What tumor markers should I check in a patient with suspected cancer?

Tumor Marker Selection in Suspected Cancer

The tumor markers you should check depend entirely on the suspected primary site based on clinical presentation, imaging findings, and patient demographics—there is no universal panel to order in all cases of suspected cancer. 1

Algorithmic Approach to Tumor Marker Selection

Step 1: Identify the Suspected Primary Site

The choice of tumor markers is results-driven, meaning you must first have clinical or radiological suspicion before ordering specific markers. 1

Step 2: Order Markers Based on Suspected Primary

Males with Suspected Germ Cell Tumor

• AFP (alpha-fetoprotein) and β-hCG (beta-human chorionic gonadotropin) 1, 2
• These are mandatory in males with retroperitoneal masses, mediastinal masses, or testicular abnormalities 2

Males with Possible Prostate Cancer

• PSA (prostate-specific antigen) 1, 2
• Use threshold >30 ng/mL for suspected malignancy (excluding acute prostatitis) 3

Females with Suspected Gynecological Primary

• CA125 and CA15-3 1
• For ovarian cancer specifically: CA125 should be measured before surgery and before chemotherapy in all suspected cases 4
• Critical caveat: CA125 only detects 50% of stage I ovarian cancers, so normal levels do not exclude early disease 4
• If CA125 is not elevated in suspected ovarian cancer, add CA19-9 (particularly for clear cell, mucinous, or endometrioid tumors) 4
• In young women, add AFP and β-hCG to exclude germ cell tumors 4

Suspected Gastrointestinal Primary

• CEA (carcinoembryonic antigen), CA19-9, and CA72-4 1
• CEA is NOT recommended for screening or diagnosis of colorectal cancer 1
• CEA may be ordered preoperatively if it assists in staging and surgical planning 1
• Use threshold >15 ng/mL for suspected malignancy (>20 ng/mL in renal or liver disease) 3
• CA19-9 threshold >200 U/mL (adjust higher with liver disease, jaundice, or effusions) 3

Suspected Neuroendocrine Malignancy

• Chromogranin A 1, 2

Suspected Hepatocellular Carcinoma

• AFP 2, 5
• Use threshold >40 ng/mL (>80 ng/mL in patients with liver disease) 3

Step 3: Understand What Tumor Markers CANNOT Do

Tumor markers should NOT be used for:

• Screening in asymptomatic, average-risk populations 6, 7
• Primary diagnosis of cancer (they lack sensitivity and specificity) 6, 8
• Sole basis for treatment decisions without imaging or histological confirmation 1, 4, 8

The only exceptions are PSA screening in select high-risk groups and AFP for hepatocellular carcinoma surveillance in cirrhotic patients. 7

Critical Pitfalls to Avoid

False Positives Are Common

• CEA, CA19-9, CA15-3, and CA125 frequently elevate in benign conditions including endometriosis, pelvic inflammatory disease, liver disease, and effusions 4, 8
• Always interpret tumor markers in conjunction with clinical findings, imaging, and histology 4, 8

Chemotherapy Effects

• CEA may falsely elevate during the first 4-6 weeks of new therapy, especially with oxaliplatin 1
• Wait until chemotherapy is finished before initiating CEA surveillance 1

Marker-Negative Cancers Exist

• Many cancers are not detected by their "dominant" markers but by elevation of unexpected markers 5
• In one screening study, multiple markers detected cancers that would have been missed by single-marker strategies 5

When Tumor Markers ARE Useful

Monitoring Treatment Response (Primary Utility)

• CEA is the marker of choice for monitoring metastatic colorectal cancer during systemic therapy 1, 2
• Measure at treatment start and every 1-3 months during active treatment 1, 2
• Persistently rising values suggest progressive disease even without radiographic confirmation 1

Post-Treatment Surveillance

• Postoperative CEA should be measured every 3 months for at least 3 years in stage II-III colorectal cancer patients who are candidates for surgery or systemic therapy 1, 2
• CA125 should be measured before each chemotherapy cycle and one month after the last cycle in ovarian cancer 4

Prognostic Information

• Elevated preoperative CEA (≥5 mg/mL) correlates with poorer prognosis in colorectal cancer, though insufficient data support using it to determine adjuvant therapy 1, 2

Cancer of Unknown Primary (CUP) Scenario

If you have metastatic disease without an obvious primary, the ESMO 2023 guidelines provide the most current approach: 1

Order markers based on pathology and clinical presentation:

• Males: AFP, β-hCG, PSA
• Females: CA125, CA15-3, mammography
• All patients with suspected GI primary: CEA, CA19-9, CA72-4
• Suspected neuroendocrine: Chromogranin A

Despite frequent non-specific elevations, these markers can still be used to monitor disease course and treatment response in CUP patients. 1