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Purpose: Most insulinomas are small solitary, benign neoplasms. Imaging and surgical techniques improved over the last 20 years. Thus, the aim of the present study was to analyze changes in diagnosis and surgery of insulinoma patients in a referral center over two decades., Methods: Operated patients with a histologically proven insulinoma were retrieved from a prospective database. Clinico-pathological characteristics and outcomes were retrospectively analyzed with regard to the time periods 2000-2010 (group 1) and 2011-2020 (group 2)., Results: Sixty-one of 202 operated patients with pNEN had an insulinoma, 37 (61%) in group 1 and 24 (39%) in group 2. Of those 61 insulinomas, 49 (80%) were sporadic benign, 8 (13%) benign MEN1-associated insulinomas, and 4 (7%) sporadic malignant insulinomas. In 35 of 37 (95%) patients of group 1 and all patients of group 2, the insulinoma was preoperatively identified by imaging. The most sensitive imaging modality was endoscopic ultrasound (EUS) with correctly diagnosed and localized insulinomas in 89% of patients in group 1 and 100% in group 2. In group 1, significantly less patients were operated via minimally invasive approach compared to group 2 (19% (7/37) vs. 50% (12/24), p = 0.022). Enucleation was the most frequently performed operation (31 of 61, 51%), followed by distal resection (15 of 61, 25%) without significant differences between groups 1 and 2. The rate of relevant postoperative complications was not different between groups 1 and 2 (24% vs. 21%, p = 0.99). Two patients with benign insulinoma (1 out of each group) experienced disease recurrence and underwent a second resection. After a median follow-up of 134 (1-249) months, however, all 57 (100%) patients with benign insulinoma and 3 out of 4 patients with malignant insulinoma had no evidence of disease., Conclusion: Insulinoma can be preoperatively localized in almost all patients, allowing for a minimally invasive, parenchyma-sparing resection in selected patients. The long-term cure rate is excellent., (© 2023. The Author(s).)

Objectives: Pancreatic neuroendocrine neoplasias (pNENs) in multiple endocrine neoplasia type 1 are predominantly found in the dorsal anlage. Whether their growth velocity and incidence might be related to their location in the pancreas has not been investigated yet., Methods: We studied 117 patients using endoscopic ultrasound., Results: Growth velocity could be calculated for 389 pNENs. Increase of largest tumor diameter (% per month) was 0.67 (standard deviation [SD], 2.04) in the pancreatic tail (n = 138), 1.12 (SD, 3.00) in the pancreatic body (n = 100), 0.58 (SD, 1.19) in the pancreatic head/uncinate process-dorsal anlage (n = 130), and 0.68 (SD, 0.77) in the pancreatic head/uncinate process-ventral anlage (n = 12). Comparing growth velocity of all pNENs in the dorsal (n = 368, 0.76 [SD, 2.13]) versus ventral anlage, no significant difference was detected. Annual tumor incidence rate was 0.21 in the pancreatic tail, 0.13 in the pancreatic body, 0.17 in the pancreatic head/uncinate process-dorsal anlage, 0.51 dorsal anlage together, and 0.02 in the pancreatic head/uncinate process-ventral anlage., Conclusions: Multiple endocrine neoplasia type 1 pNENs are unequally distributed between ventral (low prevalence and incidence) and dorsal anlage. However, there are no regional differences in growth behavior., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Insulinoma is a rare tumor of the pancreas that can lead to spontaneous hypoglycemia due to excessive insulin secretion. Seventy-two-hour fast is the gold standard for finding the correct diagnosis. Endoscopic ultrasound (EUS) is an established examination method to identify the suspicious lesion. Previous studies correlate the measured size of insulinoma and their endocrine behavior. This study was designed to find a relation between these variables., Methods: We took the data of patients who had a histologically confirmed insulinoma after receiving an endoscopic ultrasound in our department. Size and echogenicity were correlated with the endpoint of the 72-hour fast and hormone levels., Results: A total of 45 patients were identified. Most insulinomas were small with a volume of<2 cm 3 (median 1.15 cm 3 ). There was no correlation between the duration of fasting, hormone levels, and the size of the insulinoma. In addition, in a subgroup analysis, no connection could be established between the size of the insulinoma and the amount of insulin released after oral glucose exposure. We found that homogeneous tumors were significantly smaller and had a lower Ki-67 index. Furthermore, there was a tendency towards a shorter duration for the 72-hour fast for the small tumors., Discussion: This data suggests that the measured size of insulinoma by EUS is not related to the time until termination of the 72-hour fast and measured hormone levels. The echogenicity seems more important, showing that homogenous tumors are an indicator of a higher differentiation, which can result in a shorter duration of the fasting period. The differences in the secretion behavior of the insulinomas could complicate the correlation of size and the 72-hour fast period., Competing Interests: Jan Adelmeyer declares that there is no conflict of interest., (Thieme. All rights reserved.)

