Ectopic ACTH Production in Medullary Thyroid Carcinoma-A Study of Two Cases

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from thyroid parafollicular C-cells, accounting for 1-2% of all thyroid cancers. An exceedingly rare manifestation of MTC is ectopic adrenocorticotropic hormone (ACTH) production, causing Cushing's syndrome and complicating management. This report presents two cases of MTC with ectopic ACTH production, highlighting diagnostic challenges, therapeutic strategies, and clinical outcomes. A comprehensive literature review on this rare paraneoplastic syndrome is included and supplements the case findings. Case 1 involves a 49-year-old man presenting with abdominal pain, weight loss, and pulmonary nodules, diagnosed with MTC and ectopic ACTH-related Cushing's syndrome. Surgical resection and targeted therapy with selpercatinib improved cortisol levels but were complicated by adverse drug reactions. Case 2 details a 65-year-old woman with severe hypercortisolism and locally advanced MTC. Selpercatinib successfully reduced hormone levels and achieved partial tumor regression. Both cases underscore the critical role of tyrosine kinase inhibitors (TKIs) in controlling tumor progression, and paraneoplastic hormone production is exemplified in both cases, as treatment initiation was followed by a biochemical response with declining levels of ACTH, cortisol, and calcitonin. Ectopic ACTH production in MTC is a rare but clinically significant entity associated with aggressive disease. Early recognition, comprehensive biochemical and imaging evaluations, and a multidisciplinary approach are pivotal for optimal management. The advent of targeted therapies, such as selpercatinib, has transformed the therapeutic landscape, offering improved control of both tumor burden and hormone excess. This report highlights the importance of integrating genomic insights and precision medicine in addressing these complex cases.