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Cited by 250Adrenal and Paraganglionic TumorsAdrenal Hormones and DisordersRenal cell carcinoma treatment

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

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Bancos, Irina, Taylor, Angela E, Chortis, Vasileios, Sitch, Alice J, Jenkinson, Carl, Davidge-Pitts, Caroline J, Lang, Katharina, Tsagarakis, Stylianos +139 more·2020·The Lancet Diabetes & Endocrinology
DOI 10.1016/s2213-8587(20)30218-7PMC PMC7447976
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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.

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  • A recent meta-analysis comparing patients with CAH and matched controls found slightly decreased BMD in patients with CAH.

    “A recent meta-analysis comparing patients with CAH and matched controls found slightly decreased BMD in patients with CAH (725).”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [725]

    The Introduction describes a meta-analysis of imaging tests for adrenal masses, not a comparison of bone mineral density in patients with congenital adrenal hyperplasia and matched controls. Searches for CAH, BMD, and bone density found no passage in our copy addressing the claimed finding. (LLM, conf=0.78)

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Research works printed but not linked: 17

  1. [1]Song JH Chaudhry FS Mayo-Smith WW The incidental adrenal mass on CT: prevalence of adrenal disease in 1,049 consecutive adrenal masses in patients with no known malignancy AJR Am J Roentgenol 190 2008 1163 1168 18430826
  2. [2]Bovio S Cataldi A Reimondo G Prevalence of adrenal incidentaloma in a contemporary computerized tomography series J Endocrinol Invest 29 2006 298 302 16699294
  3. [3]Terzolo M Stigliano A Chiodini I AME position statement on adrenal incidentaloma Eur J Endocrinol 164 2011 851 870 21471169
  4. [5]Nieman LK Approach to the patient with an adrenal incidentaloma J Clin Endocrinol Metab 95 2010 4106 4113 20823463 PMC2936073
  5. [6]Young WF Jr The incidentally discovered adrenal mass N Engl J Med 356 2007 601 610 17287480
  6. [9]Lenders JW Duh QY Eisenhofer G Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline J Clin Endocrinol Metab 99 2014 1915 1942 24893135
  7. [10]Mantero F Terzolo M Arnaldi G A survey on adrenal incidentaloma in Italy J Clin Endocrinol Metab 85 2000 637 644 10690869
  8. [11]Iniguez-Ariza NM Kohlenberg JD Delivanis DA Clinical, biochemical, and radiological characteristics of a single-center retrospective cohort of 705 large adrenal tumors Mayo Clin Proc Innov Qual Outcomes 2 2018 30 39 30225430 PMC6124341
  9. [12]Kloos RT Gross MD Francis IR Korobkin M Shapiro B Incidentally discovered adrenal masses Endocr Rev 16 1995 460 484 8521790
  10. [14]Fassnacht M Dekkers O Else T European Society of Endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors Eur J Endocrinol 179 2018 G1 46 30299884
  11. [15]Dinnes J Bancos I Ferrante di Ruffano L Imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis Eur J Endocrinol 175 2016 R51 R64 27257145 PMC5065077
  12. [16]Fassnacht M Arlt W Bancos I Management of adrenal incidentalomas: European Society of Endocrinology clinical practice guideline in collaboration with the European Network for the Study of Adrenal Tumors Eur J Endocrinol 175 2016 G1 34 27390021
  13. [17]Hamrahian AH Ioachimescu AG Remer EM Clinical utility of noncontrast computed tomography attenuation value (Hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience J Clin Endocrinol Metab 90 2005 871 877 15572420
  14. [19]Bancos I Arlt W Diagnosis of a malignant adrenal mass: the role of urinary steroid metabolite profiling Curr Opin Endocrinol Diabetes Obes 24 2017 200 207 28234802
  15. [21]Velikanova LI Shafigullina ZR Lisitsin AA Different types of urinary steroid profiling obtained by high-performance liquid chromatography and gas chromatography-mass spectrometry in patients with adrenocortical carcinoma Horm Cancer 7 2016 327 335 27370636 PMC10355950
  16. [22]Mansmann G Lau J Balk E Rothberg M Miyachi Y Bornstein SR The clinically inapparent adrenal mass: update in diagnosis and management Endocr Rev 25 2004 309 340 15082524
  17. [24]Bancos I Tamhane S Shah M The diagnostic performance of adrenal biopsy: a systematic review and meta-analysis Eur J Endocrinol 175 2016 R65 R80 27257146

