BACKGROUND: Cyclical Cushing's syndrome (CCS) is an uncommon form of endogenous hypercortisolism characterized by alternating periods of cortisol excess and remission. Its intermittent nature delays diagnosis and localization of the adrenocorticotropic hormone (ACTH) source and complicates therapeutic decision-making. CASE PRESENTATION: We report a 46-year-old man with an incidentally detected anterior mediastinal mass, diagnosed as a well-differentiated neuroendocrine tumor (NET) with ectopic ACTH production. He presented with clinical and biochemical features of ACTH-dependent Cushing's syndrome. Despite tumor resection and multiple subsequent therapies, including somatostatin analogues, chemotherapy (without concomitant glucocorticoids), and radiotherapy, the disease course was marked by recurrent peaks of hypercortisolism interspersed with partial remissions, consistent with CCS. Episodes were associated with hypertension, diabetes mellitus, hypokalemia, infections, and thromboembolism. Due to refractory disease, bilateral adrenalectomy was performed, achieving biochemical remission but requiring lifelong glucocorticoid replacement. DISCUSSION: CCS poses significant diagnostic and therapeutic challenges. Intermittent cortisol secretion may obscure diagnosis during remission phases and complicate assessment of treatment response. In NET-related CCS, tumor progression and therapeutic interventions may influence ACTH secretion, contributing to cyclical patterns. The "timing paradox", whether to treat during peaks or remission, remains a key clinical dilemma. CONCLUSION: CCS requires prolonged biochemical surveillance, early recognition of cyclicity, and multidisciplinary management. The cumulative burden of recurrent hypercortisolism highlights the need for individualized strategies integrating endocrine and oncologic care. Bilateral adrenalectomy remains a life-saving option when sustained control is not achieved.
Peixe et al. (2026) studied this question.