Sporadic Zollinger-Ellison syndrome in a patient with isolated mesenteric gastrinoma

Abstract

Introduction

Zollinger-Ellison syndrome (ZES) is due to a gastrin-producing neuroendocrine tumor (gastrinoma) with subsequent gastric acid hypersecretion, gastroesophageal reflux disease (GERD), peptic ulcers, and chronic diarrhea.

Case presentation

A 40-year old patient presented with epigastric pain associated with diarrhea evolving for 10 years, he has been treated by acid-suppressive medications without substantial clinical improvement. Gastro-duodenal endoscopy was performed with gastric biopsies that showed peptic ulcerations, a serum gastrin assay that showed high levels exceeding 10 times the upper limit of the normal range. The abdominal contrast-enhanced computed tomography scan (CT-Scan) showed a solid-cystic mass with contrast enhancement in the right colon mesentery. The histopathological analysis of the resected mass showed a well-differentiated neuroendocrine tumor, and the diagnosis of a sporadic Zollinger-Ellison syndrome (ZES) was disclosed. Eighteen months after the surgical treatment the patient has no symptoms of the disease.

Clinical discussion

Patients with ZES present often with long-standing clinical symptoms with delayed diagnosis. The surgical resection of the causative gastrinoma remains the most effective therapeutic treatment.

Conclusion

Patients with refractory chronic diarrhea and epigastric pain should be suspected of having ZES in order to benefit from adequate clinical management.

Highlights

• •Patients with chronic epigastric pain refractory to acid-suppressive treatments should be investigated for alternative etiology as Helicobacter pylori gastritis is not always the cause.
• •Fasting serum gastrin assay and imaging techniques should be performed in such patients.
• •Zollinger-Ellison syndrome (ZES) defined as a triad of peptic ulcer, hypergastrinemia and gastrinoma is a classic cause of epigastric pain.
• •The surgical resection of the gastrin secreting tumor (gastrinoma) is the effective management of this syndrome.

1. Introduction

Zollinger-Ellison syndrome (ZES) was first described in 1955 by Robert M. Zollinger and Edwin H. Ellison as a gastrin-producing neuroendocrine tumor (gastrinoma) with subsequent gastric acid hypersecretion, gastroesophageal reflux disease (GERD), peptic ulcers, and chronic diarrhea [1,2]. ZES is usually sporadic but maybe part of a genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1) [2,3]. The causative gastrin-producing neuroendocrine tumor is often located in the duodenum, the pancreas or the small intestine, rare locations could however be found in liver, stomach, mesentery, ovaries, or extra-abdominal sites [3]. Abdominal pain, GERD and persistent diarrhea are common clinical symptoms. Gastrin is responsible for the secretion of histamine by gastric enterochromaffin-like cells and the subsequent hydrochloric acid overproduction by parietal cells [3]. Also, gastrin overproduction stimulates intestinal and colonic secretions with lipid malabsorption leading to osmotic diarrhea.

The diagnosis of ZES is often delayed as the clinical symptoms may be improved by acid-suppressive therapies. The average time between the clinical onset and the definitive diagnosis of ZES is 5 years [3].

In order to emphasize the need for adequate management of any patient presenting with chronic epigastric pain and diarrhea, we present herein, a case of a sporadic Zollinger-Ellison syndrome in a 40-year old patient, with a mesenteric gastrinoma and long-standing clinical symptoms.

This manuscript has been reported in line with SCARE's 2023 Criteria [4].

2. Case presentation

A 40-year old patient with unremarkable medical history presented with epigastric pain associated with diarrhea evolving for 10 years. The patient has been treated by acid-suppressive medications using proton-pump inhibitors (PPI) without substantial clinical improvement. Gastro-duodenal endoscopy was performed with gastric biopsies that showed peptic ulcerations. The colonoscopic examination was normal. The gastroenterologist then ordered a serum gastrin assay that showed high levels (>1000 pg/ml) exceeding 10 times the upper limit of the normal range. A diagnosis of a sporadic Zollinger-Ellison was suspected, and imaging techniques were performed. The abdominal contrast-enhanced computed tomography scan (CT-Scan) showed a 75 × 63 mm solid-cystic mass with contrast enhancement. The mass was located in the right colon mesentery without invasion of the surrounding organs (duodenum, small intestine and colon). There were no other mass elsewhere especially in the pancreas, liver or intestinal wall (Fig. 1). Open surgical resection of the mass was decided. After general anesthesia, laparotomy with midline abdominal incision was performed, an isolated mesenteric, well-circumscribed solid-cystic mass with smooth surface was discovered (Fig. 2a, b). The tumor was embedded in the mesentery without connections with the pancreatic head, the duodenum, the jejunum or the colon. There were no ascites or lymphadenopathy. Also, there were no other tumor locations found by a thorough surgical exploration. The tumor was resected “en bloc” after mobilization and dissection of the right colic flexure in order to expose it well. Lymphadenectomy was not performed. The patient left the hospital the 5th day after the surgical management as he did well.

Fig. 1.

Enhanced computed tomography scan showing a well-circumscribed solido-cystic mesenteric mass (arrow).

Fig. 2.

a: The surgical view of the tumor (arrow). b: The resected specimen with smooth surface.

