Breast Diseases Case File

Breast Diseases Case File

Eugene C. Toy MD, Donald Briscoe, MD, FA  AFP, Bruce Britton, MD, Joel J. Heidelbaugh, MD, FA  AFP, FACG

Case 49

A 32-year-old woman presents for evaluation of a lump that she noticed in her right breast on self-examination. She says that while she does not perform breast self-examination often, she thinks that this lump is new. She denies nipple discharge or breast pain, although the lump is mildly tender on palpation. She has never noticed any breast masses previously and has never had a mammogram. She has no personal or family history of breast disease. She takes oral contraceptive pills (OCPs) regularly, but no other medications. She does not smoke cigarettes or drink alcohol. She has never been pregnant. On examination, she is a well-appearing, somewhat anxious, and thin woman. Her vital signs are within normal limits. On breast examination, in the lower outer quadrant of the right breast, there is a 2-cm, firm, well-circumscribed, freely mobile mass without overlying erythema that is mildly tender to palpation. There is no skin dimpling, retraction, or nipple discharge. While no other discrete breast masses are palpable, the bilateral breast tissue is noted to be firm and glandular throughout. There is no evidence of axillary, supraclavicular, or cervical lymphadenopathy. The remainder of her physical examination is unremarkable.

⯈ What is the most likely diagnosis of this breast lesion?

⯈ What is the first step in evaluation?

⯈ What is the recommended follow-up for this patient?

ANSWER TO CASE 49

Breast Diseases

Summary: A 32-year-old woman presents for evaluation of a lump in her right breast that she found on breast self-examination (BSE). The lump is estimated to be 2 cm in size, firm, and freely mobile. There is no lymphadenopathy noted on physical examination.

• Most likely diagnosis: Breast cyst.
• First step in evaluation: Needle aspiration of cyst.
• Follow-up: If aspiration of the cyst results in complete resolution of the mass, and if the fluid is clear/yellow, then follow-up clinical examination in 1 to 2 months is recommended to ensure no recurrence; if aspiration does not make the mass disappear, if the fluid is bloody, or if the lesion recurs, then further evaluation with ultrasound and biopsy of the lesion is indicated.

ANALYSIS

Objectives

1. Learn how to workup a breast mass.
2. Know the risk factors for breast cancer.
3. Know how to manage benign breast diseases.

Considerations

A palpable breast mass is a potentially frightening finding for a woman. In 2013, an estimated 232,340 new cases of invasive breast cancer and 64,640 in situ breast cancer were diagnosed, with 39,620 expected deaths. Breast cancer incidence rates are highest in non-Hispanic white women, followed by African-American women, and are lowest among Asian/Pacific Islander women. Nearly one in eight women will be diagnosed with breast cancer in their lifetime.

The evaluation of the breast mass should definitively answer the question of whether or not the lesion is benign or malignant. Statistically, most palpable breast masses are benign cysts or fibroadenomas, not cancers. Unfortunately, a definitive determination of whether or not a lesion is benign or malignant cannot be made solely by history or physical examination.

Certain factors have been identified as increasing a woman's risk of breast cancer:

• A family history of breast cancer in a first-degree relative ( eg, parent, sibling), especially if the cancer occurred in a premenopausal woman and was bilateral, is associated with an increased risk that could indicate deleterious BRCA1/BRCA2 genes.
• Early age at menarche ( <12 years), late age of menopause (>55 years), and nulliparity or first live birth after the age of 30 years.
• The use of hormones, either estrogen alone or combined with progesterone, are considered to confer higher risks, although recent studies question whether oral contraceptives pose any significant risk.
• Lifestyle considerations, including obesity, physical inactivity, and alcohol use (>3 drinks per day).
• History of previous breast disease, especially biopsies showing atypical hyperplasia, carcinoma in situ, or prior breast cancer.

In the case presented, there are several clues that suggest the likelihood of a benign process. While breast cancer can occur at any age, approximately 70% of breast cancers occur in women older than age 50. The possibility of malignancy in a woman in her thirties cannot ever be excluded, but the likelihood of cancer is lower compared to a woman in her fifties. The characteristics of the lesion are most consistent with a benign, likely cystic, lesion. It is described as well-circumscribed, firm, mobile, tender, and with no overlying skin changes. Lesions that are hard, fixed in place, nontender, have indistinct borders, or have overlying skin dimpling/ retraction are highly suggestive of malignancy. It is important to note that no individual characteristic on examination is diagnostic of a benign or malignant lesion, and an appropriate evaluation is imperative.

