Version July 2025
INTRODUCTION —
Gastrinomas are duodenal or pancreatic neuroendocrine tumors (NETs) that hypersecrete gastrin and lead to Zollinger-Ellison syndrome (ZES). ZES is the clinical syndrome of gastric acid hypersecretion caused by the gastrinoma that results in severe peptic ulcer disease, abdominal pain, and diarrhea. (See "Peptic ulcer disease: Clinical manifestations and diagnosis".)
Gastrinomas either occur sporadically or are associated with an inherited disorder called multiple endocrine neoplasia type 1 (MEN1), which accounts for approximately 25 percent of cases (figure 1) [1]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)
This topic will discuss the management and prognosis of gastrinomas and their associated hormone-mediated syndrome ZES. Of note, not all NETs producing gastrin will result in hypergastrinemia or ZES. Furthermore, the differential diagnosis of hypergastrinemia includes not only gastrinomas but also other entities such as proton pump inhibitor (PPI) therapy (most common), antral-predominant Helicobacter pylori infection, and antral G-cell hyperplasia. The clinical presentation and diagnosis of gastrinoma and ZES are discussed separately. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)
GOALS OF THERAPY —
For patients with gastrinoma and ZES, the goals of therapy are control of the clinical symptoms and complications resulting from the tumor's autonomous secretion of the hormone gastrin (ie, ZES) and control of the tumor burden itself (ie, the gastrinoma) [2].
Pharmacologic acid-suppressive therapy is the standard of care for most patients with gastrinoma and ZES as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome. By contrast, many patients with localized sporadic gastrinoma are candidates for surgical therapy in addition to pharmacologic therapy. Successful resection of sporadic gastrinomas both reduces the risk of eventual morbidity and death from metastatic spread of the tumor and either decreases or eliminates the need for pharmacologic acid-suppressive therapy for the associated ZES. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "Multiple endocrine neoplasia type 1: Management" and 'Surgical resection' below.)
In patients with metastatic gastrinoma, therapies aimed at reducing tumor burden (eg, resection, locoregional hepatic therapies, systemic therapy) may also simultaneously treat the associated symptoms of ZES by reducing or eliminating gastrin-secreting tumor cells. (See 'Metastatic disease' below.)
Prior to the development of effective acid-suppressive therapy, the major morbidity and mortality of gastrinoma and ZES were related to complications of fulminant peptic ulcer disease; total gastrectomy was the only effective measure to protect patients from these problems [3]. The development of H2 antagonists and the more powerful proton pump inhibitors (PPIs) has resulted in a significant decrease in morbidity and mortality from ulcer disease and has obviated the need for gastrectomy [4]. Of 212 patients with ZES studied prospectively for a mean of approximately 14 years, a cancer-related cause of death could be identified in only half of the 31 percent who died. All of the cancer-related deaths were due to tumor spread; none were due to hypersecretory complications [5].
PHARMACOLOGIC ACID-SUPPRESSIVE THERAPY —
For patients with gastrinoma and ZES, management of ZES with pharmacologic acid-suppression medications limits the clinical manifestations, related symptoms, and complications of ZES (mainly peptic ulcer disease). Agents that limit acid secretion, such as proton pump inhibitors (PPIs), reduce the symptoms (eg, heartburn, dysphagia) and the endoscopic findings (eg, esophagitis, esophageal strictures, Barrett's esophagus) of acid reflux commonly seen in patients with gastrinoma and ZES [6]. It is customary among many gastroenterologists to initiate and maintain PPIs at high doses, using symptoms and endoscopic findings as a signal to increase the dose. There have been few, if any, episodes of major peptic diathesis associated with this approach.
Because peptic symptoms with ZES are sometimes a poor surrogate marker of acid secretion, formal acid-secretory studies were previously advocated to guide the dose of acid suppressants, with the goal of reducing gastric acid secretion to below 10 mEq/hour prior to the next dose [7]. However, such studies are not commonly available, even in major medical centers.
Of note, pharmacologic acid-suppressive therapy aimed at managing the hormone-mediated symptoms of ZES do not typically impact tumor burden from the associated gastrinoma, which needs to be treated separately. (See 'Localized disease' below and 'Metastatic disease' below.)