Objectives: Pancreatic neuroendocrine neoplasias (pNENs) frequently occur in multiple endocrine neoplasia type 1 (MEN1). Their distribution referring to embryology, that is, the pancreatic anlagen, has not been investigated yet., Methods: In the time between 1998 and 2019, we studied the distribution of pNENs in MEN1 concerning the embryologic origin of the pancreas, that is, the dorsal versus ventral anlage using endoscopic ultrasound in 117 MEN1 patients: 56 women, 61 men; aged 40 years (standard deviation, 14 years) at first endoscopic ultrasound., Results: In 105 patients, a total of 628 pNENs were detected. They were located in the pancreatic tail: 231; pancreatic body: 177; pancreatic head/uncinate process: 220. Of the latter, 22 were located in the ventral anlage, 176 in the dorsal anlage, and 22 remained undefined. In summary, just 3.5% of all detected pNENs were located in the ventral anlage, 93.0% in the dorsal anlage, and 3.5% could not be assigned., Conclusions: Our study indicates that the vast majority of pNENs in MEN1 is located in the dorsal anlage, whereas the ventral anlage of the pancreas seems to be to a large extend spared from pNENs. Implications for new surgical strategies might be considered., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Diagnosis and pathological classification of insulinomas are challenging., Aim: To characterize localization of tumors, surgery outcomes, and histopathology in patients with insulinoma., Methods: Patients with surgically resected sporadic insulinoma were included., Results: Eighty patients were included. Seven had a malignant tumor. A total of 312 diagnostic examinations were performed: endoscopic ultrasonography (EUS; n = 59; sensitivity, 70%), MRI (n = 33; sensitivity, 58%), CT (n = 55; sensitivity, 47%), transabdominal ultrasonography (US; n = 45; sensitivity, 40%), somatostatin receptor imaging (n = 17; sensitivity, 29%), 18F-fluorodeoxyglucose positron emission tomography/CT (n = 1; negative), percutaneous transhepatic venous sampling (n = 10; sensitivity, 90%), arterial stimulation venous sampling (n = 20; sensitivity, 65%), and intraoperative US (n = 72; sensitivity, 89%). Fourteen tumors could not be visualized. Invasive methods were used in 7 of these 14 patients and localized the tumor in all cases. Median tumor size was 15 mm (range, 7 to 80 mm). Tumors with malignant vs benign behavior showed less staining for insulin (3 of 7 vs 66 of 73; P = 0.015) and for proinsulin (3 of 6 vs 58 of 59; P < 0.001). Staining for glucagon was seen in 2 of 6 malignant tumors and in no benign tumors (P < 0.001). Forty-three insulinomas stained negative for somatostatin receptor subtype 2a., Conclusion: Localization of insulinomas requires many different diagnostic procedures. Most tumors can be localized by conventional imaging, including EUS. For nonvisible tumors, invasive methods may be a useful diagnostic tool. Malignant tumors showed reduced staining for insulin and proinsulin and increased staining for glucagon., (Copyright © 2019 Endocrine Society.)

