How should I work up an elevated CA‑125 in a patient with a family history of colorectal cancer?

Work-up for Elevated CA-125 with Family History of Colorectal Cancer

Order comprehensive CT imaging of chest, abdomen, and pelvis immediately, along with transvaginal ultrasound with color Doppler, and measure CEA and CA 19-9 to distinguish ovarian from gastrointestinal malignancy. 1

Critical Context: Family History of Colorectal Cancer

Your patient's family history of colorectal cancer is highly relevant because:

• At least 32.6% of women with ovarian metastases from colorectal adenocarcinoma have elevated CA-125 levels (range 39-556 U/mL, median 143 U/mL). 2
• Colorectal cancer and breast cancer are documented non-gynecological malignancies that can elevate CA-125. 3
• The clinical and imaging features of metastatic colorectal cancer to the ovary can mimic primary ovarian cancer, creating a diagnostic pitfall. 2

Initial Diagnostic Algorithm

Step 1: Additional Tumor Markers (Order Immediately)

• Measure CEA and CA 19-9 alongside CA-125 to help distinguish primary ovarian tumors from gastrointestinal metastases. 4, 1
• A CA-125/CEA ratio >25:1 favors ovarian origin over gastrointestinal origin. 3, 5
• A CA-125/CEA ratio <25:1 should raise suspicion for gastrointestinal primary, particularly given the family history of colorectal cancer. 4

Step 2: Imaging Studies

Primary imaging modalities:

• Transvaginal ultrasound with color or power Doppler is the first-line imaging study to evaluate for ovarian masses. 3

  • Look for solid components, papillary projections, thick septations, ascites, or complex masses indicating malignancy. 3
  • Use O-RADS US risk stratification: O-RADS 2 (<1% malignancy risk), O-RADS 3 (1-10%), O-RADS 4 (10-50%), O-RADS 5 (≥50%). 3
  • Ultrasound-based models (IOTA Simple Rules or IOTA ADNEX) are superior to CA-125 alone for distinguishing benign from malignant ovarian tumors. 4

• CT of thorax, abdomen, and pelvis with contrast is essential for staging and surgical planning. 4, 1, 5

  • Evaluate for peritoneal implants, omental caking, ascites, lymphadenopathy, and pleural effusions. 5
  • Assess for primary colorectal lesions or hepatic metastases given family history. 2

Step 3: Endoscopy Consideration

• If CEA or CA 19-9 is elevated, or if CA-125/CEA ratio is <25:1, perform colonoscopy and upper endoscopy to exclude gastrointestinal primary malignancy. 4, 1
• This is particularly critical given the family history of colorectal cancer. 2

Referral Pathway

Immediate referral to gynecologic oncologist is warranted if:

• Postmenopausal status with elevated CA-125 3
• Nodular or fixed pelvic mass on examination 3
• Imaging shows suspicious ovarian mass (O-RADS 4 or 5) 3
• Evidence of metastatic disease or ascites 3

However, consider gastroenterology or surgical oncology consultation first if:

• CA-125/CEA ratio <25:1 4, 5
• Imaging suggests gastrointestinal primary 2
• Colonoscopy reveals colorectal malignancy 2

Common Pitfalls to Avoid

Do not assume ovarian primary based solely on elevated CA-125:

• CA-125 is elevated in only 50% of early-stage (FIGO stage I) ovarian cancers, making it a poor screening tool. 4, 3
• CA-125 lacks specificity and is elevated in numerous benign conditions (endometriosis, ovarian cysts, pelvic inflammatory disease, cirrhosis, heart failure, renal failure). 4, 3, 6
• Metastatic colorectal cancer to the ovary can present with elevated CA-125 without established history of gastrointestinal malignancy. 2

Do not order CA-125 in patients with ascites of any cause:

• Ascites universally elevates CA-125 because mesothelial cells under pressure produce the antigen, making it nonspecific. 3
• Serosal involvement (peritoneal, pleural, or pericardial fluid) requires cautious interpretation of CA-125 levels. 7

Do not use CA-125 alone to make surgical decisions:

• Always combine CA-125 with imaging findings and clinical assessment. 3
• Values up to 5,000 U/mL can occur in benign conditions. 6

Tissue Diagnosis

• Definitive diagnosis requires pathological examination of adequate tumor tissue from either diagnostic biopsy or surgical specimen. 4
• If neoadjuvant chemotherapy is planned, ensure sufficient tissue for genetic tumor testing. 4
• Surgical exploration with comprehensive staging and intraoperative frozen section is the gold standard. 5

Special Considerations for This Patient

Given the family history of colorectal cancer:

• Lynch syndrome screening may be indicated if ovarian cancer is confirmed, as mismatch repair gene mutations confer 10-12% lifetime risk of ovarian cancer (typically endometrioid or clear cell subtypes). 4
• BRCA1/2 testing is less relevant unless there is also family history of ovarian or breast cancer, as these mutations are associated with high-grade serous ovarian cancer. 4