Ectopic Corticotropin-Releasing Hormone/Adrenocorticotropic Hormone-Co-Secreting Neuroendocrine Tumors Leading to Cushing's Disease: A Case Presentation and Literature Review.

Background: Adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) are essential regulators of cortisol production within the hypothalamic-pituitary-adrenal (HPA) axis. Elevated cortisol levels, resulting from excessive ACTH, can lead to Cushing's syndrome, a condition associated with significant morbidity. Neuroendocrine tumors (NETs) can ectopically produce both ACTH and CRH, a rare phenomenon that further contributes to this syndrome.

Summary: This review discusses the pathophysiology, types, clinical presentation, diagnosis, and management of NETs that ectopically secrete CRH and ACTH. Particular emphasis is placed on the importance of identifying dual CRH/ACTH secretion, which complicates diagnosis and treatment. Furthermore, the review highlights the prognosis, common complications, and future directions for research in this area. We further report the case of a 53-year-old female patient who presented with severe Cushing's syndrome and was diagnosed with ectopic ACTH syndrome. Despite initial findings suggesting pituitary-dependent hypercortisolism, further investigations revealed the presence of a highly differentiated, atypically located tumor in the lung. Immunohistochemistry of the tumor tissue demonstrated not only ACTH but also CRH and CRH-R1 expression. The simultaneous expression of these molecules supports the hypothesis of a positive endocrine feedback loop within the NET, in which the release of CRH stimulates ACTH expression via binding to CRH-R1.

Key messages: This case report highlights the challenges in diagnosing and managing ectopic ACTH syndrome, emphasizing the importance of a comprehensive diagnostic approach to identify secondary factors influencing cortisol production, such as CRH secretion and other contributing neuroendocrine mechanisms. Recognizing the dual secretion of CRH and ACTH in NETs is crucial for accurate diagnosis and optimizing patient management.