in the female runners of the 2012 London women (65%).62 In a subsequent clinical trial involving 87
marathon, 75% reported bra fit issues, most commonly chaffing women, complete resolution was seen in 82.5%, with significant
and shoulder strap discomfort, suggesting that poor bra fit may improvement in 15% of women abstaining from methylxan-
be a factor in activity-related breast pain.60 thines.50 Resumption of methylxanthines was associated with
recurrence of symptoms in this cohort. These data are supported
by nonrandomized studies, including retrospective data from 90
Management of Mastalgia pairs of twins63 in which the twin with breast pain was found to
As might be anticipated, there is a long list of suggested modalities be more likely to consume more coffee than the unaffected twin.
for the treatment of a ubiquitous entity whose cause is unknown Ernster and colleagues randomized 82 of 158 women to abstain
and whose relationship to fibrocystic breast disease and cancer from methylxanthine and 76 women to no dietary instruction.64
is poorly understood. Breast pain may resolve spontaneously, Differences in clinically palpable breast findings were significantly
and 19% of patients have marked responses to placebo therapy. less in the caffeine-abstaining group, but absolute changes were
minor. Bullough and colleagues studied daily methylxanthine placebo (p = .093) in intent-to-treat analysis.73 Two more random-
ingestion from drug and dietary sources and found that both ized controlled trials have not supported or contradicted this
breast pain and fibrocystic disease are positively correlated with evidence of the efficacy of EPO in the treatment of mastalgia. In
caffeine and with total methylxanthine ingestion.65 Minton a large multicenter trial, Goyal and associates74 evaluated mastal-
reported the evaluation of 315 patients with ANDI for a mean of gia in 555 women and compared EPO plus antioxidants, EPO
3 years (range, 1–11 years),53 demonstrating improvement off plus placebo antioxidants, antioxidants plus placebo EPO, and
caffeine and return of symptoms with resumption of caffeine. placebo antioxidants and placebo EPO. After 4 months, the inves-
Other case-controlled studies, however, have not confirmed tigators found no difference in recorded pain scores between
these clinical findings. A study of an age- and race-matched cohort women taking EPO plus vitamins versus placebo plus vitamins
of approximately 3000 women who were a part of the Breast (15.2 vs. 14.9; p = .3). Similarly, Blommers and colleagues75 found
Cancer Detection Demonstration Project demonstrated no asso- no significant difference between EPO and placebo in the fre-
ciation between methylxanthine consumption and breast tender- quency or severity of pain at 6 months. In this trial, 120 women
ness in women with fibrocystic disease or in controls.66 In a were studied in four comparison groups: EPO plus placebo oil,
single-blind clinical trial of 56 women randomized to a control fish oil plus placebo oil, fish oil plus EPO, and two placebo oils
(no dietary restrictions), a placebo (cholesterol-free diet), and an alone. Furthermore, a large recent meta-analysis performed by
experimental group (caffeine-free diet) for 4 months, Allen and Srivastava and associates76 reviewing the data from all randomized
Froberg showed that caffeine restriction did not lessen breast pain controlled trials using EPO revealed no significant beneficial effect
or tenderness.67 Another factor is the significant difference in the of EPO over placebo. This new evidence in part, questions or
length of withdrawal of caffeine seen between positive and nega- refutes the utility of EPO as a first-line agent in the treatment of
tive studies. Minton’s work has been criticized for lack of control mastalgia, and the United Kingdom has withdrawn the prescrip-
subjects and blinding as well as the general instability of findings tion license for EPO because of its lack of efficacy.77 Flaxseed oil,
in patients with mastalgia.68 An unflawed, large-scale, prospective, a source of alpha-linolenic acid, has also been shown to reduce
long-term study that would count methylxanthines from all breast pain. In a small, randomized controlled trial, women receiv-
sources and use reliable dependent variables to assess pain, either ing 25 g flaxseed daily had reduced cyclical breast pain at both
to prove or disprove the value of methylxanthine withdrawal, has 1- and 2-month time points compared with placebo.78
yet to be performed. Until then, clinicians may want to suggest a Iodine. The exact influence of iodine on breast tissue is not
methylxanthine-restricted diet, especially in light of its no-cost, understood. In contrast to iodides, which are thyrotrophic, Eskin
no-side-effect status and the other unwanted health consequences and colleagues demonstrated that iodine is involved primarily in
of caffeine. extrathyroidal activities, particularly in the breast.79 Ghent and
Low Dietary Fat. As with breast cancer, mastalgia is less coworkers theorized that the absence of iodine may render the
common in the global East and in Eskimos, whose diets are epithelium of the terminal intralobular ducts more sensitive to
notably lower in fat. Reduction of dietary fat intake (to <15% of estrogen stimulation and proceeded to perform three studies.59 In
total calories for 6 months) significantly improves cyclic breast an uncontrolled study with sodium-bound iodide (313 volunteers
tenderness and swelling.56 In one study, Sharma and colleagues for 2 years) and protein-bound iodide (588 volunteers for 5 years),
demonstrated significant elevations in high-density lipoprotein subjects had 70% and 40% clinical improvement, respectively.
cholesterol and the ratio of high-density lipoprotein cholesterol The rate of side effects was high. In a prospective controlled
to low-density lipoproteins, as well as a decrease in the ratio of crossover study, 145 patients in whom treatment with protein-
total cholesterol to high-density lipoprotein cholesterol in 32 bound iodide failed were given molecular iodine (0.08 mg/kg)
cyclic and 25 noncyclic mastalgia patients.69 Response to a low-fat and compared with 108 volunteers treated initially with molecular
dietary regimen was significant only in the cyclic mastalgia group, iodine. Objective improvement was noted in 74% of the patients
suggesting that cyclic mastalgia may be from cyclic aberrations in in the crossover series and in 72% of those receiving molecular
lipid metabolism and that dietary management may need to be iodine as first-line therapy. The third part of the study was a
pursued. A good or partial response was seen in 19 of 21 of the controlled double-blind study in which 23 patients received
cyclic and 11 of 15 of the noncyclic patients. It is unclear what molecular iodine (0.07–0.09 mg/kg) and 33 patients received
would lead to such a lipid profile abnormality—whether excessive placebo. In the treatment group, 65% had subjective and objec-
intake, a genetic predisposition, or both. Nevertheless, dietary tive improvement. In the control group, 33% showed subjective
manipulation of this kind is difficult to achieve, is difficult to placebo effect and 3% showed objective deterioration. Molecular
monitor, and requires a high degree of compliance.70 iodine was found to be nonthyrotropic, without side effects, and
Evening Primrose Oil and Gamma-Linolenic Acid. Studies beneficial for breast pain. In a randomized double-blind, placebo
have shown that women with severe cyclic mastalgia have abnor- multicenter trial, Kessler33 has since reported on the efficacy of
mal blood levels of some essential fatty acids,71 which have been Iogen for cyclical mastalgia. Iogen is a novel iodine formulation
implicated in the control of PRL secretion and steroid hormone that generates molecular iodine (I2), a substance thought to be less
receptor alterations.27 Early clinical experience with evening prim- thyrotoxic on dissolution in gastric juices. In Kessler’s study of
rose oil (EPO), a source of gamma-linolenic acid, produced a 58% 111 women with breast pain, 50% of patients reported a signifi-
response rate with cyclic mastalgia and a 38% response rate with cant decrease in pain after 3 months in the 6-mg treatment group
noncyclic mastalgia.6 Symptoms of pain and nodularity were sig- but not in the 1.5-mg and placebo groups.
