Zollinger-Ellison syndrome – 10 Interesting Facts, Symptoms, Risk Factors, Prognosis and Treatment

What is Zollinger-Ellison Syndrome

Zollinger-Ellison syndrome is a rare clinical syndrome resulting from hypersecretion of the hormone gastrin by neuroendocrine tumors known as gastrinomas

Key Points

1. Zollinger-Ellison syndrome is characterized by refractory peptic ulcer disease, esophagitis, and secretory diarrhea
2. Gastrinomas occur most commonly in the duodenum or pancreas and are malignant in 60% to 90% of cases
3. Although the majority of cases are sporadic, approximately 20% to 30% of cases are associated with multiple endocrine neoplasia type 1 
4. Patients commonly present with severe refractory heartburn and epigastric pain, often accompanied by diarrhea; maintain a high index of suspicion in patients with a long history of peptic ulcer disease or gastroesophageal reflux disease that is refractory to or recurrent after treatment
5. Diagnosis of Zollinger-Ellison syndrome is based on demonstration of an elevated fasting serum gastrin level (ie, hypergastrinemia) in the presence of elevated gastric acidity; tumor is localized by imaging studies and characterized according to histopathologic findings 
6. Management depends on anatomic site, size and type of tumor, presence of local or distant metastasis, and general status of patient
7. Medical treatment in all patients consists of proton pump inhibitors to manage gastric acid hypersecretion
8. Surgical resection is the mainstay of treatment in sporadic cases and the only curative treatment; provides a significant survival advantage in patients with localized, regional, and metastatic disease
9. Systemic therapy with somatostatin analogues may control symptoms related to gastrin hypersecretion and prolong survival and improve quality of life in patients with progressive or recurrent disease
10. Molecular targeted therapy and/or cytotoxic chemotherapy may be necessary for progressive disease

Pitfalls of Zollinger-Ellison syndrome

• Diagnosis of Zollinger-Ellison syndrome may be missed owing to the overlap with peptic ulcer disease and gastroesophageal reflux disease and masked by use of proton pump inhibitors; maintain a high index of suspicion in patients with a long history of peptic ulcer disease or gastroesophageal reflux disease and recurrence after treatment
• Exercise caution when interrupting proton pump inhibitor therapy for diagnostic testing. Use high-dose H₂ blockers during a 1 week washout, owing to risk of rapid development of acid-peptic complications 

Important Facts

• Untreated gastric acid hypersecretion can result in rapid development of complications and requires adequate treatment before trying to establish a diagnosis
• Perforated gastric ulcer or severe upper gastrointestinal bleeding requires emergency treatment, including endoscopic and/or surgical management to stop bleeding and stabilize hemodynamically

Clinical Clarification

• Zollinger-Ellison syndrome is a rare clinical condition resulting from hypersecretion of the hormone gastrin by neuroendocrine tumors known as gastrinomas; this syndrome is characterized by refractory peptic ulcer disease, esophagitis, and secretory diarrhea 
  • Gastrinomas occur most commonly in duodenum or pancreas and more than half are malignant 

Classification

• Site of origin
  • Duodenum 
    • Most are sporadic
    • Most are associated with multiple endocrine neoplasia type 1
    • Up to 10% are associated with liver metastasis
  • Pancreas 
    • Site of origin in about a quarter of cases
    • Tumors originating in the pancreas are usually larger and more frequently associated with liver metastasis (20%-35% of cases) than those originating in the duodenum (less than 10% of cases)
  • Other sites (eg, stomach, jejunum, peripancreatic lymph nodes, splenic hilum, mesenteric root, omentum, liver, gallbladder, common bile duct, ovary)
    • Site of origin for a small percentage of cases 
    • Solitary tumors in these sites are less likely to be malignant than those in pancreas 
• Type of disease
  • Sporadic (nonfamilial) 
    • More than half of Zollinger-Ellison cases are sporadic 
    • Sporadic gastrinomas in Zollinger-Ellison syndrome are almost always solitary 
    • Sporadic gastrinomas most frequently involve pancreas; slightly less often they involve duodenum 
    • Are malignant about half the time 
  • Associated with multiple endocrine neoplasia type 1 (familial) 
    • Autosomal-dominant syndrome that is present in 20% to 30% of patients with Zollinger-Ellison syndrome 
    • Most commonly involves duodenum; tumors are often small and almost always multiple 
    • Seem to be malignant in less than 12% of patients, but because there are multiple small tumors it is difficult to find the tumor that is secreting gastrin; surgery is not likely to be curative 
• TNM staging system for neuroendocrine tumors of pancreas 
  • Primary tumor (T)
    • TX: tumor cannot be assessed
    • T1: tumor limited to pancreas, 2 cm or smaller
    • T2: tumor limited to pancreas, 2 to 4 cm
    • T3: tumor limited to pancreas, larger than 4 cm; or tumor invading duodenum or common bile duct
    • T4: tumor involves adjacent organs (ie, stomach, spleen, colon, adrenal gland) or wall of large vessels (ie, celiac axis, superior mesenteric artery)
  • Regional lymph nodes (N)
    • NX: regional lymph nodes cannot be assessed
    • N0: no regional lymph node metastasis
    • N1: regional lymph node metastasis
  • Distant metastases (M)
    • M0: no distant metastases
    • M1: distant metastases
      • M1a: metastasis confined to liver
      • M1b: metastases in 1 or more extrahepatic site
      • M1c: both hepatic and extrahepatic metastases
  • Anatomic stage/prognostic groups
    • Stage I: T1, N0, M0
    • Stage II:
      • T2, N0, M0
      • T3, N0, M0
    • Stage III:
      • T4, N0, M0
      • Any T, N1, M0
    • Stage IV: any T, any N, M1
• TNM staging system for neuroendocrine tumors of jejunum and ileum 
  • Primary tumor (T)
    • TX: primary tumor cannot be assessed
    • T0: no evidence of primary tumor
    • T1: tumor invades lamina propria or submucosa and is 1 cm or smaller
    • T2: tumor invades muscularis propria or is larger than 1 cm
    • T3: tumor invades through muscularis propria into subserosal tissue without penetrating serosa
    • T4: tumor invades visceral peritoneum, other organs, or adjacent structures
  • Regional lymph nodes (N)
    • NX: regional lymph nodes cannot be assessed
    • N0: no regional lymph node metastasis
    • N1: regional lymph node metastasis, fewer than 12 nodes
    • N2: mesenteric masses larger than 2 cm and/or 12 or more nodes
  • Distant metastases (M)
    • M0: no distant metastases
    • M1: distant metastases
      • M1a: metastasis is confined to liver
      • M1b: metastases in 1 or more extrahepatic location (eg, lung, ovary, nonregional lymph node, peritoneum, bone)
      • M1c: both hepatic and extrahepatic metastases
  • Anatomic stage/prognostic groups
    • Stage 0: Tis, N0, M0
    • Stage I: T1, N0, M0
    • Stage II:
      • T2, N0, M0
      • T3, N0, M0
    • Stage III:
      • T1, N1/N2, M0
      • T2, N1/N2, M0
      • T3, N1/N2, M0
      • T4, N0, M0
      • T4, N1/N2, M0
    • Stage IV: any T, any N, M1
• WHO histologic grading system for gastroenteropancreatic tumors 
  • Grade G1 (low grade): well-differentiated, Ki-67 index 2% or less, mitotic count less than 2 mitoses per 10 high-power fields
    • Ki-67 is a cellular protein found only in the nucleus during interphase, moving to the cell surface during mitosis; provides a mechanism for determination of the rate of cellular proliferation
  • Grade G2 (intermediate grade): well-differentiated, Ki-67 index 3% to 20%, mitotic count 2 to 20 mitoses per 10 high-power fields
  • Grade G3 (high grade): poorly differentiated, Ki-67 index higher than 20%, mitotic count higher than 20 mitoses per 10 high-power fields

