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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Gastrinoma

.

National Institutes of Health, Bethesda, Maryland, U.S.A.

Introduction, history and definition

The terms Zollinger-Ellison syndrome (ZES) and gastrinoma are now used interchangeably to indicate a neuroendocrine tumor that ectopically secretes gastrin, causing hypergastrinemia and gastric acid secretion (1, 2). Whereas some tumors by immunocytochemistry contain gastrin (bronchogenic carcinomas, colorectal cancers, etc.) and are called gastrinomas by some pathologists, they are not associated with hypergastrinemia and are not included by most experts in this definition (1). Although case reports that now fit the diagnostic criteria for gastrinoma were published prior to 1955 (1), the critical association of a neuroendocrine tumor with refractory peptic ulcer disease and gastric acid hypersecretion likely due to ectopic release of a hormone by the tumor was first made by two surgeons at Ohio State University in 1955 (R.M. Zollinger and E.H. Ellison).

Gastrinomas may occur either in a nonfamilial form (sporadic) (75%) or as part of the familial syndrome, multiple endocrine neoplasia-type 1 (MEN-1). MEN-1 is an autosomal dominant syndrome characterized by tumors or hyperplasia of multiple endocrine tissues (3). Hyperparathyroidism due to parathyroid hyperplasia (> 95%), pancreatic endocrine tumors (PET's) (80–100%), anterior pituitary adenomas (16–100%), and adrenal adenomas (27–36%) are the most common (2, 3). Nonfunctional PET's (80–100%) are the most common followed by gastrinomas (54%), insulinomas (21%), and glucagonomas (3%). It is now known that MEN-1 is due to mutations in a 10-exon gene on chromosome 11q.13 which encodes for a 610 amino acid nuclear protein, MENIN, whose function is unclear (3). Recognition of the presence of MEN-1 is important because these patients differ from sporadic cases in the role of surgery, other management decisions, natural history, and need for genetic screening (2, 4).

Epidemiology

Gastrinomas have an incidence of 0.5–1 new cases per million population per year and in recent studies are equally common to insulinomas, nonfunctional PET's, 2–4 times more common than VIPomas and 8–15 times more common than glucagonomas or somatostatinomas (1, 4).

Clinical features (table I)

The clinical features are dealt with in detail in a recent review (4). Data from three large studies (57) are shown in table I including data from the original ZES registry (5). The mean age of onset remains approximately 50 years (range 7–90), there is a slight male predominance (60%) and 20–25% have MEN-1. In > 99% of cases the initial symptoms are due to the gastric acid hypersecretion and only late in the disease course are symptoms due to the gastrinoma per se (pain, cachexia). Abdominal pain alone or with diarrhea remains the most common initial symptom (> 75%). Diarrhea may be initially the only symptom in 9–20%. Gastroesophageal reflux disease (GERD) may be the initial symptom in up to 31% and 49–61% of patients have GERD at initial evaluation.

Table I. Comparison of clinical features of patients with Zollinger-Ellison syndrome from various large series.

Table I

Comparison of clinical features of patients with Zollinger-Ellison syndrome from various large series.

In early studies (4, 5) most patients had peptic ulcers, frequently in atypical locations; however, presently most patients have typical duodenal ulcer and 20–30% have no ulcer (4).

Diagnosis and differential diagnosis

There is a mean delay of 4–7 years in the diagnosis (table I). There are a number of clinical and laboratory features that should suggest the diagnosis of ZES (table II). ZES should be particularly suspected in patients with peptic ulcer disease or GERD with diarrhea, without H. pylori infection, with refractory or recurrent disease despite treatment for H. pylori, with failure of drug therapy or associated with a personal or family history of endocrinopathies (table II) (4).

Table II. Clinical and laboratory conditions that should lead to suspicion of Zollinger-Ellison syndrome (ZES).

Table II

Clinical and laboratory conditions that should lead to suspicion of Zollinger-Ellison syndrome (ZES).

If the diagnosis is suspected, a fasting gastrin level is generally the initial test recommended (8). Fasting gastrin levels are elevated in > 98% of patients with ZES. If the fasting gastrin level is elevated, it should be repeated with an assessment of gastric pH. The most common cause of hypergastrinemia is achlorhydria/hypochlorhydria frequently due to antisecretory drug treatment (especially with proton pump inhibitors (PPI's)). If the gastric pH off gastric antisecretory drugs is > 2.5, ZES is unlikely the cause of the hypergastrinemia (4). If patients by history can stop the PPI, it should be discontinued for at least one week (1, 4).