Approach To:

Diseases of the Breast

DEFINITIONS

ACROMEGALY: A condition that results from the excessive production of growth hormone by a pituitary adenoma. Among the numerous physical effects of the excessive growth hormone, menstrual irregularities and breast discharge may result.

GALACTORRHEA: The spontaneous release of milk from the breast, not associated with childbirth or nursing.

FIBROADENOMA: A benign noncancerous lesion of the breast composed of fibrous and glandular tissue.

DUCT ECTASIA: Inflammation of a mammary duct below the nipple, which can lead to duct obstruction, a tender mass, and duct discharge.

INTRADUCTAL PAPILLOMA: A benign tumor growth into a mammary duct, often with a resultant palpable small mass and duct discharge.

CLINICAL APPROACH

Palpable Breast Mass

Following a complete history, with an emphasis on factors that may confer an increased risk of breast cancer, a careful examination of both breasts should be performed. The complete clinical breast examination (CBE) should include a

visual inspection for skin changes, dimpling, retraction, and asymmetry in both the seated and supine positions, and should note the presence and quality of any nipple discharge ( eg, color, presence of blood, etc). Starting in their 20s, women should be instructed on the benefits and limits of the BSE. Women should be aware of how their breasts normally appear and feel and should be encouraged to

report any changes to their physician. In women with breast implants, it is reasonable for them to do BSEs, and it is helpful to have the surgeon help to identify the borders of the implants. For women who choose to perform the BSE, the optimal time to conduct the assessment is when the breasts are not tender or swollen. The BSE has been shown to increase the likelihood of discovering a palpable lesion, raising anxiety, increasing the number of biopsies, and has not been shown to decrease mortality.

Examination by palpation should be performed in a systematic manner to include all quadrants of the breast, as well as the superficial, intermediate, and deep breast tissue. Specific characteristics of any palpable lumps, including size, location, tenderness, mobility, firmness, and distinction of the mass from the surrounding tissue should be noted, both to assist in developing a diagnosis and to allow for serial examinations to determine if the mass is changing. The breast examination should also include palpation of the axilla and supraclavicular regions to identify the presence of any palpable or enlarged lymph nodes. The characteristics of the mass and the age of the woman will provide initial clues toward likely diagnosis (Table 49-1).

The identification of a new solid breast mass particularly in women older than 35 years should prompt triple assessment, including a clinical breast examination, imaging (mammography and/or ultrasound), and pathologic assessment via core biopsy or surgical excision.

For women younger than 35 years, suspected lesions characteristic of fibroadenoma or fibrocystic changes can be assessed by ultrasonography, and rarely mammography followed by fine-needle aspiration (FNA) with histologic evaluation. Ultrasonography can be used as an adjunct to mammography in an effort to determine if the lesion is solid or cystic. It can also be used in women with large and/or dense breasts or in women with persistent breast pain without evidence

Data from Lippman ME. Breast cancer. In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison's Principles of Internal

Medicine. 17th ed. New York, NY: McGraw-Hill; 2008:564.

of mass via mammography. For pregnant females with a new breast complaint, targeted ultrasonography is the first-line choice for imaging.

Fine-needle aspiration can be both diagnostic and therapeutic and is performed if the mass is cystic and symptomatic. An FNA that identifies fluid that is clear, yellow, or green-tinged and that results in complete resolution of the mass is diagnostic of a benign cyst. In this setting, the fluid can be discarded and no further workup is necessary. Cystic lesions that resolve after FNA do not require further evaluation unless they recur. If CBE, FNA, or imaging suggest benign disease, then the CBE should be repeated within 4 to 6 weeks to evaluate for potential recurrence of the lesion.

If the breast mass does not completely resolve, if the fluid withdrawn is bloody, if no fluid is aspirated, if the lesion has a complex nature (containing cystic and solid components), or if the lesion recurs on follow-up CBE, then further evaluation is indicated via stereotactic core-needle or excisional biopsy. FNA can be performed on solid lesions; however, it should be used for lesions most likely to be cystic, which may require ultrasonography for characterization. It is the least invasive and most simple procedure, but also has the highest risk of false-negative or nondiagnostic results.

