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ENDOCRINE TUMOURS OF THE PANCREAS DAVID J. BYRNES Bruce H a l l Department o f Gastroenterology a n d Garvan Institute for Medical Research, St Vincent’s Hospital, Sydney. THE importance of the pancreas in glucose homeostasis was recognized by Banting and Best (1921) who observed that an active hypoglycaemic agent could be extracted from the pancreas with acid ethanol. The active factor was called “insulin”, and in 1927 Wilder et alii described a patient with a pancreatic tumour and a clinical state consistent with hypoglycaemia, presumably due to insulin secreted by the tumour. The presence of a second major hormone, glucagon, in normal pancreatic islets, was recognized at about the same time as insulin, but received little attention until less than a decade ago. Nevertheless, it was known that in some animals, such as birdsand reptiles, removal of the pancreas resulted not i n hyperglycaemia but in death from profound hypoglycaemia, indicating that the presence of a hyperglycaemic factor in the pancreas must also be of considerable importance in the maintenance of normal glucose regulation. The presence of glucagon-secreting tumours (McGavran et alii, 1966) was only recognized after the introduction of radioimmunoassays for glucagon. With the development of radioimmunoassays and irnmunohistological staining techniques for other gut hormones, it has become apparent that the pancreas also contains cells which secrete gastrin, somatostatin (growth hormone release inhibitory factor), pancreatic polypetide, and also, within nerve fibres, vasoactive intestinal peptide. Clinical syndromes associated with pancreatic tumours secreting each of these hormones have now been described. The endocrine cells of the pancreas, like the other gut hormone secreting cells, have been shown to be derived embryologically from the primitive neural crest and share common histochemical properties of amine precursor uptake and decarboxylation, leading to their collective description as APUD cells Reprints Dr David J Byrnes. F R A C P , St Vincent s Medical Centre. 376 Victoria Street Darlinghurst N S W 2010
242
and their corresponding tumours as apudomas (Pearse, 1969). Tumours of different cell members of the APUD series often occur simultaneously, and when familial, are referred to as the syndrome of multiple endocrine adenomata (Wermer, 1954, 1963). GASTRINOMA The first reported case of carcinoma of the pancreatic islets with associated hyperinsulinism also included recurrent peptic ulceration despite surgery and renal calculi, but these did not receive comment. Similarly in the description of two cases of insulinoma by Wulff (1949) and Strom (1952) little mention was made of the additional presence of intractable peptic ulceration. It was Zollinger and Ellison who, in 1955, finally described a clinical syndrome of intractable peptic ulceration, “massive hypersecretion of gastric acid“ associated with pancreatic islet cell tumours. They postulated that the gastric hypersecretion might be due to the release of a hormone from the pancreatic tumours. This hypothesis was supported by: (a} the isolation of a gastric secretagogue from the tumour (Gregory et alii, 1960); ( b ) demonstration of a gastric stimulant in the serum and gastric juice (Sircus, 1964) and urine (Bonfils and Bader, 1966) of such patients; (c) demonstration of a peptide with the immunological properties of gastrin in the serum and tumours (McGuigan and Trudeau, 1968); and ( d ) isolation from islet cell tumours of two peptides with an amino acid composition similar to gastrin I and It (Gregory e l alii, 1969). F u r t he r studies u s i n g radio i m m u n oassay techniques have demonstrated that most of the gastrin from tumour and serum of such patients is not ”heptadecapeptide” gastrin (17 amino acids) but a “big” gastrin with 34 amino acids. In all 17 different isomers of gastrin have been described (Rehfeld et alii, 1975) from the serum of patients VOL.48-No. 3, JUNE, 1978 AUST.N.Z. J. SUAG..