nificantly improved with EPO (3 g/day) in a placebo-controlled
trial after 4 months, and treatment was associated with an eleva- Endocrine Therapy
tion of essential fatty acids toward normal levels.72 A recent small Although it is difficult to prove, hormonal factors clearly play a
pilot study of 41 patients randomized to receive EPO (3 g/day), role in the cause of cyclic mastalgia. This is evidenced by the fact
vitamin E (1200 IU/day), or both found an improvement in that the condition manifests itself primarily during the ovulatory
worst pain in all three treatment groups but no difference with years, with symptoms that fluctuate during the course of the
menstrual cycle, intensifying premenstrually and subsiding with Gestrinone. Gestrinone is an androgen derivative of
menses.80 19-nortestosterone. As such, its mode of action and side effects
are similar to those of danazol. However, side effects occur less
Androgens frequently with the reduced dosage required for treatment (5 mg
Testosterone. One of the earliest effective hormonal treat- vs. 1400–2800 mg/wk). With its androgenic, antiestrogenic, and
ments for mastalgia was testosterone injections. Its use has been antiprogestagenic properties, gestrinone may inhibit the midcycle
limited by its adverse side effects. However, results from a placebo- gonadotropin surge and act directly on the pituitary gland, in the
controlled trial using 40 mg twice daily of the undecenoate oral ovary, directly at the estrogen receptor of the mammary gland.90
form of testosterone demonstrated a reduction in mastalgia pain In a multicenter trial evaluating the safety and efficacy of
scores of 50%, with acceptable tolerance.81 gestrinone,91 105 patients were randomized to receive gestrinone
Danazol. Danazol is an attenuated androgen and the or placebo 2.5 mg twice weekly for 3 months. Of patients treated
2,3-isoxazol derivative of 17α-ethinyl testosterone (ethisterone). with gestrinone, 55% had a clinically favorable response, with a
Danazol competitively inhibits estrogen and progesterone recep- placebo effect of 25%. Complete resolution of symptoms with
tors in the breast, hypothalamus, and pituitary82; inhibits multiple gestrinone occurred only in 22% of patients. Further trials with
enzymes of ovarian steroidogenesis83; inhibits the midcycle surge gestrinone have not been performed.
of LH in premenopausal women; and reduces gonadotropin levels
in postmenopausal women.84 The precise mechanism of danazol Others
in reducing breast pain is unknown. It is the only medication Luteinizing Hormone–Releasing Hormone Agonist. The
approved by the US Food and Drug Administration (FDA) for mechanisms of LHRH analogs are thought to be their antigo-
the treatment of mastalgia. nadotropic action and direct inhibition of ovarian steroidogenesis,
In initial studies, a double-blind crossover trial comparing two which almost completely induce ovarian ablation, resulting in
dosages of danazol (200 vs. 400 mg/day) in 21 patients with mas- extremely low levels of the ovarian hormones estradiol, progester-
talgia demonstrated significant decreases in pain and nodularity at one, androgens, and PRL. In a nonrandomized trial, Monosonego
both dosages.85 Onset of response and side effects were higher with and colleagues92 gave intramuscular LHRH agonist (3.75 mg as
the higher dosage. Of the participants, 30% had amenorrhea and a monthly depot) to 66 patients during a 3- to 6-month period.
weight gain. There was significant reduction in mean pain scores A complete response was observed in 44% of the patients treated
and mammographic density using danazol in a randomized trial with an LHRH agonist alone, and a partial response was seen in
with daily treatments of 200 or 400 mg of danazol for 6 months.86 45%. Monthly injections of the LHRH analog goserelin resulted
Patients relapsed more quickly (9.2 vs. 12.2 months) and to a in significantly diminished pain in 67% of patients with either
greater extent (67% vs. 52%) in women taking 200 versus 400 mg cyclic or noncyclic mastalgia in a randomized multicenter study
of danazol. Gateley and colleagues found a clinically useful response of 147 premenopausal women. Side effects, which included
to danazol (200 mg/day) in 92% of 324 patients with cyclical vaginal dryness, hot flashes, decreased libido, oily skin or hair, and
mastalgia and 64% of 90 patients with noncyclical mastalgia with decreased breast size, were seen more frequently in patients receiv-
30% experiencing adverse events (mainly weight gain and men- ing goserelin (27 of 73 patients) than sham (4 of 74 patients).93
strual irregularity) and 43 patients having to stop treatment despite Significantly, treatment with an LHRH agonist-induced remark-
19 having an effective response.87 Because the side effects of danazol able loss of trabecular bone.94 For this reason, only short courses
are dose related, Harrison and colleagues88 and Sutton and of LHRH analogs should be administered and only for acute and
O’Malley89 developed low-dose regimens. Patients responding to a severe cases of mastalgia.
dosage of 200 mg/day of danazol after 2 months were given a Thyroid Hormone. Data from in vitro studies have suggested
dosage of 100 mg/day for 2 months and then 100 mg every other that thyroid hormones may antagonize the effects of estrogen at
day or 100 mg daily only during the second half of the menstrual the pituitary receptor levels of lactotrophs, such as TRH, although
cycle.88 If previous reductions were well tolerated, the danazol was there is no conclusive support for this.37 Relative estrogen domi-
discontinued.89 Symptoms were controlled without side effects at a nance is suggested as a cause for the increase in PRL responsive-
total average monthly dose of 700 mg. Of 20 women, 13 (65%) ness to TRH in patients with mastalgia.
of whom had experienced previous side effects, none reported side Kumar and colleagues42 found a generalized abnormality of
effects while taking this low dose. Some relief of pain was seen in hypothalamic-pituitary axis in 17 patients with cyclic mastalgia
all women, with a complete response maintained in 55%. Other compared with 11 controls by using a combined TRH and
reported side effects of danazol include muscle cramps, acne, oily gonadotropin-releasing hormone test. The release of PRL, LH,
hair, hot flashes, nervousness, hirsutism, voice change, fluid reten- and FSH was significantly greater in patients with cyclic mastalgia
tion, increased libido, depression, headaches, and dyspareunia, than in controls, although estrogen and progesterone levels were
which usually resolve after discontinuation of treatment. The drug normal. Bhargav and colleagues studied 201 women with BBD,
is contraindicated in women with a history of thromboembolic none of whom had previously suspected hypothyroidism. The
disease. For women of childbearing age, adequate nonhormonal prevalence of hypothyroidism was 23.2%, and relief of BBD
contraception is essential. symptoms was attained in 83% of patients with hypothyroidism
Recommendations for the administration of danazol are with thyroid replacement alone.95 A large, randomized, placebo-
100 mg twice daily for 2 months while the patient keeps a breast controlled trial of levothyroxine is needed before any recommen-
pain record. If no response or an incomplete response is obtained, dation is made for its use as a standard treatment.
