Nipple Discharge

Nipple discharge is the third most common breast-related complaint:
- After breast pain and breast nodule
During their reproductive years:
- Up to 80% of women will have an episode of nipple discharge
Most nipple discharge:
- Is of benign origin
The primary goals of evaluation and management are to:
- Differentiate patients with benign nipple discharge from those who have an underlying papilloma, high-risk lesion, or cancer and to manage patients with underlying pathologic nipple discharge
Types and causes of nipple discharge:
- Based on the characteristics of presentation nipple discharge is categorized as:
  - Normal milk production (lactation)
  - Physiologic nipple discharge (galactorrhea)
  - Pathologic (suspicious) nipple discharge
- Lactation:
  - The normal secretory products of the breast are:
    - Milk and colostrum
  - During pregnancy and the postpartum period:
    - The mammary glands develop and produce milk in response to a number of physical and biochemical forces
    - Milk secretion can continue for at least six months after delivery or after cessation of breastfeeding
- Physiologic nipple discharge (galactorrhea):
  - Is defined as nonpathologic nipple discharge unrelated to pregnancy or breastfeeding
  - Galactorrhea:
    - Is usually manifested as bilateral milky nipple discharge involving multiple ducts
    - The nipple discharge, although usually bilateral and white or clear:
      - May also be unilateral and a variety of other colors, including yellow (straw colored), green, brown, or gray, but not bloody
    - Galactorrhea is often caused by hyperprolactinemia, which may be secondary to medications, pituitary tumors, endocrine abnormalities, or other medical conditions
- Pathologic (suspicious) nipple discharge:
  - Secretory production of fluids other than milk may be due to a pathological process in the breast
  - The discharge is usually:
    - Unilateral and localized to a single duct, persistent, and spontaneous
  - It can be serous (clear or yellow), sanguineous (bloody), or serosanguineous (blood tinged)
  - Common etiologies of pathologic nipple discharge include:
    - Benign Papilloma:
      - Is the most common cause of pathologic nipple discharge:
        52% to 57% of the cases
      - A papilloma is a papillary tumor growing from the lining of the breast duct
      - The discharge associated with a papilloma can range from clear to grossly bloody
      - Solitary papillomas:
        Can occasionally harbor areas of atypia or ductal carcinoma in situ (DCIS)
    - Duct ectasia:
      - Is another common benign cause of pathologic nipple discharge
        Seen in approximately 14% to 33% of pathologic nipple discharge cases
    - Cancer:
      - Cancer is found in 5% to 15% of cases of pathologic nipple discharge
      - The most common malignancy associated with nipple discharge in the absence of other findings is DCIS
    - Infection:
      - Purulent nipple discharge can be seen in association with periductal mastitis
Clinical evaluation:
- A thorough history and physical examination should be performed in all women with nonlactational nipple discharge to determine if it is physiologic or pathologic
- History:
  - The clinical history is most helpful in distinguishing physiologic from pathologic nipple discharge
  - While a complete medical history should be obtained, specific areas to address are:
    - The appearance of the discharge:
      - Bloody versus nonbloody
    - Frequency of the discharge
    - Whether the discharge is spontaneous or provoked by manipulation of the breast and/or nipple-areolar complex
    - Whether the discharge is:
      - Unilateral or bilateral
      - Uniductal or multiductal
  - Physiologic nipple discharge:
    - Is usually bilateral and multiductal and occurs with breast manipulation
  - The risk of cancer is higher when the discharge is:
    - Spontaneous
    - Bloody
    - Unilateral
    - Uniductal
    - Associated with a breast mass
    - Occurs in a woman over 40 years of age
  - A history of recent trauma should also be elicited:
    - Trauma can include mammographic imaging with compression as well as vigorous manipulation of the nipple
  - Recent onset of amenorrhea or other symptoms of hypogonadism (hot flashes, vaginal dryness):
    - Should prompt consideration of hyperprolactinemia
    - Several classes of medications can cause hyperprolactinemia:
      - First generation antipsychotics
      - Second generation antipsychotics
      - Cyclic antidepressants
      - SSRI antidepressants
      - Other antidepressants
      - Antiemetic or gastrointestinal
  - Anticoagulants can cause blood nipple discharge in patients who sustain trauma to the breasts, even that as mild as mammographic manipulation
- Physical examination:
  - A complete breast examination should be performed as detailed elsewhere
  - The specific goals of the examination are to:
