Introduction Pancreatic endocrine tumors (p-NETs) include both pancreatic neuroendocrine tumors (p-NETs) associated with a functional syndrome (functional p-NETs) or those associated with no distinct clinical syndrome (non-functional p-NETs) [1,2,3,4]. Non-functional p-NETs frequently secrete pancreatic polypeptide, chromogranin A, neuron-specific enolase, human chorionic gonadotrophin subunits, calcitonin, neurotensin or other peptides, but they do not usually produce specific symptoms and thus are considered clinically to be non-functional tumors [2,3,5,6,7]. Only the functional p-NETs will be considered in this section. The two most common functional p-NETs (gastrinomas, insulinomas) are considered separately, whereas the other well-described and possible rare functional p-NETs are considered together as a group called rare functional p-NETs (RFTs) (table 1) [1,2,3,4]. Gastrinomas are neuroendocrine neoplasms, 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 peptic disease (peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD)) [8,9,10]. In this section, ZES due to both duodenal and pancreatic gastrinomas will be covered together because clinically they are similar [8,10]. Specific points related to gastrinomas associated with the genetic syndrome of Multiple Endocrine Neoplasia type 1 (MEN1) (25% of cases) will also be mentioned [11,12]. Insulinomas are neuroendocrine neoplasms located in the pancreas that secrete insulin, which causes a distinct syndrome characterized by symptoms due to hypoglycemia [2,13,14,15]. The symptoms are typically associated with fasting and the majority of patients have symptoms secondary to hypoglycemic central nervous system (CNS) effects (headaches, confusion, visual disturbances, etc.) or due to catecholamine excess secondary to hypoglycemia (sweating, tremor, palpitations, etc.) [2,3,13,14,15]. RFTs can occur in the pancreas or in other locations (VIPomas, somatostatinomas, GRHomas, ACTHomas, p-NETs causing carcinoid syndrome or hypercalcemia (PTHrp-omas)) (table 1) [1,2,3,4,5,7]. Each of the established RFT syndromes is associated with a distinct clinical syndrome reflecting the actions of the ectopically secreted hormone. Other RFTs are listed as causing a possible specific syndrome either because there are too few cases or there is disagreement about whether the described features are actually a distinct syndrome (table 1) [1,2,3,4,5,7]. Epidemiology and Clinicopathological Features of Functional p-NETs Gastrinomas: Minimal Consensus Statement on Epidemiology and Clinicopathological Features Gastrinomas - Epidemiology and Site of Origin - Specific (table 1) [1,2,3,8,9,16,17] The incidence of gastrinomas is 0.5-2/million population/year. They are the most common functional, malignant p-NET syndrome and comprise up to 30% of these [1,2,8,9]. Duodenal tumors, which were originally thought to be uncommon (i.e. 1 cm, showing local invasion and/or proximal lymph node metastases [8,16,17,20,31]. Liver metastases (LM) occur much more frequently with pancreatic gastrinomas (22-35%) than duodenal gastrinomas (0-10%) [8,17,18,31]. Pancreatic gastrinomas are generally large in size (mean 3.8 cm, 6% 2 mitoses per 20 HPF, Ki67 index >2, poor differentiation [8,9,18,25,31,41,42,45,46,47,48]. Insulinomas: Minimal Consensus Statement on Prognosis and Survival - Specific Greater than 90-95% of insulinomas are benign at presentation, and 95-100% of these can be surgically cured [1,2,13,14,15,26,49]. The 2% and various molecular features (chromosomal instability; chromosomal loss of 3p or 6q; chromosomal gain on 7q, 12q or 14q) all are predictors of metastatic disease, which is associated with decreased survival [51]. RFTs: Minimal Consensus Statement on Prognosis and Survival - Specific Most RFTs present with metastatic disease and their 5-year survival is increasingly determined by the growth of the tumor, rather than the hormone excess state. Five-year survival for the group with advanced disease is 29-45% [1,2,4,5]. All of the survival/prognostic data on the individual RFTs comes from retrospective studies and in recent studies their results are often included in non-insulinoma/non-gastrinoma series that include non-functional p-NETs. These studies demonstrate tumor Ki67 ≥2%, presence of LM, presence of cytokeratin-19 staining and various molecular features (chromosome 7p gain), chromosomal instability) were associated with a poor prognosis [2,42,51]. MEN1: Minimal Consensus Statement on Prognosis and Survival - Specific The prognostic significance of MEN1 in patients with p-NETs is not entirely clear. Some studies in patients with gastrinomas suggest these patients have a better prognosis, even though the gastrinomas are almost always multiple [8,31,41,43]. However, because the patients present at an earlier age, this could affect the survival results [31,41]. Patients with MEN1 frequently have multiple insulinomas, however, these are usually cured surgically [11,52]. There are no comparative studies on survival in MEN1 patients with insulinomas compared to sporadic cases. In older studies, survival was primarily determined by the development and adequacy of treatment of ZES, development of renal failure from inadequately treated hyperparathyroidism and the malignant nature of the p-NETs [11,53]. With the ability to treat both the ZES and the hyperparathyroidism, recent studies show in patients with MEN1, the natural history of the p-NET increasingly becoming a determinant of survival [11]. In the French registry that included 758 patients with MEN1, thymic tumors and duodenopancreatic tumors, including