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review article
current concepts
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The new england journal of medicine
or a moderate increase (relative risk, >2.0) (Table Underlying and acquired genetic changes are
1).12 The levels of risk have been established by also associated with benign breast lesions (Fig. 1).
means of long-term follow-up, and the specific le- Loss of heterozygosity, as a result of deletions of
sions were defined by a consensus conference.12,13 small segments of DNA,18-22 is commonly found in
An important basis of the classification is the degree benign breast lesions. Lesions are frequently mul-
of cellular proliferation.12-14 tifocal, with each lesion exhibiting loss of hetero-
zygosity of different regions of DNA. Women with
mutations in the BRCA1 or BRCA2 genes have a high
causal factors
in benign breast disorders frequency of multiple benign or malignant breast
lesions on meticulous examination of specimens
Clinical observations of women receiving estro- obtained from bilateral mastectomy.23 These find-
gens and antiestrogen drugs suggest that hormonal ings support the current theory of an underlying
events play a causative role in the development of predisposition to mutations in some patients as
benign lesions. Among postmenopausal women the cause of multiple breast lesions. This phenom-
receiving estrogens with or without progestins for enon (i.e., a predisposition to mutations) has been
more than eight years, the prevalence of benign termed a field effect and, more recently, a mutator
breast lesions increased by a factor of 1.70 (95 per- phenotype.24
cent confidence interval, 1.06 to 2.72).15 The anti-
estrogen drug tamoxifen, when used in the preven-
progression
tion of breast cancer, is associated with a reduction to malignant disease
of 28 percent in the prevalence of benign breast le-
sions (relative risk, 0.72; 95 percent confidence in- By analogy to the linear model of the development of
terval, 0.65 to 0.79), including those classified as colon cancer,25 breast lesions are believed by many
adenosis, cysts, mammary-duct ectasia, and hyper- investigators to progress in a linear fashion from
plasia.16 usual ductal hyperplasia (ductal hyperplasia with-
Table 1. Classification of Benign Breast Lesions on Histologic Examination, According to the Relative Risk
of Breast Cancer.
* Percentages indicate the percentage of breasts examined at autopsy in which the lesion was found. Data are from Sandison.11
Data are from Goehring and Morabia.8
Most phyllodes tumors are considered to be benign fibroepithelial tumors, but some have malignant clinical and histo-
logic features.
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current concepts
out atypia) or from unfolded lobules20 to atypical ties (37 percent), social activities (12 percent), and
ductal hyperplasia and then to ductal carcinoma school activities (8 percent).28,31 Whether caffeine,
in situ and invasive cancer. Several biologic and iodine deficiency, alterations in levels of fatty acid
molecular changes (Fig. 1) have been observed in in the breast, fat intake in the diet, or psychological
association with this progression, but causal rela- factors have a causative role in cyclic breast pain has
tionships have not been established. not been established.32,33
Noncyclic breast pain is unrelated to the men-
strual cycle. Detection of focal tenderness is helpful
clinical features
of benign breast disease diagnostically and suggests a tender cyst, rupture
through the wall of an ectatic duct, or a particularly
breast pain tender area of breast nodularity. Acute enlargement
Cyclic breast pain usually occurs during the late of cysts and periductal mastitis may cause severe,
luteal phase of the menstrual cycle, in association localized pain with a sudden onset.
with the premenstrual syndrome or independent-
ly,26-31 and resolves at the onset of menses (Table nonbreast pain
2).26,27 In a study of 1171 healthy premenopausal Pain arising from the chest wall may be mistakenly
American women, 11 percent had moderate-to- attributed to the breast. Pain that is limited to a par-
severe cyclic breast pain and 58 percent had mild ticular area and characterized as burning or knife-
discomfort.28,31 Breast pain interfered with usual like in nature may arise from the chest wall. Several
sexual activity among 48 percent of the patients, distinct types of pain can be distinguished, including
and among others it interfered with physical activi- localized or diffuse lateral chest-wall pain, radicular
Factor of
Variable Increase
Proliferation rate 5
ERa:ERb-2 ratio 20
c-erbB-2 (HER2/neu) 80
TGF-a 8
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The new england journal of medicine
Downloaded from www.nejm.org on December 29, 2009 . Copyright 2005 Massachusetts Medical Society. All rights reserved.
current concepts
6.0
5.3
5.0
4.0
3.4
Relative Risk
3.0
2.4
2.2
2.0
1.0 1.2
1.0
0.0
0 110 >1025 >2550 >5075 >75
Breast Density (%)
Figure 2. Risk of Breast Cancer According to Breast Density in Premenopausal and Postmenopausal Women.