Clinical Presentation

History

• Patients commonly present with the following symptoms: 
  • Up to three-quarters of patients have high-volume—often secretory and watery—diarrhea that does not respond to fasting or eating
    • Severe diarrhea may be the only symptom in up to 20% of patients 
  • Epigastric pain (most patients)
  • Bleeding (up to three-quarters of patients)
  • Severe refractory heartburn (about half of patients)
• Symptoms may be masked by use of proton pump inhibitors 
  • Maintain a high index of suspicion in patients with a long history of peptic ulcer disease or gastroesophageal reflux disease that is recurrent or refractory to treatment
• Other associated symptoms include the following: 
  • Hematemesis or melena (up to three-quarters of patients) 
  • Weight loss (up to half of patients)
  • Nausea and vomiting (up to one-third of patients)
  • Anemia symptoms (eg, weakness, fatigue, dizziness, lightheadedness)
• History of renal colic, nephrolithiasis, or hypercalcemia is common among patients with multiple endocrine neoplasia type 1

Most patients with Zollinger-Ellison syndrome are between 20 and 50 years old and present with PUD or diarrhea. Ulcers are typically duodenal. The diarrhea resembles steatorrhea and results from a combination of high volumes of acid and neutralization of pancreatic enzymes. The syndrome is either sporadic or associated with multiple endocrine neoplasia (MEN) syndrome I. In patients with Zollinger-Ellison syndrome associated with MEN I, signs and symptoms may be related to parathyroid or pituitary disease.

Physical examination

• Physical examination is frequently unremarkable; most common findings, when present, are related to gastrointestinal bleeding (eg, melena, hematemesis) and anemia or dehydration (eg, pallor, tachycardia, orthostatic hypotension)
• Dental erosion may be indicative of gastroesophageal reflux disease, resulting from erosion caused by acidic gastric contents
• Possible abdominal tenderness or mass, hepatomegaly, or jaundice in advanced disease

Causes of Zollinger-Ellison syndrome

• Neoplastic production of gastrin leads to gastric acid hypersecretion due to stimulation of parietal cells in gastric antrum 
  • This leads to multiple, recurrent, and often refractory peptic ulcers and chronic secretory diarrhea
  • Profound diarrhea is caused by high osmotic load combined with malabsorption, which develops from pancreatic enzyme inactivation due to low pH 
• Gastrin-secreting tumors (gastrinomas) are derived from enteroendocrine cells and develop predominantly in pancreas and proximal small intestine

Risk factors of Zollinger-Ellison Syndrome

Age

• Sporadic gastrinomas: usual age at presentation is 48 to 55 years 
• Multiple endocrine neoplasia type 1–associated Zollinger-Ellison syndrome: usual age at presentation is 32 to 35 years 

Sex

• Male-to-female ratio ranges from 2:1 to 3:2 

Genetics

• Most cases are sporadic; however, 20% to 30% arise in the context of multiple endocrine neoplasia type 1 
  • Multiple endocrine neoplasia type 1 has an autosomal dominant pattern of inheritance (OMIM #131100) 

Other risk factors/associations

• Over 80% of patients with duodenal gastrinomas have a long-term history of high alcohol consumption (more than 50 g/day) 

How is Zollinger-Ellison Syndrome diagnosed

• Zollinger-Ellison syndrome diagnosis algorithm.

