HE4 Elevation: What It Means and How It Relates to Ovarian Cancer
HE4 Elevation: What It Means and How It Relates to Ovarian Cancer
HE4 (Human Epididymis Protein 4) has emerged as an important tumor marker in the evaluation of ovarian cancer. Compared with CA125—traditionally the most widely used marker—HE4 offers improved specificity and is less influenced by benign gynecologic conditions. This makes it a valuable complementary test in the diagnostic work-up of pelvic masses.
Below is a comprehensive review of what HE4 is, how it is used, and what an elevated level may indicate.
1. What Is HE4?
HE4 is a glycoprotein encoded by the WFDC2 gene. In healthy adults, serum levels remain low, but expression increases in certain malignancies—most notably epithelial ovarian cancer.
HE4 is not intended as a standalone diagnostic test.
Instead, it serves as:
- A complementary marker to CA125
- A tool for risk stratification when a pelvic mass is present
- A marker for monitoring treatment response and recurrence
2. Clinical Uses of HE4
① Assessing the Malignancy Risk of Ovarian Masses
When an adnexal mass is discovered, HE4 can help differentiate:
- Benign ovarian tumors
- Malignant epithelial ovarian cancer
HE4 is particularly useful when CA125 may be falsely elevated, such as in:
- Endometriosis
- Menstruation
- Pregnancy
- Pelvic inflammatory disease
② Diagnostic Support & Follow-Up in Epithelial Ovarian Cancer
HE4 can be used to:
- Establish a baseline level before treatment
- Monitor response after surgery or chemotherapy
- Detect early recurrence during follow-up
However, HE4 cannot replace imaging or histologic diagnosis.
3. HE4 vs. CA125
| Feature | HE4 | CA125 |
|---|---|---|
| Specificity | Higher | Lower |
| Influence from menstruation/endometriosis | Minimal | Significant |
| Early-stage epithelial ovarian cancer | Helpful as a complementary marker | Limited sensitivity |
| Mucinous ovarian cancer | Low sensitivity | Low sensitivity |
➡️ HE4 and CA125 are complementary rather than interchangeable.
4. ROMA Score (Risk of Ovarian Malignancy Algorithm)
One of the key clinical applications of HE4 is its use in calculating the ROMA score, which combines:
- HE4
- CA125
- Menopausal status
ROMA categorizes patients into:
- Low-risk
- High-risk for epithelial ovarian cancer
Typical ROMA cutoff values:
- Premenopausal: >11.4% = high risk
- Postmenopausal: >29.9% = high risk
⚠️ ROMA is not a screening test.
It is used only when a pelvic mass has already been identified.
5. Test Method
- Sample: Serum
- Assays:
- ECLIA (Electrochemiluminescence Immunoassay)
- CMIA and other automated immunoassays
Because values can vary between platforms, it is recommended to use the same laboratory and assay for serial monitoring.
6. Reference Ranges
Reference intervals vary by lab and assay, but typically:
- Premenopausal: ≤ 70 pmol/L
- Postmenopausal: ≤ 104 pmol/L
HE4 levels can be influenced by:
- Age
- Renal function
Therefore, HE4 should never be interpreted in isolation.
7. Causes of Elevated HE4
🔺 Malignant Causes
- Epithelial ovarian cancer (especially serous subtype)
- Endometrial cancer
- Some lung cancers
🔺 Non-Malignant Causes
- Chronic kidney disease
- Reduced renal function
- Liver cirrhosis
- Older age
- Smoking
➡️ Elevated HE4 does not automatically mean ovarian cancer.
8. Limitations of HE4
- Not suitable for screening the general population
- Low sensitivity in mucinous ovarian cancer
- Risk of false elevation in renal impairment
- Assay variability between laboratories
9. Clinical Interpretation Summary
HE4 is useful when:
- Evaluating a pelvic mass
- Calculating ROMA score
- Complementing CA125
- Monitoring patients diagnosed with epithelial ovarian cancer
However, accurate interpretation requires combining:
- HE4
- CA125
- Menopausal status
- Imaging studies
- Clinical symptoms
10. Conclusion
HE4 is a valuable tumor marker that enhances diagnostic accuracy in the evaluation of ovarian masses, particularly when CA125 alone is insufficient. While HE4 adds important information, it should always be interpreted within a broader clinical context.
For patients undergoing evaluation for ovarian cancer or follow-up after treatment, HE4 provides meaningful insights—especially when used alongside CA125 and imaging studies.
📚 References
- Moore RG, et al. Gynecologic Oncology. 2008;108(2):402–408.
- Moore RG, et al. Gynecologic Oncology. 2009;112(1):40–46.
- Ferraro S, et al. Journal of Clinical Pathology. 2013;66(4):273–281.
- Duffy MJ, et al. International Journal of Gynecological Cancer. 2005;15(5):679–691.