HE4 (Human Epididymis Protein 4)

HE4 Overview

Human Epididymis Protein 4 (HE4) is a glycoprotein encoded by the WFDC2 gene. It was initially identified in the epididymis and is thought to play a role in male fertility. However, its clinical significance has broadened significantly, primarily due to its elevation in various epithelial cancers, most notably ovarian cancer.

HE4 is now recognized as a valuable biomarker, particularly in the management of epithelial ovarian cancer, complementing the established tumor marker CA125. Its measurement in blood (serum) assists in risk stratification, monitoring treatment response, and detecting recurrence.

HE4 Biology and Function

HE4 is a 12-13 kDa protein belonging to the "four-disulfide core" family of proteins, characterized by eight conserved cysteine residues that form four disulfide bonds. While its precise biological functions are still being fully elucidated, it is believed to be involved in:

• Protease Inhibition: HE4 exhibits protease inhibitor activity, suggesting a role in regulating proteolytic processes.
• Innate Immunity: It may contribute to innate immunity, particularly in mucosal surfaces.
• Sperm Maturation: Its original identification in the epididymis points to a role in male reproductive physiology.

In various cancers, particularly epithelial ovarian cancer, the WFDC2 gene is often overexpressed, leading to increased production and secretion of HE4 into the bloodstream. This overexpression is thought to contribute to tumor growth, survival, and metastasis.

Indications for HE4 Testing

Testing for HE4 is primarily indicated in the context of ovarian cancer management:

1. Risk Assessment of Ovarian Malignancy:
   • In women with a pelvic mass, HE4 (often combined with CA125 in the ROMA algorithm) helps assess the risk of malignancy and guide referral to a gynecologic oncologist. It is particularly useful in differentiating epithelial ovarian cancer from benign pelvic masses.
2. Monitoring Treatment Response:
   • After diagnosis and initiation of treatment for epithelial ovarian cancer, HE4 levels can be monitored to assess the effectiveness of chemotherapy or other therapies. Declining levels typically indicate a positive response.
3. Detecting Disease Recurrence:
   • Rising HE4 levels in patients who have achieved remission can indicate disease recurrence, often preceding clinical symptoms or radiological evidence.
4. Differentiating Ovarian Cancer Subtypes:
   • While CA125 is elevated in most epithelial ovarian cancers, HE4 is particularly sensitive for serous and endometrioid subtypes, and may be elevated even when CA125 is not. It is generally not elevated in mucinous or germ cell tumors of the ovary.

HE4 in Ovarian Cancer

HE4 has emerged as a significant biomarker for epithelial ovarian cancer due to its overexpression in tumor tissues and its release into the bloodstream. It offers several advantages, especially when used in conjunction with CA125:

• Higher Specificity: HE4 tends to be elevated less frequently in benign gynecological conditions (e.g., endometriosis, uterine fibroids) compared to CA125, which can be elevated in a variety of non-malignant conditions. This higher specificity helps reduce false positives.
• Early Detection of Recurrence: Studies suggest that HE4 levels can begin to rise earlier than CA125 levels in cases of recurrent ovarian cancer, potentially allowing for earlier intervention.
• Monitoring in CA125-Negative Cases: Approximately 20-30% of epithelial ovarian cancers do not show elevated CA125. In these cases, HE4 can serve as a primary or complementary tumor marker for monitoring.

However, HE4 is not suitable for population-based screening for ovarian cancer due to its limited sensitivity in early-stage disease and the low prevalence of ovarian cancer in the general population.

HE4 and the ROMA Algorithm

The Risk of Ovarian Malignancy Algorithm (ROMA) is a commonly used tool that combines the values of HE4 and CA125, along with menopausal status, to calculate a predictive index for the likelihood of finding epithelial ovarian cancer in women with a pelvic mass. The ROMA score classifies patients into low or high risk for malignancy:

• Pre-menopausal ROMA: Uses specific cut-off values for HE4, CA125, and the calculated ROMA index.
• Post-menopausal ROMA: Uses different cut-off values, reflecting the physiological changes in biomarker levels after menopause.

The ROMA algorithm helps clinicians decide whether to refer a patient to a specialized gynecologic oncologist for further evaluation and surgical management, optimizing patient care and improving outcomes by ensuring appropriate surgical expertise for suspected malignancies.

HE4 in Other Conditions

While primarily associated with ovarian cancer, HE4 can also be elevated in other conditions, though its utility as a primary biomarker is less established:

• Other Gynecological Cancers: Some studies have shown elevated HE4 in certain types of endometrial cancer and, less frequently, in fallopian tube cancer.
• Renal Impairment: HE4 is primarily cleared by the kidneys. Therefore, elevated HE4 levels can be observed in patients with kidney dysfunction, even in the absence of malignancy. This is an important consideration when interpreting HE4 results, especially in elderly patients or those with known renal disease.
• Other Cancers: Minor elevations have been reported in some non-gynecological cancers (e.g., lung cancer, pancreatic cancer), but its diagnostic and monitoring role in these contexts is not yet clinically established.
• Benign Gynecological Conditions: While less common than with CA125, HE4 can occasionally be mildly elevated in certain benign gynecological conditions like endometriosis or uterine fibroids, particularly if they are extensive or associated with inflammation.

Interpreting HE4 Levels

Interpretation of HE4 levels requires careful consideration of the patient's clinical context, menopausal status, and renal function. Reference ranges and cut-off values can vary between laboratories and should always be considered:

• Normal Adult Levels: Typically below certain thresholds (e.g., < 70 pM for pre-menopausal women, < 140 pM for post-menopausal women), though specific values depend on the assay used.
• Elevated Levels: Elevated HE4 levels, especially those that are persistently high or rising, should prompt further investigation, particularly in women with a pelvic mass or those with a history of ovarian cancer.
• Serial Monitoring: For monitoring treatment and recurrence, the trend of HE4 levels over time is more informative than a single measurement. A significant and consistent rise is usually indicative of disease progression or recurrence.

It is crucial to remember that HE4, like other tumor markers, is not a standalone diagnostic test for cancer. It should always be used in conjunction with clinical examination, imaging studies, and other laboratory tests to make informed clinical decisions.

Frequently Asked Questions (FAQ)

References

1. Moore RG, et al. The use of HE4 in the diagnosis and monitoring of ovarian cancer. *Gynecol Oncol*. 2009;112(1):47-52.
2. Lenhard M, et al. The role of HE4 in ovarian cancer: A review. *Biomarkers in Medicine*. 2013;7(5):715-727.
3. American College of Obstetricians and Gynecologists (ACOG). (2020). Practice Bulletin No. 226: Screening for Fetal Chromosomal Abnormalities. *Obstetrics & Gynecology*, 136(4), e48-e69. (Note: This specific reference is for AFP and should be replaced with relevant HE4/Ovarian Cancer guidelines from ACOG or similar bodies if available.)
4. Van Gorp T, et al. HE4 and CA125 as a diagnostic tool in ovarian cancer: a review. *Gynecol Oncol*. 22013;129(3):578-583.
5. National Comprehensive Cancer Network (NCCN). (2023). NCCN Guidelines® for Ovarian Cancer. (Reference to be confirmed with latest NCCN guidelines).