Zollinger-Ellison syndrome (ZES) is characterized by the development of multiple (and recurrent) duodenal and jejunal ulcers and is occasionally associated with diarrhea. The overall incidence is low (<3/1 million population per year), with the majority of cases occurring in adults (95%–98% vs <5% in children) (1,2). The mean delay in the diagnosis of ZES (ie, first onset of symptoms to correct diagnosis) is 5 to 6 years (1,3). Because metastatic disease reduces patient survival, it is essential to recognize the clinical manifestations of the disease as quickly as possible. We report an adolescent boy presenting with abdominal pain, fever, and (cystic) lesions in the liver. The initial differential diagnosis did not include ZES. Two years following his initial presentation and subsequent treatment, the patient presented with multiple small bowel perforations. The present case illustrates that (cystic) liver lesions may be the first presentation of ZES. Consequently, the levels of disease markers, such as gastrin and chromogranin A, should be determined at an early stage. A 14-year-old boy presented with severe abdominal pain and fever. Abdominal ultrasound demonstrated multiple lesions in the liver, including cystic lesions. Biopsy of the lesions yielded old blood; no microorganisms were present. Candida was cultured from the free fluid of the abdominal cavity. The patient was therefore treated with fluconazole. Extensive immunological investigations revealed no abnormalities. The patient was free of symptoms during the follow-up period, but the lesions in the liver remained. Two years later, the patient had an episode of severe abdominal pain, accompanied by nausea, anorexia, severe weight loss, and intermittent diarrhea. A large hypodense mass, or heterogeneous lesion, with both necrotic and cystic lesions (Hounsfield units >20 and <20, respectively) was evident on abdominal ultrasound and multiphase contrast-enhanced (Xenetix 300, Guerbet, Roissy, France) computed tomography (CT) scanning (Fig. 1). Levels of fluid were present in some of the pockets. The bowel walls were thickened, and there was free air in the abdomen. At laparoscopy, the patient had 6 perforations in the small bowel at the level of Treitz (Fig. 2), peritonitis, and an irregular aspect of the liver with blue translucent lesions. Histological investigation of the liver lesion disclosed a neuroendocrine tumor with positive staining for chromogranin A, synaptophysin, somatostatin, and gastrin. The serum gastrin and plasma chromogranin A levels were 3400 pg/L (reference value <70 pg/L) and 1749 μg/L (reference value <120 μg/L), respectively. Based on these findings, the patient was diagnosed as having ZES. Subsequent testing of a stored serum sample 2 years earlier revealed a serum gastrin level of 1400 pg/L (in absence of acid-reducing therapy). CT scanning and magnetic resonance imaging (MRI) revealed no additional lesions. Gastroduodenoscopy demonstrated hyperplastic gastric mucosal folds with multiple duodenal ulcerations, but no primary tumor or lesion. Somatostatin receptor scintigraphy (SRS) was unable to detect any metastases because of the large accumulation of 111In-pentetreotide in the liver that obscured the adjacent structures. All of the pituitary-endocrine axes were intact, and genetic testing for germline mutations in the MEN-1 gene was negative. The patient was treated with a proton pump inhibitor (PPI; 120–160 mg/day omeprazole orally) and octreotide (3 times 100 μg/day subcutaneously). Hemihepatectomy of the right liver lobe was performed with the primary goal to remove all of the liver lesions. No primary tumor in the stomach, duodenum, or pancreas was found during surgery. Postoperatively, plasma chromogranin A and serum gastrin levels decreased dramatically to 117 and 91 pg/L, respectively. A repeat SRS revealed 4 metastases in the remaining left liver lobe and deposition of 111In-pentetreotide at the level of vertebra T11 or T12. Gastroduodenoscopy was repeated. The duodenal ulcerations had disappeared, but a small neuroendocrine tumor near the gastric outlet was identified (Fig. 3). The histology of this tumor, including gastrin staining, confirmed the diagnosis of gastrinoma. At the time of writing, 5 months after diagnosis, the patient was free of symptoms with PPI and octreotide pharmacotherapy. In the case of disease progression, the patient would be treated with radioactive-labeled somatostatin analogue therapy.FIGURE 1: Two frames of multiphase contrast-enhanced (Xenetix 300) CT scanning of the abdomen are shown, identifying a large hypodense mass (with a diameter of about 15 cm), or heterogeneous lesion, with both necrotic and cystic lesions (Hounsfield units >20 and <20, respectively). The tumor is located in the right liver lobe; fluid levels in some of the pockets are indicated by white arrows.FIGURE 2: Three of 6 small-bowel perforations near the ligament of Treitz.FIGURE 3: Small gastrinoma near the gastric outlet.DISCUSSION At the first presentation, the liver lesions of this patient were diagnosed as cystic liver lesions. Imaging had been limited to abdominal ultrasound, without performing CT scanning or MRI. Two years later, with changes in the clinical manifestations, the patient was diagnosed with a hepatic tumor with both cystic and necrotic lesions, with a remarkable difference in density, resulting in a new differential diagnosis. The etiology of cystic liver lesions and hepatic tumors is shown in Table 1. The etiology of cystic hepatic tumors is also included in the table for comparison. Cystic lesions of the liver include simple cysts, multiple cysts arising in the setting of polycystic liver disease, echinococcal or hydatid cysts caused by infestation with the parasite Echinococcus, abscesses, and cystic tumors (4). Liver abscesses can be amebic, fungal, or bacterial in origin, and pyogenic abscesses are