REVIEW

LAKSHMI VAIDYANATHAN, MD KAREN BARNARD, MD, MPH D. MICHAEL ELNICKI, MD Section of General Internal Medicine, Department of Section of General Internal Medicine, Department of Professor of Medicine, University of Pittsburgh Medicine, University of Pittsburgh Medical Center Medicine, University of Pittsburgh Medical Center School of Medicine; Director, Section of General Shadyside, Pittsburgh, PA Shadyside, Pittsburgh, PA Internal Medicine, Department of Medicine, University of Pittsburgh Medical Center Shadyside, Pittsburgh, PA

Benign disease: When to treat, when to reassure, when to refer

■ ABSTRACT ANY WOMEN HAVE SYMPTOMS of breast M disease, but few have cancer. Yet these Many women have breast symptoms—swelling and symptoms are understandably a source of great tenderness, nodularity, pain, palpable lumps, concern for women. discharge, or breast infections and inflammation. The challenge for physicians is to distin- Fortunately, relatively few have . Physicians guish between benign and malignant lesions, must distinguish benign breast conditions from malignant and to know when prompt referral to a surgeon ones, and know when to refer the patient to a specialist. or other specialist is necessary. We have included some of the newer diagnostic techniques Making such discriminations is not easy, as and the approach to patients with nonpalpable lesions the conditions are diverse and vary in presen- tation. They include: detected on a screening mammogram. • Physiologic swelling and tenderness • Nodularity ■ KEY POINTS • • Palpable breast lumps Formerly, the term “fibrocystic disease” was used to • describe all benign breast conditions. However, this term • Breast infections and inflammation. caused confusion in distinguishing between normal This article presents an approach to physiologic changes and pathologic ones. benign breast conditions for the primary care physician, including their diagnosis, manage- Breast pain is the second most common breast symptom ment, and appropriate referral. A systematic for which women seek medical attention, the first being a approach and a careful history and physical lump in the breast. Most women with breast pain do not examination will simplify this seemingly com- have cancer. plicated group of disorders. ■ SYMPTOMS COMMON, A benign mass is usually three-dimensional, mobile, and BUT RARELY MALIGNANT smooth, has regular borders, and is solid or cystic in consistency. The incidence of benign is diffi- cult to assess clinically.1 A malignant mass is usually firm in consistency, has A retrospective cohort study in a health irregular borders, and may be fixed to the underlying skin maintenance organization found that 16% of or soft tissue. There may also be skin changes or nipple women 40 to 70 years of age presented with retraction. breast symptoms,2 but only 6% of those with symptoms had breast cancer. In another study in Sheffield, UK, 60% of women referred to surgical outpatient or out-

