==== Front World J HepatolWJHWorld Journal of Hepatology1948-5182Baishideng Publishing Group Inc jWJH.v10.i7.pg51710.4254/wjh.v10.i7.517Case ReportLarge primary hepatic gastrinoma in young patient treated with trisegmentectomy: A case report and review of the literature Pipek Leonardo Zumerkorn Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 05403, Brazil. leonardo.pipek@fm.usp.brJardim Yuri Justi Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 05403, BrazilProgram in Global Surgery and Social Change, Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA 02115, United Statesde Mesquita Gustavo Heluani Antunes Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 05403, BrazilNii Fernanda Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 05403, BrazilMedeiros Kayo Augusto de Almeida Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 05403, BrazilCarvalho Bárbara Justo Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 05403, BrazilMartines Diego Ramos Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 05403, BrazilIuamoto Leandro Ryuchi Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 05403, BrazilWaisberg Daniel Reis Departamento de Gastroenterologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 05403, BrazilD’Albuquerque Luiz Augusto Carneiro Departamento de Gastroenterologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 05403, BrazilMeyer Alberto Departamento de Gastroenterologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 05403, BrazilAndraus Wellington Departamento de Gastroenterologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 05403, BrazilAuthor contributions: Pipek LZ, Jardim YJ, Mesquita GHA, and Martines DR wrote the article; Nii F, Medeiros KAA, and Carvalho BJ performed the literature search; Waisberg DR and D’Albuquerque LAC identified the case and revised the manuscript for important intellectual content; Iuamoto LR, Andraus W, and Meyer A reviewed the final version of the article. Correspondence to: Leonardo Zumerkorn Pipek, MBBS, Faculdade de Medicina FMUSP, Universidade de São Paulo, Av Dr Arnaldo 455, São Paulo 05403, Brazil. leonardo.pipek@fm.usp.br Telephone: +55-11-30617000 Fax: +55-11-30617000 27 7 2018 27 7 2018 10 7 517 522 28 3 2018 25 4 2018 30 5 2018 ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.2018This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.Primary hepatic gastrinoma is a rare disease, with fewer than 40 cases reported in the medical literature. Because it is located in an organ in which metastases are common, its diagnosis is difficult. We report a case of a 19 years old male patient with a history of gastric ulcers since the age of nine. Following gastric surgery, an antrectomy and a vagotomy, there was some alleviation of symptoms. Subsequently, the patient reported various intermittent episodes of diarrhea, diffuse abdominal pain, and vomiting. The patient underwent tomography, which revealed the presence of a hepatic mass measuring 19.5 cm × 12.5 cm × 17 cm. Primary hepatic gastrinoma was diagnosed based on laboratory examinations that indicated hypergastrinemia and a positron emission tomography/magnetic resonance study with somatostatin analogue that confirmed the liver as the primary site. After hepatic trisegmentectomy (II, III, IV, V, VIII), the patient’s symptoms improved. The case is notable for the presence of a rare tumor with uncommon dimensions. GastrinomaPrimary hepatic gastrinomaZollinger-Ellison syndromeHepatic trisegmentectomyGastric surgery ==== Body Core tip: Primary hepatic gastrinoma is a very rare disease. Due to its location in an organ in which metastases are common, its diagnosis is difficult. We report a case of a 19 years old male patient with a history of gastric ulcers since the age of nine. Hypergastrinemia and a PET/MR study with somatostatin analogue confirmed that the liver was the primary site. After hepatic trisegmentectomy, the patient’s symptoms improved. The case is notable for the presence of a rare tumor with uncommon dimensions. INTRODUCTION Zollinger-Ellison syndrome[1] is characterized by gastric hypersecretion, resulting in peptic disease and diarrhea[2]. Diagnosis is confirmed by gastrin levels of over 1000 pg/mg. This syndrome was first described by