Proton pump inhibitors — For all patients with gastrinoma and ZES, we recommend upfront initiation of a high-dose PPI (eg, omeprazole 40 mg twice daily, pantoprazole 80 mg twice daily) rather than other acid-suppressing agents [2,8,9]. PPIs (eg, omeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and esomeprazole) effectively block acid secretion by irreversibly binding to and inhibiting the hydrogen/potassium ATPase that resides on the luminal surface of the parietal cell. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders".)
PPIs are generally safe in high doses for the treatment of ZES, even when used for extended periods of time [10]. Some patients require an early upward titration of these doses; however, once control of acid output has been achieved, a gradual dose reduction is usually possible [11]. In a study of 37 patients who had received high-dose omeprazole for almost two years, nearly 50 percent were able to titrate the maintenance dose down to 20 mg daily [12]. Overall, 95 percent of patients without multiple endocrine neoplasia type 1 (MEN1), severe gastroesophageal reflux, or previous partial gastrectomy had safe reductions in their medication dose.
PPIs are generally well tolerated and can control the increased acid secretion due to hypergastrinemia in ZES for 10 years or longer (although some patients experience low vitamin B12 levels) [10,13-15]. As an example, a prospective study of the safety and efficacy of omeprazole with extended follow-up (nine years) revealed no tachyphylaxis or important toxicity [10]. In another observational study of patients with ZES on long-term acid-suppressive therapy (mean of 5.6 years for those on PPIs), the rate of vitamin B12 deficiency was 21 percent [15].
The adverse effects of PPIs are discussed separately. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Adverse effects'.)
Other agents
Potassium-competitive acid blockers — Potassium-competitive acid blockers (PCABs), a separate class of acid-suppressive medications, are an option for pharmacologic therapy in patients with ZES. PCABs can be used as an alternative to upfront acid-suppressive therapy with PPIs or as second-line therapy for those with symptoms refractory to PPIs. There are limited high-quality data for PCABs in the context of gastrinoma/ZES, and further studies are necessary.
PCABs work by competing for potassium on the luminal side of parietal cells, causing rapid and reversible inhibition of pumps and, therefore, acid secretion [16]. PCABs have a rapid onset of action and can achieve near-full therapeutic effects within the first dose. Vonoprazan is a PCAB that is approved by the US Food and Drug Administration for the treatment of erosive esophagitis, nonerosive gastroesophageal reflux disease, and H. pylori infection [17,18]. (See "Antiulcer medications: Mechanism of action, pharmacology, and side effects", section on 'Potassium-competitive acid inhibitors'.)
PCABs could be used as an alternative to upfront acid-suppressive therapy with PPIs in ZES. In randomized controlled trials, PCABs have been comparable to PPI therapy in ulcer healing and prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers [19-21]. However, these trials excluded patients with ZES.
PCABs could also be used as second-line therapy for those with symptoms refractory to PPIs. In one case report, vonoprazan was successfully used to treat a patient with ZES (duodenal gastrinoma) and acid hypersecretion symptoms refractory to lansoprazole [22]. Upon switching to vonoprazan, the patients had steady clinical improvement of ulcers and submucosal tumors on day eight endoscopy.
Somatostatin analogs — When PPIs are unable to control gastric acid secretion, somatostatin analogs such as octreotide and lanreotide can inhibit secretion of gastrin [23,24]. For patients with symptomatic hypergastrinemia, somatostatin analogs are not used as upfront pharmacologic therapy for symptom control due to the unpredictability of the response. However, somatostatin analogs may be helpful for symptoms that are refractory to initial therapy with PPIs.
H2-receptor antagonists — We do not use H2-receptor antagonists as initial pharmacologic therapy. In patients with ZES, the failure rate of these agents is 50 percent [1]. In addition, the dose used to treat ZES is usually four to eight times the dose used to treat peptic ulcer disease unrelated to ZES.
LOCALIZED DISEASE —
Eighty percent of curable gastrinomas lie within the gastrinoma triangle, which is comprised of the head of the pancreas and the duodenal sweep. Sporadic gastrinomas are often solitary and >2 cm and located in the pancreas; gastrinomas arising in the setting of multiple endocrine neoplasia type 1 (MEN1) most commonly arise in the duodenum and are typically small (<2 cm) and multiple (figure 1) [25].