the dose may be increased to 200 mg twice daily. If there is still
no response, another drug should be tried. Therapy should not Nonendocrine Therapy
continue longer than 6 months (because side effects may develop), Bromocriptine. Results of recent studies point toward a PRL
and the drug should be tapered, as described by Harrison and secretory hypersensitivity for estradiol in patients with cyclic mas-
associates88 and Sutton and O’Malley.89 talgia (see Fig. 5.1). Watt-Boolsen and colleagues44 studied 20
women with cyclic mastalgia and compared them with 10 women TABLE
who were asymptomatic. Basal serum PRL levels were signifi- 5.3 Medications Causing Mastalgia
cantly elevated, although within the normal range, in the mastal-
gia group versus controls. Cole and associates30 have demonstrated Category Examples
that PRL is involved in the regulation of water and electrolyte Cardiac and Digoxin, methyldopa, minoxidil,
balance in the nonlactating breast. An increase in serum PRL antihypertensive spironolactone, other diuretics
levels could possibly cause an influx of water and electrolytes in
the breast, thus increasing tension and causing pain. However, in Gynecologic Oral contraceptive pills, hormone
women with true hyperprolactinemia, levels of mammotrophic replacement therapy
hormones are entirely different because ovarian steroid levels are Psychiatric Selective serotonin reuptake inhibitors,
suppressed. Bromocriptine is an ergot alkaloid that acts as a dopa- venlafaxine, haloperidol, other
minergic agonist on the hypothalamic-pituitary axis. One result antipsychotics
of this action is suppression of PRL secretion. Antimicrobials Ketoconazole, metronidazole
Mansel and colleagues96 reported a double-blind crossover
study using bromocriptine in a group of patients with mastalgia. Other Cimetidine, cyclosporine, domperidone,
Lowered PRL levels associated with a significant clinical response penicillamine, methadone
were seen in patients with cyclic breast pain but not in those with Data from Smith RL, Pruthi S, Fitzpatrick LA. Evaluation and management of breast pain.
noncyclic breast pain. In a double-blind controlled trial of danazol Mayo Clin Proc. 2004;79:353-372.
and bromocriptine, Hinton and associates97 reported a clinical
response with bromocriptine in two-thirds of patients with cyclic
pain but no response in patients with noncyclic pain. In contrast,
Pye and coworkers98 reported a minimal response rate of 20%
with bromocriptine in patients with noncyclic mastalgia versus reduction).104 However, another small, randomized, double-blind
47% in those with cyclic mastalgia. The European Multi-Center study did not show a benefit or oral NSAIDs over placebo.105
Trial of bromocriptine in cyclic mastalgia confirmed the efficacy Abstention From Medications. Onset of breast pain with the
of bromocriptine. Side effects occurred in 45% of patients and recent prescription of any medication should be suspect (Table
were severe enough to warrant discontinuation of therapy in 11%. 5.3). This is particularly so with estrogen replacement therapy,
Side effects were reduced by an incremental buildup of doses over and withdrawal of such can produce dramatic results. Tenderness
2 weeks. However, reports of serious side effects of bromocriptine caused by this therapy can be circumvented with initial low-dose
prescribed for lactation cessation, including seizures (63), strokes therapy and dosage escalation or with short “drug holidays” when
(31), and deaths (9), have resulted in its removal from the indica- patients become symptomatic.
tion list of bromocriptine by the FDA.99 Despite its apparent
effectiveness, because of the seriousness and frequency of the Refractory Mastalgia
reported side effects, we do not recommend bromocriptine for use Tamoxifen. Tamoxifen is an estrogen agonist-antagonist com-
in mastalgia. monly used in the treatment of breast cancer. It is thought to
Cabergoline, another long-lasting, potent, dopamine, has been competitively inhibit the action of estradiol on the mammary
demonstrated to be as effective as bromocriptine with fewer side gland. In 1985 Cupceancu106 first reported a noncontrolled pro-
effects. In a multicenter, open-label study of 140 women with spective study of tamoxifen given for 10 to 20 days of the men-
cyclic mastalgia randomized to receive bromocriptine (5 mg/day strual cycle at a dosage of 20 mg/day for up to six cycles; breast
during the second half of the menstrual cycle) or cabergoline pain disappeared in 71% of patients and symptoms were amelio-
(0.5 mg/wk during the second half of the menstrual cycle), 66.6% rated in 27%. Controlled trials at dosages of 10 and 20 mg per
of women receiving bromocriptine and 68.4% of women receiv- day produced greater than 50% reduction in mean pain scores in
ing cabergoline has a positive response. Side effects were, however, 90% of patients with cyclic mastalgia and in 56% of those with
much lower in the cabergoline group, with less frequent vomiting noncyclic mastalgia.107,108 The higher dose was no more effective,
(4.5% vs. 28%), nausea (20.9% vs. 39%), and headache (6% vs. but side effects were more prominent. In a double-blind, con-
23%) when comparing cabergoline to bromocriptine. In this trolled, crossover trial of tamoxifen (20 mg/day) given during a
small study, the serious side effects observed with bromocriptine 3-month period, pain relief was seen in 75% of patients receiving
(i.e., seizure, stroke, or death) did not occur.100 tamoxifen and in 22% of those receiving placebo. Major side
Analgesics. In a retrospective questionnaire survey of 71 effects included hot flashes (26%) and vaginal discharge (16%).
patients, a negligible response was seen to conium cream, phyto- In an effort to reduce side effects while maintaining efficacy, the
lacca cream, metronidazole, aspirin, cyproterone acetate, and ibu- tamoxifen dosage was lowered to 10 mg/day for 3 to 6 months.
profen cream.101 Recently, a prospective but nonrandomized trial Side effects were seen in approximately 65% of patients taking
administering nimesulide, an oral analgesic, was reported. All but 20 mg and in 20% of those taking 10 mg.108 The efficacy of
2 of 60 patients had a clinically useful response (97%) after 2 tamoxifen for the treatment of mastalgia is well supported by the
weeks of therapy. Of 60 patients, 28 (47%) had complete resolu- recent meta-analysis of randomized controlled trials for mastalgia
tion of their symptoms. Two patients could not take the analgesic performed by Srisvastava and associates76 in which tamoxifen
because of complaints of gastritis.102 In a randomized controlled achieved a relative risk of pain relief of 1.92. These results have
trial of 108 women, Diclofenac, a topical nonsteroidal antiinflam- led these authors to their recommendation that tamoxifen should
matory drug (NSAID), has been shown to be effective for the be used as a first-line agent for the treatment of breast pain.
treatment of both cyclical and noncyclical mastalgia.103 Topical However, possible links between tamoxifen use and endometrial
NSAID was also shown to be more effective at controlling carcinoma have relegated its use only for patients in whom symp-
breast pain than EPO (92% vs. 64% clinically significant pain toms are severe and in whom all standard therapies have failed.
Gong and colleagues109 have hypothesized that toremifene, a

newer member of the family of selective estrogen receptor modu-
lators (SERMs), may be a better medication than tamoxifen for
mastalgia. Compared with tamoxifen as adjuvant endocrine
therapy for breast cancer, toremifene has a comparable therapeutic
effect yet is associated with fewer adverse effects. In their double-
blind, randomized control trial, patients treated for cyclical mas-
talgia with 30 mg daily of toremifene noted a 76.7% response rate
compared with a 34.8% response rate seen in placebo treatment
(p < .001); patients with noncyclical mastalgia had a 48.1%
response rate with toremifene compared with 24% for placebo.