Primary diagnostic tools

• Suspect the diagnosis in patients with peptic ulcer disease that is: 
  • Recurrent or severe
  • Familial
  • In absence of risk factors (eg, infection with Helicobacter pylori, use of NSAIDs or aspirin)
  • Associated with severe gastroesophageal reflux disease
  • Refractory to treatment
  • Associated with complications (ie, perforation, penetration, bleeding)
  • Associated with diarrhea, particularly if diarrhea rapidly resolves with proton pump inhibitor treatment
  • Associated with endocrinopathies (eg, hypo- or hyperthyroidism)
  • Occurring in patients with prominent gastric folds at endoscopy (present in up to 92% of patients with Zollinger-Ellison syndrome)
  • Involving unusual location (eg, second part of duodenum, jejunum)
• Suspect diagnosis in patients with known multiple endocrine neoplasia type 1 because it is present in up to 30% of patients with Zollinger-Ellison syndrome 
• Base diagnosis on inappropriately elevated fasting serum gastrin level (ie, hypergastrinemia) in presence of gastric hyperchlorhydria or acidic pH 
  • Markedly elevated fasting serum gastrin level of 1000 ng/L or higher, or more than 10 times normal (with a gastric pH of less than 2) excludes hypergastrinemia from having another cause and establishes the diagnosis 
    • Diagnosis may be complicated by any of the following:
      • Unreliability of commercial gastrin assays (especially with previously available techniques)
        • Immunoassay is now used: starting with very accurate sample dilutions, highly selective antibodies react only with active gastrin molecules, resulting in improved accuracy on gastrin concentration-inhibition curve 
      • Secretin unavailable for provocation testing
      • Widespread use of proton pump inhibitors (which can cause falsely elevated gastrin levels) 
    • Continue proton pump inhibitors in patients with overt symptoms of gastrinoma and/or risk of complications 
      • Although it is recommended to discontinue proton pump inhibitors for 1 week before testing, it is usually not done
    • If serum gastrin level testing is nondiagnostic or is low but tumor is still suspected, perform additional testing with secretin provocation test 
    • If secretin provocation testing does not provide a diagnosis but Zollinger-Ellison syndrome remains clinically suspected, consider calcium infusion provocation testing 
    • Basal acid output measurement is rarely used
• In almost all cases, upper gastrointestinal endoscopy has already been performed but if not, perform it with close inspection of duodenum and obtain fluid sample to determine gastric pH
• Localize and stage tumor, initially using abdominal or pelvic multiphasic CT or MRI 
  • Assess for metastases and local invasion
  • May be difficult to identify lesions because significant clinical symptoms may occur in presence of very small tumors
    • Consider somatostatin receptor–based imaging and endoscopic ultrasonography
    • Selective arterial cannulation and localized secretin test may be indicated if imaging and endoscopy fail to identify a discrete lesion
    • Surgical exploration, with particular attention to pancreas and duodenum, may be indicated if imaging tests or invasive techniques fail to identify a primary lesion 
• Evaluate for possibility of multiple endocrine neoplasia type 1; includes measurement of serum prolactin, calcium, parathyroid hormone, and pancreatic polypeptide
• Obtain biopsy specimen (usually at surgical resection) to confirm histopathologic diagnosis and classification
• Stage tumor according to the American Joint Committee on Cancer TNM staging criteria

A high level of suspicion is required for the diagnosis of gastrinoma. Serum gastrin should be measured in all patients undergoing peptic ulcer surgery. If the gastrin level is in the range of 1000 to 2000 pg/mL, gastric pH analysis demonstrating acid production confirms the diagnosis. If the gastrin level is minimally elevated, the patient should undergo gastric pH analysis and a secretin test. The secretin test is performed by comparison of basal serum gastrin level with gastrin level after the administration of secretin. Gastrinoma is suspected in patients with an increase in the serum gastrin level of 200 pg/mL after secretin administration. Normal patients have no change or a reduction in serum gastrin after secretin administration. Because achlorhydria is more common than gastrinoma, an elevation in serum gastrin is due more commonly to lack of acid as opposed to ectopic gastrin production. Therefore measurement of acid production is also essential in making the appropriate diagnosis. Serum chromogranin A is a general marker for neuroendocrine tumors, and although it does not differentiate between the various types, it is also elevated in Zollinger-Ellison syndrome.