It is possible for the experienced surgeon to identify over 90 percent of sporadic gastrinomas. The combination of preoperative localization techniques, including contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), and somatostatin receptor positron emission tomography (SSTR PET) [1,2,26]. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis", section on 'Tumor localization'.)
Intraoperative ultrasound or transduodenal illumination and duodenotomy are of particular value in detecting very small gastrinomas arising in the wall of the duodenum [1,27,28]. Of note, radio-guided surgery (wherein the surgeon uses a handheld radiation detector to localize tissues that are tagged with radioactive material) is an emerging technique that may improve intraoperative lesion detection (especially in gastrointestinal neuroendocrine tumors [NETs]). However, the optimal tracer and other technical details have not been established, and the overall impact on clinical outcomes remains unclear [29]. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Intraoperative localization techniques'.)
Surgical resection
Sporadic gastrinoma — For patients with sporadic gastrinoma and ZES without evidence of metastatic spread of disease, we recommend the addition of exploratory laparotomy and resection to pharmacologic therapy. Surgery is offered with curative intent, even in the event of negative imaging studies (which occurs in approximately 17 percent of patients) [27]. Between 60 to 90 percent of gastrinomas are malignant; therefore, in addition to eliminating (or at least decreasing) the need for pharmacologic acid-suppressive therapy for the hormone-mediated symptoms of ZES, successful resection of sporadic gastrinomas protects against the possibility of eventual morbidity and death from metastatic spread of the tumor [2,3,27,30-32]. For patients with small localized duodenal tumors, endoscopic resection is an organ-sparing alternative, if technically feasible and local expertise is present.
The likelihood of surgical cure is especially high for extrapancreatic gastrinomas (eg, those in the duodenum or peripancreatic lymph nodes). In the hands of an experienced surgeon, up to 50 percent of these patients will be cured [30,33]. Data suggest a 10-year disease-free survival of 25 to 50 percent, 20-year overall survival of 58 to 71 percent, and 20-year disease-specific survival of 73 to 88 percent [27,34]. Removal of the primary tumor also appears to reduce the risk of liver metastases [30,35,36]. Lymphadenectomy with the removal of more than 10 lymph nodes at the time of surgery has been shown to achieve a higher biochemical cure as compared with selective or no lymphadenectomy [37,38]. The number of positive lymph nodes (or lymph node ratio) has prognostic significance in gastrinoma and other pancreatic NETs. Recognizing the potential for cure in patients undergoing complete tumor removal (particularly with modern imaging tools and our ability to control acid hypersecretion throughout the perioperative period), the merits (and risks) of surgery need to be considered in the context of the life expectancy and comorbidities of each patient [13]. In the unlikely event that a sporadic gastrinoma cannot be identified at surgery, we suggest deferring a Whipple's procedure in favor of closure, with the intent of serial imaging every six months to try to localize the neoplasm [39].
Further details on the surgical approaches and techniques used to manage sporadic gastrinoma based on size and tumor location are discussed separately. (See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms", section on 'Resection of gastrinoma'.)
Gastrinoma due to MEN1 — In patients with multiple endocrine neoplasia type 1 (MEN1) who have gastrinoma and ZES that is controlled with pharmacologic acid-suppressive therapy and no other clinically evident hormonal excess syndrome or imaged tumors, the use of duodenal-pancreatic surgery is controversial. Because clinical outcome data are not definitive, the potential advantages and risks of both options should be discussed with the patient. While we do not strongly advocate for surgery, we do not discourage a patient who wishes to have surgery for MEN1-associated gastrinoma if the individual recognizes that evidence for improved survival is lacking and the surgeon is experienced and knowledgeable. Furthermore, if such a patient requires abdominal surgery for another reason (such as insulinoma), it seems appropriate to include duodenectomy in the procedure.