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T ABLE 1 T ABLE 2 Pathologic classification Clinical classification of benign breast disease of benign breast disease Nonproliferative lesions Physiologic swelling and tenderness Cysts Nodularity Mild hyperplasia of the usual type Breast pain Epithelial-related calcifications Palpable lumps Nipple discharge Papillary apocrine change Breast infections and inflammation BASED ON LOVE S, GELMAN RS, SILEN W. Proliferative lesions without atypia FIBROCYSTIC “DISEASE” OF THE BREAST—A NONDISEASE? Sclerosing adenosis N ENGL J MED 1982; 307:1010–1014. Radial and complexing sclerosing lesions Moderate and florid hyperplasia of the usual type Intraductal papillomas the Nashville series. Unless the patient has a Atypical proliferative lesions family history of breast cancer, proliferative Atypical lobular hyperplasia disease without atypical hyperplasia increases Atypical ductal hyperplasia the risk of breast cancer only slightly: the rel- BASED ON LOVE S, GELMAN RS, SILEN W. ative risk in the Nashville series was 1.3 with- FIBROCYSTIC “DISEASE” OF THE BREAST—A NONDISEASE? out a family history and 2.4 with a family his- N ENGL J MED 1982; 307:1010–1014. tory. Atypical hyperplasia accounted for 4% of cases in the Nashville series. It is associated reach clinics because of breast symptoms were with a fourfold to fivefold increase in the risk diagnosed with benign breast disease.3 of breast cancer, and a family history in the presence of atypical hyperplasia boosts the risk Breast ■ TWO CLASSIFICATION SYSTEMS of breast cancer even more.6 nodularity and Formerly, the term “fibrocystic disease” was Clinical classification pain usually used to describe all benign breast conditions. The clinical classification of benign breast dis- respond to However, this term caused confusion in distin- ease (TABLE 2) is based on guishing between normal physiologic changes and is more useful for the primary care physi- conservative and pathologic ones.4 cian. The rest of this paper is based on the measures Currently, two classification systems are in clinical classification. use: pathologic and clinical. ■ PHYSIOLOGIC SWELLING Pathologic classification AND TENDERNESS The pathologic classification (TABLE 1), based on findings on , is useful in assessing the Most women in their reproductive years expe- risk of breast cancer in women with benign rience varying degrees of breast swelling, full- breast disease. Most benign breast lesions are ness, or tenderness. These changes occur pre- not associated with an increased risk of breast menstrually and are cyclic, physiologic, and cancer. hormonally mediated.7,8 Physical examina- Nonproliferative disease accounted for tion reveals nodularity, lumpiness, or tender- 70% of cases of benign breast lesions in a series ness. of more than 10,000 consecutive breast biop- If in doubt about the nature of the lumpi- sies performed in three hospitals in Nashville, ness, ask the patient to return after one or two Tenn.5 It is not associated with an increased menstrual cycles during midcycle when these risk of breast cancer. changes regress.9 At this point, both tender- Proliferative disease without atypical ness and lumpiness should be significantly hyperplasia accounted for 27% of the cases in diminished.

426 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 5 MAY 2002 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. Patients with these physiologic changes rant, diffuse, and may radiate to the axilla or should be reassured. Treatment, if needed, upper arm.8,12 consists of analgesics and a well-fitting Mastalgia is broadly classified as either brassiere.8 cyclic or noncyclic, based on its relationship to the menstrual cycle.12 ■ NODULARITY Cyclic mastalgia usually starts 1 to 3 days before the onset of menses and subsides after Nodularity is also a physiologic, hormonally menses are completed. It accounts for about mediated change characterized by lumpiness two thirds of all cases of mastalgia and is more of the breast and varying degrees of pain and responsive to treatment than noncyclic tenderness. The symptoms are most promi- mastalgia.13 nent about 1 week before menstruation and Noncyclic mastalgia is unrelated to the subsequently decrease. menstrual cycle and shows a poorer response Physical examination may reveal an area to treatment. of nodularity or thickening, poorly differenti- ated from the surrounding tissue and often in Follow-up of breast pain the upper outer quadrant of the breast. If the Any palpable mass or asymmetry on clinical changes are symmetric (ie, the same in both breast examination should be further evaluat- ), they are rarely pathologic.9 ed. Diffuse nodularity, often bilateral, is not uncommon and is a benign finding. Follow-up of asymmetric nodularity If the breast examination is normal, most Follow-up of asymmetric nodularity (ie, not women younger than 35 years do not need any the same in both breasts) should be scheduled further diagnostic evaluation, as the risk of at midcycle after one or two menstrual cycles.9 breast cancer is low.11,14 On the other hand, If the nodularity or thickness persists, the women older than 35 years should have a patient should be referred to a surgeon for mammogram even if the physical examina- evaluation and undergo bilateral mammogra- tion is normal to detect the rare presence of phy if older than 35 years.9 For patients .14,15 Symmetric younger than 35 years, an ultrasound may be A patient with mild pain of less than 6 breast helpful. However, these patients also need a months’ duration who is started on conserva- surgical referral. tive treatment should be followed up after 3 to nodularity is 6 months unless the pain gets worse.14 If the rarely cancer Treatment of nodularity pain persists or is severe despite initial treat- A variety of treatments have been reported for ment, or if the patient has concerns, referral breast nodularity. Conservative measures to a breast specialist is indicated for possible include mild analgesics and supportive initiation of medical therapy.15 brassieres.8 Other treatments are described in the next section on breast pain, as most of the Treatment of breast pain studies evaluating the efficacy of treatment Up to 85% of patients respond to nonmedical were conducted in women with both breast treatment and reassurance that breast cancer nodularity and pain or tenderness. is a rare cause of breast pain. Therefore, the first-line approach to all patients with mastal- ■ BREAST PAIN gia should include education and recommend- ing the use of a well-fitting brassiere. Breast pain, or mastalgia, is the second most Dietary modifications such as caffeine common breast symptom for which women reduction or avoidance, a diet low in saturat- seek medical attention,3,10 the first being a ed fat, and vitamin E supplementation are lump in the breast. Most women with breast often recommended, even though they have pain do not have cancer.11 not shown benefit in clinical trials.16,17 Common symptoms associated with Nevertheless, they can’t hurt. mastalgia are heaviness and tenderness. The Evening primrose oil, an herbal supple- discomfort is often in the upper outer quad- ment, can be used as a first-line agent since it

