Longterm outcome of rare functioning pancreatic neuroendocrine neoplasms

Longterm outcome of rare functioning pancreatic neuroendocrine neoplasms | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Longterm outcome of rare functioning pancreatic neuroendocrine neoplasms Martina Sevcik, Max B. Albers, Dominik Wiese, Jerena Manoharan, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4000625/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Rare functional pancreatic neuroendocrine neoplasms (rf-pNENs), such as VIPomas, calcitoninomas and glucagonomas are extremely rare tumors. Thus, their characteristics and long-term prognosis have not yet been well defined. Methods: Clinicopathological characteristics, including preoperative diagnostics, surgical procedures, other treatments and long-term outcome of patients with rf-pNEN operated in the ENETS Center of Excellence Marburg were retrospectively analyzed. Results: Between 2002 and 2022, 12 of 216 (5,5%) patients with pNEN had rf-pNEN, including three VIPomas, four glucagonomas and five calcitoninomas. Among these 5 were women and 7 were men with a median age of 60 (range 28-73) years at the time of the first surgery. The tumor was visualized by preoperative imaging in all 12 patients, and six patients had distant metastases at the time of diagnosis. The tumor was located in the pancreatic tail in 9 patients and the median tumor size was 82 (range 12-220) mm. Eleven patients underwent tumor resections (2 robotic, 9 conventional), and 9 of these 11 patients received R0 resections. After a median follow-up of 75 (range 1-247) months, six patients were alive, five of whom had no evidence of disease. All patients who remained disease-free had an initial R0 resection of the primary tumor and no initial liver involvement. Conclusion: rf-pNENs are a heterogeneous group of tumors with a good long-term prognosis, if detected early and initially radically resected. Long-term survival, however, can be also achieved in patients with metastasized tumors using multimodal treatment. glucagonoma VIPoma calcitoninoma Figures Figure 1 Introduction Rare functioning pancreatic neoplasms (rf-pNENs) include glucagonomas, VIPomas, Calctitonin-producing pNENs, somatostatinomas, PTHrp-omas, GRHomas, ACTHomas and p-NENs secreting renin, luteinizing hormone, erythropoietin and insulin-like growth factor II [ 1 , 2 ]. Rf-pNENs are extremeley rare and account for only approximately 5% of functioning pNENs, with annual incidence of approximately 0.05–0.1/1.000000/year [ 2 , 3 , 4 , 5 ]. The most frequent familial condition associated with rf-pNEN is the multiple endocrine neoplasia typ 1 (MEN1), with glucagonomas occurring in 5% and VIPomas in 3% of MEN1-patients [ 2 , 6 ]. Glucagonomas in the setting of MEN1 usually do not cause a syndome, although glucagon serum levels may be significantly elevated. The diagnosis of an rf-pNEN requires at least the demonstration of an inappropriate elevation of the specific serum hormone (i.e., vasoactive polypeptide or glucagon), ideally combined with symptoms caused by of oversecretion of the destinct hormone. The diagnosis of rf-pNEN cannot be based solely on positive immunohistochemical results of resected specimens [ 2 , 5 ]. As of 2022, approximately 600 glucagonomas [ 7 , 8 , 9 , 10 ], 100 Vipomas [ 11 , 12 , 13 ] and 60 calcitonin-producing pNEN [ 14 , 15 ] have been reported in case reports or small case series, whereas reports on other rf-pNENs do not exceed 10–25 cases per subtype [ 1 , 16 , 17 , 18 , 19 , 20 ]. Glucagonoma, first described in 1942 by Becker [ 21 ], and is a pancreatic alpha-cell tumor that produces glucagon. It causes the glucagonoma syndrome, which includes necrolytic migratory erythema (NME), diabetes, venous thromboembolism, diarrhea, stomatitis and anemia. However, in some series, only half of patients had NME and only 20% developed diabetes prior to the diagnosis [ 10 , 22 ]. Thus, published characteristics of glucagonoma patients represent a mixed cohort of patients, either suffering from the classic glucagon-secreting tumour with full-blown glucagonoma syndrome or those secreting less active forms of glucagone without impressive clinical significance. VIPomas were first reported by Verner and Morrison in 1958 [ 23 ] and are characterized by excessive secretion of vasoactive intestinal peptide (VIP), which may cause typical watery diarrhea, hypokalemia, and achlorhydria, the so-called WDHA syndrome. Calcitonin-producing pNENs (CT-pNENs) are an extremely rare cause of hypercalcitoninemia, which is usually highly suggestive of medullary thyroid carcinoma [ 24 ]. Hormonal excess of CT-pNEN may cause diarrhea and abdominal pain. CT-pNEN appear to have a unique molecular signature compared to other pNEN subtypes [ 15 ]. A recent pathological study showed that approximately 10% of all pNENs show a positive calcitonin immunoreactivity, whereas the corresponding serum CT levels are rarely elevated [ 14 ]. The average age at diagnosis of rf-pNENs is between 50 and 60 years with an equal gender distribution. A significant number of patients with rf-pNENs present with metastatic disease (40–80%) in the liver at initial diagnosis. The management of rf-pNEN is challenging, because high level evidence recommendations currently are lacking, especially for the treatment of symptomatic patients with diffuse metastatic tumors [ 5 ]. Surgical resection of all lesions is considered the only curative option. Symptom and tumor growth control can be achieved either with somatostatin analogs (SSAs), chemotherapy, and targeted therapy with sunitinib or peptide radionucleotide receptor therapy (PRRT) [ 5 ]. Debulking surgery and/or other cytoreductive techniques such as liver transarterial (chemo)embolization (TACE) or radioembolization can also be employed [ 5 , 16 ]. Nevertheless, because of the rarity of these tumors, experiences with more novel and specific therapeutic tools such as PRRT are still sparse. We present a series of 12 patients with rf-pNEN from a tertiary referral center who were treated during a 20 years period. Clinicopathological characteristics, therapeutic modalities and prognosis were evaluated. Patients and methods Rf-pNENs were defined according to the ENETS guidelines such as VIPoma, glucagonoma or calcitonin-producing pNEN [ 5 ]. The diagnosis of a distinct rf-pNEN was confirmed, if the pNEN was associated with at least 2-fold elevated serum hormone levels and positive immunostaining for the respective hormone. Patients diagnosed with rf-pNENs were identified from the prospective pancreatic database of the Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, which was established in 2002 as a prerequisite for certification as an ENETS Center of Excellence. The demographics, preoperative imaging, type of surgery, postoperative complications, and long-term cure rates of all patients were retrospectively analyzed for all patients. Immunohistochemistry for synaptophysin, chromogranin A and Ki67 was re-evaluated by an experienced pathologist (M.J.). The fact that initially elevated serum hormone levels dropped to normal levels after potentially curative surgery was considered as evidence that the resected pNEN was the source of hormone hypersecretion. Data collection and analysis were approved by the local ethics committee of the University of Marburg (no. RS 22–51). Selective clinical data from our patients with calcitonin-producing pNEN have been reported previously [ 15 , 25 ]. Preoperative imaging routinely includes abdominal ultrasonography, multidetector computed tomography (CT), and/or magnetic resonance imaging (MRI) with gadolinium and endoscopic ultrasonography (EUS). Some patients also underwent somatostatin receptor scintigraphy (SRS) until 2013, since 2014 Gallium-68-positron-emission-tomography (Ga68-DOTATOC PET/CT) was applied instead. In the case of resectable disease, and if fit for surgery, patients underwent oncological pancreatic resection with or without metastasectomy. In cases of diffuse metastatic disease without complications (e.g., bowel obstruction), palliative debulking surgery was performed after a multidisciplinary tumor board decision. After potentially curative resection, no adjuvant treatment was administrered according to ENETS guidelines [ 5 , 26 ]. Tumors were classified according to the WHO classification 2017 [ 27 ] and defined as malignant in the presence of lymphatic and/or distant metastases at the initial diagnosis or during follow-up [ 28 ]. All tumors were stained for synaptophysin and chromogranin A. Ki67 expression was determined as the percentage of positively stained tumor cells among the total number of malignant cells assessed. Potentially secreted hormones, such as vasoactive intestinal peptide, glucagon and calcitonin, were verified by immunohistochemistry as described previously [ 15 , 29 ]. Postoperative complications were classified according to Clavien-Dindo [ 30 ]. Clinically relevant postoperative pancreatic fistula (POPF) types B and C were defined according to the International Study Group of Pancreatic Fistula [ 31 ]. The length of hospital stay was not evaluated, because several institutional changes in patient demission management over the years would have induced a significant bias. Follow-up was calculated from the time of the initial surgery to the evaluation date of July 31, 2023. Disease-free survival was defined as the time from potential curative surgery to disease recurrence. An annual clinical follow-up was performed at our or hospital or by a personal physician with laboratory workup, including the preoperatively increased specific hormone level, MRI of the abdomen, and in case of suspicion of recurrence or metastatic disease with somatostatin-receptor imaging. Patients were classified as having no evidence of disease, if there was no suspicion of symptom recurrence, the respective serum hormone levels were not elevated, and there were no visible tumor lesions on imaging. In the case of palliative surgical procedures and/or unresectable disease, patients were treated with a variety of modalities such as PRRT, transarterial chemoembolization (TACE), somatostatin analogs or chemotherapy, upon recommendation of the multidisciplinary tumor board. Results In the study period from January 2002 to December 2022, 216 patients with pNENs underwent surgery at the ENETS Center of Excellence Marburg. This included 156 patients with sporadic and 60 with MEN1-associated pNEN. Overall, 79 (36.6%) patients had functioning tumors, of which twelve (12/216, 5.5%) had rf-pNEN according to the actual ENETS definition [5]. Five patients had a calcitoninoma, four patients had a glucagonoma and three patients had a VIPoma, respectively. Except for one patient with MEN1-associated VIPoma, the other 11 tumors were sporadic. Five patients were female. The median age at the time of surgery was 60 years (range 28-73 years). All twelve patients had at least 2-fold elevated serum levels of the specific tumor released homone (median 31-fold, range 2-189-fold). CgA was measured preoperatively in ten patients and was elevated in eight cases. All but three patients with CT-producing pNEN were symptomatic. Six patients had full hormone-associated syndrome (three Vipomas, two glucagonomas and one CT-producing pNEN). Diarrhea was the most common symptom, presenting in 6 of 12 patients (3 VIPomas, 1 calcitoninoma and 2 glucagonomas). The time between diagnosis and the first surgery varied between 1 and 137 months. The demographic characteristics and symptoms of the 12 patients are summarized in Table 1. Preoperative imaging revealed the rf-pNENs in all 12 patients. All but one tumor had a size >20mm. For the visualization of the primary tumor EUS and MRI were most sensitive with 100% detection and accuracy. Four patients underwent SRS scintigraphy until 2013, since 2014 Ga68-DOTATOC PET/CT was performed in another 5 patients. SRS imaging showed the primary tumor in 8 of 9 patients, lymph node metastases in none of the patients, but liver metastases in all six patients with histologically confirmed distant metastases. It should be noted that only EUS and MRI detected a small (12 mm) glucagonoma in the pancreatic head. The preoperative imaging data are summarized in Table 2. EUS-guided FNA was performed in 4 patients and confirmed the presence of pNEN in all 4 cases. The tumor was located in the pancreatic tail in 9 patients and in the pancreatic head in three patients. Eleven of the 12 rf-pNENs were considered completely resectable based on preoperative imaging. Eight patients underwent distal splenopancreatectomies, one patient PPPD, one patient underwent total pancreatectomy and one patient underwent enucleation of the pancreatic head for the above-mentioned small (12mm) glucagonoma. The remaining patient with a large VIPoma with far advanced diffuse metastatic disease in the liver and the peritoneum had only an exploratory laparotomy with palliative ileocecal resection for bowel obstruction without removal of the primary tumor. Ten patients