Ectopic Cushing’s Syndrome in Advanced Small-Cell Lung Cancer (SCLC): Clinical Challenges and Therapeutic Insights
by
,
Aleksandra Gamrat-Żmuda
1,2,
Mari Minasyan
1,
Piotr J. Wysocki
3
,
Alicja Hubalewska-Dydejczyk
1 and 
Aleksandra Gilis-Januszewska
1,* 1
Department of Endocrinology, Jagiellonian University Medical College, 30-688 Kraków, Poland
2
Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 31-530 Kraków, Poland
3
Department of Oncology, University Hospital, 31-501 Kraków, Poland
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(10), 1611; https://doi.org/10.3390/cancers17101611
Submission received: 22 April 2025
/
Accepted: 7 May 2025
/
Published: 9 May 2025
(This article belongs to the Special Issue Neuroendocrine Tumors: From Diagnosis to Therapy)
Simple Summary
Ectopic Cushing’s syndrome (ECS) is a rare and serious condition caused by excessive production of adrenocorticotropic hormone (ACTH) by tumors, leading to dangerously high cortisol levels. Small-cell lung cancer (SCLC) is one of the most common causes of ECS, but its incidence may be underestimated. Patients with SCLC-related ECS often present with nonspecific but severe symptoms such as muscle weakness, weight loss, and life-threatening hypokalemia, which can delay diagnosis. In this study, we analyze symptoms, diagnostic challenges, and treatment effectiveness in SCLC-ECS. Managing cortisol levels can improve patients’ conditions and even enable oncological treatment. Our findings highlight the importance of early recognition of ECS in SCLC patients and the need for a multidisciplinary approach. Increasing awareness among oncologists and primary care physicians may lead to earlier diagnosis and better patient outcomes.
Abstract
Background/Objectives: Ectopic Cushing’s syndrome (ECS) is a rare, life-threatening condition caused by uncontrolled ACTH secretion from tumors, most commonly small-cell lung cancer (SCLC). ECS is traditionally reported in 1–6% of SCLC cases; however, recent data suggest it may be much higher. This study compares the clinical presentation of SCLC-related ECS (ECS-SCLC) with other ECS etiologies and analyzes the diagnosis, treatment, and outcomes of ECS-SCLC. Methods: We retrospectively analyzed the records of 39 ECS patients diagnosed between 2000 and 2024 at a tertiary endocrinology center. Seven cases (18%) were due to SCLC. Diagnosis was based on clinical signs, biochemical testing, imaging, and histopathology. Results: ECS-SCLC patients (five men, two women; median age 61), compared to other ECS etiologies, had a shorter time to diagnosis (median 1 vs. 2 months; p = 0.03), worse general condition (ECOG 4 vs. 3; p = 0.01), greater muscle weakness (Lovett scale median 2[IQR 1–2] vs. 2[IQR 2–3]; p = 0.04), more severe hypokalemia (2.12 vs. 2.7 mmol/L; p = 0.03), and required higher potassium supplementation (200 vs. 120 mEq/day; p = 0.001). All ECS-SCLC patients experienced weight loss (median 5 kg). Cortisol-lowering therapy (metyrapone or osilodrostat) was initiated in six patients (mean initiation time 3.7 days), leading to clinical improvement. Oncological treatment (chemotherapy or radiotherapy) was administered in five patients after stabilization. The median follow-up time was 3 months. Conclusions: Early recognition of ECS-SCLC and a multidisciplinary approach are critical. Severe hypokalemia and muscle weakness should prompt timely evaluation for hypercortisolism. Cortisol-lowering therapy may improve clinical status and facilitate oncological treatment.
