When are tumor markers, such as Cancer Antigen (CA)-125, recommended for evaluating ovarian cysts in female patients, particularly those in the postmenopausal age group?

When to Order Tumor Markers for Ovarian Cysts

Tumor markers such as CA-125 should NOT be routinely ordered for simple ovarian cysts, but are recommended for intermediate-risk (O-RADS 4) and high-risk (O-RADS 5) lesions in postmenopausal women, and when ultrasound shows indeterminate or suspicious features such as solid components, papillary projections, or complex morphology. 1, 2, 3

Risk-Stratified Approach to Tumor Marker Testing

When CA-125 is NOT Indicated

• Simple unilocular cysts: CA-125 testing provides limited diagnostic value and should not be ordered, as ultrasound alone is superior for distinguishing benign from malignant lesions 2, 3
• Premenopausal women with simple cysts <5 cm: These functional cysts typically resolve spontaneously and do not require tumor marker evaluation 4
• Cysts with only thin septations (<3 mm) and no other concerning features: These have malignancy risk <0.4% and do not warrant CA-125 testing 2

When CA-125 Should Be Considered

Postmenopausal women with:

• Cysts ≥5 cm in diameter: Postmenopausal status eliminates functional cysts, making persistent masses more concerning 4, 5
• O-RADS 4 lesions (10-50% malignancy risk): CA-125 helps determine whether referral to gynecologic oncology is needed 1
• O-RADS 5 lesions (50-100% malignancy risk): While these warrant direct referral to gynecologic oncology regardless of CA-125 level, the marker aids in surgical planning 1
• Complex morphology on ultrasound: Features including solid components, papillary projections, thick septations, or ascites 3, 4

Symptomatic patients presenting with:

• Persistent abdominal distension or bloating 4
• Early satiety or loss of appetite 4
• Pelvic or abdominal pain 4
• Increased urinary urgency and frequency 4

Critical Limitations of CA-125

Sensitivity Issues

• Only 50% sensitive for stage I ovarian cancer, meaning it misses half of early malignancies even when present 2, 3
• CA-125 may be low or normal in low-grade malignancies and borderline tumors 3

Specificity Considerations

• While CA-125 has 98.5% specificity in postmenopausal women using the 35 U/mL threshold, it is frequently elevated in benign conditions 2, 6
• False-positive elevations occur with: endometriosis, adenomyosis, pelvic inflammatory disease, and benign hemorrhagic cysts 2, 3

Interpretation Pitfalls

• A normal CA-125 does not exclude malignancy in a postmenopausal woman with suspicious ultrasound features (O-RADS 4 or 5) 1
• Serial measurements showing progressive elevation are more concerning than single elevated values, as malignancies demonstrate rising trends over time 3, 7
• An elevated CA-125 in a premenopausal patient with features suggesting endometriosis may unnecessarily elevate concern for malignancy 1

Recommended Diagnostic Algorithm

Step 1: Ultrasound First

• Transvaginal ultrasound with color/power Doppler is the gold standard initial evaluation 2, 3
• Apply O-RADS classification to stratify malignancy risk based on morphologic features 1, 3
• Color Doppler differentiates true solid components from hemorrhagic debris, which is critical for accurate diagnosis 3

Step 2: Risk-Based CA-125 Testing

• O-RADS 1-2 (simple cysts): No CA-125 needed 2
• O-RADS 3 (<10% risk): CA-125 generally not required; manage with gynecologist 1
• O-RADS 4 (10-50% risk): CA-125 helps determine need for gynecologic oncology referral, particularly in postmenopausal women 1
• O-RADS 5 (≥50% risk): Direct referral to gynecologic oncology; CA-125 aids in subclassification of malignant lesions (stage 2-4 invasive vs. metastatic) 1

Step 3: Advanced Imaging When Needed

• MRI with IV contrast (not CT) is the next step for cysts that become indeterminate on ultrasound 2
• MRI is superior to CT for characterizing adnexal masses and determining organ of origin 2

Key Clinical Caveats

• Never use CA-125 as a standalone screening test for ovarian cysts, as this leads to false reassurance when normal and unnecessary intervention when elevated 3
• Postmenopausal women with cysts >3 cm require follow-up even with normal CA-125, as functional cysts should not occur after menopause 2, 7
• Ultrasound morphology takes precedence over CA-125 levels in determining management—suspicious features warrant referral even with normal CA-125 1, 3
• All postmenopausal women with CA-125 <35 U/mL and unilocular cysts <13 cm had benign histopathology in surgical series, supporting conservative management in this specific scenario 6