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 Marina; Marianne 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; ENSAT EURINE-ACT Investigators; Wiebke Arlt

doi:10.1016/S2213-8587(20)30218-7

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, ENSAT EURINE-ACT Investigators, Wiebke Arlt^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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

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.

Original language	English
Pages (from-to)	773-781
Number of pages	9
Journal	The Lancet Diabetes & Endocrinology
Volume	8
Issue number	9
DOIs	https://doi.org/10.1016/S2213-8587(20)30218-7
Publication status	Published - Sept 2020

Keywords

MALIGNANCY
MASS-SPECTROMETRY
PREVALENCE
SOCIETY

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Bancos, I., Taylor, A. E., Chortis, V., Sitch, A. J., Jenkinson, C., Davidge-Pitts, C. J., Lang, K., Tsagarakis, S., Macech, M., Riester, A., Deutschbein, T., Pupovac, I. D., Kienitz, T., Prete, A., Papathomas, T. G., Gilligan, L. C., Bancos, C., Reimondo, G., Haissaguerre, M., ... Arlt, W. (2020). Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study. The Lancet Diabetes & Endocrinology, 8(9), 773-781. https://doi.org/10.1016/S2213-8587(20)30218-7

@article{8b4c491c18674a0ab4de762c39585613,

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 vsFindings 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.",

keywords = "MALIGNANCY, MASS-SPECTROMETRY, PREVALENCE, SOCIETY",

author = "Irina Bancos and Taylor, {Angela E.} and Vasileios Chortis and Sitch, {Alice J.} and Carl Jenkinson and Davidge-Pitts, {Caroline J.} and Katharina Lang and Stylianos Tsagarakis and Magdalena Macech and Anna Riester and Timo Deutschbein and Pupovac, {Ivana D.} and Tina Kienitz and Alessandro Prete and Papathomas, {Thomas G.} and Gilligan, {Lorna C.} and Cristian Bancos and Giuseppe Reimondo and Magalie Haissaguerre and Ljiljana Marina and Grytaas, {Marianne A.} and Ahmed Sajwani and Katharina Langton and Ivison, {Hannah E.} and Shackleton, {Cedric H. L.} and Dana Erickson and Miriam Asia and Sotiria Palimeri and Agnieszka Kondracka and Ariadni Spyroglou and Ronchi, {Cristina L.} and Bojana Simunov and Delivanis, {Danae A.} and Sutcliffe, {Robert P.} and Ioanna Tsirou and Tomasz Bednarczuk and Martin Reincke and Stephanie Burger-Stritt and Feelders, {Richard A.} and Letizia Canu and Haak, {Harm R.} and Graeme Eisenhofer and Dennedy, {M. Conall} and Ueland, {Grethe A.} and Miomira Ivovic and Antoine Tabarin and Massimo Terzolo and Marcus Quinkler and Darko Kastelan and Martin Fassnacht and {ENSAT EURINE-ACT Investigators} and Wiebke Arlt",

note = "Funding Information: This work was supported by the European Commission under the Seventh Framework Programme (FP7/2007–13, grant agreement 259735, ENSAT-CANCER, awarded to GE, MF, FB, and WA), the UK Medical Research Council UK (Strategic Biomarker Grant G0801473 awarded to WA), the Claire Khan Trust Fund at University Hospitals Birmingham Charities (project grant to WA), the Mayo Clinic Foundation for Medical Education and Research (Mayo Scholarship awarded to IB), and the Wellcome Trust (Clinical Research Training Fellowship WT101671 awarded to VC). This research was also partly supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health (NIH), under award K23DK121888 (IB). JJD is a National Institute for Health Research (NIHR) Senior Investigator and AJS, JJD, and WA receive support from the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (BRC-1215-20009). The views expressed are those of the authors and not necessarily those of the NIHR, the UK Department of Health and Social Care, or the NIH. Funding Information: This work was supported by the European Commission under the Seventh Framework Programme (FP7/2007–13, grant agreement 259735, ENSAT-CANCER, awarded to GE, MF, FB, and WA), the UK Medical Research Council UK (Strategic Biomarker Grant G0801473 awarded to WA), the Claire Khan Trust Fund at University Hospitals Birmingham Charities (project grant to WA), the Mayo Clinic Foundation for Medical Education and Research (Mayo Scholarship awarded to IB), and the Wellcome Trust (Clinical Research Training Fellowship WT101671 awarded to VC). This research was also partly supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health (NIH), under award K23DK121888 (IB). JJD is a National Institute for Health Research (NIHR) Senior Investigator and AJS, JJD, and WA receive support from the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (BRC-1215-20009). The views expressed are those of the authors and not necessarily those of the NIHR, the UK Department of Health and Social Care, or the NIH. Publisher 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 & Endocrinology",

