Double Hormone Syndromes in Two Pancreatic Neuroendocrine Tumours

Neuroendocrine tumours of the pancreas have an annual incidence of approximately per 100,000 population. Up to 85% ofthese tumours secrete peptides, many of which cause characteristic clinical syndromes. While pancreatic neuroendocrine tumours frequently express immunoreactivity for multiple peptides, they rarely produce more than one clinical syndrome due to excess peptide secretion. We report two patients with pancreatic neuroendocrine neoplasia in each of whom there were characteristic clinical features due to hypersecretion oftwo bioactive peptides.


INTRODUCTION
Neuroendocrine tumours of the pancreas have an annual incidence of approximately per 100,000 population. Up to 85% of these tumours secrete peptides, many of which cause characteristic clinical syndromes. While pancreatic neuroendocrine tumours frequently express immunoreactivity for multiple peptides, they rarely produce more than one clinical syndrome due to excess peptide secretion. We report two patients with pancreatic neuroendocrine neoplasia in each of whom there were characteristic clinical features due to hypersecretion oftwo bioactive peptides. In July 1990 he developed symptomatic hypercalcaemia (4.5 mmol/1, normal 2.1-2.6 mmol/1), which was treated with forced diuresis, calcitonin and biphosphonates. Serum parathyroid hormone was undetectable, but parathyroid hormone-related protein (PTHRP) was elevated at 7.8 pmol/1 (normal < 0.5 pmol/1). Somatostatin was also markedly elevated at 774 pmo 1/1 (normal < 100 pmo 1/ 1); vasoactive intestinal peptide, pancreatic polypeptide, gastrin, glucagon, and neurotensin levels were all normal. Hepatic artery embolisation reduced the PTHRP level to 6.1 pmol/1, and at a second embolisation the splenic artery and an accessory artery to the left liver from the left gastric artery were occluded; thereafter serum calcium returned to normal. In December 1990 he was noted to be mildly diabetic and was started on glibenclamide.
In October 1991 the patient returned with severe hypercalcaemia (4.1 mmol/1) and was transferred to this unit for surgical debulking of his tumour.
At operation a 20 cm tumour was found arising from the body and tail of the pancreas involving the left kidney and splenic flexure of colon. An en bloc distal pancreatectomy, splenectomy, left nephrectomy and left hemicolectomy was performed, from which he made an uncomplicated recovery.
By the seventh postoperative day the serum calcium was 2.7 mmol/1 and PTHRP was 1.1 pmol/1; however somatostatin remained elevated at 1141 pmol/1. Histological examination of tumour tissue showed typical features of a pancreatic neuroendocrine tumour with nests of polygonal cells and a focal 262 J.G. GEOGHEGAN et al. trabecular pattern. Vascular invasion and lymph node involvement were noted. Immunohistochemical staining of the resected tumour was positive for neuron specific enolase, chromogranin and somatostatin and was negative for pancreatic polypeptide, insulin, and VIP.
In February 1992 he was readmitted to hospital with severe hypercalcaemia associated with seizures. His general condition deteriorated and he died within three weeks.

DISCUSSION
The clinical manifestation of two hormone syndromes in pancreatic endocrine neoplasia has only been reported with malignant tumours. In a five-year analysis of the results from a supraregional assay service in the U.K., Wynick and colleagues reported that 24 of 353 (6.8%) patients with functioning malignant tumours developed a second hormone syndrome at a median interval of 19 months after initial diagnosis 1. The most common presenting tumours in this group were glucagonomas, followed by gastrinomas. The development of a second peptide syndrome was associated with marked clinical deterioration and death in over 90% of these patients. Both our patients showed features of two clinical syndromes. The first patient had gallstones and mild diabetes, typical features of the somatostatinoma syndrome. He did not exhibit diarrhoea, the other typical finding in this syndrome. He subsequently developed severe hypercalcaemia due to secretion of PTHRP, a recently described peptide that mimics the physiological action of parathyroid hormone 2. PTHRP ex, pression has been demonstrated in both normal ant neoplastic islet cell tissue by Asa and colleagues In our second patient, the intractable ulcer diathesis and subsequent neuroglycopenic episodes were clear consequences of first gastrin and then insuli hypersecretion. Resection of the pancreatic tumour: was associated with decreases in the serum levels oftht: peptides responsible for the clinical syndromes in both patients. Immunoreactivity for the relevant peptides was confirmed in the excised tumours, with the exception of PTHRP for which immunohistochemical examination was not performed. Concomitant secretio of insulin and gastrin has previously been reported it. a small number of cases 4-6. In an extensive review of the Zollinger-Ellison tumour registry, 2% of patients also had insulin-secreting tumours 7. Production of PTHRP in pancreatic neuroendocrine tumours in sufficient quantity to cause symptomatic hypercalcaemia has been reported in a few patients 8,9, including one patient in whom concomitant secretion of soma tostatin and PTHRP was documented 10.
,Secretion of more than one peptide may occur as a result of cellular dysdifferentiation. Small numbers of proliferative cells, uncommitted to a particular differentiation pathway, are present in normal islet tissue and are increased in number in regenerating tissue. If these cells undergo malignant transformation, they may synthesize more than one biocative peptide in sufficient amounts to cause clinical syndromes of peptide excess.
Serum peptide levels should be regularly checked in patients who are being treated for malignant pancreatic neuroendocrine tumours to detect development of a second hormone syndrome. Recent improvements in DUAL HORMONE SYNDROMES IN PANCREATIC TUMOURS 263 survival of these patients because of advances in chemotherapy and radiological and surgical interventional techniques may make this a commoner clinical scenario.