Laboratory

• Fasting serum gastrin level 
  • Elevated in more than 98% of patients with Zollinger-Ellison syndrome;  however, cannot diagnose patient based on this finding alone because many other disorders increase serum gastrin level; concurrent assessment of gastric acid secretion by serially measuring gastric pH was used in the past but now is rarely done and is logistically difficult in some patients
    • Elevated gastrin levels in serum can also be found in patients with hypo- or achlorhydria due to atrophic gastritis, pernicious anemia, Helicobacter pylori infection, chronic renal failure, and vagotomy, and in those taking proton pump inhibitors
  • Testing ideally is performed after proton pump inhibitor therapy is stopped for 1 week (ie, 1 week washout) 
    • Provide high-dose H₂ blockers while reducing proton pump inhibitor therapy 
    • Use caution when interrupting proton pump inhibitor therapy; it should be continued in patients with overt symptoms of gastrinoma and/or risk of complications 
    • If it is not possible to stop proton pump inhibitor therapy, serum gastrin (and, in some patients, gastric acid) can be tested during slow progressive reduction of this therapy at a center of excellence or by a gastroenterologist who specializes in this testing 
  • Elevated fasting gastrin level (1000 ng/L or higher, or 10 times normal) is diagnostic of a gastrinoma, assuming retained gastric antrum has been eliminated 
    • Retained gastric antrum is a rare condition that can occur in patients who have undergone a Billroth II gastrectomy
  • If fasting gastrin levels are not elevated enough to make diagnosis, may need to perform secretin provocation test to confirm
  • Falsely low gastrin levels, in presence of gastrinoma, have been reported; may occur because tumors secrete a variety of bioactive gastrin precursor molecules, not all of which are detected by commercially available assays 
• Secretin provocation test 
  • Simplest and most sensitive confirmatory test when fasting serum gastrin level is nondiagnostic or is low but suspicion for tumor remains 
  • In patients with gastrinoma, rapid secretin infusion of 2 units/kg typically produces marked increase in serum gastrin levels (120 pg/mL over baseline) 
    • In healthy patients, increase in serum gastrin is less than 50% above baseline; gastrin secretion decreases in normal cells exposed to secretin 
  • Do not perform during proton pump inhibitor therapy as this may obtain false positive results 
• Calcium infusion provocation test 
  • Measures increase in serum gastrin after IV calcium infusion
  • Indicated for confirming Zollinger-Ellison syndrome when clinically suspected despite negative or nondiagnostic secretin provocation test
  • Although this test is less sensitive than secretin provocation test (62% vs 94%), 38% to 50% of patients suspected of having Zollinger-Ellison syndrome who have a nonconfirmatory secretin provocation test have a positive calcium provocation test
  • Several cutoff values for serum gastrin have been proposed; the most sensitive, with 100% specificity, is an increase of 396 pg/mL
• Gastric pH level 
  • Measurement of gastric pH, usually during endoscopy, is required to exclude secondary hypergastrinemia (eg, secondary to atrophic gastritis, pernicious anemia, vagotomy); isolated gastric acid testing is rarely employed 
  • Gastric pH of less than 2 is diagnostic of a gastrinoma in presence of an elevated fasting gastrin level (1000 ng/L or higher, or 10 times normal), assuming retained gastric antrum has been eliminated based on history (ie, lacks history of Billroth II procedure) 
  • Gastric pH of 3 or greater in absence of antisecretory drugs excludes Zollinger-Ellison syndrome 
• Basal acid output
  • Performed by aspirating gastric contents via nasogastric tube or at endoscopy
    • Rarely used anymore; diagnosis usually requires elevated serum gastrin level (with gastric pH of less than 2) and secretin stimulation testing
  • Basal acid output above 15 mmol/hour is suggestive of Zollinger-Ellison syndrome in more than 85% of patients without previous gastric acid–reducing surgery 
    • Values in 10 to 15 mmol/hour range are borderline, and less than 10 mmol/hour excludes diagnosis 
  • In patients who have previously undergone gastric acid–reducing surgery, a basal acid output above 5 mEq/hour suggests Zollinger-Ellison syndrome 
• Chromogranin A test
  • Can be used to help confirm diagnosis, to establish baseline for follow-up, and to estimate tumor burden 
  • Elevated levels in 60% or more of patients with pancreatic neuroendocrine tumors (threshold value depends on specific assay used); however, up to 30% of patients with gastrinomas have normal levels 
  • False elevation can occur if patients have renal or hepatic impairment or are taking proton pump inhibitors
  • When serum level is elevated, can be used to assess response to treatment and detect progression or recurrence at an earlier stage 

Imaging

• Multiphasic abdominal/pelvic CT or MRI scan; CT of chest
  • Standard imaging modes used for diagnosis and staging. They are recommended in all cases and have good diagnostic accuracy for lesions more than 3 cm in diameter
  • Assess disease burden, possible primary location, and evaluate regional/mesenteric lymph nodes and liver metastases
  • MRI has superior soft tissue contrast resolution and is optimal method for imaging hepatic metastases
• Somatostatin receptor–based imaging 
  • Guidelines recommend performing if initial investigation fails to detect tumor; however, some experts advocate performing this imaging, in addition to CT or MRI, in all patients with gastrinoma 
    • Helps identify additional metastases in regional and distant lymph nodes and in bone
  • Has highest sensitivity (86%-100%) and specificity (79%-100%) for identifying primary tumors and metastatic lesions when using gallium Ga 68–labeled somatostatin analogues 
  • Method of choice depends on local availability and expertise
    • Somatostatin receptor scintigraphy with indium In 111–labeled octreotide is the primary modality used
    • Gallium Ga 68–labeled DOTATATE (tetraazacyclododecane tetraacetic acid–octreotate) PET/CT has emerged as a superior modality and is being used with increasing frequency
• Endoscopic ultrasonography 
  • May be performed if initial investigation fails to identify tumor; particularly useful for localizing small pancreatic tumors (smaller than 2 cm)
    • Provides superior diagnostic sensitivity (70%) compared with CT (50%) and MRI (25%-50%) 
    • Less sensitive for identifying duodenal gastrinomas 
  • Can provide visual guidance for both fine-needle aspiration (cytology) and core biopsy (histopathologic examination)

Procedures

Upper gastrointestinal endoscopy (esophagogastroduodenoscopy) 