    - Note the symmetry and contour of the breasts, position of the nipples, scars, and vascular pattern as well as any evidence of skin retraction, dimpling, edema or erythema, ulceration or crusting of the nipple, and changes in skin color
    - In particular, the skin covering the breast and nipple-areolar complex should be examined for lesions that may be staining the woman’s clothes and mimicking nipple discharge:
      - Some examples are Paget disease, insect bites, local infections, and eczema:
        Suspicious skin lesions should be biopsied
  - Elicit discharge from a nipple and identify the involved duct or ducts:
    - Pressure in a clockwise fashion around the areola can help identify a specific site or duct that is producing the discharge
    - If fluid is elicited, the location of the duct(s) should be noted
    - If no discharge is elicited, a warm compress placed on the breasts will enhance the chances of detecting mammary secretion
    - Gentle, firm pressure should be applied to the base of the areola (not on the nipple), at the site where the newborn’s mouth is normally applied
    - Massage from the periphery towards the nipple-areolar complex may also help
    - It is important to observe whether the discharge comes from one or more ducts on the nipple:
      - A good light and magnifying lens can help with this identification
  - Detect enlarged axillary or supraclavicular lymph nodes
  - Delineate and document breast masses
  - Identify localized areas of tenderness and relate them to areas of pain noted by the woman and to other physical findings
  - For patients with bilateral discharge:
  - The physical examination should include:
    - Checking for a chiasmal syndrome (eg, bitemporal field loss) and signs of hypothyroidism or hypogonadism
Diagnostic evaluation:
- Patients with suspected physiologic nipple discharge require laboratory evaluation, whereas those with suspected pathologic nipple discharge should undergo imaging studies
- Physiologic discharge:
  - Nipple discharge that is bilateral and nonbloody is likely physiologic, which requires medical evaluation for possible hyperprolactinemia, but no specific breast imaging, provided that, for women, routine screening mammography is up to date
  - Some non-bloody-appearing discharge may still contain heme, and heme-occult testing may be considered
  - Laboratory evaluation (galactorrhea workup) should include a:
    - Pregnancy test, prolactin levels, renal and thyroid function tests, and appropriate follow-up with an endocrinologist if there are abnormal findings
    - Further endocrinological evaluation is also indicated for other systemic abnormalities, such as menstrual irregularity, infertility, headaches, visual disturbances, or symptoms of hypothyroidism
  - Pathologic discharge:
    - After clinical evaluation, all patients presenting with one of the following should undergo breast imaging to search for any underlying abnormality in the duct (or elsewhere in the breast) and direct surgical intervention:
      - Unilateral nipple discharge
      - Bloody nipple discharge
      - Nipple discharge associated with a mass or skin lesions
    - Laboratory tests for galactorrhea are not indicated for evaluation of suspected pathologic nipple discharge
- Mammography and ultrasound:
  - For patients who present with pathologic nipple discharge, I usually start with diagnostic mammography and / or focused breast ultrasonography
  - Age is predictive of the risk of cancer in women with nipple discharge:
    - In one series of women with isolated nipple discharge malignancy was present in:
      - 3% of those less than 40 years of age
      - 10% of those 40 to 60 years of age
      - 32% of those over 60 years of age
    - In men, nipple discharge is associated with an even higher incidence of breast cancer (23% to 57%), and nipple discharge may be their only clinical manifestation
  - Consequently, the choice and sequence of imaging modalities will depend on age and sex of the patient:
    - Women ≥ 40 years of age should undergo both diagnostic mammography and focused breast ultrasonography:
      - Patients who have had a recent mammogram (less than 6 months) or are pregnant may undergo breast ultrasonography alone
    - Women between 30 and 39 years of age should undergo diagnostic mammography first, followed by breast ultrasonography if necessary
    - Women less than 30 years of age should undergo breast ultrasonography first; mammography is only performed if the initial ultrasound shows a suspicious finding or if the patient is genetically predisposed to hereditary breast cancer
    - Given the rarity of cases and higher risk of breast cancer than women, men with pathologic nipple discharge should undergo both diagnostic mammography and breast ultrasonography to assist in diagnosis and guidance for biopsy if necessary
  - Mammography (digital with or without tomosynthesis):
    - Is the first-line imaging modality for evaluation of pathologic nipple discharge in most practices
