MARCO CONCEPTUAL

According to various independent studies, the incidence o f pancreatic islet cell tumour involvement in M ENl varies from 30-80% (Crosier et al., 1971; Majewski and Wilson, 1979; Eberle and Grun, 1981; Marx et al., 1982; Benson et al., 1987; Vasen et al., 1989; Grama et al., 1992). The pancreatic neoplastic lesion is characteristically multicentric, and ranges from hyperplasia, through micro adenoma and carcinoma. Malignant transformation of pancreatic endocrine tumours, determined by the presence of métastasés, occurs in approximately 50% of M ENl patients with pancreatic involvement (Donow et al., 1991). The reported age of onset for pancreatic endocrine lesions ranges from 6 to 81 years (Eberle and Grun, 1981; Lips et al., 1984), but larger series suggest the fourth to fifth decades of life as the most common period for diagnosis (Marx et al.,

1986). Biochemical screening reduces the age o f diagnosis by two decades resulting in a decrease in tumour-related symptoms from 75% to 10%, and a lowering o f the number o f malignant tumours by 75% (Skogseid et al., 1994). Endocrine pancreatic cells secrete pancreatic polypeptide (PP), glucagon, insulin, somatostatin, gastrin, vasoactive intestinal polypeptide (VIP) and neurotensin in descending order of prevalence (Kloppel et al.,

1986). Although pancreatic neoplasms frequently secrete a multitude o f clinically relevant peptides, one secretory product usually predominates and might cause a specific clinical syndrome. Occasionally, the tumour may be non-functioning.

1.4.3a Gastrinomas

These tumours represent over 50% of all pancreatic lesions in M EN l (Eberle and Grun, 1981; Marx et al., 1986; Vasen et al., 1989). They are non-(3-islet cell tumours which result in elevated plasma concentrations of gastrin, increased gastric acid production and recurrent peptic ulceration, known as the Zollinger-Ellison syndrome (Zollinger and Ellison, 1955). Additional clinical features o f this syndrome include diarrhoea and steatorrhoea. Gastrinomas are the major cause of morbidity and mortality in M EN l patients due to the reccurrence of severe multiple peptic ulcers which may perforate. Diagnosis is by demonstrating a raised fasting serum gastrin concentration in association with an increased basal gastric acid secretion (Wolfe and Jensen, 1987). The Zollinger- Ellison syndrome in association with M E N l, does not appear to occur in the absence o f hyperparathyroidism (Betts et al., 1980; Benson et al., 1987) and, hypergastrinaemia has been shown to be associated with hypercalcaemia (Thompson et al., 1976). Hyperparathyroidism alone can also cause peptic ulcer disease and hyp ergastrinaemia. Thus, Zollinger-Ellison syndrome in some M ENl patients may be difficult to diagnose.

Gastrinomas were inti ally thought to originate only in the pancreas but in 1961, Oberhelman et al. reported ulcerogenic tumours in the duodenum, and they have subsequently been described at other extrap an creatic sites, such as the stomach, jejunum, liver, ovary, kidney and lymph nodes (Royston et al., 1972; Cocco et al., 1975; Freisen et al., 1975; Nord et al., 1986). Multicentric duodenal gastrinomas occur frequently, and are usually small lesions of less than 1 cm (Pipeleers-Marichal et al., 1990; Pipeleers- M arichal et al., 1993). Gastrinomas associated with M EN l are predominantly of duodenal origin and frequently multicentric, whereas sporadic gastrinomas are single and more often pancreatic.

Treatment of M ENl patients with the Zollinger-Ellison syndrome involves reducing the output of gastic acid, which can be achieved medically with large doses of antisecretory drugs such as the histamine H2-receptor antagonists cimetidine and ranitidine (Deveney et al., 1983; Jensen et al., 1984), or with the parietal cell -K^-ATPase inhibitor, omeprazole (McArthur et al., 1985). Surgical treatment by total gastrectomy is reserved only for persistently non-responsive patients (Zollinger et al., 1980; Jensen, 1983). Surgery is effective in treating only non-metastatic gastrinomas located in the pancreas. Treatment of disseminated gastrinomas is difficult and chemotherapy with streptozotocin and 5-fluorouracil (Moertel et al., 1980), hormonal therapy with octreotide which is a somatostatin analogue (Kvols et al., 1987), hepatic artery embolisation (Carrasco et al., 1983), administration o f human leucocyte interferon (Eriksson et al., 1986), and removal of all resectable tumour (Norton et al., 1986) have all occassionally been successful. The combined data from five recent reports indicate a surgical cure rate of only 11% (Melvin et al., 1993).