Early attempts to treat the gastrinoma surgically in patients with MEN1 involved resection of palpable tumors or partial pancreatectomy, but historically, this approach typically failed to cure the hypersecretion of gastrin [40,41]. The recognition that patients with MEN1 often have small, multifocal tumors in the duodenum, not infrequently accompanied by lymph node metastases [42,43], is consistent with these failures and led to a reexamination of the role of surgery. The role of surgery in the management of MEN1-associated gastrinoma remains a controversial area, and there is a dearth of high-quality prospective studies to provide guidance. Some surgeons are less inclined to operate, while others regularly operate on patients with MEN1 and gastrinoma. Among those favoring surgery, the indications for intervention and the timing, surgical approach, and extent of resection are debated. Groups favoring surgery argue that although most patients with MEN1 and gastrinoma have good short- to midterm outcomes (ie, over 5 to 20 years), the relatively young age at diagnosis (typically 30 to 40 years) means that many may still be at risk of dying prematurely from disease.
●Patients who do not have surgery – For patients with ZES that is pharmacologically controlled with acid-suppressive therapy and who do not have surgery for the underlying gastrinoma, we monitor symptoms and perform periodic imaging studies (CT/MRI, EUS), with a preference toward minimizing radiation exposure in younger patients. It should also be borne in mind that patients with duodenal gastrinomas may have concomitant nonfunctioning pancreatic tumors, although irrespective of the functional status of the pancreatic lesion, surgery is likely to be beneficial for pancreatic tumors >2 cm [44]. (See "Multiple endocrine neoplasia type 1: Management", section on 'Clinically nonfunctional pancreatic neuroendocrine tumors'.)
●Patients who elect for surgery – Laparotomy is not routinely performed for all patients with gastrinoma and ZES as part of MEN1 since the multifocal nature of the tumors in this disorder almost uniformly precludes cure of gastrin hypersecretion [2,33]. However, because few MEN1-associated tumors can have aggressive growth patterns, some clinicians obtain imaging studies or even perform surgical exploration to identify those exceeding 2 cm with the intent of resecting them. Furthermore, other groups have taken a more aggressive approach in MEN1 patients with gastrinomas (especially to control acid secretion), pursuing surgical resection based on imaging (including SSTR PET imaging) with or without localization with the selective arterial secretagogue injection test to achieve a biochemical cure [45-47].
Whipple resections (pancreaticoduodenectomy) are not routinely performed in all patients with gastrinoma due to MEN1. For patients who elect for surgery, this surgical approach is reserved for pancreatic head or duodenal lesions that cannot be removed by enucleation [46,47]. The debate is ongoing, however, with some suggesting that initial pancreaticoduodenectomy is the superior surgical procedure for gastrinoma in the setting of MEN1 [47], while others reserve pancreaticoduodenectomy for control of hormone secretion and removal of large tumors in the setting of MEN1 [46]. In such cases, the potential benefits of pancreaticoduodenectomy, including improved lymph node retrieval, need to be weighed against the risks of complications.
Surgical techniques — Enucleation is preferred when feasible in gastrinoma, but local resection is often required for pancreatic head lesions and a distal pancreatectomy may be necessary for large tail lesions [13]. Minimally invasive surgery is controversial in gastrinoma compared with other pancreatic NETs, owing to the need for more extensive exploration of the gastrinoma triangle, lymphadenectomy, and duodenectomy in many cases [13]. Surgical resection of sporadic pancreatic NETs, including gastrinoma, is discussed in detail separately. (See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms", section on 'Gastrinoma'.)
Endoscopic resection is an attractive organ-sparing option for selected cases (eg, duodenal lesion <1 cm, limited to submucosa without lymph node involvement), but the risk of missing micrometastatic disease is possible [1], and identifying such small tumors can be challenging. Endoscopic resection techniques vary and can include endoscopic mucosal resection, endoscopic submucosal dissection, and endoscopic full-thickness resection.
