Second-line tests in the differential diagnosis of neoplastic and non-neoplastic hypercortisolism: a systematic review and meta-analysis

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Abstract

Purpose

The clinical and hormonal overlap between neoplastic (CS) and non-neoplastic (NNH/pCS) hypercortisolism is a challenge. Various dynamic tests have been proposed to allow an early discrimination between these conditions, but to date there is no agreement on which of them should be used.

Aim

To provide an overview of the available tests and to obtain a quantitative synthesis of their diagnostic performance in discriminating NNH/pCS from CS.

Methods

The included articles, published between 1990 and 2022, applied one or more second line tests to differentiate NNH/pCS from CS patients. For the NNH/pCS group, we admitted the inclusion of patients presenting clinical features and/or biochemical findings suggestive of hypercortisolism despite apparent lack of a pCS-related condition.

Results

The electronic search identified 339 articles. After references analysis and study selection, we identified 9 studies on combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test, 4 on Desmopressin test and 3 on CRH test; no study on Dex-Desmopressin met the inclusion criteria. Dex-CRH test provided the highest sensitivity (97%, 95 CI% [88%; 99%]). CRH tests showed excellent specificity (99%, 95% CI [0%; 100%]), with low sensitivity. Although metaregression analysis based on diagnostic odds ratio failed to provide a gold standard, CRH test (64.77, 95% CI [0.15; 27,174.73]) seemed to lack in performance compared to the others (Dex-CRH 138.83, 95% CI [49.38; 390.32] and Desmopressin 110.44, 95% CI [32.13; 379.63]).

Discussion

Both Dex-CRH and Desmopressin tests can be valid tools in helping discrimination between NNH/pCS and CS. Further studies are needed on this topic, possibly focusing on mild Cushing’s Disease and well-characterized NNH/pCS patients.

Systematic review registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359774, identifier CRD42022359774.

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Most cited references 35

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QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.

Penny F Whiting, Anne Rutjes, Marie E Westwood … (2011)

In 2003, the QUADAS tool for systematic reviews of diagnostic accuracy studies was developed. Experience, anecdotal reports, and feedback suggested areas for improvement; therefore, QUADAS-2 was developed. This tool comprises 4 domains: patient selection, index test, reference standard, and flow and timing. Each domain is assessed in terms of risk of bias, and the first 3 domains are also assessed in terms of concerns regarding applicability. Signalling questions are included to help judge risk of bias. The QUADAS-2 tool is applied in 4 phases: summarize the review question, tailor the tool and produce review-specific guidance, construct a flow diagram for the primary study, and judge bias and applicability. This tool will allow for more transparent rating of bias and applicability of primary diagnostic accuracy studies.

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Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies

Matthew McInnes, David Moher, Brett D. Thombs … (2018)

Systematic reviews of diagnostic test accuracy synthesize data from primary diagnostic studies that have evaluated the accuracy of 1 or more index tests against a reference standard, provide estimates of test performance, allow comparisons of the accuracy of different tests, and facilitate the identification of sources of variability in test accuracy.

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Is Open Access

Utilization of the PICO framework to improve searching PubMed for clinical questions

Connie Schardt, Martha Adams, Thomas Owens … (2007)

Background Supporting 21st century health care and the practice of evidence-based medicine (EBM) requires ubiquitous access to clinical information and to knowledge-based resources to answer clinical questions. Many questions go unanswered, however, due to lack of skills in formulating questions, crafting effective search strategies, and accessing databases to identify best levels of evidence. Methods This randomized trial was designed as a pilot study to measure the relevancy of search results using three different interfaces for the PubMed search system. Two of the search interfaces utilized a specific framework called PICO, which was designed to focus clinical questions and to prompt for publication type or type of question asked. The third interface was the standard PubMed interface readily available on the Web. Study subjects were recruited from interns and residents on an inpatient general medicine rotation at an academic medical center in the US. Thirty-one subjects were randomized to one of the three interfaces, given 3 clinical questions, and asked to search PubMed for a set of relevant articles that would provide an answer for each question. The success of the search results was determined by a precision score, which compared the number of relevant or gold standard articles retrieved in a result set to the total number of articles retrieved in that set. Results Participants using the PICO templates (Protocol A or Protocol B) had higher precision scores for each question than the participants who used Protocol C, the standard PubMed Web interface. (Question 1: A = 35%, B = 28%, C = 20%; Question 2: A = 5%, B = 6%, C = 4%; Question 3: A = 1%, B = 0%, C = 0%) 95% confidence intervals were calculated for the precision for each question using a lower boundary of zero. However, the 95% confidence limits were overlapping, suggesting no statistical difference between the groups. Conclusion Due to the small number of searches for each arm, this pilot study could not demonstrate a statistically significant difference between the search protocols. However there was a trend towards higher precision that needs to be investigated in a larger study to determine if PICO can improve the relevancy of search results.

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Author and article information

Contributors

F. Ceccato:

ORCID: http://orcid.org/0000-0003-1456-8716

filippo.ceccato@unipd.it

Journal

Journal ID (nlm-ta): J Endocrinol Invest

Journal ID (iso-abbrev): J Endocrinol Invest

Title: Journal of Endocrinological Investigation

Publisher: Springer International Publishing (Cham )

ISSN (Print): 0391-4097

ISSN (Electronic): 1720-8386

Publication date (Electronic): 20 April 2023

Publication date PMC-release: 20 April 2023

Publication date (Print): 2023

Volume: 46

Issue: 10

Pages: 1947-1959

Affiliations

[1 ]Endocrinology Unit, Department of Medicine DIMED, University of Padova, ( https://ror.org/00240q980) Via Ospedale Civile, 105, 35128 Padua, Italy

[2 ]Endocrine Disease Unit, University-Hospital of Padova, ( https://ror.org/05xrcj819) Padua, Italy

[3 ]Department of Neuroscience DNS, University of Padova, ( https://ror.org/00240q980) Padua, Italy

Author information

A. Mondin http://orcid.org/0000-0002-6046-5198

M. Barbot http://orcid.org/0000-0002-1081-5727

G. Voltan http://orcid.org/0000-0002-3628-0492

I. Tizianel http://orcid.org/0000-0003-4092-5107

M. Boscaro http://orcid.org/0000-0003-2596-1652

C. Scaroni http://orcid.org/0000-0001-9396-3815

F. Ceccato http://orcid.org/0000-0003-1456-8716

Article

Publisher ID: 2099

DOI: 10.1007/s40618-023-02099-z

PMC ID: 10514124

PubMed ID: 37079177

SO-VID: 5c4178d1-0021-419d-bae0-8e4d08f93669

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 10 February 2023

Date accepted : 13 April 2023

Funding

Funded by: Università degli Studi di Padova

Open Access :

Open access funding provided by Università degli Studi di Padova within the CRUI-CARE Agreement.

Custom metadata

Keywords: pseudo-cuhing,non-neoplastic hypercortisolism,acth-dependent cushing’s syndrome,cushing’s disease,crh test,desmopressin test,dexamethasone

Data availability:

Keywords: pseudo-cuhing, non-neoplastic hypercortisolism, acth-dependent cushing’s syndrome, cushing’s disease, crh test, desmopressin test, dexamethasone

Second-line tests in the differential diagnosis of neoplastic and non-neoplastic hypercortisolism: a systematic review and meta-analysis

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Most cited references 35

QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.

Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies

Utilization of the PICO framework to improve searching PubMed for clinical questions

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