Case reports
Adrenocortical carcinoma with tumour-induced hypoglycaemia 1
M H A Rustin BSC MRCP2 S J Bowcock MB BS3 E N Coomes MD FRCP St Stephen’s Hospital, London SW10 9TH
Adrenocortical carcinomas are rare, with an incidence of 0.04% to 0.2% of all malignant tumours (Bradley 1975, Didolkar et al. 1981). They most commonly present as an abdominal mass but they also may present as functioning tumours producing feminization, virilization, Cushing’s syndrome or hypoglycaemia (Hutter & Kayhoe 1966a, MacFarlane 1958). We describe a patient presenting with a right hemiparesis secondary to hypoglycaemia induced by an adrenocortical carcinoma. Hemiparesis is an uncommon manifestation of hypoglycaemia (Montgomery et al. 1964) but may be recognized by the accompanying signs of excessive adrenergic discharge and full recovery on prompt adminis- tration of glucose.
Case report
A 29-year-old female market research worker gave a two-month history of tingling in the hands and lips occurring at 18:00 hours most weekdays but not during the weekends. Three weeks prior to admission she complained of abdominal dis- tension and a constant left loin pain. She was brought to casualty unconscious. On examination she was sweating, had a right hemiparesis, a right extensor plantar and dilated but equally reacting pupils. In the left hypochondrium there was a firm, irregular mass which did not move with respiration and had an upper edge below the costal margin. The plasma glucose was 1.4 mmol/l (normal range 3.3 to 5.6) and serum insulin 2mu/1 (normal range 3 to 20). Following a dextrose infusion, the patient regained consciousness and all the neurological signs resolved.
The following investigations were normal: urea and electrolytes, glucose tolerance test, 09:00 hours and midnight serum cortisol, 24-hour urinary vanillyl-mandelic acid collections,
’ Case presented to Clinical Section, 12 February 1982. Accepted 17 May 1982
2 Present address: St Bartholomew’s Hospital, London EC1
3 Present address: Westminster Hospital, London SW1
synacthen test, tumour marker screen, gastro- intestinal polypeptides, plasma oestradiol and testosterone.
An intravenous pyelogram showed downward displacement of the left kidney by a large extrinsic mass which was also pushing the spleen upwards. A CT scan of the abdomen showed a large retroperitoneal tumour which was partly vascular and necrotic lying above the left kidney and extending as high as the diaphragm. The lumen of the inferior vena cava (IVC) was expanded and of varying density, suggesting the presence of either simple thrombus or tumour thrombus. There was no evidence of liver metastases. Arteriography confirmed the presence of a large tumour with a pathological circulation, lying above the left kidney and receiving blood from the inferior suprarenal artery and from a mass of vessels coming directly off the aorta. An abdominal ultrasound scan showed that the intraluminal material within the IVC was extending from the level of the right renal artery to 7 cm below the entrance of the cava into the right atrium.
The differential diagnosis was of an adreno- cortical carcinoma or a retroperitoneal tumour. Laparotomy was performed to yield a tissue diagnosis and to remove the tumour. An 890 gram, well-encapsulated tumour was removed and the abdomen was noted to be free of metastases. The IVC was not explored because it was technically impossible to gain access to it behind the liver. Microscopy showed a pleomorphic adrenocortical carcinoma ranging from well differentiated to frankly anaplastic. The tumour had invaded extra-adrenal lymphatics and blood vessels.
Postoperatively, the patient has had no further hypoglycaemic attacks and has received radio- therapy to the IVC, para-aortic nodes and renal veins.
Discussion
Tumor hypoglycaemia was recognized in 1927 when insulinomas were first described (Wilder et al. 1927). Over the next few years hypoglycaemia was associated with several other tumours: mesenchy- mal, hepatomas, adrenocortical carcinomas, lymphomas and leukaemias. The hypoglycaemia occurs after periods of fasting, especially in the early morning and late afternoon, and may occur at any time during the course of the disease.
This patient presented with a hemiparesis and dilated pupils, both of which resolved with intravenous glucose. We concluded that the
neurological signs were due to hypoglycaemia rather than an embolus of either simple thrombus or tumour thrombus, because of the rapid resolution of the signs and a normal CT brain scan.
The cause of the hypoglycaemia is probably multifactorial but the suggested mechanisms can be divided into three categories : first, the secretion of insulin or insulin-like substance by the tumour; second, increased glucose utilization by the tumour or peripheral tissues; and third, the failure of compensatory mechanisms (Kahn 1980).