To compare endoscopic ultrasonography (EUS) and magnetic resonance imaging (MRI) in terms of their sensitivities to localize pancreatic neuroendocrine tumors (pNET) preoperatively. Systematic analysis of the literature; sensitivity of EUS and MRI in insulinomas and pancreaticoduodenal NETs in multiple endocrine neoplasia type 1 (MEN1) in series of at least 20 subjects referring to tumors confirmed by surgery and histopathology. Other imaging methods reported were also assessed. Eighteen publications on insulinomas (782 cases) could be analyzed, no study in MEN1 fulfilled the inclusion criteria and compared EUS to MRI. Data quality was moderate: all publications referred to case series. Mean correct detection / localization rates (sensitivity) were calculated: EUS 80%, MRI 66%, computed tomography 63%, angiography 52%, somatostatin receptor scintigraphy 42%, ultrasonography 23%; arterial calcium stimulation with hepatic venous sampling regionalized correctly in 80%. EUS seems to be more sensitive than MRI in localizing pancreatic neuroendocrine tumors. If a specialized endosonographist is available, EUS is the preferable imaging procedure. Otherwise, MRI is a suitable alternative.

Background: Radiological tumor size of non-functioning pancreatic neuroendocrine neoplasms (Nf-pNENs) associated with multiple endocrine neoplasia type 1 (MEN1) is a crucial parameter to indicate surgery. The aim of this study was to compare radiological size (RS) and pathologic size (PS) of MEN1 associated with pNENs., Methods: Prospectively collected data of MEN1 patients who underwent pancreatic resections for pNENs were retrospectively analyzed. RS was defined as the largest tumor diameter measured on endoscopic ultrasound (EUS), magnetic resonance imaging (MRI) or computed tomography (CT). PS was defined as the largest tumor diameter on pathological analysis. Student's t test and linear regression analysis were used to compare the median RS and PS. p < 0.05 was considered significant., Results: Forty-four patients with a median age of 37 (range 10-68) years underwent primary pancreatic resections for pNENs. Overall, the median RS (20 mm, range 3-100 mm) was significantly larger than the PS (13 mm, range 4-110 mm) (p = 0.001). In patients with pNENs < 20 mm (n = 27), the size difference (median RS 15 mm vs PS 12 mm) was also significant (p = 0.003). However, the only modality that significantly overestimated the PS was EUS (median RS 14 mm vs 11 mm; p = 0.0002). RS overestimated the PS in 21 patients (21 of 27 patients, 78%). Five of 11 patients (12%) with a Nf-pNEN and a RS > 20 mm had in reality a PS < 20 mm. MRI was the imaging technique that best correlated with PS in the total cohort (r = 0.8; p < 0.0001), whereas EUS was the best correlating imaging tool in pNENs < 20 mm (r = 0.5; p = 0.0001)., Conclusion: Preoperative imaging, especially EUS, frequently overestimates the size of MEN1-pNENs, especially those with a PS < 20 mm. This should be considered when indicating surgery in MEN1 patients with small Nf-pNENs.

Aim: Pancreatic neuroendocrine tumors (pNETs) can occur in patients with a familial syndrome either as multiple endocrine neoplasia type 1 (MEN-1) or as sporadic tumors. Endoscopic ultrasound (EUS) has become one of the first-line investigations for pNET characterization. The ultrasonographic features of pNETs may differ depending on the familial versus sporadic pathogenesis of the tumor. Therefore, the EUS findings could help and direct the definition of a pNET with an impact on the most appropriate diagnostic and therapeutic patient management., Methods: In this single-center retrospective study, we reviewed the EUS features of 94 pNETs from 37 MEN-1 patients and 15 pNETs from 11 sporadic disease patients at the time of their first EUS assessment. We analyzed the most relevant morphological and ultrasonographic characteristics of the tumors and compared the findings between the 2 patient groups., Results: Patients with MEN-1 more likely present with multiple pNETs than patients with sporadic disease. Sporadic pNETs are usually much bigger than those due to MEN-1. Moreover, pNETs are more heterogeneous in patients with sporadic disease than in those with MEN-1. No statistical difference with regard to definition of the margins, morphology, and vascularization of the pNETs appears between the 2 groups., Conclusions: Patients with sporadic disease usually present with bigger and more heterogeneous pNETs than patients with MEN-1, who tend to present with a higher number of lesions. EUS can facilitate the precise characterization of a pNET, and the ultrasonographic features of the lesion can help and distinguish MEN-1-related versus sporadic disease., (© 2018 S. Karger AG, Basel.)