frequently associated with an underlying immune deficiency (5,6). True intrahepatic neoplastic cysts, such as cystadenoma and cystadenocarcinoma, are extremely rare in children (7). Most cystic tumors are metastases with central necrosis, a phenomenon that has also been described for neuroendocrine tumors (8,9). Although hemangiomas usually present as a solid lesion, atypical cystic presentations have also been described (10). Hepatic tumors include hepatoblastoma, hepatocellular carcinoma, benign vascular tumors, sarcoma, mesenchymal hamartoma, focal nodular hyperplasia, hepatic or biliary adenomas, and others (11–14). The heterogeneous liver lesions present in our patient were the result of a necrotic neuroendocrine tumor that was responsible for the ZES.TABLE 1: Etiology of cystic liver lesions and hepatic tumors in childrenZES is a disease of the gastrointestinal tract caused by a neuroendocrine tumor producing gastrin and chromogranin A (1,2). Hypersecretion of gastric acid causes abdominal pain, vomiting, hematemesis, melena, diarrhea, and occasionally small bowel perforations (1). It has been estimated that the mean delay in diagnosing ZES is 5 to 6 years, resulting in 60% to 80% of patients with ZES ultimately having metastatic disease (2). The diagnostic delay in our patient was about 2 years. Most gastrinomas are located in the duodenum or pancreas, although in children, primary gastrinomas seem to occur frequently in the liver and lymph nodes (1,2); however, it remains unclear whether these latter neoplasms are true primary tumors or “metastatic” lesions from a primary tumor that could not be identified (11). The presence of liver metastases is a poor prognostic finding, reducing 10-year survival from 90% to 100% to 10% to 20% (1,3). Bone metastases are usually late manifestations (3). In 20% to 30% of patients with ZES, the gastrinomas are associated with MEN-1(1). Fasting serum gastrin levels are severely elevated (>100 pg/mL) in >99% of the patients with ZES, with a level >1000 pg/mL being virtually diagnostic of this disease (12,15). Moreover, gastrin levels correlate with disease extent and prognosis (3,12). For an accurate interpretation of the gastrin level, it is recommended that pharmacotherapy be interrupted with PPIs and histamine 2 receptor blockers (H2RA), but this may not be possible because of the risk of recurrent upper gastrointestinal bleeding and/or perforation (1). The primary tumor and metastases must be localized for proper adjustment of the therapeutic program, but detection of these small tumors can be extremely difficult (1). Conventional imaging methods (ultrasound, CT, MRI) have a limited sensitivity, varying between 10% and 40% (1,16). The sensitivity of SRS using a labeled somatostatin analog, which binds to the somatostatin receptor subtypes (predominantly sst2, sst3, and sst5) expressed on the membrane of the tumor cell, ranges between 58% and 92% for both primary tumors and metastases (16). Small tumors with a diameter of <1 cm can be missed in up to 70% of cases (1,15,16). Endoscopic ultrasound has a sensitivity of 50% for the localization of small duodenal tumors (17). Overall sensitivity of combined endoscopic ultrasound and SRS has been reported to be 93% for gastrinoma (18). An invasive technique with a high sensitivity and specificity (both >90%) is the selective arterial secretagogue injection test (even in tumors <5 mm) (19). The injection of secretin and calcium into the feeding artery of the neuroendocrine tumor results in a further release of gastrin, possibly providing detailed information on its localization (19). The treatment of ZES includes control of acid hypersecretion and surgical treatment of the primary gastrinoma and its possible metastases. Acid hypersecretion can be safely treated through the administration of high-dose PPIs, but the only curative option for the treatment of a sporadic gastrinoma is total surgical resection (1). The occurrence of micrometastases is frequent, however, and only 25% to 40% of the patients are in complete remission 5 to 10 years postsurgery (15,20). Although not curative, cytoreductive surgery will increase the survival of patients with advanced disease (21). In selected cases, radiofrequency ablation, hepatic artery embolization (or chemoembolization), and liver transplantation are treatment options for patients with liver metastases (1,22,23). Only patients with progressive disease are eligible for (palliative) systemic antitumor therapy (24,25). Because of the lack of prospective randomized controlled trials, the heterogeneous composition of patient groups and the small number of patients with ZES, only limited evidence-based data are available on the different therapies (26). The recommended targeted therapy consists of biotherapy with somatostatin analogs (eg, octreotide, lanreotide) and/or interferon-α (24). Combined chemotherapy with streptozotocin plus doxorubicin and/or 5-fluorouracil has a short response duration, but can be considered a good alternative in the case of rapid progressive disease, whereas etoposide and cisplatin may be a good treatment option for poorly differentiated gastrinoma (24,27,28). Patients with octreoscan-positive tumors may benefit from peptide receptor radionuclide therapy with 90Y- or 177Lu-labeled somatostatin analogs (1,29,30). An overall survival time of >48 months is reported using this therapy (28). Future therapeutic options, such as angiogenesis inhibitors and tyrosine kinase inhibitors, are under investigation (24). In an atypical presentation of peptic ulcer disease, ZES should be considered. Our case report demonstrated that heterogeneous liver lesions, including cystic liver lesions, may on occasion be the first presentation of ZES. In suspected ZES, we suggest using serum gastrin assays more often to shorten the diagnostic delay and thus improve the prognosis for patients with ZES.