non-secreting pancreatic tumors but not insulinomas, increased the risk of death [53,54]. Thymic carcinoid occur primarily in males (>90%) and are a particularly aggressive tumor causing not only local encasement of vital structures in the mediastinum, but also the early development of distal metastases to liver and bone [11,53,55]. Clinical Presentation of Functional p-NETs Minimal Consensus Statement on Clinical Presentation of Functional p-NETs Gastrinomas: Minimal Consensus Statement on Clinical Presentation - Specific (table 1) [3,8,9,10,12,32,56,57,58,59] 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, peptic symptoms, GERD symptoms or ulcer complications and diarrhea. Multiple ulcers or ulcers in unusual locations are a less frequent presenting feature than in the past [3,8,9,10,12,32,56,57,58,59]. With the widespread use of gastric antisecretory drugs, particularly proton pump inhibitors (PPIs), symptoms may be masked and the diagnosis most often suggested by the long history of PUD/GERD symptoms or their recurrence after treatment [3,32,57,59,60]. 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% [8,10,57]. At presentation, >97% of patients have an elevated fasting serum gastrin (FSG) level, 87-90% have marked gastric acid hypersecretion (basal acid output >15 mEq/h) and 100% have a gastric acid pH 90%. Therefore, lack of H. pylori should lead to a suspicion of ZES in a patient with recurrent PUD not taking gastrotoxic drugs [8,57,69]. Minimal Consensus Statement on Diagnosis with or without MEN1 - Specific ZES Suspect ZES Diagnosis [3,8,10,57,60,66,67] ZES should be suspected if: recurrent, severe or familial PUD is present; PUD without H. pylori or other risk factors (NSAIDs, aspirin) is present; PUD associated with severe GERD is present; PUD resistant to treatment or associated with complications (perforation, penetration, bleeding) is present; PUD occurs with endocrinopathies or diarrhea; PUD occurring with prominent gastric folds at endoscopy (present −92% of ZES patients), or with hypercalcemia or hypergastrinemia [3,8,10,57,60,66]. It should be sought for in all patients with MEN1 [8,11]. ZES should also be suspected in PUD patients in whom diarrhea promptly resolved with treatment with PPIs. ZES Diagnosis: Biochemistry/Laboratory Studies Whereas the initial study usually performed to support the clinical suspicion of ZES is a FSG level, which is an excellent screening test because it is elevated in >98% of all ZES patients, it alone does not establish the diagnosis because of the many other causes of hypergastrinemia [2,32,58,60,66,67,70]. The fasting gastrin assay should be performed by a known, reliable laboratory [68]. To establish the diagnosis of ZES, FSG and gastric pH should be determined (following interruption of PPI for at least 1 week with H2 blocker coverage, if possible). If FSG levels are >10-fold elevated and gastric pH 85% of patients without previous gastric acid-reducing surgery will have a value >15 mEq/h [61]. The criterion for a positive secretin test (2 U/kg rapid infusion) is a >120 pg/ml increase over the basal FSG, which has a sensitivity of 94% and a specificity of 100% [72]. A second way to perform the secretin test has been described using a 1-hour infusion of 3 U/kg secretin with assessment of acid output and serum gastrin levels [73]. This method has been shown to be very effective with thresholds of 99% specificity for gastrin levels and acid outputs, but it necessitates the measurement of gastric acid outputs for at least 2 h and therefore is now less frequently used. Calcium stimulation of gastrin release can also be used to diagnose ZES, but because of its lower sensitivity, specificity and higher side-effect profile, it is now rarely used, except in situations where secretin is not available or the diagnosis of ZES is strongly suspected, but the secretin test is negative [57,72,74,75]. PPIs can complicate the diagnosis of ZES because they can cause elevations of FSG in patients without ZES, can lead to false positive secretin tests [76] and can also mask the symptoms of a patient with ZES [3,32,57,59,60,77]. PPIs presence can delay the diagnosis of ZES as discussed above. Because of this it is generally not possible to diagnose ZES while a patient is taking PPIs. Therefore to make the diagnosis of ZES, patients are usually switched to H2 receptor antagonists to replace the PPI for at least 1 week. This needs to be performed with caution because some patients will require high, frequent doses, and because stopping PPI can cause complications due to acid hypersecretion in ZES patients (ulcer bleeding, diarrhea with dehydration or hypokalemia) [222]. Therefore, it is best performed by a specialty unit experienced in diagnosing ZES. The diagnosis of ZES in patients with MEN1 has a number of unusual features and is discussed below in the MEN1 section. Minimal Consensus Statement on Diagnosis in a Patient with ZES, Insulinomas or RFTs - Specific MEN1 ZES: Suspect MEN1 [11,12] The presence of MEN1 should be particularly sought in patients with ZES because 20-25% have MEN1 and the patient may present with symptomatic ZES only [11,12,62]. In a patient with ZES, MEN1 should be suspected if there is a family or personal history of endocrinopathies or familial history of recurrent peptic disease; other endocrinopathies are found during the evaluation; there is a history of renal colic or nephrolithiases; history of hypercalcemia or p-NET syndromes, or if multiple p-NETs/duodenal NETs are present. Furthermore, if carcinoid tumors of the thymus, lung or stomach (type 2) are found, MEN1 