Purpose: This study was aimed to investigate the role and relevance of endoscopic ultrasound-guided fine-needle aspiration biopsy in the diagnostic work-up of insulinomas., Methods: We have analysed the frequency, clinical indications, success rate (obtaining diagnostic tissue), diagnostic accuracy (in comparison to the pathological diagnosis after surgery), complications, and tolerability of endoscopic ultrasound-guided fine-needle aspiration biopsy and the localization and size of the lesions in 47 consecutive patients (29 females, 18 males; 46 ± 15 years) who had surgery for insulinoma following fasting test and were explored by single investigator EUS 1994-2015., Results: Endoscopic ultrasound-guided fine-needle aspiration biopsy was performed in 21 % (10/47) of the patients. The clinical indications for endoscopic ultrasound-guided fine-needle aspiration biopsy were non-conclusive result of fasting test (n = 7), missing toxicology (n = 2), suspected malignancy at EUS (n = 1), suspicious extra-pancreatic localization of the lesion (n = 1). The diagnostic success rate of the procedure was 80 % (8/10 cases), the diagnostic accuracy of the fine-needle aspiration biopsy 70 % (7/10 cases). The lesions undergoing endoscopic ultrasound-guided fine-needle aspiration biopsy were localized in the cauda (n = 5), corpus (n = 2), caput/processus uncinatus (n = 3), the diameter of the tumors was 21 ± 18 (10-70) mm. Only one accidental vascular puncture without any clinical complication occurred and all patients tolerated the procedure well., Conclusions: In the majority of cases, positive fasting test, negative toxicology, and detection of a typical pancreatic lesion at endoscopic ultrasound is sufficient for the diagnosis of insulinoma and the definition of the appropriate surgical strategy. Based on our data, we suggest including endoscopic ultrasound-guided fine-needle aspiration biopsy in the diagnostic work-up of organic hyperinsulinism in selected patients with inconclusive or uncertain diagnosis before surgery.

Context: Sixty to 80% of multiple endocrine neoplasia type 1 (MEN1) patients develop pancreatic neuroendocrine neoplasias (pNENs), which reveal an aggressive behavior in 10%-20% of patients. Causative MEN1 mutations in the interacting domains of the encoded Menin protein directly alter its regulation abilities and may influence the phenotype., Objective: The objective of the study was the evaluation of an association between MEN1 mutations in different interacting domains of Menin and the phenotype of pNENs., Design: This was a retrospective analysis of a prospectively collected cohort of 71 genetically confirmed MEN1 patients at a tertiary referral center., Main Outcome Measures: Analysis of patients' characteristics and clinical phenotype of pNENs regarding the mutation type and its location in Menin interacting domains was measured., Results: Sixty-seven patients (93%) developed pNENs after a median follow-up of 134 months. Patients with mutations leading to loss of interaction (LOI) with the checkpoint kinase 1 (CHES1) interacting domain codons (428-610) compared with patients with mutations resulting in LOI with other domains (eg, JunD, Smad3) had significantly higher rates of functioning pNENs (70% vs 34%), malignant pNENs (59% vs 16%), and aggressive pNENs (37% vs 9%), respectively. Patients with CHES1-LOI also had an increased pNEN-related mortality (20% vs 4.5%). Neither gender, age, nor the ABO blood types were associated with the phenotype of pNENs., Conclusions: MEN1 patients with MEN1 mutations leading to CHES1-LOI have a higher risk of malignant pNENs with an aggressive course of disease and disease-related death.