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has a low side-effect profile.15 One placebo- replacement therapy in postmenopausal controlled trial demonstrated a clinically sig- women alleviates mastalgia. nificant improvement in breast pain at a dose Diuretics have been tried for the treatment of 1,500 mg twice daily. The drug is available of nodularity and breast tenderness, but there is in US health food stores and by prescription very little evidence to support their use.21 in the United Kingdom.9 Various drugs have been studied for treat- ■ PALPABLE BREAST LUMP ing mastalgia and nodularity but are rarely prescribed for these conditions because of Most breast lumps are benign.22,23 Neverthe- their side effects. They are mentioned for less, they are a considerable source of anxiety completeness: to patients. Danazol, an antigonadotropin, has been Key points in the history are the onset, shown in randomized studies to relieve pain in duration, and progress of the lump, any past 97% of patients and to decrease premenstrual history of breast problems, and any surgical nodularity in 73% to 93%.18 It is approved by procedures of the breast. Any risk factors for the US Food and Drug Administration (FDA) breast cancer should be noted, eg, age, family for treating mastalgia. Common side effects history of breast cancer, personal history of include acne, weight gain, hirsutism, and breast cancer, or biopsy showing atypical menstrual dysfunction, including amenorrhea. hyperplasia, but most women with breast can- Women in their reproductive years should use cer have no identifiable risk factors. barrier contraception in view of this drug’s ter- A careful examination of the breast and atogenicity and interaction with birth control the axillary and supraclavicular lymph nodes pills. is essential. A benign mass is usually three- Tamoxifen, a synthetic antiestrogen, dimensional, mobile, and smooth, has regular relieved pain in 75% to 96% of patients in dif- borders, and is solid or cystic in consistency. A ferent randomized trials.15 The drug is not malignant mass is usually firm in consistency, approved by the FDA for treating mastalgia. has irregular borders, and may be fixed to the Any discrete Patients should be evaluated every 3 months underlying skin or soft tissue. There may also solid masses while taking tamoxifen to monitor for irregu- be skin changes or nipple retraction. lar menstrual bleeding or menopausal symp- should prompt toms. The relapse rate is as high as 39% to Follow-up of breast lumps a surgical 48% after tamoxifen is stopped.15 Women older than 35 years with a discrete The long-term effects of tamoxifen in (solid or cystic) should undergo referral for women of reproductive age are uncertain, and bilateral diagnostic mammography to look for tissue diagnosis it is not considered to be a first-line drug. evidence of malignancy.9 In contrast, breast Tamoxifen may induce ovulation, so birth con- cancer is rare in women younger than 35 years, trol measures need to be addressed carefully. and the diagnostic yield of a mammogram is Bromocriptine, a dopamine receptor ago- low due to dense breast tissue.22 Therefore, in nist, inhibits prolactin release. Many patients young women a mammogram should be (29%) stop taking bromocriptine because of obtained only if the mass is suspicious for its side effects, such as headache and dizzi- malignancy on clinical examination or if there ness.19 In addition, bromocriptine is terato- is a strong family history of breast cancer. genic and can interfere with birth control If the mass is cystic on examination, the pills. Its use is restricted to patients who do not next step is needle aspiration. If the aspirate is respond to danazol or tamoxifen. nonbloody and the mass disappears complete- Hormonal agents. Estrogen-proges- ly, all the patient needs is a follow-up clinical terone combinations have been shown to breast examination after 4 to 6 weeks. If the alleviate breast nodularity associated with fluid is bloody or if there is a residual mass on breast pain in 70% to 90% of women.20 clinical breast examination, the aspirate Medroxyprogesterone improved these symp- should be sent to the laboratory for cytologic toms in 85% of women.8 Reducing the study and the patient should be referred to a dosage of estrogen or stopping hormone surgeon. Recurrent cyst formation is another