The incidence of an intolerable adverse effect was not increased
with toremifene therapy. However, toremifene has been reported
to cause serious heart arrhythmias.
A recent study by Mansel and coworkers110 evaluated the safety
and efficacy of a topical gel containing the potent tamoxifen
metabolite, afimoxifene (4-hydroxytamoxifen) for the treatment
of cyclical mastalgia in premenopausal women. In their phase II • Fig. 5.2 The most common site of a trigger point causing severe non-
trial, 130 women were randomized to placebo versus 2 or 4 mg cyclical breast pain, which is usually at the junction of the lower third and
of the transdermal agent for four menstrual cycles. After four upper two-thirds of the scapula.
cycles, patients in the 4-mg group were more likely to demonstrate
improvements in pain (p = .010), tenderness (p = .012), and
nodularity (p = .017) compared with placebo. Afimoxifene deliv- and may form a physiologic basis for mastalgia (see Fig. 5.1). A
ered percutaneously had 1000-fold lower serum levels than levels study by Preece and colleagues found similarly low psychoneu-
achieved after oral delivery of tamoxifen. There was no change in rotic scores for patients presenting with cyclical and noncyclical
plasma hormone levels or any serious side effects in any of the mastalgia and those presenting with varicose veins in comparison
treatment arms. to high scores seen with outpatient psychiatric patients. However,
Ormeloxifene is another SERM, currently not available in the a small subgroup of patients (5.4%) with treatment-resistant
United States, that has recently been compared with tamoxifen in mastalgia did have characteristics that were similar to those of
the treatment of mastalgia with equivalent results in pain relief a psychiatric patient group.115 Subsequently, Jenkins and associ-
after 3 months, but higher incidence of side effects including diz- ates116 hypothesized that patients with severe or resistant mastalgia
ziness, menstrual irregularity, and ovarian cysts.111 are likely to exhibit psychiatric problems. To investigate this
Trigger Point Injections for Extramammary Pain (Scapulo- hypothesis, 25 patients with severe mastalgia completed a psychi-
thoracic Bursitis) Mimicking Noncyclical Breast Pain. Because atric evaluation using the Composite International Diagnostic
of the extensive confluence of afferent signals from the shoulder Interview (CIDI) and a general health questionnaire. On the basis
region to the dorsal horn of the spinal cord, the location of symp- of the CIDI examination, 17 had current anxiety, 5 had panic
toms may or may not correspond to the proximity of the pain disorders, 7 had somatization disorders, and 16 had current major
source. As expected, pain may involve the shoulder, the scapular depressive disorders. Jenkins suggested that in patients in whom
area, the axilla, the arm, and, more commonly unrecognized, the “standard pharmacologic interventions” for mastalgia fail, evalu-
breast.112 A thorough history and physical examination is essential ation by a psychiatrist and a trial of tricyclic antidepressants may
for patients presenting with mastalgia. Scapulothoracic bursitis be indicated.
should be ruled out in any postmenopausal woman presenting Surgical Approaches. Surgery, such as a subcutaneous mas-
with breast pain. Trigger points along the medial scapular border tectomy117 or excisional breast biopsy for mastodynia, is ill-advised
are diagnostic of bursitis but may or may not be present. Injec- and should be a tool of last resort. It should be offered only at the
tions containing a mixture of lidocaine (for diagnostic purposes), behest of the patient and then only after significant counseling.
bupivacaine, and steroids in the trigger point(s) result in relief In general, surgical excision of localized trigger spots without an
within 15 minutes (Fig. 5.2).10 In conjunction with daily heat to identifiable breast abnormality is unsuccessful 20% of the time
the scapulothoracic bursa (shoulder blade) and nonsteroidal anal- and runs the risk of replacing a painful area with a painful scar.118
gesics, this results in long-lasting relief in most patients. In a study
of 461 patient with breast/chest pain, 103 were diagnosed with Ineffective Treatments
shoulder bursitis, with 83.5% having complete relief of pain after Diuretics. Diuretics have never been tested in a double-blind,
injection of local anesthetic and corticosteroid.113 Similarly, placebo-controlled trial. However, Preece and colleagues demon-
musculoskeletal chest wall pain, costochondritis with tenderness strated that premenstrual fluid retention in patients with mastal-
of the costochondral or chondrosternal joints, and Tietze syn- gia is no different from that in symptom-free control subjects,
drome with pain and nonsuppurative swelling of the costochon- limiting the rationale for the use of diuretics.119
dral junctions particularly of the second and third ribs also Progesterones. Studies by Maddox and associates (among
respond to rest, heat, NSAIDs, and reassurance.87 others) using a randomized, controlled, double-blind, crossover
Psychiatric Approaches. Lack of treatment for patients with design with 20 mg of medroxyprogesterone acetate during the
mastalgia stems from the prevailing belief, as first proclaimed by luteal phase showed no benefit for the patient with mastalgia.120
Sir Astley Cooper, that all unexplained breast pain is a psychoso- Vitamins. Abrams121 reported a favorable response to vitamin
matic complaint seen in the neurotic female, not a real physiologic E in an uncontrolled trial in 1965. In a small, prospective, double-
entity.114 Indeed, in states of acute emotional stress, PRL is released blind, crossover study of the efficacy of vitamin E or placebo,
Lab
History
• Age-appropriate mammogram
• Assess meds as causative
• Ultrasound
• Neck, back, or shoulder injury
• Prolactin for nipple discharge
Physical
exam
Mammographic
Scapular
Normal or ultrasound
bursitis
abnormality
Mild to
Severe Biopsy
moderate
Reassurance
Off methylxanthines
Low-fat diet
Trigger
NSAIDs Danocrine Lupron Tamoxifen point
injection
• Fig. 5.3 Algorithm of a plausible approach to mastalgia. NSAIDs, Nonsteroidal antiinflammatory drugs.
10 of 12 patients receiving 300  IU/day and 22 of 26 patients developed a protocol of daily doses of 20 mg of beta-carotene
receiving 600  IU/day showed improvement after 4 weeks of interrupted with 300,000 IU of retinol acetate starting 7 days
taking vitamin E. Serum levels of dehydroepiandrosterone, but before each menstrual period and continuing for 7 days for each
not estrogen or progesterone, were significantly higher in the cycle.130 Twenty-five patients with cyclic mastalgia were treated
responders to the drug before and normalized after administration with this regimen for 6 months. Two patients had a complete
of vitamin E. Meyer and associates122 conducted a double-blind, response, and the remaining patients had a modest partial
placebo-controlled, crossover trial that randomized 105 women response. No side effects were reported. This regimen was not
to receive either vitamin E (600  IU/day) for 3 months or placebo. effective for noncyclic mastalgia. Controlled trials have failed to
Although 37% reported improvement while taking vitamin E, demonstrate a role for vitamins in the treatment of breast pain.
versus 19% reporting improvement with placebo, this was not
statistically significant. Parsay and colleagues, however, showed a Summary
significant improvement in cyclic mastalgia in women treated Fig. 5.3 suggests a plausible algorithm for the treatment of breast
with vitamin E (400  IU/day) versus placebo in a randomized, pain.
