Case Report: Three Rare Cases of Ectopic ACTH Syndrome Caused by Adrenal Medullary Hyperplasia.

Ectopic ACTH syndrome (EAS) accounts for 10-20% of endogenous Cushing's syndrome (CS). Hardly any cases of adrenal medullary hyperplasia have been reported to ectopically secrete adrenocorticotropic hormone (ACTH). Here we describe a series of three patients with hypercortisolism secondary to ectopic production of ACTH from adrenal medulla. Cushingoid features were absent in case 1 but evident in the other two cases. Marked hypokalemia was found in all three patients, but hyperglycemia and osteoporosis were present only in case 2. All three patients showed significantly elevated serum cortisol and 24-h urinary cortisol levels. The ACTH levels ranged from 19.8 to 103.0pmol/L, favoring ACTH-dependent Cushing's syndrome. Results of bilateral inferior petrosal sinus sampling (BIPSS) for case 1 and case 3 confirmed ectopic origin of ACTH. The extremely high level of ACTH and failure to suppress cortisol with high dose dexamethasone suppression test (HDDST) suggested EAS for patient 2. However, image studies failed to identify the source of ACTH secretion. Bilateral adrenalectomy was performed for rapid control of hypercortisolism. After surgery, cushingoid features gradually disappeared for case 2 and case 3. Blood pressure, blood glucose and potassium levels returned to normal ranges without medication for case 2. The level of serum potassium also normalized without any supplementation for case 1 and case 3. The ACTH levels of all three patients significantly decreased 3-6 months after surgery. Histopathology revealed bilateral adrenal medullary hyperplasia and immunostaining showed positive ACTH staining located in adrenal medulla cells. In summary, our case series reveals the adrenal medulla to be a site of ectopic ACTH secretion. Adrenal medulla-originated EAS makes the differential diagnosis of ACTH-dependent Cushing's syndrome much more difficult. Control of the hypercortisolism is mandatory for such patients.

Ectopic ACTH syndrome of different origin-Diagnostic approach and clinical outcome. Experience of one Clinical Centre.

PURPOSE: Ectopic Cushing Syndrome (EAS) is a rare condition responsible for about 5-20% of all Cushing syndrome cases. It increases the mortality of affected patients thus finding and removal of the ACTH-producing source allows for curing or reduction of symptoms and serum cortisol levels. The aim of this study is to present a 20-year experience in the diagnosis and clinical course of patients with EAS in a single Clinical Centre in Southern Poland as well as a comparison of clinical course and outcomes depending on the source of ectopic ACTH production-especially neuroendocrine tumors with other neoplasms. METHODS: Twenty-four patients were involved in the clinical study with EAS diagnosed at the Department of Endocrinology between years 2000 and 2018. The diagnosis of EAS was based on the clinical presentation, hypercortisolemia with high ACTH levels, high dose dexamethasone suppression test and/or corticotropin-releasing hormone tests. To find the source of ACTH various imaging studies were performed. RESULTS: Half of the patients were diagnosed with neuroendocrine tumors, whereby muscle weakness was the leading symptom. Typical cushingoid appearance was seen in merely a few patients, and weight loss was more common than weight gain. Patients with neuroendocrine tumors had significantly higher midnight cortisol levels than the rest of the group. Among patients with infections, we observed a significantly higher concentrations of cortisol 2400 levels in gastroenteropancreatic neuroendocrine tumors. Chromogranin A correlated significantly with potassium in patients with neuroendocrine tumors and there was a significant correlation between ACTH level and severity of hypokalemia. CONCLUSION: EAS is not common, but if it occurs it increases the mortality of patients; therefore, it should be taken into consideration in the case of coexistence of severe hypokalemia with hypertension and muscle weakness, especially when weight loss occurs. Because the diagnosis of gastroenteropancreatic neuroendocrine tumor worsens the prognosis-special attention should be paid to these patients.

Ectopic ACTH syndrome associated with large-cell neuroendocrine carcinoma of the lung.

Although ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a well-known paraneoplastic phenomenon, an association with large-cell neuroendocrine carcinoma of the lung (LCNEC) has not been reported. We describe a 63-year-old man with metastatic LCNEC to the left temporomandibular joint (TMJ) who presented with progressive muscle weakness and bilateral lower leg edema for 2 weeks. He did not have a typical Cushingoid appearance nor used diuretics. His newly noted hypertension, hypokalemia (plasma potassium (K) concentration 1.8 mEq/L) with renal K wasting, and metabolic alkalosis suggested a state of mineralocorticoid excess. His plasma renin activity and aldosterone concentrations were low, but cortisol and ACTH levels were extremely elevated, consistent with ACTH-dependent Cushing's syndrome. Nonsuppressible plasma cortisol level and normal sella turcica on magnetic resonance imaging pointed to EAS. A strongly positive stain for ACTH from the metastatic left TMJ mass supported LCNEC-related EAS. His hypokalemia and hypertension were controlled with spironolactone and K supplementation. This is the first reported case of EAS in LCNEC and should be kept in mind as a cause of hypokalemia in lung cancer patients.

