OC42 - Ectopic Cushing's syndrome (ECS) - a diagnostic challenge. Differences between ECS and Cushing's disease (CD) - European Cushing's syndrome registry, ERCUSYN, Kraków

Background/Introduction Ectopic Cushing’s syndrome (ECS) is a rare cause of endogenous hypercortisolism (9–18% of Cushing’s syndrome,CS), resulting from ectopic ACTH secretion by various tumors. ECS prevalence, especially in small-cell lung cancer (SCLC), is likely underestimated. Its diverse clinical presentation hampers diagnosis, and due to severe hypercortisolism, rapid recognition and treatment are critical. Purpose To investigate the differences between patients with ECS and age- and sex- matched patients with pituitary-dependent ACTH secretion(CD). Methods We retrospectively analyzed 200 CS patients (2000–2025) from the ERCUSYN registry (Krakow). We identified 106 CD and 42 ECS cases. After excluding 8 SCLC patients, ECS cases were matched by age and sex with CD controls. Clinical data and course of diagnosis were compared. Results ECS patients had a mean age of 58.7 years; 53% were female. Causes included gastrointestinal NETs(29%), pulmonary carcinoids(15%), medullary thyroid cancer(9%), pheochromocytoma(6%), thymic carcinoids(3%), rare tumors(6%), and other malignancies(18%). In 4 cases, the source remained unknown. ECS was diagnosed significantly faster than CD(median 2 vs 12 months,p<0.001). In compare to CD catabolic symptoms predominated in ECS: weight loss(median -4 vs +10 kg,p=0.001), bruising (71% vs 44%,p=0.027), tendency to infections(68% vs 35%,p=0.008), and muscle weakness(Lovett scale median 3 [IQR 2–3] vs 3 [IQR 3–4],p=0.003). Hypokalemia was the most common initial sign in ECS, with lower potassium levels(Me:3.3 vs 4.0 mmol/L, p<0.001) and higher supplementation needs(Me:80 vs 0 mEq/d, p<0.001). Classic Cushingoid features were less frequent in ECS than CD: striae(21% vs 62%,p<0.001), fat redistribution(18% vs 59%,p=0.03). ECS patients had higher cortisol (6AM: 26.2 vs 7.5 µg/dL; 12AM: 40.0 vs 18.7 µg/dL;both p<0.001) and ACTH (231.5 vs 104.0 pg/mL;p<0.001). Mortality was significantly higher in ECS (64.7% vs 8.8%;p<0.00001), with shorter follow-up (3 vs 30 months,p=0.001). Conclusion(s) The clinical presentation of patients with ECS differs significantly from that of CD, with catabolic symptoms being more prominent. Greater awareness of these catabolic signs, along with severe hypokalemia and the distinct clinical course of ECS, may enhance diagnostic accuracy.