Aim: To assess the characteristics and long-term outcome after surgery in patients with multiple endocrine neoplasia type 1 (MEN1)-associated insulinoma., Methods: Retrospective analysis of prospectively collected data of MEN1 patients with organic hyperinsulinism at a tertiary referral center., Results: Thirteen (17%) of 74 patients with MEN1 had organic hyperinsulinism. The median age at diagnosis was 27 (range 9-48) years. In 7 patients insulinoma was the first manifestation of the syndrome. All patients had at least one pancreatic neuroendocrine neoplasm (pNEN) upon imaging, including CT, MRI or endoscopic ultrasonography. Seven patients had solitary lesions upon imaging, 4 patients had one dominant tumor with coexisting multiple small pNENs, and 2 patients had multiple lesions without dominance. Eight patients had limited resections (1 segmental resection, 7 enucleations), 4 subtotal distal pancreatectomies, and 1 patient a partial duodenopancreatectomy. There was no postoperative mortality. Six patients experienced complications, including pancreatic fistula in 5 patients. Pathological examination revealed median three (range 1-14) macro-pNENs sized between 6 and 40 mm, and a total of 14 potentially benign insulinomas were detected in the 13 patients. After median follow-up of 156 months, only 1 patient developed recurrent hyperinsulinism after initial enucleation. Twelve patients developed new pNENs in the pancreatic remnant and 4 patients underwent reoperations (3 for metastatic ZES, 1 for recurrent hyperinsulinism). One of 5 patients with an initial extended pancreatic resection developed insulin-dependent diabetes mellitus., Conclusion: Enucleation and limited resection provide long-term cure for MEN1 insulinoma in patients with solitary or dominant tumors. Subtotal distal pancreatectomy should thus be preserved for patients with multiple pNENs without dominance given the risk of exocrine and endocrine pancreas insufficiency in the mostly young patients., (© 2013 S. Karger AG, Basel.)

Purpose: This study was made to evaluate long-term results of an aggressive surgical approach for pancreaticoduodenal neuroendocrine neoplasms (pNENs) in patients with multiple endocrine neoplasia type 1 (MEN1)., Methods: MEN1 patients with either biochemical evidence of functioning or non-functioning pNENs larger than 1 cm in size on imaging underwent duodenopancreatic surgery. Since 1997, patients were followed annually by biochemical testing and imaging studies., Results: Thirty-eight genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 22) or non-functioning (n = 16) pNENs, nine patients were yet not operated. Malignant disease occurred in 12 (35%) patients defined by either lymph node (12 patients) and/or distant metastases (2 patients). Six patients with Zollinger-Ellison syndrome (ZES) required pylorus-preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure and 32 patients underwent other duodenopancreatic resections. Ten (26%) patients underwent up to four reoperations for either recurrent or metastatic disease that resulted in completion pancreatectomy in four patients. After median 109 months, 44 patients were alive and three patients died, one due to thymic carcinoid and two of unrelated causes. All eight patients with organic hyperinsulinism and 7 of 13 patients with ZES were biochemically cured. However, 24 of 38 (78%) patients developed new pNENs in the pancreatic remnant, but none developed distant metastases., Conclusions: Early resection of pNENs in MEN1 may prevent the development of distant metastases. However, the majority of patients develop new pNENs in the duodenopancreatic remnant which may require completion pancreatectomy in the long term.

Objective: Familial pancreatic cancer (FPC) accounts for approximately 3% of all pancreatic cancer (PC) cases. It has been suggested that high-risk individuals (HRIs) should be offered a screening programme., Aim: To evaluate the diagnostic yield of a prospective screening programme in HRIs from families with FPC over a period of 5 years., Methods: HRIs of families with FPC of the National German Familial Pancreatic Cancer Registry (FaPaCa) were counselled and enrolled in a prospective, board-approved PC screening programme. Screening included clinical examination, laboratory tests, endoscopic ultrasound (EUS) and MRI with magnetic resonance cholangiopancreaticography (MRCP) and MR angiography., Results: Between June 2002 and December 2007, 76 HRIs of families with FPC took part in the screening programme with a total of 182 examination visits. Twenty-eight patients revealed abnormalities in EUS (n = 25) and/or MR/MRCP (n = 12). In 7 patients fine needle aspiration cytology was performed. Operative pancreatic explorations were performed in 7 individuals, resulting in limited resections in 6 cases. Histopathological examination of the resected specimens showed serous oligocystic adenomas (n = 3), pancreatic intraepithelial neoplasia 1 (PanIN1) lesions with lobular fibrosis (n = 1), PanIN2 lesions (n = 1) and PanIN1 lesion plus a gastric type intraductal papillary mucinous neoplasm (IPMN) (n = 1)., Conclusions: In FPC an EUS/MR/MRCP-based screening programme leads to the detection of potential precursor lesions of PC. However, the yield of an extensive screening programme is low, especially since the tumourigenic value of low grade PanIN lesions is not yet defined. Taking into account the enormous psychological stress for the tested individual and the high costs, a general PC screening in HRIs is not justified.