Once the tumor is resected and sent for histopathologic evaluation, clinicopathologic correlation is needed to designate the tumor as a gastrinoma; in other words, the patient must also demonstrate symptoms and clinical findings of ZES, the clinical syndrome that results from tumor production and secretion of gastrin. A tumor should not be designed as a gastrinoma solely based on its morphologic appearance or the presence of gastrin in the secretory granules. Not all patients with ectopic gastrin secretion have the symptoms associated with ZES, as in many cases, the hormone is not processed to biologically active gastrin. Therefore, if a tumor incidentally stains for gastrin or secretes gastrin but does not produce clinical symptoms of ZES, it should not be classified as a gastrinoma. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)
Benefits of surgery — In most patients, gastric secretion is often reduced significantly but may not return to the normal range following gastrinoma resection because of a residual excess of gastric parietal cells, a consequence of the trophic effect of chronically elevated gastrin levels. Up to 40 percent of patients will require prolonged antisecretory therapy to control hyperacidity following curative resection, and such patients need continued monitoring for gastric acid hypersecretion [48,49]. As an example, in one observational study, 50 patients with gastrinoma and ZES who underwent curative resection of their tumors and were designated as disease-free (normal fasting serum gastrin concentration, negative gastrin provocation testing with secretin, and no evidence of tumor on imaging studies) and had long-term follow-up (mean of eight years) were evaluated for gastric hypersecretion as measured by basal acid output in the stomach. With long-term follow-up (mean of eight years), among those 50 patients, gastric hypersecretion was seen in 31 patients (62 percent), which included 17 patients (34 percent) with moderate hypersecretion and 14 patients (28 percent) with extreme hypersecretion. Normal gastric secretion was seen in the remaining 19 patients (38 percent) [50].
The reduction in mortality associated with surgical therapy for patients without metastatic disease was illustrated in a prospective study of 124 patients with gastrinoma presumed to be free of metastasis by imaging studies [36]. Only 3 percent of the 98 patients who underwent resection developed liver metastases during a mean follow-up period of 6.3 years [36]. By contrast, over a slightly longer follow-up period (8.7 years) of 26 patients treated pharmacologically, approximately 23 percent developed metastatic disease. Two deaths due to metastatic gastrinoma occurred in the pharmacologically treated group compared with no disease-specific deaths in the operative group.
Reoperation for recurrence — Although surgery decreases the incidence of hepatic metastases and improves survival, long-term biochemical cure is achieved in less than 30 percent. Reoperation may be of benefit to those with recurrent gastrinoma, in whom the tumor can be identified and localized. In one study, for example, 17 patients with recurrent disease that was unequivocally imaged underwent 18 reoperations [51]. Five patients were disease-free after operation, with a median follow-up of 28 months. There were no deaths in the cured group; two patients in the group with persistent disease died during a median follow-up of 34 months [52].
Radiation therapy for nonsurgical candidates — There is limited experience with radiation therapy (RT) in the management of gastrinomas. Although pancreatic NETs were previously thought to be radioresistant, limited observational data suggest that RT can produce high rates of symptomatic palliation and freedom from local progression in patients who are not candidates for surgical resection [53-59].
METASTATIC DISEASE —
The liver is the most common site of metastatic disease for gastrinomas, as it is with other islet cell tumors. The second most common site is bone (7 percent of patients in one series), almost all of which occur in patients who also have liver metastases [60]. The axial skeleton (spine or sacrum) is the primary site of bone metastasis, but other sites can be involved [60]. Gallium Ga-68 dotatate positron emission tomography (PET)-CT is often used to assess for metastatic disease [61,62]. Metastatic disease is the most common cause of morbidity and mortality in patients with gastrinoma. Unfortunately, for patients with metastatic gastrinoma, the goals of therapy are generally palliative and not curative.
Resectable, liver-isolated metastatic disease
Hepatic resection — For patients with limited, resectable liver-isolated metastatic gastrinoma (either sporadic or familial), we suggest the addition of surgical resection of all sites of disease (ie, hepatic metastases and the primary tumor) to pharmacologic therapy. Although cure is unlikely, given the slow-growing nature of the tumor, extended survival is sometimes possible.
Hepatic resection can be used to treat metastatic liver disease in the absence of diffuse bilobar involvement, compromised liver function, or extensive extrahepatic metastases (eg, pulmonary, peritoneal). In general, for both patients with sporadic gastrinoma or gastrinoma due to multiple endocrine neoplasia type 1 (MEN1) [44], surgical resection is most appropriate for patients with a limited number of hepatic metastases and is most successful when greater than 90 percent cytoreduction can be achieved. Although cure is unlikely with surgery, prolonged survival is often possible, given the slow-growing nature of these tumors [63-65]. Patients with functional neuroendocrine tumors (NETs) often also experience a reduction of symptoms with liver surgery [65]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection' and "Surgical resection of sporadic pancreatic neuroendocrine neoplasms", section on 'Potentially resectable metastatic disease'.)
