Elizabeth B. McCabe
Breast Disorders
Evaluation of breast complaints and screening for breast cancer account for a significant number of primary care visits. The most frequent breast complaints include breast pain, breast masses, and nipple discharge. Most breast masses and other breast complaints are a result of benign conditions, but some breast disease can impart actual risk for the development of breast cancer.1 Studies have shown that women with certain kinds of benign breast disease have a relative risk for breast cancer of 1.35 to 1.6 compared with women in the general population.2
For these reasons, accurate evaluation of all breast complaints and appropriate follow-up are essential. In addition, failure to adequately reassure women about their breast symptoms after a benign diagnosis heightens the need for appropriate support for women with ongoing breast symptoms.1 Research shows that even after a benign diagnosis, up to one third of women report that they are either unsure or not reassured about their breast symptoms. A significant percentage of women who undergo evaluation and receive a benign diagnosis for their breast symptoms remain anxious about the possibility of breast cancer or another form of breast disease.
The initial breast evaluation should be comprehensive and include a risk assessment to determine average to high-risk status, history of the present breast concern, workup to date including imaging and pathology reports of recent or past breast biopsies, past relevant medical and surgical history, and family history of both breast and ovarian cancer on both the maternal and paternal sides of the family. Education about breast health tailored to age and risk status, including screening recommendations and follow-up, should be clearly outlined for every patient regardless of the underlying breast condition.
Risk Assessment
Risk Factors
A thorough history and breast cancer risk assessment should be performed for every woman who sees her health care provider with a breast complaint. The absolute lifetime risk for development of breast cancer is approximately 12%.3 Determination of level of risk is an important part of the risk assessment process. Several well-established risk factors associated with the development of breast cancer have been thoroughly studied and are defined by four major groups: family history or genetic factors, reproductive or hormonal factors, proliferative benign breast disease, and mammographic density.4
Individuals with a single first-degree relative with breast cancer have an estimated twofold risk. Individuals with two first-degree relatives have a threefold risk, and three or more impart a fourfold risk. A first-degree relative younger than 40 years at the time of diagnosis results in a threefold risk compared with a twofold risk for relatives 40 to 50 years old and a 1.5-fold risk for relatives 50 to 65 years old. Risks are also greater if relatives have bilateral breast cancer.4 Other risks in this category include male breast cancer, ovarian cancer, and Ashkenazi Jewish ancestry.
In terms of reproductive factors, nulliparous women have the same risk as that of women who delivered their first child at the age of 30 years of age or older. Subsequent births and substantial periods of breastfeeding offer some degree of risk protection. Early menarche and late menopause result in increased duration of ovulation with the resultant hormonal effects. Women who are using hormone replacement therapy (HRT) have up to a 5% increased risk per year of use, which returns to baseline levels within a year of stopping hormone use.4
Certain types of benign breast disease impart significant risk for development of invasive breast cancer. Women with lobular carcinoma in situ have a 10-fold relative risk, and women with atypical ductal hyperplasia and atypical lobular hyperplasia carry a fourfold to fivefold relative risk. A doubling of risk is seen with proliferative lesions without atypia, such as intraductal papillomas. Nonproliferative lesions, such as fibroadenomas and cysts, do not increase risk.4
Mammographic density, estimated by the percentage of the mammogram covered by opaque tissue, has been determined to be the single most important risk factor in the population of women receiving mammograms. Description of density can be found on the final mammogram report and is described as extremely dense, heterogeneously dense, scattered density, or fatty replacement of the breast tissue. Fifty percent to 75% density on a mammogram imparts a twofold to threefold risk. Approximately 14% of the population falls into this category, compared with 5% whose density is greater than 75%. Mammographic density as a risk is not well understood.