General explanation

• Enables direct visualization of upper gastrointestinal tract using a video gastroscope
• Can use biopsy of tissue specimen obtained during procedure to exclude malignancy and determine if Helicobacter pylori infection is present
• Can use to measure gastric acid secretion and pH

Indication

• Recommended for all patients in whom basic acid-control therapy is unsuccessful or malignancy is a concern
• To evaluate for complications such as erosive inflammation, stricturization, and perforation in patients with long-standing acid hypersecretion 

Contraindications

• Clinical evidence of acute perforation

Complications

• Perforation
• Bleeding

Interpretation of results

• May demonstrate thickened gastric folds, erosive inflammation, ulceration,  stricturization, or perforation owing to long-standing acid hypersecretion
• Prominent gastric folds are present in approximately 92% of patients with Zollinger-Ellison syndrome 
• May localize site of gastrinoma in duodenum

Selective arterial secretin test

General explanation

• Invasive test used to locate gastrinomas that involves selective cannulation of splenic, hepatic, gastroduodenal, and superior mesenteric artery and infusion of small amount of secretin locally. Serial gastrin measurements then are taken from right hepatic vein, establishing relative site of lesion 
• Hepatic venous levels of gastrin will greatly exceed peripheral levels when secretin is injected into vessel that supplies gastrinoma 

Indication

• Performed to localize gastrinomas when other imaging modalities fail 

Calcium infusion provocative test 

General explanation

• Common protocol includes: IV infusion of 10% calcium gluconate solution (5 mg calcium/kg/hour or 54 mg calcium gluconate/kg/hour) for 3 hours
• Measure serum glucose and calcium levels simultaneously 30 or 15 minutes before, immediately before, and 30, 60, 90, 120, 150, and 180 minutes after calcium infusion

Indication

• Suspected Zollinger-Ellison syndrome with negative or equivocal secretin provocation test 

Contraindications

• Hypercalcemia
• Renal disease
• Cardiac disease

Complications

• Abdominal pain
• Nausea and/or vomiting
• Phlebitis
• Headache
• Paresthesias
• Severe fatigue
• Arrhythmias
• Increase in blood pressure
• QT shortening on ECG

Interpretation of results 

• Increase in serum calcium of 1.5 mEq/L or more indicates valid testing
• Test considered positive for Zollinger-Ellison syndrome with increase in calcium (delta calcium) of 395 pg/mL or more after standard infusion, the most commonly used criterion

Biopsy

General explanation

• Collection of tissue specimen for histopathologic examination, performed via upper gastrointestinal endoscopy, open surgical resection, or percutaneously under CT guidance

Indication

• Obtain tissue for diagnosis, histologic classification, and identification of biomarkers

Interpretation of results

• Classify tumor based on anatomic site and histologic characteristics
• Determine mitotic rate, level of Ki-67 (an antigen that is a cell proliferation marker; coded for by MK167), and presence of nonischemic tumor necrosis
• Use specific immunohistochemical markers (eg, chromogranin A, synaptophysin, gastrin), as needed, to establish neuroendocrine differentiation and verify hormone production
• Assign tumor grade according to WHO tumor grading system for gastroenteropancreatic neuroendocrine tumors 
  • Grade 1 (low grade, well differentiated)
    • Mitotic count: fewer than 2 mitoses per 10 high-power fields
    • Ki-67 index: less than 3%
  • Grade 2 (intermediate grade, well differentiated)
    • Mitotic count: 2 to 20 mitoses per 10 high-power fields
    • Ki-67 index: 3% to 20%
  • Grade 3 (high grade, poorly differentiated)
    • Mitotic count: more than 20 mitoses per 10 high-power fields
    • Ki-67 index: greater than 20%

Differential Diagnosis of Zollinger-Ellison Syndrome

Most common

• Helicobacter pylori–associated atrophic gastritis
  • Loss of gastric glandular cells and replacement by intestinal-type epithelium, pyloric-type glands, and fibrous tissue owing to colonization of stomach with gram-negative bacteria Helicobacter pylori; involves gastric antrum, corpus, and fundus
  • Like Zollinger-Ellison syndrome, results in hypergastrinemia with symptoms such as refractory heartburn and epigastric pain, with or without diarrhea 
  • Unlike Zollinger-Ellison syndrome, gastric acid production is reduced
  • Differentiation is based on blood, breath, stool, or biopsy test result positive for Helicobacter pylori; gastric pH is rarely measured
• Chronic autoimmune atrophic gastritis (pernicious anemia) 
  • Autoimmune destruction of gastric glandular cells and replacement by intestinal-type epithelium, pyloric-type glands, and fibrous tissue; involves gastric corpus and fundus
  • Like Zollinger-Ellison syndrome, patients may present with severe hypergastrinemia, and symptoms such as refractory heartburn and epigastric pain, with or without diarrhea
  • Unlike Zollinger-Ellison syndrome, gastric acid production is reduced (rarely measured)
  • Differentiation is based on presence of megaloblastic anemia, and intrinsic cell and parietal cell antibodies
• Antral G cell hyperplasia or hyperfunction 
  • Pseudo–Zollinger-Ellison syndrome characterized by hypergastrinemia and associated with increase in number of gastric G cells
  • Like Zollinger-Ellison syndrome, patients exhibit hypergastrinemia, increased gastric acid production, and symptoms such as refractory heartburn and epigastric pain, with or without diarrhea
  • Differentiation is based on equivocal response to secretin stimulation, exaggerated response to food ingestion (standard test meal), and absence of gastrinoma on diagnostic imaging tests 

