TY - JOUR
T1 - Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study
T2 - A prospective test validation study
AU - Bancos, Irina
AU - Taylor, Angela E.
AU - Chortis, Vasileios
AU - Sitch, Alice J.
AU - Jenkinson, Carl
AU - Davidge-Pitts, Caroline J.
AU - Lang, Katharina
AU - Tsagarakis, Stylianos
AU - Macech, Magdalena
AU - Riester, Anna
AU - Deutschbein, Timo
AU - Pupovac, Ivana D.
AU - Kienitz, Tina
AU - Prete, Alessandro
AU - Papathomas, Thomas G.
AU - Gilligan, Lorna C.
AU - Bancos, Cristian
AU - Reimondo, Giuseppe
AU - Haissaguerre, Magalie
AU - Marina, Ljiljana
AU - Grytaas, Marianne A.
AU - Sajwani, Ahmed
AU - Langton, Katharina
AU - Ivison, Hannah E.
AU - Shackleton, Cedric H. L.
AU - Erickson, Dana
AU - Asia, Miriam
AU - Palimeri, Sotiria
AU - Kondracka, Agnieszka
AU - Spyroglou, Ariadni
AU - Ronchi, Cristina L.
AU - Simunov, Bojana
AU - Delivanis, Danae A.
AU - Sutcliffe, Robert P.
AU - Tsirou, Ioanna
AU - Bednarczuk, Tomasz
AU - Reincke, Martin
AU - Burger-Stritt, Stephanie
AU - Feelders, Richard A.
AU - Canu, Letizia
AU - Haak, Harm R.
AU - Eisenhofer, Graeme
AU - Dennedy, M. Conall
AU - Ueland, Grethe A.
AU - Ivovic, Miomira
AU - Tabarin, Antoine
AU - Terzolo, Massimo
AU - Quinkler, Marcus
AU - Kastelan, Darko
AU - Fassnacht, Martin
AU - Beuschlein, Felix
AU - Ambroziak, Urszula
AU - Vassiliadi, Dimitra
AU - O'Reilly, Michael W
AU - Young, William F
AU - Biehl, Michael
AU - Deeks, Jonathan J.
AU - Arlt, Wiebke
AU - ENSAT EURINE-ACT Investigators
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
KW - MASS-SPECTROMETRY
KW - SOCIETY
KW - PREVALENCE
KW - MALIGNANCY
U2 - 10.1016/S2213-8587(20)30218-7
DO - 10.1016/S2213-8587(20)30218-7
M3 - Article
C2 - 32711725
SN - 2213-8587
VL - 8
SP - 773
EP - 781
JO - Lancet Diabetes & Endocrinology
JF - Lancet Diabetes & Endocrinology
IS - 9
ER -