It is also known that other risk factors are largely independent of one another. Efforts are ongoing at looking at all risk factors and using the information to provide individual risk status and prevention strategies.4
Risk Assessment Models
There are varied breast cancer risk assessment tools available (www.cancer.gov/bcrisktool). Two models that have been used to determine a woman’s absolute risk for development of breast cancer are the Gail model and the Claus model. The Gail model is based on several risk factors: age, race, age at menarche, number of breast biopsies, number of biopsies with atypical hyperplasia, number of first-degree relatives with breast cancer, and age at first live birth. (ww5.komen.org/BreastCancer/GailAssessmentModel.html). A 5-year score of 1.67% or greater is considered high risk. The Gail model was not designed for women younger than 35 years, with a personal history of breast cancer or ductal or lobular carcinoma in situ, or whose history suggests a possible hereditary breast cancer.5 The Claus model predicts the cumulative probability for development of breast cancer of a woman who has a family history with both first- and second-degree relatives. This model has been most useful in assessing risk in younger women (aged 29 to 35 years) with a family history of breast cancer. There have been more validation studies performed on the Gail model, and this model tends to be more frequently used in the clinical setting.5
Genetic Testing
Women with a strong family history of breast cancer may be candidates for genetic testing for BRCA mutations. The decision to undergo genetic testing raises many psychosocial and ethical issues and should be considered after a discussion with a genetics counselor. Strong consideration to involve family members is recommended. Women who are known BRCA1 or BRCA2 mutation carriers have a 40% to 70% lifetime risk for development of breast cancer.6,7 These women are considered to be at extremely high risk and require education and counseling about screening and risk reduction strategies. Screening recommendations include clinical breast examination every 6 months, annual mammography, and breast magnetic resonance imaging (MRI).
Risk Reduction
The best nonsurgical risk reduction strategy for BRCA mutation carriers is adjuvant MRI. It has been shown to be successful in detecting twice as many invasive cancers as mammography, with the majority of cancers being at an early stage at diagnosis.8 Surgical risk reduction strategies include prophylactic mastectomy and oophorectomy. Women who undergo mastectomy reduce their breast cancer risk by 90%, and premenopausal women who undergo prophylactic oophorectomy decrease their breast cancer risk by 75%.6 Once a woman has been identified as a mutation carrier, choices for risk reduction are typically made on the basis of age and childbearing status.
Screening Recommendations
There is ongoing debate about the appropriate age at which to initiate screening mammography in the average-risk patient, defined as a woman whose relative risk for developing breast cancer is 1.5-fold or lower and whose 5-year Gail score is below 1.7%.6 In addition to mammography, clinical breast examination and breast self-examination have historically been recommended as routine screening practices for women.
In 2015, the U.S. Preventive Services Task Force (USPSTF) issued a continued biennial recommendation for screening mammography for women aged 50 to 74 years of age and determined that the evidence to continue screening women after age 75 was inconclusive.9 USPSTF screening recommendations for women aged 40 to 49 continue to be individualized based on the risks and benefits of biennial screening, although the American College of Radiology (ACR), Society of Breast Imaging (SBI), and American College of Obstetricians and Gynecologists (ACOG) recommend annual mammography for women ages 40 to 74.9 For women aged 75 or older, the USPSTF found there was insufficient evidence to recommend for or against breast cancer screening, yet the American Cancer Society and American College of Obstetricians and Gynecologists continue to recommend annual mammography.9 Teaching breast self-examination to patients is still not recommended by the USPSTF, although women should be encouraged to discuss breast changes with their primary care provider.9,10
There is strong evidence to suggest that mammography is most useful in women aged 50 to 65 years and that mammography remains the best method for breast cancer screening among average-risk patients.9,10 Regular breast self-examination is a very individualized decision. For those women who are interested in learning proper techniques for performing self-examination and who are interested in promoting awareness of their breast health, time needs to be allotted for providing this information.