should be suspected because these are rarely present in sporadic ZES, but are much more frequent with MEN1 [12,53,55,78,79]. Insulinomas, RFTs: Suspect MEN1 [11] MEN1 should be suspected in a patient with insulinomas with a personal or family history of any endocrinopathy, especially hyperparathyroidism; a concomitant gastrinoma or other RFT is present or develops with time; a non-functional p-NET is present; or if there are multiple insulinomas or recurrent disease occurs after resection. Biochemistry/Laboratory Studies to Diagnose MEN1 in a Patient with a p-NET Because of the frequency of MEN1 in ZES (20-25%) and because up to 40% of MEN1/ZES patients have no family history [10,11,12], all patients with ZES should have biochemical studies for MEN1. Serum parathormone levels (preferably an intact molecule assay - IRMA), ionized calcium levels and prolactin levels should be performed when initially seen and during yearly follow-up. Ionized calcium levels are much more sensitive than a total calcium- or albumin-corrected calcium determination [11,12,63]. In some cases, an oral tolerance calcium test might be performed [63]. ZES can be difficult to diagnose in MEN1 patients after a parathyroidectomy, because if successful, the serum calcium can return to the normal range as well as the serum gastrin, and the secretin test can become negative, masking the presence of the gastrinoma [11,12,80,81,82,83]. Furthermore, an effective parathyroidectomy can result in a marked decrease in acid secretory rates [80], further masking the presence of ZES and making the diagnosis more difficult. Genetic Study for MEN1 and Other Inherited Syndromes Associated with p-NETs 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 considered. Genetic testing for MEN1 should include sequencing of the entire gene and its splice variants. If genetic testing is considered, genetic counseling should be performed, prior to testing [11,84,85]. If clinical features suggest von Hippel-Lindau disease (VHL), tuberous sclerosis or NF-1, appropriate gene testing should be considered after genetic counseling [11]. Diagnosis of Insulinomas - General Suspect Insulinoma Diagnosis Hypoglycemic symptoms can be grouped into those resulting from neuroglycopenia (commonly including headache, diplopia, blurred vision, confusion, dizziness, abnormal behavior, lethargy, amnesia, whereas, rarely, hypoglycemia may result in seizures and coma) and those resulting from the autonomic nervous system (including sweating, weakness, hunger, tremor, nausea, feelings of warmth, anxiety, and palpitations) [13,14,15,50]. Because occasionally symptoms are not specific and insulinoma can mimic several pathological conditions, a broad differential diagnosis should be considered. A major distinction should be made between patients with insulinoma and non-insulinoma pancreatogenous hypoglycemia [86] and from hypoglycemia occurring after various gastric bypass surgeries for obesity. The latter is usually not fasting in nature, but is postprandial, and in some cases is caused by nesidioblastosis [2,87,88]. However, the original description of Whipple's triad to suspect insulinoma remains fundamentally sound [15]. This triad consists of: (1) symptoms of hypoglycemia, (2) plasma glucose level ≤2.2 mmol/l (≤40 mg/dl), and (3) relief of symptoms with administration of glucose. Minimal Consensus Statements for Diagnosis of Insulinomas - Specific [1,2,3,13,14,15,50,66,67,89,90] Classically, clinical symptoms are required for the diagnosis of insulinoma and the diagnosis of insulinoma is absolutely established using the following six criteria: (1) documented blood glucose levels ≤2.2 mmol/l (≤40 mg/dl); (2) concomitant insulin levels ≥6 μU/ml (≥36 pmol/l; ≥3 U/l by ICMA); (3) C-peptide levels ≥200 pmol/l; (4) proinsulin levels ≥5 pmol/l; (5) β-hydroxybutyrate levels ≤2.7 mmol/l, and (6) absence of sulfonylurea (metabolites) in the plasma and/or urine. Further controlled testing includes the 72-hour fast, which is the classical gold standard for establishing the diagnosis of insulinoma, although some studies, but not others, report a 48-hour fast may be adequate [1,2,3,13,14,15,50,66,67,89,90]. When the patient develops symptoms and the blood glucose levels are ≤2.2 mmol/l (≤40 mg/dl), blood is also drawn for C-peptide, proinsulin and insulin. Failure of appropriate insulin suppression in the presence of hypoglycemia substantiates an autonomously secreting insulinoma [1,2,3,13,14,15,50,66,67,89,90]. Recently, increasingly, instead of using the standard insulin radioimmunoassay, which can cross-react in many cases with proinsulin, insulin-specific assays (immunoradiometiric, immunochemiluminescent assays) are being used which have no cross-reactivity with proinsulin and give lower insulin values (up to 60% of patients with insulinomas has insulin levels ≤6 μU/ml with these assays). In one recent comparative study the most sensitive criterion for diagnosing insulinomas using these assays was the combination of an elevated proinsulin level with a fasting glucose value 50% of cases [8,103]. Therefore, because most duodenal gastrinomas are 90% of recurrence [8,11,47,52,147,149,157]. Therefore, routine surgical exploration is controversial in patients with MEN1/ZES [8,11,47,52,146,147,148,157]. Indeed, these patients usually have multiple duodenal gastrinomas, frequently with lymph node metastases, with other p-NETs (non-functional primarily), are rarely cured and have an excellent life expectancy if only small tumors ( 2 cm [8,11,47,52,125]. Even if some limited series reported potential long-term biochemical remission