If gastric pH is < 2.5 and the fasting gastrin level > 1000 pg/ml (nl < 100–200 pg/ml) and retained antrum syndrome can be excluded by history (i.e., no previous Billroth II resection) the diagnosis is confirmed. If the gastrin level is increased < 10-fold (101–999 pg/ml) (66% of patients with ZES), a secretin test as well as determination of basal acid output (BAO) for one hour should be performed (1, 4). Most patients (66–95%) have a BAO > 15 mEq/hr (no previous acid-reducing surgery) or > 5 mEq/hr (if such surgery) and 87% have a positive secretin test (≥ 200 pg/ml in gastrin increase over the preinjection level). If patients are not achlorhydric, there are no false positive tests using currently available formulations of secretin (1).

Other causes of fasting hypergastrinemia and hyperchlorhydria that can be excluded by these studies include antral G cell hyperplasia/hyperfunction, H. pylori infection, chronic renal failure, retained gastric antrum syndrome, post massive small bowel resection and gastric outlet obstruction (1, 4).

MEN-1 can be diagnosed by assessing for the presence of hyperparathyroidism (total and ionized calcium, parathormone levels) and pituitary disease (CT or MRI of sella, serum prolactin and growth hormone). In most, but not all patients with ZES and MEN-1, parathyroid or pituitary disease precedes the development of the ZES (4).

Pathology, tumor biology and pathogenesis

Pathology and tumor biology

In older studies the ratio of pancreatic to duodenal gastrinomas was 5 : 1, whereas in recent studies duodenal gastrinomas are > 2-times more common than pancreatic tumors (1). In the duodenum 57% are in D-1, 31% D-2, 6% in D-3 and only 3% in D-4 (1). In recent studies the distribution in the pancreas is 1 : 1 : 2 in the head : body : tail. Sixty to 90% of gastrinomas occur in the duodenal : pancreatic head area or gastrinoma triangle (1). In 8–23% of patients only gastrinoma in a lymph node is found and resection results in cure. It remains controversial whether these represent a primary tumor or occult slow growing metastases (1). In 9% of patients gastrinomas are found in a nonduodenal, nonpancreatic, nonlymph node location (heart, ovary, stomach, liver, gallbladder, biliary tract, mesentery, omentum, spleen, hilum) (1).

In older studies 60–90% of gastrinomas were malignant (1, 4). Recent NIH studies show that long-term, 31% of the 122 patients followed for a mean of 14 years (range 0.1–31) died of gastrinoma-related causes (9). In these and other studies (10) two different growth pattern are now recognized. In 75% of patients the tumor pursues a non-aggressive growth pattern (10-year survival - 96%) and in 25% it pursues an aggressive growth pattern (10-year survival - 30%). An aggressive course was characterized by the presence or development of liver metastases, patients were more frequently female (67% vs. 32%), MEN-1 was uncommon (6% vs. 21%), a short disease duration was present at diagnosis, a higher fasting gastrin, a larger tumor, a gastrinoma pancreatic in location, and different flow cytometry characteristics (1, 10).

Overall, approximately one-third of patients have hepatic metastases at presentation (1, 4). In 221 patients seen at the NIH, 70% had localized disease, 17% hepatic metastases and in 13% no tumor was found (1). Thirty-six percent had only a primary tumor found, 29% a primary with lymph node metastases, 23% a primary with liver metastases, 3% liver metastases only, and 16% only lymph node involvement (1).

The growth of hepatic metastases also highly variable and this has an impact on their treatment (11). In one study (11) in 40% of patients with hepatic metastases the lesions grow rapidly and all deaths occurred in this group.

Recent studies demonstrate that bone metastases occur in 31% of patients with hepatic metastases and similar to the development of ectopic Cushing's syndrome, are an independent prognostic factor for poor survival (9).

Pathogenesis

All of the symptoms, except late in the disease course, are due to the gastric acid hypersecretion. The chronic hypergastrinemia not only increases the basal acid output, it also stimulates the growth of the gastric mucosa, resulting in parietal cell hyperplasia and proliferation of enterochromaffin-like cells (ECL cells) (1). The increased parietal cell mass results in an increased maximal acid output. The ECL hyperplasia can result in gastric carcinoid tumors, some of which are malignant, especially in patients with ZES and MEN-1 (12).

