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

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.

Automated summary

The study aimed to provide an overview of available dynamic tests for discriminating between neoplastic and non-neoplastic hypercortisolism and to quantify their diagnostic performance. The combined Dex-CRH test showed the highest sensitivity, while the CRH test demonstrated excellent specificity. Further research is needed, particularly in mild Cushing's Disease and well-characterized non-neoplastic hypercortisolism patients.