In a woman of reproductive or post‑menopausal age with a pre‑treatment Cancer Antigen 125 (CA‑125) level of 56 U/mL, what is the clinical significance and recommended work‑up?

Elevated CA-125 at 56 U/mL: Clinical Significance and Work-Up

A CA-125 of 56 U/mL requires immediate transvaginal ultrasound with color Doppler as the first-line diagnostic test, with menopausal status critically determining the level of concern—this value exceeds the postmenopausal threshold of 35 U/mL but falls within acceptable premenopausal ranges. 1, 2

Menopausal Status Determines Clinical Significance

Postmenopausal Women

• A CA-125 of 56 U/mL in a postmenopausal woman is abnormal and warrants urgent gynecologic oncology referral, as the upper limit of normal is 20 U/mL for those without bleeding and 35 U/mL for those with vaginal bleeding 3
• The American College of Obstetricians and Gynecologists specifically recommends referral for postmenopausal women with elevated CA-125, particularly when combined with a pelvic mass 1
• In postmenopausal patients with CA-125 >65 U/mL and a pelvic mass, the predictive value for malignancy reaches 98%, though at 56 U/mL the risk is lower but still significant 4

Premenopausal Women

• For premenopausal women, 56 U/mL falls within the normal range (upper limit 50-62 U/mL depending on menstrual phase), though it warrants imaging evaluation if a mass is present 3
• CA-125 fluctuates significantly with menstrual cycle: 62 U/mL during menses, 51 U/mL during proliferative phase, and 32 U/mL during luteal phase 3
• The predictive value for malignancy in premenopausal women with elevated CA-125 is only 49%, compared to 98% in postmenopausal women 4

Immediate Diagnostic Work-Up

Primary Imaging

• Transvaginal ultrasound with color or power Doppler is the mandatory first-line investigation to evaluate for ovarian masses and assess vascularity patterns 1, 5
• Look for high-risk features: solid components, papillary projections, thick septations (>3mm), ascites, complex masses, or irregular internal architecture 1, 5
• The American College of Radiology O-RADS classification system should guide risk stratification: O-RADS 4 (10-50% malignancy risk) or O-RADS 5 (≥50% risk) require gynecologic oncology consultation 1

Additional Tumor Markers

• Measure CEA and CA 19-9 in addition to CA-125 to distinguish primary ovarian tumors from gastrointestinal metastases 1, 5
• Calculate the CA-125/CEA ratio: a ratio >25 favors ovarian origin, while <25 suggests gastrointestinal primary 1, 2
• If the CA-125/CEA ratio is <25 or if CEA or CA 19-9 are elevated, consider colonoscopy and gastroscopy to exclude gastrointestinal malignancy 5
• In women under age 35, also measure AFP and beta-hCG to exclude germ cell tumors 2

Advanced Imaging

• If ultrasound findings are indeterminate, MRI with IV contrast is the next best step for further characterization 5
• CT chest/abdomen/pelvis is indicated if imaging confirms a suspicious mass to evaluate for metastatic disease 1

Critical Pitfalls to Avoid

Do Not Rely on CA-125 Alone

• Never make surgical decisions based solely on CA-125 levels—only 50% of stage I ovarian cancers have elevated CA-125, and numerous benign conditions cause false positives 1, 2
• CA-125 >65 U/mL is associated with benign conditions in 13% of cases at tertiary centers, with endometriosis being the most common benign cause 6
• Benign conditions causing CA-125 elevation include: endometriosis, pelvic inflammatory disease, ovarian cysts, cirrhosis with ascites, heart failure, renal failure, and hepatitis 1, 7

Presence of a Mass Changes Everything

• The presence of an abdominopelvic mass dramatically increases malignancy risk—approximately 90% of patients with CA-125 >65 U/mL and no mass have benign disease 6
• Conversely, patients with both elevated CA-125 and a pelvic mass require subspecialty gynecologic oncology consultation before surgery 6

Do Not Test CA-125 in Ascites

• CA-125 is universally elevated and nonspecific in patients with ascites from any cause (cirrhosis, heart failure, peritonitis)—do not order this test in that setting 1

When to Refer to Gynecologic Oncology

Immediate referral is indicated for: 1

• Postmenopausal women with CA-125 >35 U/mL and any pelvic mass
• Any patient with CA-125 >65 U/mL and a pelvic mass
• Ultrasound findings showing O-RADS 4 or 5 features
• Presence of ascites or metastatic disease on imaging
• Family history of breast or ovarian cancer with elevated CA-125