Gastrinoma (Duodenal and Pancreatic)

Gastrinomas are neuroendocrine tumors (NETs), usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger-Ellison syndrome (ZES). ZES is characterized by gastric acid hypersecretion resulting in severe acid-related peptic disease (peptic ulcer disease, PUD; gastro-esophageal reflux disease, GERD) [1,2,3] and diarrhea. In this section ZES, due to both duodenal and pancreatic gastrinomas, will be covered together because clinically they are similar [2, 3]. Specific points related to gastrinomas associated with the genetic syndrome of multiple endocrine neoplasia type 1 (MEN1) will also be mentioned. Some specific points related to duodenal gastrinomas will also be covered in the duodenal carcinoid section.The incidence of gastrinomas is 0.5–3/million population/year. They are the most common functional and, malignant pancreatic endocrine tumor (PET) syndrome and comprise up to 30% of these tumors [3, 4]. Duodenal tumors, which were originally thought to be uncommon (i.e. <20%), now make up 50–88% of gastrinomas in sporadic ZES patients and 70–100% of gastrinomas in MEN1/ZES patients. In rare cases, gastrinomas occur in other nonpancreatic, nonduodenal abdominal (stomach, liver, bile duct, ovary) (5–15%) and extra-abdominal (heart, small cell lung cancer) locations [5,6,7,8].The WHO classification [10] subdivides gastrinomas, similar to other gastroenteropancreatic neuroendocrine tumors (GEP-NETs), into three general categories: (1) well-differentiated endocrine tumors with benign or uncertain behavior at the time of diagnosis (10–30%); (2) well-differentiated endocrine carcinomas with low-grade malignant behavior (50–80%), and (3) poorly differentiated endocrine carcinomas with high-grade malignant behavior (1–3%). The 50–80% of gastrinomas of the pancreas and duodenum that fall into the category of well-differentiated endocrine carcinomas are usually larger than 1 cm and show local invasion and/or proximal lymph node metastases [6, 11]. Liver metastases occur much more frequently with pancreatic gastrinomas (22–35%) than duodenal gastrinomas (0–10%) [6, 12]. Pancreatic gastrinomas are generally large in size (mean 3.8 cm, 6% <1 cm), whereas duodenal gastrinomas are usually small (mean 0.93 cm, 77% <1 cm). While the pancreatic gastrinomas may occur in any portion of the pancreas, duodenal gastrinomas are predominantly found in the first part of the duodenum including the bulb [7]. At surgery 70–85% of gastrinomas are found in the right upper quadrant (duodenal and pancreatic head area), the so-called ‘gastrinoma triangle’ [4, 5, 13]. MEN1 is an autosomal-dominant syndrome that is present in 20–30% of patients with ZES [14]. In these patients duodenal tumors are usually (70–100%) responsible for the ZES. The duodenal tumors are almost always multiple [15,16,17] and originate from diffuse gastrin cell proliferations [18].Histologically, most gastrinomas are well-differentiated and show a trabecular and pseudoglandular pattern. Their proliferative activity (i.e. the Ki-67 index) varies between 2 and 10%, but is mostly close to 2%. Immunohistochemically, all gastrinomas stain for gastrin.Approximately one fourth of ZES patients have gastrinomas that pursue an aggressive course and aggressive growth occurs in 40% of patients with liver metastases. At diagnosis, 5–10% of duodenal gastrinomas and 20–25% of pancreatic gastrinomas are associated with liver metastases. Liver metastases are the most important prognostic factor, the 10-year survival being 90–100% without liver metastases and 10–20% with. Poor prognostic factors besides liver metastases include: inadequate control of gastric acid hypersecretion; presence of lymph node metastases (p = 0.03); female gender (p < 0.001); absence of MEN1 (p <0.001); short disease history from onset to diagnosis (p <0.001); markedly increased fasting gastrin levels (p < 0.001); presence of a large primary tumor (>3 cm) (p < 0.001); a pancreatic primary gastrinoma (p < 0.001); development of ectopic Cushing’s syndrome or bone metastases (p < 0.001); the presence of various flow cytometric features, molecular features (high HER2/neu gene expression (p = 0.03), high 1q LOH, increased EGF of IGF1 receptor expression), or histological features including angioinvasion, perineural invasion, >2 mitoses per 20 HPF, Ki-67 index >2 [5, 6,19,20,21,22,23,24].At the onset of symptoms, the mean age of patients with sporadic gastrinomas is 48–55 years; 54–56% are males, and the mean delay in diagnosis from the onset of symptoms is 5.2 years. All of the symptoms except those late in the disease course are due to gastric acid hypersecretion. The majority of ZES patients present