Zollinger and Ellison[2] in 1955. With an incidence of around 0.5 to 2 per million, the majority of patients are diagnosed between 20 and 50 years of age, with a higher prevalence among men. The majority of gastrinomas are sporadic, and 20%-30% are associated with type 1 endocrine neoplasias, NEM-1[3]. The classical clinical presentation of the syndrome is the presence of abdominal pain (75%) and chronic diarrhea (73%). Half of patients present with burning as a result of gastroesophageal reflux. There is still a significant population (17%-25%) that presents with weight loss and gastrointestinal bleeding[4]. Over 90% of cases of gastrinomas are present in the so-called “gastrinoma triangle”, delimited by the cystic duct, the junction between the second and third portions of the duodenum, and the junction between the colon and the pancreatic body. Occasionally, gastrinomas have also been described in other areas, including lymph nodes, biliary tree, ovaries, kidneys, heart, gallbladder, omentum, and liver[5-7]. This article describes a case of primary hepatic gastrinoma in a 19 years old hypergastremic patient who underwent hepatic trisegmentectomy to remove the tumor. CASE REPORT A male patient, 19 years of age, was referred as a result of intermittent abdominal pain over the previous 10 years. He reported an attack of diffuse abdominal pain for 1 month at the age of nine. At that time, a gastric ulcer was diagnosed, and due to the failure of clinical treatment, he underwent antrectomy with vagotomy in another service. In the years following the surgery, the patient presented sporadic episodes of non-specific diffuse abdominal pain associated with nausea and vomiting. Diarrhea was also present, but dyspeptic characteristics were not. During that time, emergency treatment was sought with regularity, with improvement following clinical treatment. A loss of around 16 kg of body weight was reported over the year prior to admission to our service (from 68 to 52 kg). Upper digestive endoscopy was carried out. In the third distal, close to the esophageal transition, the mucosa was pearlescent and thickened, which was associated with confluent erosions larger than 5 mm. This covered 100% of the circumference of the organ, with ulcerations and fibrin (intense erosive distal esophagitis-Los Angeles Class D). Furthermore, an image compatible with extrinsic compression of the stomach was revealed (Figure 1). Figure 1 Upper digestive endoscopy showing intense erosive distal esophagitis and extrinsic compression of the stomach. A: Intense erosive distal esophagitis; B: Extrinsic compression of the stomach. Computed tomography (CT) and magnetic resonance (Figure 2) were carried out, showing increased dimensions of the liver, as the result of a voluminous expansive hypervascularized lesion with necrotic central areas. Involvement in the portal vein was identified, and the mass mainly occupied the central portion of the liver and hilum, affecting segments I, II, III, IV, VIII and measuring 19.5 cm × 12.5 cm × 17.0 cm. Figure 2 The computed tomography of hepatic lesion. A and B: Computed tomography showing a voluminous heterogeneous hepatic lesion, with a neoplasic aspect and dimensions 19.5 cm × 12.5 cm × 17.0 cm; C: Compression of the right hepatic vein. A biopsy was carried out with the following immuno-histochemical characteristics: cytokeratin 7 negative, cytokeratin 20 negative, chromogranin positive, synaptophysin positive, CD99 positive, Hep par 1 negative, polyclonal CEA positive (standard cytoplasma and membrane), and Ki 67 positive (around 5%). It was concluded that the profile was compatible with a well-defined neuroendocrine tumor (NET Grade 2). The diagnosis was confirmed by the discovery of gastrin hypersecretion, via chemiluminescence, with a resulting value of 6709.0 pg/mL. Considering that the liver is a common location for metastasis, it was important to define whether or not the tumor was primary. To do this, positron emission tomography associated with magnetic resonance was carried out - PET-MR - with somatostatin analogue (Figure 3). The examination was carried out following the administration of 2.7 mCi of Galium-68-DOTA-Octreotate (68Ga-DOTATATE) intravenously. The examination showed