Management of ectopic Cushing syndrome in medullary thyroid carcinoma: from case reports to systematic literature review.

Background: Ectopic Cushing's syndrome (ECS) secondary to medullary thyroid carcinoma (MTC) is a rare endocrine manifestation associated with aggressive disease and considerable morbidity from severe hypercortisolism. Methods: We conducted a systematic review of PubMed and Web of Science from inception to January 25, 2026, in accordance with PRISMA guidelines, to identify all published cases of ECS due to MTC. Data were extracted on clinical presentation, RET mutational status, treatments, outcomes, and causes of death. In addition, we described four previously unreported patients from "C. I. Parhon" National Institute in Bucharest, Romania, analyzed independently from the systematic review dataset. Results: The systematic review identified 99 published cases of ECS caused by MTC. The mean age at diagnosis was 46.3 years (range 12-84), with male predominance (69.7%). Among cases with available genetic data, most were sporadic 32/43 cases (74.4%), frequently harboring somatic RET M918T mutation. MTC stage at diagnosis was available in 90 cases, of which 48 patients (53.3%) presented with distant metastases. ECS and MTC were diagnosed concomitantly in 45/89 patients (50.6%), while MTC preceded ECS in 43/89 patients (48.3%), with a median delay of 42 months. Hypercortisolism manifestations predominated and often masked locoregional thyroid disease. Thyroid surgery was the initial therapeutic approach in 62/77 cases (80.5%). Hypercortisolism was difficult to control and often refractory to multiple treatment strategies. Bilateral adrenalectomy was required in 33 patients, including 12 in whom it served as rescue treatment following failure of medical therapy. Selective RET inhibitors, particularly selpercatinib, have recently emerged as a promising treatment option, with all five reported cases demonstrating rapid biochemical improvement and radiologic responses. Among cases with available outcome data, mortality was primarily driven by complications of uncontrolled hypercortisolism and progressive metastatic MTC. Complementing the systematic review, regarding the four cases from our center, we have observed substantial disease burden, with thyroid surgery performed in every patient. Two cases received vandetanib producing favorable biochemical (calcitonin) and radiologic responses. Hypercortisolism proved challenging to manage, with three patients failing to achieve remission despite multimodal therapy, including surgery, targeted therapy, adrenalectomy, or medical treatment. Conclusion: ECS secondary to MTC is an exceptionally rare and highly morbid manifestation that occurs predominantly in metastatic sporadic MTC. Management of both tumor burden and hypercortisolism is complex and often requires multimodal therapy. Emerging data suggests that selective RET inhibitors may lead to simultaneous control of both tumor progression and cortisol excess in RET-mutated disease, although current data remain limited to case reports. The four institutional cases offer additional real-world clinical context and are presented separately from the systematic review to maintain methodological rigor.