after pancreaticoduodenotomy in MEN1-ZES patients, the real impact on the long-term survival remains controversial and the long-term side effects of pancreaticoduodenotomy remain largely undefined [8,9,96,142,146,148,157]. In contrast to the case for insulinomas, laparoscopic resection of gastrinomas is controversial and not generally recommended, because frequently the primary is not seen on preoperative imaging studies, the tumors are submucosal in the duodenum and they frequently have lymph node metastases [8,47,96,158]. Surgical Treatment of Insulinomas - General [2,13,14,15,26,50,159] In contrast to gastrinomas and some RFTs (somatostatinomas, GRHomas) (table 1), insulinomas are often unique in that they are in benign in 90% and located, similar to a few other RFTs (table 1) (i.e. glucagonomas, >90% VIPomas) entirely within the pancreas [2,13,14,15]. This intrapancreatic location facilitates the localization with EUS, which has a greater sensitivity/specificity for intrapancreatic than extrapancreatic localization of p-NETs. However, when insulinomas are small ( 50%) missed during SRS studies preoperatively [2,13,14,15,26,47,50]. Insulinomas also differ from the other PETs in that they are malignant in 90%) [2,13,14,15,26,50,159]. In contrast to the other PETs, laparoscopic resection is increasingly used in patients with insulinomas in whom the tumor can be localized preoperatively [26,158,159,160,161]. Minimal Consensus Statement on Surgical Treatment of Insulinoma - Specific [3,8,9,11,47,96,111,142,145,146,148,150] For sporadic insulinoma, the standard surgical treatment should include pancreas exploration by both palpation and IOUS. When the tumor is located further than 2-3 mm from the pancreatic duct, an enucleation is preferred to pancreatic resection. Otherwise, a partial pancreatic resection (central or distal or pancreatic head resection) is needed. In all settings, no lymphadenectomy is needed [3,8,9,11,47,96,111,142,145,146,148,150]. If the insulinoma is localized preoperatively, enucleation from the pancreatic body/tail and distal pancreatectomy can be performed safely by laparoscopy [8,26,158,159,161,162]. When a sporadic insulinoma is not localized preoperatively, surgical exploration is indicated [3,8,9,11,47,96,111,142,145,146,148,150]. Intraoperative tumor location can require, additionally to IOUS, intraoperative insulin sampling and frozen section [163]. In rare patients with suspicion of malignant insulinoma or recurrence, a radical surgery aiming to treat either locoregional recurrence and/or LM is indicated. When insulinoma is not located either preoperatively or intraoperatively including samplings, blind distal resection is not recommended [3,8,9,11,47,96,111,142,145,146,148,150]. In the presence of MEN1, in which multiple tumors are frequently present, the aim of surgery is to control inappropriate insulin secretion by excising all insulinomas. Preoperative localization of which pancreatic tumors are the insulinomas is mandatory, because these patients frequently have other pancreatic NETs (which are usually non-functional) [2,11,52,142]. In these patients, preoperative intra-arterial calcium injections with hepatic venous insulin sampling as well as intraoperative insulin sampling may be required [8,11,50,107,163]. Surgical Treatment of RFTs - General [2,5,111,142,144] Indications for surgery depend on clinical symptom control, tumor size/location/extent, malignancy and metastatic spread [1,2,5,111,142,144]. Curative surgery should be sought whenever possible, even in the presence of metastatic disease, including ‘localized’ metastatic disease to the liver, if thought potentially resectable and the patient can tolerate the surgery [1,2,5,111,142,144]. The type of surgery depends on the location of the primary tumor - pancreaticoduodenal resection (Whipple's operation), distal pancreatic resection, tumor enucleation or enucleation in combination with resection. Since malignancy is frequent in RFTs, adequate lymph node clearance is mandatory [1,2,5,111,142,144]. In the case of localized LM or more extensive disease spread, surgery should also be considered if at least 90% of gross tumor is thought resectable [8,98,142,152,164,165,166,167,168,169], as discussed in a latter section. Minimal Consensus Statement on Surgical Treatment of RFTs - Specific [2,5,98,111,142,144,167] Curative surgery is always recommended whenever feasible after optimal symptomatic control of the clinical syndrome by medical treatment. Due to the usually large size of the tumor and the high prevalence of LM in RFT, curative surgery should include pancreatic resection with lymphadenectomy through laparotomy. Laparoscopic resection is not recommended because of the need for lymphadenectomy and careful inspection for invasion/metastases [5]. Bilateral adrenalectomy can be indicated in some selected patients with Cushing syndrome [2,5,111]. Surgery of LM may be performed during treatment of the primary tumor. Cytoreductive surgery should be considered when the metastatic disease is localized or if >90% of tumor load is thought resectable which may help to improve hormonal control and perhaps extend survival, although this is not proven [8,142,152,164,165,166,167,168,169]. This will be discussed in the next section. Minimal Consensus Statement on Surgical Treatment of Advanced Symptomatic p-NETs - Specific [2,5,8,15,98,111,142,144,164,165,167,168,169] Symptomatic control of the hormone excess state of all functional p-NETs may be facilitated by therapy directed against the tumor per se in the form of cytoreductive surgery either alone or