Human Epididymis Protein 4 (HE4)
Other names: Human Epididymis Protein 4, HE4, OVARIAN CANCER MONITORING
Optimal Result:
0 - 140 pmol/L.
Clinical Takeaway
A high HE4 result does not diagnose cancer, and a normal result does not exclude it. During epithelial ovarian cancer follow-up, rising HE4 may signal progression or recurrence. Kidney dysfunction and assay changes can also affect the result. [1, 2]
At a Glance
Human epididymis protein 4 (HE4) is a serum tumor marker reported in pmol/L. HE4 helps monitor epithelial ovarian cancer, particularly when it was elevated before treatment. HE4 is not a cancer screening test. Before planned surgery for a pelvic mass, HE4 may instead be measured as part of a ROMA risk assessment. [1–4]
Understanding your HE4 result
| Result or context | What it suggests | What to check next |
|---|---|---|
| HE4 within your report's range | Cancer or recurrence remains possible. | Whether HE4 was elevated before treatment; symptoms and imaging. [1, 2] |
| HE4 above your report's range | Cancer is one possibility. Mayo also lists benign gynecologic conditions, hypertension, congestive heart failure, and kidney or liver disease. | Prior values and clinical findings; the specific benign conditions are listed below. [1] |
| HE4 rising during cancer follow-up | Progression or recurrence may need evaluation. | The overall clinical assessment and whether the measurements are comparable. [1, 2] |
| HE4 falling during treatment | Response is possible if HE4 was elevated initially. | Other evidence of response; a fall alone cannot establish remission. [1, 2] |
| HE4 ordered with CA 125 before surgery for a pelvic mass | The ROMA score combines HE4, CA 125, and menopausal status to help assess malignancy risk. HE4 alone is not that score. | The reported ROMA result, imaging, and existing surgical plan. ROMA does not determine whether surgery is needed. [3, 4] |
Which reference range applies?
HE4 upper reference limits depend on the laboratory, assay, and population. The examples below come from the named laboratories, not from a universal cancer cutoff. [1, 3]
| Laboratory | Assay | HE4 upper reference limit |
|---|---|---|
| Mayo Clinic Laboratories | ECLIA | Mayo lists ≤140 pmol/L for females; males: not applicable. [1] |
| Quest Diagnostics, ROMA panel | Abbott ARCHITECT CMIA | Quest lists ≤70 pmol/L before menopause and ≤140 pmol/L after menopause. [3] |
Use the reference range on your own laboratory report. The default range shown on this website cannot represent every assay or menopausal group. A reference limit is not a treatment target or a threshold that proves or excludes cancer.
If you remember only one thing
HE4 is a monitoring clue, not a cancer verdict. Mayo Clinic Laboratories considers a change in serum HE4 of 20% or more significant. That is Mayo's guidance, not a universal recurrence cutoff; a change still needs clinical assessment. [1]
Two people, same result
The following HE4 value is hypothetical, not a diagnostic threshold. Both people have HE4 of 180 pmol/L.