428 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 5 MAY 2002 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. indication for surgical referral. charge is seen occasionally in the third Any discrete solid masses should prompt a trimester of pregnancy. It usually resolves surgical referral for tissue diagnosis even if the spontaneously and needs a full workup only if mammogram is negative.7,9,14 In women it persists after delivery. younger than 35 years such a mass is usually a Common causes of physiologic nipple dis- fibroadenoma. A tissue diagnosis can be charge are extensive nipple manipulation, obtained by fine needle aspiration, core nee- vigorous aerobic exercise, stress, pregnancy, dle biopsy, or excisional biopsy. and Montgomery tubercles in adolescents.9,28 According to Van Dam and associates,24 Follow-up. If the discharge is determined the sensitivity of mammography alone for the to be physiologic, the patient should be reas- diagnosis of breast cancer in women with sured, and surgical referral is not needed. A breast masses is 94% and its specificity is 55%. follow-up visit should be scheduled to ensure Therefore, a normal mammogram cannot that no new symptoms develop and that the exclude a cancer suspected on clinical problem resolves. grounds. Some centers advocate a combination of Persistent nonlactational physical examination, fine needle aspiration Galactorrhea is a spontaneous, milky, nonlac- cytology, and mammography or ultrasonogra- tational discharge, usually bilateral and from phy.25 If all three are positive for cancer, the multiple ducts, resulting from elevated pro- diagnosis is confirmed on open biopsy in lactin levels. If it persists, it suggests an under- more than 99% of cases; when all three are lying medical condition and should be evalu- benign, cancer is found in fewer than 0.5% of ated, especially if there are certain concurrent cases.26 symptoms. For example, amenorrhea and If it is unclear on clinical examination visual symptoms should raise the possibility of whether the mass is solid or cystic, needle a pituitary tumor. Other causes of galactorrhea aspiration can be performed in the office as a include chest wall trauma, cirrhosis, spinal first step. Alternatively, the patient can be cord lesions, hypothyroidism, anovulatory directly referred to a breast specialist. syndromes, and drugs such as estrogens, tri- Persistent If the clinical breast examination and cyclic antidepressants, and cimetidine. galactorrhea, mammogram are normal but the patient says Follow-up. A medical evaluation should she can feel a lump, a follow-up clinical breast be started, including the serum prolactin amenorrhea, examination should be scheduled after 3 level, the thyroid-stimulating hormone level, and visual months.5 Diffuse nodularity without a discrete magnetic resonance imaging (MRI) of the lump should be followed clinically at midcycle brain to evaluate the pituitary gland, and a symptoms raise after one or two menstrual cycles.9 funduscopic examination to look for the possibility papilledema. ■ NIPPLE DISCHARGE Medications that cause galactorrhea of a pituitary should be discontinued. Patients with galac- tumor In a prospective study, Urban27 found that torrhea can be treated with bromocriptine.29 11.8% of women with nonlactational nipple A patient on bromocriptine should be initial- discharge had carcinoma of the breast; the ly followed at intervals of 3 months. The drug number was 32% in patients older than 60 may be discontinued in 3 months if the symp- years who had spontaneous bloody nipple dis- toms subside. Bromocriptine can restore fertil- charge. ity in patients with amenorrhea; therefore, patients should be warned about the possibili- Physiologic nipple discharge ty of getting pregnant. Physiologic nipple discharge is usually seen only with nipple manipulation. It is usually Pathologic nipple discharge bilateral and involves multiple ducts. The dis- Pathologic nipple discharge is usually unilateral, charge may be milky, yellow, green, brown, or confined to one duct, spontaneous, commonly black, and is generally nonbloody and nonwa- bloody or watery, purulent, cloudy, serous, tery. A spontaneous nonmalignant bloody dis- milky, and sometimes associated with a mass.