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with gastrinomas. With the exception of two nterminal fragments, all of the gastrin isomers isolated and studied have had gastric stimulatory activity, although of markedly different potencies. Frequency. - The importance of gastrinomas as a cause of recurring and intractable peptic ulceration has only been realized now that diagnostic radioimmunoassays for gastrin are now readily available.ln our own experience (Lusby et alii, 1977) an amazing 25% of patients who were subjected to serum gastrin estimations because of recurrent ulceration after surgery were found to have gastrin secreting tumours. By extrapolation it would appear that the incidence of gastrinomas in patients with duodenal ulceration of sufficient severity to warrant surgery is of the order of 1%, making gastrinoma the commonest form of pancreatic endocrine tumour. Clinical spectrum. - A decade ago the diagnosis of a gastrinoma was made after a mean of five unsuccessful operations (Ellison and Wilson, 1964) for intractable peptic ulceration. Certainly now the diagnosis should be sought and confirmed after a maximum of one unsuccessful operation. An even earlier diagnosis would require the routine use of preoperative gastrin estimations as a screening procedure, and when the cost of a single unsuccessful operation is considered, such screening is easily justified on a cost/benefit basis. Although the presence of ulcers in unusual sites (second part of duodenum or upper jejunum), intractability, associated diarrhoea, or giant gastric rugae, should alert one to the correct diagnosis, it is important to realize that thevast majorityof patients harbouring a gastrinoma present to the surgeon with a duodenal ulcer in the usual site and with several years’ history of periodic symptoms. Conversely, it is also pertinent to note that gastrinomas rarely, i f ever, present with a primary (i.e., unassociated with a duodenal ulcer) gastric ulcer. Diagnosis (a) Fasting serum gastrin estimation. - Once the diagnosis of gastrinoma has been considered, it should be confirmed by a fasting serum gastrin estimation. The normal range for serum gastrins varies with different laboratories (often due to different specificities of antibody used), but is usually in theorder of 0-50 pMoM (pMol = lO-’*mol). Patients with gastrinomas usually have serum gastrin levels over 100 pMol/l. Elevated serum levels of gastrin are also observed in other situations, as if the patient has not been fasted, has an associated hypochlorhydria ( i n c l u d i n g primary gastric ulceration and pernicious anaemia), or has’ had AUST N.Z. J. SURG.VOL. 4 8 - 4 0 3, JUNE, 1978
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previous vagotomy, surgically excluded antral tissue or chronic renal failure. ( b ) Secretin stimulation test. -the detection of an elevated serum gastrin level in a truly fasted patient with duodenal ulceration is an indication for a secretin stirnulation test. This depends upon the observation (Isenberg ef alii, 1972) that whereas secretin stimulation normally results in a decrease in serum gastrin, patients with gastrinornas exhibit a paradoxical response, with an abrupt increase in the serum levels of gastrin after secretin. This test has proved extremely reliable without any reports of false positive responses, and using a 50% rise in gastrin after secretin, 35 out of 39 patients were found to give a positive response i n one series of gastrinomas (Bradley and Galambos, 1976), and the remaining four patients in the series, although not achieving a 50% rise, did have some increase in the serum gastrin level after secretin. As yet in our laboratory, only one patient with a proven gastrinoma has been found not to respond to secretin. The protocol for the secretin test is as follows: (1) The patient is fasted overnight; (2) An intravenous catheter is inserted for rapid venous sampling; (3) Basal serum samples are collected (at least 2 or 3); (4) Secretin 1 clinical unit/kg is given intravenously over 30-60 seconds; (5) Serum samples are taken at 0, 2, 4, 6, 10. 15 and 20 minutes. (c) Calcium infusion tests. - Induction of hypercalcaemia has also been advocated as a diagnostic test for the presence of a gastrinoma and depends upon the observation that whereas normal subjects demonstrate only a small increase in serum gastrin after calcium infusion, those patients who have a gastrinoma usually show a 50%+ rise in gastrin. However, this test is prolonged, uncomfortable, and diagnostically less reliable than the secretin test and is therefore not recommended. ( d ) Gastric secretory tests. - Prior to the availability of serum gastrin estimations, a preoperative diagnosis of gastrinoma centred on the demonstration of an elevated basal gastric acid output and concentration. However, this test, perhaps not surprisingly, is quite unreliable, since collection errors arise from pancreaticoduodenal reflux from previous surgery, gastrinomas have been shown to also secrete somatostatin (a hormone which is a potent inhibitor of gastric secretion), and finally, approximately 6%of patients with simple duodenal ulceration have gastric secretory rates similar to those seen in association
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with gastrinomas. Thus with the ready availability of gastrin estimations, it appears unjustifiable, either clinically or economically, t o attempt screening for gastrinomas by gastric secretory data. (e) Other diagnostic aids. - It has been claimed that a large proportion of patients with pancreatic apudomas (including gastrinomas) also secrete pancreatic polypeptide, and that measurement of P.P. levels in serum may be useful in the diagnosis of these tumours (Polak et alii, 1976). Unfortunately, neither Taylor et alii (1977) nor ourselves have found P.P. estimations to be of value in diagnosing gastrinomas. There is also a claim (Welbourn, 1977) that serum somatostatin is frequently elevated in patients with gastrinoma, but this has not yet been substantiated. Treatment Once the diagnosis of a gastrinoma has been made, care should be taken to exclude the 20% probability that the patient has an additional end o c r ine t u mo u r - part ic uIar Iy pa rat hy ro id , pituitary or pancreatic (insulinoma). If a parathyroid tumour is present, removal of this should be p e r f o r m e d f i r s t , as w i t h c o r r e c t i o n o f hypercalcaemia there is usually a dramatic fall in the serum gastrin level, which is often followed by many years of remission from the manifestations of the gastrinoma. Recognition of the presence of an insulinoma is equally important because postoperative hypoglycaemia and coma may follow attempted removal of a gastrinoma and the cause not be appreciated. The primary treatment for gastrinomas is, at present, total gastrectomy because ( a ) it removes the immediate cause of death in these patients (complications of peptic ulceration), and ( b ) total gastrectomy has been reported t o have been followed by evidence of tumour regression (Freisen, 1968). Such an event could be explained by complete loss of the stimulus for secretin release (acid) and therefore removal of a potent stimulus from the tumour cells. Unfortunately a lot of the reports of tumour regression were documented before gastrin assays were available, and since these assays have become available there have not been any further reports of tumour regression. We have seen one patient who had a progressive sequential fall in serum gastrin for an 18-month period after total gastrectomy, but his gastrin levels are now rising again, indicating further tumour growth. An alternative form of treatment is attempted turnour removal. Unfortunately, because of the high incidence of malignancy and multiple tumours, it 244
