S Partelli and others A review on surgery of NETs 171:4 R153–R162 Review GEP–NETS UPDATE A review on surgery of gastro-entero-pancreatic neuroendocrine tumors 1 Stefano Partelli, Angela Maurizi, Domenico Tamburrino , Andrea Baldoni, Correspondence Vanessa Polenta, Stefano Crippa and Massimo Falconi should be addressed to M Falconi Pancreatic Surgery Unit, Universita` Politecnica delle Marche, Via Conca, 71, 60126 Ancona, Italy and 1Department Email of Surgery, University of Verona, Verona, Italy [email protected] Abstract The incidence of neuroendocrine tumors (NETs) has increased in the last decades. Surgical treatment encompasses a panel of approaches ranging from conservative procedures to extended surgical resection. Tumor size and localization usually represent the main drivers in the choice of the most appropriate surgical resection. In the presence of small (!2 cm) and asymptomatic nonfunctioning NETs, a conservative treatment is usually recommended. For localized NETs measuring above 2 cm, surgical resection represents the cornerstone in the management of these tumors. As they are relatively biologically indolent, an extended resection is often justified also in the presence of advanced NETs. Surgical options for NET liver metastases range from limited resection up to liver transplantation. Surgical choices for metastatic NETs need to consider the extent of disease, the grade of tumor, and the presence of extra-abdominal disease. Any surgical procedures should always be balanced with the benefit of survival or relieving symptoms and patients’ comorbidities. European Journal of Endocrinology (2014) 171, R153–R162 European Journal of Endocrinology Introduction Neuroendocrine tumors (NETs) arise from the cells present classifications for NETs. The gastro-entero-pancreatic throughout the diffuse endocrine system. They comprise (GEP) NETs present as functioning or nonfunctioning a broad family of tumors, the most common of which tumors. Functioning tumors are commonly associated arise in the lungs and bronchi, small intestine, appendix, with a specific hormonal syndrome directly related to a rectum, and pancreas. These neoplasms were previously hormone secreted by the neoplasm, such as insulinomas, regarded as rare, but in fact are increasing in incidence gastrinomas with Zollinger–Ellison or carcinoid syndrome (3.65/100 000 individuals per year) (1) and occur as (3). Most of NETs share the characteristic of longer survival frequently as testicular tumors, Hodgkin’s disease, glio- than adenocarcinomas originating from the same organs. mas, and multiple myeloma (2).Therearemultiple As a consequence, surgery plays a key role not only for Invited Author’s profile Dr M Falconi is currently Associate Professor of Surgery and Chairman of the Pancreatic Unit, University Politecnica delle Marche (Ancona, Italy). He studied medicine at the University of Verona, specializing in general surgery, gastroenterology, and endoscopy. He has participated in international medical research projects in such diverse places as Germany, Spain, Ecuador, and Japan. A member of many medical societies, including IAP, EPC, and EHPBA, Prof. M Falconi is currently on the executive committees of ENETS and IAP. www.eje-online.org Ñ 2014 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-14-0173 Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 02:07:32PM via free access Review S Partelli and others A review on surgery of NETs 171:4 R154 localized tumors but also for advanced NETs. Tumor imaging-based observation with a first control after grading and tumor stage represent the main prognostic 6 months from diagnosis seems to be reasonably safe. factors of NETs. Well- and moderately differentiated NETs Preliminary reports have demonstrated the safety of this defined by a value of Ki67 !20% have a significantly conservative approach (9, 12, 13). Lee et al. (12) retro- better survival compared with poorly differentiated spectively analyzed 134 patients with pancreatic NET neuroendocrine carcinomas. Similarly, a small tumor !2 cm. Of those, 57 underwent surgery with a risk of size, along with the absence of metastases, is associated complications of nearly 50%. The remaining 77 patients with a lower risk of recurrence after surgery (4). Sub- were conservatively managed and they were all free of sequently, surgical treatment of NETs is strictly related to progression disease. In addition, Gaujoux et al. (13) the localization of NETs, the grade of tumor, and the stage published a bi-institutional study where they observed of disease. Surgery can be a valid option in all stages of 46 patients with small, incidentally discovered pancreatic disease ranging from conservative approach to radical NETs. Overall, eight patients (17%) underwent surgery operations that include multiple organs resection and also after a median time of 41 months. All resected tumors were liver transplantation (LT). This article aims to elucidate the T stage 1 (nZ7) or 2 (nZ1), node negative with neither best surgical management of patients with GEP NET and to vascular or peripancreatic fat invasion. address the role of different surgical procedures. On the other hand, surgery still represents the treatment of choice for pancreatic NETs O2 cm and/or for symptomatic forms. Radical surgery for pancreatic Management of localized disease NETs includes both typical and atypical pancreatic The management of localized GEP NET depends mainly resections. Typical resections differ according to tumor on tumor size, tumor localization, and patients’ comor- site: lesions of the pancreatic head are treated with bidities. Surgical resection is often the best treatment for a pancreaticoduodenectomy, while lesions of the body the majority of localized NETs, although a conservative and tail with a distal pancreatectomy. Currently, when approach is currently advocated for small, incidentally performed in high-volume centers, pancreatic typical discovered tumors. Small, benign neoplasms are usually resections have an acceptable mortality rate (!5%), readily curable by surgical resection with a favorable although the percentage of complications is still signi- prognosis, although all these tumors should always be ficant ranging from 40 to 50% (14, 15). Typical pancreatic considered as potentially malignant (3).Themain resections are also associated with a high incidence of European and North American guidelines recommend exocrine and endocrine insufficiency (16). Risk of long- European Journal of Endocrinology surgical resection for localized NETs irrespective of tumor term pancreatic impairment has increased the use of grading (5, 6, 7). parenchyma-sparing techniques or atypical resections such as enucleation and middle pancreatectomy that Pancreatic NETs " The incidence of small, incidentally consists of the resection of the central part of the gland. discovered pancreatic NETs has increased significantly in Currently, these procedures are limited only for small the last decade with the widespread use of high-quality functioning tumors (!2 cm) (17). In particular, surgery imaging techniques (8). Incidental diagnosis of pancreatic still plays an important role in the management of NETs is associated with a significantly better survival after insulinomas. Recurrence after surgery for insulinomas is curative resection compared with patients with symptoms exceptional and these neoplasms can be safely resected (9). Moreover, Bettini et al. (10) demonstrated that with enucleation that can be performed both with an patients with incidental diagnosis associated with a ‘open’ approach and laparoscopically (18, 19). The role of tumor size !2 cm had a 5-year overall survival of 100% lymphadenectomy for patients with pancreatic NET is still with a minimal risk of recurrence. On the basis of these unclear (20). Lymph node metastases occur only in the experiences, the European Neuroendocrine Tumor Society 30% of patients affected by these tumors (20), but the (ENETS) guidelines now recommend a ‘wait and see’ association between node metastases and poorer survival policy in selected patients with asymptomatic sporadic is still debated (4). pancreatic NETs (5). This management should be considered only in the presence of a low-grade (G1) NET. Gastric NETs " Borch et al. (21) studied a total of Consequently, tumor grading should always be assessed 65 patients with gastric NETs of different types from by fine-needle aspiration or biopsy (11). Although a 24 hospitals and managed with a differentiated treatment follow-up protocol has not been investigated, a yearly in relation to type. The conclusion of this study is that the www.eje-online.org Downloaded from Bioscientifica.com at 10/02/2021 02:07:32PM via free access Review S Partelli and others A review on surgery of NETs 171:4 R155 type of gastric NETs is helpful in the prediction of metastases are common also with small tumors (33). These malignant potential and long-term survival and it is a metastases will often grow conspicuously large and may be guide to management. Three types of gastric NETs are mistaken to represent the primary tumor. As tumor spread generally recognized: type 1 (associated with chronic to the lymph nodes and liver can occur also in patients atropic gastritis), type 2 (associated with Zollinger–Ellison with small primary tumors, surgery of the primary tumors syndrome), and type 3 (sporadic) (22). Types 1 and 2 should adhere to oncological principles. This involves gastric NETs are both associated with