Cushing Syndrome Is Associated with Worse Survival and Higher Morbidity in Neuroendocrine Neoplasms

Ectopic Cushing syndrome (ECS) is a severe paraneoplastic complication of neuroendocrine neoplasms (NENs), but its association with survival and clinically relevant outcomes remains insufficiently defined in matched real-world cohorts.

To assess the association of code-defined Cushing syndrome compatible with ECS with OS and clinical outcomes in patients with NENs using a large propensity score-matched cohort.

Retrospective cohort study with 1:1 propensity score matching.

Electronic medical records from TriNetX Global Collaborative Network, a federated database aggregating clinical data from international healthcare organizations.

Adult patients (≥18 years) with NEN (n = 105,854), including 265 in the ECS-compatible cohort. After matching, 264 patients in the ECS-compatible cohort were compared with 264 patients without documented Cushing syndrome.

Primary outcome was OS. Secondary outcomes included hospitalization, emergency care use, severe infections, venous thromboembolism, metabolic complications, organ failure, and metastatic progression.

ECS was associated with significantly reduced OS compared with non-ECS patients (8-year survival: 55.3% vs 71.2%; hazard ratio [HR] 1.848 [95% confidence interval 1.348-2.534]; P < 0.001). ECS patients had increased risks of hospitalization, severe infections, venous thromboembolism, and metabolic complications including hypertension, diabetes mellitus, and hypokalemia, as well as organ failure (kidney and liver failure). No significant increase in metastatic progression was observed.

ECS-compatible Cushing syndrome was associated with worse survival and substantially higher morbidity in patients with NENs, mainly reflected by hypercortisolism-related complications rather than tumor progression. Early recognition and treatment of hypercortisolism may be critical to improve outcomes.