How is Zollinger-Ellison Syndrome treated

• Control gastric acid hypersecretion
• Resect gastrinoma(s), and prevent progression or recurrence

Disposition

Admission criteria

Admit patients with complications of peptic ulcer disease such as bleeding, perforation, gastric outlet obstruction, or severe diarrhea

Admit patients for surgical resection of tumor

Criteria for ICU admission

• Massive bleeding or perforation may necessitate emergency care and ICU admission

Recommendations for specialist referral

• Refer patients on proton pump inhibitor therapy to a gastroenterologist or specialty center experienced in diagnosing Zollinger-Ellison syndrome if unable to safely discontinue proton pump inhibitor during testing. It is generally not possible to diagnose while a patient is taking proton pump inhibitors, and stopping treatment risks complications due to acid hypersecretion (eg, ulcer bleeding, diarrhea with dehydration, hypokalemia)
• Management requires multidisciplinary approach that may include a gastroenterologist, surgeon, oncologist, nuclear medicine specialist, and histopathologist

Treatment Options

• General medical management
  • Medical treatment in all patients consists of proton pump inhibitors to manage gastric acid hypersecretion
    • Most patients require doses higher than those needed for patients with idiopathic peptic ulcer disease
    • May be required long term (in lower doses), even after surgical resection of primary tumor 
    • Consider octreotide or lanreotide for symptom control, if needed

For which patients with Zollinger Ellison syndrome is surgical intervention indicated? 

Surgery is the treatment of choice for patients with nonmetastatic sporadic gastrinoma. In addition, patients with metastatic gastrinoma who are unable to tolerate or are refractory to medical management should be considered for operative intervention. Sporadic gastrinomas are often solitary and located in the pancreas or duodenum, but not both, and are amenable to surgical resection and cure. Although gastrinomas seen with MEN syndrome are usually multiple, virtually always in the duodenum, and often multicentric, they are also found in the pancreas and are more difficult to cure surgically. Gastrinoma associated with hypercalcemia should suggest MEN syndrome complicated by hyperparathyroidism, and parathyroidectomy is essential for management of gastric acid hypersecretion. Elevated serum gastrin levels postoperatively after gastrinoma surgery indicate residual gastrinoma(s) that should be treated medically. Medical management is also generally indicated for patients with metastatic gastrinoma. Medical management consists of high-dose PPIs with the goal of reducing gastric acid output to less than 10 mEq/h for the hour that immediately precedes the next scheduled dose of antisecretory medication.

• Surgical management and advanced medical treatment 
  • All patients with sporadic gastrinomas should undergo surgical exploration by a surgeon experienced in managing gastrinoma, assuming no medical contraindications
    • Patients with gastrinoma—either associated with multiple endocrine neoplasia type 1 or 2 cm or smaller—are not routinely recommended for surgery because they have good prognosis with medical management
  • Surgical approach depends on anatomic site of tumor, presence of local or distant metastasis, and general status of patient
    • Local or locoregional disease
      • Gastrinoma in head of pancreas 
        • Enucleation and removal of paraduodenal nodes if the tumors are exophytic or peripheral (not immediately adjacent to pancreatic duct)
        • Pancreatoduodenectomy for deeper or invasive tumors and with proximity to main pancreatic duct
      • Gastrinoma in distal pancreas 
        • Distal pancreatectomy with or without splenectomy
        • Systematic removal of lymph nodes in peritumoral area (ie, peritumoral lymph node dissection)
      • Gastrinoma in duodenum 
        • Duodenotomy and intraoperative ultrasonography to guide extent of surgery
        • Local resection or enucleation of tumor(s) and periduodenal node dissection
      • Occult gastrinoma (not identified on imaging studies) 
        • Exploratory surgery with thorough examination of pancreas and duodenum, which includes duodenotomy and intraoperative ultrasonography. This is the preferred treatment, assuming no medical contraindication 
          • If primary tumor is identified, requires local resection or enucleation of tumor(s) and periduodenal node dissection
          • Postoperatively, observation until progression occurs is appropriate in patients treated preoperatively with chemotherapy or radiation therapy when surgical specimens have negative borders and lymph node biopsies are all negative (ie, less chance of residual disease) 
    • Unresectable locoregional and/or metastatic disease 
      • If complete resection is possible, consider curative surgery to remove both primary tumor and metastases
        • For patients who are asymptomatic or have low volume disease, consider observation with biomarkers and imaging every 3 to 12 months 
        • For symptom control and to possibly delay progression, consider lanreotide or octreotide
      • For advanced, unresectable disease, consider lanreotide or octreotide if not already receiving, and/or any of the following: 
        • Molecular targeted therapy (for advanced/metastatic disease) 
          • Everolimus
          • Sunitinib
        • Cytotoxic chemotherapy (for progressive, unresectable disease)
          • Common regimens to consider:
            • Temozolomide and capecitabine
            • Streptozocin, 5-fluorouracil, and doxorubicin
            • Streptozocin and doxorubicin
            • Streptozocin and 5-fluorouracil
        • For patients with progressive hepatic-predominant metastatic disease, hepatic-directed therapies include arterial embolization, radioembolization, chemoembolization, ablative therapy, or cytoreductive surgery 
        • Peptide receptor radionuclide therapy using radiolabeled somatostatin analogues for metastatic tumors with high somatostatin receptor expression (currently investigational) 
          • ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE are the most widely used agents