double-blind study of 150 women at both 2- and 4-month time
intervals.123 In contrast, double-blind, placebo-controlled trials Benign Breast Disorders
by London and coworkers124 (128 patients receiving 150, 300,
and 600  IU vitamin E for 2 months) and Ernster and col- The classification system developed by Page separates the various
leagues125 (73 patients receiving 600  IU for 2 months) reported types of BBD into three clinically relevant groups: nonprolifera-
no benefits from vitamin E. tive lesions, proliferative lesions without atypia, and proliferative
Supplementation with vitamins B1 and B6126,127 is thought to lesions with atypia. This classification eliminates potentially con-
be of no benefit. A recent report by McFayden and associates101 fusing terminology and incorporates histologic criteria that are
retrospectively reviewed treatment of 289 patients with pyridox- associated with an increased risk of the development of breast
ine (100 mg/day) for 3 months; 49% had a beneficial response, cancer and was adopted by the American College of Patholo-
with only 2% reporting side effects. However, a double-blind gists.131,132 The histologic features of the breast biopsy specimen,
controlled trial in 42 patients showed no benefit. together with the patient’s personal and family history, establishes
Vitamin A was first used for mastodynia by Brocq and col- the relative risk of cancer. These data, combined with mammo-
leagues in 1956 at a daily dose of 50,000 IU for 2 months, which graphic and physical examination findings, determine the man-
led to significant reductions in pain.128 In a small, nonrandomized agement strategy and follow-up for the patient.1
trial in patients with symptomatic breast pain, 9 of 12 patients A study from the Mayo Clinic found that the relative risk of
had marked pain reduction after 3 months of therapy with daily breast cancer in a large cohort of women with benign breast
doses of 150,000 IU of vitamin A (all transretinal).129 These disease was 1.56, and this risk remains for up to 25 years after
results were associated with toxic effects often severe enough to biopsy. Furthermore, they found that histologic features, age at
stop or interrupt treatment. Santamaria and Bianchi-Santamaria biopsy and degree of family history were major factors in the risk
cyst is aspirated, it can be followed with repeat imaging in 6

months if it remains asymptomatic and cytology is negative. A
biopsy of the cyst wall should be obtained if the cyst does not
resolve after aspiration, if there is asymmetric wall thickening, or
if there is atypical cellularity in the aspirate.137
Percutaneous removal is an alternative approach to manage-
ment of complicated cysts. This approach obtains complete
removal as well as tissue for examination. This is particularly
useful for large macrocysts where aspiration is sure to be followed
by reaccumulation. Percutaneous excision with a vacuum-assisted
device can remove all the fluid as well as remove a piece of the
cyst wall, preventing reaccumulation.
Multiple cysts and cyst aspirations are clinical markers of
associated underlying histologic breast proliferation.138 Women
who have undergone aspiration of multiple breast cysts have an
increased risk of breast cancer, and they should be advised to
practice regular self-examination, in addition to undergoing peri-
• Fig. 5.4 Multiloculated cyst. odic clinical examination and age-appropriate mammography and
ultrasound.138,139
for developing breast cancer after a diagnosis of benign breast Apocrine Metaplasia
disease. Regarding the histologic classification of benign breast Apocrine metaplasia presents pathologically as dilated ducts and
lesions, the relative risk associated with nonproliferative lesions cysts containing inspissated secretions. It is commonly associated
without a family history is 0.89, nonproliferative lesions with a with fibrocystic change and does not increase the risk of cancer
family history is 1.62, proliferative lesions without atypia the rela- without atypia. Apocrine metaplasia typically presents as a cluster
tive risk is 1.88, and for atypical hyperplasia it is 4.24.133 of microcysts or a microlobulated mass seen sonographically but
can also present as thick-walled cysts or complex cystic lesions that
may require biopsy.137,140 In addition, it has been associated with
Nonproliferative Lesions of the Breast enhancing lesions on magnetic resonance imaging (MRI) and has
Nonproliferative lesions of the breast account for approximately been responsible for up to 11% of benign MRI biopsies.141 These
70% of benign lesions. Cysts and apocrine metaplasia, duct lesions may require biopsy or short-term follow-up based on clini-
ectasia, ductal epithelial hyperplasia, calcifications, fibroadeno- cal and radiographic findings.
mas, and related lesions are included in this category.
Duct Ectasia and Periductal Mastitis
Breast Cysts Duct ectasia is present in nearly half of women older than 60 years
Cysts are defined by the presence of fluid-filled, epithelialized of age and is considered part of the normal aging process.142 Duct
spaces (Fig. 5.4).134,135 Cysts in the breast vary greatly in size and ectasia involves the large and intermediate ductules of the breast.143
number and can be microscopic or macroscopic. These lesions are Duct ectasia is most often recognized by the presence of palpable
almost always multifocal and bilateral, and they are almost never dilated ducts filled with desquamated ductal epithelium and pro-
malignant. Cysts originate from the terminal duct lobular unit or teinaceous secretions. Periductal inflammation is a distinguishing
from an obstructed duct ectasia. The typical macroscopic cyst is histologic characteristic in this condition. The pathogenesis of
round, appears bluish (blue-domed cyst), and usually contains duct ectasia is obscure but probably periductal mastitis, leading
dark fluid ranging in color from green-gray to brown. The epithe- to weakening of the muscular layer of the ducts and secondary
lium of the cyst is often flattened, and apocrine metaplasia of the dilation, is the primary process.144 The presenting symptoms of
epithelium lining the wall of the cyst is occasionally seen. duct ectasia are nipple discharge, nipple retraction, inflammatory
Cysts are categorized by their imaging characteristics as simple, masses, and abscesses. Both duct dilation and duct sclerosis rep-
complicated, or complex. Simple cysts are typically benign with resent disorders of involution. Periductal fibrosis can occur in the
anechoic content, imperceptible walls, and posterior acoustic absence of duct ectasia or inflammation and alternatively repre-
enhancement. Complicated cysts are probably benign with sents part of the normal involutional process.145 The clinical sig-
hypoechoic content, thin walls, and with or without posterior nificance of severe duct ectasia lies in its mimicry of invasive
acoustic enhancement. Finally, complex cysts are of an indetermi- ductal carcinoma, but there is no demonstrated relationship to
nate nature and have thick walls, septa, and solid components. breast cancer risk.
