The gastrinoma syndrome, or Zollinger-Ellison syndrome, has traditionally been associated with a severe, fulminant ulcer diathesis, often with multiple ulcers, and ulcers in unusual locations such as the post-bulbar region and proximal jejunum. However, with increasing recognition of this syndrome, as well as the availability of a radioimmunoassay for serum gastrin, most patient's with gastrinoma now present with either milder forms of peptic ulcer disease, or with secretory diarrhea. The syndrome can exist in multiple forms, including benign sporadic, malignant metastatic, and as part of the MEN-I syndrome. Approximately 66% of gastrinomas are sporadic. Sporadic tumors are believed to be malignant in approximately 40-85% of cases. Sporadic gastrinomas occur primarily in the gastrinoma triangle, defined as the confluence of the cystic and common bile duct superiorly, the second and third portions of the duodenum inferiorly, and the neck and body of the pancreas medially. Passaro and colleagues suggest that sporadic gastrinomas originating in the gastrinoma triangle, including those in the duodenal wall and lymph nodes, are of ventral pancreatic bud stem cell origin (1). Although they can occur in the pancreas, the duodenum has been shown to be the most common site of gastrinomas, based on the pioneering work of Debas and colleagues, Thompson and colleagues, and others. Duodenal wall gastrinomas have been identified in 43-77% of patients. These duodenal wall tumors are frequently small and multiple. Sporadic tumors occurring in the pancreas tend to be solitary. Primary tumors may also occur in a variety of ectopic sites, including the body of the stomach, jejunum, peripancreatic lymph nodes, splenic hilum, root of the mesentery, omentum, liver, gallbladder, common bile duct, and the ovary. A recent immunohistochemical study in 20 autopsy patients suggests that primary nodal gastrinomas are due to entrapment of neuroendocrine cells during development (2). Overall, about 5.6% of patients have a primary gastrinoma located in an ectopic site (3). Solitary tumors in ectopic sites are less likely to be malignant than solitary tumors in pancreatic sites. Although traditionally surgical cure rates have been less than 50%, the increasing recognition of the duodenal wall as the most common location of gastrinoma has resulted in an increasing number of surgical cures.

GASTRINOMAS IN MEN-1

About 33% of gastrinomas are associated with the MEN-I syndrome. Gastrinomas in MEN-I patients present a variety of unique problems. The tumors are usually multiple, and often small and undetectable. Most cases are discovered at a younger age than in sporadic cases. Although these tumors are less frequently (7-12%) malignant, the frequency of malignancy may truly be considerably higher than this. Because of the multiplicity of the tumors and their small size, it is generally quite difficult to find the specific tumor(s) that are secreting gastrin. Thus, the likelihood of surgical cure in MEN-I patients is considerably less than in sporadic patients, unless a specific site or sites responsible for the hypergastrinemia has been identified preoperatively.

Gastrinoma can metastasize to a variety of locations, including the lymph nodes and liver. The presence of gastrinoma in peripancreatic lymph nodes is not evidence of incurability, if the nodes can be completely resected at the time of surgery for the primary tumor. Some have advocated an aggressive approach to liver metastases, including debulking procedures. The tumor related mortality in patients with metastatic gastrinoma can be as high as 79%.

DIAGNOSIS

Prior to the development of the radioimmunoassay for serum gastrin, 80% of gastrinoma patients presented with a severe ulcer diathesis, bleeding, obstruction, or perforation. Two thirds of patients had at least one operation. Currently, only 20% of patients present with severe ulcer complications, and only one third have had prior surgery. H. pylori infection is not a risk factor for peptic ulceration in patients with gastrinoma (4). In a study of 84 gastrinoma patients, the prevalence of H. pylori exposure was only 23%, 10% with active infection, 4 less than the general population. The possibility of gastrinoma should be considered in all patients with peptic ulcer disease, and those with unexplained secretory diarrhea. All such patients should undergo measurement of fasting serum gastrin levels. An aggressive testing policy has been shown to be cost effective.