Core-needle biopsy and mammotome biopsy use larger cutting needles to obtain larger tissue samples. These are usually performed using ultrasound or mammographic guidance by a radiologist or surgeon. These procedures have a greater likelihood of providing a diagnostic sample yet are more invasive and costlier than FNA. Although surgical excision is the most invasive and expensive diagnostic method, it is indicated when stereotactic biopsies detect atypical ductal hyperplasia and can be therapeutic by offering complete removal of the lesion.

Breast Pain

Breast pain (mastalgia) is the most frequent breast-related complaint for which women present for evaluation. The etiology of chronic mastalgia is unknown and likely multifactorial. Similar to the presentation of a breast lump, the patient's primary fear, whether spoken or unspoken, is whether or not the pain is a manifestation of breast cancer. Thus, the evaluation of the woman with mastalgia should include a history to evaluate for an increased breast cancer risk, a careful breast examination, and a screening mammography in women for whom it is routinely indicated. Any abnormalities detected in the primary evaluation should be evaluated as outlined above. Breast pain is not a common presentation of breast cancer, particularly when the pain is bilateral.

Most cases of breast pain are categorized as cyclic mastalgia, noncyclic mastalgia, or extramammary pain. Cyclic mastalgia is usually diffuse, bilateral, often radiates to the axilla and upper arm, and is related to the woman's menstrual cycle. Pain generally occurs during late luteal phase and resolves with onset of menses. In some cases, it can be unilateral. Noncyclic mastalgia may be either continuous or intermittent, and is not associated with the menstrual cycle. It is more commonly unilateral and more prevalent in postmenopausal women. Extra-mammary pain is defined as breast pain secondary to other etiologies including chest wall pain, yet often the underlying cause may be difficult to determine.

Common Causes of Mastalgia

The etiology of most cases of chronic mastalgia is unknown. Common causes include the following:

• Pregnancy
• Mastitis
• Thrombophlebitis
• Cyst
• Benign tumors
• Cancer
• Musculoskeletal cause
• Stretching of Cooper ligaments
• Pressure from brassiere
• Fat necrosis from trauma
• Hidradenitis suppurativa
• Medications such as OCPs, antidepressants, antipsychotics, and antihypertensives

Laboratory testing is usually unnecessary in the evaluation of mastalgia, although a pregnancy test should be performed in reproductive-age women. Hormonal contraceptives or hormone replacement therapy may be causes of breast pain and consideration should be given to discontinuation or reduction of estrogen dosages. An appropriately fitted supportive bra and lifestyle changes including tobacco cessation and stress reduction techniques, are often successful in alleviating symptoms. While nonsteroidal anti-inflammatory drugs (NSAIDs) are often beneficial in providing pain relief, evening primrose oil, caffeine reduction, and various vitamin supplements have not been shown to provide significant relie£ Other low-risk treatments with possible efficacy include soy protein, a low-fat and high-carbohydrate diet, and chasteberry extract. For women with unrelenting pain in spite of the above modifications, danazol, an antigonadotropin, is Food and Drug Administration (FDA) approved for the treatment of breast pain, but is relatively expensive and has numerous side effects (eg, hair loss, acne, weight gain, and irregular menses). Other options include tamoxifen, toremifene, and bromocriptine, which are hormonal therapies with significant risks that have some evidence for efficacy in refractory cases.

Nipple Discharge and Galactorrhea

Nipple discharge is usually caused by a benign process. Up to 25% of women will have this symptom during their life. Nipple discharge that occurs only with nipple stimulation, that is clear, yellow, or green, and that appears from multiple ducts is usually physiologic and does not require extensive investigation. This discharge often resolves when efforts are made to reduce nipple stimulation, including ceasing efforts to check to see if the discharge will still occur.

Nipple discharge that is spontaneous, persistent, bloody, from a single duct, associated with a mass, and occurs in women over 40 years is more likely to represent a pathologic process and requires prompt evaluation. In this setting, the most common causes of discharge include intraductal papillomas, duct ectasia, cancers, and infections. If the discharge is not obviously bloody, then testing for occult blood via a guaiac-based assay should be performed.

Following the initial history and physical examination, mammography should be performed in all women with a spontaneous or bloody nipple discharge and in any woman in whom routine breast cancer screening is indicated. For most women, this should commence at age 40. All palpable breast masses should be evaluated appropriately and promptly. The treatment of most cases of unilateral, spontaneous, or bloody nipple discharge is surgical excision of the terminal duct involved, allowing for both resolution and diagnosis.