a relatively well-defined expansive lesion on the liver, with lobulated contours, situated in the left lobe. Heterogeneity in T2 and an anomalously high concentration of radiopharmacus was noted. It was heterogeneously distributed, with central and peripheral areas with hypoconcentration of radiotracer (which can correspond to necrosis/liquefaction), measuring around 18.1 cm × 11.3 cm at the largest axes. Contact and constriction of the inferior vena cava, which was permeable, were sustained. There were no signs of invasion of the head or body of the pancreas. Figure 3 Positron emission tomography associated with magnetic resonance with somatostatin analogue confirmed that the liver was the primary site of the tumor. From these examinations it was possible to confirm the diagnosis of primary hepatic gastrinoma and to recommend surgical resection. Prior to the surgical procedure, there were a number of intracavity adher–ences. Hepatic trisegmentation (II, III, IV, V, VIII) was carried out (Figure 4), identifying a large volume mass, mainly occupying the left lobe of the liver. Segments V and VIII were most affected, with atrophy in segment II, as well as compensatory hypertrophy in segments VI and VII. The remaining liver maintained approximately 80% of the volume of a functional liver. The patient was readmitted in the early postoperative phase with abdominal pains and leaking of bile through the drain due to a biliary fistula. The patient was submitted to a surgical procedure with a good outcome. Six months after the resection, the patient was well, had no relapses, and had a gastrin level of 40.5 pg/mL. At 1 year after the surgery, exam showed a gastrin level of 89.2 pg/mL. The normal range of gastrin is 13 to 115 pg/mL. Figure 4 Intraoperative appearances. A: After hepatic posterior sector mass separation; B: Aspect of the remaining liver after surgical removal; C: Surgical piece. DISCUSSION Zollinger-Ellison syndrome (ZES) is predominantly sporadic, although in 20%-30% of cases its origin is type 1 multiple endocrine neoplasia (MEN1). MEN 1 is a genetic disease that occurs in the gene MEN1, leading to the formation of various neoplasias; pancreatic endocrine tumors, pituitary adenomas, and hyperplasia of the parathyroid are the most prevalent. Despite the evidence of ulcers in this patient at the age of nine, ZES should be considered, principally because of the patient’s history and hypergastrinemia. There was no report of the occurrence of MEN1 together with primary hepatic gastrinoma, including in our case. Gastropancreatic neuroendocrine neoplasias, which can cause ZES, are classified according to their prognosis. Well-defined neuroendocrine tumors have a clinical course that is much less aggressive and can be subclassified as G1 (Ki-67 < 3) and G2 (Ki-67 of 3%-20%), according to the Ki-67 index that assesses the level of differentiation of cells in tissue. Poorly defined tumors are in category G3, presenting Ki-67 > 20%. Histopathological analysis of the patient’s tumor revealed a Ki-67 of 5% (G2)[8]. The most common gastrinomas, duodenal and pancreatic, present a mean diameter of 1 and 3 cm, respectively[9]. The tumor in this case had dimensions of 19.5 cm × 12.5 cm × 17.0 cm. Primary ectopic gastrinomas are neuroendocrine tumors located outside of the triangle of gastrinoma and are responsible for less than 10% of cases. One specific site in which they occur is the liver, with only 26 cases described in the literature in a review from 2012[10]. In recent years, there were a few more cases described, but the total number is still very low. According to a recent study[11], in ZES patients, primary gastrinomas of the liver were the second most common extrapancreatic, extraintestinal site for a primary gastrinoma and may metastasize to regional lymph nodes. Compared with typical ZES patients, the epidemiology of primary hepatic gastrinoma is a little different. The patients are generally affected much younger, with a predominance of males and no association with MEN 1, as it was in our case[12]. This rare hepatic gastrinoma is slow growing, with around 65% of cases malignant and 30%-40% of those cases being metastatic at initial presentation. This relatively high rate of metastases arises