In a postmenopausal woman with an adnexal mass, how does cancer antigen 125 correlate with ovarian cancer and what are its sensitivity, specificity, positive predictive value, and negative predictive value?

CA-125 and Ovarian Cancer: Correlation and Statistical Performance

Correlation with Ovarian Cancer

CA-125 is elevated (>35 U/mL) in approximately 75-84% of women with ovarian epithelial carcinoma at diagnosis, with the highest detection rates in advanced-stage disease (84-91% in stages III-IV) and serous histology subtypes. 1, 2

The correlation between CA-125 and ovarian cancer varies significantly by several factors:

Stage-Dependent Detection

• Early-stage disease (Stage I): CA-125 detects only 50-59% of cases, meaning it misses approximately half of early ovarian cancers 2, 3, 1
• Advanced-stage disease (Stages III-IV): CA-125 is elevated in 84-91% of cases, demonstrating much stronger correlation with tumor burden 1, 2

Histology-Dependent Correlation

• Serous carcinomas: CA-125 is elevated in 80-90% of cases, representing the strongest correlation 2
• Mucinous tumors: CA-125 shows significantly lower correlation and is often normal even with malignancy 3, 1
• Low-grade and borderline tumors: CA-125 may remain normal despite malignancy 4

Progressive Elevation Pattern

• Serial measurements showing progressive elevation over time are more indicative of malignancy than single values, even when levels remain within the normal range 5, 2, 6

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Statistical Performance in Postmenopausal Women

Sensitivity

CA-125 has poor sensitivity for early-stage ovarian cancer at 50-62%, but improves to 75-84% when all stages are included. 3, 1

• The low sensitivity for early disease is the primary limitation preventing CA-125 from being used as a screening test 3, 7
• Sensitivity increases with tumor burden and stage progression 1

Specificity

CA-125 demonstrates excellent specificity of 98.5% in postmenopausal women over age 50 when using the standard threshold of 35 U/mL. 5, 2, 6

• Specificity is substantially lower (94.5%) in premenopausal women due to physiologic fluctuations 5
• The high specificity in postmenopausal women makes CA-125 clinically useful for risk stratification when combined with imaging 2, 4
• Specificity approaches nearly 100% when using thresholds of 30-35 U/mL 6

Positive Predictive Value (PPV)

The positive predictive value of CA-125 is extremely low at approximately 2% in average-risk asymptomatic women, meaning 98% of elevated results are false positives. 6

• PPV improves dramatically when CA-125 is used in conjunction with suspicious ultrasound findings rather than as a standalone test 2, 4
• In postmenopausal women with complex adnexal masses on imaging, the PPV increases substantially, making the test clinically useful in this context 2, 4

Negative Predictive Value (NPV)

While specific NPV data is not explicitly stated in the guidelines, the 50% false-negative rate in early-stage disease means a normal CA-125 cannot exclude ovarian cancer, particularly in early disease. 2, 4

• A normal CA-125 provides some reassurance in postmenopausal women with simple cysts or benign-appearing ultrasound features 6
• Suspicious ultrasound features warrant referral to gynecologic oncology even with normal CA-125 levels 4

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False-Positive Conditions

CA-125 is frequently elevated in numerous benign conditions, which explains its poor PPV when used in isolation: 5, 3, 8

• Gynecologic: Endometriosis, adenomyosis, pelvic inflammatory disease, menstruation, uterine fibroids, benign ovarian cysts, ovarian hyperstimulation syndrome
• Non-gynecologic: Peritonitis, pleural effusion, ascites from any cause, pregnancy
• Marked elevations >1000-5000 U/mL can occur in benign conditions, further limiting diagnostic utility 8

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Clinical Integration Algorithm

When to Order CA-125

CA-125 should be measured before surgery in postmenopausal women with adnexal masses that demonstrate concerning features on ultrasound, not as a standalone screening test. 2, 4

• Order CA-125 if ultrasound shows: Complex morphology with solid components, papillary projections, thick septations (>3mm), O-RADS 4 or 5 classification, or any indeterminate features 2, 4
• Do NOT order CA-125 for: Simple cysts, purely septated cysts without solid components, or as routine screening in asymptomatic women 6, 7

Interpretation Framework

Always interpret CA-125 results in conjunction with transvaginal ultrasound findings with color Doppler—ultrasound morphology takes precedence over CA-125 levels in determining management. 2, 4

• Elevated CA-125 (>35 U/mL) + suspicious ultrasound features: Immediate referral to gynecologic oncology 4
• Normal CA-125 + suspicious ultrasound features: Still warrants gynecologic oncology referral due to 50% false-negative rate 4
• Elevated CA-125 + benign ultrasound features: Consider MRI with IV contrast for further characterization, not CT 4, 6

Additional Markers When Indicated

• If CA-125 is normal and imaging suggests mucinous, clear cell, or endometrioid histology: Measure CA 19-9 2
• In women under age 35: Also measure AFP and beta-hCG to exclude germ cell tumors 2, 6
• Do NOT use: HE4 or ROMA for determining the status of an undiagnosed pelvic mass, as these are not recommended by guidelines despite FDA approval 6

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Critical Pitfalls to Avoid

• Never rely on CA-125 alone to make surgical decisions or exclude malignancy—it lacks sufficient sensitivity for early disease 2, 4
• Do not test CA-125 in patients with ascites from any cause, as it is universally elevated and nonspecific in this setting 2
• Do not assume a normal CA-125 excludes ovarian cancer, particularly in premenopausal women, early-stage disease, or mucinous histology 2, 4, 3
• Do not use CA-125 for screening asymptomatic average-risk women—the 2% PPV leads to overwhelming false positives and no survival benefit 6, 3, 7
• Elevated CA-125 should not be interpreted as diagnostic of malignancy without correlating with ultrasound morphology, given the numerous benign causes 4, 8