Departments of Endocrinology, *Cardiothoracic Surgery, **Pathology & â Radiodiagnosis, Postgraduate Institute ..... Williams textbook of endocrinology.
Indian J Med Res 129, January 2009, pp 33- 41
Ectopic Cushing’s syndrome: Experience from a tertiary care centre A. Bhansali, Rama Walia, S.S. Rana*, P. Dutta, B.D. Radotra**, N. Khandelwal† & S.K. Bhadada
Departments of Endocrinology, *Cardiothoracic Surgery, **Pathology & †Radiodiagnosis, Postgraduate Institute of Medical Education & Research, Chandigarh, India
Received June 8, 2007 Background & objectives: Ectopic secretion of adrenocorticotropic hormone (ACTH) is rare, contributing to 10 per cent cases of endogenous Cushing’s syndrome. We describe our experience of about two decades of patients with ectopic Cushing’s syndrome (ECS) seen at a tertiary care centre from north India. Methods: Records of patients with ECS from 1985 to 2006 were retrospectively reviewed that included the presenting manifestations, clinical symptoms and signs, biochemical investigations including plasma cortisol, ACTH and high dose dexamethasone suppression test (HDDST), imaging modalities to localize the non pituitary source of ACTH production, management and follow up of these patients. Results: The study group included 12 patients (7 men) with mean (±SD) age at presentation 27.6 ± 9.5 yr (range 13 to 48 yr) and the mean lag period between onset of symptoms and the diagnosis was 18.3 ± 12.9 months with a range of 3 to 48 months. The weight loss (41.7%) followed by hyperpigmentation (25%) and infections (16.7%) were the common presenting manifestations. Cuticular atrophy (100%), hypertension (100%), bruise (92%) and proximal myopathy (83%) were the commonest signs. Plasma cortisol at 0800 h was 1267.3 ± 483.3 nmol/l and at 2200 h was 1214.9 ± 442.6 nmol/l indicating loss of circadian rhythm. The mean plasma ACTH was 221.1 ± 55.9 (range 21.7 to 950 pg/ml). All but 2 patients had non-suppressibility of 0800 h plasma cortisol with HDDST. Five patients had thymic carcinoid, 3 had bronchial and one each had islet, hepatic and gut carcinoid and one had medullary thyroid carcinoma as a cause of ectopic ACTH secretion. The mean duration of follow up of these patients was 42.6 months and only two could sustain cure while remaining had either residual or recurrence. Interpretation & conclusion: Ectopic Cushing’s syndrome is a rare disease with varied manifestations and associated with increased morbidity and mortality. It presents with clinical features quite similar to classical Cushing’s. Surgery with removal of primary tumour was found to be treatment of choice. Key words Carcinoid - corticotrophin - Cushing’s disease - ectopic Cushing’s syndrome - neuroendocrine tumour
inordinately (75-80%) caused by adrenocorticotropic hormone (ACTH) secreting pituitary adenomas and the remaining 20-25 per cent is contributed by adrenal
Cushing’s syndrome refers to the symptoms and signs that result from excessive tissue exposure to glucocorticoids. Endogenous Cushing’s syndrome is 33
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neoplasias (10-15%) and ectopic ACTH secretion (10%)1,2. Non pituitary (ectopic) sources of ACTH include small cell carcinoma of the lung in half the patients and rest are from the various neuroendocrine tumours namely bronchial and thymic carcinoids, and rarely from gut carcinoid3,4. Ectopic Cushing is very rare with a prevalence of one case per million per year and most of these have been described as lone case reports and a few series3-17. Characteristically ectopic ACTH production is said to cause a clinical syndrome which, unlike pituitary dependent Cushing disease is of rapid onset associated with rapid weight loss, muscle weakness, hypokalemic metabolic alkalosis, glucose intolerance, high levels of plasma cortisol and ACTH. In such patients there is usually an obvious underlying tumour and most commonly it is a small cell carcinoma of the lung. However, relatively benign tumours, in particular slowly growing carcinoid tumours2,3 can give rise to a clinical syndrome which is indistinguishable from pituitary Cushing disease. Clinical manifestations of glucocorticoid and/or androgen excess may be the only clues for carcinoids, though they sometimes may present with marked hyperpigmentation, diarrhoea, flushing, and/or palpitations18. Biochemically, these neoplasms have been described to secrete various biologically active substances including gastrin, insulin, calcitonin and vasoactive intestinal peptide, as well as corticotropin. Nevertheless, localization of ectopic source of ACTH is not always easy and sometimes it could be delayed from months to years. Because of this, these patients have increased morbidity and consequently culminating into enhanced mortality. We describe our experience of patients with ectopic Cushing’s syndrome from a tertiary care centre in north India, seen during last 22 years. Material & Methods Between 1985 and 2006, 156 patients attending Endocrine Clinic at Nehru Hospital, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, were diagnosed to have endogenous Cushing’s syndrome (CS). Of these 12 had ectopic ACTH syndrome constituting 7.7 per cent of cases. The case records of these patients were reviewed retrospectively. The diagnosis of Cushing’s syndrome was based on clinical features of protein catabolism and/or features of androgen excess. Protein catabolism was evident in the form of striae, easy bruisability, muscle weakness, and cuticular
and pulp atrophy. Androgen excess manifested as hirsutism, virilization and defeminization as oligo/amenorrhoea in women. The diagnosis of endogenous Cushing’s syndrome was based on stepwise approach: first, the definitive determination of the presence of hypercortisolemic state; second whether CS is ACTH dependent or not, and third if CS is ACTH dependent, then localization of the source of ACTH production. Biochemically, diagnosis was based on elevated basal cortisol levels with loss of circadian rhythm, inappropriately elevated ACTH levels in relation with 2200 h cortisol and nonsuppressible serum cortisol to low dose dexamethasone. ACTH dependency of CS was indicated by high ACTH levels (> 23 pg/ml) in the presence of elevated cortisol levels ( >210 nmol/l)26. The ectopic source of ACTH was localized by imaging including computerized tomography, (Light speed GE Medical System, USA) and magnetic resonance imaging (Somatom, Siemens, Germany 1.5 Tesela) wherever indicated in all of these patients. Biochemical methods: Plasma cortisol was measured by in-house radioimmunoassay (RIA) by using tritium labelled cortisol after dextran charcoal separation with intra-assay and inter-assay coefficients of variation being