combined with RFA. Cytoreductive surgery should be considered when the metastatic disease is localized or if >90% of tumor load is thought resectable [8,98,142,152,164,165,166,167,168,169]. RFA can also be used with resection or alone through laparoscopic approach if there are 90% of patients with malignant p-NETs [170]. Medical Treatment of Functional p-NETs [1,2,5,8,13,14,15,57,168,169,171] Medical Treatment of ZES: Treatment of the Gastric Acid Hypersecretion - General [2,3,8,32,57,172,173] It is essential to control the gastric acid hypersecretion in all patients to prevent peptic complications which can rapidly develop in these patients, because the basal gastric acid output can be >5 normal in many patients with ZES (mean 45 mEq/h) [8,61]. Both H2 blockers and PPIs can control acid hypersecretion in all patients who can take oral medications and are cooperative [2,8,32,57,172,173]. The preferred drugs are now PPIs, because of their long duration of action [8,32,57,172,174,175,176,177,178]. H2 blockers to be effective are usually required at higher doses than used in conventional peptic disease (frequently up to 10 times the usual dose) and 4-6 h dosing is frequent [2,3,57,75]. Patients have been treated for up to 15 years with PPIs with no evidence of tachyphylaxis and no dose-related side effects. Vitamin B12 deficiency but not iron deficiency has been reported with long-term PPI use in ZES, but it is unclear if it causes clinically significant vitamin B12 deficiency [8,179,180,181]. Although either intravenous PPIs (intermittent use) or continuous infusion of high doses of H2 blockers can satisfactorily control acid secretion when parenteral drug is needed [2,3,8,32,57,75], because of the intermittent use parenteral PPIs are recommended. In patients with MEN1/ZES the correction of the hyperparathyroidism can reduce the fasting gastrin level, BAO, and increase the sensitivity to acid antisecretory drugs [82,83]. Gastric acid hypersecretion can continue even after a curative resection in up to 40% of the patients and require low doses of antisecretory drugs [182,183]. Although rarely used at present, a parietal cell vagotomy can reduce the BAO long term and decrease the dosage of antisecretory drug needed [8]. Minimal Consensus Statement on Medical Treatment of the Gastric Acid Hypersecretion in ZES Patients - Specific Acid hypersecretion needs to be controlled acutely and long-term in all ZES patients to prevent acid-related peptic complications [8,57,75,172,173,175,176]. PPIs are the drugs of choice because of their long duration of action allowing once or twice a day dosing in most patients. Studies show all available PPIs (omeprazole, lansoprazole, pantoprazole, rabeprezole, esomeprazole) are effective [8,32,57,172,174,175,176,177,178]. The recommended starting dose is equivalent to omeprazole 60 mg once per day in sporadic ZES and 40-60 mg b.i.d. in MEN1/ZES [8,57,75,172,173,175,176]. To control acid hypersecretion in ZES patients with complicated disease (presence of MEN1 with hypercalcemia, presence of severe GERD symptoms, presence of previous Billroth II resection), higher doses of all antisecretory drugs are required and more frequent dosing may be needed, even with PPIs [8,75,82,83,184]. In these patients, PPIs should be started at equivalent to 40-60 mg b.i.d of omeprazole. On follow-up visits, PPI drug dosage can be reduced in most patients with sporadic ZES and in 30-50% of MEN1/ZES patients. With long-term treatment, serum vitamin B12 levels should be monitored once per year [8,179,180,181]. Recent studies suggest an increased incidence of bone fractures, particularly of the hip in patients on continuous long-term PPIs, although no studies have been performed specifically on ZES patients [179,180]. The exact mechanism that PPIs may be producing bone fractures is unclear and no specific recommendations have been generally accepted for the follow up of patients maintained long term on PPIs. Oral doses of histamine H2 receptor antagonists can also be effective, but high, frequent dosing is required [8,57,75]. During periods when oral drugs cannot be taken such as during surgery, parenteral PPIs are the drugs of choice, although a continuous infusion of histamine H2 receptor antagonist can also be effective but high doses are required [8,57,75]. Long-acting somatostatin analogues also control acid secretion, but they are not recommended for this purpose in ZES, because of the ease and effectiveness of PPIs, which can be given orally. Medical Treatment of Insulinoma: General [13,14,15,185] Appropriate dietary management can help prevent prolonged periods of fasting. Because the vast majority of patients with insulinomas can be cured surgically, medical management is reserved only for preoperative control of blood glucose levels, for patients with unresectable metastatic disease, or for patients who are unable or unwilling to undergo surgical treatment [13,14,15,26,50]. Minimal Consensus Statement on Medical Treatment of Insulinoma - Specific Prior to surgery or in patients with metastatic insulinomas, in addition to frequent small feedings and intravenous glucose administration, the hypoglycemia frequently needs to be controlled by drug therapy. Diazoxide (50-300 mg/day, can be increased up to 600 mg/day) inhibits insulin release by direct action on the β cells [2,13,14,15]. Diazoxide is the most effective drug for controlling hypoglycemia [2,13,14,15]. However, side effects are: edema, weight gain, renal impairment, and hirsutism. Verapamil and diphenylhydantoin have also been reported to be successful in the control of