Levels of immunoreactive insulin are below normal during periods of hypoglycaemia induced by non-islet cell tumours (Skrabanek & Powell 1978), which is in contrast to insulinomas. This suggests that insulin and liver insulinase inhibition do not play a role, but insulin-like factors may be important.
Before insulin radioimmunoassays had been developed, the hormone activity was assayed by biological in vitro systems. When insulin antibody was added, the activity of the insulin was suppressed by 10% and the portion not suppressed was called non-suppressible insulin-like activity (NSILA). NSILA is a heterogenous mixture of proteins of differing molecular weights, the low molecular weight peptides NSILA-s being soluble in acid ethanol, whereas the high molecular weight NSILA-p are precipitated (Zapf et al. 1978).
NSILA-s is composed of insulin-like growth factors I and II (IGF) and somatomedins. The amino acid sequences of IGF I and II have been determined and they seem to be structurally similar to proinsulin but immunologically distinct. The structure of somatomedins has yet to be determined and there is still debate as to whether they are different from IGF.
IGF and somatomedins are 2% as potent as insulin in glucose metabolism but are 50 times more potent than insulin in the promotion of growth (judged by the incorporation of thymidine into DNA and sulphate into cartilage). Thus IGF may have two roles, producing hypoglycaemia and influencing the growth of tumours from which it is produced. An assay for NSILA-p has only recently been developed and the exact part this plays remains unknown.
Concentrations of IGF have been measured by radioreceptor assays in a number of patients with non-islet cell tumours (Gorden et al. 1981). Of 52 patients, 37% had elevated levels and in a preliminary study the level of IGF returned to normal in one patient after tumour treatment had resolved the hypoglycaemia. This suggests a potential use of IGF as a tumour marker.
The second possible mechanism of tumour hypoglycaemia is increased glucose utilization by
either the tumour or by other tissues. Evidence for this has come mainly from the finding that large doses of glucose, up to 500 g per day, are needed to maintain normoglycaemia. Arteriovenous sampling of tumours has shown no difference in blood glucose levels, but so far no measurements of tumour blood flow have been determined and this is needed to provide quantitative data.
Measurement of glucose consumption by tumour slices in vitro has been estimated to be up to 200 mg glucose/g tumour/day. The body should be able to keep up with these demands since the liver can produce 700 g glucose/day. However, if there is failure of any of the compensatory mechanisms, hypoglycaemia will occur.
Therapy of the hypoglycaemia associated with non-islet cell tumours is difficult since no specific agents are available. Several techniques can be employed such as frequent feeding or the use of hormones that have hyperglycaemic effects.
The only way of curing a patient is en bloc dissection of the tumour. Even if metastases are present, removal of the tumour is still indicated and then adjuvant chemotherapy and radio- therapy can be given. Because of the rarity of this tumour, few prospective therapeutic trials have been performed. The greatest clinical experience has been with ortho para DDD (Mitotane), a derivative of the insecticide DDD, but its use has been limited by toxicity. It produces a disease response rate of 34%-61% and an overall clinical response rate of 35%-54% (Hutter & Kayhoe 1966b, Lubitz et al. 1973). The prognosis remains appalling, with a median survival of 14 months from diagnosis and a five-year survival of 24%.
References
Bradley E L (1975) Surgery, Gynecology and Obstetrics 141, 507-511
Didolkar M S, Bescher R A, Elias E G & Moore R H (1981) Cancer 47, 2153-2161
Gorden P. Hendricks C M, Kahn C R, Megyesi K & Roth J (1981) New England Journal of Medicine 305, 1452-1455
Hutter A M & Kayhoe D E
(1966a) American Journal of Medicine 41, 572-580
(1966b) American Journal of Medicine 41, 581-592 Kahn C R
(1980) Clinics in Endocrinology and Metabolism 9, 335-360
Lubitz J A, Freeman L & Okun R
(1973) Journal of the American Medical Association 223, 1109-1112
MacFarlane D A
(1958) Annals of the Royal College of Surgeons of England 23, 155-186
Montgomery B M, Pinner C A & Newberry S C (1964) Archives of Internal Medicine 114, 680-684
Skrabanek P & Powell D
(1978) Clinical Endocrinology 9, 141-154
Wilder R, Allan F N, Power M H & Robertson H E (1927) Jornal of the American Medical Association 89, 348-355
Zapf J, Rinderknecht E, Humbel R E & Froesch E R (1978) Metabolism 27, 1803-1828