History of Present Illness
A 41-year-old, gravida 2, para 2, presents to your office complaining of bilateral clear nipple discharge experienced intermittently over the last three months. She notices scant amounts of discharge in her sport bra and can evoke discharge with squeezing the areola. The patient denies any breast pain and does not note any masses. Her routine screening mammogram ten months prior was normal.
She has a levonorgestrel-releasing intrauterine system (LNG-IUS) in place for contraception, and her periods stopped a few months after it was initiated. She has no medical problems and has no significant surgical history. Her last pregnancy was five years prior. Her only medication is a daily multivitamin, and she runs approximately 12 miles per week for exercise.
Physical Examination
- General appearance
Well-developed, healthy appearing woman
- Vital Signs
All within normal limits
- Temperature
36.9°C
- Pulse
75 beats/min
- Blood pressure
105/70 mmHg
- Respiratory rate
14 breaths/min
- Height
63 inches
- Weight
122 lb
- BMI
21.6 kg/m2
- HEENT
No focal deficits. Visual fields intact. No palpable thyroid masses.
- BREASTS
Symmetric. No skin changes or trauma. No palpable masses or lymphadenopathy. Gentle squeeze/pressure at the base of the areola evokes a minute amount of clear nipple discharge (not bloody) from 2 to 3 ducts bilaterally.
- ABDOMEN
Thin, soft, non-tender. No palpable masses.
Laboratory Studies
- Urine pregnancy test
Negative
- Screening mammo-gram ten months prior
BI-RADS 1, Negative
How Would You Manage This Patient?
This patient has bilateral clear nipple discharge, which, in most cases, is benign. The findings from the history and physical examination of bilateral, multi-ductal, discharge, which occurs with breast manipulation, support a benign process. While medications can be a common cause of galactorrhea, this patient is only taking a multivitamin. Neurogenic stimulation, either from chronic breast stimulation or from clothing such as a poorly fitting bra, is another possibility, and in this case is likely since she may wear a sports bra that produces significant rubbing during her exercise routine.
A diagnostic mammogram should be obtained given that the patient is over 40 years old. Based on these findings, a breast ultrasound may be considered. A thyroid-stimulating hormone and prolactin levels were obtained and were normal. The patient should be reassured that she has physiologic nipple discharge and should be counseled to avoid provoking nipple stimulation by herself, her partner, or possibly by a poorly fitting sports bra. She was asked to monitor her symptoms for three months with this awareness and return for her well-woman exam. After this counseling and reassurance, the patient embarked on bra resizing. She avoided all personal nipple stimulation and all spontaneous nipple discharge resolved within two months. She should continue with age-appropriate screening mammograms thereafter.
Clear Nipple Discharge
Nipple discharge is the third most common breast issue women experience after breast pain and breast masses [1]. Up to 80 percent of women in their reproductive years can express some fluid from their nipples [2]. Nipple discharge can evoke fear, and, even when benign, can be bothersome to the patient.
Nipple discharge is typically categorized in one of three ways. Normal or benign/physiologic nipple discharge is generally bilateral, multi-ductal, and provoked, as in the patient described earlier. Lactation is also physiologic but is related to pregnancy and the puerperium and may persist for up to one year postpartum or after cessation of breastfeeding. Milky nipple discharge that is outside of pregnancy or occurring more than one year after nursing cessation and is not caused by intrinsic breast disease is defined as galactorrhea. In the case of galactorrhea, elevated levels of prolactin that lead to galactorrhea can be caused by medications, by pituitary gland changes, or by persistent breast stimulation [1]. Pathologic nipple discharge indicates a concerning process within the breast. The discharge is typically spontaneous and unilateral, usually from a single duct opening on the nipple and can be clear, serous, or bloody [3]. While most nipple discharge is caused by benign conditions, up to 15 percent may be associated with an underlying malignancy.
Evaluation of a patient with nipple discharge should therefore start with a history to determine if the nipple discharge is unilateral or bilateral, bloody, or spontaneous or provoked. Non-pathologic nipple discharge is usually bilateral and non-bloody and occurs as a provoked event with breast manipulation and mechanical stimulation of the nipple/duct system. In contrast, spontaneous discharge, which raises concern for pathology, is typically serous, sanguineous, or serosanguineous and produced in larger amounts that can often be noted on the patient’s clothing or personal garments.
The patient’s age, duration of nipple discharge, pregnancy, and lactation history should be noted [2]. As it is normal for many women to express milky discharge spontaneously or with external pressure up to one year postpartum or after cessation of breastfeeding, in this timing and context, reassurance can be provided. Women under age 40 years with provoked (non-spontaneous) or multi-duct discharge that is not serous or serosanguineous should be educated to stop compression/manipulation of the breast and should be observed. Women 40 years of age or older with the same findings should receive the same guidance but should also have a diagnostic mammogram and ultrasound if not done recently [4].