underwent conventional open surgery, and the remaining two patients underwent robotic-assisted procedures. In addition to the pancreatic resection, five patients also underwent resection of liver metastases. In 9 of the 12 patients, complete (R0) resection of the primary tumor and, if present, liver metastases was achieved, so that serum hormone levels dropped to normal levels postoperatively. Postoperative complications (Clavien-Dindo > III) occured in four patients (all three with VIPoma and one with glucagonoma), all of which had to be reoperated. One of them was due to peritonitis, with a suspected anastomotic leak. However, this has not been confirmed. The second patient required intraoperative intra-abdominal lavage and drainage of an intraabdominal abscess. The third patient underwent a reoperation because of bleeding from the spleen, which required splenectomy. The last patient who had initially only an explorative laparotomy, underwent two reoperations because of tumor-associated perforation of the small intestine. He died on the 30th postoperative day after the initial exploration due to multiorgan failure. None of the patients developed postoperative pancreatic fistula type B or C. Rf-pNEN was confirmed by histopathological examination in all patients. All 12 primary tumors were immunohistochemically positive for chromogranin A, synaptophysin and their respective secreted hormones. All primary tumors were well differentiated and graded G1 in three patients and G2 in the remaining nine patients. The tumor was classified as T1 in three patients, T2 in three, T3 in three and T4 in two patients, respectively. Six patients had locoregionally limited, Stage I-III rf-pNENs, and the other six patients had stage IV disease. The median tumor size was 82 (range 12-220) mm. Five of the twelve patients had lymph node metastasis. A median of 13 (range 5-28) lymph nodes were removed. In 9 of the12 patients, resection was defined as R0 resection. Histopathology results and hormon levels after initial surgery are summarized in Table 3. Follow-up The median follow-up period was 75 months (range 1-247 months). Four of the six curatively resected patients with localized disease (stages I-III) remained disease-free for a median of 61 (range 6-108) months. In this group one patient experienced local recurrence 6 months after glucagonoma enucleation from the pancreatic head, which required subsequent pylorus-preserving pancreatic head resection. Since this reoperation the patient has remained disease-free until the evaluation date for 90 months. Another patient in this group experienced local recurrence 84 months after the first surgery due to a 22cm sized initially locoregionally metastasized VIPoma in the pancreatic tail. This patient underwent a total of 7 redo-surgeries and more than 40 cycles of multimodal therapy (SSA, Interferon, PRRT, Chemotherapy) due to tumor recurrence and/or progression (All the treatment modalities are summarized in Figure 1). The sequence of multimodal treatment led to a survival rate of 247 months after initial diagnosis. In the six patients with stage IV disease multimodal treatment, including somatostatin analogs, chemotherapy regimens with Dacarbazine, Doxorubicin, Streptozotocin, Capecitabine, targeted therapy with sunitinib, radiofrequency ablation or TACE of liver metastases, recurrent PRRTs and reoperations were performed. One patient with a stage IV CT-producing pNEN developed a local lymph node recurrence 11 months after the initial surgery, and excision of this metastasis was performed. He was alive with the disease after 49 months of follow-up. The remaining 5 patients died of disease 1, 20, 48, 52, 114 and 247 months after the initial surgery, respectively (Follow up are summarized Table 4). One year survival in our cohort was 91%, the true 5-years survival rate was 55%. In three patients 5 years survival was not reached. A comparison of the characteristics, treatments and follow-up between the individual tumor subtypes are summarized in Table 5. Discussion In our series, patients with rf-pNEN had a median age of 61.5 (range 28–73 years), which is in the range reported in the literature [ 7 , 14 , 22 , 32 , 33 ]. In addition, no sex predominance was noted in either our series, nor in the literature. All three patients with VIPoma presented with the classic symptomatology of watery diarrhea, which is typical in these patients [ 11 , 12 , 32 ]. However, only two of four patients with glucagonoma in the present series had necrolytic migratory erythema (NME), and only one patient had diabetes. This is in line with a previous Swedish study of 23 patients [ 22 ]. Only 22% of these patients had developed diabetes prior to the diagnosis of glucagonoma and NME was diagnosed in only 52% of patients. In a recent clinicopathological study of 25 CT-pNEN 16 were not associated with signs or symptoms of hormonal hypersecretion and the other 9 with symptoms of hyperinsulinism [ 14 ]. Elevated serum calcitonin levels were not reported in the clinical records of any of these 25 cases. The here presented 5 patients all had significantly elevated CT serum levels up to 150-fold. However, only the patient with a 150-fold elevated CT had diarrhea, which is typical for excessive hypercalcitonemia. Abdominal pain due to tumor size has been one leading symptom in 3 of our 12 (25%) patients with rf-pNEN, which was reported to be present in 19,8%-33% of other case series [ 7 , 10 , 34 , 35 ]. In the present cohort there was a predominant tumor location in the left pancreas (75%), which is in line with previous case series of VIPomas, glucagonomas and CT-pNEN [ 7 , 14 , 22 , 32 , 33 ]. The median diameter in our cohort was 82 (range 12–220), and only one patient with a glucagonoma had a tumor size < 20mm. In an older literature review of 407 patients with glucagonoma 80 (29%) patients had small tumors of 20mm or less and these patients had a rate of metastasis of 8,8% [ 7 ]. The median tumor size in the present cohort was larger than that previously reported for VIPoma with a median diameter of 32–57,5mm [ 33 ], glucagonoma with a median size from 50 to 55mm [ 22 , 36 ], and CT-pNEN with a median size of 48mm [ 14 ]. As in other studies patients with rf-pNEN frequently show liver metastases at the time of initial diagnosis as in 50% of patients in our cohort. This is in the range of reported rates for VIPoma of 36–75% [ 32 , 33 , 37 , 38 ] and glucaogonoma of 50–78% [ 8 , 22 , 36 ]. It is of note, in the present series, 2 of 5 CT-pNEN presented with liver metastases, whereas in a previous series only 4 of 23 (17%) tumors did so [ 14 ]. None of our patients with rf-pNEN showed initially bone metastases compared to reports of up to 6–15% [ 7 , 8 , 32 ]. However, the low rates might be due to the lower sensitivity of SRS scintigraphy imaging used in the early 2000 years. All 12 rf-pNENs in the present cohort were G1 (n = 3) or low G2 (n = 9) tumors with a Ki67 index in the primary tumor of at most 10%. This is in line with the Ki67 index in the majority of reported glucogonomas [ 22 , 36 ] and CT-pNEN [ 14 ]. For VIPoma, however, G3 tumors have been described in up to 27% of cases [ 37 ]. In the present cohort, all rf-pNENs could be visualized by preoperative imaging with either CT or MRI because of the large tumor size, as reported in previous series [ 37 , 39 , 40 , 41 ]. EUS was used in only half of our patients and had an additional value in only one patient with 12 mm glucagonoma in the pancreatic head. According to recent guidelines [ 3 , 5 ], imaging with 68Ga-labeled somatostatin analogs with PET/CT is more sensitive and highly specific for rare p-NENs and is therefore recommended as the first-line diagnostic imaging method for staging in patients with rf-pNENs. Our cohort supports this recommendation, since 8 of 9 patients who underwent SRS imaging showed positive primary tumors and in all 5 patients who underwent SRS imaging metastasis could be visualized. In patients with rapid tumor growth and/or high G2 or G3 tumors, 18-FDG-PET/CT can also be considered to assess tumor burden [ 42 , 43 ]. In our cohort this was not applied, because we had only G1 and low G2-tumors. The indications for surgery are influenced by clinical symptom control, the technical possibility of local R0 resection and the presence and extent of metastatic spread [ 3 , 5 , 44 ]. Curative surgery should always be indicated, even in the presence of metastatic disease, if a complete resection can be achieved and the patient is fit for surgery [ 5 , 38 ]. In the present cohort, we could achieve a potential curative R0 resection, documented by postoperative normal serum hormone levels, in 9 of 12 (75%) patients of whom 3 patients had also liver metastases. The surgery rate as well as the R0 resection rate are comparably high to other series, ranging from 28 to 63% [ 11 , 37 , 38 , 40 , 45 ]. In two CT-pNEN patients with liver metastases, R0 resection was attempted based on preoperative imaging, but only a R1 resection could be achieved. However, this fact, however, is not considered a failure since elevated hormone levels dropped to the normal range postoperatively. In addition, according to ENETS guidlines debulking surgery can be considered in rf-pNEN, if at least 80% of gross tumor is thought resectable [ 5 , 44 ]. The type of surgery for rf-pNENs depends on the location of the primary tumor. Because of the usually large rf-pNEN size and high prevalence of liver metastases, curative surgery usually requires formal pancreatic resection with lymphadenectomy [ 2 , 5 , 44 ]. This was performed in 10 of 11 resected patients in the present series, as well as in the majority of patients in other series [ 11 , 37 ]. Even for small rf-pNEN parenchyma-sparing resection, such as enucleation, might be insufficient. One of our patients had a robotic-assisted enucleation of 12mm sized glucagonoma out of the pancreatic head with negative lymph node sampling and developed local recurrence 6 months later. Consequently, the patient underwent partial pancreaticoduodenectomy, which resulted in a disease-free survival of 90 months so far. Five of the six patients with recurrent disease and one patient with an unresectable VIPoma underwent several cycles of multimodal treatment, including redo surgery, somatostatin analogues, chemotherapy, targeted therapy with sunitinib, local ablative therapies with TACE and/or radiofrequency ablation and PRRT (see Table 5 ). Although more therapies have become available for pNEN during the last decade, including targeted therapies with e.g sunitinib, new chemotherapy regimens (e-g. Tem/Cap, Folfirinox) and PRRT, no significant data has yet been compiled on the onoclogical outcomes in patients with rf-pNEN. Thus, the discussion of the possible advantages and disadvantages of individual treatments and their sequence is somewhat vague and is beyond the scope of this article. However, somatostatin analogs, were used as the mainstay treatment in several other series [ 11 , 32 , 37 , 41 ] when curative surgery was not an option. They can control symptoms caused by excessive hormone secretion and prolong progression-free survival [ 46 ]. This was the case in six of seven patients with recurrent or persistent disease in our cohort. Since the majority of rf-pNEN somatostatin receptor-positive grade 1/2 tumors, 8 of 9 investigated in the presented series, PRRT is currently a very good option to control symptoms of hormonal excess as well as tumor growth progression [ 11 , 47 , 48 ]. In a previous series, PRRT was the most efficacious second-line treatment in patients with VIPoma who had refractory WDHA syndrome despite the maximum doses of SSA [ 32 ]. It is also noteworthy that repeated surgery for disease recurrence should always be considered in the multimodal concept. One of our patients with a 22cm sized VIPoma underwent - embedded in SSA treatment, chemotherapy and PRRT - a total of 7 reoperations, which resulted in a survival of over 20 years are summarized in Fig. 1 . Since the treatment armentarium is complex, all patients with advanced rf-pNEN should be discussed in a multidisciplinary tumor board, ideally in centers of excellence. In the present study the eight patients with potential curative surgery had a 5-year survival of 63%, which is similar to that reported by others [ 8 , 38 , 49 , 50 , 52 ]. The study from Azizian et al. showed that patients who underwent surgery had a longer overall survival than patients who were treated with other therapeutic modalities (44 vs. 33 months) [ 11 ]. Five (42%) patients remained free of disesase median 74 months after initial surgery. This outcome is similar to that of previous studies of rf-pNENs ranging from 15 to 180 months [ 40 , 51 , 52 , 53 ]. A study by Sakurai et al. reported a disease-free interval after an initial surgery of 180 months. This patient underwent after 180 months of disease-free interval a second curative surgery for the locally recurrent VIPoma. The patient is alive with no relapse following 14 months