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      Ectopic Cushing’s syndrome from a corticotropin-releasing hormone-secreting medullary thyroid carcinoma: a rare pitfall of inferior petrosal sinus sampling


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          This case report describes a rare presentation of ectopic Cushing’s syndrome (CS) due to ectopic corticotropin-releasing hormone (CRH) production from a medullary thyroid carcinoma (MTC). The patient, a 69-year-old man, presented with symptoms of muscle weakness, facial plethora, and easy bruising. An inferior petrosal sinus sampling test (IPSS) demonstrated pituitary adrenocorticotrophic hormone (ACTH) secretion, but a whole-body somatostatin receptor scintigraphy ( 68Ga-DOTATOC PET/CT) revealed enhanced uptake in the right thyroid lobe which, in addition to a grossly elevated serum calcitonin level, was indicative of an MTC. A 18F-DOPA PET/CT scan supported the diagnosis, and histology confirmed the presence of MTC with perinodal growth and regional lymph node metastasis. On immunohistochemical analysis, the tumor cell stained positively for calcitonin and CRH but negatively for ACTH. Distinctly elevated plasma CRH levels were documented. The patient therefore underwent thyroidectomy and bilateral adrenalectomy. This case shows that CS caused by ectopic CRH secretion may masquerade as CS due to a false positive IPSS test. It also highlights the importance of considering rare causes of CS when diagnostic test results are ambiguous.

          Learning points
          • Medullary thyroid carcinoma may secrete CRH and cause ectopic CS.

          • Ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive test.

          • Plasma CRH measurements can be useful in selected cases.

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          Most cited references10

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          Cushing’s syndrome: epidemiology and developments in disease management

          Cushing’s syndrome is a rare disorder resulting from prolonged exposure to excess glucocorticoids. Early diagnosis and treatment of Cushing’s syndrome is associated with a decrease in morbidity and mortality. Clinical presentation can be highly variable, and establishing the diagnosis can often be difficult. Surgery (resection of the pituitary or ectopic source of adrenocorticotropic hormone, or unilateral or bilateral adrenalectomy) remains the optimal treatment in all forms of Cushing’s syndrome, but may not always lead to remission. Medical therapy (steroidogenesis inhibitors, agents that decrease adrenocorticotropic hormone levels or glucocorticoid receptor antagonists) and pituitary radiotherapy may be needed as an adjunct. A multidisciplinary approach, long-term follow-up, and treatment modalities customized to each individual are essential for optimal control of hypercortisolemia and management of comorbidities.
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            Cushing's syndrome: from physiological principles to diagnosis and clinical care.

            The physiological control of cortisol synthesis in the adrenal cortex involves stimulation of adrenocorticotrophic hormone (ACTH) by hypothalamic corticotrophin-releasing hormone (CRH) and then stimulation of the adrenal by ACTH. The control loop of the hypothalamic-pituitary-adrenal (HPA) axis is closed by negative feedback of cortisol on the hypothalamus and pituitary. Understanding this system is required to master the diagnosis, differential diagnosis and treatment of endogenous hypercortisolism--Cushing's syndrome. Endogenous Cushing's syndrome is caused either by excess ACTH secretion or by autonomous cortisol release from the adrenal cortex. Diagnosis of cortisol excess exploits three physiological principles: failure to achieve the normal nadir in the cortisol diurnal rhythm, loss of sensitivity of ACTH-secreting tumours to cortisol negative feedback, and increased excretion of free cortisol in the urine. Differentiating a pituitary source of excess ACTH (Cushing's disease) from an ectopic source is accomplished by imaging the pituitary and sampling for ACTH in the venous drainage of the pituitary. With surgical removal of ACTH or cortisol-secreting tumours, secondary adrenal insufficiency ensues because of the prior suppression of the HPA axis by glucocorticoid negative feedback. Medical therapy is targeted to the anatomical location of the dysregulated component of the HPA axis. Future research will focus on new diagnostics and treatments of Cushing's syndrome. These are elegant examples of translational research: understanding basic physiology informs the development of new approaches to diagnosis and treatment. Appreciating pathophysiology generates new areas for inquiry of basic physiological and biochemical mechanisms.
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              Bilateral inferior petrosal sinus sampling

              Simultaneous bilateral inferior petrosal sinus sampling (BIPSS) plays a crucial role in the diagnostic work-up of Cushing’s syndrome. It is the most accurate procedure in the differential diagnosis of hypercortisolism of pituitary or ectopic origin, as compared with clinical, biochemical and imaging analyses, with a sensitivity and specificity of 88–100% and 67–100%, respectively. In the setting of hypercortisolemia, ACTH levels obtained from venous drainage of the pituitary are expected to be higher than the levels of peripheral blood, thus suggesting pituitary ACTH excess as the cause of hypercortisolism. Direct stimulation of the pituitary corticotroph with corticotrophin-releasing hormone enhances the sensitivity of the procedure. The procedure must be undertaken in the presence of hypercortisolemia, which suppresses both the basal and stimulated secretory activity of normal corticotrophic cells: ACTH measured in the sinus is, therefore, the result of the secretory activity of the tumor tissue. The poor accuracy in lateralization of BIPSS (positive predictive value of 50–70%) makes interpetrosal ACTH gradient alone not sufficient for the localization of the tumor. An accurate exploration of the gland is recommended if a tumor is not found in the predicted area. Despite the fact that BIPSS is an invasive procedure, the occurrence of adverse events is extremely rare, particularly if it is performed by experienced operators in referral centres.

                Author and article information

                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                06 September 2023
                01 July 2023
                : 2023
                : 3
                : 23-0057
                [1 ]Department of Endocrinology and Internal Medicine , Aarhus University Hospital, Aarhus, Denmark
                [2 ]Department of Internal Medicine , Regional Hospital, Horsens, Denmark
                [3 ]Department of Pathology , Aarhus University Hospital, Aarhus, Denmark
                [4 ]Department of Internal Medicine, Gødstrup Hospital, Herning,Denmark
                [5 ]Department of Clinical Medicine , Aarhus University, Aarhus University Hospital, Aarhus, Denmark
                [6 ]Steno Diabetes Center Aarhus , Aarhus University Hospital, Aarhus, Denmark
                [7 ]Department of Pathology, University Health Network, Toronto,Canada
                [8 ]Department of Otorhinolaryngology , Head and Neck Surgery, Aarhus University Hospital, Aarhus, Denmark
                Author notes
                Correspondence should be addressed to V-N Mäkinen; Email: vivmaa@ 123456rm.dk
                Author information
                © the author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..

                : 09 May 2023
                : 06 September 2023
                Error in Diagnosis/Pitfalls and Caveats
                Error in Diagnosis/Pitfalls and Caveats

                adult,male,white,denmark,pituitary,thyroid,error in diagnosis/pitfalls and caveats,september,2023


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