with a single duodenal ulcer or GERD symptoms and ulcer complications. Multiple ulcers or ulcers in unusual locations are a less frequent presenting feature than in the past. Abdominal pain primarily due to PUD or GERD occurs in 75–98% of the cases, diarrhea in 30–73%, heartburn in 44–56%, bleeding in 44–75%, nausea/vomiting in 12–30% and weight loss in 7–53%. At presentation, >98% of patients have an elevated fasting serum gastrin level, 87–90% have marked gastric acid hypersecretion (basal acid output greater than 15 mEq/h) and 100% have a gastric acid pH ≤2. Patients with MEN1 with ZES (20–30%) present at an earlier age (mean 32–35 years) than patients without MEN1 (i.e. sporadic disease). In 45% of MEN1/ZES patients, the symptoms of ZES precede those of hyperparathyroidism, and they can be the initial symptoms these patients present with. However, almost all MEN1/ZES patients have hyperparathyroidism at the time the ZES is diagnosed, although in many patients it can be asymptomatic and mild and therefore can be easily missed if ionized calcium and serum parathormone levels are not performed. Twenty five percent of all MEN1/ZES patients lack a family history of MEN1, supporting the need to screen all ZES patients for MEN1.The diagnosis of ZES generally requires the demonstration of an inappropriate elevation of fasting serum gastrin by demonstrating hypergastrinemia in the presence of hyperchlorhydria or an acidic pH (preferably ≤2). In most cases the first study done nowadays is the fasting serum gastrin (FSG) determination. The FSG alone is not adequate to make the diagnosis of ZES because hypergastrinemia can be caused by hypochlorhydria/achlorhydria (chronic atrophic fundus gastritis, often associated with pernicious anemia) as well as other disorders causing hypergastrinemia with hyperchlorhydria besides ZES (Helicobacter pylori infection, gastric outlet obstruction, renal failure, antral G cell syndromes, short bowel syndrome, retained antrum). No level of FSG alone can distinguish ZES from that seen in achlorhydric states.Recent data show that the widespread use of proton pump inhibitors (PPIs) is making the diagnosis of ZES more difficult and is delaying the diagnosis. This is occurring with PPIs because they are potent inhibitors of acid secretion with a long duration of action (i.e. up to 1 week), which has two effects that can lead to misdiagnosis of ZES. First, this results in hypergastrinemia in patients without ZES frequently with peptic symptom history thus mimicking ZES. This means the PPI needs to be stopped to make the proper diagnosis; however, it can be difficult to stop the drug in some patients, especially those with severe GERD. Second, the potent inhibition of acid secretion results in control of symptoms in most ZES patients with conventional doses used in idiopathic peptic disease, in contrast to H2 blockers where conventional doses were frequently not adequate. The result is that PPIs mask the diagnosis of ZES by controlling the symptoms in most patients and that breakthrough symptoms, which may lead to a suspicion of ZES and are frequently seen with H2 blockers, are infrequent with PPIs.Patients with ZES with PUD have H. pylori infections in 24–48% in contrast to patients with idiopathic peptic disease who have H. pylori in >90%. Therefore, lack of H. pylori should lead to a suspicion of ZES in a patient with recurrent peptic ulcer disease [30].ZES should be suspected if: recurrent, severe or familial PUD is present; PUD without H. pylori is present; PUD resistant to treatment or associated with complications (perforation, penetration, bleeding) is present; PUD occurs with endocrinopathies or diarrhea; PUD occurs with prominent gastric folds on barium studies or at endoscopy (present –92% of ZES patients), or with hypercalcemia or hypergastrinemia [25].Initially to make the diagnosis, FSG and gastric pH should be determined (following interruption of PPI for at least 1 week with H2-blocker coverage, if possible). If FSG is <10-fold elevated and gastric pH ≤2, then a secretin test and basal acid output should be performed. Also, if repeated fasting serum gastrin are performed on different days <0.5% of ZES patients will have all normal values. If a BAO is performed, >85% of patients without previous gastric acid-reducing surgery will have a value >15 mEq/h [26].MEN1 should be suspected if there is a: family or personal history of endocrinopathies or recurrent peptic disease; history of renal colic or nephrolithiases; history of hypercalcemia or pancreatic endocrine tumor syndromes.All patients with ZES should have serum parathormone levels (preferably an intact molecule assay – IRMA), fasting