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Zollinger‑Ellison Associated Gastrin‑Negative Tumor

Overview

Zollinger‑Ellison syndrome (ZES) is a rare disorder caused by a gastrin‑secreting neuroendocrine tumor (NET) that leads to excessive stomach acid production. In a very small subset—estimated at 1–5 % of all ZES cases—the tumor is gastrin‑negative, meaning it does not produce measurable levels of gastrin despite causing the same clinical picture of acid hypersecretion.<sup>[1] Mayo Clinic</sup>

These tumors are usually located in the pancreas or duodenum and are classified as non‑functioning pancreatic neuroendocrine tumors (NF‑PNETs). Because they lack the classic biochemical hallmark (high serum gastrin), they are more difficult to detect and often present later.

• Age group: Most patients are diagnosed between 40 and 70 years old.
• Gender: Slight male predominance (≈55 % male).
• Prevalence: ZES overall occurs in about 1 in 100,000 people; gastrin‑negative variants constitute roughly 1–5 % of these cases.<sup>[2] NIH</sup>

Symptoms

Because the tumor produces acid without raising gastrin, the symptom pattern mirrors classic ZES but may be less pronounced early on.

Gastro‑intestinal symptoms

• Refractory peptic ulcer disease – ulcers that persist despite standard proton‑pump inhibitor (PPI) therapy.
• Upper abdominal pain – often burning or gnawing, worsened by meals.
• Diarrhea – caused by acid inactivation of pancreatic enzymes and damage to the intestinal mucosa.
• Heartburn / gastro‑esophageal reflux – acid overload of the esophagus.
• Nausea & vomiting – especially after large meals.
• Gastrointestinal bleeding – melena or hematemesis from ulcer erosion.

Systemic & nutritional symptoms

• Weight loss – due to malabsorption and chronic diarrhea.
• Fatigue / anemia – from chronic blood loss and nutrient deficiencies.
• Steatorrhea – fatty stools from pancreatic enzyme inactivation.

Signs related to tumor mass

• Abdominal fullness or a palpable mass – more common when the tumor grows larger.
• Back or flank pain – if the lesion invades nearby structures.

Causes and Risk Factors

The exact trigger for gastrin‑negative NETs is unknown, but several mechanisms have been identified:

• Genetic syndromes – Multiple endocrine neoplasia type 1 (MEN‑1) and von Hippel‑Lindau (VHL) disease increase the risk of pancreatic NETs, including gastrin‑negative variants.<sup>[3] Cleveland Clinic</sup>
• Somatic mutations – Alterations in the MEN1, DAXX, ATRX, and mTOR pathways are frequently found in sporadic NF‑PNETs.
• Chronic inflammation – Long‑standing pancreatitis has been linked to increased neuroendocrine cell proliferation.

Risk factors

• Family history of MEN‑1 or other hereditary tumor syndromes.
• Personal history of pancreatic or duodenal neuroendocrine tumors.
• Age >40 years (incidence rises sharply after the fifth decade).
• Smoking – modestly raises the risk of pancreatic NETs.

Diagnosis

Because serum gastrin levels are normal, physicians rely on a combination of imaging, endoscopy, and histology.

Laboratory tests

• Serum gastrin – typically normal in gastrin‑negative tumors; useful to exclude classic ZES.
• Chromogranin A (CgA) – elevated in ~70 % of NETs; however, PPIs and renal insufficiency can cause false‑positives.<sup>[4] WHO</sup>
• Pancreastatin – a more specific NET marker; may be used when CgA is ambiguous.

Imaging studies

• Multiphasic contrast‑enhanced CT or MRI – first‑line for tumor localization; NETs often appear hypervascular.
• Endoscopic ultrasound (EUS) – highly sensitive (up to 90 %) for lesions <2 cm in the pancreas or duodenum.
• Somatostatin receptor imaging – ^68Ga‑DOTATATE PET/CT detects tumors expressing somatostatin receptors (SSTR2/5). This is the most sensitive functional test for NF‑PNETs.
• Secretin stimulation test – used to rule out classic gastrin‑producing ZES; a negative test supports the gastrin‑negative diagnosis.

Histopathology

A tissue sample obtained via EUS‑guided fine‑needle aspiration (FNA) or surgical biopsy is examined for:

• Neuroendocrine morphology (nested or trabecular patterns).
• Immunohistochemical stains: chromogranin A, synaptophysin positive; gastrin negative.
• Ki‑67 proliferation index – helps grade the tumor (G1: ≤2 %, G2: 3–20 %, G3: >20 %).<sup>[5] WHO Classification</sup>

Treatment Options

Treatment is individualized based on tumor size, location, grade, and whether metastases are present.

