Ectopic Cushing's syndrome: Clinical presentation and diagnosis

ectopic Cushing syndrome (ECS) is a rare endocrinological disease caused by neuroendocrine tumors capable of secreting ATCH or POMC derived immature peptides. It accounts for 10-20 percent of Cushing syndrome cases. ACTH secretion usually leads to clinically severe hypercortisolism with a predominance of glucocorticoids catabolic effects on clinical presentation. It has been suggested that ECS should be divided into two phenotypes, aggressive and indolent. The first one is characterized by classical Cushingoid features, like weight gain, purple striae and so on. The latter is characterized by underlying tumor progression with more pronounced glucocorticoid catabolic effect on muscles, bones and skin tissues. Time from symptoms onset to diagnosis and survival can be reduced in ECS compared to other Cushing syndrome (CS) etiologies. ECS diagnosis can be challenging and is based on four points: clinical suspicion, hypercortisolism confirmation, differential diagnosis with pituitary Cushing (Cushing disease; CD) and tumor localization. All available screening tools for hypercortisolism are used in ECS with good sensitivity and specificity. Between the most used dynamic tests there are: CRH stimulation test, desmopressin test and high dose dexamethasone suppression test (HDDST); inferior petrosal sinus sampling (IPSS) is considered the gold standard for differential diagnosis. CT scan, MRI and functional imaging using radionuclide labelled tracers can help in localizing the responsible tumor even if smaller tumors can become radiologically evident only during follow-up. Circulating Mi-RNAs sequencing and machine learning algorithms may also help in the future for differential diagnosis and therapy personalization.