Home Ovarian and Gynecologic Cancer Biomarkers HE4 Test for Ovarian Cancer: High Levels, Risk Assessment, ROMA Score, and...

HE4 Test for Ovarian Cancer: High Levels, Risk Assessment, ROMA Score, and Meaning

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Learn what an HE4 test measures, what high HE4 levels can mean, how kidney function affects results, and how HE4 and CA-125 are used in the ROMA ovarian cancer risk score.

Human epididymis protein 4, usually shortened to HE4, is a blood biomarker that can help estimate the chance that an ovarian or adnexal mass is cancerous. It is most useful when interpreted with imaging, clinical findings, menopausal status, and often CA-125 rather than as a stand-alone cancer test. HE4 is also one of the two laboratory values used in the Risk of Ovarian Malignancy Algorithm, or ROMA. A high HE4 result can raise concern for epithelial ovarian cancer, but it does not prove cancer is present. Kidney disease, age, smoking, and some non-ovarian conditions can also increase HE4. Just as important, some ovarian cancers produce little or no HE4. For these reasons, the result is best viewed as one piece of a larger risk assessment that helps clinicians decide whether a person with a pelvic mass may benefit from evaluation by a gynecologic oncologist.

  • HE4 measures a protein that is often elevated in epithelial ovarian cancer, especially some serous and endometrioid tumors.
  • A high HE4 result is not a diagnosis of ovarian cancer; kidney dysfunction, older age, smoking, and other factors can raise the level.
  • ROMA combines HE4, CA-125, and menopausal status to classify risk in people who already have an adnexal or pelvic mass.
  • HE4 reference limits vary by assay and menopausal status, so the laboratory’s own cutoff should be used.
  • HE4 is not recommended as a general population screening test for ovarian cancer in people without a suspicious mass or other clinical indication.

Table of Contents

What the HE4 Test Measures

HE4 is a protein encoded by the WFDC2 gene. Small amounts are produced in several normal tissues, but many epithelial ovarian cancers produce larger amounts. A laboratory measures HE4 in a blood sample, most often in picomoles per liter, or pmol/L.

The test is different from a biopsy. A biopsy looks directly at tumor tissue, while HE4 measures a circulating protein that may be released into the bloodstream. Because many noncancerous processes can affect blood biomarkers, HE4 cannot identify a tumor type or stage by itself.

HE4 is mainly associated with epithelial ovarian cancer, the most common broad category of ovarian malignancy. It tends to perform better for some serous and endometrioid cancers than for mucinous tumors. It is not a dependable marker for every ovarian cancer subtype. For example, germ cell tumors and sex cord-stromal tumors are usually evaluated with other markers. A person being assessed for a possible ovarian germ cell tumor may instead have tests such as AFP or beta-hCG, depending on the clinical picture.

HE4 also differs from a hereditary cancer test. It does not tell whether a person inherited a pathogenic BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, or Lynch syndrome-related variant. Once ovarian cancer is diagnosed, genetic and tumor testing may be important for treatment and family risk assessment, but those questions require separate tests.

One reason HE4 attracted clinical interest is that it may be more specific than CA-125 in some settings. CA-125 can increase with endometriosis, menstruation, fibroids, pelvic inflammation, pregnancy, liver disease, and other benign conditions. HE4 is often less affected by several of these gynecologic causes. That does not make HE4 “better” in every patient. Its greatest value comes from using it in the right population and interpreting it with the rest of the workup.

When HE4 Testing Is Used

HE4 is most commonly used when a person has an adnexal mass, meaning a mass near the uterus that may arise from the ovary, fallopian tube, or surrounding structures. The goal is not to confirm cancer from the blood test. The goal is to improve preoperative risk assessment.

A clinician may order HE4 when ultrasound or other imaging has found a pelvic mass and the treatment team is deciding how concerning that mass appears. In this setting, the question is often practical: should surgery be performed by a general gynecologist, or is the chance of malignancy high enough that referral to a gynecologic oncologist would be safer?

The test may be ordered by itself, with CA-125, or as part of a laboratory calculation such as ROMA. The exact approach depends on local practice, the test platform, and the patient’s age and menopausal status.

HE4 is not a stand-alone screening test for people at average risk who do not have a mass or symptoms. Ovarian cancer screening is difficult because no blood marker has shown the combination of sensitivity, specificity, and outcome benefit needed for routine population screening. An abnormal HE4 value in someone without a defined clinical indication can lead to anxiety and unnecessary imaging or procedures.