The resected tumor weighs 100 g, with fleshy brown solid component and cystic parts with hemorrhagic liquid content. The histopathological analysis showed a well-defined tumor with trabecular and solid cribriform patterns with interspersed fibro-vascular stroma (Fig. 3). The tumor cells were uniformly round with eosinophilic cytoplasm and oval nuclei with smooth chromatin and inconspicuous small nucleolus. The specimen was sent to France for additional immunohistochemical analysis. The tumor cells express cytokeratin 7, cytokeratin 20, chromogranin A (Fig. 4) and synaptophysin. The cellular proliferative index assessed by Ki-67 was 1 %. These histopathological features were consistent with a low grade, well-differentiated neuroendocrine tumor. The clinical symptoms, associated with hypergastrinemia and a neuroendocrine tumor in our patient are characteristic of a sporadic Zollinger-Ellison syndrome (ZES).

Fig. 3.

Histopathological aspect of the tumor (hematoxylin-eosin staining, ×200).

Fig. 4.

The immunohistochemical analysis showing positive staining with chromogranin A (×400).

Eighteen months after the surgical treatment the patient has no symptoms of the disease and the serum gastrin is now within normal limits.

3. Discussion

Our patient had characteristic clinical presentation of ZES defined as acid hypersecretion, gastroesophageal reflux disease (GERD), peptic ulcers, and chronic diarrhea. Gastrinoma is a classic cause of epigastric pain as well as a chronic diarrhea [5]. The spread use of proton-pump inhibitors (PPI) and their well-known tolerance and efficacy in relieving symptoms, have led to delayed diagnoses of ZES, with the average time from symptoms onset to definitive diagnosis exceeding 5 years [3,5]. Patients with MEN-1 have a tendency to present symptoms of ZES at younger age compared to patients with sporadic ZES, 33.7 years versus 43.2 years in a study of 261 cases with ZES by Roy et al. [6]. Also, gastro-intestinal bleeding and intestinal perforation have been reported in patients with ZES as inaugural clinical symptoms [7,8]. Our patient had clinical symptoms of ZES evolving for 10 years before the definitive diagnosis was reached after the surgical treatment.

High levels of fasting serum gastrin (>10 times the normal average level) and a low gastric pH < 2, are characteristic features of ZES. Imaging techniques or endoscopic examination is used to identify the causative gastrin-secreting tumor. However, when the tumor size is <2 cm, its detection by magnetic resonance imaging (MRI) or CT-scan is challenging [9]. Small-sized tumors are better detected by special techniques such as somatostatin receptor scintigraphy and 68 Ga-Dotatate positron emission tomography/computed tomography [9,10]. However, surgical exploration is another efficient way of detecting small gastrinomas even in patients with negative imaging techniques [11]. In our case, the tumor has been diagnosed by abdominal CT-scan in the right colon mesentery, beyond the classical “gastrinoma triangle” that includes the proximal parts of duodenum, the pancreas (neck and body) and the distal biliary tract [2,5,9]. A thorough surgical exploration did not find other tumor location in our patient, making this case report very particular because of this rare tumor location. Primary mesenteric neuroendocrine tumors (NETs) are very rarely reported [12,13], however these cases would perhaps be secondary tumors from latent unretrieved small tumors from the pancreas or the digestive tract.

Gastrinoma, the etiology of ZES, is in fact a functional neuroendocrine neoplasm (NEN) that produces gastrine. Usually, gastrinomas are histologically well-differentiated NENs graded as grade 1 or grade 2 according to the latest World Health Organization (WHO) classification of the tumors of the digestive system [14,15]. The histopathological diagnosis of NETs is based on morphological analysis often combined by immunohistochemical staining with neuroendocrine markers (chromogranin and synaptophysin) and Ki-67 for grading purpose [15].

The surgery remains the gold standard in the treatment of patients with ZES whenever possible, associated with acid-suppressing treatment to control clinical symptoms. The surgical treatment is usually reserved for patients with localized tumors [5,9]. These patients have usually a good prognosis with a high rate of cure even in patients with MEN-1 [3,16]. Our patient is expected to be cured eighteen months after the surgical resection as he has no clinical symptoms and he no longer takes acid-suppressive drugs.

Patients with metastatic gastrinomas or multifocal tumors (especially in patients with MEN-1) not amenable to surgical treatment, are treated by long-term acid-suppressive drugs (PPI), chemotherapy, tyrosine kinase inhibitors or somatostatin analogues [2,3]. The results of all these palliative treatments remain controversial. Despite relieving symptoms, PPI do not have positive effect in reducing tumor volume and the subsequent hypergastrinemia may be tumorigenic [16]. Gastrinomas express somatostatin receptors, making them targetable by somatostatin analogues, however there is little literature data reporting clinical outcomes of patients treated by these drugs [17]. Thus, management of ZES patients with multiple tumor (metastases or MEN-1 syndrome) locations is still complex and controversial [18].

4. Conclusion

Our case had a unique clinical presentation with an uncommon tumor location (mesenteric gastrinoma) and a long disease evolution of about 10 years before the definitive diagnosis. Patients with refractory chronic diarrhea and epigastric pain should be suspected of having ZES in order to benefit from adequate clinical management.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ethical approval

N/A. This study is exempt from ethical approval from the institution.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Author contribution

All authors contributed to the information collection of this case report. BE conceived and drafted the manuscript. HN reviewed the manuscript. All authors read and approved the final manuscript. All authors have consented to the publication of this manuscript.

Guarantor

Dr. Boubacar Efared.

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Conflict of interest statement

None declared.