Objective: Endoscopic ultrasound (EUS) is a highly reliable procedure to localize insulinomas preoperatively. It has been considered to be important in planning surgical strategy, especially considering a minimal invasive approach. However, even under ideal conditions experienced examiners miss about 10-20% of insulinomas by EUS imaging., Design and Methods: This retrospective study aimed to identify factors associated with negative EUS imaging. Twenty-nine consecutive patients (24 benign and 5 malignant) with sporadic pancreatic insulinomas confirmed by successful surgery and positive histopathology were included. All EUS examinations were performed by one single experienced examiner over a period of one decade., Results: Three of the tumors were not detected by preoperative EUS as they were isoechoic to the surrounding healthy pancreatic tissue; 25 could be detected as hypoechoic lesions, (including all malignant tumors), and one lesion was hyperechoic. Low body mass index (P=0.053) and young age (P=0.037) were associated with negative EUS imaging. All patients with negative imaging were females. The position on the examiner's learning curve, the diameter and location of insulinoma, and endocrine parameters (insulin concentrations and insulin-glucose ratios in the prolonged fasting test) had no influence on the success of EUS imaging., Conclusions: Some insulinomas are missed by preoperative EUS imaging as they are completely isoechoic. A low body mass index, female gender, and young age might be risk factors for negative imaging.

Correct localisation of pancreatic gastrinomas by endoscopic ultrasound seems to be possible in most cases. However, success rate in the duodenal wall is disappointing, even if the examination is performed under optimal circumstances by a very experienced examiner. Nevertheless, in certain conditions endoscopic ultrasound may yield important information, besides detection of the primary tumor for example about structures suspected to be metastases in the region of the gastrinoma triangle.

Endoscopic ultrasound (EUS) enables detection and localization of pancreatic neuroendocrine tumours. Even small tumours down to a diameter of 1-2 mm can be visualized. Since such small tumours usually cannot be detected by computed tomography (ct), magnetic resonance imaging (mri) and somatostatin receptor scintigraphy (srs), and experience with EUS imaging is limited, there is no clear evidence for clinical management in multiple endocrine neoplasia type 1 (MEN1). Knowledge about the natural course of growth and metastatic distribution is mandatory to come to appropriate clinical decisions and guidelines. This prospective study was aimed to assess the natural course of small (<15 mm) neuroendocrine pancreatic tumours without clinical symptoms due to endocrine activity or mechanical problems and without clear indication for surgical therapy in MEN1 by EUS. A total of 82 asymptomatic tumours<15 mm (5.9+/-3.2 mm diameter at baseline) in 20 patients with MEN1-disease (8 female/12 male, 43+/-13 years) were studied over a period of 20+/-12 months (33.8 patient years, 106.7 tumour years) by EUS. Change in largest diameter of each tumour and annual tumour incidence rate in the patients' cohort were calculated. Increase of largest tumour diameter was found to be 1.3+/-3.2% per month, annual tumour incidence rate 0.62 new tumours per patient year. In one patient, rapid progressive pancreatic manifestation of MEN1 was observed. There was no evidence in ct and/or srs and/or mri for metastatic disease in all patients. Only 4/84 (4.8%) pancreatic tumours could be visualized by computed tomography, 5/79 (6.3%) by somatostatin receptor imaging and 4/39 (10.3%) by magnetic resonance imaging. Small asymptomatic neuroendocrine pancreatic tumours in MEN1 usually seem to grow slowly. Annual tumour incidence rate is low. However, faster growing tumours and patients with rapidly progressive disease can be observed. Risk for obvious metastatic disease from asymptomatic neuroendocrine pancreatic tumours<15 mm in MEN1 seems to be low.