Liver transplantation — Until more data become available, liver transplantation is an investigational approach for metastatic islet cell tumors, including gastrinoma. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Liver transplantation'.)
There are few patients with liver-isolated metastatic disease in whom orthotopic liver transplantation has been attempted, and follow-up data are insufficient to judge whether a complete cure has truly been achieved. The limited availability of donor organs in many regions has restricted investigation of this procedure [66].
Unresectable, liver-predominant metastatic disease — For patients with unresectable liver-predominant metastatic disease, other treatments include hepatic artery embolization, radiofrequency ablation, and cryoablation.
Hepatic artery embolization — Liver metastases derive most of their blood supply from the hepatic artery, whereas healthy hepatocytes derive approximately 70 percent of their blood supply from the portal vein. This provides the rationale for therapeutic embolization of the hepatic artery, with the goal of inducing necrosis of the metastases with minimal damage to normal liver parenchyma.
It is not known with certainty if one type of embolization is preferable to another, and randomized trials are necessary. Hepatic arterial embolization with or without selective hepatic artery infusion of chemotherapy is frequently applied as a palliative technique in patients with symptomatic hepatic metastases who are not candidates for surgical resection [67-70]. Response rates are over 50 percent, as measured by a decrease in hormonal secretion or by radiographic regression. Radioembolization with selective internal radiation therapy using Yttrium microspheres is also used selectively [70]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)
Radiofrequency ablation and cryoablation — Other approaches to the treatment of hepatic-predominant disease include radiofrequency ablation and cryoablation, either alone or in conjunction with surgical debulking [71-73]. These procedures, which can be performed using percutaneous or laparoscopic approaches, appear to be less morbid than either hepatic resection or hepatic artery embolization. However, both techniques are applicable only to smaller lesions, and their long-term efficacy is uncertain. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Ablation'.)
Metastatic disease not limited to the liver — For patients with metastatic gastrinoma not limited to the liver, systemic therapy can control metastatic tumor growth and associated symptoms. Available therapies include somatostatin analogs, chemotherapy, molecularly targeted agents, and peptide receptor radionuclide therapy, among other agents. The use of these agents in metastatic gastrinoma is the same as other patients with well-differentiated low-grade (G1) and intermediate-grade (G2) gastroenteropancreatic NETs, which is discussed in detail separately. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors" and "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors" and "Treatment of the carcinoid syndrome".)
There are limited studies evaluating systemic agents specifically in metastatic gastrinoma. Data that are available for specific agents are as follows:
●Somatostatin analogs – Somatostatin analogs are an option for patients with symptomatic, somatostatin receptor (SSTR)-positive metastatic gastrinoma. Most gastrinomas express somatostatin receptors (80 to 100 percent) [74,75]. Somatostatin analogs are highly effective in controlling the symptoms associated with hormone hypersecretion in other pancreatic islet cell tumors that express SSTRs such as glucagonomas and VIPomas, as well as extrapancreatic NETs. However, data for somatostatin analogs in metastatic gastrinoma are limited, and their efficacy is less predictable in this population [76-78]. Data are as follows:
•Octreotide – Although octreotide can reduce gastrin levels and may slow tumor growth, objective evidence of antitumor activity specifically in patients with gastrinoma is rare [78-82]. As an example, in an observational study of 15 patients treated with octreotide for malignant gastrinoma and progressive hepatic metastases, seven patients had stabilization of tumor growth, and one had an objective decrease in tumor size [81]. The median duration of benefit was 25 months.
•Lanreotide – Lanreotide has similar clinical efficacy to octreotide, and is available in a long-acting depot form [76,83]. Limited data suggest that lanreotide can reduce gastrin levels, improve symptoms, and/or stabilize tumor growth in patients with gastrinoma [23,83,84]. In selected cases of refractory disease, administering above-label dosing is an option [85].
●Other agents – Other agents that have been studied in patients with metastatic gastrinoma (either specifically or as a subgroup in a broader population of NETs) include sunitinib [86], everolimus [87], capecitabine plus temozolomide [88], and peptide receptor radionuclide radiotherapy (eg, lutetium Lu-177 dotatate) [89-91].
