Ovarian cancer markers CA-125 and HE4: uses and limitations

Ovarian cancer is often detected at an advanced stage because early symptoms are nonspecific. Persistent bloating, early fullness, abdominal or pelvic pain and changes in urination warrant medical assessment. Prognosis depends on stage, histological type, the patient’s condition and treatment; a single survival percentage cannot apply to every case.

Most adnexal masses are benign. Assessment of a suspicious mass includes history, examination, primarily ultrasound and, when indicated, other imaging and laboratory investigations. Definitive diagnosis usually requires morphological examination of tissue. Tumor markers supplement this assessment but do not replace it.

CA-125

CA-125 is a tumor-associated antigen that may rise in epithelial ovarian cancer. Normal tissues also produce it. Elevation can occur during menstruation, endometriosis, pregnancy, pelvic inflammatory disease, liver disease, fluid accumulation in the abdominal or pleural cavity and certain other malignancies.

A high CA-125 does not prove ovarian cancer, and a normal result does not exclude it. Sensitivity is particularly limited in early-stage disease and certain histological types. Once cancer is diagnosed, serial measurements may help assess treatment response and possible recurrence alongside clinical findings and imaging.

HE4

HE4 (human epididymis protein 4) was first described in epididymal epithelium; expression has also been found in other tissues. Blood HE4 may rise in some epithelial ovarian tumors. It can be used as an additional marker, including follow-up in selected patients with established epithelial ovarian cancer.

HE4 is not a universally more accurate replacement for CA-125. Test performance depends on tumor type, population, method and cutoff. Not all tumors express HE4: its usefulness is limited in mucinous and nonepithelial tumors. Other tumors and noncancerous conditions, especially impaired kidney function, can also raise HE4; age and smoking are relevant as well.

HE4 trends are assessed using the same method alongside other findings. A rise does not prove progression, and a fall does not guarantee absence of tumor. There is no universal percentage change that independently determines recurrence or treatment.

ROMA: Risk of Ovarian Malignancy Algorithm

ROMA combines CA-125, HE4 and menopausal status. With the relevant assay systems, it helps classify adult women with an existing adnexal mass for which surgery is planned as having a higher or lower likelihood of malignancy. It is an adjunct to decisions about referral and the need for gynecologic oncology expertise.

ROMA is not intended to screen healthy women, establish a diagnosis independently or determine whether surgery is needed. A low result does not exclude cancer; a high result does not confirm it. Applicability depends on the particular system’s instructions; results cannot automatically be applied to women under 18, those previously treated for cancer or those receiving chemotherapy.

Reference values and screening

HE4 and ROMA cutoffs depend on the manufacturer, analytical platform and menopausal status. Previously cited HE4 <150 pmol/L and ROMA 12.5%/14.4% values must not be used as universal normal ranges: interpret the values and limits in the current laboratory report and method instructions. Methods and algorithms from different manufacturers are not interchangeable.

CA-125, HE4 and ROMA are not reliable ovarian cancer screening tests for asymptomatic women. CA-125 and transvaginal ultrasound screening has not shown a mortality reduction in the general population. A strong family history or inherited risk warrants individualized consultation, including genetic counseling when indicated; a normal tumor marker does not cancel that risk.