was found that in only approximately one patient in three was the tumour completely removed, and the remaining two-thirds of patients required an immediate further definitive operation. However, now that it has been shown that the ulcer diathesis can be effectively controlled with long-term H2 blockade by cimetidine (Stage et alii, 1976), it is pertinent to re-examine the place of surgery for attempted t u m o u r removal w i t h long-term cimetidine administration being reserved for those patients who have persistently raised gastrin levels following attempted tumour removal. lnsulinoma lnsulinomas represent the longest-recognized of the functioning islet cell tumours (Wilder et alii, 1927). The symptoms observed in patients with insulinomas are due to thesubacute hypoglycaemia induced by an inappropriate and excessive release of insulin. This results in a variety of neuropsychiatric symptoms ranging from transient trembling, diplopia, and dysarthria, through inappropriate or psychotic behaviour t o epilepsy and coma. Typically the symptoms occur initially before breakfast, are induced by strenous exercise, and are quickly relieved by food or glucose. It is important t o note that the symptoms of hypoglycaemia in these patients do not include the sweating and flushing which are features of acute hypoglycaemia. The importance of considering a diagnosis of insulinoma in every patient with episodic neuropsychiatric symptoms or unexplained coma is outlined in a recent report by Best et alii (1978) of insulinomas diagnosed in a major Australian city over a five year period. It is apparent from this paper that the possibility of an insulinoma was not considered for a considerable period of time, and frequently not before the patient became comatose. Diagnosis Once considered, the diagnosis of an insulinoma is straightforward. It depends upon the demonstration of fasting hypoglycaemia (blood glucose less than 2.2 mMol/l) associated with an inappropriate level of insulin, i.e., "normal"or high levels of insulin .despite the hypoglycaemia. This pathognomonic combination is seen in more than 95% of patients with insulinomas (Marks, 1971). Increasing the duration of fasting (up to 72 hours) and the number of samples taken increases the diagnostic return. It must be emphasized that the hypoglycaemia be demonstrated in the fasting state in order to differentiate insulinomas from reactive hypoglycaemia secondary to early diabetes or previous gastric surgery, that care should be taken to use a AUST.N.Z. J. SURG., VOL 48-40.3,
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specific estimation for blood glucose, and that the fast be carefully monitored in hospital. Other aids for the diagnosis of insulinomas are seldom required but include: ( a ) provocative tests with the infusion of glucagon, tolbutamide or oral leucine. These tests each have an approximate 20% false positive and negative rate due to the marked variability in insulin release in both normal subjects and patients with insulinomas; ( b ) the proportion of proinsulin in serum is frequently above normal (37%) in patients with insulinoma, regardless of the actual level of total insulin; (c) the fasting serum pancreatic polypeptide level is increased in approximately 80% of patients with insulinomas, but is not specific. Localization of the tumour. - One important reason for recognizing the possibility of an insulinoma is that it is usually (80%-90%) totally curable, with malignant and multiple tumours each accounting for only 10% of the total (compare with gastrinoma). However, the insulinomas are frequently of the same colour and consistency as the remainder of the pancreas, and therefore may not be identifiable at operation. For this reason it is prudent to perform preoperative angiography, which demonstrates a tumour blush in approximately 70% of patients. 'Treatment. - Complete removal of the tumour can usually be accomplished without morbidity. The complete removal can often beconfirmed in the operating room by detecting a sudden and steep rise in the blood glucose level immediately following tumour excision. If the tumour is found to be malignant, i.e., with metastases outside the pancreas (there art: no histological criteria for malignancy of is1L.t cell tumours), it is still reasonable to remcve as much of the tumour tissue as can be safely axomplished because the main clinical problem is usually not one of the neoplastic invasion, but of the hormone produced by the tumour mass. If no tumour is discernible after careful exploration of the pancreas, sites of accessory pancreas, nodes, and liver, and the patient has been adequately evaluated before operation; the surgeon has the choice of performing a distal (or subtotal) pancreatectomy or of taking multiple blood samples from veins draining various parts of the pancreas for later insulin and proinsulin estimation with the aim of a further exploration when the tumour has been more precisely localized immunochemically. In the patients in whom all of the tumour cannot be removed because of metastases, the infusion of a specific islet cell toxin (streptozotocin) may give a dramatic remission. AUST N.Z. J. SURG., VOL 48-No. 3, JUNE,1978
RAREPANCREATIC ENDOCRINE TUMOURS Viporna In 1958 Verner and Morrison drew attention to the association of severe refractorywaterydiarrhoea with non-insulin secreting islet cell tumours of the pancreas. The main features of this syndrome have led to it being called the W.D.H.A. syndrome (watery diarrhoea, hypokalaemia, and achlorhydria). Because of the profuse (up to 10 litres per day) and often fatal watery diarrhoea, the syndrome has also been called "pancreatic cholera". Other features of the syndrome include diabetes mellitus, hypercalcaemia, and skin flushing. It has now been shown that vasoactive intestinal peptide (V.I.P.) is elevated in the serum of these patients and has also been extracted from the tumour tissue. Diagnosis. - This syndrome has not yet been reported in Australia, but its spectacular nature should lead to a clinical diagnosis by those who are aware of the syndrome. The diagnosis, once suspected, can be confirmed by the demonstration of a single elevated level (200 pg/ml) of V.I.P. in plasma by radioimmunoassay (Bloom and Polak, 1975). Treatment. - Only 30% of patients with a vipoma have a single surgically removable tumour. Again, as with other apudomas. it seems reasonable to remove as much of the tumour as can be done with safety, even when it is malignant. In those patients with residual tumour, treatment with corticosteroids or chemotherapy with streptozotocin may be helpful.