from the difficulty of diagnosis, especially in palliative care and hepatic metastases[13]. Despite this, our patient did not present metastases in radiological examinations. A clinical presentation of ZES similar to gastroesophageal reflux can lead to treatment with proton-pump inhibitors. This medication masks the symptoms and alters gastrin levels, prolonging the time necessary to identify the real cause of the disease. A study[14] showed that prior to widespread use of proton-pump inhibitors (before 1985), the rate of metastases was only 19%. Ten years later, this number had risen to 55%. Prior to the advent of proton-pump inhibitors, partial and full gastrectomies were common to reduce the incidence of ulcers. In the report of this case, the fact that the patient had previously undergone antrectomy with vagotomy meant that his symptoms were less apparent than they would otherwise have been. A second factor that can complicate diagnosis is related to the morphofunctional characteristics of the liver. It is known that the liver is a common site of metastasis for a variety of tumors, and classifying the neoplasia as primarily hepatic requires some examinations to confirm the absence of other primary sites. One of the examinations currently used is PEC/CT with 68 gallium-dotatate. This radiopharmacum is associated with computerized tomography and is a somatostatin analogue, which allows the identification of tumors[15]. The sensitivity of the examination was 93% (95%CI: ± 2%) and the specificity was 91% (95%CI: 82%-97%), as identified in a meta-analysis[9]. Once the neuroendocrine tumors present somatostatin receptors, it is possible to confirm whether the hepatic gastrinoma is primary or the result of metastasis[16,17]. In this case, the existence of a single focus in the liver combined with a high level of gastrin highly suggested it as a primary site. Is important to emphasize the importance of the follow up of gastrin levels to ensure that there is not a small small duodenal primary gastrinoma that could not have been detected in the PET/CT and surgery[11]. Despite few reported cases, surgical resection should be the treatment of choice and, furthermore, the only chance of a cure. The rate of success in these cases is 86%, and 60% present early postoperative eugastrinemia, 40% after five years. In the event that surgery is not possible, such as in cases of diffuse metastasis or comorbidities, it is possible to follow conventional treatment: Ablation by radiofrequency, chemotherapy (doxorubicin, streptozocin, 5-fluorouracil), interferon, and transplantation[13]. A study with 160 patients with gastrinoma showed that 15-year disease-related survival was 98% for operated and 74% for unoperated (P = 0.0002)[18]. In conclusion, primary hepatic gastrinomas are extremely rare tumors that cause Zollinger-Ellison syndrome. Due to their clinical presentation and the liver being a significant site of metastases, diagnosis of the disease is time consuming and difficult. Following diagnosis, the treatment of choice is surgery, and, in cases where there are no metastases, the prognosis is good. Therefore, it is important to diagnose properly the primary gastrinoma. ARTICLE HIGHLIGHTS Case characteristics Primary hepatic gastrinoma in a 19 years old hypergastremic patient who underwent hepatic trisegmentectomy to remove the tumor. Clinical diagnosis Primary hepatic gastrinoma. Differential diagnosis Gastrointestinal tumors, MEN 1. Laboratory diagnosis Gastrin levels were 6709.0 pg/mL before surgery. After the procedure it was 40.5 pg/mL. Imaging diagnosis Computed tomography (CT) showed a voluminous heterogeneous hepatic lesion, with a neoplasic aspect and dimensions 19.5 cm × 12.5 cm × 17.0 cm. Pathological diagnosis Histopathological analysis of the patient’s tumor revealed a Ki-67 of 5% (G2). Treatment Hepatic trisegmentectomy. Term explanation Gastrinoma: A gastrinoma is a tumor that secretes an excess of gastrin, leading to ulceration in the duodenum, stomach, and the small intestine. Experiences and lessons Primary hepatic gastrinoma is a very difficult to diagnose. Meticulous examination is necessary for appropriate diagnosis and treatment. ACKNOWLEDGEMENTS The authors are thankful to Justin Axel-Berg for the English corrections. Informed consent statement: Written informed consent and permission to write this manuscript was obtained from the patient of this case report. Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported. Manuscript source: Unsolicited manuscript Peer-review started: March 29, 2018 First decision: April 23, 2018 Article in press: May 31, 2018 Specialty type: Gastroenterology and hepatology Country of origin: South Korea Peer-review report classification Grade A (Excellent): A Grade B (Very good): B Grade C (Good): C, C, C Grade D (Fair): D, D Grade E (Poor): 0 P- Reviewer: Gencdal G, Jensen RT, Kaya M, Luo GH, Ozenirler S, Singh S, Tsuchiya A S- Editor: Ji FF L- Editor: Filipodia E- Editor: Tan WW ==== Refs 1 Ellison EC Johnson JA The Zollinger-Ellison syndrome: a comprehensive review of historical, scientific, and clinical considerations Curr Probl Surg 2009 46 13 106 19059523 2 Zollinger RM Ellison EH Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas Ann Surg 1955 142 709 723; discussion, 724-728 13259432 3 Bergsland E Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis Available from: https://www.uptodate.com/contents/zollinger-ellison-syndrome-gastrinoma-clinical-manifestations-and-diagnosis?source=search_resultsearch=gastrinomaselectedTitle=1~90 4 Roy PK Venzon DJ Shojamanesh H Abou-Saif A Peghini P Doppman JL Gibril F Jensen RT Zollinger-Ellison syndrome. Clinical presentation in 261 patients Medicine (Baltimore) 2000 79 379 411 11144036 5 Smyrniotis V Kehagias D Kostopanagiotou G Tripolitsioti P Paphitis A Primary hepatic gastrinoma Am J Gastroenterol 1999 94 3380 3382 6 Thompson NW Vinik AI Eckhauser FE Strodel WE Extrapancreatic gastrinomas Surgery 1985 98 1113 1120 4071387 7 Norton JA Alexander HR Fraker DL Venzon DJ Gibril F Jensen RT Possible primary lymph node gastrinoma: occurrence, natural history, and predictive factors: a prospective study Ann Surg 2003 237 650 657; discussion 657-9 12724631 8 Klimstra DS Yang Z Pathology classification, and grading of neoplasms arising in the digestive system Available from: https://www.uptodate.com/contents/pathology-classification-and-grading-of-neuroendocrine-tumors-arising-in-the-digestive-system?source=search_resultsearch=gastrinoma%20ki-67selectedTitle=1~150 9 Ogawa S Wada M Fukushima M Shimeno N Inoue S Chung H Fujita M Suginoshita Y Okada A Inokuma T Case of primary hepatic gastrinoma: Diagnostic usefulness of the selective arterial calcium injection test Hepatol Res 2015 45 823 826 25145887 10 Harvey A Pasieka JL Al-Bisher H Dixon E Primary hepatic gastrinoma causing zollinger-ellison syndrome: a rare and challenging diagnosis Cancers (Basel) 2012 4 130 140 24213231 11 Incidence and Prognosis of Primary Gastrinomas in the Hepatobiliary Tract JAMA Surg 2018 153 e175083 29365025 12 Moriura S Ikeda S Hirai M Naiki K Fujioka T Yokochi K Gotou S Hepatic gastrinoma Cancer 1993 72 1547 1550 8348490 13 Tsalis K Vrakas G Vradelis S Dimoulas A Pilavaki M Papaemmanouil S Micheli A Lazarides C Kartalis G Primary hepatic gastrinoma: Report of a case and review of literature World J Gastrointest Pathophysiol 2011 2 26 30 21607163 14 Evans JT Nickles S Hoffman BJ Primary hepatic gastrinoma: an unusual case of zollinger-ellison syndrome Gastroenterol Hepatol (NY) 2010 6 53 56 15 Treglia G Castaldi P Rindi G Giordano A Rufini V Diagnostic performance of Gallium-68 somatostatin receptor PET and PET/CT in patients with thoracic and gastroenteropancreatic neuroendocrine tumours: a meta-analysis Endocrine 2012 42 80 87 22350660 16 Mojtahedi A Thamake S Tworowska I Ranganathan D Delpassand ES The value of (68)Ga-DOTATATE PET/CT in diagnosis and management of neuroendocrine tumors compared to current FDA approved imaging modalities: a review of literature Am J Nucl Med Mol Imaging 2014 4 426 434 25143861 17 Deppen SA Liu E Blume JD Clanton J Shi C Jones-Jackson LB Lakhani V Baum RP Berlin J Smith GT Safety and Efficacy of 68Ga-DOTATATE PET/CT for Diagnosis, Staging, and Treatment Management of Neuroendocrine Tumors J Nucl Med 2016 57 708 714 26769865 18 Norton JA Fraker DL Alexander HR Gibril F Liewehr DJ Venzon DJ Jensen RT Surgery increases survival in patients with gastrinoma Ann Surg 2006 244 410 419 16926567