Complex cysts should undergo biopsy, percutaneous removal,
and/or surgical excision because they can be associated with a wide Mild Ductal Epithelial Hyperplasia
range of diagnoses from benign to malignant conditions.136 The fundamental feature of epithelial hyperplasia is an increased
Simple cysts do not need to be aspirated by their very presence. number of nonstromal cells relative to the normally observed two
If age-appropriate mammography and ultrasound demonstrate a cell layers along the basement membrane.131 Subtypes include
benign cyst, then no further intervention is required. In fact, it is apocrine, ductal, and lobular types (Box 5.1). Mild ductal epithe-
discouraged because it can cause future mammographic and ultra- lial hyperplasia, as opposed to florid ductal epithelial hyperplasia,
sound artifact. If the cyst is painful or very large, aspiration can which is discussed later, does not increase the risk for breast
be performed under ultrasound guidance. Aspirated fluid that is cancer. In general, some degree of epithelial hyperplasia is seen in
bloody or contains debris should be sent for cytology. Once the the majority of women over 70 years of age.146
• BOX 5.1 Epithelial Hyperplasia of the Breast disorder of the normal process, and giant and multiple fibro-
adenomas fit in the disease end of the spectrum. The incidence
Apocrine Type of carcinoma arising in a fibroadenoma is approximately 0.1%
Apocrine metaplasia (most commonly seen in the lining of cysts) to 0.3%, with invasive carcinomas more frequently of the
lobular type.150
Ductal Type Diagnosis is based on the combination of clinical exami-
Sclerosing adenosis
nation, imaging, and percutaneous tissue aspiration or biopsy
Mild ductal hyperplasia
Moderate ductal hyperplasia
(the “triple” test). A clinical diagnosis of fibroadenoma alone is
Florid ductal hyperplasia unreliable and does not exclude malignancy, even in younger
Atypical ductal hyperplasia women. Ultrasound, in combination with mammography in
select patients, should be performed. A subsequent core needle
Lobular Type biopsy is the most accurate means of establishing the diagnosis.
Atypical lobular hyperplasia Because of the heterogeneity of fibroadenomas and the over-
Ductal involvement of cells of atypical lobular hyperplasia lapping features of fibroepithelial tumors, an accurate diagnosis
Modified from Hutter RVP. Consensus meeting: is “fibrocystic disease” of the breast precancerous? from core needle biopsy can be challenging. Any atypical epithe-
Arch Pathol Lab Med. 1986;110:171-173; and Dupont WD, Page DL. Risk factors for breast cancer lial proliferation or unusual stromal changes on biopsy should
in women with proliferative breast disease. N Engl J Med. 1985;312:146-151. prompt complete excision to rule out malignant transformation
or phyllodes tumor.149 In the future, gene expression profiling may
prove useful in discerning these differences along the spectrum
of fibroepithelial lesions. In a recent study, the levels of expres-
sion of proliferation-related genes (e.g., CCNB1 and MKI67)
and mesenchymal/epithelial-related genes (e.g., CLDN3 and
EPCAM) were used to distinguish fibroadenoma from malignant
phyllodes tumor.151
Traditionally, symptomatic fibroadenomas, as well as those
greater than 2 to 3 cm, have been treated by surgical excision.137,152
Currently, alternatives to surgical excision include percutaneous
removal153 radiofrequency ablation154 or cryoablation.155 Core
biopsy–proven fibroadenomas in young women (<35 years) that
are mobile, less than 2.5 cm, and otherwise clinically benign can
be safely observed.156
Complex Fibroadenoma. Complex fibroadenomas are fibro-
adenomas harboring one or more complex features including
epithelial calcifications, apocrine metaplasia, sclerosing adenosis,
or cysts greater than 3 mm. Imaging features that can help dis-
tinguish complex fibroadenomas include irregular shape, noncir-
cumscribed borders, complex echo structure, microcalcifications,
• Fig. 5.5 A well-marginated multilobulated fibroadenoma.
and posterior acoustic enhancement.157 The risk of invasive car-
cinoma developing in women with complex fibroadenoma was
found to be three times that of the general population.158 The
Fibroadenoma and Related Lesions literature supports excision of complex fibroadenomas.159
Fibroadenoma. Autopsy studies demonstrate that fibroade- Fibroadenomatosis (Fibroadenomatoid Mastopathy).
nomas are present in approximately 10% of women.147 The peak Fibroadenomatosis is a benign breast lesion with the composite
incidence occurs between the second and third decades of life. histologic features of a fibroadenoma and fibrocystic changes that
However, these lesions are occasionally seen in the elderly. They may represent a morphologic stage in the development of fibro-
are often solitary lesions, but 50% of patients will present with adenomas. The lesion is characterized by microscopic fibroad-
multiple masses. Fibroadenomas are benign, well-marginated, enomatoid foci intermingled with dilated ducts, epitheliosis, and
pseudoencapsulated tumors (Fig. 5.5). They are a subset of adenosis and was found in more than 10% of cases of BBD.160
fibroepithelial tumors that comprise stromal and epithelial com- Although there is no clear etiology of fibroadenomatosis, there
ponents.148 The histologic pattern depends on which of these have been case reports of cyclosporine-induced fibroadenomatosis
components is predominant. Common stromal patterns include in immunosuppressed patients after renal transplantation.161,162
diffuse myxoid change, hyalinization, and increased cellularity; Tubular Adenoma. Tubular adenomas are rare, benign epi-
less commonly foci of smooth muscle differentiation or pseudo- thelial tumors that usually present in young women of reproduc-
angiomatous stromal hyperplasia can be seen.149 Other histologic tive age. They are well-defined, freely mobile tumors that clinically
characteristics include biphasic tumor, low cellularity, no pleo- resemble fibroadenomas being composed of benign epithelial ele-
morphism, 1 to 2 mitoses per 10 HPF (high-power field), and ments with sparse stroma.163 The sparse stroma is the histologic
very low Ki-67 index.149 feature that differentiates adenomas from stromal-rich fibroad-
Fibroadenomas are very responsive to hormonal stimulus enomas.164 Tubular adenomas or pure adenomas have not been
and may enlarge premenstrually or during pregnancy. Growth associated with an increased risk of breast cancer development.165
beyond 5 cm is considered a giant fibroadenoma. Fibroad- Lactating Adenoma. Lactating adenomas present during
enoma fits well into the ANDI classification: small fibroad- pregnancy or during the postpartum period. On microscopic
enomas are normal, clinical fibroadenomas (1–3 cm) are a examination, lactating adenomas have lobulated borders and are
composed of glands lined by cuboidal cells that possess secretory Radial Scar and Complex Sclerosing Lesions
activity identical to that normally observed in breast tissue during Radial scars and complex sclerosing lesions of the breast are char-
pregnancy and lactation. They are usually slow growing and acterized by central sclerosis and varying degrees of epithelial
seldom reach a size larger than 3 cm. In rare cases, rapid growth proliferation, apocrine metaplasia, and papilloma formation.178
can occur resulting in giant lactating adenomas greater than The term radial scar is reserved for smaller pathologic lesions (up
5 cm.166 to 1 cm in diameter), whereas complex sclerosing lesion is used
Hamartoma. Hamartomas are rare, benign tumors that can for larger masses. Radial scars originate at the point of terminal
lead to unilateral breast enlargement without a palpable, localized duct branching. With the naked eye, the appearance is often
mass lesion. On imaging, they appear as rounded, well- unremarkable, but with magnification, the characteristic histo-
circumscribed masses of mixed, heterogeneous densities with a logic changes radiate from a central white area of fibrosis, which
mottled center and a thin capsule. No consensus has been reached contains elastic elements. In a review by Degnim and colleagues
on definitive histologic criteria, but characteristic findings include radial scars appear to have a twofold increased risk for future
the presence of lobules within a fibrotic stroma that surrounds breast cancer.179 However, others have suggested that this risk is
and extends between individual lobules and obliterates the usual close to that imparted by proliferative disease overall.178,180 Short-
loose stroma.167 Multiple hamartomas are associated with Cowden term follow-up may be appropriate for radial scars without atypia
disease, which carries a higher risk of breast cancer.168 and those that are sampled with 12 or more cores by a large biopsy
Adenolipoma/Lipoma. Adenolipomas/lipomas are common needle (11-gauge or greater) due to lower reported rates of upgrade
and consist of sharply circumscribed nodules of fatty tissue that to cancer (5% or less).179
have normal lobules and ducts interspersed.169 Microscopically the
fat is normal, and the lobules and ducts are fairly evenly distrib- Florid Ductal Epithelial Hyperplasia
uted throughout the tumor. They represent no increased risk of Florid hyperplasia is found in more than 20% of biopsy samples
breast cancer. and thus is the most common proliferative lesion of the breast. It
is associated with a minor increased risk of breast cancer.131,133 This
Pseudoangiomatous Stromal Hyperplasia entity is characterized by an increase in cell number within the
Pseudoangiomatous stromal hyperplasia (PASH) generally pre- ducts, with a proliferation of cells that occupies at least 70% of
sents as a painless mass. It is characterized by myofibroblast-lined, the duct lumen. Architecturally, epithelial hyperplasia is either
slitlike spaces resembling blood vessels surrounded by dense, col- solid or papillary and is characterized by intracellular spaces that
lagenous stroma that may require differentiation from low-grade are irregular, slitlike, and variably shaped. It has been suggested
angiosarcoma.170 It presents sonographically as a hypoechoic mass that the expression of estrogen receptor alpha in adjacent normal
or mammographically as a noncalcified, circumscribed mass.152 lobules may increase the breast cancer risk in patients with epi-
After diagnosis by core needle biopsy, these lesions may be safely thelial hyperplasia lacking atypia.181
followed with routine screening assessment in the absence of
interval growth or other suspicious radiologic findings.171 There Intraductal Papilloma
have been reports of PASH being responsible for rapid breast Solitary intraductal papillomas are tumors of the major lactiferous
enlargement documented in the literature.172–174 ducts and are most commonly observed in premenopausal women.