High-risk women are those with a 5-year Gail score higher than 1.7% and whose relative risk is 1.5- to 5-fold. Screening recommendations for this group include annual clinical breast examination and mammography, consideration for chemoprevention, and discontinuation of hormonal therapy if the patient has been receiving it for more than 2 years.6
Very-high-risk women include those with a personal history of invasive breast cancer, ductal carcinoma in situ, or lobular carcinoma in situ. This imparts a fourfold to fivefold risk for development of a new primary breast cancer. Other women who fall into this category are those with a prior breast biopsy showing atypical hyperplasia, known BRCA mutation carriers, and those with a history of mantle radiation of the chest wall for Hodgkin disease before the age of 30. Screening recommendations for this group include clinical breast examination every 6 months, annual mammography, consideration for chemoprevention, and genetic testing.6 Screening for this population may begin as early as 25 years of age. Digital mammography and adjuvant MRI may be recommended for many of these women.10
Determination of average- or high-risk status for each patient is an integral step in the process of providing individualized care. Both average- and high-risk women require education about the screening tools available and how the use of these tools can be tailored to meet their individualized needs.
Breast Pain (Mastalgia, Mastodynia)
Definition and Epidemiology
Breast pain, often referred to as mastalgia or mastodynia, is the most common breast problem encountered in primary care and surgical practices.11 Although increased awareness and overestimation of breast cancer risk may prompt women to be more inclined to seek medical treatment for breast concerns, mastalgia is generally underreported.12 Premenstrual, or cyclic, breast pain is the most common type of mastalgia and usually occurs during the late luteal phase of the menstrual cycle, in association with the premenstrual syndrome or independently, and resolves after menses.13 Studies of healthy women in the United States have shown that 11% have moderate to severe cyclic breast pain and 58% have mild discomfort.13
Noncyclic mastalgia involves constant or intermittent pain that is unrelated to the menstrual cycle.12,13 It is less common than cyclic mastalgia and occurs most frequently in women 40 to 50 years old. It accounts for about 31% of women being seen for mastalgia.12 Noncyclic mastalgia may result from pregnancy, mastitis, thrombophlebitis, macrocysts, benign tumors, fibrocystic breast changes, or cancer; however, these conditions explain only a minority of noncyclic mastalgia cases. Most noncyclic mastalgia occurs for unknown reasons, but it is thought to be related more often to an anatomic cause than to a hormonal one. Noncyclic breast pain usually resolves spontaneously without treatment.12
Pathophysiology
The actual pathophysiologic mechanism of breast pain is not well understood. Cyclic mastalgia occurs during the luteal phase of the menstrual cycle and resolves with the onset of menstruation.14 This predictable pattern of pain is likely to be hormonally mediated, despite the failure of studies to show any difference in estrogen levels among women with or without pain. It has also been shown that progesterone levels may be lower in these women and that prolactin release may be increased as a response to thyrotropin-releasing hormone.15
Essential fatty acids such as dietary gamma-linolenic acid have been suggested as inhibitors of prostaglandins, which possibly cause breast pain. Low plasma levels of these essential fatty acids may result in a hypersensitivity of breast tissue to circulating hormones.14
There is little evidence to support a relationship between breast pain and histologic findings consistent with cysts, apocrine metaplasia, and ductal hyperplasia.15
Clinical Presentation
Cyclic mastalgia usually starts in the luteal phase of the menstrual cycle, increases in intensity until menses begin, and then dissipates, although pain may be present during the entire cycle with increased intensity premenstrually.12 Cyclic mastalgia usually begins in the third or fourth decade of life. It is usually bilateral and poorly localized, although it typically involves the upper outer breast area and radiates to the upper arm and axilla. Women will describe the pain as dull, heavy, or aching. Symptoms tend to persist with intermittent relapses, but remission can occur with hormonal events such as pregnancy and menopause. Only 14% of women with cyclic mastalgia experience spontaneous resolution of symptoms, whereas 42% experience resolution at menopause.12 In contrast, noncyclic mastalgia is often unilateral, localized, and described as a sharp, burning pain. Mastalgia is rarely the sole presenting symptom of breast cancer.11
There may be an association between breast pain and anxiety, depression, emotional distress, somatization, and a history of emotional abuse. Women with breast pain may experience greater cyclic fluctuations in anxiety and depression, but it remains unclear whether there is any kind of causal or consequential relationship between breast pain and psychological distress.12
Physical Examination
A thorough history and breast examination must be performed for every woman who is seen with any breast problem and must be directed at identification and characterization of breast-related symptoms. The provider should elicit current symptoms, such as type of pain (cyclic, noncyclic, bilateral, or unilateral), presence or absence of nipple discharge with characteristics of the discharge (color, whether it is spontaneous or nonspontaneous, large or scant volume), presence of a breast mass, change in mass with the menstrual cycle, axillary masses, skin dimpling, ulceration, inflammation, and history of recent breast infections or trauma.
