Endocrine Abstracts

Introduction: Cyclic Cushing’s syndrome (cCS) is a rare condition characterized by periods of excessive cortisol secretion (peaks), alternating with phases of eucortisolism (through). In most cases, cCS is caused by an ACTH-secreting pituitary tumor, while only few cases of cyclic ectopic ACTH secretion (cEAS) have been described.

Case presentation: In February 2023, a 58-year-old woman was referred to our Endocrine Unit due to a 10-year history of recurring episodes of decompensated diabetes, hypertension, and hypokalemia, coupled with body and facial swelling, and weight gain, occurring approximately once a year and alternated with periods of clinical remission. Physical examination during such episodes was highly suggestive of CS. Remarkably, the patient’s family history disclosed several cases of functioning pituitary adenomas. Previous endocrine investigations in different centers had revealed a cyclical adrenocorticotropic hormone (ACTH) -dependent hypercortisolism, with high ACTH and 24h urine free cortisol, and lack of cortisol suppression after dexamethasone suppression test during disease periods, yet the precise localization of the disease remained elusive. Indeed, magnetic resonance imaging had identified a 3-mm ‘possible pituitary adenoma’, but inferior petrosal sinus sampling had demonstrated no center:periphery ACTH gradient, and 68-Ga-PET-CT had only shown focal uptake in the left thyroid lobe, prompting a subsequent total thyroidectomy with the diagnosis of a follicular adenoma. Upon the recurrence of a peak phase, we performed a corticotropin-releasing hormone test and a desmopressin test, both resulted in inadequate ACTH and cortisol responses suggestive of an ectopic source of ACTH hypersecretion. New 68-Ga-PET-CT and 18-FDG-PET-CT scans during this active period both revealed focal uptake in the middle lobe of the right lung, where a "fungus ball" lesion had been previously described. A pulmonary right middle lobectomy was indicated, while a ‘bridge therapy’ with Osilodrostat waiting for surgery allowed clinical and biochemical improvement. Histological examination identified a typical ACTH-staining carcinoid (Ki67 1.5%), and the diagnosis was confirmed by post-surgical hypoadrenalism, still persistent.

Conclusion: The diagnosis of cyclic ACTH-dependent hypercortisolism poses major difficulties due to its intermittent nature. Up to now, less than 40 cases of cEAS have been described in the literature, although its actual prevalence may be underestimated. The main pitfalls are the low diagnostic accuracy of both hormonal and imaging procedures, especially if performed irrespective of cortisolaemic status, and the intrisinc challeging diagnosis of ectopic neuroendocrine tumors. Thus, an exhaustive diagnostic work-up during periods of florid disease, as well clinical experience, are paramount to avoid misdiagnoses.