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Intraductal papilloma is the most com- duct ectasia, in which lactiferous ducts become mon cause of pathologic nipple discharge, fol- obstructed with cellular debris and lipid-laden lowed by mammary duct ectasia.27 Other caus- material. This is followed by retrograde entry es include cancer and . of bacteria from the skin, producing periductal Follow-up. A pathologic discharge war- inflammation and formation. rants immediate surgical referral and bilateral This disease has a chronic recurrent mammograms (specifying the patient’s symp- course. The patient presents with noncyclic toms so that optimal views are obtained).22 If mastalgia, nipple discharge or retraction, peri- the discharge is not bloody but shows signs of areolar abscess, subareolar mass, or cellulitis of a pathologic process, it should be tested for overlying skin. Spontaneous peripheral occult blood. The role of nipple fluid cytology in nonlactating women are generally and galactography is controversial and will associated with conditions such as diabetes depend on local practice style.27 Most patients and immunosuppressive diseases such as with pathologic discharge will need terminal human immunodeficiency virus infection. duct excision, which is diagnostic and, in the Follow-up. Subareolar and periareolar case of benign causes such as papillomatosis nonlactational abscesses require surgical refer- and duct ectasia, therapeutic. ral, as these need prolonged antibiotic treat- ment and duct excision. Nonlactational ■ BREAST INFECTIONS AND INFLAMMATION peripheral duct abscesses should be drained, and the underlying cause (eg, diabetes) should Mastitis or inflammation of the breast can be also be treated. Patients with sporadic, infec- broadly classified as lactational or nonlacta- tious, nonlactational mastitis and Mondor dis- tional.30 The diagnosis of lactational mastitis ease should undergo mammography.7,15 is generally straightforward, but it is important Mondor disease is an uncommon self- for the general internist to be able to differen- limiting condition of the breast character- tiate nonlactational breast infections from ized by superficial thrombophlebitis.31 inflammatory breast cancer. Clinical features include sudden-onset If mastitis breast pain and visible, palpable, tender, does not Lactational mastitis cord-like, branching cutaneous grooves. Lactational mastitis occurs when breast ducts These findings usually resolve spontaneous- resolve in are blocked with engorged milk, and bacteria ly over 6 weeks to 6 months. The treatment 1 month enter from cracks in the nipple skin. A wedge- is mainly symptomatic, with analgesics and shaped abscess in the peripheral part of the warm compresses. on antibiotics, breast tissue subsequently develops. There Inflammatory breast cancer causes pain, referral is may be associated and redness, and induration of the skin, usually axillary lymphadenopathy. affecting the dependent portion of the breast. warranted Treatment includes symptom-relieving The progression of symptoms is very rapid, and measures such as warm compresses and aceta- within 1 month the breast may have the peau minophen for pain and fever. Encourage the d’orange appearance (dimpled, like the skin of patient to continue breast-feeding with the an orange). Any patient in whom presumed unaffected breast, and once letdown occurs in mastitis does not resolve completely after 1 the affected breast, feed with the affected month of treatment with antibiotics warrants breast until it is completely empty. A 10-day surgical referral to rule out inflammatory course of a penicillinase-resistant antibiotic breast cancer. such as dicloxacillin or nafcillin should be started. A localized abscess will require inci- ■ NONPALPABLE ABNORMALITIES sion and drainage, and the material should be DETECTED ON SCREENING sent for culture. MAMMOGRAPHY

Nonlactational mastitis The American College of Radiology recom- Nonlactational mastitis is characterized by mends standardized terminology for reporting periareolar abscesses, typically resulting from mammography results:

