Ectopic cushing syndrome caused by intestinal neuroendocrine tumors: a systematic review

Ectopic Cushing syndrome is a potentially life-threatening disorder most caused by thoracic or pancreatic neuroendocrine tumors. Intestinal neuroendocrine tumors are an exceptionally uncommon and poorly characterized source, creating important diagnostic and therapeutic challenges. We aimed to systematically characterize the clinical presentation, diagnostic pathways, treatment strategies, and outcomes of ectopic Cushing syndrome caused by intestinal neuroendocrine tumors.

Systematic review of published case reports, complemented by an illustrative unpublished case. Four electronic databases were searched from inception to February 2026 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. Individual patient data on clinical presentation, tumor localization, treatment, and outcomes were extracted and analyzed descriptively.

Twenty-four published cases were identified. Ectopic Cushing syndrome was the initial manifestation in 87.5% of patients and frequently presented with an aggressive clinical phenotype (70.8%). Tumor localization was often challenging. Conventional imaging detected the primary lesion in fewer than half of cases, whereas functional imaging, particularly gallium-68 somatostatin receptor positron emission tomography, showed higher detection rates. Surgical resection was performed in 87.5% of patients and biochemical remission was achieved in 72.7%. However, 50% required medical therapy for hypercortisolism and 20.8% underwent bilateral adrenalectomy. Recurrence occurred in 14.3%.

Intestinal neuroendocrine tumors are a rare but clinically relevant cause of ectopic Cushing syndrome. They commonly present with severe hypercortisolism and delayed tumor localization. Management requires both tumor-directed treatment and rapid endocrine control. Recurrence may occur despite initial remission, supporting prolonged surveillance and a multimodal diagnostic and therapeutic approach.