Management

General

Similar to other functional PET's all patients with gastrinomas have two distinct problems requiring treatment (1, 2, 4). Treatment must be directed at controlling the results of the hormone-excess state (i.e., the gastric acid hypersecretion) and against the gastrinoma per se because the majority are malignant. Surgical cure would treat both problems; however, it is only possible in 30–40% of all patients, 30–50% in patients with sporadic disease and none of the patients with ZES with MEN-1 (1, 12). Furthermore, because the gastric acid hypersecretion can lead to severe peptic ulcer disease complications if not treated (4, 5), it is essential that it be treated as soon as the diagnosis is suspected.

Management of the gastric acid hypersecretion

It is now possible to control the acid hypersecretion medically in all patients (> 98%) except the small percentage who can not or will not take regular oral gastric antisecretory drugs (2). The drugs of choice, because of their potency, are the PPI's (omeprazole, lansoprazole, pantoprazole) (2, 13). Because of their long duration of action acid hypersecretion can be controlled in almost all patients (> 90%) with once or twice a day dosing (13). In patients without complicated ZES (with MEN-1, moderate to severe GERD, or a previous Billroth II resection) the initial dose should be 60 mg daily of omeprazole or lansoprazole (1, 13). It is recommended acid secretion be checked one hour prior to the dose the following day and if it remains > 10 mEq/hr the dose should be increased to 80 mg/day and the study repeated. Doses ≥ 100 mg should be given as a twice-a-day dose because a BID dose is more effective than a single larger once-a-day dose (13). In patients with complicated ZES the initial dose should be 40 mg BID of omeprazole (13).

In patients with previous Billroth II resections or moderate to severe GERD, greater suppression of acid secretion may be needed to allow mucosal healing and prevent symptom recurrence. In these patients acid secretion should be reduced to < 5 mEq/hr prior to the next medication dose and if symptoms continue or repeat endoscopy shows mucosal abnormalities, the dose should be increased to reduce acid secretion to < 1 mEq/hr.

Acid secretion is controlled in most patients with < 80 mg/day of omeprazole and rarely > 200 mg/day is needed (1, 13). Tachyphylaxis does not develop with time and patients been treated for > 10 years without loss of efficacy (1, 13). In 95% of patients without complicated ZES and 35% of patients with complicated ZES, over time the omeprazole dose can be reduced to 20 mg daily or twice daily.

Many patients with ZES have circumstances (surgery, etc.) where parenteral gastric antisecretory therapy is required (1, 4, 13). Intravenous bolus administration of omeprazole is effective in ZES but is not available in the U.S. Therefore, parenteral administration of a histamine H2-receptor antagonist is required (1, 13). Ranitidine and cimetidine have been the best studied (14); these studies demonstrate ranitidine or cimetidine are best given by continuous intravenous infusion (14). After a bolus injection of 150 mg of ranitidine, a continuous infusion of 1 mg/kg body weight/hr of ranitidine or 3-fold more of cimetidine should be started. Acid secretion should be checked after 3–4 hours and the dose increased by a 0.5 mg/kg/hr increments if acid secretion is not < 10 mEq/hr. Patients have been treated for up to two months without loss of efficacy (14).

Surgical treatment of gastric hypersecretion by total gastrectomy is now rarely performed. A parietal cell vagotomy (PCV) decreases acid hypersecretion in ZES and may decrease antisecretory drug requirement (15). It has recently been recommended that PCV at the time of laparotomy for cure should be considered in all patients who do not have altered gastric emptying. However, specific surgery should not be performed just to perform the PCV because most patients continue to require low doses of antisecretory drugs if not cured (15). Parathyroidectomy in a patient with hyperparathyroidism and MEN-1 with ZES can have a dramatic effect on decreasing basal acid output, fasting serum gastrin levels and increasing sensitivity to gastric antisecretory drugs (12, 16).

Gastrinoma localization

After control of the acid hypersecretion, establishment of the diagnosis of ZES, determination of the presence or absence of MEN-1, treatment needs to be directed at the gastrinoma per se by determining its location and extent (1, 4). Possible surgical resection, the need for medical treatment directed against advanced disease and possible cytoreductive surgery all require an accurate assessment of tumor extent (4).

Numerous tumor localization methods including conventional imaging modalities (computerized tomographic scan (CT), ultrasound, selective angiography, magnetic resonance imaging (MRI)), functional localization measuring hormonal gradients, endoscopic ultrasound and somatostatin receptor scintigraphy (SRS) using 111In-DTPA-DPhe1] -octreotide are all reported useful in different studies. Recent studies (17) demonstrate SRS is now the imaging modality of choice (fig. 1) in that for both extrahepatic disease and hepatic metastases it is equal in sensitivity to all four conventional imaging studies combined. SRS will localize an hepatic gastrinoma in 68% of patients and hepatic metastases in 92% of patients with proven liver metastases (17). If the SRS is negative, then endoscopic ultrasound should be performed because recent studies show it localizes most pancreatic gastrinomas and has an additive effect with SRS (18) (fig. 1). If endoscopic ultrasound is negative, selective angiography with secretin injections intra-arterially and hepatic venous gastrin sampling should be considered because of its sensitivity for localizing duodenal gastrinomas (1) (fig. 1).