Glumgonoma Very few cases of glucagonoma have been reported, but the diagnosis should be considered in any patient who is diabetic and has a skin rash. The diagnosis is confirmed by the demonstration of an elevated serum level of glucagon as determined by radi oi mmunoassay. Somatostatinoma and Pancreatic Peptidoma A single case of each of these has been reported,
and in each case diarrhoea was a striking feature of the condition. Thus tumours secreting somatostatin or pancreatic polypeptide now join the differential diagnosis for hormonally induced diarrhoea (thyrotoxicosis, medullary carcinoma of the thyroid secreting thyrocalcitonin, gastrinomas, vipomas, glucagonomas, and carcinoid tumours). REFERENCES BANTING,F.G. and BEST.C.H. (1921) J. Lab. din. Med., 7 : 464. BEST,J.D., CHISHOLM. D.J. and ALFORD, F.P. (1978), Med. J. Aust. in press.
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BLOOM.S.R. and POLAK. J.M. (1975). in Gastrointestinal Hormones, edited by THOMPSON, J. University of Texas Press, Austin and London: 635. BONFILS.S. and BADER.J. (1966). in Progress in Gastroenterology, edited by GLASSJ. Vol. 2, Grune and Stratton, New York: 332. BRADLEY. E.L. and GALAMBOS. J.T. (1976), Surg. Gynec. Obstet., 143: 784. ELLISON,E.H. and WILSON,S.D. (1964). Ann. Surg., 160: 512. FREISEN,S.R. (1968), Ann. Surg. 168: 484. K.I. and GROSSMAN, M.I. GREGORY, R.A.. TRACY.H.J., AGARWAL, (1969), Gut, 10: 603. GREGORY. R.A., TRACY,H.J., FRENCH, J.M.andS1~cus.W.(1960). Lancet, 1: 1045. ISENBERG. J.I., WALSH, J.H.. PASSARO. E., MOORE, E.W. and GROSSMAN. M.I. (1972). Gastroneterology, 62: 626. LUSBY.R.J., BYRNES. D.J. and HUGHT.B. (1977), Med. J. Aust., 2: 389. MARKSV. (1971). Gut. 12: 835. L., POLK,H.C., KILO, C. MCGAVRAN. M.H., UNGER, R.H., RECANT, and LEWEN,M.E. (1966), New. Engl. J. Med. 274: 1408. MCGUIGAN. J.E. a n d T f l u i ~ ~W.L. ~ u . (1968). New. Engl. J. Med., 278: 1308.
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PEARSE. A.G.E. (1969), J. Histochem. Cytochem., 17: 303. M.G., BLOOM,S.R., HEITZ,P.H. POLAK, J.. ADRAIAN,T.E.. BRYANT. and PEARSE. A.G.E. (1976), Lancet, 1: 328. REHFELD. J.F.. STADIL.F., MALSTROM, J. and MiYATA.M. (1975).in Gastrointestinal Hormones, edited by Thompson J., University Texas Press, Austin and London: 43. SIRCUS. W. (1964). Lancet, 11: 671. STAGE, J.G., RUNE,S.J., STADIL,F. and WORNING.H., Cimetidine, edited by BURLAND.W. and ALISONSIMKINS,M.A. (1976), Excerpta Med. (Amst.): 306. STROM. R. (1952), Acta. chir. scand., 104: 252. TAYLOR, I. L.. WALSH.J. H.,ROTTER, J. and PASSARO, E. P. (1977), Gastroenterology, 72, A1 16/1. VERNER. J. V. and MORRIS0N.A. 8. (1958),Amer. J. Med., 29,529. WELBOURN.R. 8. (1977). Gastrointestinal Hormones, edited by BLOOM.S., Churchil Livingston, Edinburgh. WERMER, P. (1954), Amer. J. Med., 16: 363. WERMER,P. (1963), Amer. J. iwed., 35: 205. WILDER.R. M.. ALLAN.F. N., POVER,M. H. and ROBERTSON H. E. (1927), J. Amer. med. Ass..89: 348. WULFF H. (1949), Nord. Med., 41: 557. R . M. and ELLISON.E. H. (1955). Ann. Surg., 142: 709. ZOLLINGER.