Common presenting features include serous or bloody nipple
discharge.182,183 Grossly, these lesions are pinkish-tan, friable, and
Proliferative Lesions Without Atypia are usually attached to the wall of the involved duct by a stalk.
Proliferative breast disorders without atypia make up approxi- Microscopically, they are composed of multiple branching papil-
mately 30% of benign breast disease and include sclerosing adeno- lae with a central fibrous vascular core that is lined by a layer of
sis, radial scars and complex sclerosing lesions, florid ductal epithelial cells. Central papillomas tend to be single whereas
epithelial hyperplasia, and intraductal papillomas. peripheral papillomas are more likely to be multiple and impart
The diagnostic workup for each of these lesions is similar and a higher risk of atypia and subsequent carcinoma.184,185 Lewis and
involves stereoscopic or open biopsy depending on the facilities colleagues reported a relative risk of breast cancer of twofold in
and experience available and the perceived risk of malignancy single papillomas without atypia, fivefold in those with atypia,
from the radiologic appearance. It is widely accepted that it is and a relative risk of threefold and sevenfold in multiple papil-
impossible to differentiate these lesions with certainty from cancer lomas without and with atypia, respectively.186
by mammographic features.175 It is often difficult to differentiate between benign papilloma
and papillary cancer on core biopsy due to the heterogeneity
Sclerosing Adenosis of papillary lesions, which often require review of the entire
Sclerosing adenosis is more common in perimenopausal women lesion to ensure accurate diagnosis.179 Standard surgical excision
and is found in approximately 28% of benign biopsies.176 It is a after diagnosis of a papillary lesion reveals an upgrade rate of
proliferative lesion characterized by an increased number of acinar 10% to 38%179,187,188; however, in reviewing only the papillary
structures and fibrosis of the lobular stroma while the normal lesions diagnosed without atypia, others have shown much lower
two-cell population along the enveloping basement membrane is upgrade rates ranging from 0% to 6%.189–191 Furthermore, some
maintained. The borders of the lesion are irregular, while it main- studies have found no pathologic upgrades when patients with
tains its lobular architecture. Sclerosing adenosis commonly nipple discharge or palpable masses are excluded, suggesting that
occurs in the context of multiple microscopic cysts and diffuse there might be a subset of patients that can be followed with
microcalcifications that make screening mammography difficult. observation rather than excision as long as there is radiographic-
Recent data suggest that sclerosing adenosis may double the risk pathologic concordance.189,190,192 Alternatively, small papillo-
for developing breast cancer compared with benign breast disease mas can be percutaneously removed in their entirety via newer
without sclerosing adenosis.177 biopsy devices.
Juvenile papillomatosis is a rare subset of papillary breast TABLE

disease occurring primarily in children and young adults. It gener- 5.4 Risk for Development of Invasive Carcinoma
ally presents as a firm, well-circumscribed mass, similar to fibro-
adenoma. Ultrasound reveals ill-defined, heterogeneous masses Lesion Relative Risk
with surrounding small cystic spaces. Management generally Nonproliferative lesions of the breast 0a to 1.6-fold
involves complete surgical excision with annual surveillance. More
than 25% of patients with juvenile papillomatosis have a family Sclerosing adenosis 2-fold
history of breast cancer, suggesting it may be a marker of a familial Radial scar 2-fold
predisposition for breast cancer. The family of affected patients
may also benefit from screening.184,193 Florid epithelial hyperplasia 1.5-fold
Intraductal papilloma 2- to 5b-fold
Proliferative Lesions With Atypia Atypical lobular hyperplasia 4-fold
Atypical proliferative lesions include both ductal and lobular Atypical ductal hyperplasia 4-fold
lesions. These lesions have some, but not all, of the features of
carcinoma in situ. At times, even the most experienced patholo- Data from references 133, 177, 179, 186.
a
Relative risk = 0.89.
gists disagree as to whether a given lesion is atypical hyperplasia b
5-fold increased risk with atypia.
or carcinoma in situ.194
Results from the Nurses’ Health Study reveal an odds ratio for
breast cancer of 4.1 among all women with atypical hyperplasia.195
Similar results were described by Degnim and colleagues.196 Their uniform cellular placement, and (3) hyperchromatic nuclei. Atyp-
study found an increased risk of breast cancer development in ical ductal hyperplasia has some, but not all, of these features. The
patients with multifocal atypia and younger age, with the risk natural history of atypical ductal hyperplasia suggests an interme-
remaining elevated for more than 20 years. diate risk (approximately fourfold) for the development of inva-
Atypical hyperplasia has been shown to increase the future sive cancer200 with similar results from the Nurses’ Health Study
cancer risk in both breasts. In a group of nearly 700 women fol- (odds ratio 3.1)195 (Table 5.4). When ADH was diagnosed by
lowed for a mean of 12.5 years, approximately 20% developed percutaneous biopsy, the rate of upgrading to DCIS or invasive
breast cancer. This study reported a 2 : 1 ratio of ipsilateral to carcinoma at surgery was found to be in the range of 13% to
contralateral breast cancer with ipsilateral predominance in the 31%,179,204,205 and subsequent surgical excision is recommended
first 5 years and long-term bilateral risk continuing thereafter.197 for most patients.179 Refer to Chapter 8 for further management
of atypical hyperplasia.