after the second surgery [ 53 ]. Those cases demonstrates the importance of long-term observation of patients. The study from Murakami et al. showed, that the median survival time for patients with VIPoma was 71 months [ 33 ]. In the present study the three patients with VIPoma showed the 5 years tumor survival 33% and the median survival time 100 months. It is crucial to separate between cases in which all metastases and the primary tumour are resectable and cases in which complete resection of all lesions is not possible (debulking surgery). The survival of the palliatively operated 3 patients in the present study was 48, 49 and 52 months. Brugel et al. showed in a retrospective analysis in 4 cases, a debulking surgery with palliative intent. The median progression- free survival was 21 months [ 38 ]. It should be mentioned that CT-pNEN might be less aggressive than VIPoma or glucagonoma, since according to a recent study of 25 CT-pNEN 60% of patients were alive with no evidence of disease and 20% survived with disease after 5 years follow-up [ 14 ]. This tendency can be confirmed by the present study. The present study had two major limitations. First, the collective size is very small, as it is usual for these very rare tumor entities. Second, the retrospective design implicates bias and missing data. Thus, prospective registration in international databases (e.g, the ENETS-Database) is required to better understand the characteristics and outcomes of these extremely rare tumors due to different therapeutic approaches. Conclusion In conclusion, rf-pNENs are a heterogeneous group of tumors with good long-term prognosis, if initially radically resected. Long-term survival can even be achieved in metastasized tumors using multimodal treatment. As these tumors are extremely rare, treatment in expert centers is recommended. Declarations Statement of Ethics: The study was conduced in accordance with the Declaration of Helsinki. Data collection and analysis were approved by the local ethics committee of the University of Marburg (protocol code RS 22-51). Conflict of interest statement: The authors have no conflicts of interest to declare. Funding : This research was supported by Open Access funding provided by Open Access Publication Fund of the Philipps University Marburg, Germany with support of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation). Author Contributions : Conceptualization: D.K.B., M.S.; methodology and software: M.S., collecting patient data: J.M., M.A., D.W. D.K.B, writing-original draft preparation: MS, D.K.B.; review and editing: D.K.B., M.A., JM, MJ, AR, DW; supervision: D.K.B. Acknowledgments: The authors are grateful to all patients who participated in the study. Data Availability Statement: The data that support the findings of this study are not publicly available because they contain information that could compromise the privacy of research participants but are available from one of the authors [M.S.] upon reasonable request. References O'Toole D, Salazar R, Falconi M, Kaltsas G, Couvelard A, de Herder WW, Hyrdel R, Nikou G, Krenning E, Vullierme MP, Caplin M, Jensen R, Eriksson B; Frascati Consensus Conference; European Neuroendocrine Tumor Society. Rare functioning pancreatic endocrine tumors. Neuroendocrinology. 2006;84(3):189-95. doi: 10.1159/000098011. Epub 2007 Feb 20. PMID: 17312379. 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Tables Table 1: Demographic data and laboratory values Patient No. Gender Age at Dx Age at initial surgery Symptoms before surgery Tumor localisation Serum hormone elevated Serum hormone level before first surgery elevated (x-fold) CgA level before first surgery elevated ( x-fold) 1 * M 31 32 WDHA, abdominal pain tail VIP 10-fold NA 2 F 61 73 WDHA tail VIP 2-fold 2,6-fold 3 M 60 70 WDHA, weight loss tail VIP 2,5-fold 21,8-fold 4 F 68 70 abdominal pain tail calcitonin 20,6-fold 15-fold 5 M 54 54 No tail calcitonin 189-fold NA 6 M 69 69 No head calcitonin 16,5-fold 2-fold 7 F 66 66 No tail calcitonin 17,6-fold 0-fold 8 F 62 62 diarrhea, abdominal pain tail calcitonin 15-fold 2,7-fold 9 F 49 50 NME, wasting, anemia tail glucagon 46-fold 56-fold 10 M 66 66 NME, foot and leg exanthem, weight loss, diarrhea head glucagon 26,5-fold 1,2-fold 11 M 73 73 diarrhea, nausea, vomiting head glucagon 3-fold 2,6-fold 12 M 27 28 diabetes mellitus, weight loss tail glucagon 2,3-fold 0-fold * - associated with MEN 1, F - female, M - male, Dx - Dignosis, VIP - vasoactive intestinal peptide, NME - necrolytic migratory erythema, WDHA - watery diarrhea, hypokalemia, and achlorhydria, Verner-Morrison-syndrome, NA - not available Table 2: Preoperative imaging Preoperative imaging US EUS CT MRI SRS Ga68-DotatocPET/CT IOUS Number of patients 12 10/12 6/12 8/12 8/12 4/12 5/12 12/12 Primary tumor visualized 12/12 10/10 6/6 8/8 8/8 3/4 5/5 12/12 Lymph node metastases visualized 2/5 1/5 2/5 1/5 1/5 0/4 0/5 0/5 Distant metastases visualized 6/6 6/6 0/6 4/4 4/4 4/4 2/2 6/6 US - ultrasonography, EUS - endoscopic ultrasonography, CT - computed tomography, MRI – magnetic resonance imaging, SRS - somatostatin receptor scintigraphy, Ga68 DOTATOC-PET-CT - Gallium68 positron emission tomography, IOUS - intraoperative ultrasonography Table 3: Histopathology and hormon levels after initial surgery Patient No. Tumor TNM UICC R Ki-67 % Index Tumor Grade Tumor size (mm) Post-OP cure of symptoms Post-OP normalized hormone level 1 VIP 1 T4N1(8/24)M0 III R0 1 1 220 Yes Yes 2 VIP 2 TxNxM1(HEP) IV R2 1 1 35 No No 3 VIP 3 T4N1(3/12)M1 (HEP) IV R0 10 2 80 No No 4 CT 1 T2N0(0/6)M1 (HEP) IV R1 5 2 40 Yes Yes 5 CT 2 T3N1(7/22)M0 III R0 5 2 130 Yes Yes 6 CT 3 T2N0(0/22)M0 II R0 6 2 75 - Yes 7 CT 4 T2N0(0/16)M0 II R0 4 2 35 - Yes 8 CT 5 T3N1(1/10)M1 (HEP) IV R1 3 2 113 - Yes 9 Glu 1 T1N1(1/15)M1 (HEP) IV R0 10 2 45 Yes No 10 Glu 2 T3N1(1/17)M1 (HEP) IV R0 5 2 85 Yes Yes 11 Glu 3 1.T1NXM0 2. T1N0(0/17)M0 I R0 2 1 12 11 Yes Yes 12 Glu 4 T1N0(0/17)M0 I R0 3 2 117 Yes Yes VIP - Vipoma, CT - calcitoninoma, Glu - glucagonoma, HEP – hepar, - no symptoms before surgery Table 4: Follow-up Patient No. Tumor Follow-up after the first surgery (months) Recurrence of disease (months) Development of distant metastases Disease status 1 VIP 1 247 84 Hep, P, KL DOD 2 VIP 2 52 persistent disease persistent disease DOD 3 VIP 3 1 No No DOD 4 CT 1 48 9 Hep DOD 5 CT 2 108 No No NED 6 CT 3 92 No No NED 7 CT 4 50 No No NED 8 CT 5 49 11 Hep, LN AWD 9 Glu 1 20 3 Hep, LN DOD 10 Glu 2 114 3 Hep DOD 11 Glu 3 96 6 No NED 12 Glu 4 26 No No NED VIP - Vipoma, CT - calcitoninoma, Glu - glukagonoma, Hep - hepar, LN - lymph node, P - peritoneum, KL - kidney left, NED - no evidence of disease, AWD - alive with disease, DOD - death of disease Table 5: Characteristics of the patients with regard to entity Rf-pNEN(n=12) CT-pNEN (n=5) Glucagonoma (n=4) VIPoma (n=3) Median age at initial surgery (range) 60 (28-73) 64 (54-70) 54 (28-73) 58 (32-73) Sex (male/female) 7/5 2/3 3/1 2/1 Presence of MEN1 or VHL 1/12 0/5 0/4 1/3 Tumors size, mm, median (range) 82 (12-220) 79 (35-130) 65 (12-117) 112 (35-220) Tumor location (PH/PB/ PT) 3/0/9 1/0/4 2/0/2 0/0/3 Ki 67 % Index median (range) 5 (1-10) 5 (3-6) 5 (2-10) 4 (1-10) Stage I/II/III/IV 2/2/2/6 0/2/1/2 2/0/0/2 0/0/1/2 Surgical resection primary tumor 11/12 5/5 4/4 2/3 Potential curative resection 9/12 3/5 4/4 2/3 Additional treatment 6/12 (50%) 2/5 2/4 2/3 Somatostatin analogues 6/12 2/5 2/4 2/3 Chemotherapy 3/12 0/5 1/4 2/3 Sunitinib 1/12 0/5 1/4 0/3 PRRT 2/12 0/5 1/4 1/4 TAE/TACE 1/12 1/5 0/5 0/5 Radiofrequency ablation 1/12 1/5 0/5 0/5 Recurrence after curative resection, number (%) 5/12 (42%) 1/5 3/4 1/1 Tumor deaths, number (%) 6/12 (50%) 1/5 2/4 3/3 5-years tumor survival (%) 55 % 50 % 50 % 33 % Follow- up (months) 73 69 64 100 rf-pNEN - rare functional pancreatic neuroendocrine neoplasms, VIP - Vipoma, CT - calcitoninoma, Glu - glucagonoma, PH - pancreatic head,PB - pancreatic body, PT - pancreatic tail, PRRT - peptide receptor radionuclide therapy, RFA - radiofrequency ablation, TAE/TACE - transarterial embolisation / transarterial chemoembolization Additional Declarations No competing interests reported. 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Albers","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIiWNgGAWjYDACdh4wJQfEBkAsAeKwQaQO4NDCDNFiTLqWxAaIFgbCWvibeQ8+rvizLX1te/MGZt4dFgy67WefPebdU8vAd7wBqxaJw3zJhmfbbuduO3OsgJn3jASD2Zl0c2OeZ8cZJM/gsOYwj5lkYwNQy40cA2beNon6bQfS2KR5DhxjMLiRgFWH/GEe858Nf26nm91/A9bCYHb+GVTL/QdYtRgAbWFsYLudYHaDB6rlBtiWGqAt2N1lCPSLZGPbbcNtZ9IKDs4Fa3nGbjjnwAEeyTPYHSZ3vPfgR6DD5M2OH9744G1bHdBhaWwP3hyok+M7jsP7yABZyWEewurRQB3JOkbBKBgFo2DYAgDWgWHxntueVQAAAABJRU5ErkJggg==","orcid":"","institution":"Philipps University of Marburg","correspondingAuthor":true,"prefix":"","firstName":"Max","middleName":"B.","lastName":"Albers","suffix":""},{"id":275769550,"identity":"faa73698-1b55-45b0-ba53-337ba33ddd12","order_by":2,"name":"Dominik Wiese","email":"","orcid":"","institution":"Philipps University of Marburg","correspondingAuthor":false,"prefix":"","firstName":"Dominik","middleName":"","lastName":"Wiese","suffix":""},{"id":275769551,"identity":"fed1d590-5d44-42c7-82bd-86cd7196462d","order_by":3,"name":"Jerena Manoharan","email":"","orcid":"","institution":"Philipps University of Marburg","correspondingAuthor":false,"prefix":"","firstName":"Jerena","middleName":"","lastName":"Manoharan","suffix":""},{"id":275769552,"identity":"75fc8ea7-7863-43d9-8aac-1d6eda0c7cc7","order_by":4,"name":"Anja Rinke","email":"","orcid":"","institution":"Philipps University of Marburg","correspondingAuthor":false,"prefix":"","firstName":"Anja","middleName":"","lastName":"Rinke","suffix":""},{"id":275769553,"identity":"ade3a6bf-4d18-4049-900d-de7b5c3a067a","order_by":5,"name":"Moritz Jesinghaus","email":"","orcid":"","institution":"Philipps University of Marburg","correspondingAuthor":false,"prefix":"","firstName":"Moritz","middleName":"","lastName":"Jesinghaus","suffix":""},{"id":275769554,"identity":"b20672b6-2f94-40b5-b745-7c2962378a9b","order_by":6,"name":"Detlef K. Bartsch","email":"","orcid":"","institution":"Philipps University of Marburg","correspondingAuthor":false,"prefix":"","firstName":"Detlef","middleName":"K.","lastName":"Bartsch","suffix":""}],"badges":[],"createdAt":"2024-02-29 17:08:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4000625/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4000625/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52031258,"identity":"3dd75822-2c27-4ed4-874e-fc675ff44e88","added_by":"auto","created_at":"2024-03-05 16:24:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":212232,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCourse of a VIPoma patient over 20 years\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Surgery: DPR - distal pancreatectomy, SE - splenectomy, CR - colon resection, TR - tumor resection, DR - diaphragm resection, CHE - cholecystectomy, NF - nephrectomy left, S - segment, GR - gastric resection, PBR - pancreatic body resection\u003c/p\u003e\n\u003cp\u003e2. Multimodal therapy: SAA - somatostatin analogs, PRRT - peptide rezeptor radionuclid therapy\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4000625/v1/90d69d2889452de2eda91ea7.png"},{"id":53241951,"identity":"e90536f4-830e-4cd6-b493-bb9854e8e31a","added_by":"auto","created_at":"2024-03-22 10:13:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":570787,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4000625/v1/bccfac76-436e-4468-8486-4d8751c1a2a3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Longterm outcome of rare functioning pancreatic neuroendocrine neoplasms","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRare functioning pancreatic neoplasms (rf-pNENs) include glucagonomas, VIPomas, Calctitonin-producing pNENs, somatostatinomas, PTHrp-omas, GRHomas, ACTHomas and p-NENs secreting renin, luteinizing hormone, erythropoietin and insulin-like growth factor II [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Rf-pNENs are extremeley rare and account for only approximately 5% of functioning pNENs, with annual incidence of approximately 0.05\u0026ndash;0.1/1.000000/year [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The most frequent familial condition associated with rf-pNEN is the multiple endocrine neoplasia typ 1 (MEN1), with glucagonomas occurring in 5% and VIPomas in 3% of MEN1-patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Glucagonomas in the setting of MEN1 usually do not cause a syndome, although glucagon serum levels may be significantly elevated. The diagnosis of an rf-pNEN requires at least the demonstration of an inappropriate elevation of the specific serum hormone (i.e., vasoactive polypeptide or glucagon), ideally combined with symptoms caused by of oversecretion of the destinct hormone. The diagnosis of rf-pNEN cannot be based solely on positive immunohistochemical results of resected specimens [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. As of 2022, approximately 600 glucagonomas [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], 100 Vipomas [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and 60 calcitonin-producing pNEN [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] have been reported in case reports or small case series, whereas reports on other rf-pNENs do not exceed 10\u0026ndash;25 cases per subtype [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGlucagonoma, first described in 1942 by Becker [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], and is a pancreatic alpha-cell tumor that produces glucagon. It causes the glucagonoma syndrome, which includes necrolytic migratory erythema (NME), diabetes, venous thromboembolism, diarrhea, stomatitis and anemia. However, in some series, only half of patients had NME and only 20% developed diabetes prior to the diagnosis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Thus, published characteristics of glucagonoma patients represent a mixed cohort of patients, either suffering from the classic glucagon-secreting tumour with full-blown glucagonoma syndrome or those secreting less active forms of glucagone without impressive clinical significance.