issn = "2213-8587",

publisher = "Elsevier Science",

number = "9",

}

Bancos, I, Taylor, AE, Chortis, V, Sitch, AJ, Jenkinson, C, Davidge-Pitts, CJ, Lang, K, Tsagarakis, S, Macech, M, Riester, A, Deutschbein, T, Pupovac, ID, Kienitz, T, Prete, A, Papathomas, TG, Gilligan, LC, Bancos, C, Reimondo, G, Haissaguerre, M, Marina, L, Grytaas, MA, Sajwani, A, Langton, K, Ivison, HE, Shackleton, CHL, Erickson, D, Asia, M, Palimeri, S, Kondracka, A, Spyroglou, A, Ronchi, CL, Simunov, B, Delivanis, DA, Sutcliffe, RP, Tsirou, I, Bednarczuk, T, Reincke, M, Burger-Stritt, S, Feelders, RA, Canu, L, Haak, HR, Eisenhofer, G, Dennedy, MC, Ueland, GA, Ivovic, M, Tabarin, A, Terzolo, M, Quinkler, M, Kastelan, D, Fassnacht, M, ENSAT EURINE-ACT Investigators & Arlt, W 2020, 'Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study', The Lancet Diabetes & Endocrinology, vol. 8, no. 9, pp. 773-781. https://doi.org/10.1016/S2213-8587(20)30218-7

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 - ENSAT EURINE-ACT Investigators

AU - Arlt, Wiebke

N1 - Funding Information: This work was supported by the European Commission under the Seventh Framework Programme (FP7/2007–13, grant agreement 259735, ENSAT-CANCER, awarded to GE, MF, FB, and WA), the UK Medical Research Council UK (Strategic Biomarker Grant G0801473 awarded to WA), the Claire Khan Trust Fund at University Hospitals Birmingham Charities (project grant to WA), the Mayo Clinic Foundation for Medical Education and Research (Mayo Scholarship awarded to IB), and the Wellcome Trust (Clinical Research Training Fellowship WT101671 awarded to VC). This research was also partly supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health (NIH), under award K23DK121888 (IB). JJD is a National Institute for Health Research (NIHR) Senior Investigator and AJS, JJD, and WA receive support from the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (BRC-1215-20009). The views expressed are those of the authors and not necessarily those of the NIHR, the UK Department of Health and Social Care, or the NIH. Funding Information: This work was supported by the European Commission under the Seventh Framework Programme (FP7/2007–13, grant agreement 259735, ENSAT-CANCER, awarded to GE, MF, FB, and WA), the UK Medical Research Council UK (Strategic Biomarker Grant G0801473 awarded to WA), the Claire Khan Trust Fund at University Hospitals Birmingham Charities (project grant to WA), the Mayo Clinic Foundation for Medical Education and Research (Mayo Scholarship awarded to IB), and the Wellcome Trust (Clinical Research Training Fellowship WT101671 awarded to VC). This research was also partly supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health (NIH), under award K23DK121888 (IB). JJD is a National Institute for Health Research (NIHR) Senior Investigator and AJS, JJD, and WA receive support from the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (BRC-1215-20009). The views expressed are those of the authors and not necessarily those of the NIHR, the UK Department of Health and Social Care, or the NIH. Publisher 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 vsFindings 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.

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 vsFindings 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.

KW - MALIGNANCY

KW - MASS-SPECTROMETRY

KW - PREVALENCE

KW - SOCIETY

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

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

M3 - Article

SN - 2213-8587

VL - 8

SP - 773

EP - 781

JO - The Lancet Diabetes & Endocrinology

JF - The Lancet Diabetes & Endocrinology

IS - 9

ER -