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HE4 – Tumor Marker for Ovarian Cancer Explained

HE4 (Human Epididymis Protein 4) is a blood biomarker used for the early detection and monitoring of ovarian cancer.

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Things worth knowing about "HE4"

HE4 (Human Epididymis Protein 4) is a blood biomarker used for the early detection and monitoring of ovarian cancer.

What is HE4?

HE4 stands for Human Epididymis Protein 4, a glycoprotein originally discovered in the tissue of the epididymis (a structure near the testicles). However, it is also overproduced by certain tumor cells, particularly those of ovarian cancer (ovarian carcinoma). In modern laboratory diagnostics, HE4 is measured as a tumor marker in blood serum to help detect ovarian cancer early, monitor disease progression, and assess the risk of malignancy.

Biological Function

HE4 belongs to the family of WFDC proteins (Whey Acidic Protein Four-Disulfide Core). Its precise physiological function is not yet fully understood, but it is thought to play a role in immune defense and tissue protection. In healthy women, HE4 is detectable in blood at only very low concentrations. Elevated levels may indicate the presence of a malignant condition.

Medical Importance and Applications

HE4 is used in gynecology and oncology for several diagnostic purposes:

Early detection of ovarian cancer: HE4 is one of the most sensitive markers for ovarian cancer, particularly for serous and endometrioid subtypes.
Differential diagnosis: HE4 helps distinguish between benign and malignant adnexal masses (abnormalities involving the ovaries and fallopian tubes).
Treatment monitoring: HE4 is used during and after cancer treatment to assess how well the therapy is working.
Recurrence monitoring: A renewed rise in HE4 levels after successful treatment may indicate a relapse.
ROMA Score: HE4 is frequently used in combination with the well-known marker CA-125 in the ROMA score (Risk of Ovarian Malignancy Algorithm) to statistically better estimate the risk of ovarian malignancy.

Diagnosis: How is HE4 Measured?

HE4 is determined from a simple blood sample (serum sample). The blood is analyzed in a laboratory using an immunological test method (e.g., ELISA or electrochemiluminescence immunoassay). Results are reported in units of pmol/L (picomoles per liter).

Reference Values

Reference values may vary slightly depending on the laboratory and test method used. General reference thresholds are:

Premenopausal women: typically below 70 pmol/L
Postmenopausal women: typically below 140 pmol/L

Values above these thresholds may, but do not necessarily, indicate ovarian cancer and require further diagnostic evaluation.

Causes of Elevated HE4 Levels

An elevated HE4 level is not exclusively caused by ovarian cancer. Other factors and conditions can also raise the value:

Ovarian carcinoma – most common malignant cause
Endometrial carcinoma (uterine cancer)
Other malignant tumors (e.g., lung or breast cancer)
Renal insufficiency (impaired kidney function)
Benign lung or kidney diseases
Smoking (can slightly elevate HE4 levels)

Therefore, HE4 must always be interpreted within the overall clinical context and in combination with further diagnostic procedures (e.g., ultrasound, CA-125, biopsy).

Advantages Over Other Tumor Markers

A key advantage of HE4 over the conventional marker CA-125 is its higher specificity: HE4 is less likely to produce false-positive results in benign conditions such as endometriosis or uterine fibroids, which improves the diagnostic value of the test. Nevertheless, no single marker is sufficient on its own to reliably diagnose or rule out ovarian cancer.

When to See a Doctor

An elevated HE4 value alone is not proof of cancer. However, if the HE4 level is elevated or if suspicious findings are identified during a check-up, a gynecologist or oncologist should be consulted promptly. Symptoms that should be taken seriously alongside an elevated HE4 level include:

Persistent pelvic pain or bloating
Unexplained weight loss
Changes in bowel or bladder function
A feeling of fullness in the abdomen

References

Hellström I, Raycraft J, Hayden-Ledbetter M, et al. - The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Research, 2003.
Moore RG, McMeekin DS, Brown AK, et al. - A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecologic Oncology, 2009.
European Medicines Agency (EMA) - Scientific guidelines on biomarkers and tumor markers in oncology, 2020.

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