What is the most appropriate tumor marker for screening a postmenopausal woman with a history of hormonal imbalance and obesity for uterine cancer?

Tumor Marker for Uterine Cancer

Direct Answer

There is no validated tumor marker for screening or diagnosing uterine (endometrial) cancer. CA-125 may be helpful only in monitoring patients with already-confirmed extrauterine disease, but it has no role in screening, diagnosis, or detecting early-stage disease 1.

Why CA-125 is NOT Appropriate for Uterine Cancer Screening

No Validated Screening Test Exists

• The NCCN explicitly states that "currently, no validated screening test for endometrial carcinoma exists" 1
• Approximately 90% of patients with endometrial carcinoma present with metrorrhagia (abnormal bleeding), making clinical symptoms far more useful than any tumor marker 1

Limited Role of CA-125 in Uterine Cancer

• CA-125 is only recommended for monitoring treatment response in patients with extrauterine disease (disease that has spread beyond the uterus), not for screening or initial diagnosis 1
• CA-125 levels can be falsely elevated in numerous benign conditions including peritoneal inflammation, infection, or radiation injury 1
• CA-125 may be normal even in patients with isolated vaginal metastases and may not predict recurrence in the absence of other clinical findings 1

Appropriate Diagnostic Approach for Uterine Cancer

Primary Diagnostic Method

• Office endometrial biopsy is the gold standard for diagnosis, with a false-negative rate of approximately 10% 1
• If endometrial biopsy is negative but the patient remains symptomatic (persistent postmenopausal bleeding), fractional dilation and curettage (D&C) under anesthesia must be performed 1
• Hysteroscopy may be helpful for evaluating the endometrium for lesions such as polyps in cases of persistent or recurrent bleeding 1

Important Caveat

• Endometrial biopsy may not accurately diagnose malignancies of the uterine wall such as mesenchymal tumors (sarcomas), which require different diagnostic approaches 1

Genetic Testing Considerations (Not Tumor Markers)

Lynch Syndrome Screening

• Universal testing of endometrial tumors for DNA mismatch repair (MMR) defects is recommended (MLH1, MSH2, MSH6, PMS2) 1
• MSI testing is recommended if MMR results are equivocal 1
• Screening for genetic mutations should be considered, especially for patients under 50 years of age 1
• Patients with Lynch syndrome have up to 60% lifetime risk for endometrial cancer and require close monitoring 1

When to Refer for Genetic Counseling

• All patients with MMR deficiencies (except isolated MLH1 loss with promoter methylation) should receive genetic counseling 1
• Patients with significant family history of endometrial and/or colorectal cancer should be referred for genetic evaluation, even without MMR defects 1

Critical Distinction: Uterine vs. Ovarian Cancer

Do not confuse uterine cancer with ovarian cancer—they are entirely different malignancies with different tumor markers:

• CA-125 is the primary tumor marker for ovarian cancer (elevated in 80-90% of serous ovarian carcinomas), not uterine cancer 2
• For postmenopausal women over 50, CA-125 has 98.5% specificity for ovarian cancer at a threshold of 35 U/mL 2, 3
• However, CA-125 only detects 50% of stage I ovarian cancers, limiting its screening utility even for ovarian malignancies 2

Bottom Line for Clinical Practice

For a postmenopausal woman with hormonal imbalance and obesity concerned about uterine cancer:

• Do not order CA-125 or any other tumor marker for screening 1
• Evaluate for abnormal uterine bleeding as the primary clinical indicator 1
• If bleeding is present, perform endometrial biopsy immediately 1
• Consider imaging (ultrasound, MRI) to assess endometrial thickness and exclude masses, but tissue diagnosis remains essential 1
• Obesity and hormonal imbalance are risk factors for endometrial cancer, but they do not change the diagnostic approach—tissue diagnosis through biopsy remains the standard 1