Presentation, management, and outcomes of ectopic Cushing syndrome: an international, multicentre, retrospective, cohort study

Ectopic Cushing syndrome is a rare condition with scarce outcome data.

We sought to characterise its course and determinants of complications and mortality. In this international, multicentre, retrospective, cohort study, 49 high-volume endocrine referral centres across Asia, Europe, North America, South America, and New Zealand identified consecutive eligible patients.

We included patients with a clinical diagnosis of ectopic Cushing syndrome, defined by expert adjudication at the treating institution with at least one of the following criteria: inferior petrosal sinus sampling or dynamic testing supportive of ectopic Cushing syndrome, biochemical remission of hypercortisolism following treatment of the ectopic Cushing syndrome source (surgical excision, radiotherapy, or cryoablation), evidence of a non-metastatic tumoural source of ectopic Cushing syndrome, either on initial or subsequent imaging, or evidence of a metastatic tumoural source of ectopic Cushing syndrome either on imaging or from chart notes. Data collection was completed between May 31, 2024 and April 22, 2025.

Clinical features, biochemical severity, management, complications, and mortality were assessed. The primary outcome was Cushing syndrome-related mortality (investigator-adjudicated).

Secondary outcomes were overall mortality and incidence of complications. Outcomes were stratified based on biochemical remission and timeline since diagnosis.

Early (within 6 months of diagnosis) and late (>6 months after diagnosis) outcomes were analysed using landmark methods. Among 1463 patients (median age 51 years [IQR 37-64; range 3-87], 824 [56·3%] women, 639 [43·7%] men, and 1021 [69·8%] of White race), 836 (57·1%) had metastatic disease.

Severe hypercortisolism (1204 [91·1%] of 1321) and hypokalaemia (1111 [79·a clinically meaningful level] of 1399) were common. Median duration of follow-up was 57 months (IQR 19-124).

Cushing syndrome-related death occurred in 196 (13·a clinically meaningful level) patients. 626 (42·8%) patients died overall.

Infection occurred in 464 (31·7%) patients, venous thromboembolism in 124 (8·5%), cardiovascular events in 93 (6·a clinically meaningful level), and cerebrovascular events in 37 (2·5%). Achievement of complete biochemical remission within 6 months of diagnosis was independently associated with lower risk of late complications (adjusted HR 0·55 [95% CI 0·38-0·80]) and Cushing syndrome-related mortality (0·49 [0·27-0·89]), whereas no association was observed with non-Cushing syndrome-related mortality.

Outcomes in ectopic Cushing syndrome are driven by early control of hypercortisolism.

Failure to achieve remission within 6 months is associated with markedly worse complications and mortality, supporting ectopic Cushing syndrome as a time-critical endocrine emergency.