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ENDOCRINE TUMOURS OF THE PANCREAS DAVID J. BYRNES Bruce H a l l Department o f Gastroenterology a n d Garvan Institute for Medical Research, St Vincent’s Hospital, Sydney. THE importance of the pancreas in glucose homeostasis was recognized by Banting and Best (1921) who observed that an active hypoglycaemic agent could be extracted from the pancreas with acid ethanol. The active factor was called “insulin”, and in 1927 Wilder et alii described a patient with a pancreatic tumour and a clinical state consistent with hypoglycaemia, presumably due to insulin secreted by the tumour. The presence of a second major hormone, glucagon, in normal pancreatic islets, was recognized at about the same time as insulin, but received little attention until less than a decade ago. Nevertheless, it was known that in some animals, such as birdsand reptiles, removal of the pancreas resulted not i n hyperglycaemia but in death from profound hypoglycaemia, indicating that the presence of a hyperglycaemic factor in the pancreas must also be of considerable importance in the maintenance of normal glucose regulation. The presence of glucagon-secreting tumours (McGavran et alii, 1966) was only recognized after the introduction of radioimmunoassays for glucagon. With the development of radioimmunoassays and irnmunohistological staining techniques for other gut hormones, it has become apparent that the pancreas also contains cells which secrete gastrin, somatostatin (growth hormone release inhibitory factor), pancreatic polypetide, and also, within nerve fibres, vasoactive intestinal peptide. Clinical syndromes associated with pancreatic tumours secreting each of these hormones have now been described. The endocrine cells of the pancreas, like the other gut hormone secreting cells, have been shown to be derived embryologically from the primitive neural crest and share common histochemical properties of amine precursor uptake and decarboxylation, leading to their collective description as APUD cells Reprints Dr David J Byrnes. F R A C P , St Vincent s Medical Centre. 376 Victoria Street Darlinghurst N S W 2010
242
and their corresponding tumours as apudomas (Pearse, 1969). Tumours of different cell members of the APUD series often occur simultaneously, and when familial, are referred to as the syndrome of multiple endocrine adenomata (Wermer, 1954, 1963). GASTRINOMA The first reported case of carcinoma of the pancreatic islets with associated hyperinsulinism also included recurrent peptic ulceration despite surgery and renal calculi, but these did not receive comment. Similarly in the description of two cases of insulinoma by Wulff (1949) and Strom (1952) little mention was made of the additional presence of intractable peptic ulceration. It was Zollinger and Ellison who, in 1955, finally described a clinical syndrome of intractable peptic ulceration, “massive hypersecretion of gastric acid“ associated with pancreatic islet cell tumours. They postulated that the gastric hypersecretion might be due to the release of a hormone from the pancreatic tumours. This hypothesis was supported by: (a} the isolation of a gastric secretagogue from the tumour (Gregory et alii, 1960); ( b ) demonstration of a gastric stimulant in the serum and gastric juice (Sircus, 1964) and urine (Bonfils and Bader, 1966) of such patients; (c) demonstration of a peptide with the immunological properties of gastrin in the serum and tumours (McGuigan and Trudeau, 1968); and ( d ) isolation from islet cell tumours of two peptides with an amino acid composition similar to gastrin I and It (Gregory e l alii, 1969). F u r t he r studies u s i n g radio i m m u n oassay techniques have demonstrated that most of the gastrin from tumour and serum of such patients is not ”heptadecapeptide” gastrin (17 amino acids) but a “big” gastrin with 34 amino acids. In all 17 different isomers of gastrin have been described (Rehfeld et alii, 1975) from the serum of patients VOL.48-No. 3, JUNE, 1978 AUST.N.Z. J. SUAG..
