Pathophysiology and Symptoms

The altered physiology of patients with Z-E syndrome is due to the effects of high concentrations of gastrin in the circulation. The primary effects of the hypergastrinemia are gastric acid hypersecretion and parietal cell hyperplasia (Fig. 82-1). Gastrin acts directly on specific receptors of the parietal cell to promote gastric acid secretion. Because gastrin is also a trophic hormone, chronic hypergastrinemia causes an absolute increase in the number of parietal cells, thus increasing gastric acid hypersecretion even more.30 Pancreatic volume and bicarbonate output are similarly increased by a combination of increased duodenal acid load and a direct trophic effect of gastrin on pancreatic acinar cells.31

The patient's response to the marked gastric acid hypersecretion is variable (see Fig. 82-1). Complications such as bleeding, perforation, and outlet obstruction may occur. Some patients with Z-E syndrome appear to have more than

FIGURE 82-1. Pathophysiology of the ZollingerEllison syndrome and tumor locations. Gastrinomas may be (a) submucosal in duodenal wall; (b) pedunculated, arising from pancreatic surface; (c) in parapan-creatic lymph nodes; (d) in pancreatic parenchyma; (e) liver metastases. (From Wilson S. Gastrinoma. In: Howard JM, Jordan GLJR, Reber HA [eds], Surgical Diseases of the Pancreas. Philadelphia, Lea & Febiger, 1987.)

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the usual duodenal and gastric mucosal resistance to peptic ulceration and initially may not experience peptic ulceration. In these patients, the combination of the increased gastric and pancreatic secretions may overwhelm the normal absorptive capacity of the intestine, and a watery "overflow" diarrhea may be the initial complaint.32 Erosive duodenitis and jejunitis can usually be documented in these patients by endoscopy.33

Seven diagnostic clues suggest the presence of a gastrinoma:

1. Diarrhea in a patient with peptic ulcer disease

2. Peptic ulcers persisting after therapy with H2 receptor antagonists or omeprazole

3. Recurrent ulcer after an adequate ulcer operation

4. Pathognomonic jejunal ulcers

5. Large gastric rugal folds, often associated with duodenitis, jejunitis, and rapid transit

6. Multiple atypical peptic ulcers

1. Marked gastric acid hypersecretion (>15 mEq/hour)

Although these clues suggest the presence of a gastrinoma, the clinician should remember that most patients with Z-E syndrome present with signs and symptoms similar to those seen in patients with ordinary acid peptic ulcer disease. Most Z-E syndrome patients (approximately 70%) present with pain related to acid peptic disease. Cramping pains associated with diarrhea are not uncommon (20% to 30%), and in some patients (about 10%) diarrhea may be the only complaint. Symptoms have been present longer than a year in four of five patients. Gastric acid hypersecretion can produce a characteristic gastrointestinal radiologic picture (i.e., atypical ulcers, large gastric folds, rapid transit, and flocculation of barium); however, three of four patients exhibit ulceration in the usual duodenal ulcer locations.34,35 Nearly one third of Z-E syndrome patients have had symptoms for 5 years before presenting to a physician, and four of five patients have radiologic findings of an ordinary duodenal ulcer.34,35

Pathology

Gastrinomas are composed of cells that resemble the G cells of the gastric antrum and duodenum.36 Variability in tumor histology, extrapancreatic sites, and multiplicity of lesions are characteristics of Z-E syndrome (see Fig. 82-1). Although first called pancreatic islet cell tumors, many gastrinomas are located outside the pancreas, with sites in the duodenal wall, stomach, jejunum, peripan-creatic tissue, ovaries, and liver. In some series, fewer than 50% of Z-E syndrome patients have a histologically documented pancreatic primary tumor. The existence of primary (i.e., nonmetastatic) gastrinoma in a lymph node as a cause of Z-E syndrome is controversial, but numerous patients have been cured by removing one or more lymph nodes.37"39

At least 60% of gastrinomas are malignant. Even tumors that appear histologically benign may be associated with metastases. I consider all gastrinomas to be potentially malignant neoplasms. However, gastrinomas may have an indolent course, and Z-E syndrome patients with proven lymph node metastases may live for several decades without apparent tumor progression.37,40

The first gastrinomas were described as "noninsulin-producing islet-cell tumors" by Zollinger and Ellison because the tumors appeared to be islet cell lesions histologically, they produced a hormone, and conventional staining techniques indicated an absence of beta granules in the cytoplasm of the tumor cells. Islet cell tumor is a misnomer because these gastrin-producing neuroendocrine tumors probably do not develop from pancreatic islet cells directly. Current theory is that these tumors develop from pluripotential neuroendocrine stem cells located within the duct epithelium of the exocrine pancreas and gastrointestinal tract.41,42

The morphologic appearance of gastrinomas is similar to that of carcinoid tumors and other neuroendocrine tumors of the pancreas. The arrangement of the tumor cells is variable; the common patterns are ribbon, rosette, follicular, and solid sheets of small, uniform, and usually well-differentiated cells separated by trabeculae. Distinction between a benign and a malignant tumor usually cannot be made on the basis of histology alone.43,44

Immunohistochemical staining techniques, using specific antibodies, can identify gastrin granules within cytoplasm of the gastrinoma cells. Chromogranin A, neuron-specific enolase, and synaptophysin are proteins that can also be found in gastrinomas by these techniques, further characterizing these tumors as neuroendocrine in nature.45

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