    - Although it is the best modality for identifying suspicious lesions in the breast, mammography may fail to show cancers or high-risk lesions that are small, lack calcifications, or are entirely intraductal
    - The sensitivity and specificity of mammography for detection of cancer or high-risk lesions such as papilloma or atypia range from 7% to 10% and 94% to 100%, respectively
  - Focused ultrasonography:
    - Provides a useful tool for the diagnosis of ductal disease as it is directed to the periareolar area and provides visualization of dilated ducts and any nodules inside them
    - Ultrasound is especially useful for identifying lesions within the mammary ducts; it allows visualization of ductal pathology as small as 0.5 mm in diameter
    - When evaluating pathologic nipple discharge, ultrasound can identify 63% to 69% percent of lesions not visible on mammography
    - Ultrasound is also used to guide percutaneous biopsy of lesions and/or wire localization for surgery
    - Although ultrasound is more sensitive than mammography, it is less specific in differentiating benign from malignant lesions:
      - In a series of 52 patients with suspected ductal disease, ultrasonography had a sensitivity of 97% and a specificity of 60% with a positive predictive value of 95%
  - Magnetic resonance imaging:
    - Patients with pathologic nipple discharge but negative mammogram and ultrasound may undergo breast magnetic resonance imaging (MRI)
    - The use of breast MRI does have the risk of identifying additional findings that may lead to further imaging and biopsy, most of which are benign
    - Breast MRI is a relatively sensitive imaging modality with moderate specificity
    - Contrast-enhanced MRI has demonstrated sensitivities of 93% to 100% for invasive cancers as well as benign papillary lesions; however, specificity has been reported to be as low as 37%
    - The role of MRI in the evaluation of nipple discharge is evolving. Some studies support the use of MRI over ductoscopy due to its higher sensitivity and specificity; however, this remains an area of controversy
    - A meta-analysis comparing MRI versus galactography for pathologic nipple discharge found a higher diagnostic accuracy for MRI in cancer detection
    - MRI is also capable of identifying an etiology of discharge that is remote from the vicinity of the nipple
    - If MRI is going to be used in this setting, it should be done in a facility that has MRI-guided biopsy capabilities
  - Less commonly used studies:
    - At institutions where it is available, galactography (ductography) or ductoscopy may also be performed to evaluate pathologic nipple discharge in patients who have negative mammogram and ultrasound
    - However, these studies are less widely available, and any lesions identified are not accessible to needle biopsy and, therefore, require surgical excision with the duct
    - Galactography is a delicate, technically challenging study that can only be performed if the nipple discharge is reproducible on physical examination. During a galactography examination, the discharging nipple orifice is cannulated and injected with a small amount of contrast material, which allows a subsequent mammogram to visualize a filling defect. The intraductal lesion will appear as an intraductal filling defect, a complete ductal obstruction, or a wall irregularity. Although peripheral intraductal masses have been reported, the vast majority of intraductal masses are centrally located, near, or immediately deep to the nipple-areolar complex . In one study, galactography was associated with a sensitivity of 76% and specificity of 11%. The positive predictive value of galactography in this series was 19%. A successful galactography may help locate the lesion, which can aid the surgeon in more precisely localizing the proper area at the time of surgery, thereby limiting the amount of tissue excised. However, the absence of a lesion on galactogram does not exclude a cancer. Galactography should not be performed in patients with mastitis or a breast abscess, as it could worsen the inflammation. Galactography can cause mastitis if too much contrast material is injected or if too much pressure is used during injection, resulting in perforation of the duct and extravasation of contrast material.
    - Magnetic resonance (MR) galactography is a different technique than standard breast MRI. It utilizes heavy T2 weighting, which accentuates the visibility of fluid-containing structures. No directly instilled or intravenous contrast material is necessary. MR galactography provides a three-dimensional image and can show the precise shape and location of the abnormal duct and lesion in the breast. However, this technique will not reveal ducts that are not dilated or those with low signal intensity on heavily T2-weighted images due to hemorrhage or the presence of proteinaceous contents within the duct.
