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

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

In: The Lancet Diabetes and Endocrinology, Vol. 8, No. 9, 09.2020, p. 773-781.

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@article{6d693bb9dd48492db4766c5cd6205504,
title = "Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study",
abstract = "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.",
keywords = "Adrenal Gland Neoplasms/diagnosis, Adult, Aged, Diagnosis, Europe/epidemiology, Female, Follow-Up Studies, Humans, Incidental Findings, Male, Metabolomics/methods, Middle Aged, Prospective Studies, Steroids/urine, Differential",
author = "{ENSAT EURINE-ACT Investigators} and Irina Bancos and Angela Taylor and Vasileios Chortis and Alice Sitch and Carl Jenkinson and Caroline Davidge-Pitts and Katharina Lang and Stylianos Tsagarakis and Magdalena Macech and Anna Riester and Timo Deutschbein and Ivana Pupovac and Tina Kienitz and Alessandro Prete and Thomas Papathomas and Lorna Gilligan and Cristian Bancos and Giuseppe Reimondo and Magalie Haissaguerre and Ljiljana Marina and Marianne Grytaas and Ahmed Sajwani and Katharina Langton and Hannah Ivison and Cedric Shackleton and Dana Erickson and Miriam Asia and Sotiria Palimeri and Agnieszka Kondracka and Ariadni Spyroglou and Cristina Ronchi and Bojana Simunov and Danae Delivanis and Sutcliffe, {Robert Peter} and Ioanna Tsirou and Tomasz Bednarczuk and Martin Reincke and Stephanie Burger-Stritt and Richard Feelders and Letizia Canu and Harm Haak and Graeme Eisenhofer and Dennedy, {Michael Conall} and Grethe Ueland and Miomira Ivovic and Antoine Tabarin and Massimo Terzolo and Marcus Quinkler and Darko Kastelan and Martin Fassnacht and Felix Beuschlein and Urszula Ambroziak and Dimitra Vassiliadi and Michael O'reilly and Young, {William F} and Michael Biehl and Jon Deeks and Wiebke Arlt",
note = "Copyright {\textcopyright} 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. ",
year = "2020",
month = sep,
doi = "10.1016/S2213-8587(20)30218-7",
language = "English",
volume = "8",
pages = "773--781",
journal = "The Lancet Diabetes and Endocrinology",
issn = "2213-8587",
publisher = "Elsevier",
number = "9",

}

RIS

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 - ENSAT EURINE-ACT Investigators

AU - Bancos, Irina

AU - Taylor, Angela

AU - Chortis, Vasileios

AU - Sitch, Alice

AU - Jenkinson, Carl

AU - Davidge-Pitts, Caroline

AU - Lang, Katharina

AU - Tsagarakis, Stylianos

AU - Macech, Magdalena

AU - Riester, Anna

AU - Deutschbein, Timo

AU - Pupovac, Ivana

AU - Kienitz, Tina

AU - Prete, Alessandro

AU - Papathomas, Thomas

AU - Gilligan, Lorna

AU - Bancos, Cristian

AU - Reimondo, Giuseppe

AU - Haissaguerre, Magalie

AU - Marina, Ljiljana

AU - Grytaas, Marianne

AU - Sajwani, Ahmed

AU - Langton, Katharina

AU - Ivison, Hannah

AU - Shackleton, Cedric

AU - Erickson, Dana

AU - Asia, Miriam

AU - Palimeri, Sotiria

AU - Kondracka, Agnieszka

AU - Spyroglou, Ariadni

AU - Ronchi, Cristina

AU - Simunov, Bojana

AU - Delivanis, Danae

AU - Sutcliffe, Robert Peter

AU - Tsirou, Ioanna

AU - Bednarczuk, Tomasz

AU - Reincke, Martin

AU - Burger-Stritt, Stephanie

AU - Feelders, Richard

AU - Canu, Letizia

AU - Haak, Harm

AU - Eisenhofer, Graeme

AU - Dennedy, Michael Conall

AU - Ueland, Grethe

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

AU - Young, William F

AU - Biehl, Michael

AU - Deeks, Jon

AU - Arlt, Wiebke

N1 - Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

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 - Adrenal Gland Neoplasms/diagnosis

KW - Adult

KW - Aged

KW - Diagnosis

KW - Europe/epidemiology

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Incidental Findings

KW - Male

KW - Metabolomics/methods

KW - Middle Aged

KW - Prospective Studies

KW - Steroids/urine

KW - Differential

UR - http://www.scopus.com/inward/record.url?scp=85089288930&partnerID=8YFLogxK

U2 - 10.1016/S2213-8587(20)30218-7

DO - 10.1016/S2213-8587(20)30218-7

M3 - Article

C2 - 32711725

VL - 8

SP - 773

EP - 781

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

SN - 2213-8587

IS - 9

ER -