Surgical resection of sporadic pancreatic neuroendocrine tumors

INTRODUCTION — Pancreatic neuroendocrine neoplasms (PNENs) are rare, accounting for fewer than 3 percent of all pancreatic tumors [1,2]. PNENs exhibit a wide spectrum of clinical behavior that has made classification and staging difficult. While the majority of PNENs are associated with relatively good survival, there can be significant variability in outcomes based on their biological heterogeneity [3-5]. The classification, epidemiology, clinical presentation, localization, and staging of PNENs is discussed separately. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)

The term "pancreatic neuroendocrine neoplasm" is preferred to encompass a diverse set of tumors arising in the pancreas that share a common progenitor cell [6]. The well-differentiated forms are referred to as pancreatic neuroendocrine tumors (PNETs). In general, poorly differentiated PNENs are high-grade lesions that are referred to as neuroendocrine carcinomas with aggressive biologic behavior, and medical rather than surgical therapy is usually more appropriate. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

This topic will focus predominantly on well-differentiated PNETs. (See 'Staging and tumor classification' below.)

In the past, PNETs were often referred to as pancreatic "islet cell" tumors or pancreatic "carcinoids." With time, the term "carcinoid" has come to mean a very specific group of well-differentiated tumors, predominantly arising in the tubular gastrointestinal tract, which produces only serotonin. However, endocrine tumors of the pancreas can express other hormones or can be biochemically inert. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology'.)

While most PNETs are sporadic, PNETs can also be associated with genetic syndromes. The surgical management of sporadic PNETs is reviewed here. The management of PNETs associated with genetic syndromes is discussed separately. (See "Multiple endocrine neoplasia type 1: Management" and "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Tuberous sclerosis complex: Management and prognosis" and "Neurofibromatosis type 1 (NF1): Management and prognosis".)

PREOPERATIVE EVALUATION — Surgical planning must take into account the characteristics of the tumor, as well as the patient's overall health and wishes. An accurate history and review of pertinent laboratory and prior imaging studies is essential for planning resection of pancreatic neuroendocrine tumors (PNETs).

Genetic background — The patient's history and genetic testing help determine whether the tumor is sporadic or associated with a genetic syndrome. This is important because the association of a genetic syndrome, multiple endocrine neoplasia type 1 (MEN1) for instance, affects the number and extent of primary PNETs, which greatly impacts surgical decision making [7,8]. The management of PNETs associated with genetic syndromes is discussed separately. (See "Multiple endocrine neoplasia type 1: Management" and "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Tuberous sclerosis complex: Management and prognosis" and "Neurofibromatosis type 1 (NF1): Management and prognosis".)

Tumor characteristics — Characteristics of a sporadic PNET that are important for determining optimal surgical management include the tumor's functional status, whether the tumor is benign or malignant, and, for malignant tumors, the extent of tumor invasion of contiguous structures and presence or absence of metastatic disease (algorithm 1). It is extremely difficult to predict the course of disease in the patient with PNET. As an example, a small tumor size does not necessarily mean that it is benign [9]. Similarly, a diagnosis of malignant PNET cannot always be secured or excluded simply based upon histology. The only reliable indicators of a malignant tumor are the presence of invasion, metastases, or tumor recurrence. The natural history of malignant PNETs is also variable, with some large metastatic tumors having a very indolent course and some small, isolated tumors having a very aggressive course. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Morphology and immunohistochemistry'.)

Functionality — A clinical classification divides sporadic PNETs into functional and nonfunctional tumors. Clinical symptoms and biochemical evidence of hormone excess determine the tumor's functional status (not histologic appearance or the results of immunohistochemical staining). In the preoperative period, once the diagnosis of a functional tumor is made biochemically, the next step is to localize and stage the tumor radiographically. Although functionality may impact prognosis (eg, insulinomas are generally indolent tumors), the biologic behavior of most functional neuroendocrine tumors is defined by the grade and stage of the tumor. (See 'Localization and malignant potential' below and 'Staging and tumor classification' below and "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Functionality and nomenclature'.)