Endoscopic ultrasound enables imaging of the pancreas with high resolution. Today, it is considered to be the best preoperative imaging procedure in insulinomas. Since the result of endoscopic ultrasound may influence surgical strategy (minimally invasive approach), it needs to be performed in all patients. Furthermore, positive endoscopic ultrasound is able to confirm the diagnosis of insulinoma, since fasting test also may have been positive due to the intake of sulfonylureas or glinides which may have been missed Patiin toxicological analysis. However, false-positive and false-negative results always have to be taken into account. Gastrinomas which are located in the pancreas are usually detected by endoscopic ultrasound, yet often missed when localized in the duodenal wall. Thus, endoscopic ultrasound is not very helpful in treatment planning here. In multiple endocrine neoplasia type 1 (MEN1), endoscopic ultrasound is by far the best method to analyze the morphology of the pancreas. Clinical consequences are difficult, since the unclear prognosis of very small neuroendocrine pancreatic tumors in MEN1 on the one hand and possible side effects of surgical treatment (perioperative complications, diabetes mellitus following pancreatic surgery) on the other hand need to be discussed.

Endosonography enables detection and localization of small pancreatic neuroendocrine tumors (PETs) which cannot be detected by computed tomography, magnetic resonance imaging, or somatostatin receptor scintigraphy. Knowledge about the prognosis of very small PETs in MEN1 is limited, and if there are no clinical symptoms, endocrine activity or mechanical problems and thus no clear indication for surgical therapy, an appropriate decision for the management of such patients might be to control their follow-up by endosonographic imaging. Therefore, the reproducibility of the measurement of the diameter of very small PETs by endosonographic imaging was investigated in this prospective study. We included 33 PETs smaller than 15 mm in their largest diameter detected by endosonographic imaging (Pentax FG 32 UA) in ten patients with genetically confirmed MEN1-disease. Three repeated measurements of each tumor were performed. Reproducibility was expressed as mean coefficient of variation of intra-observer variability. Mean tumor diameter was 6.9 +/- 3.4 mm (range 2.8 - 14.2 mm). Mean coefficient of variation was 5.5 +/- 4.6 % (range 0.0 - 19.4 %): in tumors < 5 mm (n = 13) 7.1 +/- 6.3 %, in tumors > 5 mm (n = 20) 4.4 +/- 2.6 %. Least significant change (p < 0.05) was calculated as 15.4 % (tumors < 5 mm: 19.9 %; tumors > 5 mm: 12.3 %). In conclusion, endosonographic imaging enables the measurement of small PETs with an acceptable reproducibility. Changes of tumor diameter of more than 20 % have to be taken as statistically significant.

Objective: To evaluate the outcome of an aggressive surgical approach for duodenopancreatic neuroendocrine tumors (PETs) associated with multiple endocrine neoplasia type 1 (MEN1)., Summary Background Data: The management of PETs is still controversial in the setting of the autosomal dominant inherited MEN1 syndrome., Methods: MEN1 patients that had either biochemical evidence of functioning PETs or visualized nonfunctioning PETs larger than 1 cm in size on imaging were operated. Since 1997, patients were followed annually by biochemical testing and imaging studies., Results: Twenty-six genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 17) or nonfunctioning (n = 9) PETs. Ten (38%) patients had malignant PETs as characterized by the presence of lymph node (10 patients) and/or distant metastases (2 patients). The surgical approach was selected based on the type, location, and size of PETs. Four Zollinger-Ellison syndrome (ZES) patients required pylorus preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure, 20 patients underwent other duodenopancreatic resections, and 2 patients had simple enucleations of PETs. After median 83 months (range, 5-241 months), 24 patients were alive and 2 patients died of an unrelated cause. All patients with insulinoma or vipoma and 7 of 11 patients with ZES were biochemically cured, including the ZES patients who underwent PPPD. However, 19 of 26 (73%) patients developed new small PETs (<1 cm) in the pancreatic remnant, but no patient had yet detectable metastases on imaging., Conclusions: Early and aggressive surgery of PETs in MEN1 patients prevents the development of liver metastases, which are the most life-threatening determinant. PPPD might be the procedure of choice for MEN1-ZES, which has to be proven in large scale studies.