Diagnosis of gastrinoma syndrome depends on the demonstration of: 1) elevated serum gastrin levels; 2) a positive secretin stimulation test; and 3) gastric acid hypersecretion. Hypergastrinemia in the absence of increased acid production is not due to gastrinoma. It is vital to stop H2 blockers, proton pump inhibitors, and octreotide at least 24 hours before performing these tests for gastrinoma. (Assay available at Inter Science Institute-800-255-2873).

Serum gastrin levels are usually greater than 150 pg/ml in patients with gastrinoma syndrome. The exception is a small fraction of patients who secrete a biologically active variant not recognized by the antiserum used for the assay. A careful history and physical is required, as gastrin levels may be elevated for a variety of other reasons (table 1). Measurement of gastric pH is also useful, because in the absence of antisecretory drugs, a pH of 3.0 or higher excludes Zollinger-Ellison Syndrome.

Establishment of the presence of gastric acid hypersecretion should include measurements of volume as well as basal and pentagastrin-stimulated acid secretion. The diagnosis is confirmed if: a) the volume of gastric secretion is large, typically greater than 10 liters per 24 hours; b) the basal acid output is over 15 mmol/h. Values in the 10-15 range are borderline, and less than 10 mmol/h exclude diagnosis of Zollinger-Ellison Syndrome. In patients who have previously undergone vagotomy, basal acid output in gastrinoma is over 3 mmol/h; c) the ratio of basal acid output to maximal pentagastrin stimulated acid output is greater than 0.6.

The most accurate and sensitive test remains the Secretin Stimulation test for gastrin secretion. No new test has emerged with a greater sensitivity or specificity. Secretin, 2 mcg/kg is given intravenously, and blood samples for gastrin are drawn at 2, 5, 10, 20, and 30 minutes. A rise of more than 100 pg/ml is strongly suggestive of Zollinger-Ellison Syndrome. False positive results are rare, and are usually found in hypochlorhydric states.

Mention must be made of the g-cell hyperplasia syndrome, which can be sometimes confused with the gastrinoma syndrome. Patients with g-cell hyperplasia typically have an equivocal response to secretin stimulation, and an exaggerated response to food ingestion, thus distinguishing them from patients with gastrinoma.

The possibly of gastrinoma should be considered in all patients with Multiple Endocrine Neoplasia type I, since 50-60% of such patients will develop gastrinoma. Patients with hyperparathyroidism should also be screened for gastrinoma, since up to 38% of patients will be found to have gastrinoma.

LOCALIZATION

Tumor localization is important in gastrinoma patients, as it may have a direct bearing on patient management. A variety of non-invasive and invasive techniques have been used, with varying levels of success (see table 2). Non-invasive techniques include ultrasound, CT scan, MRI, and most recently somatostatin receptor scintigraphy. Transabdominal ultrasound and CT have proven to be of limited value, as these tumors are frequently small and below the resolution of the techniques. In addition, the density of these tumors is similar to that of surrounding pancreatic tissue, making them difficult to detect. MRI has not been shown to be superior to the previous techniques. Perhaps the greatest value of CT scan is that it identifies most patients with liver metastases.

Some have advocated endoscopic ultrasound. In experienced hands, localization rates of 80-100% in patients with pancreatic gastrinomas have been reported. However, the ability to detect small lesions less than 5 millimeters in size, or occult duodenal lesions, is uncertain. The pancreatic head is examined with the scanner positioned in the duodenum, and the body and tail of the pancreas are studied with the scanner in the stomach. Some have used a special saline filled balloon at the tip of the instrument with installation of approximately 400 cc of saline into the stomach to provide an interface between the ultrasonic unit and the stomach wall.