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with gastrinomas. With the exception of two nterminal fragments, all of the gastrin isomers isolated and studied have had gastric stimulatory activity, although of markedly different potencies. Frequency. - The importance of gastrinomas as a cause of recurring and intractable peptic ulceration has only been realized now that diagnostic radioimmunoassays for gastrin are now readily available.ln our own experience (Lusby et alii, 1977) an amazing 25% of patients who were subjected to serum gastrin estimations because of recurrent ulceration after surgery were found to have gastrin secreting tumours. By extrapolation it would appear that the incidence of gastrinomas in patients with duodenal ulceration of sufficient severity to warrant surgery is of the order of 1%, making gastrinoma the commonest form of pancreatic endocrine tumour. Clinical spectrum. - A decade ago the diagnosis of a gastrinoma was made after a mean of five unsuccessful operations (Ellison and Wilson, 1964) for intractable peptic ulceration. Certainly now the diagnosis should be sought and confirmed after a maximum of one unsuccessful operation. An even earlier diagnosis would require the routine use of preoperative gastrin estimations as a screening procedure, and when the cost of a single unsuccessful operation is considered, such screening is easily justified on a cost/benefit basis. Although the presence of ulcers in unusual sites (second part of duodenum or upper jejunum), intractability, associated diarrhoea, or giant gastric rugae, should alert one to the correct diagnosis, it is important to realize that thevast majorityof patients harbouring a gastrinoma present to the surgeon with a duodenal ulcer in the usual site and with several years’ history of periodic symptoms. Conversely, it is also pertinent to note that gastrinomas rarely, i f ever, present with a primary (i.e., unassociated with a duodenal ulcer) gastric ulcer. Diagnosis (a) Fasting serum gastrin estimation. - Once the diagnosis of gastrinoma has been considered, it should be confirmed by a fasting serum gastrin estimation. The normal range for serum gastrins varies with different laboratories (often due to different specificities of antibody used), but is usually in theorder of 0-50 pMoM (pMol = lO-’*mol). Patients with gastrinomas usually have serum gastrin levels over 100 pMol/l. Elevated serum levels of gastrin are also observed in other situations, as if the patient has not been fasted, has an associated hypochlorhydria ( i n c l u d i n g primary gastric ulceration and pernicious anaemia), or has’ had AUST N.Z. J. SURG.VOL. 4 8 - 4 0 3, JUNE, 1978
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previous vagotomy, surgically excluded antral tissue or chronic renal failure. ( b ) Secretin stimulation test. -the detection of an elevated serum gastrin level in a truly fasted patient with duodenal ulceration is an indication for a secretin stirnulation test. This depends upon the observation (Isenberg ef alii, 1972) that whereas secretin stimulation normally results in a decrease in serum gastrin, patients with gastrinornas exhibit a paradoxical response, with an abrupt increase in the serum levels of gastrin after secretin. This test has proved extremely reliable without any reports of false positive responses, and using a 50% rise in gastrin after secretin, 35 out of 39 patients were found to give a positive response i n one series of gastrinomas (Bradley and Galambos, 1976), and the remaining four patients in the series, although not achieving a 50% rise, did have some increase in the serum gastrin level after secretin. As yet in our laboratory, only one patient with a proven gastrinoma has been found not to respond to secretin. The protocol for the secretin test is as follows: (1) The patient is fasted overnight; (2) An intravenous catheter is inserted for rapid venous sampling; (3) Basal serum samples are collected (at least 2 or 3); (4) Secretin 1 clinical unit/kg is given intravenously over 30-60 seconds; (5) Serum samples are taken at 0, 2, 4, 6, 10. 15 and 20 minutes. (c) Calcium infusion tests. - Induction of hypercalcaemia has also been advocated as a diagnostic test for the presence of a gastrinoma and depends upon the observation that whereas normal subjects demonstrate only a small increase in serum gastrin after calcium infusion, those patients who have a gastrinoma usually show a 50%+ rise in gastrin. However, this test is prolonged, uncomfortable, and diagnostically less reliable than the secretin test and is therefore not recommended. ( d ) Gastric secretory tests. - Prior to the availability of serum gastrin estimations, a preoperative diagnosis of gastrinoma centred on the demonstration of an elevated basal gastric acid output and concentration. However, this test, perhaps not surprisingly, is quite unreliable, since collection errors arise from pancreaticoduodenal reflux from previous surgery, gastrinomas have been shown to also secrete somatostatin (a hormone which is a potent inhibitor of gastric secretion), and finally, approximately 6%of patients with simple duodenal ulceration have gastric secretory rates similar to those seen in association
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with gastrinomas. Thus with the ready availability of gastrin estimations, it appears unjustifiable, either clinically or economically, t o attempt screening for gastrinomas by gastric secretory data. (e) Other diagnostic aids. - It has been claimed that a large proportion of patients with pancreatic apudomas (including gastrinomas) also secrete pancreatic polypeptide, and that measurement of P.P. levels in serum may be useful in the diagnosis of these tumours (Polak et alii, 1976). Unfortunately, neither Taylor et alii (1977) nor ourselves have found P.P. estimations to be of value in diagnosing gastrinomas. There is also a claim (Welbourn, 1977) that serum somatostatin is frequently elevated in patients with gastrinoma, but this has not yet been substantiated. Treatment Once the diagnosis of a gastrinoma has been made, care should be taken to exclude the 20% probability that the patient has an additional end o c r ine t u mo u r - part ic uIar Iy pa rat hy ro id , pituitary or pancreatic (insulinoma). If a parathyroid tumour is present, removal of this should be p e r f o r m e d f i r s t , as w i t h c o r r e c t i o n o f hypercalcaemia there is usually a dramatic fall in the serum gastrin level, which is often followed by many years of remission from the manifestations of the gastrinoma. Recognition of the presence of an insulinoma is equally important because postoperative hypoglycaemia and coma may follow attempted removal of a gastrinoma and the cause not be appreciated. The primary treatment for gastrinomas is, at present, total gastrectomy because ( a ) it removes the immediate cause of death in these patients (complications of peptic ulceration), and ( b ) total gastrectomy has been reported t o have been followed by evidence of tumour regression (Freisen, 1968). Such an event could be explained by complete loss of the stimulus for secretin release (acid) and therefore removal of a potent stimulus from the tumour cells. Unfortunately a lot of the reports of tumour regression were documented before gastrin assays were available, and since these assays have become available there have not been any further reports of tumour regression. We have seen one patient who had a progressive sequential fall in serum gastrin for an 18-month period after total gastrectomy, but his gastrin levels are now rising again, indicating further tumour growth. An alternative form of treatment is attempted turnour removal. Unfortunately, because of the high incidence of malignancy and multiple tumours, it 244