Rationale 

• Treatment with proton pump inhibitors controls symptoms and complications of gastric acid hypersecretion
• Surgical resection eradicates tumors and/or reduces tumor burden
• Treatment with somatostatin analogues controls symptoms related to gastrin hypersecretion and may delay progression in advanced disease
• Treatment with molecular targeted therapy and/or cytotoxic chemotherapeutic agents for advanced/metastatic disease

Outcomes

• Surgery, including complete resection of the primary tumor and involved lymph nodes, is the only curative treatment of sporadic gastrinoma
  • Surgical resection decreases rate of liver metastasis and increases survival in patients with locoregional disease 
    • Also provides survival advantage in patients with metastatic disease
  • Long-term cure after surgery (excluding pancreaticoduodenectomy) occurs in 20% to 45% of patients with sporadic Zollinger-Ellison syndrome 
• Systemic therapy may control symptoms related to gastrin hypersecretion and prolong survival and improve quality of life in patients with progressive or recurrent disease
  • Octreotide has been found to decrease baseline gastrin levels by 76% and to decrease basal acid output and peak acid output by 68% in patients with gastrinoma. This synthetic hormone also delays progression in patients with advanced gastroenteropancreatic neuroendocrine tumors (including limited number with gastrinoma) 
  • Targeted molecular therapies (sunitinib and everolimus) delay tumor progression in advanced and metastatic disease 
  • Cytotoxic chemotherapy is typically reserved for patients with progressive unresectable disease 

Drug therapy

• Proton pump inhibitors 
  • Omeprazole
    • Omeprazole Oral capsule, gastro-resistant sprinkles; Adults and Adolescents 17 years and older: 60 mg PO once daily initially, then titrated and given in single or multiple daily doses, with dosage titration up to 120 mg PO 3 times daily. Dosages greater than 80 mg/day should be administered in divided doses. Some patients with Zollinger-Ellison syndrome have been treated continuously for more than 5 years.
  • Lansoprazole
    • Lansoprazole Oral disintegrating tablet; Adults: Initially, 60 mg PO once daily in the morning at least 30 minutes before a meal. Individualize dosage and continue treatment for as long as clinically indicated. Doses up to 90 mg PO twice daily have been used. If the total dosage is greater than 120 mg/day, give in divided doses.
  • Pantoprazole
    • Pantoprazole Sodium Solution for injection; Adults: Initially, 80 mg IV infused q12h. Dosage range: 80—120 mg IV q8—12h. Max: 240 mg/day IV given in divided doses. Switch to PO when feasible.
• Somatostatin analogues 
  • Octreotide
    • Subcutaneous injection (short acting) 
      • Octreotide Acetate Solution for injection; Adults: 100 mcg to 600 mcg/day subcutaneously, given in 2 to 4 divided doses, for the first 2 weeks. The mean dosage is 300 mcg/day; some patients may require doses up to 1500 mcg/day
    • Intramuscular injections (long acting)
      • Octreotide Acetate Suspension for injection; Adults: 30 mg IM every 4 weeks. 
  • Lanreotide 
    • Lanreotide Solution for injection; Adults: 120 mg by deep subcutaneous injection every 4 weeks.
• Chemotherapy agents 
  • Molecular targeted agents
    • Everolimus (mTOR inhibitor)
    • Sunitinib (receptor tyrosine kinase inhibitor)
  • Anthracycline antibiotics
    • Doxorubicin
  • Antimetabolites
    • Capecitabine
    • 5-fluorouracil
  • Alkylating agents
    • Streptozocin
    • Temozolomide

Nondrug and supportive care

• Surgical management is individualized based on anatomic site, tumor type, and stage
  • Relevant procedures include enucleation, pancreaticoduodenectomy, and distal pancreatectomy, with or without splenectomy or lymphadenectomy; may be performed via open or minimally invasive approach
  • May also include complete excision or debulking of hepatic metastases
• Supportive therapy is tailored to meet each patient’s needs based on age, performance status, disease status, specific surgical approach, therapeutic agents used, and risk of complications 
  • Antidiarrheal agents, if clinically indicated
  • Medical alert bracelet
  • Presplenectomy vaccination for pneumococcus, Haemophilus influenzae type b, meningococcal group C
  • Prophylactic cholecystectomy at time of curative surgery to prevent cholelithiasis in patients who are anticipated to receive somatostatin analogues (octreotide or lanreotide)

Special populations

• Patients with multiple endocrine neoplasia type 1
  • Patients with multiple endocrine neoplasia type 1–associated Zollinger-Ellison syndrome usually have multiple duodenal gastrinomas, frequently with lymph node metastases
  • Surgical resection in patients with multiple endocrine neoplasia type 1–associated Zollinger-Ellison syndrome is controversial in light of the following:
    • Gastric acid hypersecretion can be well controlled with medical therapy 
    • Multifocal disease makes it difficult to achieve surgical cure, and biochemical relapse occurs in more than 95% of patients within 3 years of surgery 
    • Patients with pancreatic tumors smaller than 2 cm in diameter have good long-term life expectancy (up to 100% survival at 15 years) without intervention 
  • Generally, surgery with aim of preventing metastasis is recommended for multiple endocrine neoplasia type 1 pancreatic tumors 2 cm or larger in diameter. Surgery may also be considered if acid hypersecretion is refractory to medical management or tumor is growing rapidly over 6 to 12 months 
    • Generally, enucleation is the recommended approach 
    • Extensive surgery (eg, pancreatoduodenectomy) may result in long-term remission; however, it is often associated with significant short-term and long-term complications, and the impact on long-term survival remains unclear 