calcium levels and prolactin levels. Recent studies show that an ionized calcium level is much more sensitive than a total calcium- or albumin corrected-calcium determination. If the family history is positive for MEN1, suspicious clinical or laboratory data for MEN1 are found or multiple tumors are present raising the possibility of MEN1, then MEN1 genetic testing should be done. If the genetic testing is positive for MEN1, genetic counseling should be performed.Ectopic Cushing’s syndrome develops in 5–15% of patients with advanced metastatic disease and has a very poor prognosis. It should be routinely assessed for in patients with advanced metastatic disease by careful clinical examination, history and routine 24-hour urinary cortisol determinations and serum cortisol assessment. A secondary hormonal syndrome develops in 1–10% of patients, especially those with metastatic disease or MEN1. These should be assessed for by a careful clinical history and routine hormonal assays are not recommended. Tumor localization studies are required in all patients with ZES. All aspects of management of ZES require knowledge of tumor extent. It is important to remember that 60–90% of gastrinomas are malignant and that the natural history of the gastrinoma is now the most important determinant of long-term survival in many studies.Tumor localization studies are necessary to determine whether surgical resection is indicated; to localize the primary tumor; to determine the extent of the disease and whether metastatic disease to the liver or distant sites is present, and to assess changes in tumor extent with treatments. Numerous localization studies have been recommended including conventional imaging studies (CT, MRI, ultrasound), selective angiography, functional localization methods (angiography with secretin stimulation for hepatic venous gastrin gradients, portal venous sampling for gastrin gradients), somatostatin receptor scintingraphy (SRS) and endoscopic ultrasound (EUS) as well as various intraoperative localization methods, including intraoperative ultrasound, intraoperative transillumination of the duodenum [35] and routine use of a duodenotomy [21, 33, 34,36,37,38,39]. Prospective studies show for primary gastrinomas that conventional imaging studies localize 10–40%, angiography 20–50% and SRS 60–70%.The use of SRS changes management in 15–45% of patients [33, 34, 40]. SRS’s sensitivity is equal to all conventional imaging studies combined [34]. For SRS, as well as all conventional studies, tumor size is an important variable and tumors <1 cm are missed in >50% of cases [41, 42]. Therefore, because most duodenal tumors are <1 cm they are frequently missed. EUS is particularly sensitive for pancreatic lesions; however, its ability to detect small duodenal tumors is controversial [21, 43, 44]. Functional localization studies are not limited by tumor size but are invasive studies [45, 46]. Prospective studies show for metastatic gastrinoma to the liver that CT and ultrasound detect their presence in 30–50% of patients with metastases, MRI and angiography in 60–75% and SRS in 92% [33, 34]. At surgical exploration duodenotomy is essential to detect up to one-half of duodenal tumors and its use increases the cure rate.Intraoperative transillumination of the duodenum is frequently used to help identify the site for the duodenotomy. Intraoperative ultrasound should be routinely used to assess and identify pancreatic lesions [35, 37, 38].Tumor localization studies are required in all patients with ZES biochemically established. Most recommend initially a UGI endoscopy with careful inspection of the duodenum followed by a helical CT and SRS. If these studies are negative and surgery is being considered, endoscopic ultrasound should be performed. If results are still negative, selective angiography with secretin stimulation and hepatic venous sampling should be considered. SRS is the best study to initially stage the disease and detect both liver and distant metastases. Intraoperative ultrasound and routine duodenotomy for duodenal lesions preferably preceded by transillumination of the duodenum should be done in all patients at surgery. Bone metastases occur in up to one-third of patients with liver metastases and should be sought in all patients by using SRS and an MRI of the spine [47, 48].The diagnosis of a gastrinoma requires the presence of a NET immunohistochemically expressing gastrin and associated with ZES. Gastrin-producing NETs without ZES are not considered gastrinomas. Gastrinomas do not show any histological features that distinguish them from other NETs. The histological features that are predictive of the biological behavior