A review of the patient’s current medications should be undertaken, noting those that can inhibit dopamine, such as phenothiazines, antipsychotic drugs, metoclopramide, methyldopa, verapamil, and combined oral contraceptives. These medications are common causes of iatrogenic galactorrhea and, when discontinued, will likely result in alleviation of symptoms [4]. A personal or family history of breast conditions or malignancy of the breast or ovary should be obtained.
Clinical breast examination includes visual inspection of the breasts by having the patient seated with her hands on her waist, noting breast size, symmetry, and skin integrity. The skin over the nipple areolar complex should be examined for lesions or trauma that may mimic nipple discharge. Palpation should be performed to assess for any breast masses or lymphadenopathy. An attempt to reproduce the nipple discharge with gentle pressure at the base of the areola should be performed to provoke symptoms and to determine whether the discharge originates from a single duct or multiple ducts. Discharge originating from a single duct is more concerning of a pathologic process than discharge from multiple ducts. Cytology of nipple discharge has poor sensitivity and specificity and does not add to clinical decision making and should not be performed [2]. The thyroid should also be palpated to determine enlargement or the presence of a palpable mass [2].
A pregnancy test should be obtained even in the setting of highly effective, long-acting, reversible contraception, followed by measurement of a thyroid-stimulating hormone (TSH) and prolactin levels in the context of discharge that is bilateral and/or milky in nature [4]. When TSH or prolactin levels are abnormal, corrective medical management should resolve the nipple discharge. When prolactin levels are in excess of normal, resulting in nipple discharge, and the evaluation does not confirm pregnancy, lactation, or medication side effects, an MRI of the head should be performed to look for a mass lesion (pituitary adenoma) in the hypothalamic-pituitary region.
When appropriate laboratory tests and/or studies are normal and the history and physical examination suggest an otherwise benign, physiologic process, patients should be reassured that this is benign physiologic discharge. Approximately two-thirds of non-lactating women have small amounts of fluid secreted from the nipple with manual expression [2]. Repeated stimulation of the nipple by a woman, her partner, or her clothing can promote nipple discharge; however, the discharge often resolves when the nipple is left alone, so observation is appropriate.
Suspicious/pathologic nipple discharge is often spontaneous (non-provoked), unilateral, and bloody or serosanguineous; arises from a single duct opening; and is persistent. Malignancy is found in 5–15 percent of patients with suspicious/pathologic nipple discharge, so it requires further evaluation [2]. The most common cause of pathologic nipple discharge is a benign papilloma (48%) followed by ductal ectasia (15–20%). The least likely but most significant finding is carcinoma (10–15%) [1]. Women under 30 years of age with a concerning history or clinical exam finding should undergo a breast ultrasound and possible diagnostic mammogram. Women aged 30 years or older should have both a diagnostic mammogram and an ultrasound. Concerning findings should lead to a tissue biopsy in most cases. Ductograms or breast MRI may be considered if initial radiologic findings are uncertain [5].
Key Points
The evaluation of nipple discharge in nonpregnant patients starts with the clinical history and physical examination.
Benign/physiologic discharge is typically bilateral and non-bloody, and can be provoked from multiple ducts.
Laboratory evaluation should include a pregnancy test, followed by TSH and prolactin levels. Breast imaging depends on the clinical presentation and the age of the patient.
Benign physiologic nipple discharge typically resolves when the nipple is left alone and not stimulated. Observation is thus appropriate.
Nipple discharge that is persistent, spontaneous, unilateral, uniductal, or bloody suggests possible underlying pathology and requires further evaluation.
References
History of Present Illness
A 38-year-old nulligravid woman presents to the office with the complaint of nipple discharge. The discharge is present in the left breast only, is bloody, appears spontaneously without nipple stimulation, and is reproducible on application of pressure on the left upper-outer quadrant of the breast. There is no nipple discharge from the right breast. She discovered the discharge for the first time two weeks ago. She has not noticed any breast lump, and denies breast pain, recent trauma, or fevers. She has no previous history of breast problems and no prior pregnancies. Her menarche was at age 14 and she has regular menstrual cycles. She has no medical problems or prior surgeries and is on no medications and has no known drug allergies. She does not smoke, nor use drugs or alcohol. Her family history is negative for cancer.