\u003c/p\u003e \u003cp\u003eVIPomas were first reported by Verner and Morrison in 1958 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and are characterized by excessive secretion of vasoactive intestinal peptide (VIP), which may cause typical watery diarrhea, hypokalemia, and achlorhydria, the so-called WDHA syndrome.\u003c/p\u003e \u003cp\u003eCalcitonin-producing pNENs (CT-pNENs) are an extremely rare cause of hypercalcitoninemia, which is usually highly suggestive of medullary thyroid carcinoma [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Hormonal excess of CT-pNEN may cause diarrhea and abdominal pain. CT-pNEN appear to have a unique molecular signature compared to other pNEN subtypes [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A recent pathological study showed that approximately 10% of all pNENs show a positive calcitonin immunoreactivity, whereas the corresponding serum CT levels are rarely elevated [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe average age at diagnosis of rf-pNENs is between 50 and 60 years with an equal gender distribution. A significant number of patients with rf-pNENs present with metastatic disease (40\u0026ndash;80%) in the liver at initial diagnosis. The management of rf-pNEN is challenging, because high level evidence recommendations currently are lacking, especially for the treatment of symptomatic patients with diffuse metastatic tumors [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Surgical resection of all lesions is considered the only curative option. Symptom and tumor growth control can be achieved either with somatostatin analogs (SSAs), chemotherapy, and targeted therapy with sunitinib or peptide radionucleotide receptor therapy (PRRT) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Debulking surgery and/or other cytoreductive techniques such as liver transarterial (chemo)embolization (TACE) or radioembolization can also be employed [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Nevertheless, because of the rarity of these tumors, experiences with more novel and specific therapeutic tools such as PRRT are still sparse. We present a series of 12 patients with rf-pNEN from a tertiary referral center who were treated during a 20 years period. Clinicopathological characteristics, therapeutic modalities and prognosis were evaluated.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003eRf-pNENs were defined according to the ENETS guidelines such as VIPoma, glucagonoma or calcitonin-producing pNEN [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The diagnosis of a distinct rf-pNEN was confirmed, if the pNEN was associated with at least 2-fold elevated serum hormone levels and positive immunostaining for the respective hormone. Patients diagnosed with rf-pNENs were identified from the prospective pancreatic database of the Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, which was established in 2002 as a prerequisite for certification as an ENETS Center of Excellence.\u003c/p\u003e \u003cp\u003eThe demographics, preoperative imaging, type of surgery, postoperative complications, and long-term cure rates of all patients were retrospectively analyzed for all patients. Immunohistochemistry for synaptophysin, chromogranin A and Ki67 was re-evaluated by an experienced pathologist (M.J.). The fact that initially elevated serum hormone levels dropped to normal levels after potentially curative surgery was considered as evidence that the resected pNEN was the source of hormone hypersecretion. Data collection and analysis were approved by the local ethics committee of the University of Marburg (no. RS 22\u0026ndash;51). Selective clinical data from our patients with calcitonin-producing pNEN have been reported previously [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePreoperative imaging routinely includes abdominal ultrasonography, multidetector computed tomography (CT), and/or magnetic resonance imaging (MRI) with gadolinium and endoscopic ultrasonography (EUS). Some patients also underwent somatostatin receptor scintigraphy (SRS) until 2013, since 2014 Gallium-68-positron-emission-tomography (Ga68-DOTATOC PET/CT) was applied instead. In the case of resectable disease, and if fit for surgery, patients underwent oncological pancreatic resection with or without metastasectomy. In cases of diffuse metastatic disease without complications (e.g., bowel obstruction), palliative debulking surgery was performed after a multidisciplinary tumor board decision. After potentially curative resection, no adjuvant treatment was administrered according to ENETS guidelines [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTumors were classified according to the WHO classification 2017 [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] and defined as malignant in the presence of lymphatic and/or distant metastases at the initial diagnosis or during follow-up [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. All tumors were stained for synaptophysin and chromogranin A. Ki67 expression was determined as the percentage of positively stained tumor cells among the total number of malignant cells assessed. Potentially secreted hormones, such as vasoactive intestinal peptide, glucagon and calcitonin, were verified by immunohistochemistry as described previously [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Postoperative complications were classified according to Clavien-Dindo [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Clinically relevant postoperative pancreatic fistula (POPF) types B and C were defined according to the International Study Group of Pancreatic Fistula [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The length of hospital stay was not evaluated, because several institutional changes in patient demission management over the years would have induced a significant bias.\u003c/p\u003e \u003cp\u003eFollow-up was calculated from the time of the initial surgery to the evaluation date of July 31, 2023. Disease-free survival was defined as the time from potential curative surgery to disease recurrence. An annual clinical follow-up was performed at our or hospital or by a personal physician with laboratory workup, including the preoperatively increased specific hormone level, MRI of the abdomen, and in case of suspicion of recurrence or metastatic disease with somatostatin-receptor imaging. Patients were classified as having no evidence of disease, if there was no suspicion of symptom recurrence, the respective serum hormone levels were not elevated, and there were no visible tumor lesions on imaging.\u003c/p\u003e \u003cp\u003eIn the case of palliative surgical procedures and/or unresectable disease, patients were treated with a variety of modalities such as PRRT, transarterial chemoembolization (TACE), somatostatin analogs or chemotherapy, upon recommendation of the multidisciplinary tumor board.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn the study period from January 2002 to December 2022, 216 patients with pNENs underwent surgery at the ENETS Center of Excellence Marburg. This included 156 patients with sporadic and 60 with MEN1-associated pNEN. Overall, 79 (36.6%) patients had functioning tumors, of which twelve (12/216, 5.5%) had rf-pNEN according to the actual ENETS definition [5].\u003c/p\u003e\n\u003cp\u003eFive patients had a calcitoninoma, four patients had a glucagonoma and three patients had a VIPoma, respectively. Except for one patient with MEN1-associated VIPoma, the other 11 tumors were sporadic. Five patients were female. The median age at the time of surgery was 60 years (range 28-73 years). All twelve patients had at least 2-fold elevated serum levels of the specific tumor released homone (median 31-fold, range 2-189-fold). CgA was measured preoperatively in ten patients and was elevated in eight cases. All but three patients with CT-producing pNEN were symptomatic. Six patients had full hormone-associated syndrome (three Vipomas, two glucagonomas and one CT-producing pNEN). Diarrhea was the most common symptom, presenting in 6 of 12 patients (3 VIPomas, 1 calcitoninoma and 2 glucagonomas).\u003c/p\u003e\n\u003cp\u003eThe time between diagnosis and the first surgery varied between 1 and 137 months. The demographic characteristics and symptoms of the 12 patients are summarized in Table 1.\u0026nbsp;Preoperative imaging revealed the rf-pNENs in all 12 patients. All but one tumor had a size \u0026gt;20mm. For the visualization of the primary tumor EUS and MRI were most sensitive with 100% detection and accuracy.\u0026nbsp;Four patients underwent SRS scintigraphy until 2013, since 2014 Ga68-DOTATOC PET/CT was performed in another 5 patients.\u0026nbsp;SRS imaging showed the primary tumor in 8 of 9 patients, lymph node metastases in none of the patients, but liver metastases in all six patients with histologically confirmed distant metastases. It should\u0026nbsp;be noted that only EUS and MRI detected a small (12 mm) glucagonoma in the pancreatic head. The preoperative imaging data are summarized in Table 2.\u0026nbsp;EUS-guided\u0026nbsp;FNA was performed in 4 patients and confirmed the presence of pNEN in all 4 cases.\u003c/p\u003e\n\u003cp\u003eThe tumor was located in the pancreatic tail\u0026nbsp;in 9 patients and in the pancreatic head in three patients.\u0026nbsp;Eleven of the 12 rf-pNENs were considered completely resectable based on preoperative imaging.\u0026nbsp;Eight patients underwent distal splenopancreatectomies, one patient PPPD, one patient underwent total pancreatectomy and one patient underwent enucleation of the pancreatic head for the above-mentioned small (12mm) glucagonoma. The remaining patient with a large VIPoma with far advanced diffuse metastatic disease in the liver and the peritoneum had only an exploratory laparotomy with palliative ileocecal resection for bowel obstruction without removal of the primary tumor. Ten patients underwent conventional open surgery, and the remaining two patients underwent robotic-assisted procedures. In addition to the pancreatic resection, five patients also underwent resection of liver metastases. In 9 of the 12 patients, complete (R0) resection of the primary tumor and, if present, liver metastases was achieved, so that serum hormone levels dropped to normal levels postoperatively.\u003c/p\u003e\n\u003cp\u003ePostoperative complications (Clavien-Dindo\u0026nbsp;\u003cu\u003e\u0026gt;\u003c/u\u003eIII) occured in four patients (all three with VIPoma and one with glucagonoma), all of which had to be reoperated. One of them was due to peritonitis, with a suspected anastomotic leak. However, this has not been confirmed. The second patient required intraoperative intra-abdominal lavage and drainage of an intraabdominal abscess. The third patient underwent a reoperation because of bleeding from the spleen, which required splenectomy. The last patient who had initially only an explorative laparotomy, underwent two reoperations because of tumor-associated perforation of the small intestine. He died on the 30th postoperative day after the initial exploration due to multiorgan failure. None of the patients developed postoperative pancreatic fistula type B or C.