How should CA-125 be interpreted and managed in a patient with an ovarian cyst, taking into account age and menopausal status?

CA-125 Interpretation in Ovarian Cysts

CA-125 should always be interpreted in conjunction with transvaginal ultrasound findings and menopausal status—ultrasound morphology takes precedence over CA-125 levels in determining management, and suspicious ultrasound features warrant referral to gynecologic oncology even when CA-125 is normal. 1, 2

Primary Diagnostic Approach

• Transvaginal ultrasound with color Doppler is the gold standard for evaluating ovarian cysts and is superior to CA-125 alone in distinguishing benign from malignant lesions. 1, 2

• CA-125 performed worse than ultrasound alone in multiple studies for differentiating benign from malignant ovarian masses and only improved specificity for lesions already suspected to be malignant on imaging. 1, 2

• The combination of CA-125 with ultrasound provides better diagnostic accuracy than either test alone, but ultrasound findings should drive clinical decision-making. 1

When to Order CA-125

CA-125 should be measured preoperatively when:

• Transvaginal ultrasound shows suspicious features including solid components, papillary projections, thick septations (>3mm), or abnormal vascular flow on Doppler. 1, 2

• The patient is postmenopausal with a complex cyst, as CA-125 has 98.5% specificity in women over age 50 using the 35 U/mL threshold. 1, 2

• The cyst is classified as O-RADS 4 (10-50% malignancy risk) or O-RADS 5 (50-100% malignancy risk) on ultrasound. 2

CA-125 should NOT be routinely ordered for:

• Simple ovarian cysts without concerning ultrasound features, as it provides limited diagnostic value and may lead to unnecessary interventions. 3

• Premenopausal women with functional-appearing cysts, as CA-125 has lower specificity (94.5%) due to physiologic fluctuations and frequent elevation in benign conditions like endometriosis, adenomyosis, and menstruation. 1

Critical Limitations of CA-125

Sensitivity issues:

• CA-125 detects only 50% of stage I ovarian cancers—a normal CA-125 does not exclude early malignancy. 1, 2

• CA-125 may be low or normal in low-grade malignancies and borderline tumors. 2

Specificity issues:

• CA-125 is frequently elevated in numerous benign gynecologic conditions including endometriosis, adenomyosis, pelvic inflammatory disease, functional hemorrhagic cysts, uterine fibroids, and menstruation. 1, 2

• Non-gynecologic conditions causing false-positive elevations include cirrhosis, hepatitis, renal failure, heart failure, peritonitis, pleural effusion, ascites of any cause, and pregnancy. 4, 1

Interpretation by Menopausal Status

Postmenopausal Women

• Use a threshold of 35 U/mL, which has 98.5% specificity in women over age 50. 1, 2

• Refer to gynecologic oncology when CA-125 >35 U/mL is combined with any of the following:

  • Nodular or fixed pelvic mass on examination 2
  • Complex morphology on ultrasound (solid components, papillary projections, thick septations) 2
  • O-RADS 4 or O-RADS 5 classification 2
  • Ascites or evidence of metastatic disease 2

• For postmenopausal women with persistent unilocular cysts <50mm and normal CA-125, expectant management with serial ultrasound is appropriate, as these lesions remain benign in the majority of cases. 5

Premenopausal Women

• Use a higher threshold for referral: CA-125 >200 U/mL (some experts suggest >50 U/mL as an alternative threshold). 2

• Specificity is lower (approximately 94.5%) due to physiologic fluctuations and benign conditions. 1

• Refer to gynecologic oncology when:

  • CA-125 exceeds the threshold AND ultrasound shows indeterminate or suspicious features 2
  • There is ascites, metastatic disease, or strong family history of breast/ovarian cancer 2

• In young women under age 35, also measure AFP and beta-hCG to exclude germ cell tumors. 1

Additional Tumor Markers

• Measure CA 19-9 when CA-125 is normal but imaging suggests clear cell, mucinous, or endometrioid tumors. 1

• Use the CA-125:CEA ratio to differentiate ovarian primary malignancy from gastrointestinal metastases when both markers are elevated—a high CA-125:CEA ratio favors ovarian origin, while a low ratio suggests gastrointestinal primary. 1

Serial Monitoring

• Progressive elevation of CA-125 over time, even within the normal range, is more concerning than isolated values and should prompt further evaluation. 1, 3

• Serial measurements demonstrating a rising trend are more indicative of malignancy than single static values. 1

Follow-Up Imaging When CA-125 is Elevated

• When CA-125 is elevated with an indeterminate mass on ultrasound, MRI with IV contrast is the next best step for further characterization, not CT scanning. 1, 3

• MRI is superior to CT for characterizing adnexal masses and determining organ of origin. 3

Common Pitfalls to Avoid

• Never rely on CA-125 alone to make surgical decisions, as it lacks sufficient sensitivity for early disease. 1

• Do not test CA-125 in patients with ascites from any cause, as it is universally elevated and nonspecific in this setting. 1

• Do not assume a normal CA-125 excludes ovarian cancer, particularly in premenopausal women or early-stage disease. 1, 2

• Do not use CA-125 as a screening test in asymptomatic women, as the positive predictive value is only 2% in average-risk populations. 3, 6

• Ultrasound morphology takes precedence—suspicious features warrant referral even with normal CA-125, as 50% of early cancers will have normal markers. 1, 2