HE4 can also be measured after an ovarian cancer diagnosis in some patients. If the tumor produced HE4 before treatment, falling levels may parallel response and rising levels can sometimes accompany recurrent disease. However, follow-up strategies vary, and HE4 is not universally used as the main surveillance marker. CA-125 remains more established for many epithelial ovarian cancers.

No special fasting is usually required for an HE4 blood test. The person having the test should still tell the clinician about kidney disease, smoking, medications, pregnancy status, and whether the test is being compared with a previous result from another laboratory. Changing assay platforms can complicate trend interpretation.

Understanding HE4 Results

The most important rule is simple: use the reference range printed by the laboratory that performed the test. HE4 assays are not perfectly interchangeable, and cutoffs can differ by manufacturer, population, and menopausal status.

Many laboratories report HE4 in pmol/L and provide a reference limit rather than a broad “normal range.” Premenopausal and postmenopausal patients may have different cutoffs. Some published studies have used thresholds in the neighborhood of roughly 70 pmol/L for premenopausal patients and 140 pmol/L for postmenopausal patients, but these values should not be substituted for the laboratory’s validated threshold.

A result above the reference limit means the blood concentration is higher than expected for that assay. It does not tell how large a tumor is, whether cancer has spread, or whether surgery is required. The meaning depends heavily on pretest probability.

For example, a modestly high HE4 value in an older smoker with reduced kidney function and a simple-appearing ovarian cyst may have a very different meaning from the same value in a patient with a complex solid-cystic mass, ascites, and a high CA-125.

A very high HE4 result can increase concern, especially when imaging is suspicious and CA-125 is also elevated. Even then, pathology from surgery or biopsy is generally required for a definitive diagnosis.

A “normal” HE4 result also does not exclude ovarian cancer. No tumor marker detects every case. Some early-stage cancers, mucinous cancers, borderline tumors, and non-epithelial ovarian tumors may produce little HE4. This is why clinicians do not use a normal HE4 value to override clearly concerning imaging or symptoms.

When serial measurements are being followed, the trend can be more informative than a single number. A consistent rise on the same assay may deserve attention, while a one-time small fluctuation can reflect biological and analytical variation. Changes should be interpreted together with symptoms, examination, imaging, kidney function, and other tumor markers.

How HE4 Is Used in the ROMA Score

ROMA stands for Risk of Ovarian Malignancy Algorithm. It combines three pieces of information: HE4, CA-125, and whether the patient is premenopausal or postmenopausal. The laboratory or test platform then calculates a percentage-like risk score and classifies the patient into a lower-risk or higher-risk category.

ROMA is designed for risk stratification in people with an adnexal mass who are being evaluated for surgery. It is not intended to tell the general population who does or does not have ovarian cancer.

The exact mathematical formula and high-risk cutoff depend on the assay system. For that reason, patients should not calculate ROMA from internet formulas using values obtained on unrelated laboratory platforms. The report should state the assay-specific interpretation.

A higher-risk ROMA result suggests that the combination of HE4, CA-125, and menopausal status resembles patterns seen more often in epithelial ovarian malignancy. It can support referral to a specialist, but it does not replace ultrasound morphology, clinical judgment, or pathology.

A lower-risk ROMA result means the biomarker pattern is less concerning, but malignancy remains possible. Borderline tumors, early-stage disease, and histologic subtypes that do not secrete much HE4 or CA-125 can be missed.

ROMA is one of several approaches to adnexal mass triage. Ultrasound-based systems and models can also perform well. Some centers use structured ultrasound assessment, O-RADS categories, the IOTA ADNEX model, the Risk of Malignancy Index, or multianalyte blood tests. A clinician may also consider OVA1 or Overa in specific preoperative settings.

No score should be interpreted in isolation. The safest question is not “Is the ROMA score positive?” but “How does this result change the overall estimated risk given the imaging, age, symptoms, examination, and planned surgery?”

False-Positive and False-Negative Results

HE4 is useful partly because it can be more specific than CA-125 for ovarian malignancy in women with pelvic masses. Still, false-positive and false-negative results occur.

Kidney function can have a major effect

Reduced renal clearance is one of the most important noncancer causes of high HE4. Chronic kidney disease can raise HE4 substantially, sometimes into a range that would otherwise appear very concerning. An elevated result should therefore be interpreted with creatinine, estimated glomerular filtration rate, and the person’s renal history when appropriate.

