What lab tests should be ordered for a patient presenting with nipple discharge?

Laboratory Testing for Nipple Discharge

The laboratory workup for nipple discharge depends entirely on whether the discharge is physiologic or pathologic—physiologic discharge requires serum prolactin and TSH testing, while pathologic discharge requires no routine laboratory testing and should proceed directly to imaging. 1

Initial Characterization: The Critical First Step

Before ordering any laboratory tests, you must characterize the discharge as physiologic versus pathologic, as this determines the entire diagnostic pathway 1:

Physiologic discharge characteristics:

• Bilateral presentation 1
• Multiple ducts involved 1
• White, green, yellow, or clear color 1
• Only occurs when provoked (not spontaneous) 1
• No association with breast cancer 2

Pathologic discharge characteristics:

• Unilateral presentation 1
• Single duct origin 1
• Spontaneous occurrence 1
• Bloody or serous appearance 1
• Associated with malignancy in 3-29% of cases 2

Laboratory Testing for Physiologic Discharge

When physiologic discharge is suspected (particularly bilateral, milky discharge suggesting hyperprolactinemia), the following laboratory tests should be ordered 1, 3:

Essential Initial Tests

Serum prolactin level:

• This is the first and most essential laboratory test 3
• Can be drawn at any time of day without fasting 1, 3
• Use age-specific and sex-specific reference ranges for interpretation 1, 3
• Prolactin >4,000 mU/L (188 μg/L) suggests prolactinoma and warrants pituitary MRI 1, 3

Thyroid-stimulating hormone (TSH):

• Primary hypothyroidism causes hyperprolactinemia in 40-43% of frank hypothyroidism cases 1, 3
• This is a common and treatable cause that must be excluded 3

Additional Essential Tests

Renal function tests (creatinine, BUN):

• Chronic kidney disease increases prolactin secretion and reduces renal clearance 1, 3

Liver function tests:

• Severe liver disease is associated with hyperprolactinemia in adults 1, 3

Special Considerations for Prolactin Interpretation

Macroprolactin testing:

• Check for macroprolactin when prolactin is mildly or incidentally elevated 1, 3
• Macroprolactin accounts for 10-40% of hyperprolactinemia cases 1, 3
• This is biologically inactive and can lead to unnecessary investigations if not identified 3

Serial dilutions for "hook effect":

• When there is a large pituitary mass but paradoxically normal or mildly elevated prolactin, request serial dilutions 1, 3
• This prevents missing a large prolactinoma due to assay artifact 3

Repeat testing for modest elevations:

• For prolactin up to 5 times the upper limit of normal, consider serial measurements on a different day 3
• Use an indwelling cannula with 2-3 samples at 20-60 minute intervals to exclude stress-related elevation 3

No Laboratory Testing for Pathologic Discharge

For pathologic discharge (unilateral, single duct, spontaneous, bloody/serous), proceed directly to imaging without routine laboratory testing 1, 2:

• Diagnostic mammography/digital breast tomosynthesis (DBT) and ultrasound are the first-line modalities 1, 2
• Age-appropriate imaging should be conducted: mammography/DBT + ultrasound for age ≥40 years or ≥30 years; ultrasound alone for <30 years 1, 2
• Cytology of discharge fluid has limited utility and is not routinely recommended 4
• Ductography has been largely replaced by MRI when initial imaging is negative 5

Critical Pitfalls to Avoid

Before attributing hyperprolactinemia to prolactinoma:

• Conduct a thorough medication review, as dopamine antagonists (antipsychotics, antiemetics, certain antidepressants) are among the most common causes of hyperprolactinemia 1, 3
• Always exclude physiologic causes (pregnancy), medications, hypothyroidism, and renal/hepatic disease first 3

Do not rely on a single mildly elevated prolactin value:

• Stress-related elevation is common and requires confirmation with repeat testing 3

Do not miss macroprolactin:

• This benign condition can mimic true hyperprolactinemia and lead to unnecessary treatment if not identified 3

Do not order unnecessary tests for pathologic discharge:

• Ductography, cytology, and laboratory studies have little role when diagnostic breast imaging is negative 4
• The focus should be on imaging and potential surgical excision, not laboratory workup 1, 2