Physical Examination
- General appearance
Alert, no acute distress
Vital Signs
- Temperature
36.8 °C
- Pulse
95 beats/min
- Blood pressure
125/80
- Respiratory rate
14 breaths/min
- Oxygen saturation
98% on room air
- BMI
24
Breast Exam
- Inspection
Symmetric breast tissue. No dimpling of the skin. No erythema, swelling or color changes of nipple and skin. Nipples show no retraction, crusting, or ulceration.
- Palpation
No masses in all four quadrants bilaterally. On palpation of the left upper outer quadrant, there is discharge of a small sanguineous droplet, reproducible on applying pressure at the periphery of the areola sweeping toward the nipple, possibly involving the area of one duct. No enlarged lymph nodes palpable in the axillary and supraclavicular stations.
Laboratory Studies
- Urine pregnancy test
Negative
Imaging
Diagnostic mammogram – Cranial caudal images showed an oval mass with circumscribed margins in the subareolar position in the left breast (Figure 33.1)
Left breast ultrasound – oval, circumscribed intraductal mass within a dilated duct in subareolar position (Figure 33.2)
BI-RADS® Category 4 – suspicious, with a recommendation of biopsy and tissue diagnosis
Insertion of Mammogram and Ultrasound images. Courtesy of Dr. D. L. Lam, University of Washington
(a) Mammogram cranio-caudal view.
(b) Mammogram medio-lateral view.
Figure 33.2 Ultrasound: left breast subareolar anti-radial.
How Would You Manage This Patient?
This patient has pathologic nipple discharge, since it is unilateral, spontaneous, bloody, and associated with an intraductal mass within a dilated duct on mammogram and ultrasound. A core needle breast biopsy was performed and pathology showed an intraductal papilloma without atypia. A selective duct excision was performed both for diagnosis and therapy to stop the nipple discharge. The final pathology of the excised duct confirmed a benign intraductal papilloma. At her postoperative follow-up visit, the patient presented with a well-healed incision on the breast, and reported that the nipple discharge had disappeared.
Bloody Nipple Discharge
Nipple discharge is the third most common cause for referrals to breast clinics, following breast lumps and pain. It is anxiety provoking for patients. It is important to distinguish if the discharge is benign or suspicious for an underlying pathology such as a papilloma, high-risk lesion, or cancer.
The clinical history is important in assessing risk, including timing of any lactation in the last year; color of the discharge (milky, white, green, brown, gray versus clear, serosanguineous or sanguineous); bilateral or unilateral; multi-ductal or uniductal; persistent, spontaneous, or only present when provoked by stimulation; and whether associated with a mass or enlarged lymph node. Risk factors for breast cancer and any family history that would identify the patient as a candidate for genetic screening should be determined, along with any prior breast procedures.
Bilateral, multi-ductal, non-bloody discharge is usually benign. Bilateral milky discharge outside of pregnancy, postpartum period, and one year after cessation of breastfeeding is called galactorrhea and is not caused by intrinsic breast disease [2, 3]. In contrast, pathologic discharge is usually spontaneous, unilateral, possibly localized to a single duct, and persistent. It can be serous (clear), sanguineous, or serosanguineous. Bloody nipple discharge is associated with a significantly higher risk for breast cancer than non-bloody discharge. One of the strongest risk factors for an underlying malignancy is patient’s age, with older patients being much more likely to receive the diagnosis of cancer.
A complete clinical breast examination including axillary, infra-, and supraclavicular areas should be performed to detect any palpable mass. Attempts should be made to provoke the discharge from the nipple by massaging from the periphery of the areola toward the center in a clockwise fashion. The nipple should be inspected for areas of retraction, crusting, scaling, erythema, thickened areas, or ulceration, particularly when patients note bloody stains on their clothing without obvious nipple discharge. Skin findings of scaly, raw, vesicular, or ulcerated lesion associated with bloody discharge can be a sign of Paget’s disease of the breast, and require a biopsy of the nipple.
Most cases (65–95 percent) of bloody nipple discharge are benign in origin. However, intraductal hyperplasia or carcinoma (ductal carcinoma in situ [DCIS] or invasive carcinoma) must always be ruled out. Intraductal papillomas, which are wart-like benign tumors that grow from the lining of the breast duct, are the most common diagnosis associated with bloody nipple discharge. Solitary and centrally located papillomas that are close to the duct opening often present with bloody nipple discharge and are less commonly palpable as a mass. They are not usually associated with malignancies on pathology, but there can be atypical cells or DCIS within the papillomas. When intraductal papillomas are multiple and peripheral (sometimes even in both breasts), patients do not typically present with nipple discharge, because the location of the lesions are peripheral and deep. However, patients with multiple papillomas are at higher risk for coexisting breast cancer or development of cancer later in life [3].