hypoglycemia. In refractory cases, glucocorticoids such as prednisolone can be effective as well. Somatostatin analogues like octreotide and lanreotide can be useful in preventing hypoglycemia in those patients with somatostatin receptor subtype 2-positive tumors, but can worsen hypoglycemia in some patients [185]. Interferon-α has been shown to be beneficial in selected cases. Recently, in a small number of cases with malignant insulinomas, mTOR inhibitors (everolimus, rapamycin) have controlled the insulin secretion and hypoglycemia [2,3,186,187,188]. Medical Treatment of RFT Functional Syndrome - General [2,3,5,171] In the past, patients frequently died from the untreated effects of the hormone excess state, therefore it is important it be controlled [2,5,42]. This can be accomplished in most cases at present by using a combination of medical, surgical, radiological approaches. Only the medical aspects are dealt with in detail here because treatment directed at the tumor per se which can also help control the functional aspects of the p-NET in patients with advanced disease is dealt with in a separate chapter. Both somatostatin analogues and interferon have been shown to be effective in the control of symptoms in functioning p-NETs and this also includes RFTs [1,2,3,5,171]. Approximately 80-90% of patients with VIPomas and glucagonoma improve very promptly, overcoming diarrhea and skin rash, and 60-80% have a reduction in VIP and glucagon levels [1,2,3,5,171]. Symptomatic relief is not always related to reduction in circulating hormone levels, indicating that somatostatin analogues have direct effects on the peripheral target organ. Escape from symptomatic control can be seen quite frequently but an increase in the dose of somatostatin analogues can help temporarily [1,2,3,5,171]. Somatostatin analogues can also have anti-growth effects on p-NETs, and that is covered in the chapter on the treatment of advanced disease. For the control of symptoms, somatostatin analogue therapy should be initiated with short-acting substance (octreotide 100 μg s.c. × 2-3) for 1-2 days with titration according to clinical response. Then the patient can be transferred to slow-release Lanreotide-SR® i.m. Lanreotide autogel® s.c. or Sandostatin-LAR® i.m. (every 4 weeks) [5,189]. Likewise, interferon-α treatment may help control symptoms of the hormone excess state in functional low proliferating tumors although it has been less well studied than the use of somatostatin analogues. It is reported to be effective in VIPomas not responding to somatostatin analogues and also in isolated cases when combined with somatostatin to control the symptoms of a functional p-NET, which with somatostatin treatment alone there was inadequate symptom control, however, this requires confirmation in a controlled manner [1,5,190]. Minimal Consensus Statements on Medical Treatment of RFT Functional Syndrome - Specific [2,3,5,171] Somatostatin analogues are an effective treatment in the control of symptoms in RFTs, especially in patients with VIPomas, GRHomas and glucagonomas [2,3,5,50,171]. Long-acting somatostatin analogues are also reported to be effective in controlling the ectopic hormone secretion in some cases of somatostatinomas. In patients with Cushing's syndrome, the majority of which have metastatic disease at presentation, primarily adrenal-blocking agents (ketoconazole [,]metyrapone) are used prior to adrenectomy. In some cases long-acting somatostatin analogues may be effective and there is increased interest in the use of glucocorticoid receptor antagonists, like mifepristone, which are investigational at present [191,192]. If somatostatin analogues are ineffective or lose efficacy in controlling the hormone excess state, treatment with interferon-α may be effective at controlling the symptoms either alone or in combination with somatostatin analogues. Promising results with the multiligand somatostatin receptor congener pasireotide have recently been presented. Also, the dopamine agonist cabergoline might have a role in controlling ectopic ACTH secretion [191,193,194]. Medical Treatment of Functional p-NET Syndromes in Patients with Advanced, Metastatic Disease - General Treatment of advanced disease is updated in a separate and comprehensive chapter [195]. Here, is a brief summary. Somatostatin analogues may be of value also in subgroups of patients with slowly progressive low proliferative NET (G1) of pancreatic and gastroduodenal origin and its use is supported by literature data on retrospective and non-randomized prospective trials in more than 500 patients [171,196,197,198]. In patients with gastric carcinoids, somatostatin analogues have been shown to exert anti-proliferative effects in animals and in man, however, data is not available in cases of LM [199]. Two prospective randomized trials in metastatic gastroenteropancreatic NET have shown that somatostatin analogues, IFN or the combination of both have comparable anti-proliferative effects when used after prior disease progression [196,197]. Chemotherapy is recommended in pancreatic NET, G2 foregut NET of extrapancreatic site, and in neuroendocrine carcinoma (G3) of any site. Systemic cytotoxics are indicated in patients with inoperable progressive LM from well-differentiated NET of pancreatic tumor origin using combinations of streptozotocin and 5-FU and/or doxorubicin with objective response rates in the order of 35-40% [199,200,201]. These response rates are considerably lower than the 69% reported by Moertel et al. [202] in 1992. There is long-standing experience with streptozotocin-based chemotherapy