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRf-pNEN was confirmed by histopathological examination in all patients. All 12 primary tumors were immunohistochemically positive for chromogranin A, synaptophysin and their respective secreted hormones. All primary tumors were well differentiated and graded G1 in three patients and G2 in the remaining nine patients. The tumor was classified as T1 in three patients, T2 in three, T3 in three and T4 in two patients, respectively. Six patients had locoregionally limited, Stage I-III rf-pNENs, and the other six patients had stage IV disease. \u0026nbsp;The median tumor size was 82 (range 12-220) mm. Five of the twelve patients had lymph node metastasis. A median of 13 (range 5-28) lymph nodes were removed. In 9 of the12 patients, resection was defined as R0 resection. Histopathology results and hormon levels after initial surgery are summarized in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up period was 75 months (range 1-247 months). Four of the six curatively resected patients with localized disease (stages I-III) remained disease-free for a median of 61\u0026nbsp;(range\u0026nbsp;6-108) months. In this group one patient experienced local recurrence 6 months after glucagonoma enucleation from the pancreatic head, which required subsequent\u0026nbsp;pylorus-preserving pancreatic head resection. Since this reoperation the patient has remained disease-free until the evaluation date for 90 months. Another patient in this group experienced local recurrence 84 months after the first surgery due to a 22cm sized initially locoregionally metastasized VIPoma in the pancreatic tail. This patient underwent a total of 7 redo-surgeries and more than 40 cycles of multimodal therapy (SSA, Interferon, PRRT, Chemotherapy) due to tumor recurrence and/or progression (All the treatment modalities are summarized in Figure 1). The sequence of multimodal treatment led to a survival rate of 247 months after initial diagnosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the six patients with stage IV disease\u0026nbsp;multimodal treatment, including somatostatin analogs, chemotherapy regimens with Dacarbazine, Doxorubicin, Streptozotocin, Capecitabine, targeted therapy with sunitinib, radiofrequency ablation or TACE of liver metastases, recurrent PRRTs and reoperations were performed. One patient\u0026nbsp;with a stage IV CT-producing pNEN developed a local lymph node recurrence 11 months after the initial surgery, and excision of this metastasis was performed.\u0026nbsp; He was alive with the disease after 49 months of follow-up. The remaining 5 patients died of disease 1, 20, 48, 52, 114 and 247 months after the initial surgery, respectively (Follow up\u0026nbsp;are summarized\u0026nbsp;Table 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOne year survival in our cohort was 91%, the true 5-years survival rate was 55%. In three patients 5 years survival was not reached. A comparison of the characteristics, treatments and follow-up between the individual tumor subtypes are summarized in Table 5.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our series, patients with rf-pNEN had a median age of 61.5 (range 28\u0026ndash;73 years), which is in the range reported in the literature [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In addition, no sex predominance was noted in either our series, nor in the literature. All three patients with VIPoma presented with the classic symptomatology of watery diarrhea, which is typical in these patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, only two of four patients with glucagonoma in the present series had necrolytic migratory erythema (NME), and only one patient had diabetes. This is in line with a previous Swedish study of 23 patients [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Only 22% of these patients had developed diabetes prior to the diagnosis of glucagonoma and NME was diagnosed in only 52% of patients. In a recent clinicopathological study of 25 CT-pNEN 16 were not associated with signs or symptoms of hormonal hypersecretion and the other 9 with symptoms of hyperinsulinism [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Elevated serum calcitonin levels were not reported in the clinical records of any of these 25 cases. The here presented 5 patients all had significantly elevated CT serum levels up to 150-fold. However, only the patient with a 150-fold elevated CT had diarrhea, which is typical for excessive hypercalcitonemia. Abdominal pain due to tumor size has been one leading symptom in 3 of our 12 (25%) patients with rf-pNEN, which was reported to be present in 19,8%-33% of other case series [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the present cohort there was a predominant tumor location in the left pancreas (75%), which is in line with previous case series of VIPomas, glucagonomas and CT-pNEN [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The median diameter in our cohort was 82 (range 12\u0026ndash;220), and only one patient with a glucagonoma had a tumor size\u0026thinsp;\u0026lt;\u0026thinsp;20mm. In an older literature review of 407 patients with glucagonoma 80 (29%) patients had small tumors of 20mm or less and these patients had a rate of metastasis of 8,8% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The median tumor size in the present cohort was larger than that previously reported for VIPoma with a median diameter of 32\u0026ndash;57,5mm [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], glucagonoma with a median size from 50 to 55mm [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], and CT-pNEN with a median size of 48mm [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs in other studies patients with rf-pNEN frequently show liver metastases at the time of initial diagnosis as in 50% of patients in our cohort. This is in the range of reported rates for VIPoma of 36\u0026ndash;75% [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] and glucaogonoma of 50\u0026ndash;78% [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. It is of note, in the present series, 2 of 5 CT-pNEN presented with liver metastases, whereas in a previous series only 4 of 23 (17%) tumors did so [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. None of our patients with rf-pNEN showed initially bone metastases compared to reports of up to 6\u0026ndash;15% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, the low rates might be due to the lower sensitivity of SRS scintigraphy imaging used in the early 2000 years.\u003c/p\u003e \u003cp\u003eAll 12 rf-pNENs in the present cohort were G1 (n\u0026thinsp;=\u0026thinsp;3) or low G2 (n\u0026thinsp;=\u0026thinsp;9) tumors with a Ki67 index in the primary tumor of at most 10%. This is in line with the Ki67 index in the majority of reported glucogonomas [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] and CT-pNEN [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. For VIPoma, however, G3 tumors have been described in up to 27% of cases [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the present cohort, all rf-pNENs could be visualized by preoperative imaging with either CT or MRI because of the large tumor size, as reported in previous series [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. EUS was used in only half of our patients and had an additional value in only one patient with 12 mm glucagonoma in the pancreatic head. According to recent guidelines [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], imaging with 68Ga-labeled somatostatin analogs with PET/CT is more sensitive and highly specific for rare p-NENs and is therefore recommended as the first-line diagnostic imaging method for staging in patients with rf-pNENs. Our cohort supports this recommendation, since 8 of 9 patients who underwent SRS imaging showed positive primary tumors and in all 5 patients who underwent SRS imaging metastasis could be visualized. In patients with rapid tumor growth and/or high G2 or G3 tumors, 18-FDG-PET/CT can also be considered to assess tumor burden [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. In our cohort this was not applied, because we had only G1 and low G2-tumors.\u003c/p\u003e \u003cp\u003eThe indications for surgery are influenced by clinical symptom control, the technical possibility of local R0 resection and the presence and extent of metastatic spread [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Curative surgery should always be indicated, even in the presence of metastatic disease, if a complete resection can be achieved and the patient is fit for surgery [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In the present cohort, we could achieve a potential curative R0 resection, documented by postoperative normal serum hormone levels, in 9 of 12 (75%) patients of whom 3 patients had also liver metastases. The surgery rate as well as the R0 resection rate are comparably high to other series, ranging from 28 to 63% [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. In two CT-pNEN patients with liver metastases, R0 resection was attempted based on preoperative imaging, but only a R1 resection could be achieved. However, this fact, however, is not considered a failure since elevated hormone levels dropped to the normal range postoperatively. In addition, according to ENETS guidlines debulking surgery can be considered in rf-pNEN, if at least 80% of gross tumor is thought resectable [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. The type of surgery for rf-pNENs depends on the location of the primary tumor. Because of the usually large rf-pNEN size and high prevalence of liver metastases, curative surgery usually requires formal pancreatic resection with lymphadenectomy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. This was performed in 10 of 11 resected patients in the present series, as well as in the majority of patients in other series [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Even for small rf-pNEN parenchyma-sparing resection, such as enucleation, might be insufficient. One of our patients had a robotic-assisted enucleation of 12mm sized glucagonoma out of the pancreatic head with negative lymph node sampling and developed local recurrence 6 months later. Consequently, the patient underwent partial pancreaticoduodenectomy, which resulted in a disease-free survival of 90 months so far.\u003c/p\u003e \u003cp\u003eFive of the six patients with recurrent disease and one patient with an unresectable VIPoma underwent several cycles of multimodal treatment, including redo surgery, somatostatin analogues, chemotherapy, targeted therapy with sunitinib, local ablative therapies with TACE and/or radiofrequency ablation and PRRT (see Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Although more therapies have become available for pNEN during the last decade, including targeted therapies with e.g sunitinib, new chemotherapy regimens (e-g. Tem/Cap, Folfirinox) and PRRT, no significant data has yet been compiled on the onoclogical outcomes in patients with rf-pNEN. Thus, the discussion of the possible advantages and disadvantages of individual treatments and their sequence is somewhat vague and is beyond the scope of this article. However, somatostatin analogs, were used as the mainstay treatment in several other series [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] when curative surgery was not an option. They can control symptoms caused by excessive hormone secretion and prolong progression-free survival [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. This was the case in six of seven patients with recurrent or persistent disease in our cohort. Since the majority of rf-pNEN somatostatin receptor-positive grade 1/2 tumors, 8 of 9 investigated in the presented series, PRRT is currently a very good option to control symptoms of hormonal excess as well as tumor growth progression [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. In a previous series, PRRT was the most efficacious second-line treatment in patients with VIPoma who had refractory WDHA syndrome despite the maximum doses of SSA [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. It is also noteworthy that repeated surgery for disease recurrence should always be considered in the multimodal concept. One of our patients with a 22cm sized VIPoma underwent - embedded in SSA treatment, chemotherapy and PRRT - a total of 7 reoperations, which resulted in a survival of over 20 years are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eSince the treatment armentarium is complex, all patients with advanced rf-pNEN should be discussed in a multidisciplinary tumor board, ideally in centers of excellence.\u003c/p\u003e \u003cp\u003eIn the present study the eight patients with potential curative surgery had a 5-year survival of 63%, which is similar to that reported by others [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe study from Azizian et al. showed that patients who underwent surgery had a longer overall survival than patients who were treated with other therapeutic modalities (44 vs. 33 months) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Five (42%) patients remained free of disesase median 74 months after initial surgery. This outcome is similar to that of previous studies of rf-pNENs ranging from 15 to 180 months [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA study by Sakurai et al. reported a disease-free interval after an initial surgery of 180 months. This patient underwent after 180 months of disease-free interval a second curative surgery for the locally recurrent VIPoma. The patient is alive with no relapse following 14 months after the second surgery [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Those cases demonstrates the importance of long-term observation of patients.