Age and smoking matter

HE4 tends to rise with age, and smokers may have higher concentrations than nonsmokers. These effects can reduce specificity if the result is interpreted without clinical context.

Other cancers and medical conditions can raise HE4

HE4 is not unique to ovarian tissue. Elevated values have been reported in other malignancies and some nonmalignant conditions. A high result does not establish where a cancer came from.

Some ovarian cancers do not produce much HE4

A normal result can occur despite malignancy. This is particularly relevant for histologies in which HE4 expression is less reliable. The marker should never be used to dismiss a mass with high-risk imaging features.

Assay differences can change the number

Reference intervals, antibodies, calibration, and algorithms differ between manufacturers. If a patient is being monitored over time, using the same assay and laboratory when practical improves comparability.

These limitations explain why an ovarian cancer biomarker panel is not simply a collection of independent yes-or-no cancer tests. Each marker answers a narrower question and works best in a defined clinical setting.

HE4, CA-125, and Imaging

HE4 and CA-125 provide biochemical information, while ultrasound and other imaging provide structural information. In practice, these sources of information complement one another.

Transvaginal ultrasound can show whether a mass is simple or complex, cystic or solid, unilateral or bilateral, smooth or irregular, and whether features such as papillary projections, vascularity, nodularity, or ascites are present. These findings often have more immediate diagnostic value than any single tumor marker.

CA-125 is more sensitive for many epithelial ovarian cancers but is less specific because benign gynecologic and inflammatory conditions can raise it. HE4 is often more specific, particularly in premenopausal patients with benign conditions such as endometriosis. Combining the two can improve classification in selected patients, which is the rationale behind ROMA.

However, “combined” does not always mean “more accurate in every patient.” Studies comparing HE4, CA-125, ROMA, ultrasound systems, and other models have found different performance depending on the population, cancer prevalence, menopausal status, tumor subtype, and chosen cutoff. A model developed in a specialty referral center may not perform identically in a primary care population.

This is also why screening and triage should not be confused. In a surgical population with a known mass, the prevalence of cancer is much higher than in the general population. A test can have useful positive predictive value in the first setting and poor positive predictive value in the second.

If imaging strongly suggests malignancy, referral should not be delayed just because HE4 is normal. Conversely, if the imaging is convincingly benign and HE4 is only mildly elevated in a patient with kidney disease, the clinician may first investigate the noncancer explanation rather than treating the blood test as proof of malignancy.

What Happens After HE4 Testing

The next step depends on why HE4 was ordered and how the result fits the rest of the evaluation.

For a patient with an adnexal mass, a clinician may review the ultrasound, menopausal status, CA-125, HE4, ROMA classification, symptoms, family history, and surgical needs. If the overall risk is high, referral to a gynecologic oncologist is often appropriate. Specialist involvement matters because ovarian cancer surgery may require comprehensive staging and cytoreduction at the initial operation.

If the risk appears low, the plan might involve repeat imaging, observation, or surgery with a general gynecologist, depending on symptoms, mass size, growth, and patient preferences. A low-risk marker result does not automatically mean “do nothing.” Some benign-appearing masses still require treatment because of pain, torsion risk, size, or uncertainty.

If ovarian cancer is diagnosed, the focus shifts from HE4-based risk classification to tumor type, stage, molecular features, and treatment planning. Many epithelial ovarian cancers are evaluated for hereditary risk with BRCA1 and BRCA2 testing, and high-grade serous or endometrioid cancers may also undergo HRD testing to help inform PARP inhibitor decisions.

For patients whose HE4 was elevated at diagnosis, the oncology team may choose to follow it during treatment or surveillance, usually alongside more established clinical measures. A fall after surgery or chemotherapy can be reassuring when it matches the clinical response. A persistent or rising value deserves interpretation rather than an automatic conclusion that cancer has returned.

Patients should contact their care team promptly for new or worsening abdominal swelling, persistent pelvic or abdominal pain, early satiety, vomiting, unexplained weight loss, shortness of breath, or rapidly increasing abdominal size. These symptoms do not necessarily mean ovarian cancer, but they warrant clinical assessment regardless of a previous HE4 result.

References

Disclaimer

HE4 results should be interpreted by a clinician together with imaging, kidney function, menopausal status, CA-125, and the reason the test was ordered. An abnormal HE4 or ROMA result does not diagnose ovarian cancer, and a normal result does not exclude it. Seek medical evaluation for a persistent or concerning pelvic mass or symptoms regardless of the blood test result.

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