Urine Screen as Part of Triple Test Improves ID of Adrenal Cancer

Nancy A. Melville

July 29, 2020

A strategy that includes a urine steroid test along with imaging characteristics and tumor size criteria can significantly improve the challenging diagnosis of adrenocortical cancer, helping to avoid unnecessary, and often unsuccessful, further imaging and even surgery, new research shows.

"A triple test strategy of tumor diameter, imaging characteristics, and urine steroid metabolomics improves detection of adrenocortical carcinoma, which could shorten time to surgery for patients with...carcinoma and help to avoid unnecessary surgery in patients with benign tumors," say the authors in research published online July 23 in The Lancet Diabetes & Endocrinology.

The triple-test strategy can be expected to make its way into international guidelines, notes joint lead author Irina Bancos, MD, an associate professor of endocrinology at the Mayo Clinic, Rochester, Minnesota, in a press statement issued by the University of Birmingham, UK, which also had a number of researchers involved in the study.

"The findings of this study will feed into the next international guidelines on the management of adrenal tumors and the implementation of the new test will hopefully improve the overall outlook for patients diagnosed with adrenal tumors," Bancos emphasized.

More Imaging Has Led to Detection of More Adrenal Tumors

Advances in CT and MRI imaging have not only increased the ability to detect adrenal incidentalomas, which are now picked up on about 5% of scans, but the widespread use of imaging has compounded the prevalence of such findings, particularly in older people.

Adrenocortical carcinomas only represent about 2% to 12% of adrenal incidentalomas, but the prognosis is very poor, and early detection and surgery can improve outcomes, so findings of any adrenal tumor typically trigger additional multimodal imaging to rule out malignancy.

But evidence is lacking on the accuracy of imaging in determining whether such masses are truly cancerous, or benign, and such procedures add costs, as well as expose patients to radiation that may ultimately have no benefit.

However, a previous proof-of-concept study from the same authors did show that the presence of excess adrenal steroid hormones in the urine is a key indicator of adrenal tumors, and other research has supported the findings.

All Three Tests Together Give Best Predictive Value: EURINE-ACT

To further validate this work, the authors conducted the EURINE-ACT trial, a prospective 14-center study that is the first of its kind to evaluate the efficacy of a screening strategy for adrenocortical carcinoma that combines urine steroid profiling with tumor size and imaging characteristics.

The study of 2017 participants with newly diagnosed adrenal masses, recruited from January 2011 to July 2016 from specialist centers in 11 different countries, assessed the diagnostic accuracy of three components: maximum tumor diameter (≥ 4 cm vs < 4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of adrenocortical carcinoma), separately and in combination.

Of the patients, 98 (4.9%) had adrenocortical carcinoma confirmed clinically, histopathologically, or biochemically.

Tumors with diameters of 4 cm or larger were identified in 488 patients (24.2%) and were observed in the vast majority of patients with adrenocortical carcinoma (96 of 98), for a positive predictive value (PPV) of 19.7%.

Likewise, the PPV for imaging characteristics was 19.7%. However, increasing the unenhanced CT tumor attenuation threshold to 20 Hounsfield units (HU) from the recommended 10 HU increased specificity for adrenocortical carcinoma (80.0% vs 64.0%) while maintaining sensitivity (99.0% vs 100.0%).

Comparatively, a urine steroid metabolomics result suggesting a high risk of adrenocortical carcinoma had a PPV of 34.6%.

A total of 106 patients (5.3%) met the criteria for all three measures, and the PPV for all three was 76.4%.

Using the criteria, 70 patients (3.5%) were classified as being at moderate risk of adrenocortical carcinoma and 1841 (91.3%) at low risk, for a negative predictive value (NPV) of 99.7%.

"Use of radiation-free, noninvasive urine steroid metabolomics has a higher PPV than two standard imaging tests, and best performance was seen with the combination of all three tests," the authors state.

Limit Urine Test; Imaging Suggestive of Cancer in Those With Larger Tumors

They note that the use of the combined diagnostic strategy would have led to additional imaging in only 488 (24.2%) of the study's 2017 patients, compared to the 2737 scans that were actually conducted before reaching a diagnostic decision.

"Implementation of urine steroid metabolomics in the routine diagnostic assessment of newly discovered adrenal masses could reduce the number of imaging procedures required to diagnose adrenocortical carcinoma and avoid unnecessary surgery of benign adrenal tumors, potentially yielding beneficial effects with respect to patient burden and health care costs," they stress.

And regarding imaging parameters, "we also showed that using a cutoff of 20 HU for unenhanced CT tumor attenuation increases the accuracy of imaging characteristic assessment for exclusion of adrenocortical carcinoma compared with the currently recommended cutoff of 10 HU, which has immediate implications for clinical practice," they emphasize.

In an accompanying editorial, Adina F. Turcu, MD, of the Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, and Axel K. Walch, MD, of the Helmholtz Zentrum München–German Research Centre for Environmental Health, agree. "The introduction of urine steroid metabolomics into routine clinical practice would provide major advantages," they state.

However, they point out that although the overall negative predictive value of the test was excellent, the specificity was weak.

"Thus, urine steroid metabolomics should be limited to patients who have adrenal nodules larger than 4 cm and have qualitative imaging characteristics suggestive of malignancy," say Turcu and Walch.

The EURINE-ACT study results suggest this subgroup would only represent roughly 12% of all patients with adrenal incidentalomas, they add.

Issues that remain to be addressed with regard to the implementation of the screening strategy include how to best respond to patients that are classified as having intermediate or moderate risk of malignancy, and whether the diagnostic value of steroid metabolomics could be refined by adding analytes or parameters, the editorialists conclude.

The study was funded by the European Commission, UK Medical Research Council, Wellcome Trust, UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Lancet Diab Endocrin. Published July 23, 2020. Full text, Editorial

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