of a gastrinoma are discussed in the section on clinicopathological features and angioinvasion, activity and the proliferative index determined by Ki-67 of gastrinomas, other may hormonal other than but they may or may not be in to cause serum or a hormonal In MEN1/ZES patients with duodenal gastrinomas, multiple pancreatic endocrine tumors are present and often also In almost 100% of these patients the gastrinoma is in the and in the In these patients, studies with multiple should be done on all and metastases to help determine their on be by for gastrin and a index using a and a Ki-67 index are recommended. In MEN1 patients, all and metastases should also be for other to determine the of is generally not except in an intraoperative for tumor acid hypersecretion can be normal in ZES (mean mEq/h) and it is essential it be and long-term in all patients to peptic complications [2, and PPIs can control acid hypersecretion in all patients who can and are PPIs are the of because of their long duration of action or a to control symptoms in >98% of patients. H2 blockers, to be are usually required at doses than are those used in conventional peptic disease up to the and to is frequently Patients with disease of MEN1 with presence of severe GERD symptoms, presence of previous need doses of all and may need more frequent with PPIs Patients have been for up to 15 with PPIs with of and but not has been with long-term PPI use in ZES, but it is if it clinically important PPIs and of high doses of H2 blockers control acid secretion are of this PPIs are recommended In MEN1/ZES patients, of hyperparathyroidism can the fasting gastrin level and and the sensitivity to acid resection in up to the patients to show mild acid hypersecretion and require doses of cell can the BAO long-term and the of hypersecretion needs to be and long-term in all ZES patients to acid-related peptic complications. PPIs are the of because of their long duration of action or a to control symptoms in >98% of patients. The recommended is to in sporadic ZES and in Patients with disease of MEN1 with presence of severe GERD symptoms, and presence of previous need doses of PPIs and should be on PPI drug can be in most patients with sporadic ZES and a 30–50% of MEN1/ZES patients. Patients have been for up to 15 with PPIs with of long-term treatment serum levels should be per contrast to the there is now general that patients with sporadic ZES, with disease and without to surgery or with should routine surgical exploration for cure by a in these resection should be performed at and not The of type of and of surgery in patients with MEN1/ZES controversial [21, should be performed in patients who or will not cell at the time of surgery is generally not performed but it may have a in patients because it the acid and drug in patients who are not can result in patients with pancreatic gastrinomas in both sporadic and MEN1/ZES patients. However, its use is not generally recommended. It may have a in the patients with long with multiple or large gastrinomas in this that are not by resection it is essential to patients for cure by both fasting serum gastrin as well as secretin conventional imaging studies are not if the fasting gastrin and secretin test will detect recurrent tumors fasting gastrin or a of a positive secretin test is at present is the treatment that can cure gastrinomas. has been to the of development of liver metastases which is the most important prognostic for long-term survival [5, to survival resection without a occurs in of patients with sporadic ZES the surgery is performed by a in the treatment of this disease, but in of patients with MEN1/ZES in the pancreatic head should be pancreatic resection performed for tumors and duodenotomy performed routinely to detect small duodenal gastrinomas. A lymph node should be performed if primary tumor is found because lymph node primary tumors are although controversial [21, for is recommended in patients with sporadic ZES without liver metastases or surgical exploration is controversial in patients with MEN1/ZES these patients usually have multiple duodenal gastrinomas, frequently with lymph node metastases, are and have an if small tumors cm) or tumors are present on imaging is recommended if imaging studies identify tumors >2 cm in to the development of metastatic to the However, the of this contrast to resection of gastrinomas is not recommended because frequently the primary is not seen on imaging studies, the tumors are in the duodenum and they frequently have lymph node metastases are not generally recommended. It may have a in the patients with long who have multiple or large gastrinomas in this that are not by