Figure 1. Algorithm for tumor localization in patients with Zollinger-Ellison syndrome (ZES).

Figure 1

Algorithm for tumor localization in patients with Zollinger-Ellison syndrome (ZES). SRS is recommended as the initial imaging procedure because of its greater sensitivity for both the primary tumor and identification of hepatic metastases, high specificity (more...)

Treatment of gastrinoma in patients without hepatic metastases

Treatment of sporadic gastrinoma

If liver metastases are not present and the patient does not have a medical condition that is a contra-indication to surgery (advanced pulmonary or cardiac disease, etc.) that markedly limits life-expectancy (i.e., 5–10 yrs), then surgical exploration for cure should be performed (19). This surgery should be performed only by a surgeon experienced in surgery on gastrinomas and pancreatic endocrine tumors.

At exploration tumor enucleation or resection without a pancreaticoduodenotomy (Whipple resection) is recommended (1, 2). This will result in a 50% disease-free result.

Treatment of gastrinoma in patients with MEN-1 without hepatic metastases

There is no consensus on the role of surgery in the management of these patients (1, 12, 19, 20). Some recommend no exploration, others only if a tumor of ≥ 3 cm is seen, and still others recommend exploration in all of these patients (1, 12, 19, 20). Recent studies show long-term cure of the gastrinoma is almost never seen (12, 19). Because recent studies demonstrate larger tumors (9, 10) more frequently cause the development of liver metastases, therefore some recommend exploration be performed if a tumor of a certain size is imaged (1). We currently recommend surgery for tumors ≥ 2 cm (1), however, others do not agree with this (1).

Treatment of patients with gastrinomas with hepatic metastases

The primary determinant of long-term survival in all studies is the presence of liver metastases (4, 9, 10). Chemotherapy with streptozotocin and doxorubicin (± 5 fluorouracil), systematic removal of all resectable disease (cytoreductive surgery) (21), hormonal therapy with somatostatin analogues (22), biotherapy with interferon, hepatic embolization alone or with chemotherapy (chemo-embolization), liver transplantation (23), and radiotherapy with radioactive somatostatin analogues (24) have all been recommended.

At present there is no agreement on which modality should be the initial treatment. It is generally agreed that antitumor therapy should be reserved for patients with hepatic metastases in whom the tumor is increasing in size (1).

Prognosis

Long-term studies from the NIH (9, 10, 12) have recently reported that the long-term survival in patients with no liver metastases (10 yrs - 96%) is significantly greater (p = 0.028) than patients who develop liver metastases (10 yrs - 85%), or have single lobe hepatic metastases (10 yrs - 78%) and that this is significantly better than patients with diffuse liver metastases (10-year survival - 16% (fig. 2). Because surgical resection has been shown to reduce the rate of development of hepatic metastases (25), this strongly supports the role of surgery in patients with sporadic disease.

Figure 2. Survival rates from.

Figure 2

Survival rates from. Effects, extent, and time of development of liver metastases on survival are shown. Survival rates were calculated using death due to ZES-related causes as the outcome. Of 158 patients with no liver metastases, 6 died (•); (more...)