Compared to other imaging methods, endoscopic ultrasound is the best procedure to localize insulinomas preoperatively. Positive finding furthermore confirms endocrinological diagnosis, especially considering the differential diagnosis of hypoglycaemia factitia by oral antidiabetics. However, it always has to be considered that endoscopic ultrasound imaging may reveal false positive and false negative results, and quality of the findings obtained by endoscopic ultrasound imaging depends to a large extent on the examiner's experience. An important issue of endoscopic ultrasound imaging in insulinomas nowadays is planning surgical strategy. As illustrated by three cases, endoscopic ultrasound imaging enables to identify patients that qualify for laparoscopic, minimal invasive surgery.

Early identification of pancreaticoduodenal endocrine tumors (PETs) in multiple endocrine neoplasia type 1 (MEN-1) is mandatory, because these tumors represent the most common cause of death within the syndrome. The diagnostic value of imaging procedures has therefore been evaluated in a prospective observational study. Between December 1997 and June 2003 twenty-two MEN-1 patients with genetically confirmed disease were followed for PETs using a standardized screening program with serum hormone measurements, endoscopic ultrasonography (EUS), computed tomography (CT), and somatostatin-receptor scintigraphy (SRS). Results could be validated by surgery and histopathology in 13 patients during 18 operations. In 12 asymptomatic patients with tumors measuring 10 mm or less, who have not yet undergone operation, PETs were detected by EUS in 12/12, by CT in 1/12, and by SRS in 2/11 cases. In 13 patients who have undergone surgical exploration EUS, CT, and SRS were true positive in 12 of 16, 7 of 13, and 12 of 17 cases, respectively, although the number of tumors detected by each imaging procedure alone was lower than the number detected intraoperatively and histopathologically in almost every case. A solitary liver metastasis in one patient and a nonfunctioning PET recurrence in another were identified only by SRS. Endoscopic ultrasonography is the most sensitive imaging procedure for the detection of small (< or = 10 mm) PETs in MEN-1, whereas SRS is the procedure of choice for the identification of metastases of MEN-1 PETs-i.e., for staging. Detection of PETs at an early stage by an aggressive screening program using EUS may lead to prompt surgical intervention and improved prognosis of MEN-1 PETs.

Objective: Endosonography enables localization and characterization of gastroenteropancreatic neuroendocrine tumors. We have studied the problem of misleading abnormalities of pancreatic morphology as obtained by endosonographic imaging., Design and Methods: A total of 438 endosonographies performed for known or suspected diseases of the adrenal glands and/or the pancreas and/or suspected metastases in the neighboring tissues were analyzed., Results: In the pancreas, nine benign insulinomas, four non-metastatic islet cell carcinomas, and multiple benign neuroendocrine tumors in one patient with multiple-endocrine neoplasia-1 (MEN-1) disease were detected and correctly localized as proven by postoperative histology. In three further patients with genetic diagnosis of MEN-1, asymptomatic tumors were detected and are under observation. However, we also found an 8 x 4 mm hypoechoic tumor in the cauda pancreatis of a patient with severe factitial hypoglycemia (glimepiride). In another patient suffering from severe hypoglycemia, a hypoechoic area of 24 x 10 mm in the processus uncinatus/caput pancreatis was found. Although organic hyperinsulinism was excluded, this patient underwent surgery because of suspected pancreatic carcinoma. There was normal pancreatic tissue in the abnormal region, which was also localized by intraoperative sonography. In a third patient with an adrenal carcinoma, a 6 x 3 mm hypoechoic nodule in the cauda pancreatis did not change its morphology over an observation period of 13 months, its clinical relevance is completely unclear., Conclusions: Pancreatic nodules of unknown dignity were detected in nearly 1% of our patients and must be considered to be a diagnostic problem. These experiences clearly show, on the one hand, that pancreatic endosonography is a very useful diagnostic support in the management of endocrine tumor patients. However, on the other hand, endosonography of endocrine organs is not a substitute for careful endocrinological examination and testing and must be considered in the context of endocrinological findings.