Endocrine-Related Cancer (1998) 5 111-129 Tumours producing hypoglycaemia V Marks and J D Teale European Institute of Health and Medical Sciences, University of Surrey, Guildford GU2 5RF, UK and Department of Clinical Biochemistry and Nutrition, Royal Surrey County Hospital, Guildford GU2 5XX, UK (Requests for offprints should be addressed to V Marks) Introduction Classification of hypoglycaemia- Hypoglycaemia is one of the commonest of medical producing tumours emergencies, mainly due to its high frequency as a Tumours producing hypoglycaemia can, broadly complication of insulin therapy of diabetes. It sometimes speaking, be divided - on the basis of the mechanism by arises, however, ‘spontaneously’ as a manifestation of which they most commonly produce hypoglycaemia - other diseases. The present review deals exclusively with into: (1) insulin-secreting tumours; (2) non-islet cell hypoglycaemia caused by neoplastic disease. (insulin-like growth factor-II (IGF-II)-secreting) tumours; For a very brief period, between 1927 and 1930, (3) myeloma, lymphoma and leukaemia; and (4) meta- tumours capable of producing hypoglycaemia were static neoplasia. thought always to secrete insulin and arise exclusively Hypoglycaemia produced by tumours other than within the pancreas. In the intervening years it has become insulinomas is usually referred to as ‘non-islet cell tumour increasingly apparent that almost any type of neoplasm hypoglycaemia’ (NICTH) and has more than one cause. can cause hypoglycaemia through a number of different mechanisms (Marks & Rose 1964, Laurent et al. 1971, Pancreatic endocrine tumours Daughaday 1989, Fajans & Vinik 1989). Insulin-secreting tumours are the commonest hormone- producing neoplasms of the gastrointestinal tract. They Symptomatology occur with an incidence of between 0.5 and 1 per million of the population per year (Kavlie & White 1972, Hypoglycaemia may be the presenting symptom of a Atkinson et al. 1981, Cullen & Ong 1987, Watson et al. tumour, a terminal epiphenomenon or anything in 1989). More than 80% are solitary benign adenomas, between, but is always rare. It is usually episodic and composed mainly or exclusively of morphologically provoked by fasting rather than reactive to the ingestion of normal B-cells. About 10% are metastatic, i.e. malignant, food. The one notable exception is hypoglycaemia due to whilst a further 10% are multiple but behave as benign. pheochromocytoma which may be of either variety Women outnumber men in the ratio of 6:4 for benign (Gorden et al. 1981, Hiramatsu et al. 1987, Paineau et al. but not for malignant insulinomas. The highest incidence 1988, Akiba et al. 1990). is in middle aged adults, though both benign and Symptoms of acute neuroglycopenia, character- malignant insulinomas have been observed very rarely in istically associated with insulin overdose, are unusual in children and in the very elderly. tumour-induced hypoglycaemia. Instead there is a gradual loss of cognitive function associated with diminished Insulin-secreting tumours motor activity, lethargy, the onset of somnolence and a Clinically significant insulinomas are generally between gradual drift into stupor or coma. Recovery may occur 10 and 20 mm in diameter at the time of diagnosis, spontaneously at any time but is hastened by the ingestion although tumours as large as 150 mm or as small as 5 mm of carbohydrate by mouth or the injection of glucose or in diameter have been found during surgery. Occasionally glucagon. very small tumours are overlooked at operation and found Biochemically, tumour-induced hypoglycaemia is only after very thorough histopathological examination of usually associated with hypoketonaemia (<300 µmol/l) the resected pancreas, or not at all. unlike that of most other types of ‘spontaneous’ hypo- In fewer than 5% of cases of true hyperinsulinaemic glycaemia apart from insulinoma (Teale et al. 1987). Only hypoglycaemia can no tumour be found. Whilst some of rarely are patients desperately ill in between hypo- these may be due to a small tumour being overlooked glycaemic episodes except when it is a terminal event in either at operation or at autopsy others are due to a patients with liver metastases. functional abnormality of the B-cells similar to that Endocrine-Related Cancer (1998) 5 111-129 © 1998 Society for Endocrinology Printed in Great Britain 1351-0088/98/005-111 $08.00/0 111 Downloaded from Bioscientifica.com at 09/27/2021 04:07:17AM via free access Marks and Teale: Tumours producing hypoglycaemia causing persistent hyperinsulinaemic hypoglycaemia of Attempts to classify insulinomas into prognostically infants (PHHI) which may, or may not, manifest itself useful histopathological categories have been made for 60 histologically as islet hyperplasia (nesidioblastosis). This years or more with little success (Graeme-Cook et al. condition must be distinguished from the nosologically 1990). It became apparent soon after their initial distinct condition of microadenomatosis which can occur identification that classical morphological and histo- either as an isolated histopathological finding or as part of logical criteria were of little value for distinguishing multiple endocrine neoplasia type I (MEN-I) (Diarmuid et malignant from benign tumours. Only the presence of al. 1994). metastases, or their subsequent appearance, could be The natural history of insulinomas (Marks 1991) relied upon to make the distinction. suggests that apart from their propensity for causing Creutzfeldt and co-workers (1973) classified insulin- hypoglycaemia - from which death is fortunately very omas into four types on the basis of their histological, rare - they produce no adverse effects. Specifically they ultramicroscopic and immunocytological appearances. appear not to cause obstruction to the hepatic or pancreatic Type 1 is the commonest and accounts for almost half ducts or to undergo malignant transformation. There are of the cases. In this type, virtually every cell contains many reports, especially in the older literature, of typical β-granules. symptoms attributable to hypoglycaemia due to Type 2, the second commonest, accounts for 25% of insulinoma extending over a period of 25 years or more the cases. Most of the cells contain a number of atypical before its true cause was identified and removed (Fonseca granules - demonstrably different from those of normal A, et al. 1989). B, D or PP cells - in addition to typical β-granules. The The average time between onset of symptoms and atypical granules resemble the coated β-granules that are diagnosis of its cause as due to insulinoma is now about found in small numbers in normal B-cells and within 1 year. Delay, when it does occur, is almost always the which proinsulin is believed to be converted into insulin consequence of reluctance by the patient to seek help, or and C-peptide (Orci et al. 1988). failure of the practitioner to suspect hypoglycaemia. Once Type 3 tumours consist solely of cells containing suspected, diagnosis of insulinoma seldom presents any atypical β-granules. None contains typical ones. Though real difficulty (Marks & Rose 1981, Marks 1991, Marks & not specifically identified as such, these probably Teale 1996, Marks 1997, Nauck et al. 1997). correspond to predominantly, or exclusively, proinsulin- Insulinomas are distributed evenly throughout the secreting tumours (proinulinomas). pancreas and only very rarely ectopically (2%). In this Type 4 tumours included the only two metastatic respect, as in the relative infrequency of their malignancy, carcinomas in the Creutzfeldt series. None of the four insulinomas differ from other hormone-producing tumours so classified had any of the characteristic histo- tumours of the gastrointestinal tract. logical features of an insulinoma. All gave negative The commonest ectopic sites are the duodenum and reactions with classical histological and immunocyto- the immediate vicinity of the pancreas, but less than 1% of chemical stains. They all showed ultramicroscopic signs the 677 insulinomas collected from the literature by of high functional activity. Tumours of this type would Laurent and co-workers prior to 1971 were located outside possibly, in former times, have been classified as the pancreas. Only a tiny number of ectopic tumours have carcinomas of unknown origin or carcinoids rather than been reported in recent years (Yoshikawa & Wakasa 1980, ‘insulinomas’, even in experienced histopathological Miyazaki et al. 1986). laboratories. Insulinoma histology Many insulinomas are composed Berger and co-workers (1983) classified hypo- entirely of seemingly normal B-cells. More thorough glycaemia producing tumours of the pancreas on their examination, especially by electron microscopy and functional rather than histological characteristics. immunocytochemistry, usually reveals a small but Group A tumours were characterised by the almost variable number of other pancreatic endocrine cell types, complete suppressibility of insulin and proinsulin of which somatostatin-containing D-cells are the secretion by both diazoxide and somatostatin. Histo- commonest. logically they were characterised by an abundance of Insulinomas show variable and unpredictable staining well-granulated B-cells in a trabecular arrangement. with traditional as well as with immunohistological Group B tumours resisted the suppressant effects of reagents, including synaptophycin, neuron-specific diazoxide and somatostatin and their cells were arranged enolase and chromogranin, which have been used as in a