since the 1980s. Other newer chemotherapy regimens report higher response rates with various regimens and thus show promise, but larger confirmatory studies are needed (5-fluorouracil, dacarbazine, epirubicin [203] or capecitabine and temozolomide) [204]. Also transarterial embolization and/or chemoembolization as well as liver-directed therapy with radiolabeled particles, each of which have been shown to have tumor response rates of ≥50%, should be considered in patients with liver predominate metastases, especially with functional pNETs difficult to control [205,206,207]. PRRT is considered in both functioning and non-functioning NET and irrespective of the primary tumor site. Based upon small phase II trials and retrospective data, partial remission rates range between 0 and 33% [208,209] and are higher in pancreatic compared to midgut NET. In a prospective multicenter phase II trial with 90Y-edotreotide in patients with refractory carcinoid syndrome, partial remission rate was 4% and disease stabilization rate 70%. PFS was favorable with 16.3 months [210]. Regarding new molecular targeted therapies, both drugs, everolimus and sunitinib, are novel treatment options in advanced p-NET. Everolimus is thus a treatment option after failure of chemotherapy in p-NET, but can be considered as first-line therapy in selected cases as an alternative treatment to locoregional therapies or chemotherapy. The RADIANT-3 study (everolimus) included 40% therapy-naive patients, and efficacy was equally good in therapy-naive patients as in patients with previous therapies [211]. An early unselected use of the drug cannot be recommended, because long-term toxicity data are lacking, however, it is licensed in many countries for use in progessive p-NETs. Results from a phase III placebo-controlled trial support the efficacy of sunitinib, a multiple tyrosine kinase inhibitor that targets PDGF-R, VEGF-R, c-kit, RET and FLT-3, in progressive p-NET [223,224]. The majority of the patients had undergone prior systemic therapy, especially systemic chemotherapy. The main indication of sunitinib is its use as a second- or third-line therapy. Sunitinib should be considered as first-line therapy only in selected cases as an alternative treatment option if somatostatin analogues, chemotherapy and/or locoregional therapies are not feasible or promising. The role of everolimus and sunitinib in advanced disease is discussed in detail in the chapter on treatment of advanced progressive p-NETs. Minimal Consensus Statements on Medical Treatment of Functional p-NET Syndromes in Patients with Advanced, Metastatic Disease - Specific [5,8,15,212,213] The control of the hormone excess state in patients with advanced disease is similar to that outlined above for the typical patient with a p-NET, except that some added features need to be considered. Not infrequently a patient with advanced disease (non-gastrinoma) becomes refractory to the effect of medical therapy (somatostatin analogues and/or interferon, etc.) and the hormone excess state cannot be satisfactorily controlled. This does not occur with gastrinomas because PPIs are effective even with extensive disease. If symptomatic refractory disease develops this can be an indication to consider various anti-tumor therapies including liver directed therapies (embolization, chemoembolization, RFA, radiolabeled microspheres), PRRT or cytoreductive surgery, all of which are reported to improve symptomatic control in many patients [8,15,111,142,152,164,166,167,168,169,212,213,214,215,216,217,218]. With these different modalities, symptoms improve in 40-80% of patients [167,168,169,208,218,219]. The early combination use of somatostatin analogues and IFN for anti-proliferative purposes is not recommended. Also, the use of PRRT cannot be recommended as first-line therapy, but after failure of medical therapy. The presence of a strong expression of sstr2 as visualized by somatostatin receptor imaging is a prerequisite for the use of PPRT. The minimum requirements for PRRT are reported in a separate consensus guideline [220]. Everolimus and sunitinib represent novel therapeutic options in patients with surgically non-resectable progressive pancreatic NET as alternative or after progression following chemotherapy [211,223,224]. Follow-Up of Patients with Functional p-NETs (table 1) [2,3,5,8,221] Follow-Up of Patients with Functional p-NETs - General Patients with functional p-NETs with MEN1, with advanced metastatic disease, post-curative resection, or with active disease problems frequently require a different follow-up schedule than the typical p-NET patient with active but limited disease. Patients with MEN1 after initial treatment of the MEN1 problems (hyperparathyroidism, pituitary disease) should be seen at 6- to 12-month intervals and other MEN1 problems also investigated. Patients post-curative resection can be evaluated yearly unless symptoms of recurrence occur. Patients with metastatic disease require a relatively short follow-up initially (3-6 months) to determine whether progressive disease is present and interfering with symptomatic control and whether anti-tumor treatment might be needed to facilitate symptom control. Minimal Consensus Statement on Follow-Up of Patients with Gastrinoma - Specific [2,3,8,18,75,221] All patients with active non-metastatic disease should be seen initially at 3-6 months and then if stable yearly. At each evaluation, biochemical studies (vitamin B12 level, ionized calcium, PTH, gastrin), assessment of acid control if possible and tumor imaging studies (abdominal CT or MRI yearly, SRS at least