Medical therapy

• Proton‑pump inhibitors (PPIs) – high‑dose omeprazole, esomeprazole, or pantoprazole control acid‑related symptoms in >90 % of patients.<sup>[6] Mayo Clinic</sup>
• Somatostatin analogues (octreotide LAR, lanreotide) – bind SSTRs, reducing tumor secretion and sometimes shrinking the mass (tumor control in 30–50 % of cases).
• Targeted therapies – everolimus (mTOR inhibitor) and sunitinib (tyrosine‑kinase inhibitor) are approved for advanced, progressive pancreatic NETs.
• Peptide receptor radionuclide therapy (PRRT) – ^177Lu‑DOTATATE delivers radiation directly to SSTR‑positive cells; recommended for patients with metastatic disease who have adequate kidney function.

Surgical options

• Enucleation – removal of small, well‑encapsulated tumors (<2 cm) while preserving pancreatic tissue.
• Pancreaticoduodenectomy (Whipple procedure) – indicated for tumors in the head of the pancreas or duodenum, especially when malignancy is suspected.
• Distal pancreatectomy – for lesions in the body or tail.
• Debulking surgery – for metastatic disease to reduce tumor burden and improve symptom control.

Lifestyle & supportive care

• Avoid NSAIDs, aspirin, and smoking, which aggravate ulcer formation.
• Small, frequent meals and low‑fat diet to minimize acid load.
• Calcium and vitamin D supplementation if PPIs cause hypocalcemia.
• Regular bone density screening (risk of osteoporosis with long‑term PPI use).

Living with Zollinger‑Ellison Associated Gastrin‑Negative Tumor

Managing a chronic condition involves both medical follow‑up and daily habits.

Monitoring schedule

• Every 3–6 months: serum chromogranin A, kidney function, and symptom review.
• Annually: cross‑sectional imaging (CT or MRI) to detect growth or metastasis.
• Every 2 years: ^68Ga‑DOTATATE PET/CT if prior scans showed SSTR positivity.

Practical tips

• Medication adherence – set alarms for PPIs and somatostatin analogues.
• Stress management – chronic acid hypersecretion can be worsened by stress; consider mindfulness, yoga, or counseling.
• Nutrition – keep a food diary to identify triggers; work with a dietitian experienced in NETs.
• Travel – carry a list of medicines, a copy of pathology reports, and a letter from your oncologist stating the need for injectable medications.
• Support networks – join patient groups such as the Neuroendocrine Tumor Research Foundation (NETRF) for peer support.

Prevention

Because most gastrin‑negative NETs are sporadic, primary prevention is limited. However, risk can be reduced by:

• Screening high‑risk families – individuals with MEN‑1 or VHL should undergo periodic imaging starting in early adulthood.
• Cessation of tobacco – smoking cessation lowers the overall risk of pancreatic neoplasms.
• Maintaining a healthy weight – obesity is linked to pancreatic inflammation.
• Limiting chronic pancreatitis triggers – avoid excessive alcohol and manage gallstone disease promptly.

Complications

If left untreated or inadequately controlled, patients may develop:

• Peptic ulcer perforation – a surgical emergency with a mortality rate up to 30 % in older adults.
• Severe gastrointestinal bleeding – requiring transfusion or endoscopic intervention.
• Malabsorption and chronic nutritional deficiencies – leading to anemia, osteoporosis, and muscle wasting.
• Metastatic disease – liver is the most common site; once disseminated, 5‑year survival drops to 30–50 % for high‑grade tumors.
• Refractory gastro‑esophageal reflux disease (GERD) – can progress to Barrett’s esophagus and esophageal adenocarcinoma.

When to Seek Emergency Care

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Sources: [1] Mayo Clinic. Zollinger‑Ellison syndrome. link. [2] National Institutes of Health (NIH) – Rare Diseases Information Center. link. [3] Cleveland Clinic. MEN1 overview. link. [4] World Health Organization (WHO) – Neuroendocrine Tumors. link. [5] WHO Classification of Tumors of Endocrine Organs, 5th Ed., 2022. [6] Mayo Clinic. Proton pump inhibitors: Uses and safety. link.

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