PROGNOSIS —
Mortality from gastrinomas depends upon whether the tumor is localized or metastatic and the extent of disease involvement. In an observational series, 185 patients with gastrinoma and ZES were followed prospectively for a mean of 12.5 years [35]. Results were as follows:
●Liver metastases were found in 24 percent of patients at the time of diagnosis. Most of these patients had a primary pancreatic neoplasm, and 67 percent had primary tumors that were greater than 3 cm in size.
●Patients with liver metastases had a 10-year survival of only 30 percent compared with a 15-year survival of 83 percent in those without liver metastases.
●Patients with lymph node metastases had the same mortality as those who were free of visceral metastases.
●Patients with multiple endocrine neoplasia type 1 (MEN1) had a significantly lower rate of metastasis at the time of initial diagnosis (6 percent); their high overall survival rate (100 percent at 20 years) reflected this fact.
Accurate prognostic markers predicting outcomes are not available in patients with gastrinoma. However, reduced overall survival is associated with increased age, higher fasting gastrin level (FSG; ie, ≥20 times the upper limit of normal), size of coexisting pancreatic neuroendocrine tumors (NETs; ie, ≥2 cm), and presence of liver metastases [92,93]. In a report of 239 patients with gastrinoma and ZES, the level of preoperative FSG correlated with tumor size and presence of lymph nodes and liver metastases (as found at exploration), as well as primary site (pancreas tumors associated with highest levels of FSG) [94]. The five-year survival rates for patients with mild (0 to 499 picograms/mL), moderate (500 to 1000 picograms/mL), or severe elevations (>1000 picograms/mL) of FSG were 94, 92, and 86 percent, respectively. The corresponding 10-year survival rates were 86, 87, and 73 percent.
POSTTREATMENT SURVEILLANCE —
There is limited evidence from which to make recommendations for follow-up after resection of a gastrinoma. Guidelines from the National Comprehensive Cancer Network based upon expert consensus include the following recommendations for follow-up after resection of pancreatic neuroendocrine tumor (NET) [95]:
●Three to 12 months postresection – History and physical examination, serum gastrin, and abdominal multiphasic CT or MRI and chest CT with or without contrast as clinically indicated.
●Long-term surveillance – History and physical examination with tumor markers every 6 to 12 months for a maximum of 10 years. Imaging studies with abdominal multiphasic CT or MRI and chest CT with or without contrast as clinically indicated.
●Endoscopic surveillance – When clinically appropriate (ie, following either endoscopic or local surgical resections for duodenal NETs), periodic endoscopic surveillance should also be performed. Although there is scant evidence with regard to long-term outcomes of endoscopic surveillance or optimal interval between procedures, we typically follow patients with annual endoscopies for five years.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuroendocrine neoplasms".)
SUMMARY AND RECOMMENDATIONS
●General principles – Gastrinomas are duodenal or pancreatic neuroendocrine tumors (NETs) that hypersecrete gastrin and lead to Zollinger-Ellison syndrome (ZES). ZES is the clinical syndrome of gastric acid hypersecretion caused by the gastrinoma that results in severe peptic ulcer disease, abdominal pain, and diarrhea. Gastrinomas either occur sporadically or are associated with an inherited disorder called multiple endocrine neoplasia type 1 (MEN1). (See 'Introduction' above.)
●Goals of therapy – For patients with gastrinoma and ZES, the goals of therapy are to control the clinical symptoms and complications resulting from the tumor's autonomous secretion of the hormone gastrin (ie, ZES) and to control the tumor burden itself (ie, the gastrinoma). (See 'Goals of therapy' above.)
●Upfront pharmacologic acid-suppressive therapy
•Proton pump inhibitors – For all patients with gastrinoma and ZES, we recommend upfront initiation of a high-dose proton pump inhibitor (PPI; eg, omeprazole 40 mg twice daily, pantoprazole 80 mg twice daily) rather than other acid-suppressing agents (Grade 1B). This approach limits the clinical manifestations, related symptoms, and complications of ZES (mainly peptic ulcer disease) and is generally safe to administer over extended periods of time. Subsequent lowering of PPI doses without recurrence of symptoms is usually achievable. (See 'Pharmacologic acid-suppressive therapy' above and 'Proton pump inhibitors' above.)
