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Ectopic Release of GHRH and ACTH from an Adenoid Cystic Carcinoma Resulting in Acromegaly and Complicated by Pituitary Infarction

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Ectopic Release of GHRH and ACTH from an Adenoid Cystic Carcinoma Resulting in Acromegaly and Complicated by Pituitary Infarction Postgrad Med J: first published as 10.1136/pgmj.64.748.145 on 1 February 1988. Downloaded from Postgraduate Medical Journal (1988) 64, 145-148 Ectopic release of GHRH and ACTH from an adenoid cystic carcinoma resulting in acromegaly and complicated by pituitary infarction H.J. Southgate, G.P.R. Archbold, M.E. El-Sayed,' J. Wright and V. Marks Department of Clinical Biochemistry and 'Department of Radiotherapy, St. Luke's Hospital, Guildford, Surrey Summary: A 23 year old man presented with a tumour mass in the lung. Subsequent investigation showed ectopic secretion of adrenocorticotrophic hormone (ACTH) and growth hormone releasing hormone (GHRH) from an adenoid cystic carcinoma. The patient progressed to show the clinical effects of long term exposure to high blood levels of both growth hormone and cortisol. The case was complicated by pituitary infarction. The very high blood levels of ACTH, growth hormone (GH) and GHRH proved resistant to treatment with the somatostatin analogue, SMS 201-995, and a possible side effect of the drug is reported. To our knowledge this is the first reported case of ectopic hormone secretion by an adenoid cystic carcinoma. Introduction Acromegaly due to ectopic production of growth Case report by copyright. hormone releasing hormone (GHRH) has been described in association with a variety of tumours A 23 year old Caucasian man with no previous including carcinoid and pancreatic islet cell relevant medical history presented in June 1981 tumours.1 2'3'4 More than one ectopic hormone with pain in the right side of the chest and may be present in the tumour; in one reported case breathlessness. Chest X-ray showed a shadow in the of metastatic carcinoid presenting clinically with right lung which was thought to have features of a acromegaly, gigantism and Cushing's syndrome,1 dermatoteratoma. The patient refused further for example, both growth hormone (GH) and investigation, returning two years later in June 1983 GHRH were identified in the tumour. However, the complaining of a lump in the right side of the neck presence of immunoreactive hormone in tumour which had been present for some 8 months. http://pmj.bmj.com/ tissue is not necessarily synonymous with ectopic Biopsy of the neck lump showed an adenoid cystic hormone secretion; in one case of metastatic carcinoma which was presumed to be metastatic carcinoid, growth hormone was present in the from the lung primary. Computed tomographic tumour but no arteriovenous gradient was (CT) scan showed a large tumour mass in the right demonstrated across it. 5We report a case of lung, and at thoracotomy an extensive non- ectopic secretion of GHRH and adrenocortico- resectable mediastinal mass was found. Treatment trophic hormone (ACTH) from an adenoid cystic was commenced with radiotherapy to the chest carcinoma with failure to respond to the and right side of the neck. In October 1983 the on September 27, 2021 by guest. Protected somatostatin analogue SMS-201-995 (Sandoz). The patient was admitted to St. Luke's Hospital, case was further complicated by pituitary Guildford for chemotherapy. The patient was infarction. To our knowledge this is the first started on the Price-Hill chemotherapy regime reported case of ectopic secretion by adenoid cystic (intermittent courses of vincristine, bleomycin, carcinoma. methotrexate and 5 fluoro-uracil). On admission, features of acromegaly were noted but no specific investigations were performed. The patient received seven cycles of chemotherapy finishing May 1984. In July 1984 the patient was re-admitted Correspondence: H.J. Southgate B.Sc., M.R.C.P.(UK), complaining of thirst, polyuria, lethargy, un- M.R.C.Path. steadiness of gait and bilateral swelling of both Accepted: 7 August 1987 legs from foot to mid-calf. On examination, acne ©) The Fellowship of Postgraduate Medicine, 1988 P.M.-C Postgrad Med J: first published as 10.1136/pgmj.64.748.145 on 1 February 1988. Downloaded from 146 CLINICAL REPORTS vulgaris, bilateral exophthalmos and skin pigmen- occasions when they had been measured - rose in tation were noted. Marked proximal muscle wasting response to TRH/LHRH. Plasma thyroxine levels was present in all four limbs. The strong clinical and the thyroid stimulating hormone (TSH) features of acromegaly were supported by radio- response to TRH were normal. logical measurement. Hyperglycaemia persisted and the patient's Some initial biochemical investigations are shown diabetes which, in view of the high basal C-peptide in Table I. Plasma cortisol levels which were high levels appeared to be due to insulin resistance with no diurnal variation and no response to either rather than to pancreatic failure, was treated with low dose (2mg overnight) or high dose (2mg four subcutaneous insulin 68 