ACTH-dependent Cushing's syndrome in MEN1: When multiple tumors complicate the diagnosis

ACTH-dependent Cushing's syndrome (CS) is a rare manifestation of multiple endocrine neoplasia type 1 (MEN1). Identifying the ACTH source is challenging in MEN1 due to the frequent coexistence of multiple synchronous neuroendocrine tumors (NETs) in these patients.

We describe the diagnostic dilemma in a 51-year-old male with MEN1 and severe ACTH-dependent CS. To analyze the specific diagnostic pitfalls in this population, we conducted a systematic literature review focusing exclusively on documented cases of ectopic Cushing syndrome (ECS) in MEN1 patients.

The patient presented severe CS, with urinary free cortisol (UFC) at 3,188μg/24h (exceeding 25 times the upper limit of normal). Rapid biochemical control was achieved within 10 days using a high-dose (60mg/day) osilodrostat "block-and-replace" regimen. Imaging identified 3 potential sources: a 7×8mm pituitary microadenoma, a small pancreatic NET, and a large thymic NET (48×62×67mm). Despite a desmopressin stimulation test falsely suggesting a pituitary source (+118% ACTH increase), clinical severity and imaging indicated total thymectomy. Pathology confirmed a typical carcinoid tumor with ACTH expression. Postoperatively, the patient achieved complete remission. Our review of ectopic Cushing's syndrome (ECS) in MEN1 identified a total of 18 cases to date. Thymic NETs were the most frequent source (61%), followed by pancreatic NETs (28%). Notably, ectopic secretion of corticotropin-releasing hormone (CRH) was identified in 4 cases (22%), constituting a major diagnostic pitfall that led to unnecessary transsphenoidal surgery in 3 cases.

ACTH-dependent CS in MEN1 is a diagnostic "perfect storm", where pituitary incidentalomas frequently mislead clinicians. Based on our review, ectopic CRH or ACTH secretion from thoracic or abdominal NETs must be systematically considered. We advocate a strategy prioritizing resection of the most suspicious lesion identified on imaging, thereby avoiding unnecessary transsphenoidal surgery.