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The new england journal of medicine
crete palpable lesions in women more than 35 years enced cytopathologist and the specimen obtained
of age; ultrasonography provides an optional sub- is insufficient for diagnosis in up to 36 percent of
stitute among younger women. Round dense le- cases in which there are nonpalpable lesions.55
sions detected on mammography often are cysts The roles of magnetic resonance imaging (MRI)
that require ultrasonographic examination to dis- and digital mammography in the evaluation of
tinguish them from solid lesions. breast lesions are currently being investigated. Ga-
For solid lesions, core needle biopsy directed lactography (also called ductography) is useful in
with the use of radiographic or ultrasonographic the detection of focal lesions within a single duct.
techniques provides highly discriminative informa- Cytologic examination of nipple discharge is of lim-
tion with regard to the presence or absence of ma- ited value, with a sensitivity for detecting malignant
lignant disease. In core needle biopsy, a large cut- disease of only 35 to 47 percent.34,56 In the treat-
ting needle is used with a spring-loaded, automated ment of all patients with benign breast disease,
biopsy instrument to obtain tissue specimens suit- clinical judgment is required to provide the proper
able for histologic analysis. Fine-needle aspiration balance between the intense and frequent surveil-
yields cellular material suitable for cytologic evalu- lance needed for some patients and the risk of over-
ation, but the technique must be used by an experi- diagnosis and treatment for others.
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current concepts
mendations may include the use of mild analgesic piration with imaging studies repeated within six
agents such as acetaminophen, nonsteroidal antiin- months. Nonbloody fluid is discarded, but if the
flammatory drugs (NSAIDs), or aspirin.32,33,56,63-67 same cyst refills, surgical consultation is warrant-
Other approaches include tamoxifen, at a dose of ed. If bloody, the fluid should be sent for cytologic
10 mg daily for three to six months,68,69 and among analysis and consultation with a surgeon should be
patients in whom there is no response to treatment, requested.
a change to danazol, at a dose of 200 mg daily (or Usual practice requires the triple test (palpation;
only during the luteal phase of the menstrual cy- mammography, often in conjunction with ultraso-
cle).70 Evening primrose oil has been used, at oral nography; and biopsy) for women more than 35
doses of 1 to 3 g daily, on the basis of two random- years of age with dominant masses. When the re-
ized studies,71,72 but recent trials question its effica- sults of mammographic screening are negative but
cy.73,74 Gonadotropin-releasing hormone agonists a dominant mass is present, biopsy is required to
have been used successfully for severe pain.75,76 rule out breast cancer, since lobular carcinoma may
not be visible on mammography. Among younger
noncyclic pain women, mammography may be omitted if the re-
When pain is truly arising from the breast, the ap- sults of ultrasonographic testing and biopsy yield
proach outlined for cyclic pain is used. However, a definitive information. Many experts omit biopsy in
musculoskeletal cause is present in 40 percent of the evaluation of younger women with lesions char-
women referred to specialized mastalgia clinics for acteristic of fibroadenoma on ultrasonography and
pain thought to arise from the breast. In two thirds elect to follow these patients carefully with serial
of women with diffuse chest-wall pain, the condi- ultrasonography at six-month intervals for a period
tion responds to oral or topical NSAIDs.77 Among of two years and once yearly thereafter. Since care-
the remaining patients, 85 percent gain temporary ful studies have shown that a lesion that appears to
or permanent relief from the use of a combination be benign on mammography and ultrasonography
of anesthetic and steroidal drugs injected into the is benign more than 99 percent of the time, some
tender site.77 experienced clinicians opt for follow-up without bi-
opsy.51-54 However, other experienced surgeons
focal lesions disagree and believe that all fibroadenomas require
Careful examination distinguishes between solitary, diagnostic core needle biopsy or fine-needle aspira-
discrete, dominant, persistent masses and vague tion, especially among carriers of a BRCA mutation,
nodularity and thickening. The Society of Surgical in whom medullary cancer may be found. Confir-
Oncology practice guidelines78 recommend the fol- mation on biopsy of fibroadenoma eliminates the
lowing evaluation. In women 35 years of age or need for serial ultrasonography. For patients with a
younger, all dominant, discrete, palpable lesions re- diagnosis of atypical ductal hyperplasia on fine-nee-
quire referral to a surgeon. If vague nodularity, thick- dle aspiration or core needle biopsy, excisional biop-
ening, or asymmetric nodularity is present, the ex- sy is required, because more complete resection
amination should be repeated at midcycle after one often changes the diagnosis to ductal carcinoma
or two menstrual cycles. If the abnormality resolves, in situ.
the patient should be reassured, and if it does not,
the patient should be referred to a surgeon. Breast nipple discharge
imaging may be appropriate. Women older than 35 A practical algorithm (Fig. 3) divides discharge into
years of age with a dominant mass should undergo two categories according to the presence or absence
diagnostic mammography (and frequently, ultraso- of galactorrhea (defined as milk production more
nography)51,54,55 and should then be referred to a than one year after weaning or in nulligravid or
surgeon. When vague nodularity or thickening is menopausal women). The presence of a discharge
present, mammographic screening is required, with in association with a palpable mass and positive re-
physical examination repeated at midcycle one to sults on mammography or ultrasonography war-
two months afterward and referral to a surgeon if rants evaluation of the mass. Galactorrhea is con-
the abnormality persists. sidered pathologic if spontaneous. A workup for
Postmenopausal women are referred for surgical galactorrhea includes measurement of prolactin
consultation after undergoing mammography. For and thyrotropin levels and appropriate endocrino-
gross cysts, the guidelines suggest fine-needle as- logic evaluation and treatment if the levels are ele-
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282
Discharge present
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The
n engl j med 353;3
Consideration Galactography
of galactography
of
medicine
july 21 , 2005
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