units twice daily initially, times daily for 4 days) dexamethasone. Standard rising rapidly to 68 units four times a day. The luteinising hormone releasing hormone (LHRH) oedema improved with diuretic therapy. and thyrotrophin releasing hormone (TRH) tests The patient was discharged home requiring 272 were performed; the results are shown in Table II. units of insulin daily to control his diabetes. He Basal testosterone was low and there was an was readmitted the following day as an emergency exaggerated luteinising hormone (LH) response to complaining of severe frontal headaches and LHRH. Although prolactin levels were markedly vomiting. He had marked photophobia and the raised they subsequently fluctuated between 320 and history obtained from relatives suggested that he 460m U/l during a 6 hour saline infusion. Plasma had also fitted. The fundi were normal. He GH levels - which were lower than on previous recovered rapidly over 48 hours. A CT scan of the brain revealed a large sella turcica and several Table I Selected results obtained prior to treatment cerebral metastases. His symptoms were initially and pituitary infarction attributed to metastases and, despite hypercorti- solaemia, he was treated with a high dose of oral Random blood glucose 29.4 mmol/l dexamethasone (2mg q.d.s.). Irradiation to the Plasma albumin 32g/l whole brain was given over 10 days to a total dose Random plasma GH 44mU/l of 300 c GY. by copyright. Plasma IGF-l 4.16 U/1 Although a single dose of the somatostatin (insulin like growth factor I) normal range 0.4-2) analogue SMS 201-995 (Sandoz UK) 50 pg Random plasma cortisol 1016 nmol/l subcutaneously had no acute effect on circulating Random plasma C-peptide 6.7 ug/l levels of glucose, insulin, C-peptide, ACTH or Insulin antibodies none detected cortisol, treatment was commenced at a sub- Plasma total thyroxine 101 nmol/l cutaneous dose of 50pg b.d. on 30 August 1984. Plasma testosterone 6 nmol/l This produced no significant change in the clinical Urinary free cortisol grossly elevated condition, plasma growth hormone, cortisol, blood Urinary VMA excretion normal glucose levels, or insulin requirements. (vanillylmandelic acid) After 10 days acute copious diarrhoea developed. Urinary 5HIAA excretion normal http://pmj.bmj.com/ 5 hydroxy indole acetic acid) Insulin requirements fell dramatically and treatment Plasma ACTH 300 pg/l with SMS 201-995 was stopped after which the (normal range diarrhoea gradually settled. Biochemical evidence 20-80) now showed that the patient had suffered pituitary Plasma GHRH 45,000 ng/l infarction, most likely during his previous acute (normal range admission. The episode of diarrhoea is unexplained 10-60) but may have been due to the SMS 201-995. on September 27, 2021 by guest. Protected Table II TRH/LHRH stimulation test Plasma LH FSH TSH T4 GH Cortisol Prolactin IU/l IU/I mU/l nmol/l mU/I nmol/l mU/I Basal 1 1 2.2 87.0 6.2 2058 2511 100 pg LHRH and 200 pg TRH intravenously 20min - - 14.3 - 27.1 - 1538 30min 50 9 - -- - 1014 60min 27 4 10 - 11.2 - 473 Postgrad Med J: first published as 10.1136/pgmj.64.748.145 on 1 February 1988. Downloaded from CLINICAL REPORTS 147 Pituitary function tests were performed on 1 Although arterio-venous differences across the October 1984. Basal TSH, LH, follicle stimulating tumour were not measured the evidence for ectopic hormone (FSH) and growth hormone were below production is good: (i) the failure of plasma ACTH the level of detection and showed no response to and cortisol levels to respond to high dose TRH and LHRH. Both total thyroxine (34nmol/l) dexamethasone;7 (ii) the persistence, following and 'free' thyroxine (4.0 pmol/l) were low but pituitary infarction of high plasma cortisol and plasma cortisol, ACTH and GHRH levels remained ACTH levels; and (iii) the immunocytochemical high. Over the 6 months period following the demonstration of ACTH in the tumour. presumed pituitary infarction, plasma insulin-like Similarly, the presence of grossly elevated levels growth factor I (IGF-1) levels fell from 5.6 to of GHRH in peripheral venous blood, with a fall in 0.2 IU/I and prolactin levels fell to less than the high levels of growth hormone and IGF-1 but 50 mU/l. not GHRH, following pituitary infarction, together Pre-infarction plasma levels of gastrin, vasoactive with the large amounts of GHRH demonstrated intestinal polypeptide (VIP), glucagon, calcitonin, immunocytochemically in the tumour tissue, point somatostatin and bombesin were normal at all to ectopic secretion of GHRH. times. Corticotrophin releasing factor (CRF) was The somatostatin analogue, SMS 201-995, failed undetectable in plasma both before and after to suppress the elevated levels of GH, insulin, pituitary infarction. glucose, GHRH or ACTH which contrasts with the Immunoperoxidase staining of the tumour biopsy findings in regular acromegaly where somatostatin showed both ACTH and GHRH. No immuno- and its analogues consistently lower basal GH8-12 chemical CRF, GH or 5 hydroxytryptamine and insulin levels1 3 and block the response to (5HT) was demonstrated.
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