ECTOPIC ACTH SYNDROME

Ectopic ACTH syndrome represents a cancer-induced amplification of a p roperty [proopiomelanocortin (POMC) peptides production] normally pres ent in the cells from which the cancer originated but with aberrant po sttranslational processing of POMC resulting in a greatly elevated sec retion of ACTH precursors. The classic ectopic ACTH-producing tumors d escribed in the 1960s were highly malignant but more recently slowly g rowing tumors such as carcinoids are reported with increasing frequenc y. Clinical features of patients with ectopic ACTH were analyzed, incl uding biochemical abnormalities, plasma ACTH, cortisol and urinary ste roids. Dynamic tests such as high-dose dexamethasone suppression, mety rapone and ovine-CRH (oCRH) stimulation were explored, as well as infe rior petrosal sinus ACTH sampling before and after oCRH. Among the tum or markers examined, elevation of ACTH precursors was uniformly presen t followed by increased output of calcitonin, gut hormones, oncofetal and placental hormones in decreasing order. Since more than 90% of ect opic ACTH tumors are neuroendocrine in nature exhibiting APUD characte ristics, their 2 markers, neuron-specific enolase and chromogranins ar e very useful. The imaging procedures for localization of the tumor ra nged from chest X-rays to computed tomography and magnetic resonance o f the chest and abdomen. Abdominal ultrasonography was also useful. Fi nally somatostatin receptor scintigraphy permitted demonstration of un recognized tumors and/or metastases, even when the tumors were occult. The ACTH content, immunostaining for APUD markers and altered POMC pr ocessing were evaluated in ectopic tumors and/or metastases. Occult ec topic ACTH syndrome of more than 4-6 months of symptoms without the em ergence of an obvious source was reviewed. Since the tumors are often clinically and biochemically undistinguishable from pituitary-dependen t Gushing's disease, inferior petrosal sinus sampling for ACTH after o GRH stimulation established the diagnosis in over 90% of the cases. 60 % of the occult tumors were thoracic carcinoids (3/4 bronchial carcino ids), followed by small cell lung cancer and pancreatic neuroendocrine tumors. In 12% the primary etiology was not detected. The rare syndro me of ectopic CRH syndrome (6 published cases) leading to excessive st imulation of the pituitary which became hyperplastic and secreted exce ssive amounts of ACTH is discussed. Finally, the 12 published cases an d 1 unreported patient with ectopic CRH-ACTH tumors were reviewed, the majority being metastatic small cell lung carcinomas, bronchial and t hymic carcinoids.