●Nonfunctional – The majority of PNETs have no defined clinical syndrome and no elevated hormone levels. As such, the presentation of nonfunctional PNETs is often delayed. Patients often present late in their course with symptoms of mass effect or with symptoms related to metastases, including abdominal pain, weight loss, and jaundice [7,10]. As the threshold for abdominal imaging steadily decreases, nonfunctional tumors are frequently identified as incidental findings. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Clinical presentation'.)

●Functional – Patients with functional (ie, hormone-secreting) tumors present clinically with syndromes of excess gastrointestinal hormone production (insulin, serotonin, gastrin, VIP [vasoactive intestinal peptide], glucagon, or somatostatin) (table 1) [11]. In general, the aggressiveness of PNETs (grade based on histologic features) does not correlate with presence or type of hormone production. Once a diagnosis of a functional tumor has been made biochemically, it is generally unnecessary to repeat any studies. (See 'Localization and malignant potential' below.)

Briefly:

•Insulinoma – Insulinoma is the most common functional neoplasm of the endocrine pancreas. Up to 90 percent of insulinomas are benign, and they can be sporadic or associated with MEN1 syndrome. Most patients present with severe hypoglycemia. (See "Insulinoma".)

•Gastrinoma – Gastrinomas produce the hormone gastrin. The consequences of hypergastrinemia are gastric acid hypersecretion and its related peptic complications. Patients are classified as having sporadic or familial (ie, associated with MEN1) gastrinoma. This distinction is important as management differs [12]. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)

•VIPoma – VIPomas produces the hormone VIP. The consequences of excess VIP secretion include large-volume secretory diarrhea and electrolyte abnormalities. Prior to surgery, all patients with VIPoma require correction of dehydration, hypokalemia, and other metabolic abnormalities. Preoperative octreotide administration can reduce the levels of circulating VIP and is the treatment of choice to control large-volume secretory diarrhea and improve electrolyte management [13-15]. (See "VIPoma: Clinical manifestations, diagnosis, and management".)

•Glucagonoma – Glucagonomas produce the hormone glucagon. The consequences of excess glucagon secretion are a syndrome that includes a characteristic skin rash (necrolytic migratory erythema, (picture 1)), diabetes mellitus, malnutrition, weight loss, thrombophlebitis, glossitis, and anemia. (See "Glucagonoma and the glucagonoma syndrome".)

•Somatostatinoma – Somatostatinoma is the least common PNET with a reported incidence of 1 in 40 million people. Excess somatostatin secretion produces a characteristic syndrome that includes steatorrhea, mild diabetes, and cholelithiasis. The diagnosis is typically delayed, and approximately 75 percent have metastasized, often to the liver, at the time of diagnosis. (See "Somatostatinoma: Clinical manifestations, diagnosis, and management".)

Localization and malignant potential — Preoperative imaging by cross-sectional imaging (computed tomography [CT], magnetic resonance imaging [MRI]), as well as functional somatostatin receptor based diagnostic imaging (Indium-111 pentetreotide SPECT [OctreoScan] or Gallium Ga-68 DOTATATE or gallium GA-68 DOTATOC PET) with or without endoscopic ultrasound can help localize the tumor and also determine the tumor's benign or malignant nature by determining the degree of local invasion, lymph node involvement, and metastases to the liver or elsewhere. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Somatostatin-receptor-based imaging'.)

For pancreatic tumors, endoscopic ultrasound has a sensitivity ranging from 86 to 93 percent. When combined with spiral CT, the sensitivity approaches 100 percent [16]. Endoscopic fine needle aspiration biopsy of the tumor can confirm the presence of neuroendocrine cells, identify regional lymphadenopathy, and may help determine the proliferative index (eg, Ki67), which in turn can help grade the lesion, which is important for prognostic stratification and treatment. (See 'Staging and tumor classification' below.)

