Q&a attempts to provide balanced answers to those curly-yet-common questions in obstetrics and gynaecology for the broader O&G Magazine readership, including Diplomates, Trainees, medical students and other health professionals.


‘The work up of an ovarian cyst always involves an estimation of the risk of malignancy. However, how should I incorporate newer tests and algorithms into existing practice?’

The risk of malignancy index (RMI) is a well-established risk-stratification tool that may be used to identify which patients should be referred to a subspecialist gynae-oncologist to allow appropriate surgical staging or cytoreduction should a mass prove to be malignant intraoperatively.

Cancer antigen 125 (CA-125) is a component of the risk of malignancy index and is used alone as a marker for ovarian cancer. The specific shortcomings of CA-125 include its lack of sensitivity for early stage disease and poor specificity, especially in premenopausal women.

Human epididymis protein 4 (HE4) has increasingly been recognised as a marker in ovarian cancer and also endometrial cancer.

The risk of ovarian malignancy algorithm (ROMA) incorporates CA- 125 and HE4 in an attempt to overcome the shortcomings of each test. The calculation of ROMA takes into account the natural log of CA-125 and HE4 and is adjusted for menopausal status. It issues a high or low risk of malignancy based on set cutoffs.

What is HE4?

HE4 is a protein expressed in normal tissues and in specific malignancies. It is expressed in normal tissue in the lung, kidney, salivary glands, epididymis, prostate, endometrium and breast. HE4 is among the most frequently upregulated genes in epithelial ovarian cancer.

CA-125 tends to decrease with age, specifically postmenopause. HE4 tends to increase with age. The commonest cause of a false positive HE4 is renal failure where creatinine >115µmol/L. HE4 can also be increased with other benign conditions, including body cavity effusions, lung disease and liver disease, albeit less commonly than CA-125. HE4 is also elevated in other malignancies, especially lung, endometrial and endocervical adenocarcinomas.

How does HE4 and ROMA compare to CA-125 alone?

Multiple studies have evaluated the sensitivity, specificity and receiver operating characteristic for HE4, ROMA and CA-125 for identifying ovarian cancer compared to healthy controls and those with benign masses.1,3,4,5,7 CA-125 generally outperforms on sensitivity, but its main shortcoming is a lack of specificity owing to frequent elevations in benign conditions. It was hoped that by combining HE4 and CA-125 in ROMA that sensitivity and diagnostic accuracy could be improved. Published studies are conflicting as to whether there is a significant improvement with the addition of HE4 and ROMA to traditional approaches with CA-125. Jacob et al caution against the simultaneous use of CA-125, HE4 and ROMA as a routine practice as is will cause an unnecessary rise in costs for minimal benefit.

Screening asymptomatic women for ovarian cancer, by any method, is not proven and not justifiable. HE4 and ROMA, like CA-125, have no role in screening for ovarian cancer.

What is the current role for HE4 and ROMA?

Benign conditions, such as endometriosis and fibroids are frequently associated with an increase in CA-125. Multiple studies have shown that HE4 is very uncommonly elevated in healthy controls or patients with benign gynaecological conditions. Therefore, the most useful role for HE4 and ROMA in current practice is its performance following an elevated CA-125 in a premenopausal patient with a pelvic mass. Where the HE4 is not elevated, the risk of malignancy is low and more limited surgery can be safely performed.

Other potential uses of HE4?

In a large population-based study on women with endometrial cancer, Brennan et al recently demonstrated the utility of HE4 in predicting deep myometrial invasion as an aid in deciding on whether to perform lymphadenectomy. This was superior to more expensive alternatives such MRI. They were also able to determine which patients were at greatest risk of recurrence.

Bandiera et al demonstrated that high levels of HE4, ROMA and CA-125, as opposed to low levels, correlated with worsening overall survival, disease-free survival and progression-free survival in epithelial ovarian cancer.