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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Gastroenterology · Zollinger-Ellison Syndrome

Navigating Your Tests and Pathology Results

At a Glance

Zollinger-Ellison syndrome is evaluated with fasting gastrin and gastric pH, followed when needed by secretin testing and imaging. Never stop a PPI without specialist supervision, and use the pathology report’s differentiation, Ki-67, grade, and stage to guide care.

Confirming a diagnosis of Zollinger-Ellison Syndrome (ZES) and identifying the exact location of the gastrinoma requires a specialized series of tests. Because the condition is rare and complex, these results provide the roadmap for your entire treatment plan [1].

The Biochemical “Double Check”

To diagnose ZES, doctors must prove that your body is producing too much gastrin even when your stomach is already highly acidic. This requires checking two things:

  • Fasting Serum Gastrin (FSG): A blood test to measure the level of the hormone gastrin [2].
  • Gastric pH: A test to measure the acidity of your stomach fluid, often collected during an endoscopy or through a small tube [2].

A diagnosis is typically suggested when your fasting gastrin is markedly elevated (often over 1,000 pg/mL) and your gastric pH is at or below 2.0 [2][3]. If your gastrin is elevated but not quite that high, your doctor may perform a secretin stimulation test. During this test, you receive an injection of the hormone secretin, and blood is drawn several times. If your gastrin level rises significantly, it strongly suggests a gastrinoma [4][2].

CRITICAL WARNING: Managing PPIs for Testing

Never stop taking your proton pump inhibitors (PPIs) like omeprazole or pantoprazole without strict medical supervision from an experienced team.
Diagnostic protocols sometimes require pausing these medications because they artificially raise gastrin levels and stomach pH [5][6]. However, for a person with suspected or confirmed ZES, stopping these drugs unsupervised can cause a “rebound” surge of acid that risks severe ulcers, bleeding, or perforation [7][8]. There is no universal one-week protocol. Your specialist may arrange a supervised switch to an H2 blocker, require inpatient observation, or perform testing while you remain on your medication [9].

Locating the “Needle in a Haystack”

Gastrinomas are often very small, sometimes just a few millimeters wide [10]. To find and stage them, doctors use advanced imaging:

  • Ga-68 DOTATATE PET/CT: This is one of the preferred, high-performance scans for well-differentiated tumors [11]. It uses a specialized tracer that sticks to somatostatin receptors, which are found on the surface of many gastrinomas. It is important to know that while it is excellent for localizing and staging the disease, a positive scan doesn’t replace biochemical interpretation, and a negative scan does not exclude a small gastrinoma [12].
  • Endoscopic Ultrasound (EUS), CT, and MRI: A thin tube with an ultrasound probe (EUS) allows the doctor to see through the stomach wall to find tiny tumors in the pancreas or duodenum that other scans might miss [2][13]. CT and MRI scans are also frequently used.

Decoding Your Pathology Report

If a piece of the tumor is removed (a biopsy), a pathologist will examine it. The report will separate the tumor’s features into differentiation, grade, and stage.

Differentiation describes how much the tumor cells look like normal cells:

  • Well-differentiated (NET): Cells look similar to healthy cells.
  • Poorly differentiated (NEC): Cells look very abnormal and usually behave more aggressively [14][15].

Grade describes how fast the cells are multiplying, measured by the Mitotic Count and the Ki-67 Index (a percentage). Note that grading is site-specific and a small biopsy can sometimes underestimate the grade [14].

  • Grade 1 (G1): Ki-67 < 3% [14].
  • Grade 2 (G2): Ki-67 3–20% [14].
  • Grade 3 (G3): Ki-67 > 20%. Note: A Grade 3 tumor can be either a well-differentiated NET or a poorly differentiated NEC, and they are treated very differently. [14].

Understanding Staging

Finally, your report will “stage” the tumor using either the AJCC or ENETS system. The applicable system depends on whether the primary tumor is in the duodenum or the pancreas. Staging integrates imaging, operative findings, nodal information, and metastasis; a biopsy alone may not establish the stage [16][17]. Because these two systems use slightly different rules, your report should explicitly state which one was used [18].

