Clinical Endocrinology (1978) 9, 1-14.

CUSHING’S S Y N D R O M E , N O D U L A R A D R E N A L H Y P E R P L A S I A A N D V I R I L I Z I N G CARCINOMA

D . C. A N D E R S O N , D . F. C H I L D , C. H. S U T C L I F F E , C. H. B U C K L E Y , D. D A V I E S A N D D. LONGSON

Department of Medicine and Endocrine Unit, Manchester Royal I n j b n a ~and , Department of Pathology, University of Manchester, England (Received 6 July 1977; revised 7Novernber 1977; accepted 18 November 1977) SUMMARY

A 48-year-old hypertensive diabetic woman rapidly became virilized. Urine 17-0x0and oxogenic steroids and plasma testosterone, androstenedione, DHEA, DHEAsulphate and androstenediol were greatly elevated. Plasma cortisol was constantly high and was not suppressed by dexamethasone. Circulating immunoreactive ACTH was consistently detectable at 18-24 n d l . A 450 g carcinoma arising from a nodular hyperplastic right adrenal gland was resected. Production by the tumour of 17ahydroxypregnenolone, 17a-hydroxyprogesterone and five C- 19 steroids, but very little prenenolone, progesterone or cortisol, was shown by blood sampling, tumour culture and dramatic falls after operation. The plasma cortisol fell to half, with n o diurnal variation, consistent with persistent Cushing’s syndrome, and the plasma ACTH rose to 55 ng/l. She died 3 months later from a myocardial infarction. Autopsy revealed a pituitary basophil adenoma at a site where radiologically there had been an indentation in the fossa floor for at least 7 years. The left adrenal gland showed nodular hyperplasia. Therefore we conclude that mild pituitarydependent Cushing’s syndrome may have been present for many years before development of a virilizing carcinoma. This case demonstrates that adrenal carcinoma in man can sometimes develop as a consequence of nodular adrenal hyperplasia which may in turn be due to long-standing trophic hyper-stimulation. The majority of patients with Cushing’s syndrome have bilateral adrenal hyperplasia resulting from an excessive and inappropriate secretion of pituitary ACTH (Besser & Edwards, 1972). There is substantial evidence to support Harvey Cushing’s original contention (Cushing, 1932) that such patients frequently have a pituitary adenoma (Salassa et al., 1959), although studies of adrenal steroid and pituitary growth hormone secretion have suggested that the primary abnormality lies in the central nervous system (Kreiger & Click, 1972). Multinodular hyperplasia is felt by some to be a variant of pituitary-dependent Cushing’s disease Correspondence: Dr David C. Anderson, Department of Medicine, Hope Hospital, Salford M6 8HD, England. 0300-0664/78/0700-0001 #02.000 1978 BlackweU Scientific Publications

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(Neville & Symington, 1967), although the presence of low or normal ACTH levels in such cases has suggested a primary adrenal disorder (Meador ef al., 1967). The adrenal in these patients may appear t o behave autonomously, exhibiting a relative independence of ACTH control and an atypical response t o the administration of dexamethasone (Ruder et al., 1974). The minority of patients presenting with Cushing’s syndrome have either an adrenal carcinoma or adenoma. These tumours have generally been held to arise in an otherwise normal gland. Patients frequently have symptoms of marked virilization or feminization, in addtion t o or instead of the classical features of Cushing’s syndrome (Hutter & Kayhoe, 1966). In those with excess cortisol production, ACTH production is suppressed and the ‘normal’ adrenal tissue o n both sides becomes atrophic (Cope & Baker, 1955). In this paper we describe a patient with an extremely unusual group of related diseases. She presented with a virilizing adrenocortical carcinoma and biochemical Cushing’s syndrome. The carcinoma was unusual in that the rest of the adrenal gland removed a t operation showed nodular adrenal hyperplasia. After removal of the carcinoma she continued to have biochemical Cushing’s syndrome. 3 months later she died of a myocardial infarction and was found at autopsy to have multinodular hyperplasia in the other adrenal gland and a pituitary adenoma a t a site where there had been radiological indentation of the pituitary fossa for at least 7 years. Evidence is presented that the virilizing adrenal carcinoma developed in a nodularly hyperplastic adrenal gland which may have been subjected t o very longstanding chronic stimulation with ACTH. MATERIALS AND METHODS Assays

Plasma cortisol and immunoreactive testosterone levels were measured by direct radioimmunoassay of ether extracts. In the case of cortisol the anti serum used (gift of Dr -I. Robertson), was raised t o an 1 1-conjugate and the only circulating endogenous steroid apart from cortisol that binds significantly is 1 1-deoxycortisol (40% cross-reaction). Prednisolone shows 79% cross-reaction and dexamethasone 2%. For testosterone the antiserum used (gif% of Dr E. Nieschlag), was raised against a 3conjugate and is of high specificity, cross-reacting significantly only with 5a-dihydrotestosterone (40%cross-reaction). The steroids pregnenolone, progesterone, 17a-hydroxypregnenolone, 17a-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, 5-androstenediol and testosterone were also all measured by specific methods after extraction and celite column fractionation (Anderson ef al., 1976a). Dehydroepiandrosterone sulphate was measured by the method o f Buster & Abraham (1972). Plasma 1 1-hydroxycorticosteroids (1 I-OHCS) were measured by the method of Mattingly (1962). Urinary steroids were measured after extraction by the method of Shackleton er al. (1968), followed by gas liquid chromatography with columns of 3% trifluoropropylmethylsilicone (FS1) on Diatomite Q. Plasma ACTH was measured by a modification of the radioimmunoassay of Rees ef a1 (1971). The method involves prior extraction of ACTH from 5 ml plasma onto Spherosiii glass granules (Pechiney-St Gobin, Pans), and the antibody used is an N-terminal anti-human serum (No. RD05RJ306), obtained from Wellcome Reagents L m i t e d , Beckenham, Kent, England. The assay standard is human ACTH (gft from Dr C. Court, Wellcome Reagents Limited), calibrated in terms of Lerner Upton Standard ACTH. The assay was run at equilibrium, and free separated from bound by dextrancoated charcoal. The sensitivity of the