\u003c/p\u003e \u003cp\u003eThe study from Murakami et al. showed, that the median survival time for patients with VIPoma was 71 months [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In the present study the three patients with VIPoma showed the 5 years tumor survival 33% and the median survival time 100 months.\u003c/p\u003e \u003cp\u003eIt is crucial to separate between cases in which all metastases and the primary tumour are resectable and cases in which complete resection of all lesions is not possible (debulking surgery). The survival of the palliatively operated 3 patients in the present study was 48, 49 and 52 months. Brugel et al. showed in a retrospective analysis in 4 cases, a debulking surgery with palliative intent. The median progression- free survival was 21 months [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt should be mentioned that CT-pNEN might be less aggressive than VIPoma or glucagonoma, since according to a recent study of 25 CT-pNEN 60% of patients were alive with no evidence of disease and 20% survived with disease after 5 years follow-up [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This tendency can be confirmed by the present study.\u003c/p\u003e \u003cp\u003eThe present study had two major limitations. First, the collective size is very small, as it is usual for these very rare tumor entities. Second, the retrospective design implicates bias and missing data. Thus, prospective registration in international databases (e.g, the ENETS-Database) is required to better understand the characteristics and outcomes of these extremely rare tumors due to different therapeutic approaches.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, rf-pNENs are a heterogeneous group of tumors with good long-term prognosis, if initially radically resected. Long-term survival can even be achieved in metastasized tumors using multimodal treatment. As these tumors are extremely rare, treatment in expert centers is recommended.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eStatement of Ethics:\u0026nbsp;\u003c/strong\u003eThe study was conduced in accordance with the Declaration of Helsinki.\u0026nbsp;Data collection and analysis were approved by the local ethics committee of the University of Marburg (protocol code RS 22-51).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest statement:\u003c/strong\u003e The authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This research was supported by\u0026nbsp;Open Access funding provided by Open Access Publication Fund of the\u0026nbsp;Philipps University Marburg, Germany with support of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e:\u0026nbsp;Conceptualization: D.K.B., M.S.; methodology and software: M.S., collecting patient data: J.M., M.A., D.W. D.K.B, writing-original draft preparation: MS, D.K.B.; review and editing: D.K.B., M.A., JM, MJ, AR, DW; supervision: D.K.B.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e The authors are grateful to all patients who participated in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e\u0026nbsp; \u0026nbsp;The data that support the findings of this study are not publicly available because they contain information that could compromise the privacy of research participants but are available from one of the authors [M.S.] upon reasonable request.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eO\u0026apos;Toole D, Salazar R, Falconi M, Kaltsas G, Couvelard A, de Herder WW, Hyrdel R, Nikou G, Krenning E, Vullierme MP, Caplin M, Jensen R, Eriksson B; Frascati Consensus Conference; European Neuroendocrine Tumor Society. 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PMID: 25353285.\u003c/li\u003e\n\u003cli\u003eAl-Toubah T, Pelle E, Hallanger-Johnson J, Haider M, Strosberg J. ACTH-secreting pancreatic neuroendocrine neoplasms: A case-series. J Neuroendocrinol. 2023 Oct;35(10):e13336. doi: 10.1111/jne.13336. Epub 2023 Sep 9. PMID: 37688510.\u003c/li\u003e\n\u003cli\u003ede Herder WW, Hofland J. Somatostatinoma. 2023 Apr 12. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferr\u0026egrave;re B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000\u0026ndash;. PMID: 25905263.\u003c/li\u003e\n\u003cli\u003eElangovan A, Zulfiqar H. Somatostatinoma. 2023 Jun 25. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan\u0026ndash;. PMID: 31869077.\u003c/li\u003e\n\u003cli\u003eBecker SW, Kahn D, Rothman S. Cutaneous manifestations of internal malignant tumors. Arch Dermatol Syphilol. 1942;45:1069\u0026ndash;1080. doi: 10.1001/archderm.1942.01500120037004.\u003c/li\u003e\n\u003cli\u003eKindmark H, Sundin A, Granberg D, Dunder K, Skogseid B, Janson ET, Welin S, Oberg K, Eriksson B. Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years. Med Oncol. 2007;24(3):330-7. doi: 10.1007/s12032-007-0011-2. PMID: 17873310.\u003c/li\u003e\n\u003cli\u003eVerner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958 Sep;25(3):374-80. doi: 10.1016/0002-9343(58)90075-5. PMID: 13571250.\u003c/li\u003e\n\u003cli\u003eViola D, Elisei R. Management of Medullary Thyroid Cancer. Endocrinol Metab Clin North Am. 2019 Mar;48(1):285-301. doi: 10.1016/j.ecl.2018.11.006. Epub 2018 Dec 26. PMID: 30717909.\u003c/li\u003e\n\u003cli\u003eSchneider R, Waldmann J, Swaid Z, Ramaswamy A, Fendrich V, Bartsch DK, Schlosser K (2011) Calcitonin-secreting pancreatic endocrine tumors: systematic analysis of a rare tumor entity. Pancreas 40:213\u0026ndash;221.\u003c/li\u003e\n\u003cli\u003ePerren A, Couvelard A, Scoazec JY, Costa F, Borbath I, Delle Fave G, Gorbounova V, Gross D, Grossma A, Jense RT, Kulke M, Oeberg K, Rindi G, Sorbye H, Welin S; Antibes Consensus Conference participants. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pathology: Diagnosis and Prognostic Stratification. Neuroendocrinology. 2017;105(3):196-200. doi: 10.1159/000457956. Epub 2017 Feb 11. PMID: 28190015.\u003c/li\u003e\n\u003cli\u003eKl\u0026ouml;ppel G. Neuroendocrine Neoplasms: Dichotomy, Origin and Classifications. Visc Med. 2017 Oct;33(5):324-330. doi: 10.1159/000481390. Epub 2017 Oct 16. PMID: 29177160; PMCID: PMC5697503.\u003c/li\u003e\n\u003cli\u003eRindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, Ezzat S, de Herder WW, Klimstra DS, Papotti M, Asa SL. Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms. Endocr Pathol. 2022 Mar;33(1):115-154. doi: 10.1007/s12022-022-09708-2. Epub 2022 Mar 16. PMID: 35294740.\u003c/li\u003e\n\u003cli\u003ePezzilli R, Partelli S, Cannizzaro R, Pagano N, Crippa S, Pagnanelli M, Falconi M. Ki-67 prognostic and therapeutic decision driven marker for pancreatic neuroendocrine neoplasms (PNENs): A systematic review. Adv Med Sci. 2016 Mar;61(1):147-53. doi: 10.1016/j.advms.2015.10.001. Epub 2015 Oct 23. PMID: 26774266.\u003c/li\u003e\n\u003cli\u003eDindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. doi: 10.1097/01.sla.0.\u003c/li\u003e\n\u003cli\u003eChong E, Ratnayake B, Lee S, French JJ, Wilson C, Roberts KJ, Loveday BPT, Manas D, Windsor J, White S, Pandanaboyana S. Systematic review and meta-analysis of risk factors of postoperative pancreatic fistula after distal pancreatectomy in the era of 2016 International Study Group pancreatic fistula definition. HPB (Oxford). 2021 Aug;23(8):1139-1151. doi: 10.1016/j.hpb.2021.02.015. Epub 2021 Mar 18. PMID: 33820687.\u003c/li\u003e\n\u003cli\u003eAngelousi A, Koffas A, Grozinsky-Glasberg S, Gertner J, Kassi E, Alexandraki K, Caplin ME, Kaltsas G, Toumpanakis C. Diagnostic and Management Challenges in Vasoactive Intestinal Peptide Secreting Tumors: A Series of 15 Patients. Pancreas. 2019 Aug;48(7):934-942. doi: 10.1097/MPA.0000000000001347. PMID: 31268974.\u003c/li\u003e\n\u003cli\u003eMurakami M, Fujimori N, Matsumoto K, Ohno A, Teramatsu K, Takamatsu Y, Takeno A, Ueda K, Oono T, Ito T, Ogawa Y. A clinical analysis on functioning pancreatic neuroendocrine tumors (focusing on VIPomas): a single-center experience. Endocr J. 2022 Oct 28;69(10):1201-1209. doi: 10.1507/endocrj.EJ22-0111. Epub 2022 May 27. PMID: 35644576.\u003c/li\u003e\n\u003cli\u003eBrugel M, Walter T, Goichot B, Smith D, Lepage C, Do Cao C, et al. Efficacy of treatments for VIPoma: A GTE multicentric series. Pancreatology. 2021;21(8):1531\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eRodr\u0026iacute;guez G, Vargas E, Aba\u0026uacute;nza C, C\u0026aacute;ceres S. Necrolytic migratory erythema and pancreatic glucagonoma. Biomedica. 2016 Jun 3;36(2):176-81. doi: 10.7705/biomedica.v36i3.2723. PMID: 27622478.\u003c/li\u003e\n\u003cli\u003eWei J, Song X, Liu X, Ji Z, Ranasinha N, Wu J, Miao Y. Glucagonoma and Glucagonoma Syndrome: One Center\u0026apos;s Experience of Six Cases. J Pancreat Cancer. 2018 May 1;4(1):11-16. doi: 10.1089/pancan.2018.0003. PMID: 30631852; PMCID: PMC5999015.\u003c/li\u003e\n\u003cli\u003eNikou GC, Toubanakis C, Nikolaou P, et al. VIPomas: an update in diagnosis and management in a series of 11 patients. Hepato-gastroenterology. 2005 Jul-Aug;52(64):1259-1265. PMID: 16001675.\u003c/li\u003e\n\u003cli\u003eBrugel M, Walter T, Goichot B, Smith D, Lepage C, Do Cao C, Hautefeuille V, Rebours V, Cadiot G, de Mestier L; Groupe d\u0026rsquo;\u0026Eacute;tude des Tumeurs Endocrines (GTE). Efficacy of treatments for VIPoma: A GTE multicentric series. Pancreatology. 2021 Dec;21(8):1531-1539. doi: 10.1016/j.pan.2021.08.001. Epub 2021 Aug 5. PMID: 34404601.38. \u003c/li\u003e\n\u003cli\u003eKann, P.H. Is endoscopic ultrasonography more sensitive than magnetic resonance imaging in detecting and localizing pancreatic neuroendocrine tumors? Rev Endocr Metab Disord 19, 133\u0026ndash;137 (2018). \u003c/li\u003e\n\u003cli\u003eSchizas D, Mastoraki A, Bagias G, Patras R, Moris D, Lazaridis II, Arkadopoulos N, Felekouras E. Clinicopathological data and treatment modalities for pancreatic vipomas: a systematic review. J BUON. 2019 Mar-Apr;24(2):415-423. PMID: 31127985.\u003c/li\u003e\n\u003cli\u003eGiampatzis V, Kotsiari C, Bostantzis P, Chrisoulidou A, Fotiadou A, Loti S, Papantoniou S, Papadopoulou P. Pancreatic Vasoactive Intestinal Peptide-Producing Tumor as a Rare Cause of Acute Diarrhea and Severe Hypokalemia. J Med Cases. 2023 Oct;14(9-10):307-316. doi: 10.14740/jmc4141. Epub 2023 Oct 13. PMID: 37868325; PMCID: PMC10586331.\u003c/li\u003e\n\u003cli\u003eCalabr\u0026ograve; D, Argalia G, Ambrosini V. Role of PET/CT and Therapy Management of Pancreatic Neuroendocrine Tumors. Diagnostics (Basel). 2020 Dec 7;10(12):1059. doi: 10.3390/diagnostics10121059. PMID: 33297381; PMCID: PMC7762240.\u003c/li\u003e\n\u003cli\u003eMagi L, Prosperi D, Lamberti G, Marasco M, Ambrosini V, Rinzivillo M, Campana D, Gentiloni G, Annibale B, Signore A, Panzuto F. Role of [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT in the management of G1 gastro-entero-pancreatic neuroendocrine tumors. Endocrine. 2022 May;76(2):484-490. doi: 10.1007/s12020-022-03000-3. Epub 2022 Feb 11. PMID: 35149933; PMCID: PMC9068639.\u003c/li\u003e\n\u003cli\u003ePartelli S, Cirocchi R, Crippa S, Cardinali L, Fendrich V, Bartsch DK, Falconi M. Systematic review of active surveillance versus surgical management of asymptomatic small non-functioning pancreatic neuroendocrine neoplasms. Br J Surg. 2017 Jan;104(1):34-41. doi: 10.1002/bjs.10312. Epub 2016 Oct 5. PMID: 27706803.\u003c/li\u003e\n\u003cli\u003eSmith SL, Branton SA, Avino AJ, Martin JK, Klingler PJ, Thompson GB, Grant CS, van Heerden JA. Vasoactive intestinal polypeptide secreting islet cell tumors: a 15-year experience and review of the literature. Surgery. 1998 Dec;124(6):1050-5. doi: 10.1067/msy.1998.92005. PMID: 9854582.\u003c/li\u003e\n\u003cli\u003eCaplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedl\u0026aacute;čkov\u0026aacute; E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. doi: 10.1056/NEJMoa1316158. PMID: 25014687.\u003c/li\u003e\n\u003cli\u003eCamus B, Cottereau AS, Palmieri LJ, Dermine S, Tenenbaum F, Brezault C, Coriat R. Indications of Peptide Receptor Radionuclide Therapy (PRRT) in Gastroenteropancreatic and Pulmonary Neuroendocrine Tumors: An Updated Review. J Clin Med. 2021 Mar 18;10(6):1267. doi: 10.3390/jcm10061267. PMID: 33803817; PMCID: PMC8003169.\u003c/li\u003e\n\u003cli\u003eZandee WT, Brabander T, Blažević A, Kam BLR, Teunissen JJM, Feelders RA, Hofland J, de Herder WW. Symptomatic and Radiological Response to 177Lu-DOTATATE for the Treatment of Functioning Pancreatic Neuroendocrine Tumors. J Clin Endocrinol Metab. 2019 Apr 1;104(4):1336-1344. doi: 10.1210/jc.2018-01991. PMID: 30566620.\u003c/li\u003e\n\u003cli\u003eC\u0026acirc;mara-de-Souza AB, Toyoshima MTK, Giannella ML et al. Insulinoma: A retrospective study analyzing the differences between benign and malignant tumors. Pancreatology 2018;18:298-303. PMID: 29452754\u003c/li\u003e\n\u003cli\u003eSoga J, Yakuwa Y. Vipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases. J Exp Clin Cancer Res. 1998 Dec;17(4):389-400. PMID: 10089056.