Galactorrhea is a discharge of milk or a milk-like secretion from the breast in the absence of parturition or beyond 6 months postpartum in a non-breast-feeding woman. The secretion may be milky or serous (yellow) appearing, intermittent or persistent, scant or abundant, free-flowing or expressible, and unilateral or bilateral. If the clinician is uncertain whether the discharge represents benign galactorrhea, then the discharge should undergo histologic and microscopic analysis, which will commonly contain fat globules and few cells. The condition is more common in women who are 20 to 35 years and in previously pregnant women. Galactorrhea is associated with stress, physical irritation, numerous medications, hypothyroidism, chronic renal failure, hypothalamic-pituitary disorders, hormone-secreting neoplasms (most commonly pituitary adenomas), or may be idiopathic, but is not associated with breast cancer.

Numerous pharmacologic agents can cause galactorrhea via blockade of dopamine and histamine receptors, depletion of dopamine stores, inhibition of dopamine release, and stimulation of lactotrophic hormones. Common medications and classes of medications associated with galactorrhea include serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), angiotensin-converting enzyme (ACE) inhibitors, atenolol, verapamil, antipsychotics, H2 (histamine) receptor antagonists, and opiates. Estrogen in oral contraceptives can cause galactorrhea by suppressing the hypothalamic secretion of prolactin inhibitory factor and by direct stimulation of the pituitary lactotrophs.

Offending medications should be discontinued when possible. Prolactin and thyroid-stimulating hormone (TSH) levels should be obtained to evaluate for endocrine abnormalities. Evaluation of serum electrolytes and renal function can assess the woman with galactorrhea for renal failure, Cushing disease, and acromegaly. Imaging of the pituitary to evaluate for a pituitary adenoma with magnetic resonance imaging (MRI) is indicated if the prolactin level is significantly elevated.

Treatment of galactorrhea is geared at addressing the underlying condition. For example, women with hypothyroidism should be treated with levothyroxine. Treatment should also be aimed toward the severity of the prolactin level and pending fertility status. Dopamine agonists are the treatment of choice in most patients with hyperprolactinemia. Bromocriptine is the preferred agent for treatment of hyperprolactin-induced anovulatory infertility. Surgical resection rarely is required for prolactinomas and other pituitary adenomas unless the woman experiences significant hypothalamic-pituitary-gonadal axis disruption or visual deficits commensurate with compression of the optic chiasm (homonymous hemianopsia).

COMPREHENSION QUESTIONS

49.1 A 34-year-old woman presents with a history of intermittent clear-yellow breast nipple discharge for 2 months. She had been taking antipsychotic medication for a history of schizophrenia, but has not taken the medication in 3 months. Laboratory studies reveal normal TSH, free T3, and free T4 levels, and her thyroid gland is not palpable. A urine pregnancy test is negative. Which of the following is the most appropriate advice to give to this woman?

A. It is likely that the nipple discharge will become bloody.

B. Due to her clinical presentation, the likelihood of breast cancer is greater than 50%.

C. This condition is common in patients who take antipsychotic medications.

D. Unless her free T3 level becomes elevated, there is no reason for concern.

49.2 A 52-year-old woman presents to her family physician with a palpable breast lump. An attempt at FNA does not result in aspiration of fluid. Her mammogram is normal. Her mother was diagnosed with breast cancer at age 45. She does not smoke but socially drinks alcohol. She currently takes low-dose estrogen contraception pills and takes 1200 mg of calcium daily. She began her menstrual periods at age 10 and she had her first child at age 24. Which of the following is the appropriate next step in evaluation of this patient?

A. Repeat clinical examination in 4 to 6 weeks.

B. Repeat mammogram routinely in 1 year.

C. Referral for biopsy.

D. Discontinuation of her hormone replacement therapy.

49.3 A 29-year-old woman presents with the complaint of nipple discharge from the left breast. On further questioning, she states that the discharge is milky in color. She is a G2P2 with her last delivery 3½ years ago. She breast-fed both children for 9 months. She takes no medications and has regular menstrual periods. On examination, a small amount of nonbloody milky discharge can be expressed from several ducts from the left nipple, while no discharge is expressed from the right breast. Which of the following is the best initial diagnostic step for this patient?