•PCABs – Potassium-competitive acid inhibitors (PCABs) can be used as an alternative to upfront acid-suppressive therapy with PPIs or as second-line therapy for those with symptoms refractory to PPIs. There are limited high-quality data for PCABs in the context of gastrinoma/ZES. (See 'Potassium-competitive acid blockers' above.)
•Somatostatin analogs – Somatostatin analogs may be helpful for symptoms that are refractory to initial acid-suppressive therapy with PPIs. (See 'Somatostatin analogs' above.)
●Localized disease
•Gastrinoma due to MEN1 – For patients with localized gastrinoma and ZES as part of the MEN1 syndrome, pharmacologic acid-suppressive therapy alone is the standard of care. (See 'Pharmacologic acid-suppressive therapy' above.)
For those with MEN1 who have gastrinoma and ZES that is controlled with pharmacologic acid-suppressive therapy and no other clinically evident hormonal excess syndrome or imaged tumors, the use of duodenal-pancreatic surgery is controversial. Because clinical outcome data are not definitive, the potential advantages and risks of both options should be discussed with the patient. While we do not strongly advocate for surgery, we do not discourage a patient who wishes to have surgery for MEN1-associated gastrinoma if the individual recognizes that evidence for improved survival is lacking and the surgeon is experienced and knowledgeable. (See 'Gastrinoma due to MEN1' above.)
•Sporadic gastrinoma – For patients with sporadic gastrinoma and ZES without evidence of metastatic disease, we recommend the addition of exploratory laparotomy and resection to pharmacologic therapy (Grade 1B). Successful resection of sporadic gastrinomas with curative intent both reduces the risk of eventual morbidity and death from metastatic spread of the tumor and either decreases or eliminates the need for pharmacologic acid-suppressive therapy for ZES. For patients with small localized duodenal tumors, endoscopic resection is an organ-sparing alternative, if technically feasible and local expertise is present. (See 'Sporadic gastrinoma' above and 'Benefits of surgery' above and "Surgical resection of sporadic pancreatic neuroendocrine neoplasms", section on 'Resection of gastrinoma'.)
●Metastatic disease – The goals of therapy for metastatic gastrinoma are generally palliative and not curative.
•Resectable, liver-isolated metastatic disease – For patients with limited, resectable liver-isolated metastatic gastrinoma (either sporadic or familial), we suggest the addition of surgical resection of all sites of disease (ie, hepatic metastases and the primary tumor) to pharmacologic therapy (Grade 2C). Although cure is unlikely, given the slow-growing nature of the tumor, extended survival is sometimes possible. (See 'Hepatic resection' above.)
•Unresectable, liver-predominant metastatic disease – For patients with unresectable liver-predominant metastatic disease, other treatments include bland embolization, chemoembolization, selective internal radiation therapy (radioembolization), radiofrequency ablation, and cryoablation. (See 'Unresectable, liver-predominant metastatic disease' above.)
•Symptomatic metastatic disease not limited to the liver – For patients with metastatic gastrinoma not limited to liver, systemic therapies (somatostatin analogs, chemotherapy, molecularly targeted agents, and peptide receptor radionuclide therapy, among other agents) can be used to control symptoms and metastatic tumor growth. As there are limited data for these agents in metastatic gastrinoma, the approach is the same as other patients with well-differentiated low-grade (G1) and intermediate-grade (G2) pancreatic and gastrointestinal NETs, which are discussed in detail separately. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors" and "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors" and "Treatment of the carcinoid syndrome".)
●Prognosis – Mortality from gastrinomas depends upon whether the tumor is localized or metastatic and the extent of disease involvement. Metastatic disease is the most common cause of morbidity and mortality in patients with gastrinoma and ZES. (See 'Prognosis' above.)
ACKNOWLEDGMENTS —
We are saddened by the death of Mark Feldman, MD, who passed away in March 2024. UpToDate gratefully acknowledges Dr. Feldman’s role as a Section Editor on this topic and his dedicated and longstanding involvement with the UpToDate program.
The UpToDate editorial staff also thanks Stephen E. Goldfinger, MD, for his contributions as author to prior versions of this topic review.