Staging and tumor classification — In 2006 and 2007, the European Neuroendocrine Tumour Society (ENETS) proposed a staging scheme similar to those for most other types of epithelial neoplasms for neuroendocrine tumors (NETs) of the digestive tract, including PNETs; it was accompanied by a histologic grading system that could be applied to all stages of NETs [17,18]. This grading proposal was later endorsed by the joint American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC), although they modified the ENETS tumor, node, metastases (TNM) staging proposal [19]. The newest version of the TNM staging classification (eighth edition, 2017) has a staging system for neuroendocrine tumors of the pancreas (table 2) that is separate from that used for exocrine pancreatic tumors [11]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Staging system'.)

Measures of the proliferative index, like Ki67, are used to assign grades and have also been shown to have prognostic power for PNETs [20-22]. Prior to 2017, there were two categories of tumor classification. Well-differentiated neuroendocrine tumors were separated into low-grade (G1, Ki-67 index <3 percent) and intermediate-grade (G2, Ki-67 index 3 to 20 percent) categories according to proliferative rate. Poorly differentiated tumors were all considered to represent high-grade (G3, Ki-67 index >20 percent) neuroendocrine carcinomas (NECs). However, in recognition of the fact that a subset of high-grade NETs are well to moderately well differentiated, the 2017 World Health Organization (WHO) classification of tumors of endocrine organs modified the grading scheme for pancreatic NETs [23]. Well-differentiated pancreatic NETs are now classified as G1 (PanNET G1), G2 (PanNET G2), or G3 (PanNET G3), and the terminology for high-grade poorly differentiated tumors is PanNEC G3 (table 3). (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on '2010 and 2019 World Health Organization classification'.)

In general, we prefer the terms "PNET G1," "PNET G2," and "PNET G3" to designate well-differentiated PNETs or varying grades and "PNEC" to designate a high-grade poorly differentiated neuroendocrine neoplasm. The majority of sporadic PNETs are G1 or G2, and they are associated with a relatively prolonged natural history, even when metastatic. PanNEC G3 lesions behave aggressively and are typically treated with systemic chemotherapy, even when apparently localized. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

The natural history and clinical behavior of PNET G3 tumors is in between that of PNET G1/2 tumors and PNEC G3 tumors. This subject is discussed in detail elsewhere. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade, well-differentiated tumors (NET G3)'.)

An important point is that while histologic grade is a useful measure of prognosis, it is not an indicator of whether a PNET is benign or malignant. The only criteria for malignant behavior are the presence of local invasion, metastases, or recurrent disease.

Earlier classification systems from the WHO had incorporated tumor size (<2 cm, ≥2 cm) into the staging criteria for sporadic PNET. There is evidence that larger tumors are more likely to be intermediate-grade rather than low-grade and that larger tumors are more often malignant and have somewhat poorer outcomes with a higher risk of disease recurrence [24,25]. However, size alone cannot determine malignant potential. Tumors <2 cm can be malignant, and tumors >2 cm can be benign.

Medical risk assessment — Although sporadic pancreatic neuroendocrine tumors can present at any age, they generally occur in older individuals. The peak incidence is between the fourth and sixth decades, and thus, medical risk assessment should be performed to identify and manage factors that increase the risk of perioperative adverse events. (See "Evaluation of cardiac risk prior to noncardiac surgery" and "Preoperative evaluation and management of patients with cancer" and "Evaluation of perioperative pulmonary risk".)

CANDIDATES FOR RESECTION — Surgery is the only known cure for sporadic pancreatic neuroendocrine tumors (PNETs), whether functional or nonfunctional [26-28]. Surgery is indicated in patients with PNETs to alleviate systemic symptoms due to hormone overproduction and compressive symptoms due to local mass effect and to prevent malignant transformation or dissemination [29,30].

For some small, PanNEN G1 asymptomatic tumors, active surveillance has emerged as a potentially safe and effective strategy in lieu of surgery. In a meta-analysis of five studies including 327 patients who were observed for asymptomatic small PNETs (although the definition of "small" ranged from 2 cm up to any size diameter), measurable tumor growth was observed in 0 to 51 percent of patients over a median follow-up period of 28 to 45 months [31]. Only 14 percent of patients ultimately required pancreatic resection (most commonly for tumor growth), and there were no disease-related deaths.