every 3 years) should be done. For patients with MEN1/ZES, follow-up should be yearly with an assessment of tumor extent with imaging (CT/MRI abdomen and chest CT (rule out thymic carcinoid, especially in men every 3-5 years), SRS at least every 3 years, pituitary MRI every 3-5 years), biochemical assessment for MEN1 diseases (ionized calcium, serum PTH, prolactin, insulin), FSG, acid control if possible, UGI endoscopy to evaluate for gastric carcinoid [8,11,55,79,83,84]. For patients with post-curative resection, yearly evaluation with fasting gastrin levels, secretin provocative test and acid secretory control should be done if the patient is still taking PPIs/H2 blockers [8,18,151]. Imaging modalities should be performed if ZES is not cured, according to previous indications. For patients with advanced metastatic disease, follow-up should be at 3- to 6-monthly intervals with tumor imaging (CT or MRI and SRS (when clinically indicated)), FSG and acid secretory control (6 months). At least yearly, assessment for ectopic Cushing's with a urinary cortisol and serum cortisol should be considered. For patients with advanced metastatic disease or who are receiving chemotherapy or other antitumor treatments, follow-up may need to be shorter to assess for specific toxicities. Treatment of advanced disease is dealt with separately in a later chapter. Minimal Consensus Statement on Follow-Up in Patients with Insulinoma - Specific [2,3,13,15,221] Follow-up for insulinoma patients without MEN1 post-resection should be at 3-6 months and then if continued cured only if symptoms recur [213]. Post-curative resection patients with multiple insulinomas or with MEN1 should be followed yearly and also re-evaluated at any time symptoms recur. At follow-up in addition to a careful history for fasting hypoglycemic symptoms, a fasting glucose, insulin, C-peptide and proinsulin measurement should be done. Minimal Consensus Statement on Follow-Up for Patients with RFTs - Specific [2,3,5,213] Follow-up for patients with RFTs should be at 3- to 6-month intervals with metastatic disease and yearly in patients without metastatic disease. Following treatment, in patients with no evidence of residual disease, pertinent biochemical assessment (i.e. hormones known to be elevated prior to treatment, both specific and non-specific) should be initially performed and, when negative, further tests are not usually required. For patients with residual disease, specific markers coupled with contrast-enhanced mdCT scan or MRI and SRS (when clinically indicated) should be performed. Complete List of Participants List of Participants of the Consensus Conference on the 2011 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update Martin Anlauf, Germany (Martin.Anlauf@gmx.de) Rudolf Arnold, Germany (arnoldr@staff.uni-marburg.de) Detlef Bartsch, Germany (bartsch@med.uni-marburg.de) Eric Baudin, France (baudin@igr.fr) Richard Baum, Germany (info@rpbaum.de) Maria Luisa Brandi, Italy (m.brandi@dmi.unifi.it) Guillaume Cadiot, France (gcadiot@chu-reims.fr) Frederico Costa, Brazil (frederico.costa@hsl.org.br) Martyn Caplin, UK (m.caplin@medsch.ucl.ac.uk) Anne Couvelard, France (anne.couvelard@bjn.aphp.fr) Wouter de Herder, The Netherlands (w.w.deherder@erasmusmc.nl) Gianfranco Delle Fave, Italy (gianfranco.dellefave@uniroma1.it) Timm Denecke, Germany (timm.denecke@charite.de) Barbro Eriksson, Sweden (barbro.eriksson@medsci.uu.se) Massimo Falconi, Italy (massimo.falconi@univr.it) Thomas Gress, Germany (gress@med.uni-marburg.de) David Gross, Israel (gross@vms.huji.ac.il) Ashley Grossman, UK (a.b.grossman@qmul.ac.uk) Robert Jensen, USA (robertj@bdg10.niddk.nih.gov) Gregory Kaltsas, Greece (gkaltsas@endo.gr) Fahrettin Kelestimur, Turkey (fktimur@erciyes.edu.tr) Reza Kianmanesh, France (reza.kianmanesh@lmr.ap-hop-paris.fr) Günter Klöppel, Germany (guenter.kloeppel@alumni.uni-kiel.de) Klaus-Jochen Klose, Germany (klose@med.uni-marburg.de) Ulrich Knigge, Denmark (knigge@mfi.ku.dk) Paul Komminoth, Switzerland (paul.komminoth@triemli.stzh.ch) Beata Kos-Kudla, Poland (beatakos@ka.onet.pl) Eric Krenning, The Netherlands (e.p.krenning@erasmusmc.nl) Dik Kwekkeboom, The Netherlands (d.j.kwekkeboom@erasmusmc.nl) Jose Manuel Lopes, Portugal (jmlopes@ipatimup.pt) Bruno Niederle, Austria (bruno.niederle@meduniwien.ac.at) Ola Nilsson, Sweden (ola.nilsson@llcr.med.gu.se) Kjell Öberg, Sweden (kjell.oberg@medsci.uu.se) Juan O'Connor, Argentina (juanoconnor@hotmail.com) Dermot O'Toole, Ireland (dermot.otoole@tcd.ie) Ulrich-Frank Pape, Germany (ulrich-frank.pape@charite.de) Mauro Papotti, Italy (mauro.papotti@unito.it) Andreas Pascher, Germany (andreas.pascher@charite.de) Marianne Pavel, Germany (marianne.pavel@charite.de) Aurel Perren, Switzerland (aurel.perren@pathology.unibe.ch) Ursula Plöckinger, Germany (ursula.ploeckinger@charite.de) Guido Rindi, Italy (guido.rindi@rm.unicatt.it) Philippe Ruszniewski, France (philippe.ruszniewski@bjn.aphp.fr) Ramon Salazar, Spain (ramonsalazar@iconcologia.net) Hironobu Sasano, Japan (hsasano@patholo2.med.tohoku.ac.jp) Alain Sauvanet, France (alain.sauvanet@bjn.aphp.fr) Jean-Yves Scoazec, France (jean-yves.scoazec@chu-lyon.fr) Thomas Steinmüller, Germany (t.steinmueller@drk-kliniken-westend.de) Anders Sundin, Sweden (anders.sundin@radiol.uu.se) Babs Taal, The Netherlands (b.taal@nki.nl) Paola Tomassetti, Italy (paola.tomassetti@unibo.it) Eric Van Cutsem, Belgium (eric.vancutsem@uzleuven.be) Marie-Pierre Vullierme, France (marie-pierre.vullierme@bjn.aphp.fr); Bertram Wiedenmann, Germany (bertram.wiedenmann@charite.de).
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