430 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 69 • NUMBER 5 MAY 2002 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. • Category 0—incomplete assessment; personal history of atypical proliferative breast additional imaging evaluation is need- lesions), potential risk-stratifying strategies ed include ductal lavage or ductoscopy to obtain • Category 1—negative specimens for cytologic study.34 • Category 2—benign Tumor markers. Expression of P53 in • Category 3—probably benign immunohistochemical staining of fine needle • Category 4—suspicious aspiration specimens of breast lesions may • Category 5—highly suggestive of malig- help identify the subgroup of patients with nancy. benign breast lesions who are at a higher risk Patients in categories 1 and 2 need rou- of malignant transformation.35 tine, age-appropriate ; Women with benign proliferative breast those in categories 4 and 5 warrant surgical lesions who demonstrate overexpression of referral for breast biopsy. HER-2/neu amplification may be at a substan- The further workup of patients with cat- tially higher risk of developing subsequent egory 3—“probably benign”—lesions is less breast cancer.36 clear. We believe they should have a follow- MRI. A number of studies found MRI to up clinical breast examination and a follow- have a high sensitivity (88% to 100%) in up mammogram at 6 months, as suggested by diagnosing breast cancer. However, the Sickles32 in an analysis of a series of 7,484 specificity is variable (37% to 97%).37 The category 3 cases. In this series, 36 cancers role of MRI in differentiating benign from developed in 3 years of follow-up; of these, 6 malignant lesions needs to be better defined, were detected by mammography at 6 months as MRI could potentially decrease the num- and 2 more were detected by palpation ber of invasive that need to be per- between 6 months and 1 year. Although formed. In a study by Daniel et al,38 dynam- mammographic screening at 6 months ic spiral MRI of the breast could not differ- would therefore appear to have a low yield, entiate ductal carcinoma in situ from other 4 (80%) of the 5 aggressive tumors that benign lesions. occurred in this series were detected before 1 Nuclear imaging. Technetium-99m The workup year. methoxyisobutylisonitrile (MIBI) scintimam- of ‘probably On the other hand, the utility of the 6- mography may have a role in the diagnosis of month follow-up mammogram for category 3 palpable breast lesions that cannot be clearly benign’ findings has been debated. Alternatives defined by conventional mammography. In mammogram have been suggested, such as only following theory, this imaging study might decrease the up women with nonpalpable, noncalcified number of biopsies.39 lesions is not solitary nodules or using fine needle aspira- clear tion cytology.33 The general internist faced ■ REFERENCES with this predicament should refer the 1. Johnson C. Benign breast disease. Nurse Pract Forum patient to a breast specialist, especially if the 1999; 10(3):137–144. 2. Barton MB, Elmore JG, Fletcher SW. Breast symptoms patient is not satisfied with mammography among women enrolled in a health maintenance organi- as the only follow-up. zation: frequency, evaluation, and outcome. Ann Intern Med 1999; 130:651–657. ■ 3. Laver RC, Reed MW, Harrison BJ, Newton PD. The man- THE FUTURE: agement of women with breast symptoms referred to sec- NEW TUMOR MARKERS AND IMAGING ondary care clinics in Sheffield: implications for improving local services. Ann R Coll Surg Engl 1999; 81:242–247. 4. Love S, Gelman RS, Silen W. Fibrocystic “disease” of the Many new diagnostic tests such as tumor breast—a nondisease? N Engl J Med 1982; markers and imaging techniques are currently 307:1010–1014. being studied for the screening of breast can- 5. Dupont W, Page D. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med cer, its diagnosis, and its differentiation from 1985; 312:146–151. benign breast disease. 6. Dupont W, Parl F, Hartmann W, et al. Breast cancer risk Ductal lavage. For women at high risk of associated with proliferative breast disease and atypical hyperplasia. Cancer 1993; 71:1258–1265. breast cancer (eg, with either a strong family 7. Zylstra S. Office management of benign breast disease. history, personal history of breast cancer, or Clin Obstet Gynecol 1999; 42:234–248.

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