Atypical Lobular Hyperplasia
Atypical lobular hyperplasia (ALH) fulfills some, but not all, of Flat Epithelial Atypia
the criteria of lobular carcinoma in situ.198 The cytology of ALH Flat epithelial atypia (FEA) is a rare lesion that presents pathologi-
is usually quite bland, with round, lightly stained eosinophilic cally as nuclear atypia in the setting of columnar cell change or
cytoplasm. The uniformity and roundness of the cell population hyperplasia, frequently with microcalcifications seen on imaging.
is pathognomonic of ALH. The lobular unit is less than half filled Recent studies suggest it may be a nonobligate precursor to low-
with these cells, and no significant distortion of the lobular unit grade breast carcinoma.206 It has been found that, with radiologic-
is present.199 According to Page and colleagues, the risk of subse- pathologic correlation of FEA diagnosed on core needle biopsy,
quent invasive cancer in women with ALH is four times that of upgrade rates to carcinoma are up to 13%, although these rates
women who do not have this diagnosis and increased if associated are lower when calcifications are removed. For patients with pure
with a family history.200–202 Degnim and associates in the Mayo FEA on core needle biopsy, the World Health Organization
cohort did not find that family history further increased the risk Working Group advocates radiologic-pathologic correlation, and,
of this breast lesion and reported a lower relative risk of cancer of in the absence of clinically suspicious indicators, recommends
3.67 among women with ALH.194 More recently, Collins and observation.207 However, others deem surgical excision reasonable
colleagues reported an odds ratio of 7.3 for breast cancer risk given pathologic upgrade rates.179 Despite one small study in
among women with ALH (Table 5.4). There are no clear guide- which FEA demonstrated a small increase in future breast cancer
lines on the management of ALH found on percutaneous biopsy. risk (relative risk 1.5),179 there are insufficient data to indicate the
Most recent studies report pathologic upgrade rates ranging from need for clinical follow-up or risk-reducing therapies.152
0% to 22%.179,203 Although historically, surgical excision has been
recommended for cores revealing ALH, some recent reports Other Benign Breast Disorders
suggest observation with short-term follow-up may be appropriate
for lesions with concordant findings and no other high-risk lesions Nipple Discharge
within the biopsy specimen.179 In a study of 10,000 consecutive new surgical consultations for
breast complaints, 3% were for nipple discharge alone.208 Of the
Atypical Ductal Hyperplasia population with periductal mastitis/ductal ectasia complex, 15%
Atypical ductal hyperplasia is diagnosed when atypia is present to 20% have nipple discharge.209 Nonbloody, nonspontaneous,
and either the cytologic or architectural criteria for ductal carci- bilateral nipple discharge, typically from several ducts, is a benign
noma in situ (DCIS) are absent. Page and coworkers200 have condition with no increased cancer risk and is not normally an
emphasized that each of the following criteria must be met for a indication for surgical treatment.210 Bloody nipple discharge is
diagnosis of DCIS: (1) a uniform population of cells, (2) smooth associated with a significant risk of cancer, with an odds ratio
geometric spaces between cells or micropapillary formation with of 2.27 compared with patients with nonbloody discharge,211
although benign bilateral bloody nipple discharge can be seen associated skin retraction and tenderness. There is a wide spec-
with pregnancy. Duct excision remains the gold standard treat- trum of pathologic and radiographic findings that evolve over the
ment for pathologic nipple discharge that includes bloody or course of healing. Microscopically, early lesions may have anucle-
serous discharge. A few have suggested that there may be a subset ated adipocytes, foamy histiocytes, and multinucleated giant cells
of patients that presents without palpable mass and normal exami- along with signs of hemorrhage when viewed microscopically.
nation and imaging for whom observation or ductoscopy or galac- Signs of hemorrhage may be present grossly as well. Older lesions
tography may be an appropriate alternative.212–214 However, develop fibrosis and hemosiderin-laden macrophages with dystro-
excision is both diagnostic and curative. Reference Chapter 4 for phic calcification microscopically with signs of saponification,
additional information on nipple discharge. calcification, and fibrosis when viewed grossly. Mammographic
findings may change over time and can include early linear and
Nipple Inversion curvilinear calcifications and later central calcifications, typical for
Primary nipple inversion is a disorder of the development of the oil cysts. Focal asymmetries and spiculated masses may be other
terminal ducts, preventing the normal protrusion of ducts and radiographic findings.218,219
areola. Onset later in life can represent periductal fibrosis, but The tender, acute retroareolar mass of periductal mastitis often
cancer must be excluded.215 Although the results are usually sat- resolves spontaneously, so surgery is delayed and antibiotics may
isfactory, patients seeking correction for cosmetic reasons should be given if biopsy is suggestive of this diagnosis.209
be aware of the possibility of nipple necrosis, interference with
sensation, inability to breastfeed, and the possibility that postop- Subareolar Abscess and Fistula
erative fibrosis will lead to late recurrent inversion. Because the A subareolar abscess is confirmed with needle aspiration, which
benign condition results from shortening of the ducts, a complete also provides a specimen for bacterial culture.220 Aspiration can
division of the subareolar ducts is the only procedure that can be facilitated by ultrasound guidance. Repeat aspirations are often
correct it permanently. necessary, and 40% of cases involving anaerobic bacteria recur
after a short follow-up period. For recurrent symptoms, some have
Epithelial Hyperplasia of Pregnancy advocated for a total nipple core biopsy or excision of the central
Marked hyperplasia of the duct epithelium occurs in pregnancy. nipple, including the obstructed ducts. This technique achieves a
The papillary projections sometimes give rise to bilateral bloody cure rate of 91% and an overall 95% satisfaction rate in the cos-
nipple discharge. Although this resolves in most cases without metic outcome of the nipple.221
consequence, full workup to rule out carcinoma should be Terminal mammary duct obstruction may result in the forma-
pursued.216 tion of a fistulous tract from the lactiferous duct to the skin and
predisposes to recurrent subareolar abscesses. In this setting, fis-
Adolescent Hypertrophy tulectomy is recommended for definitive treatment. Smokers are
Adolescent hypertrophy is associated with gross stromal hyperpla- at particular risk, and smoking cessation is recommended. See
sia at the time of breast development and can be categorized by Chapter 6 for further detail. Nipple inversion or occlusion during
differing growth patterns. Juvenile gigantomastia demonstrates lactation are also thought to be causative factors.222,223
rapid growth over 6 months, followed by a period of slower per-
sistent growth. Adolescent macromastia, an additional subtype,
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S ECTION I I I Benign and Premalignant Lesions

Normal Disorder Disease

• Fig. 5.1 Suggested theories of causation of breast pain.

Indeed, studies by Minton and colleagues have shown “catechol- TABLE

Gong and colleagues109 have hypothesized that toremifene, a

cyst is aspirated, it can be followed with repeat imaging in 6

Juvenile papillomatosis is a rare subset of papillary breast TABLE

References 26. Sitruk-Ware LR, Sterkers N, Mowszowicz I, Mauvais-Jarvis P.

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