The history should include current medications, including hormone therapy. Prior history of any breast surgery for both cancerous and noncancerous reasons including cosmetic procedures should be obtained. In addition, age at menarche and menopause, pregnancy and lactation history, and relevant past medical and surgical history should be included. Breast cancer screening history should include the date and results of the last clinical breast examination and breast imaging. Family history of breast and ovarian cancer on both maternal and paternal sides should be obtained.
The breast examination must be methodical, and the breasts should be inspected for differences in size, skin changes, retraction or dimpling of the skin or nipple, prominent venous patterns, lesions, and signs of inflammation. The axillary, supraclavicular, and infraclavicular areas should be palpated with the woman in the sitting position. Inspection of the breasts should be performed with the woman both sitting and supine, with her hands behind her head or raised over her head. The examiner should use the flat surface of the fingertips to palpate all of the breast tissue against the chest wall. In women with a history of nipple discharge, the nipple-areola complex is compressed very gently in all directions. If this technique does not elicit discharge, firm equal pressure should be applied from the periphery toward the nipple. To distinguish discharge from multiple or single ducts, pressure must be distributed evenly over all of the ductal structures. Benign or physiologic nipple discharge is typically creamy, gray, or green. Watery, serous, or bloody fluid is considered abnormal.
Breast masses palpated on physical examination may be moveable or fixed and are typically discrete. Description of the size and location of the mass is important before obtaining any radiographic studies.
On examination of the patient with a complaint of breast pain, it is important to note if the pain is focal, regional, or diffuse. Some breast pain actually originates from the chest wall and can manifest as point tenderness.
Skin changes that may signify cancer include erythema, edema, retraction, dimpling, peau d’orange, and nipple excoriation or crustiness.
Diagnostics
Noncyclic breast pain is initially investigated with bilateral mammography in postmenopausal women, although the likelihood of an abnormal finding is low. A focused ultrasound examination is often performed to evaluate persistent, focal mastalgia in young women and in addition to mammography in older women.12 Mammography is not indicated in young women with cyclic breast pain in the absence of focal pain, suspicious findings, or risk factors. However, mammography should be considered in women 30 to 35 years or older who have a family history of breast cancer or other risk factors for breast cancer.12
Laboratory studies are not useful in general, but a pregnancy test should be done for a woman of reproductive age if the history or physical examination findings suggest that pregnancy is possible. Other hormone levels, such as estrogen, progesterone, and prolactin, are usually within normal limits in women with breast pain and therefore are not indicated as part of the workup.12
Differential Diagnosis
The differential diagnosis of breast pain includes a normal physiologic event, recent or past trauma with or without hematoma or fat necrosis, microcysts or macrocysts, infection, and malignant or benign tumor.
Chest wall or nonbreast pain accounts for about 7% of women seen with complaints of mastalgia. Pain that is limited to a particular area and characterized by a burning or knifelike sensation may be chest wall pain. There are several distinct types of chest wall pain, including localized or diffuse pain, radicular pain from cervical arthritis or slipping and cracking ribs, and pain from Tietze syndrome (also known as costochondritis).12 The pain can be reproduced with pressure over the costal cartilage rather than in the more generalized pattern of mastalgia. Movement may also precipitate chest wall pain, and there is no relationship to the menstrual cycle.13 Chest wall syndromes can occur even in the absence of a clear precipitating event, which sometimes heightens the woman’s concern that the pain has a suspicious or malignant cause.12
Management
After a thorough history, evaluation, and risk assessment, reassurance is all that is needed for 85% of women with cyclic mastalgia. For the 15% of the women not helped with reassurance alone, use of a pain chart for at least two cycles may elucidate any patterns of mastalgia. Patients can also be reassured that breast pain has a high spontaneous remission rate (60% to 80%).4 Management of cyclic mastalgia should also include reevaluation of the breast pain at a different time during the menstrual cycle, preferably soon after the menses.