References

1.
Jensen RT (1999) Zollinger Ellison syndrome. In: Doherty GM, Skogseid B (eds) Surgical Endocrinology: Clinical Syndromes. Lippincott-Raven, Philadelphia (In press)
2.
Jensen R T. Gastrinoma. Bailliere's Clin Gastroenterol. (1996);10:555–766. [PubMed: 9113315]
3.
Marx S, Spiegel A M, Skarulis M C. et al. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med. (1998);129:484–494. [PubMed: 9735087]
4.
Jensen RT, Gardner JD (1993) Gastrinoma. In: Go VLW, DiMagno EP, Gardner JD et al (eds) The Pancreas: Biology, Pathobiology and Disease. Raven Press, New York, pp 931–978 .
5.
Ellison E H, Wilson S D. The Zollinger-Ellison syndrome: Re-appraisal and evaluation of 260 registered cases. Ann Surg. (1964);160:512–530. [PMC free article: PMC1408784] [PubMed: 14206854]
6.
Mignon M, Ruszniewski P, Haffar S. et al. Current approach to the management of tumoral process in patients with gastrinoma. World J Surg. (1986);10:703–710. [PubMed: 2875567]
7.
Jensen RT, Gardner JD (1991) Zollinger-Ellison syndrome: clinical presentation, pathology, diagnosis and treatment. In: Dannenberg A, Zakim D (eds) Peptic Ulcer and Other Acid-Related Diseases. Academic Research Associates, Armonk, pp 117–212 .
8.
Jensen RT (1998) Management of pancreatic Zollinger-Ellison syndrome and other gastric hypersecretory states. In: Wolfe MM (ed) Therapy of Digestive Disorders. W.B. Saunders, Philadelphia (in press)
9.
Yu F, Venzon D J, Serrano J. et al. Prospective study of the clinical course, prognostic factors and survival in patients with longstanding Zollinger-Ellison syndrome. J Clin Oncol. (1999);17:615–630. [PubMed: 10080607]
10.
Weber H C, Venzon D J, Lin J T. et al. Determinants of metastatic rate and survival in patients with Zollinger-Ellison syndrome: a prospective long-term study. Gastroenterology. (1995);108:1637–1649. [PubMed: 7768367]
11.
Sutliff V E, Doppman J L, Gibril F. et al. Growth of newly diagnosed, untreated metastatic gastrinomas and predictors of growth patterns. J Clin Oncol. (1997);15:2420–2431. [PubMed: 9196158]
12.
Jensen R T. Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1. J Intern Med. (1998);243:477–488. [PubMed: 9681846]
13.
Jensen RT (1999) Use of omeprazole and other protein pump inhibitors in the Zollinger-Ellison syndrome. In: Olbe L (ed) Milestones in Drug Therapy. Birkhauser Verlag AG Publ, Basel, pp 205–221 .
14.
Vinayek R, Hahne W F, Euler A R. et al. Parenteral control of gastric hypersecretion in patients with Zollinger-Ellison syndrome. Dig Dis Sci. (1993);38:1857–1865. [PubMed: 8104773]
15.
McArthur K E, Richardson C T, Barnett C C. et al. Laparotomy and proximal gastric vagotomy in Zollinger-Ellison syndrome: results of a 16-year prospective study. Am J Gastroenterol. (1996);91:1104–1111. [PubMed: 8651153]
16.
Norton J A, Cornelius M J, Doppman J L. et al. Effect of parathyroidectomy in patients with hyperparathyroidism, Zollinger-Ellison syndrome and multiple endocrine neoplasia type I: A prospective study. Surgery. (1987);102:958–966. [PubMed: 2891201]
17.
Gibril F, Reynolds J C, Doppman J L. et al. Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas: a prospective study. Ann Intern Med. (1996);125:26–34. [PubMed: 8644985]
18.
de Kerviler E, Cadiot G, Lebtahi R. et al. Somatostatin receptor scintigraphy in forty-eight patients with the Zollinger-Ellison syndrome. Eur J Nucl Med. (1994);21:1191–1197. [PubMed: 7859770]
19.
Norton JA, Fraker DL, Alexander RA et al (1999) Surgery for cure in Zollinger-Ellison syndrome. N Engl J Med (in press)
20.
Thompson N W. Current concepts in the surgical management of multiple endocrine neoplasia type 1 pancreatic-duodenal disease. Results in the treatment of 40 patients with Zollinger-Ellison syndrome, hypoglycaemia or both. J Intern Med. (1998);243:495–500. [PubMed: 9681848]
21.
Norton J A, Doherty G D, Fraker D L. et al. Surgical treatment of localized gastrinoma within the liver: A prospective study. Surgery. (1998);124:1145–1152. [PubMed: 9854596]
22.
Arnold R, Trautmann M E, Creutzfeldt W. et al. Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut. (1996);38:430–438. [PMC free article: PMC1383075] [PubMed: 8675099]
23.
Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma. Transplantation. (1998);66:1307–1312. [PubMed: 9846513]
24.
Leimer M, Kurtaran A, Smith-Jones P. et al. Response to treatment with yttrium 90-DOTA-lanreotide of a patient with metastatic gastrinoma. J Nucl Med. (1998);39:2090–2094. [PubMed: 9867148]
25.
Fraker D L, Norton J A, Alexander H R. et al. Surgery in Zollinger-Ellison syndrome alters the natural history of gastrinoma. Ann Surg. (1994);220:320–330. [PMC free article: PMC1234386] [PubMed: 7916560]
Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6964

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