was found that in only approximately one patient in three was the tumour completely removed, and the remaining two-thirds of patients required an immediate further definitive operation. However, now that it has been shown that the ulcer diathesis can be effectively controlled with long-term H2 blockade by cimetidine (Stage et alii, 1976), it is pertinent to re-examine the place of surgery for attempted t u m o u r removal w i t h long-term cimetidine administration being reserved for those patients who have persistently raised gastrin levels following attempted tumour removal. lnsulinoma lnsulinomas represent the longest-recognized of the functioning islet cell tumours (Wilder et alii, 1927). The symptoms observed in patients with insulinomas are due to thesubacute hypoglycaemia induced by an inappropriate and excessive release of insulin. This results in a variety of neuropsychiatric symptoms ranging from transient trembling, diplopia, and dysarthria, through inappropriate or psychotic behaviour t o epilepsy and coma. Typically the symptoms occur initially before breakfast, are induced by strenous exercise, and are quickly relieved by food or glucose. It is important t o note that the symptoms of hypoglycaemia in these patients do not include the sweating and flushing which are features of acute hypoglycaemia. The importance of considering a diagnosis of insulinoma in every patient with episodic neuropsychiatric symptoms or unexplained coma is outlined in a recent report by Best et alii (1978) of insulinomas diagnosed in a major Australian city over a five year period. It is apparent from this paper that the possibility of an insulinoma was not considered for a considerable period of time, and frequently not before the patient became comatose. Diagnosis Once considered, the diagnosis of an insulinoma is straightforward. It depends upon the demonstration of fasting hypoglycaemia (blood glucose less than 2.2 mMol/l) associated with an inappropriate level of insulin, i.e., "normal"or high levels of insulin .despite the hypoglycaemia. This pathognomonic combination is seen in more than 95% of patients with insulinomas (Marks, 1971). Increasing the duration of fasting (up to 72 hours) and the number of samples taken increases the diagnostic return. It must be emphasized that the hypoglycaemia be demonstrated in the fasting state in order to differentiate insulinomas from reactive hypoglycaemia secondary to early diabetes or previous gastric surgery, that care should be taken to use a AUST.N.Z. J. SURG., VOL 48-40.3,
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specific estimation for blood glucose, and that the fast be carefully monitored in hospital. Other aids for the diagnosis of insulinomas are seldom required but include: ( a ) provocative tests with the infusion of glucagon, tolbutamide or oral leucine. These tests each have an approximate 20% false positive and negative rate due to the marked variability in insulin release in both normal subjects and patients with insulinomas; ( b ) the proportion of proinsulin in serum is frequently above normal (37%) in patients with insulinoma, regardless of the actual level of total insulin; (c) the fasting serum pancreatic polypeptide level is increased in approximately 80% of patients with insulinomas, but is not specific. Localization of the tumour. - One important reason for recognizing the possibility of an insulinoma is that it is usually (80%-90%) totally curable, with malignant and multiple tumours each accounting for only 10% of the total (compare with gastrinoma). However, the insulinomas are frequently of the same colour and consistency as the remainder of the pancreas, and therefore may not be identifiable at operation. For this reason it is prudent to perform preoperative angiography, which demonstrates a tumour blush in approximately 70% of patients. 'Treatment. - Complete removal of the tumour can usually be accomplished without morbidity. The complete removal can often beconfirmed in the operating room by detecting a sudden and steep rise in the blood glucose level immediately following tumour excision. If the tumour is found to be malignant, i.e., with metastases outside the pancreas (there art: no histological criteria for malignancy of is1L.t cell tumours), it is still reasonable to remcve as much of the tumour tissue as can be safely axomplished because the main clinical problem is usually not one of the neoplastic invasion, but of the hormone produced by the tumour mass. If no tumour is discernible after careful exploration of the pancreas, sites of accessory pancreas, nodes, and liver, and the patient has been adequately evaluated before operation; the surgeon has the choice of performing a distal (or subtotal) pancreatectomy or of taking multiple blood samples from veins draining various parts of the pancreas for later insulin and proinsulin estimation with the aim of a further exploration when the tumour has been more precisely localized immunochemically. In the patients in whom all of the tumour cannot be removed because of metastases, the infusion of a specific islet cell toxin (streptozotocin) may give a dramatic remission. AUST N.Z. J. SURG., VOL 48-No. 3, JUNE,1978
RAREPANCREATIC ENDOCRINE TUMOURS Viporna In 1958 Verner and Morrison drew attention to the association of severe refractorywaterydiarrhoea with non-insulin secreting islet cell tumours of the pancreas. The main features of this syndrome have led to it being called the W.D.H.A. syndrome (watery diarrhoea, hypokalaemia, and achlorhydria). Because of the profuse (up to 10 litres per day) and often fatal watery diarrhoea, the syndrome has also been called "pancreatic cholera". Other features of the syndrome include diabetes mellitus, hypercalcaemia, and skin flushing. It has now been shown that vasoactive intestinal peptide (V.I.P.) is elevated in the serum of these patients and has also been extracted from the tumour tissue. Diagnosis. - This syndrome has not yet been reported in Australia, but its spectacular nature should lead to a clinical diagnosis by those who are aware of the syndrome. The diagnosis, once suspected, can be confirmed by the demonstration of a single elevated level (200 pg/ml) of V.I.P. in plasma by radioimmunoassay (Bloom and Polak, 1975). Treatment. - Only 30% of patients with a vipoma have a single surgically removable tumour. Again, as with other apudomas. it seems reasonable to remove as much of the tumour as can be done with safety, even when it is malignant. In those patients with residual tumour, treatment with corticosteroids or chemotherapy with streptozotocin may be helpful.