    - Mammary ductoscopy is another minimally invasive method for evaluation and treatment of nipple discharge. As with galactography, ductoscopy also requires a reproducible discharge and the ability to cannulate and dilate the discharging duct. Since first introduced in 1988, the size and resolution of endoscopes have improved significantly over time. With the aid of submillimeter endoscopes and air (Asia) or saline (North America) distention of the duct, it is possible to visualize the intraductal lesions that cause pathologic nipple discharge. When a solitary intraductal lesion is identified, it is either surgically excised or biopsied, both through a separate skin incision. Surgical excision is guided by transillumination from the ductoscope; when biopsy is planned, the tip of the ductoscope is identified with ultrasound so that percutaneous biopsy of lesions located near the scope tip can be carried out. Multiple intraluminal lesions are associated with a much higher rate of clinically occult cancer and, when encountered, should be widely excised.
- Cytology of the discharge or of a ductal lavage specimen is not recommended, because the result does not impact management:
  - Technically, it would be difficult to distinguish crenated or apoptotic cells from atypical cells, and abnormal cytologic findings cannot be easily localized to a specific lesion
- Breast biopsy:
  - Imaging does not reliably differentiate cancers or high-risk lesions (eg, papilloma or atypia) from benign lesions that cause nipple discharge
  - Thus, abnormalities detected on mammography, ultrasonography, or MRI:
    - Require image-guided core needle biopsy with clip placement to mark the biopsied lesion:
      - The biopsy result will dictate further treatment
  - Skin punch biopsy:
    - Women sometimes may report finding a stain or spot of blood on their brassiere or underclothing. Although they may complain of nipple discharge, skin lesions on the nipple may be found instead:
      - Such lesions can have the appearance of dermatitis or eczema with erythematous lesions that weep or bleed
    - This presentation merits careful examination of the skin around the nipple and nipple-areolar complex, and a skin punch biopsy should be performed as these can be the first signs of Paget disease of the breast:
      - Paget disease is an uncommon form of breast cancer, characterized clinically by an eczematoid appearance with nipple crusting, scaling, or erosion.
Pathologic nipple discharge during pregnancy and lactation:
- Bloody nipple discharge can be seen in up to 20% of women during the second or third trimester of pregnancy and lactation.
- The cause is usually hypervascularity of developing breast tissue, which is benign and requires no treatment.
- However, the evaluation of breast complaints in pregnancy and lactation can be complicated by the changing breast examination.
- Surgical evaluation is warranted for those with persistent bloody nipple discharge.
- Women who develop persistent pathologic nipple discharge during pregnancy should undergo breast ultrasonography:
  - If the result is negative, they can be followed, and further workup performed after delivery if their symptoms persist.
- If a suspicious lesion is identified on ultrasound, then an ultrasound-guided core needle biopsy can be performed, and they should be treated according to the result of the biopsy.
- Some women have bloody nipple discharge during the first days of lactation:
  - This is more common with the first pregnancy, and it is thought to be caused by the increased vascularization of the lobules and ducts with the onset of milk production. There is no contraindication to infants consuming milk that contains a little blood. If bloody nipple discharge persists for more than one week, other causes of bloody milk should also be considered and the patient should be formally evaluated for pathologic nipple discharge
Treatment:
- Physiologic nipple discharge, or galactorrhea, is often caused by hyperprolactinemia, which may be secondary to medications, pituitary tumors, endocrine abnormalities, or other medical conditions:
  - If the patient is taking a medication that has been associated with galactorrhea (eg, metoclopramide, phenothiazines, selective serotonin reuptake inhibitors [SSRIs]) and the breast evaluation is otherwise negative, the patient should be educated that this is a side effect of the medication
  - If the symptom of ongoing nipple discharge is bothersome to the patient, the medication can be tapered or changed in consultation with the prescribing clinician. In other cases, continuing the medication is appropriate (eg, antipsychotic drugs)
  - Transient idiopathic galactorrhea (with normal prolactin level) can also occur, usually in premenopausal women:
    - If the workup is otherwise negative, the woman can be reassured that it is benign and be reassessed in two to three months
- Pathologic nipple discharge:
  - For nonlactating individuals with pathologic nipple discharge, I recommend surgical management after a full evaluation has been completed. The extent of the surgery will depend on the result of the imaging studies and biopsy