\u003c/li\u003e\n\u003cli\u003eGhaferi AA, Chojnacki KA, Long WD, Cameron JL, Yeo CJ. Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg. 2008 Feb;12(2):382-93. doi: 10.1007/s11605-007-0177-0. PMID: 17510774.\u003c/li\u003e\n\u003cli\u003eSmith SL, Branton SA, Avino AJ, Martin JK, Klingler PJ, Thompson GB, Grant CS, van Heerden JA. Vasoactive intestinal polypeptide secreting islet cell tumors: a 15-year experience and review of the literature. Surgery. 1998 Dec;124(6):1050-5. doi: 10.1067/msy.1998.92005. PMID: 9854582.\u003c/li\u003e\n\u003cli\u003eSakurai M, Wakabayashi T, Kondo Y, Ikeda E, Watanabe K, Takei A, Okazaki H, Okada K, Ebihara K, Kakiuchi N, Ogawa S, Fukushima N, Ishibashi S. A case of vasoactive intestinal peptide-secreting tumor (VIPoma) arising from MEN1 inactivation which recurred 15 years after the initial resection. Endocr J. 2023 Jun 28;70(6):573-579. doi: 10.1507/endocrj.EJ22-0578. Epub 2023 Mar 9. PMID: 36889692.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"973\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"9\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1: Demographic data and laboratory values\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at Dx\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at initial surgery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymptoms before surgery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor localisation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum hormone elevated\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum hormone level before first surgery elevated\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(x-fold)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCgA level before first surgery \u0026nbsp;elevated\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003e\u003cstrong\u003ex-fold)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e1 *\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003eWDHA, abdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003etail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003eVIP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e10-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003eWDHA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003etail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003eVIP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e2-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e2,6-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003eWDHA, weight loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003etail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003eVIP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e2,5-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e21,8-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003eabdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003etail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003ecalcitonin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e20,6-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e15-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003etail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003ecalcitonin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e189-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003ehead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003ecalcitonin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e16,5-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e2-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003etail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003ecalcitonin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e17,6-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e0-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003ediarrhea, abdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003etail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003ecalcitonin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e15-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e2,7-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003eNME, wasting, anemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003etail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003eglucagon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e46-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e56-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003eNME, foot and leg exanthem, weight loss,\u0026nbsp;diarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003ehead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003eglucagon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e26,5-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e1,2-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003ediarrhea, nausea, vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003ehead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003eglucagon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e3-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e2,6-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.846153846153846%\" valign=\"top\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.384615384615383%\" valign=\"top\"\u003e\n \u003cp\u003ediabetes mellitus, weight loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.794871794871795%\" valign=\"top\"\u003e\n \u003cp\u003etail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.512820512820515%\" valign=\"top\"\u003e\n \u003cp\u003eglucagon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.538461538461538%\" valign=\"top\"\u003e\n \u003cp\u003e2,3-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.564102564102564%\" valign=\"top\"\u003e\n \u003cp\u003e0-fold\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* - associated with MEN 1, F - female, M - male, Dx - Dignosis, VIP - vasoactive intestinal peptide, NME - necrolytic migratory erythema, WDHA - watery diarrhea, hypokalemia, and achlorhydria, Verner-Morrison-syndrome, NA - not available\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"936\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"9\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2: Preoperative imaging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.354700854700855%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.598290598290598%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreoperative imaging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.44017094017094%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; US\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.149572649572649%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEUS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.089743589743589%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMRI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.042735042735043%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSRS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.162393162393162%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGa68-DotatocPET/CT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIOUS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.354700854700855%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.598290598290598%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.44017094017094%\" valign=\"top\"\u003e\n \u003cp\u003e10/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.149572649572649%\" valign=\"top\"\u003e\n \u003cp\u003e6/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e8/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.089743589743589%\" valign=\"top\"\u003e\n \u003cp\u003e8/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.042735042735043%\" valign=\"top\"\u003e\n \u003cp\u003e4/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.162393162393162%\" valign=\"top\"\u003e\n \u003cp\u003e5/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e12/12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.354700854700855%\" valign=\"top\"\u003e\n \u003cp\u003ePrimary tumor visualized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.598290598290598%\" valign=\"top\"\u003e\n \u003cp\u003e12/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.44017094017094%\" valign=\"top\"\u003e\n \u003cp\u003e10/10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.149572649572649%\" valign=\"top\"\u003e\n \u003cp\u003e6/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.089743589743589%\" valign=\"top\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.042735042735043%\" valign=\"top\"\u003e\n \u003cp\u003e3/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.162393162393162%\" valign=\"top\"\u003e\n \u003cp\u003e5/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e12/12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.354700854700855%\" valign=\"top\"\u003e\n \u003cp\u003eLymph node metastases visualized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.598290598290598%\" valign=\"top\"\u003e\n \u003cp\u003e2/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.44017094017094%\" valign=\"top\"\u003e\n \u003cp\u003e1/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.149572649572649%\" valign=\"top\"\u003e\n \u003cp\u003e2/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e1/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.089743589743589%\" valign=\"top\"\u003e\n \u003cp\u003e1/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.042735042735043%\" valign=\"top\"\u003e\n \u003cp\u003e0/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.162393162393162%\" valign=\"top\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.354700854700855%\" valign=\"top\"\u003e\n \u003cp\u003eDistant metastases visualized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.598290598290598%\" valign=\"top\"\u003e\n \u003cp\u003e6/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.44017094017094%\" valign=\"top\"\u003e\n \u003cp\u003e6/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.149572649572649%\" valign=\"top\"\u003e\n \u003cp\u003e0/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e4/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.089743589743589%\" valign=\"top\"\u003e\n \u003cp\u003e4/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.042735042735043%\" valign=\"top\"\u003e\n \u003cp\u003e4/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.162393162393162%\" valign=\"top\"\u003e\n \u003cp\u003e2/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e6/6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eUS - ultrasonography, EUS - endoscopic ultrasonography, CT - computed tomography, MRI \u0026ndash; magnetic resonance imaging, SRS - somatostatin receptor scintigraphy, Ga68 DOTATOC-PET-CT - Gallium68 positron emission tomography, IOUS - intraoperative ultrasonography\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"953\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"86.88352570828961%\" colspan=\"9\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3: Histopathology and hormon levels after initial surgery\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.116474291710388%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient No.