Monitoring

• If patient is receiving proton pump inhibitor therapy, they are slowly discontinued over 1 week during the diagnostic evaluation and provided high-dose H₂ blockers while closely monitoring in an inpatient setting or with daily outpatient visits 
• Follow-up recommendations vary
  • European Neuroendocrine Tumor Society guidelines recommend the following: 
    • Patients with active, nonmetastatic disease: follow-up every 3 to 6 months, then annually if stable
      • Evaluate fasting serum gastrin, ionized calcium, parathyroid hormone, and vitamin B₁₂ levels (can be low secondary to proton pump inhibitor)
      • Assess acid control
      • Obtain imaging studies (CT or MRI annually, somatostatin receptor imaging at least every 2 years) 
    • Patients who have undergone curative resection: follow-up annually
      • Evaluate fasting serum gastrin levels and secretin provocation test results
      • Assess acid secretory control if patient is taking proton pump inhibitors
      • Obtain imaging as clinically indicated
    • Patients with advanced metastatic disease: follow-up every 3 to 6 months
      • Obtain imaging studies—CT or MRI—with somatostatin receptor imaging when clinically indicated
      • Evaluate fasting serum gastrin levels
      • Assess acid secretory control every 6 months
      • Consider evaluating for Cushing syndrome annually (ie, serum and urine cortisol)
  • National Comprehensive Cancer Network guidelines recommend the following: 
    • Patients who have undergone surgical resection: follow-up at 3 to 12 months (earlier if patient shows symptoms), then every 6 to 12 months for up to 10 years
      • Evaluate patient history, conduct physical examination, and consider biochemical markers (ie, chromogranin A, fasting serum gastrin levels)
      • Obtain imaging as clinically indicated
• Perform endoscopic surveillance at regular intervals to assess for complications of long-standing acid hypersecretion 

Complications

• Peptic ulcer–related complications (eg, gastrointestinal bleeding, anemia, perforation, penetration of ulcer into adjacent organs, gastric outlet obstruction)
• Locoregional recurrence
• Distant metastasis

Prognosis

• Prognosis varies according to tumor type, anatomic location, histologic classification, and stage at diagnosis
  • Presence of liver metastasis is the most important prognostic factor 
    • Patients with gastrinomas associated with liver metastasis at diagnosis have 10-year survival of 10% to 20% 
    • Patients with gastrinomas without liver metastasis at diagnosis have 10-year survival of 90% to 100%
  • Patients with primary pancreatic gastrinomas are more likely to develop liver metastasis than those with duodenal gastrinomas; therefore, pancreatic gastrinomas are associated with poorer outcome 
  • Sporadic cases of Zollinger-Ellison syndrome are more often malignant than those occurring in the context of multiple endocrine neoplasia type 1 
    • Long-term cure after surgery: 
      • Occurs in 20% to 45% of patients with sporadic Zollinger-Ellison syndrome
      • Occurs in only 0% to 1% of patients with multiple endocrine neoplasia type 1–associated Zollinger-Ellison syndrome; however, this type tends to be indolent and associated with excellent life-expectancy
  • Other factors associated with poorer prognosis: 
    • Inadequate control of gastric acid hypersecretion
    • Female gender
    • Markedly increased fasting gastrin levels
    • Absence of multiple endocrine neoplasia type 1
    • Short disease history from onset to diagnosis
    • Development of ectopic Cushing syndrome or bone metastasis
    • Advanced TNM classification
    • Large primary tumor

Screening

At-risk populations 

• Several guidelines and related publications recommend screening patients who are at risk for multiple endocrine neoplasia type 1 
  • Most common feature of multiple endocrine neoplasia type 1 is hyperparathyroidism, developing in more than 95% of patients
  • Zollinger-Ellison syndrome is the most common symptomatic condition of patients with multiple endocrine neoplasia type 1
  • Decision to screen a patient for multiple endocrine neoplasia type 1 is made on a case-by-case basis
• Monitoring for tumors related to multiple endocrine neoplasia type 1 may reasonably be offered to patients with a high risk of developing multiple endocrine neoplasia type 1-associated tumors: 
  • Patients with known index case of multiple endocrine neoplasia type 1
  • Patients with known germline multiple endocrine neoplasia type 1 mutations
  • At-risk first-degree family members of patient with a known mutation, whether symptomatic with manifestations of multiple endocrine neoplasia type 1 or asymptomatic

Screening tests

• Provide genetic counseling to all—patient and at-risk family members—before testing for germline multiple endocrine neoplasia type 1 mutations 
• Offer analysis for multiple endocrine neoplasia type 1 germline mutation to all first-degree relatives of a patient with a known mutation 
• Annually screen patients and family who have known germline mutation
• Biological screening (eg, serum calcium as screen for hyperparathyroidism) costs less; family members may choose this instead
• Patients with multiple endocrine neoplasia type 1, carriers of the mutation, and at-risk family members undergo regular surveillance for conditions associated with, or signs and symptoms of, multiple endocrine neoplasia type 1–associated tumors, including:
  • Nephrolithiasis
  • Peptic ulcer disease
  • Galactorrhea
  • Diarrhea
  • Erectile dysfunction
  • Amenorrhea
  • Neuroglycopenic hypoglycemia symptoms
• Annual biochemical screening includes fasting serum gastrin, parathyroid hormone, serum calcium, and prolactin levels (to screen for parathyroid, anterior pituitary, and pancreatic islet involvement)
• Radiologic screening may involve abdominal and pelvic CT or MRI; endoscopic ultrasonogram or somatostatin-receptor based imaging may be considered