The second most common cause of bloody nipple discharge is ductal ectasia (also known as plasma cell mastitis), which is a benign subareolar periductal chronic inflammatory process that is characterized by dilated ducts and can lead to ductal occlusion. It is most often seen in peri- or postmenopausal patients. Duct ectasia identified on mammogram or sonography can have underlying histologic findings such as papilloma or malignancy in about 5 percent of cases [7].
The diagnostic evaluation of nipple discharge depends on the age of the patient. For patients below 30 years of age, initial radiologic evaluation is with ultrasound only, whereas women age 30 and above are initially evaluated by combined imaging of mammogram and ultrasound. The mammogram is helpful to visualize microcalcifications, a sign of DCIS or invasive cancer, as well as to evaluate the entire breast for other areas of concern. If imaging is normal or likely benign, further evaluation with a ductogram or MRI is the next step [1]. If the imaging findings are BIRADS® Category 4 or 5 findings (suspicious or highly suggestive of malignancy), a tissue biopsy is warranted.
A ductogram can help to localize and characterize an intraductal lesion, and can also help with an intraoperative selective excision. It is only possible to locate the affected duct if it demonstrates discharge at the time of study [4]. A ductogram might be the only means to localize and resect the breast lesion associated with the discharge if physical examination and other imaging studies are negative [7].
MRI is emerging as a less invasive alternative to ductography [6]. It has a very high sensitivity for detecting breast cancer (94–100 percent) and a percutaneous MRI-guided core biopsy can be accomplished [4]. MRI, however, has variable specificity and a high false-positive rate.
Most experts do not recommend cytology of nipple discharge, including for the evaluation of bloody nipple discharge, because it is of little complementary value and may even confuse the management [5]. However, there is some controversy and there are some experts who recommend obtaining cytology because it is noninvasive and can have specificity >90 percent if it shows signs of suspected or clear malignancy.
An evaluation with biopsy is needed in the case of a palpable mass or if imaging shows a BI-RADS® Category 4 or 5 lesion [1]. Excision of the affected milk duct is still considered the gold standard for bloody unilateral discharge even in the setting of normal mammogram and ultrasound findings. Selective duct excision is called microdochectomy. A negative core needle biopsy does not guarantee a benign finding on subsequent ductal excision. Previous research has shown that some lesions identified as papilloma on core needle biopsy were upgraded to atypical ductal hyperplasia and DCIS after excision of the duct [8]. Ductoscopy is not currently offered at every center but gaining in popularity. A microendoscope is inserted into the ductal system to directly visualize the lesion. It may contribute to a more accurate resection of intraductal lesions [9] or offer the possibility of intraductal biopsy or resection.
Key Teaching Points
Benign discharge is usually bilateral, multi-ductal, and non-bloody.
Pathologic discharge is usually spontaneous, unilateral, possibly localized to a single duct and persistent. It can be serous (clear), sanguineous, or serosanguineous.
Bloody nipple discharge is associated with a significantly higher risk for breast cancer than non-bloody discharge.
Patient’s age is one of the strongest risk factors for an underlying malignancy, with older patients much more likely to have cancer.
Initial radiologic evaluation is with ultrasound only for patients below age 30 years, whereas combined imaging of mammogram and ultrasound is recommended for women age 30 and above.
If imaging is normal or likely benign, further evaluation with a ductogram or MRI is the next step.
Most experts do not recommend cytology of nipple discharge because it is of little complementary value and may even confuse the management.
The most common origin of bloody nipple discharge is (benign) intraductal papilloma, followed by ductal ectasia.
Atypical ductal hyperplasia, DCIS, and invasive carcinoma have to be ruled out.
Selective duct excision is the gold standard for evaluation and treatment of bloody unilateral, uniductal nipple discharge.
References
History of Present Illness
A 34-year-old Hispanic female, gravida 4, para 2, spontaneous abortion 1, was seen for a routine prenatal visit at 23 weeks. She reported noticing a lump in her right breast at around 19 weeks. There was no associated pain, nipple discharge, or trauma. The patient denied any change in the breast size, asymmetry, skin changes, or nipple inversion.
Her past medical history was significant for asthma and a history of chlamydia. Her past surgical history included one cesarean delivery. She breastfed her two other babies. She has never had a breast biopsy. She was married and has previously used Nuvaring, combined oral contraceptive pills, and progesterone-only pills for birth control. She breastfed her other two children without complications. She denied a family history of breast, ovarian, endometrial, or colon cancer. She had no known drug allergies. Her only medication was a daily prenatal vitamin.