| Context | What it suggests | What to check next |
|---|---|---|
| Person A: HE4 has risen from a steady baseline; kidney function is stable. | A change warrants evaluation, but stable kidney function does not establish cancer as the cause. | Prior HE4 results, assay method, symptoms, and imaging. |
| Person B: the same HE4 value occurs while eGFR is falling. | Reduced kidney function may contribute; it does not exclude simultaneous cancer progression. | Creatinine/eGFR trend and the oncology assessment. |
Why kidney function matters
Kidney disease can raise HE4 without establishing cancer progression. Read HE4 alongside creatinine and estimated glomerular filtration rate (eGFR). Kidney dysfunction can complicate interpretation; it cannot provide an all-clear about the cancer. [1, 2]
What HE4 cannot tell you
HE4 alone cannot diagnose cancer, determine its stage, or prove remission. Mayo does not recommend HE4 monitoring for mucinous or germ cell ovarian tumors because those tumors rarely express HE4. Normal HE4 should not override concerning symptoms or imaging. [1, 2]
Common interpretation mistakes
HE4 interpretation goes wrong when a reference flag becomes a diagnosis. Other mistakes include treating a normal value as proof of remission, treating Mayo's change guidance as a universal recurrence rule, or confusing HE4 concentration with a ROMA score. ROMA assesses preoperative risk in an eligible pelvic-mass population; it is not a substitute for post-treatment monitoring. [1–4]
Questions your doctor may ask
HE4 follow-up starts with why the test was ordered. Was HE4 elevated before treatment? Is the current result part of monitoring or a preoperative ROMA panel? Does the result fit symptoms and imaging? If it does not fit, could laboratory interference be involved? Mayo describes rare interference from heterophile/HAMA, streptavidin, or ruthenium antibodies. [1]
Read together with
HE4 is interpreted with CA 125, creatinine/eGFR, imaging, treatment dates, and tumor histology. For a preoperative pelvic-mass assessment, read the actual ROMA result and its laboratory interpretation. [1–4]
Clinical pearls
HE4 values from different assay methods are not interchangeable. Mayo reports that its current method gives HE4 concentrations averaging 28% higher than its previous ELISA method. This specific comparison is not a conversion factor for other assays or individual patients. When methods change, parallel testing can help establish a new baseline. [1]
In one sentence
HE4 helps follow epithelial ovarian cancer when the marker was informative before treatment; HE4 alone cannot establish the cancer's status. [1, 2]
Bottom line
An unexpected HE4 result deserves review with the team that ordered it. Use the clinical context and your own report's range to interpret the number.
FAQ about Human Epididymis Protein 4 (HE4)
-
Does a high HE4 result mean cancer?
No. High HE4 does not prove cancer. Mayo lists mild elevations with ovarian cysts, cystadenomas, fibroids, fibromas, endometriosis, hypertension, congestive heart failure, and kidney or liver disease. An elevated result needs clinical interpretation. [1] -
What is a normal HE4 level?
HE4 reference limits vary. Mayo Clinic Laboratories lists a female upper limit of 140 pmol/L. Quest's ROMA panel lists upper limits of 70 pmol/L before menopause and 140 pmol/L after menopause. Use your own report's range. A result within that range does not exclude cancer. [1, 3] -
Can a normal HE4 result rule out ovarian cancer?
No. Some ovarian cancers do not produce elevated HE4. A normal result cannot establish remission or exclude recurrence. Symptoms, imaging, and the clinical assessment remain relevant. [1, 2] -
Can I compare HE4 results from different laboratories?
Check which HE4 assay each laboratory used. Results obtained using different methods are not interchangeable. A method change may require parallel testing to establish a new baseline. [1, 2] -
Is HE4 the same as ROMA?
No. HE4 is a measured protein concentration. ROMA combines HE4, CA 125, and menopausal status to help assess ovarian malignancy risk before planned surgery for a pelvic mass. ROMA must accompany clinical and imaging assessment; it is not a screening test or a standalone diagnosis. [3, 4]
Lab Results Explained and Tracked
What does it mean if your Human Epididymis Protein 4 (HE4) result is too high?
High HE4 does not prove cancer. During epithelial ovarian cancer follow-up, a rise may warrant evaluation for progression or recurrence. Mayo also lists mild elevations with ovarian cysts, cystadenomas, fibroids, fibromas, endometriosis, hypertension, congestive heart failure, and kidney or liver disease. Review an unexpected result with the ordering team. [1]
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What does it mean if your Human Epididymis Protein 4 (HE4) result is too low?
A low HE4 result does not identify a deficiency. During cancer monitoring, a decrease may support a treatment response when HE4 was elevated before treatment. A low or normal result does not establish remission or exclude cancer; some tumors do not produce elevated HE4. [1, 2]
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