Common questions in this guide

How are Zollinger-Ellison syndrome and gastrinoma diagnosed?
Doctors usually compare a fasting serum gastrin level with the acidity of the stomach, measured as gastric pH. Markedly high gastrin, often above 1,000 pg/mL, together with a gastric pH of 2.0 or lower strongly supports Zollinger-Ellison syndrome; if the elevation is less pronounced, a supervised secretin stimulation test may help.
Can I stop my PPI before Zollinger-Ellison testing?
Do not stop omeprazole, pantoprazole, or another proton pump inhibitor on your own. These medicines can affect test results, but sudden withdrawal may cause a dangerous acid rebound with ulcers, bleeding, or perforation, so a specialist should choose and supervise the testing plan.
Which scans can find a small gastrinoma?
Ga-68 DOTATATE PET/CT, endoscopic ultrasound, CT, and MRI can help locate and stage a gastrinoma. Ga-68 DOTATATE PET/CT is useful for many well-differentiated tumors, while endoscopic ultrasound can identify small lesions in the pancreas or duodenum; a negative scan does not rule out a very small tumor.
What do differentiation, Ki-67, and grade mean on a gastrinoma pathology report?
Differentiation describes how much the tumor cells resemble normal cells, while grade estimates how quickly they are multiplying using the Ki-67 index and mitotic count. Grade 1 has a Ki-67 below 3%, Grade 2 is 3% to 20%, and Grade 3 is above 20%. A Grade 3 tumor may be either a well-differentiated neuroendocrine tumor or a poorly differentiated neuroendocrine carcinoma, which require different treatment approaches.
How is a gastrinoma staged, and what do AJCC and ENETS mean?
Staging combines the tumor’s location and size with imaging, surgical findings, lymph-node information, and whether the disease has spread. AJCC and ENETS are staging systems with somewhat different rules, and the appropriate system depends in part on whether the tumor began in the duodenum or pancreas. A biopsy alone may not establish the complete stage, so the pathology report should identify which system was used.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What was my exact fasting gastrin level and what was the measured gastric pH at that time?
  2. 2.Is it safe for me to adjust my PPI dose for testing, or should we use a protocol that allows me to stay on my medication?
  3. 3.Does the pathology report describe my tumor as well-differentiated (NET) or poorly differentiated (NEC)?
  4. 4.What are my specific Ki-67 index and mitotic count, and how do these affect my Grade (G1, G2, or G3)?
  5. 5.Which staging system (AJCC or ENETS) was used to determine my tumor's T, N, and M categories?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (18)
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    Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies.

    Rossi RE, Elvevi A, Citterio D, et al.

    World journal of gastroenterology 2021; (27(35)):5890-5907 doi:10.3748/wjg.v27.i35.5890.

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    All you need to know about gastrinoma today | Gastrinoma and Zollinger-Ellison syndrome: A thorough update.

    Chatzipanagiotou O, Schizas D, Vailas M, et al.

    Journal of neuroendocrinology 2023; (35(4)):e13267 doi:10.1111/jne.13267.

    PMID: 37042078
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    Diarrhea, Weight Loss, and an Elevated Gastrin: A Case Report.

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    Secretin Stimulation Test and Early Diagnosis of Gastrinoma in MEN1 Syndrome: Survey on the MEN1 Florentine Database.

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    PMID: 34922358
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    Assessing for Multiple Endocrine Neoplasia Type 1 in Patients Evaluated for Zollinger-Ellison Syndrome-Clues to a Safer Diagnostic Process.

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    Total gastrectomy for severe proton pump inhibitor-induced hypomagnesemia in a MEN1/Zollinger Ellison syndrome patient.

    Perrier M, Delemer B, Deguelte S, et al.

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    Severe Recurrent Gastrointestinal Bleeding and Diagnostic Dilemmas in Zollinger-Ellison Syndrome: A Case Report.

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    Validity of Secretin Stimulation Testing on Proton Pump Inhibitor Therapy for Diagnosis of Zollinger-Ellison Syndrome.

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    [Comparison of clinical characteristics between sporadic gastrinoma and multiple endocrine neoplasia type 1-related gastrinoma].

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    Catching the Zebra: Clinical Pearls and Pitfalls for the Successful Diagnosis of Zollinger-Ellison Syndrome.

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This page explains Zollinger-Ellison syndrome testing and pathology terminology for informational purposes only and does not constitute medical advice. Do not change or stop acid-blocking medication without guidance from your treating specialist.

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