How should CA‑125 be used and interpreted in the evaluation of an ovarian mass in pre‑menopausal and post‑menopausal women?

CA-125 in Ovarian Mass Evaluation

Primary Recommendation

CA-125 should never be used as a standalone test for evaluating ovarian masses; transvaginal ultrasound with grayscale morphologic assessment and color/power Doppler is the gold standard first-line diagnostic approach, with CA-125 reserved only for risk stratification when ultrasound shows indeterminate or suspicious features. 1

Fundamental Principle: Ultrasound First, CA-125 Second

• Ultrasound is superior to CA-125 in distinguishing benign from malignant ovarian lesions, with CA-125 performing worse than ultrasound alone in multiple studies 1
• CA-125 only improved specificity for lesions already suspected to be malignant on ultrasound imaging, not for general evaluation 2, 1
• The diagnostic algorithm must start with comprehensive transvaginal ultrasound including both grayscale and color/power Doppler to assess cyst morphology and vascularity patterns 1

Critical Limitations of CA-125

Sensitivity Problems

• CA-125 has only 50% sensitivity for stage I ovarian cancer, meaning it misses half of early malignancies even when present 1, 3
• CA-125 may be low or normal in low-grade malignancies and borderline tumors 1

Specificity Problems

• CA-125 is frequently elevated in benign conditions including endometriosis, adenomyosis, pelvic inflammatory disease, functional hemorrhagic cysts, menstruation, pregnancy, peritonitis, and any condition causing pleural effusion or ascites 1, 4
• Marked elevations of CA-125 greater than 1000 U/mL, and even up to 5000 U/mL, can occur in benign conditions 4

When to Order CA-125

Postmenopausal Women

• Order CA-125 if any of the following are present on ultrasound: 2, 1
  • Elevated CA-125 (>35 U/mL) combined with nodular or fixed pelvic mass
  • Complex morphology including solid components, papillary projections, or thick septations
  • O-RADS 4 lesions (10-50% malignancy risk) for determining need for gynecologic oncology referral
  • O-RADS 5 lesions (50-100% malignancy risk) for surgical planning
• The ACOG/SGO criteria recommend referral for postmenopausal women with elevated CA-125 combined with concerning clinical or imaging features 2

Premenopausal Women

• Order CA-125 only if: 2
  • Ultrasound shows indeterminate or suspicious features suggesting possible malignancy
  • There is metastatic disease or ascites present
  • Strong family history of breast or ovarian cancer exists
• The ACOG/SGO criteria recommend referral for premenopausal women with CA-125 >200 U/mL (though some experts suggest >50 U/mL is a better discriminator) 2
• In premenopausal women, ROMA (which incorporates CA-125) showed better diagnostic performance than CA-125 alone with superior specificity (0.926 vs 0.787) and accuracy (0.875 vs 0.777) 5

Additional Tumor Markers in Specific Scenarios

• In women younger than 35 years, also measure AFP and beta-hCG to exclude germ cell tumors 6, 3
• When CA-125 is normal but imaging suggests clear cell, mucinous, or endometrioid tumors, measure CA 19-9 3

Interpretation Algorithm

Step 1: Ultrasound Risk Stratification

• Apply IOTA Simple Rules or O-RADS classification based on morphologic features 1
• IOTA Simple Rules demonstrated sensitivity of 0.93 and specificity of 0.81 for predicting malignancy 2
• Benign features (IOTA B features): unilocular cyst, solid components <7 mm, acoustic shadows, smooth multilocular tumor, diameter <100 mm, no blood flow 2
• Malignant features (IOTA M features): irregular solid tumor, ascites, ≥4 papillary structures, irregular multilocular-solid tumor, diameter ≥100 mm, very strong flow 2

Step 2: CA-125 Interpretation in Context

• Postmenopausal women: Use 35 U/mL threshold (98.5% specificity) 1, 6
• Premenopausal women: Use 200 U/mL threshold per ACOG/SGO, though 50 U/mL may be more discriminatory 2
• Serial CA-125 measurements showing progressive elevation over time are more concerning than single values, as malignancies demonstrate rising trends 1, 6

Step 3: Combined Interpretation

• Normal CA-125 + benign ultrasound features: Low risk, consider surveillance 1
• Normal CA-125 + suspicious ultrasound features: Ultrasound takes precedence; suspicious features warrant referral even with normal CA-125 1, 3
• Elevated CA-125 + benign ultrasound features: Likely benign condition causing false-positive CA-125; correlate clinically 1
• Elevated CA-125 + suspicious ultrasound features: High risk; refer to gynecologic oncology 2, 1

Critical Pitfalls to Avoid

• Never use CA-125 as a screening or standalone diagnostic test, as this leads to false reassurance when normal and unnecessary anxiety/intervention when elevated 1
• Never interpret elevated CA-125 as diagnostic of malignancy without correlating with ultrasound morphology, as benign conditions frequently cause elevation 1
• Never rely on a single normal CA-125 value to exclude malignancy in a complex cyst with suspicious ultrasound features, given the 50% false-negative rate in early-stage disease 1, 3
• Never order CA-125 for simple ovarian cysts, as it provides limited diagnostic value and may lead to unnecessary interventions 6
• Never test CA-125 in patients with ascites from any cause, as it is universally elevated and nonspecific in this setting 3

Role of Advanced Imaging

• When ultrasound shows indeterminate features and CA-125 is elevated, MRI with IV contrast is the next best step for further characterization, not CT scanning 6, 3
• MRI is superior to CT for characterizing adnexal masses and determining organ of origin 6

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