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Authors
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., Marina, L., Grytaas, M. A., Sajwani, A., Langton, K., Ivison, H. E., Shackleton, C. H. L., Erickson, D., Asia, M., Palimeri, S., Kondracka, A., Spyroglou, A., Ronchi, C. L., Simunov, B., Delivanis, D. A., Sutcliffe, R. P., Tsirou, I., Bednarczuk, T., Reincke, M., Burger-Stritt, S., Feelders, R. A., Canu, L., Haak, H. R., Eisenhofer, G., Dennedy, M. C., Ueland, G. A., Ivovic, M., Tabarin, A., Terzolo, M., Quinkler, M., Kastelan, D., Fassnacht, M., Beuschlein, F., Ambroziak, U., Vassiliadi, D. A., O'Reilly, M. W., Young, W. F., Biehl, M., Deeks, J. J., Arlt, W., Glöckner, S., Sinnott, R. O., Stell, A., Fragoso, M. C., Kastelan, D., Pupovac, I. D., Simunov, B., Cazenave, S., Haissaguerre, M., Tabarin, A., Bertherat, J., Libé, R., Kienitz, T., Quinkler, M., Langton, K., Eisenhofer, G., Beuschlein, F., Brugger, C., Reincke, M., Riester, A., Spyroglou, A., Burger-Stritt, S., Deutschbein, T., Fassnacht, M., Hahner, S., Kroiss, M., Ronchi, C. L., Palimeri, S., Tsagarakis, S., Tsirou, I., Vassiliadi, D. A., Basile, V., Ingargiola, E., Reimondo, G., Terzolo, M., Canu, L., Mannelli, M., Ettaieb, H., Haak, H. R., Kerkhofs, T. M., Biehl, M., Feelders, R. A., Hofland, J., Hofland, L. J., Grytaas, M. A., Husebye, E. S., Ueland, G. A., Ambroziak, U., Bednarczuk, T., Kondracka, A., Macech, M., Zawierucha, M., Paiva, I., Dennedy, M. C., Sajwani, A., Sherlock, M., Crowley, R. K., Ivovic, M., Marina, L., Deeks, J. J., Sitch, A. J., Arlt, W., Bancos, I., Chortis, V., Giligan, L. C., Hughes, B. A., Lang, K., Ivison, H. E., Jenkinson, C., Manolopoulos, K., O'Neil, D. M., O'Reilly, M. W., Papathomas, T. G., Prete, A., Shackleton, C. H. L., Taylor, A. E., Asia, M., Sutcliffe, R. P., Guest, P., Skordilis, K., Bancos, C., Chang, A., Davidge-Pitts, C. J., Delivanis, D. A., Erickson, D., Natt, N., Nippoldt, T. B., Thomas, M., & Young Jr., W. F.
Affiliations
  • University of Birmingham (GB)
  • University of Würzburg (DE)
  • University of Turin (IT)
  • University Hospitals Birmingham NHS Foundation Trust (GB)
  • Mayo Clinic (US)
ORCID
Venue
The Lancet Diabetes & Endocrinology
Publisher
Elsevier BV
Published
2020-09
Volume
8
Issue
9
Pages
773-781
ISSN
2213-8587 (ISSN-L)
DOI
10.1016/s2213-8587(20)30218-7
PMC
PMC7447976
OpenAlex
W3045070287
Cited by
250
References
6
Citations by year
2026: 31 · 2025: 50 · 2024: 37 · 2023: 36 · 2022: 52 · 2021: 32 · 2020: 12
FWCI
30.16
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Diabetes & Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • Florence Research (University of Florence) (submittedVersion, cc-by)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • European Commission
  • Seventh Framework Programme (259735)
  • University of Birmingham (BRC-1215-20009)
  • University Hospitals Birmingham NHS Foundation Trust
  • National Institutes of Health (K23DK121888)
  • Medical Research Council (G0801473)
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • Birmingham Biomedical Research Centre
  • National Institute for Health and Care Research
  • Department of Health and Social Care
  • Wellcome Trust (WT101671)
  • Mayo Foundation for Medical Education and Research
Topics
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
Keywords
adrenal incidentaloma, adrenocortical carcinoma, differential diagnosis, diagnostic accuracy, test validation, positive predictive value, sensitivity and specificity
MeSH terms
Adrenal Gland Neoplasms, Adult, Aged, Diagnosis, Differential, Europe, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prospective Studies, Steroids, Incidental Findings, Metabolomics

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