# Tumor Markers: Utilization and Misuse

## Introduction

Tumor markers are substances produced by tumors or by the body in response to malignancy. While they play important roles in cancer management, their inappropriate use leads to unnecessary testing, false-positive results, patient anxiety, and costly workups. The pathologist must guide evidence-based utilization and understand the limitations of each marker.

## Principles of Tumor Marker Use

**Sensitivity** refers to the ability to detect cancer when present, and few markers are sensitive enough for screening. **Specificity** reflects the ability to exclude non-malignant causes, but most markers can be elevated in benign conditions. For these reasons, most tumor markers are useful for **monitoring treatment response and recurrence** rather than for screening or diagnosis. Serial measurements and trends provide more informative data than single values.

## Commonly Used Tumor Markers

### Prostate-Specific Antigen (PSA)

As a **screening** tool, PSA is controversial; the USPSTF recommends shared decision-making for men aged 55-69. PSA is elevated in prostatitis, BPH, and after prostatic manipulation. The **free-to-total PSA ratio** is useful because a lower ratio suggests malignancy. **PSA density and velocity** further improve specificity. After radical prostatectomy, PSA should be undetectable and is used for monitoring recurrence.

### Carcinoembryonic Antigen (CEA)

CEA is most useful in **colorectal carcinoma** monitoring but is not recommended for screening because it is elevated in smoking, IBD, cirrhosis, and pancreatitis. In postoperative surveillance, a rising CEA suggests recurrence. CEA is also used for monitoring medullary thyroid carcinoma.

### CA 125

CA 125 is the standard marker for **ovarian cancer**, especially high-grade serous carcinoma. It can be elevated in endometriosis, pelvic inflammatory disease, pregnancy, and peritoneal irritation, so it is not recommended for screening the general population. The **ROCA algorithm** (Risk of Ovarian Cancer Algorithm) uses serial values for surveillance of high-risk women.

### CA 19-9

CA 19-9 is used in **pancreatic and biliary tract carcinoma** but is not produced by individuals who are **Lewis antigen negative** (approximately 5-10% of the population). It can be elevated in cholestasis, pancreatitis, and other GI conditions. It is useful for monitoring treatment response but not for diagnosis.

![Tumor marker clinical utility summary table](images/tumor-marker-summary.jpg)

### Alpha-Fetoprotein (AFP)

In **hepatocellular carcinoma**, AFP is used for screening high-risk patients with cirrhosis or chronic hepatitis B, in combination with ultrasound. In **germ cell tumors**, AFP elevation indicates a yolk sac tumor component and is used for staging and monitoring. AFP is also elevated in pregnancy, hepatic regeneration, and some benign liver conditions.

### Beta-hCG

Beta-hCG is essential for quantitative monitoring in **gestational trophoblastic disease** and is elevated in **germ cell tumors** containing choriocarcinoma or mixed elements. It is highly sensitive, and serial decline post-treatment should follow expected half-life curves.

### CA 15-3 and CA 27.29

These markers are used in **metastatic breast cancer** monitoring but are not recommended for screening, diagnosis, or routine surveillance after curative treatment. Rising levels may precede clinical recurrence by weeks to months.

## Emerging and Molecular Markers

**HE4 (Human Epididymis Protein 4)** is used with CA 125 in the **ROMA score** for ovarian mass risk stratification. **ProGRP** is associated with small cell lung carcinoma. **Chromogranin A** is used for neuroendocrine tumors but is affected by proton pump inhibitor use. **Circulating tumor DNA (ctDNA)** has an emerging role in minimal residual disease detection.

## Common Misuse Patterns

Common pitfalls include ordering tumor marker panels for **cancer screening** in asymptomatic patients, using a single elevated value to **diagnose cancer**, ordering markers for tumor types with **no established clinical utility**, failing to consider **benign causes** of elevation, and switching between different assay platforms during serial monitoring (results between platforms are not interchangeable).

![Appropriate versus inappropriate tumor marker ordering scenarios](images/tumor-marker-misuse.jpg)

## Guidelines for Appropriate Use

| Marker  | Screening       | Diagnosis | Monitoring | Prognosis |
|---------|----------------|-----------|------------|-----------|
| PSA     | Shared decision | No        | Yes        | Yes       |
| CEA     | No             | No        | Yes        | Yes       |
| CA 125  | High-risk only | No        | Yes        | Yes       |
| CA 19-9 | No             | No        | Yes        | Limited   |
| AFP     | HCC in cirrhosis| Supportive| Yes       | Yes       |
| Beta-hCG| No             | Yes (GTD) | Yes        | Yes       |

## Laboratory Considerations

The **hook effect** can cause very high concentrations to give falsely low results, requiring dilution for accurate measurement. **Heterophilic antibodies** can cause false positives and should be suspected when results do not match the clinical picture. The **same assay platform** should always be used for serial monitoring, and results should be reported with reference ranges and method information.

![Serial tumor marker monitoring curve for treatment response](images/tumor-marker-monitoring.jpg)

## Clinical Pearls

No tumor marker has sufficient sensitivity or specificity for population-level cancer screening, with the exceptions of PSA in shared decision-making and AFP for HCC in patients with cirrhosis. Trends over time are more meaningful than isolated values. The laboratory should implement utilization management strategies to reduce inappropriate tumor marker ordering. The Lewis antigen phenotype should always be considered when CA 19-9 is persistently undetectable in a patient with suspected pancreatic cancer.

## References

1. Sturgeon CM, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. *Clin Chem*. 2008;54(12):e11-e79.
2. Duffy MJ, et al. Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update. *Int J Cancer*. 2014;134(11):2513-2522.
3. Harris L, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. *J Clin Oncol*. 2007;25(33):5287-5312.
4. Locker GY, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. *J Clin Oncol*. 2006;24(33):5313-5327.