Proven benefits for the treatment of cyclic mastalgia are few. Because of the extreme variability in mastalgia, only treatments that have been tested in randomized controlled trials (RCTs) can be confidently considered. Danazol (Danocrine), an antigonadotropin, is the only drug labeled by the U.S. Food and Drug Administration for the treatment of mastalgia. RCTs have demonstrated a response rate of 50% to 75% in women with cyclic breast pain who received danazol, 100 to 400 mg/day orally in two divided doses. Approximately 75% of women with noncyclic pain responded to the drug.11 Typically, the initial dose is 200 mg daily, eventually tapering to lower doses, with alternate-day or luteal-phase administration. However, initial dosages of 50 to 400 mg/day have been described. Unfortunately, side effects plague 30% of women, eventually resulting in discontinuation of the drug in approximately 15% of women, even when breast pain is improved. Adverse effects are primarily dose related and androgenic, including hirsutism, acne, hair loss, lowered voice pitch, weight gain, headache, nausea, rash, anxiety, and depression.12 The severe side effect profile and teratogenic potential of danazol support referral or collaboration before initiation of treatment.
Other pharmacologic agents used to treat mastalgia include dopamine agonists, such as bromocriptine, because one of the hormonal abnormalities detected in women with mastalgia has been an increase in thyrotropin-induced prolactin secretion. Although clinical improvement occurs in 47% to 88% of symptomatic women, up to 29% of women in some studies have stopped taking the medication because of side effects.12
The selective estrogen receptor modulator tamoxifen is used to prevent and to treat breast cancer but has also been effective in reducing pain in 71% to 96% of women with cyclic mastalgia and 56% of women with noncyclic mastalgia. Tamoxifen has a serious potential side effect profile, including deep venous thrombosis and endometrial cancer, as well as the more benign side effects of hot flashes, nausea, menstrual irregularity, vaginal dryness, and weight gain. Tamoxifen compares favorably with danazol and bromocriptine with regard to efficacy and adverse effects. As with the other hormonal agents, use of tamoxifen for breast pain should be reserved for women with severe mastalgia that is not responding to other forms of therapy.12
Supportive bras and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful. Oral contraceptives may be discontinued or changed to an alternative agent with a lower estrogen and higher progesterone content. Caffeine avoidance has been a popular treatment measure in women with breast pain, although a therapeutic benefit for caffeine restriction has not been consistently demonstrated in controlled studies. Vitamin E supplementation has also been advocated for treatment of breast pain. However, two double-blind, placebo-controlled RCTs demonstrated no benefit to this approach.11 Similar studies using evening primrose have been conducted and have shown minimal benefit in relieving breast pain.16,17
It may be difficult to quantify breast pain because it is often variable. However, assessment of pain with a pain-rating instrument or scale can be particularly useful in evaluating cyclic breast pain and response to treatment.
Complications
Mastalgia is infrequently associated with breast cancer. Despite this fact, any persistence in a patient’s symptoms should prompt further evaluation. Failure to treat or a delay in diagnosis of an underlying problem may affect a woman’s quality of life or long-term outcome.
Indications for Referral or Hospitalization
Treatment of cyclic mastalgia with antigonadotropic agents should be managed by or in consultation with a specialist because of the severity of the side effect profile and the teratogenicity of this class of drugs.
Women with mastalgia, without evidence of disease on physical examination and imaging, whose pain is refractory to basic interventions may be considered candidates for a chronic pain referral. If the pain is severe enough and interferes with a woman’s quality of life, a general surgery referral can be considered to discuss mastectomy. The benefit of this extreme intervention is not well proven.
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