Data from Norton and colleagues 211, Jensen 1999, as well as Vinik and colleagues. 90,162,329

The development of somatostatin receptor scintigraphy has been an important advance in the imaging of pancreatic neuroendocrine tumors, and specifically gastrinoma. Somatostatin receptor scintigraphy should be obtained in all patients with a diagnosis of gastrinoma. The results with this technique approach those obtained with more invasive localization methods (see table 2). A recent study of 146 patients by Gibril and colleagues from the National Institutes of Health revealed a sensitivity of 71%, specificity of 86%, and a positive predictive value of 85%, higher than any other non-invasive modality (5). Somatostatin receptor scintigraphy altered management in 47% of patients overall. Like most imaging modalities, somatostatin receptor scintigraphy tends to miss small duodenal tumors less than 1cm in diameter (6). False positives do occur in about 10% of patients, thus the clinical context must be considered and the results interpreted carefully. Our current approach is to combine somatostatin receptor scintigraphy, along with either CT scan or MRI, to provide anatomic information and to help exclude liver metastases.

With the advent of somatostatin receptor scintigraphy, there is currently less need for the use of invasive techniques. The invasive techniques are highly accurate, however they involve discomfort, considerable expense, and require the expertise of an experienced angiographer. Selective visceral angiography has been shown to be useful for localizing tumors in patients with gastrinoma, as well as identify occult metastatic disease. The addition of selective intra-arterial injection of secretin to selective angiography greatly improves the accuracy of the technique. This requires the insertion of a catheter in a hepatic vein and a peripheral vein to sample gastrin levels. When secretin is injected into a vessel that supplies the gastrinoma, the hepatic vein levels of gastrin greatly exceed the peripheral levels. It may also increase the number of patients who show a tumor blush on angiography. This technique may be more accurate than percutaneous transhepatic venous sampling (PTHVS) alone.

Percutaneous transhepatic venous sampling (PTHVS) is a highly accurate technique, however it is both costly and time consuming. This technique has been shown to be of value in those with a primary gastrinoma not detected by conventional imaging methods. It has clearly been shown that PTHVS is a useful method to regionalize a tumor. However, the success of this technique is highly operator dependent, and requires a detailed understanding of the variable venous anatomy present in the region. A variety of technical issues, including placement of cannulae to avoid vessel obstruction, and streaming of portal blood flow, can affect the results of the study. Because of potentially rapid changes in the secretory rate of gastrinomas, it is important to simultaneously measure gastrin in pancreatic veins and central arteries, to determine gradients.

TREATMENT

With the increasing recognition of the duodenum as the most common site for gastrinomas, and with the improved localization methods, at least 50% of patients with sporadic gastrinoma can be cured by tumor resection. Thus, an aggressive approach to tumor localization is useful in selecting patients for operative treatment.

The goals of treatment of gastrinoma include: 1) management of the gastric acid hypersecretion; 2) resection of what are commonly malignant tumors with the risk of distant spread, and ultimately death of the patient.

Treatment has undergone significant changes since the syndrome was originally described in 1955. Most patients underwent emergency surgery for complications such as massive hemorrhage or perforation. It became rather clear that partial gastrectomy with or without vagotomy was ineffective treatment. Total gastrectomy became the standard operation for patients with gastrinoma. Although this operation was effective in controlling acid hypersecretion, many patients went on to suffer morbidity and mortality from the tumor itself. Approximately 60% of patients with gastrinoma have malignant tumors, which, although relatively slowly growing, are the major contributing factor to mortality with long-term follow-up. Occasional cases in which the primary tumor was excised, usually combined with total gastrectomy, resulted in long-term cures.

The development of potent antisecretory drugs has changed the management of patients with gastrinoma. In most patients gastric acid hypersecretion can be controlled with long-term omeprazole. Patients on long-term omeprazole can develop gastric carcinoid tumors. In addition, significant decreases in serum vitamin B12 have been observed (7). Thus vitamin B12 levels should be monitored in these patients. Because current antisecretory agents are so effective, surgery for the control of gastric acid hypersecretion is no longer required. A study of 212 patients from the National Institute of Health at a mean follow-up of nearly 14 years showed that none of the patients suffered an acid related death (8). Overall, 31% of patients died, one half due to the gastrinoma itself. Thus, the current role of surgery is to identify and remove the responsible tumor or tumors, to prevent tumor progression and ultimately death. In early surgical series, the cure rate was relatively modest, ranging from 15-30%. Those with extra-pancreatic tumors were noted to have a cure rate as high as 50% with surgical excision. With improvements in preoperative imaging studies, the increasing recognition of the duodenum as a site for gastrinoma, and an aggressive surgical approach, the number of positive explorations has increased in one group from 64% to over 90%, primarily through the identification and resection of duodenal wall gastrinomas. Even after successful resection, many patients do recur with long-term follow-up. In a study of 151 patients by Norton and colleagues, in patients with sporadic gastrinoma the 10 year disease free survival was 34%, and the disease specific survival was 95% (9).