A. Pregnancy test.

B. Refer to a breast specialist for evaluation for unilateral nipple discharge.

C. TSH, free T4, and prolactin levels.

D. Follicle-stimulating hormone (FSH), luteinising hormone (LH), and gonadotropin-releasing hormone (GnRH) levels.

E. Send the discharge for histologic and pathologic evaluation.

49.4 A 33-year-old woman presents with the complaint of a palpable, firm, mobile, 2.5-cm mass in the 12 o'clock position on her right breast. She states that it has been present for almost 6 months, enlarges with her menstrual cycle, and becomes most painful with the onset of her menses. She smokes approximately 8 to 10 cigarettes daily, drinks three to four cups of caffeinated coffee daily, and rarely drinks alcohol. She has no family history of breast cancer. Which of the following is the most appropriate initial evaluation of this mass?

A. Surgical excision

B. Mammogram

C. Ultrasound

D. FNA

ANSWERS

49.1 C. Nipple discharges that are spontaneous, unilateral, persistent, bloody, and associated with a mass are more likely to represent pathologic processes and need to be evaluated for malignancy. While most cases are benign ( eg, papilloma, duct ectasia), evaluation and surgical intervention are usually required. In this case, the galactorrhea represents a side effect of antipsychotic medication, will not become bloody, likely has no relation to thyroid hormone levels (especially in an euthyroid patient), and does not increase her risk of breast cancer.

49.2 C. A biopsy is the next most appropriate step in this setting. A negative mammogram is not diagnostic of a benign process and does not rule out the possibility of having breast cancer. A tissue diagnosis is needed in this setting especially with a known first-degree relative with breast cancer and early age of menarche to evaluate for potential malignancy.

49.3 A. The evaluation and management of most cases of galactorrhea can be handled by the primary care physician. A pregnancy test should be the first evaluation. If pituitary adenoma is diagnosed, then the patient can be referred for specialty care. Milky discharge from multiple ducts in the nonlactating breast may occur in certain syndromes-it is usually due to an increased secretion of pituitary prolactin. Hypothyroidism can also cause hyperprolactinemia. Psychiatric agents such as chlorpromaz;ine- and estrogen-containing agents such as the oral contraceptive pills may also cause milky discharge.

49.4 C. Ultrasound is the most appropriate first step in evaluation of this lesion, which is likely a fibroadenoma. This modality can characterize whether or not the lesion is cystic or solid. If it is cystic, then FNA is the next step. If solid, then mammography is the next step.

CLINICAL PEARLS

⯈ Approximately 1 % of breast cancer occurs in men. A new palpable mass in a man's breast should prompt a diagnostic evaluation.

⯈ Remember that the question in the mind of just about every woman presenting with a breast-related complaint is, "Do I have breast cancer? "The job of the physician is to both manage the presenting complaint and to provide the appropriate diagnostic workup and reassurance.

⯈ BSEs should be discussed with all female patients of childbearing age, focusing on benefits versus limitations, and risk of unnecessary procedures.

⯈ All breast masses require some form of evaluation and should never simply be dismissed.

REFERENCES

American Cancer Society. Breast cancer facts and figures. Available at: http://www.cancer.org/ research/ cancerfactsstatistics/breast-cancer-facts-figures/. Accessed April 5, 2015. 

Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl] Med. 2012;367:1998-2005. 

Branch-Elliman W, Golen T H, Gold HS, et al. Risk factors for Staphylococcus aureus postpartum breast abscess. Clin Infect Dis. 2012; 54(1):71-77. 

Davidson N. Breast cancer and benign breast disorders. Goldman's Cecil Medicine. 24th ed. Philadelphia, PA: Elsevier/Saunders; 2012. 

Dickson G. Gynecomastia. Am Fam Physician. 2012; 85(7):716-722. Klein S. Evaluation of palpable breast masses. Am Fam Physician. 2005; 71:1731-1738. Leung A, Pacaud D. Diagnosis and management of galactorrhea. Am Fam Physician. 2004; 70(3): 543-550. 

Lippman ME. Breast cancer. In: Kasper D, Fauci A, Hauser S, et al., eds. Harrison's Principles of Internal Medicine.19th ed. New York, NY : McGraw-Hill; 2015. Available at: http://accessmedicine .mhmedical.com. Accessed May 25, 2015. 

Nelson M, Cole T, Valerio AF, et al. Diagnosis of Breast Disease. 13th ed. Institute for Clinical Systems Improvement. 2010. 

Salzman B, Fleegle S, Tully AS. Common breast problems. Am Fam Physician. 2012;86( 4):343-349. 

Santen RJ, Mansel R. Benign breast disorders. N Engl] Med. 2005;353(3):275-285. 

U.S. Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2099; 151(1):716-726.

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