Ectopic production of adrenocotropic hormone (ACTH) accounts for approximately 15% of cases of Cushing’s syndrome. Several types of malignant and non-malignant tumors of neuroendocrine origin have been implicated in ectopic ACTH production. Bronchial carcinoids account for approximately one quarter of such cases. Periodic hormonogenesis by ectopic ACTH producing tumors other than bronchial carcinoid is an unusual phenomenon that has been reported in the endocrine literature. The following represents what is believed to be the first reported case of a bronchial carcinoid with periodic ACTH production causing cyclic Cushing’s syndrome.
A 67 year old female presented with Cushing’s syndrome manifested by generalized fatigue, weakness, hypertension, Cushingoid appearance, thrush, hyperkalemia and hyperglycemia. The patient had experienced a similar episode of Cushing’s syndrome four years prior to presentation. Evaluation at that time did not reveal an etiology, and the syndrome resolved spontaneously. In interim follow-up until the recent past, the patient remained asymptomatic with normal ACTH and cortisol levels. On exam, the patient showed a marked Cushingoid appearance. There were whitish plaques on her oral mucosa, consistent with thrush. Her BP was 168/96 mm Hg. Laboratory evaluation revealed a potassium of 2.7 mmol/L, glucose of 279 mg/dL, ACTH of 101 pg/dL (normal 5-50 pg/dL), cortisol of 77 mcg/dL (normal 5-25 mcg/dL) and 24-hour urine cortisol > 6000 mcg (normal 3-34 mcg/dL). An MRI of the brain was normal. Somatostatin receptor scintigraphy with [111-In] pentetreotide did not show suspicious uptake. CT of chest and abdomen revealed an 8 mm right middle lobe nodule. Her hypokalemia was corrected and she was begun on metyrapone and ketoconazole to inhibit cortisol production. A cardiothoracic surgery consult was obtained and the patient underwent resection of the right middle lobe nodule. Pathology revealed a typical carcinoid which stained positive for chromogranin A and ACTH. On follow-up, the patient’s symptoms and metabolic abnormalities have resolved. ACTH and cortisol levels have normalized.DISCUSSION: Ectopic production of ACTH leading to hypercortisolism and Cushing’s syndrome is thought to occur in approximately 1% of bronchial carcinoids. As in this patient, diagnosis of these tumors is often delayed for years after Cushing’s syndrome becomes apparent. There are several likely explanations for such delay. First, these tumors are generally small, averaging about 1.1 cm at the time of diagnosis. Conventional imaging modalities such as CT and MRI have a sensitivity for these lesions which is considerably less than 100%. More recently, attempts at localization of ACTH producing lesions with [111-In] pentetreotide scintigraphy have proven somewhat disappointing, with sensitivities of 25-65%. In addition, up to 30% of ectopic ACTH producing lesions will show suppression on dexamethasone testing, thus making differentiation from pituitary lesions difficult without petrosal venous sampling. In this case, the unusual cyclic presentation was likely a significant contributing factor in the delay in diagnosis. Cyclic Cushing’s syndrome is defined by a pattern of hypercortisolism with intermittent periods of normal cortisol production. This pattern was documented in this patient by surveillance of ACTH and cortisol levels in the period between her episodes of Cushing’s syndrome. Reports in the endocrine literature describe cases of cyclic Cushing’s syndrome related to various types of ACTH producing neuroendocrine tumors including pituitary adenoma, thymic carcinoid and apudoma. However, this is thought to be the first reported case of an ectopic ACTH producing bronchial carcinoid causing cyclic Cushing’s syndrome. The etiology of the periodicity of hormone production in these tumors is unknown.
Ectopic ACTH producing bronchial carcinoids can exhibit periodicity of hormonogenesis such as that reported in other types of ectopic ACTH producing tumors. This characteristic leads to the entity of cyclic Cushing’s syndrome.
D.S. Frenia, None.