Correction of metabolic alkalosis by potassium chloride in ectopic adrenocorticotropic hormone syndrome.

A 57-year-old white man presented with metabolic alkalosis, hypokalemia (pH 7.58, HCO3 >50 mEq/L, serum K 1.8 mEq/L) and hypertension. The initial evaluation was significant for markedly elevated serum cortisol and adrenocorticotropic hormone (ACTH) level; neither hormone showed circadian rhythm or suppression with high-dose dexamethasone. Perihilar and supraclavicular masses were found to consist of undifferentiated small cell carcinoma. Ectopic ACTH syndrome was diagnosed. In spite of progressively rising hormone levels (ACTH, 723 pg/dL; and cortisol, 212 microgram/dL), his severe metabolic alkalosis was largely corrected by aggressive treatment with potassium chloride alone. Possible mechanisms of these clinical findings are discussed.

An evaluation of the distinction of ectopic and pituitary ACTH dependent Cushing's syndrome by clinical features, biochemical tests and radiological findings.

The efficiency of various laboratory and radiological investigations in the differentiation of ectopic from pituitary dependent Cushing's syndrome was studied, based on findings in 23 patients with verified Cushing's disease and seven patients with the ectopic ACTH syndrome. Clinical features strongly favouring the ectopic type were male sex and history for less than 18 months. Basal biochemical features strongly indicating the ectopic syndrome included plasma K+ less than 3.0 mmol/l and HCO3 greater than 30 mmol/l; serum cortisol at 9 a.m. or midnight of greater than 800 nmol/l; urine free cortisol greater than 1300 nmol/24 hours; plasma ACTH greater than 100 ng/l. In the high-dose dexamethasone suppression test, suppression by less than 50 per cent of 9 a.m. serum cortisol, urine free cortisol or 17-oxogenic steroids was usually indicative of an ectopic source of ACTH. A mean suppressed value of greater than 450 nmol/l for the 9 a.m. and midnight cortisol combined occurred in all of those with the ectopic syndrome, but in none of the 23 patients with Cushing's disease. For urine free cortisol, a mean suppressed value of less than 1000 nmol/24 hours was found in all patients with Cushing's disease, but in none of those in the ectopic group. In the metyrapone test, there was an increase of less than or equal to 3-fold in 11-deoxycortisol at 24 hours in patients with ectopic ACTH; the increase was greater than 3-fold in all but one of the patients with Cushing's disease. Failure to respond to either dexamethasone or metyrapone was found in only one of the patients with Cushing's disease (Patient 16); in the ectopic group, all patients except Patient D failed to respond to either test. It is concluded that patients presenting with clinically obvious Cushing's syndrome along with measurable plasma ACTH can be reliably divided by conventional tests into those that are driven from the pituitary and those driven by ectopic ACTH.

Diagnosis and management of ACTH-dependent Cushing's syndrome: comparison of the features in ectopic and pituitary ACTH production.

The clinical features, diagnosis and management of 16 consecutive patients with ectopic ACTH production are described and biochemical data are compared with those of 48 consecutive patients with pituitary-dependent Cushing's disease. In 10 cases the ectopic ACTH secreting tumour was completely occult to routine clinical and radiological investigation, and no basal or dynamic investigation of adrenal-pituitary function was able clearly to differentiate these patients from those with Cushing's disease. High dose dexamethasone suppression testing assessed by plasma cortisol was usually helpful but unexpected responses were seen in both diagnostic groups; the metyrapone test yielded no useful information and should now be abandoned. Hypokalaemia was seen in all patients with ectopic ACTH production but in only 10% of those with Cushing's disease who were not on diuretics at presentation. Successful diagnosis and tumour localization was most frequently achieved by a combination of CT scanning of the chest and abdomen and venous catheter sampling for ACTH. All patients in whom the ectopic ACTH-secreting tumour was obvious at presentation died of their primary tumour within 8 months, whereas seven of the 10 patients with occult tumours at presentation are alive 1.5-16.5 years later, and appear cured. Occult ectopic ACTH secretion may be impossible to distinguish from pituitary Cushing's disease. Multiple and repeated investigations are often required to make this differential diagnosis, essential for appropriate therapy.