SURGERY

Surgery for gastrinoma includes meticulous technique and a thorough exploration. The lesser sac is widely opened, and the entire pancreas is mobilized throughout its length. This allows for careful bimanual palpation of the gland. Although many of the lesions are palpable, some are quite deeply located in the gland, and may not feel dissimilar to the adjacent normal pancreatic parenchyma. Intraoperative ultrasound has been shown by a number of investigators to be useful, and should be performed in any patient undergoing exploration for gastrinoma. Intraoperative ultrasound is useful in identifying difficult to palpate and non-palpable lesions. It is also may detect signs suggestive of malignancy, as well as the relationship of the tumor to the main pancreatic duct and major blood vessels. Intraoperative ultrasound is not particularly useful in identifying duodenal wall gastrinomas, however. Intraoperative endoscopy with transillumination of the duodenum is capable of locating duodenal wall gastrinomas. However it is not useful in identifying the more than 50% of duodenal wall gastrinomas located along the medial wall. The most accurate method of detecting duodenal wall gastrinomas remains duodenotomy with careful palpation, a technique employed by experienced teams during surgical exploration for gastrinoma.

The treatment of the patient with MEN-I and gastrinoma remains controversial. Few data are available on patients with MEN-I syndrome and gastrinomas who have undergone careful preoperative evaluation followed by possible palliative or curative surgery. Therefore, a definitive statement about optimal management in these patients cannot be made at the present time, .and treatment should be individualized. If a clear-cut source of the hypergastrinemia can be identified using functional and anatomic studies, then surgical exploration, with enucleation or resection, should be strongly considered. Such an approach may offer excellent palliation, if not cure. Other groups take an even more aggressive posture (See MEN-1 Section). The malignant potential of these lesions should also be taken into account. Patients with tumors more than 3cm in size should be considered for resection, even in the absence of clear-cut function. The relatively low incidence of malignancy in gastrinoma patients with MEN-I compared to those without MEN-I does not mean that a more cavalier approach can be taken in these patients.

CHEMOTHERAPY

There is little experience with the use of adjuvant chemotherapy following surgical resection. The small number of patients treated, the relatively indolent nature of these tumors, and the short follow-up times are insufficient to recommend adjuvant chemotherapy outside of clinical trials. However, it may be appropriate to consider adjuvant chemotherapy in selected patients felt to be at high risk of subsequent recurrence, understanding that there is little data to show benefit with this approach.

The activity of chemotherapy in patients with metastatic gastrinomas is difficult to determine since most published series have studied chemotherapy for all histologic types of pancreatic endocrine tumors grouped together. In addition, the growth rate of metastatic gastrinoma varies markedly (10) , further complicating assessment of response to therapy. Streptozotocin appears to be the most active single agent in patients with metastatic gastrinoma, with objective response rates reported in up to 50% of patients. There is no evidence that the addition of 5-FU with or without doxorubicin improves the outcome compared to streptozotocin alone. Differences in the doses used, the schedules of administration, and the criteria used to assess tumor responses, make firm management recommendations difficult. Octreotide, either alone or combined with interferon, appears to have a role in management of these patients. The development of a long-acting somatostatin analogue (lanreotide) has greatly facilitated management, and is effective in reducing symptoms in 38-64% of patients (11). A known side effect is the development of gallstones. In a small study of 21 pancreatic neuroendocrine tumor patients from Marburg, Germany, 14 patients responded to combined octreotide and alpha-interferon, primarily with disease stabilization (12) . Of note, 16 of the patients failed to respond to octreotide alone.