et al., 1992; Pipeleers-Marichai et al., 1993; Ruszaiewski et al., 1993) and métastasés can occur in the liver, lymph nodes or lungs. In addition, the stomachs of patients with sustained hypergastrinaemia have been shown to develop hyperplasia and carcinoid tumours. The proliferation of these fundic endocrine argyrophil cells, which are mainly o f the enterochromaffin-like (ECL) type, has been demonstrated to be under the control o f gastrin. Experimental and pathological chronic endogenous hyp ergastrinaemia in rats as well as humans has been shown to be associated with fundic argyrophil cell hyperplasia and carcinoid tumours, suggesting a causal relationship (Larsson et al., 1986; Lehy et al., 1989; Tielemans et al., 1990; Mattsson et al., 1991). Fundic argyrophil cell hyperplasia in patients with Zollinger-Ellison syndrome has been known to occur since 1974 (Bordi et al., 1974) whereas, the first cases o f fundic argyrophil carcinoid tumours have been described more recently and have only been reported in patients with Zollinger-Ellison syndrome associated with M ENl (Mignon et al., 1986; Bordi et al., 1988; Solcia et al., 1990; Lehy et al., 1992; Cadiot et al., 1993a). These carcinoid tumours have been shown to represent another neoplastic manifestation o f the M EN l syndrome rather than being the result o f a trophic potential of gastrin (Cadiot et al., 1993b) (discussed further in section 4.3).

1.4.3b Insulinomas

(3-islet cell tumours which secrete insulin represent one third o f all pancreatic tumours in M EN l patients (Vasen et al., 1989) and occur in association with gastrinomas in 10% of M EN l patients (Crosier et a l, 1971; Peurifoy et a l, 1979; Vasen et a l, 1989). Patients with insulinoma present with hypoglycaemic symptoms which develop after a fast or exertion and improve after glucose intake. Insulinomas are diagnosed biochemically

by demonstrating an increase in plasma insulin concentrations in association with hypoglycaemia, and increased levels of C-peptide and proinsulin.

Treatment of patients with insulinomas consists o f frequent carbohydrate feeds together with the administration of diazoxide or octreotide but, this may not be successful and surgery may be required. Most insulinomas are multiple and small, but unlike gastrinomas, an extra-pancreatic location of insulinomas is extremely rare (Proye, 1987; Boden, 1989). Surgical treatment, which ranges from enucleation of a single tumour to a distal pancreatectomy or partial pancreatectomy, has been curative in some patients. Malignancy is rarer with insulinomas than with gastrinomas (Grama et al. 1992; Mignon et al., 1993), but metastatic disease can be treated with chemotherapy, using streptozotocin or somatostatin.

1.4.3c Glucagonomas

These a-islet cell tumours which secrete glucagon have been reported in only a few patients with M EN l (Crosier et al., 1971; Croughs et al., 1972; Tiengo et al., 1976; Stacpoole et al., 1981). The characteristic clinical manifestations o f a skin rash (necrolytic migratory erythema), weight loss, anaemia and stomatitis may be absent and, the presence o f the tumour only recognised by glucose intolerance and hyperglucagonaemia. The tail o f the pancreas is the most common site for glucagonomas, and surgical removal of this is effective treatment. However, approximately 50% of the patients have developed métastasés by the time o f diagnosis (Stacpoole et al., 1981), and medical treatment with somatostatin or its analogue octreotide, or with streptozotocin has been successful in some patients (Strauss et al., 1979; Marynick et al., 1980).

1.4.3 d VIPomas

VIPomas, which secrete vasoactive intestinal peptide (VIP), produce the WDHA syndrome recognised by watery diarrhoea, hypokalaemia and achlorhydia (Marks et al., 1967). The clinical syndrome has also been referred to as the Yemer-Morrison syndrome (V em er and Morrison, 1958) and the VIPoma syndrome (Bloom et al., 1973). These tumours have been reported in only a few M EN l patients (Vemer and Morrison, 1958; Brown and Crile, 1964; Long et al., 1979) and are diagnosed by observing a marked increase in plasm a VIP concentration. Similarly to glucagonomas, VIPomas are also most frequently identified in the tail o f the pancreas, and surgical removal o f this is effective. Unresectable tumour can be medically treated with streptozotocin (Kahn et al., 1975) or octreotide (Long et al., 1979).

1.4.3e PPomas

These tumours, which secrete pancreatic polypeptide (PP) are found in a large num ber o f patients with M EN l (Friesen et al., 1980; Gelston et al., 1982). The clinical significance o f PP is unknown and no clinical manifestations are apparm t from excess PP secretion although, the use o f serum PP measurements has been suggested for the detection of pancreatic tumours in M EN l patients (Lamers and Diemel, 1982; Skogseid et al., 1987).