Physical Examination
- General appearance
Well-developed, well-nourished woman in no apparent distress
Vital Signs
- Pulse
80 beats/min
- Blood pressure
101/65 mmHg
- Body mass index
23 kg/m2
- Abdomen
Gravid uterus with fundal height 24 cm
- Fetal heart tones
157 beats/min
- Breast exam
No skin changes, nipple inversion, or asymmetry seen. 2–3 cm smooth, mobile mass in right lower outer quadrant. No palpable axillary adenopathy.
How Would You Manage This Patient?
The patient has a breast mass in pregnancy, which was detected by breast self-awareness. She is young with no risk factors for breast cancer. She did not have a family history of early onset premenopausal breast cancer, had breastfed her other two babies, and had no history of previous breast biopsy. On physical examination, the breast mass was felt to be regular and mobile, but solid and non-tender, suggestive of a fibroadenoma. A breast ultrasound with possible biopsy was ordered to delineate further characteristics of the mass. Breast ultrasound demonstrated normal left breast and axilla. On the right breast, there was a 2.5 cm × 1.5 cm × 3.2 cm irregular area with an indistinct margin at 7 o’clock 5 cm from the nipple (Figures 34.1–34.3). This irregular area was hypoechoic. There was also a 1.2 cm × 0.6 cm × 1.1 cm lymph node in the right axilla with focal cortical thickening.
Figure 34.1 Ultrasound image of right breast demonstrating 2.5 × 3.2 × 1.5 cm hypoechoic irregular area.
Figure 34.2 Ultrasound of right breast with color flow demonstrating vascularity.
Biopsy was performed and pathology indicated malignant invasive ductal carcinoma and ductal carcinoma in situ cribriforming. Hormone receptor testing showed estrogen receptor negative, progesterone receptor negative, and HER2 positive. The patient was counseled on the diagnosis and need to evaluate for distant metastatic disease. To protect the fetus, chest radiograph with shielding, ultrasound of the liver, and MRI of the spine without contrast were performed. These tests showed no evidence of metastatic disease.
She was referred to a breast surgeon and a medical oncologist. The patient opted to continue with pregnancy and had a mastectomy with axillary lymph node dissection. She was stage IIA (T2N0M0) based on her final pathology. She received three cycles of Adriamycin and cyclophosphamide, with one cycle given prior to delivery. She was delivered at 37 weeks gestation, and then completed her treatment with four cycles of Taxotere/Herceptin/Pertuzumab.
Breast Masses in Pregnancy
Pregnancy-associated breast cancer or gestational cancer is usually defined as a breast cancer diagnosed during pregnancy or up to 12 months postpartum. The incidence of pregnancy-associated breast cancer is increasing as more women are postponing pregnancy to their late thirties and forties. Approximately 25 percent of all breast cancer patients are diagnosed during their reproductive years, with a reported incidence of pregnancy-associated breast cancer of 15–35 per 100,000 deliveries [1] and a mean age of 35 years at presentation. Infiltrating ductal carcinoma is the most common histologic type of pregnancy-associated breast cancer, and most are hormone receptor negative. Women with breast cancer diagnosed in pregnancy typically present with more advanced disease, especially in terms of lymph node status, than women who are not pregnant. This may stem from delay in diagnosis or difficulties in tumor detection due to breast engorgement and hypertrophy [3, 4]. Pregnancy-associated breast cancer has poorer prognosis than cancer diagnosed outside of pregnancy. The prognosis may be poorer because of delay in diagnosis and desire to limit radiation exposure to the fetus. Such delay can increase the risk of nodal involvement by 1–2 percent and adversely impact outcome. Survival is the same between pregnant and nonpregnant patients after controlling for age and stage of disease. Because of the more advanced disease at presentation, a high index of suspicion and rapid diagnostic evaluation are warranted.
Pregnancy-associated breast cancers typically present as masses, which may be benign or malignant. A benign mass may be solid or cystic, whereas a malignant mass is typically solid. Breast masses during pregnancy should have the exclusion of carcinoma by the least invasive but most reliable means possible. Breast lesions detected during pregnancy or nursing are not very different from those detected in nonpregnant women. The differential diagnosis of a breast mass in young women includes benign cyst, fibrocystic change, lactation adenoma, fibroadenoma, breast abscess, galactocele, fat necrosis, and malignancy [5]. Breast lesions most likely to develop in pregnant women (Table 34.1) include lactation adenomas, fibroadenomas, breast hamartomas, and axillary breast tissue. The hormone-induced physiological changes occurring in the pregnant breast make diagnosis more difficult.
