Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study

Irina Bancos, Angela E. Taylor, Vasileios Chortis, Alice J. Sitch, Carl Jenkinson, Caroline J. Davidge-Pitts, Katharina Lang, Stylianos Tsagarakis, Magdalena Macech, Anna Riester, Timo Deutschbein, Ivana D. Pupovac, Tina Kienitz, Alessandro Prete, Thomas G. Papathomas, Lorna C. Gilligan, Cristian Bancos, Giuseppe Reimondo, Magalie Haissaguerre, Ljiljana MarinaMarianne A. Grytaas, Ahmed Sajwani, Katharina Langton, Hannah E. Ivison, Cedric H.L. Shackleton, Dana Erickson, Miriam Asia, Sotiria Palimeri, Agnieszka Kondracka, Ariadni Spyroglou, Cristina L. Ronchi, Bojana Simunov, Danae A. Delivanis, Robert P. Sutcliffe, Ioanna Tsirou, Tomasz Bednarczuk, Martin Reincke, Stephanie Burger-Stritt, Richard A. Feelders, Letizia Canu, Harm R. Haak, Graeme Eisenhofer, M. Conall Dennedy, Grethe A. Ueland, Miomira Ivovic, Antoine Tabarin, Massimo Terzolo, Marcus Quinkler, Darko Kastelan, Martin Fassnacht, Felix Beuschlein, Urszula Ambroziak, Dimitra A. Vassiliadi, Michael W. O'Reilly, William F. Young, Michael Biehl, Jonathan J. Deeks, Wiebke Arlt, Stephan Glöckner, Richard O. Sinnott, Anthony Stell, Maria C. Fragoso, Ivana D. Pupovac, Sarah Cazenave, Jérôme Bertherat, Rossella Libé, Christina Brugger, Stefanie Hahner, Matthias Kroiss, Cristina L. Ronchi, Dimitra A. Vassiliadi, Vittoria Basile, Elisa Ingargiola, Massimo Mannelli, Hester Ettaieb, Harm R. Haak, Thomas M. Kerkhofs, Richard A. Feelders, Johannes Hofland, Leo J. Hofland, Marianne A. Grytaas, Eystein S. Husebye, Grethe A. Ueland, Malgorzata Zawierucha, Isabel Paiva, M. Conall Dennedy, Mark Sherlock, Rachel K. Crowley, R. Jonathan, Alice J. Sitch, Lorna C. Giligan, Beverly A. Hughes, Hannah E. Ivison, Konstantinos Manolopoulos, Donna M. O'Neil, Michael W. O'Reilly, Thomas G. Papathomas, Cedric H.L. Shackleton, Angela E. Taylor, Robert P. Sutcliffe, Peter Guest, Kassiani Skordilis, Alice Chang, Caroline J. Davidge-Pitts, Danae A. Delivanis, Neena Natt, Todd B. Nippoldt, Melinda Thomas, William F. Young

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Background: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. Methods: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU. Findings: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2–23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9–82·0] vs 64·0% [61·4–66.4]) while maintaining sensitivity (99·0% [94·4–100·0] vs 100·0% [96·3–100·0]; PPV 19·7%, 16·3–23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6–41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2–84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4–100·0). Interpretation: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours. Funding: European Commission, UK Medical Research Council, Wellcome Trust, and 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.

Original languageEnglish (US)
Pages (from-to)773-781
Number of pages9
JournalThe Lancet Diabetes and Endocrinology
Issue number9
StatePublished - Sep 2020

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


Dive into the research topics of 'Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study'. Together they form a unique fingerprint.

Cite this