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTNM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUICC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eKi-67 % Index\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor Grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor size (mm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-OP cure of symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-OP normalized hormone level\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eVIP 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eT4N1(8/24)M0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eVIP 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eTxNxM1(HEP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eVIP 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eT4N1(3/12)M1 (HEP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eCT \u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eT2N0(0/6)M1 (HEP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eCT 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eT3N1(7/22)M0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eCT 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eT2N0(0/22)M0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eCT 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eT2N0(0/16)M0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eCT 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eT3N1(1/10)M1 (HEP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eGlu 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eT1N1(1/15)M1 (HEP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eGlu 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eT3N1(1/17)M1 (HEP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eGlu 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003e1.T1NXM0\u003c/p\u003e\n \u003cp\u003e2. T1N0(0/17)M0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.823529411764707%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.722689075630252%\" valign=\"top\"\u003e\n \u003cp\u003eGlu 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.852941176470587%\"\u003e\n \u003cp\u003eT1N0(0/17)M0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.928571428571429%\" valign=\"top\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.512605042016807%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.773109243697479%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.088235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.03781512605042%\" valign=\"top\"\u003e\n \u003cp\u003e117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.130252100840336%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;VIP - Vipoma, CT - calcitoninoma, Glu - glucagonoma, HEP \u0026ndash; hepar, - \u0026nbsp; no symptoms before surgery\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"926\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"6\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 4: Follow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up after the first surgery \u0026nbsp;(months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecurrence of disease\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDevelopment of \u0026nbsp;distant metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eVIP 1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e247\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eHep, P, KL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eDOD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eVIP 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003epersistent disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003epersistent disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eDOD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eVIP 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eDOD\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eCT 1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eHep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eDOD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eCT 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eNED\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eCT 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eNED\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eCT 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eNED\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eCT 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eHep, LN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eAWD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eGlu 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eHep, LN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eDOD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eGlu 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eHep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eDOD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eGlu 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eNED\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.855291576673865%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1274298056155505%\" valign=\"top\"\u003e\n \u003cp\u003eGlu 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.5377969762419%\" valign=\"top\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.334773218142548%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.434125269978402%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.71058315334773%\" valign=\"top\"\u003e\n \u003cp\u003eNED\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eVIP - Vipoma, CT - calcitoninoma, Glu - glukagonoma, Hep - hepar, LN - lymph node, P - peritoneum, KL - kidney left, NED - no evidence of\u0026nbsp;disease, AWD - alive with disease, DOD - death of disease\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"945\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 5: Characteristics of the patients with regard to entity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRf-pNEN(n=12)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCT-pNEN (n=5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlucagonoma (n=4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVIPoma (n=3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eMedian age at initial surgery (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e60 (28-73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e64 (54-70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e54 (28-73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e58 (32-73)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eSex (male/female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e7/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e2/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e3/1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e2/1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003ePresence of MEN1 or VHL\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e1/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e0/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e1/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eTumors size, mm, median (range)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e82 (12-220)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e79 (35-130)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e65 (12-117)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e112 (35-220)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eTumor location (PH/PB/ PT)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e3/0/9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e1/0/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e2/0/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e0/0/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eKi 67 % Index median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e5 (1-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e5 (3-6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e5 (2-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e4 (1-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eStage I/II/III/IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e2/2/2/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e0/2/1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e2/0/0/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e0/0/1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eSurgical resection primary tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e11/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e5/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e4/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e2/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003ePotential curative resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e9/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e3/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e4/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e2/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eAdditional treatment\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e6/12 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e2/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e2/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e2/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eSomatostatin analogues\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e6/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e2/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e2/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e2/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eChemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e3/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e1/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e2/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eSunitinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e1/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e1/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e0/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003ePRRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e2/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e1/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e1/4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eTAE/TACE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e1/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e1/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eRadiofrequency ablation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e1/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e1/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eRecurrence after curative resection,\u003c/p\u003e\n \u003cp\u003enumber (%) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e5/12 (42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e1/5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e3/4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e1/1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eTumor deaths, number (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e6/12 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e1/5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e2/4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e3/3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003e5-years tumor survival (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e55\u0026nbsp;%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e50 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e50 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e33\u0026nbsp;%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.396825396825395%\" valign=\"top\"\u003e\n \u003cp\u003eFollow- up (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.576719576719576%\" valign=\"top\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.037037037037038%\" valign=\"top\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.952380952380953%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003erf-pNEN - rare functional pancreatic neuroendocrine neoplasms, VIP - Vipoma, CT - calcitoninoma, Glu - glucagonoma, PH - pancreatic head,PB - pancreatic body, PT - pancreatic tail, PRRT - peptide receptor radionuclide therapy, RFA - radiofrequency ablation, TAE/TACE - transarterial embolisation / transarterial chemoembolization\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"glucagonoma, VIPoma, calcitoninoma","lastPublishedDoi":"10.21203/rs.3.rs-4000625/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4000625/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e Rare functional pancreatic neuroendocrine neoplasms (rf-pNENs), such as VIPomas, calcitoninomas and glucagonomas are extremely rare tumors. Thus, their characteristics and long-term prognosis have not yet been well defined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003eClinicopathological characteristics, including preoperative diagnostics, surgical procedures, other treatments and long-term outcome of patients with rf-pNEN operated in the ENETS Center of Excellence Marburg were retrospectively analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eBetween 2002 and 2022, 12 of 216 (5,5%) patients with pNEN had rf-pNEN, including three VIPomas, four glucagonomas and five calcitoninomas. Among these 5 were women and 7 were men with a median age of 60 (range 28-73) years at the time of the first surgery. The tumor was visualized by preoperative imaging in all 12 patients, and six patients had distant metastases at the time of diagnosis. The tumor was located in the pancreatic tail in 9 patients and the median tumor size was 82 (range 12-220) mm. Eleven patients underwent tumor resections (2 robotic, 9 conventional), and 9 of these 11 patients received R0 resections. After a median follow-up of 75 (range 1-247) months, six patients were alive, five of whom had no evidence of disease. All patients who remained disease-free had an initial R0 resection of the primary tumor and no initial liver involvement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e rf-pNENs are a heterogeneous group of tumors with a good long-term prognosis, if detected early and initially radically resected. Long-term survival, however, can be also achieved in patients with metastasized tumors using multimodal treatment.\u003c/p\u003e","manuscriptTitle":"Longterm outcome of rare functioning pancreatic neuroendocrine neoplasms","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-05 16:24:48","doi":"10.21203/rs.3.rs-4000625/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d724cb78-2da0-4138-bdb0-80ef9f197203","owner":[],"postedDate":"March 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-22T10:05:06+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-05 16:24:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4000625","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4000625","identity":"rs-4000625","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}