Glumgonoma Very few cases of glucagonoma have been reported, but the diagnosis should be considered in any patient who is diabetic and has a skin rash. The diagnosis is confirmed by the demonstration of an elevated serum level of glucagon as determined by radi oi mmunoassay. Somatostatinoma and Pancreatic Peptidoma A single case of each of these has been reported,
and in each case diarrhoea was a striking feature of the condition. Thus tumours secreting somatostatin or pancreatic polypeptide now join the differential diagnosis for hormonally induced diarrhoea (thyrotoxicosis, medullary carcinoma of the thyroid secreting thyrocalcitonin, gastrinomas, vipomas, glucagonomas, and carcinoid tumours). REFERENCES BANTING,F.G. and BEST.C.H. (1921) J. Lab. din. Med., 7 : 464. BEST,J.D., CHISHOLM. D.J. and ALFORD, F.P. (1978), Med. J. Aust. in press.
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BLOOM.S.R. and POLAK. J.M. (1975). in Gastrointestinal Hormones, edited by THOMPSON, J. University of Texas Press, Austin and London: 635. BONFILS.S. and BADER.J. (1966). in Progress in Gastroenterology, edited by GLASSJ. Vol. 2, Grune and Stratton, New York: 332. BRADLEY. E.L. and GALAMBOS. J.T. (1976), Surg. Gynec. Obstet., 143: 784. ELLISON,E.H. and WILSON,S.D. (1964). Ann. Surg., 160: 512. FREISEN,S.R. (1968), Ann. Surg. 168: 484. K.I. and GROSSMAN, M.I. GREGORY, R.A.. TRACY.H.J., AGARWAL, (1969), Gut, 10: 603. GREGORY. R.A., TRACY,H.J., FRENCH, J.M.andS1~cus.W.(1960). Lancet, 1: 1045. ISENBERG. J.I., WALSH, J.H.. PASSARO. E., MOORE, E.W. and GROSSMAN. M.I. (1972). Gastroneterology, 62: 626. LUSBY.R.J., BYRNES. D.J. and HUGHT.B. (1977), Med. J. Aust., 2: 389. MARKSV. (1971). Gut. 12: 835. L., POLK,H.C., KILO, C. MCGAVRAN. M.H., UNGER, R.H., RECANT, and LEWEN,M.E. (1966), New. Engl. J. Med. 274: 1408. MCGUIGAN. J.E. a n d T f l u i ~ ~W.L. ~ u . (1968). New. Engl. J. Med., 278: 1308.
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BYRNES
PEARSE. A.G.E. (1969), J. Histochem. Cytochem., 17: 303. M.G., BLOOM,S.R., HEITZ,P.H. POLAK, J.. ADRAIAN,T.E.. BRYANT. and PEARSE. A.G.E. (1976), Lancet, 1: 328. REHFELD. J.F.. STADIL.F., MALSTROM, J. and MiYATA.M. (1975).in Gastrointestinal Hormones, edited by Thompson J., University Texas Press, Austin and London: 43. SIRCUS. W. (1964). Lancet, 11: 671. STAGE, J.G., RUNE,S.J., STADIL,F. and WORNING.H., Cimetidine, edited by BURLAND.W. and ALISONSIMKINS,M.A. (1976), Excerpta Med. (Amst.): 306. STROM. R. (1952), Acta. chir. scand., 104: 252. TAYLOR, I. L.. WALSH.J. H.,ROTTER, J. and PASSARO, E. P. (1977), Gastroenterology, 72, A1 16/1. VERNER. J. V. and MORRIS0N.A. 8. (1958),Amer. J. Med., 29,529. WELBOURN.R. 8. (1977). Gastrointestinal Hormones, edited by BLOOM.S., Churchil Livingston, Edinburgh. WERMER, P. (1954), Amer. J. Med., 16: 363. WERMER,P. (1963), Amer. J. iwed., 35: 205. WILDER.R. M.. ALLAN.F. N., POVER,M. H. and ROBERTSON H. E. (1927), J. Amer. med. Ass..89: 348. WULFF H. (1949), Nord. Med., 41: 557. R . M. and ELLISON.E. H. (1955). Ann. Surg., 142: 709. ZOLLINGER.
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