Adrenal hyperplasia and carcinoma

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assay (3 SD from zero) was 12.3k5.3 ng ACTH/l, plasma (mean and SD of eight assays). Basal 08.00-10.00 hours levels in forty-five unstressed hospitalized control subjects were mean 26, range 12-63 ng/l.

Test procedures All test procedures were standard ones used in the diagnosis o f patients with Cushing's syndrome; dexamethasone suppression (2 and 8 mg/day for 3 days); metyrapone stimulation (750 mg every 4 h for 24 h); and ACTH stimulation with infusion o f synthetic 1-24 ACTH (Synacthen) (10 pg/h for 6 h).

Organ culture (Dr I. Kimber) Within 2 h o f resection small 1 mm31urnps of tumour were placed in Waymouth's medium (Slow Labs, Scotland) containing 10% dimethysulphoxide and 30% fetal bovine serum, in glass vials which were then heat-sealed and frozen to -150°C in a Planar Rate-Controlled Freezer, model R201. The programme followed was; a slow fall over 20 min to 4"C, then a sharp drop over 1 min t o -2O"C, then a fall of l"/min t o -150°C. The samples were removed and stored in the vapour phase of liquid N2 at -70°C. 3 weeks later samples were thawed out rapidly, washed in medium, and short-term organ culture at 37°C in an atmosphere of 95% air: 5% C 0 2 was performed for 2 4 h in the presence of Synacthen 1 pg/ml in Waymouth's medium in microtest plates (well capacity 0.2 ml). Attempts at incubation of further fragments 2 months later did not yield any steroid products. Three attempts at monolayer culture of the cells of the tumour were unsuccessful. CASE HISTORY

I.M., a woman aged 48 years at the time o f presentation in March 1975 Renal diseases and hypertension Since 1953 she had recurrent attacks of pyelonephritis, which were treated with antibiotics. In 1964 (aged 37 years) she was found to have pulses alternans, hypertension, cardiomegaly, triple-rhythm and borderline left ventricular failure. From 1964 onwards she was noted to have a persistent neutrophil leucocytosis. In 1965 her blood pressure was 240/130 mmHg and blood urea 12.5 mmol/l. I.V.P. and renal arteriogram were normal. She was treated with methyldopa, bethanidine, digoxin and frusemide, Renal function thereafter remained unchanged. In 1971 she had an episode of probable acute pancreatitis and steatorrhoea.

Endocrine diseases In 195 1 (aged 2 4 years) after two normal pregnancies she developed painful fibroadenosis of both breasts. In 1954, following a blood stained discharge from the right nipple, a simple mastectomy was performed. Histology did not confirm breast carcinoma. In 1955 a left simple mastectomy was performed, because of the painful fibroadenosis. Shortly afterwards she developed endogenous depression. In 1963, she presented with exophthalmos, and a clinical diagnosis of thyrotoxicosis was made; she was treated with carbimazole for 1 year. In 1971 during investigation o f a transient episode of steatorrhoea, the diagnosis of Cushing's syndrome was considered because of the association of hypertension, a deep suntan and pigmentation around the lips (but without buccal pigmentation); urine 17-0x0- and oxogenic

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steroids however were normal (18 and 28.5 pmol/24 h, respectively). In October 1974 she developed diabetes mellitus which responded partially to dietary treatment. In March 1975 she presented with a history of 6 months’ increasing baldness, beard growth and 7 kg weight loss. A diagnosis of virilizing adrenal tumour was made on the basis of the clinical findings, and extremely high urinary steroids. On examination, she had bilateral exophthalmos. She was in severe congestive cardiac failure, with gross left ventricular hypertrophy and a gallop rhythm. She was extremely plethoric, and wasted, with a large protuberant abdomen and ascites. Considering her generalized wasting, the muscles were relatively weU-developed. She had very coarse facial hair, and had t o shave every day. There was an indistinct right upper abdominal mass. Her voice was normal and there was no clitoroniegaly . Itivestigations

Haernoglobin 18.4 g/dl, white blood count 11.6-12.9 X 106/1, ESR 1 rnm/lst hour. Serum urea, 1 1.2 rnmol/l, serum creatinine 106 pmol/l; creatinine clearance, 52 ml/min; plasma glucose, 15-21 mmol/l. Plasma 11-OHCS 09.00 hours 1090 nniol/l (normal 220-744); 23.00 hours 9 9 2 nmol/l (normal

Cushing's syndrome, nodular adrenal hyperplasia and virilizing carcinoma.

Clinical Endocrinology (1978) 9, 1-14. CUSHING’S S Y N D R O M E , N O D U L A R A D R E N A L H Y P E R P L A S I A A N D V I R I L I Z I N G CARCIN...
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