is important to treatment for advanced disease because it is the determinant of long-term survival in ZES patients now that acid hypersecretion can be [5, The presence of any liver metastases in ZES patients. survival with liver metastases is single or limited metastases in both is and with the presence of diffuse metastases it is The survival of a patient who develops liver metastases there were liver metastases at the initial is to [5, In 40% of patients with liver metastases the tumor aggressive growth and all of the due to disease in these patients fourth of ZES patients have tumors that aggressive growth and to cause in the the tumor growth is and from tumor is uncommon [6, hepatic or receptor and liver have all been recommended as in ZES patients with advanced disease surgery should be considered for the 5–15% of patients with liver metastases to one or who have liver metastases that be or at surgery At the time of surgery can be used for metastases. can also be used alone if there are lesions seen in the treatment should be considered in a patient with liver metastases if they are or the hepatic are in the portal is and distant disease is not of is usually are studies that show this in these and with or without should be considered for patients with diffuse liver metastases that or or have distant metastases the The varies from to in various survival is controversial at and somatostatin have been used for their effects in patients with metastatic gastrinomas. effects are in 30–50% of patients with almost all cases by of tumors that been to and somatostatin are to be more in tumors with proliferative than of gastrinomas a in tumor size with treatment with somatostatin or At present, the use of these for effects is controversial and their routine is not recommended their patients with tumors that are positive with SRS, of which most gastrinomas there may be a for this is more with larger of patients, its at present is In patients with disease to the liver who are and generally liver may be considered. Patients with a resection or aggressive gastrinoma should be with advanced metastatic disease, with and with acid-related peptic disease frequently require a different than the ZES patient with but limited Patients with metastatic disease require a short initially to determine whether disease is present and treatment is Patients treatment need at to to assess the of treatment and to Patients with MEN1/ZES initial treatment of the MEN1 should be seen in to Patients with resection can be symptoms of patients with advanced metastatic disease should be at to with tumor imaging (CT, fasting serum gastrin and acid control At least for ectopic Cushing’s with a urinary cortisol and serum cortisol should be considered. For patients with advanced metastatic disease or who are or other may need to be to assess for specific For patients with should be with an of tumor extent with imaging and for MEN1 serum fasting serum acid UGI endoscopy to for gastric carcinoid For patients with with fasting gastrin secretin test and acid control should be done if the patient is still should be performed at ZES patients without any of the should be seen with tumor (CT, fasting gastrin and acid management of gastrinomas has many to that of the management of other pancreatic endocrine tumor however, it also has some important specific that need First, the gastric acid hypersecretion is to ZES and requires management initially and at of PPIs have as the need for patients with MEN1, severe GERD or a previous resection require The long-term effects of PPI as the development of or increased development of gastric are also Second, gastrinomas have the of any of patients with MEN1 and management initially and are because both from that of the important are genetic for and gastric multiple hormonal syndromes, management of the hyperparathyroidism, and for other tumors these patients are and tumors, tumors as ZES is the most common malignant functional and in contrast to the other less common the patients often present with tumor and the primary tumors can be difficult to Therefore, careful imaging and an of the of the disease with different tumor are essential in the treatment at a in contrast to the other the of surgery in patients with MEN1/ZES is in contrast to other functional with advanced disease the symptoms of the can be in almost patient with the for treatment of the advanced disease is the symptoms due to the tumor per or tumor not hormonal of of of of and – of of of of of of and Liver of of of and of of of of of of of of and of of of of of of of of of of of of and of of of of of of of of of of and of of and of of of of of of of of of and of of of of