However, there is not complete consensus on which patient population is safe to observe. While the 2016 European Neuroendocrine Tumor Society (ENETS) guidelines and consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) both endorse intensive observation for nonfunctional PNETS <2 cm [32,33], current guidelines from the North American Neuroendocrine Tumor Society (NANETS) recommend observation for PNETS <1 cm but individualized management based on age, comorbidity, growth, grade, extent of needed surgery, and patient preference for tumors between 1 and 2 cm [34]. Thus, until more conclusive data become available, the decision to pursue nonoperative management for small nonfunctional low-grade PNETs should be made individually after weighing risks against benefits. In this context, it is important to remain cognizant of the considerable morbidity and mortality of major pancreatic resections.

Tumor functionality, grade, and stage are important factors in choosing patients for surgical treatment and determining the operative approach (algorithm 1). As an example, for patients with a clinical syndrome consistent with insulinoma (most of which are benign), who appear to have an isolated pancreatic lesion, surgical resection is the treatment of choice. Patients with metastatic disease may be considered for debulking surgery if symptoms from excess insulin are refractory to medical treatment. (See 'Insulinoma' below.)

By contrast, the majority of glucagonomas, VIPomas, somatostatinomas, and gastrinomas are malignant. With malignant tumors, the primary consideration in determining surgical treatment is whether or not the patient has distant metastatic disease, whether or not the extrapancreatic disease is potentially resectable, and whether it is high-volume or low-volume. Aggressive resection of PNETs has acceptable morbidity and mortality with studies demonstrating improved survival across all stages of disease, supporting resection for patients with localized, locoregional, and even metastatic disease, as long as the metastatic sites can be completely resected [7,29,30,35-44]. In a review of surgical resection for 125 nonfunctional and functional tumors, the most favorable outcomes were in patients with benign, functional tumors and completely resected, malignant tumors [29]. (See 'Tumor characteristics' above.)

Our approach to patients with sporadic PNET is as follows:

●No metastatic disease – For patients with well-differentiated PanNEN G1 (>2 cm), G2, or G3 tumors and no evidence of distant metastatic spread of disease, resection with curative intent should be offered to medically fit patients. Regional lymph node involvement does not preclude resection, although it does adversely affect overall survival [44-49]. For patients with locally advanced tumors, vascular resection/reconstruction and extended resections of adjacent organs can be performed with acceptable morbidity and mortality [45,50].

For patients with PanNEC G3 tumors, surgery alone is rarely curative, even for patients with apparently localized disease. Nevertheless, resection may benefit selected patients when used in conjunction with chemotherapy and/or radiation therapy in a multimodality approach. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'Localized disease'.)

●Potentially resectable metastatic disease – For patients with potentially resectable metastatic disease (typically isolated hepatic metastases), an aggressive surgical approach that includes resection of metastatic sites can offer the potential for long-term survival [44,45]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

●Unresectable metastatic disease – For patients with unresectable metastatic disease, best medical therapy including long-acting somatostatin analogues is the usual first-line approach. Other therapies, such as ablation, embolization, chemotherapy, and peptide receptor radionuclide therapy (eg, Lutetium-177 dotatate, in patients who progress on long-acting somatostatin analogs), can prolong survival and improve the quality of life. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)

In some cases, surgery for metastatic disease may be pursued even if complete resection cannot be accomplished. The most common scenario is a patient who has symptoms from hormone secretion that are refractory to medical therapy [26,39,51,52]. Surgical debulking may palliate symptoms and prolong survival in patients with neuroendocrine liver metastases from a functioning tumor [39,40,51,53]. Most authors advocate resection if 90 percent of the known disease can be resected, although there is growing support to resect if as much as 70 percent can be resected.

The decision to pursue surgery is a complex one and needs to take into account tumor histology, the volume of metastatic disease, and the growth rate:

•For patients with low-volume metastatic, well-differentiated tumors with an indolent growth rate, surgical resection including resection of metastatic sites in conjunction with adjuvant therapies such as ablation, embolization, hormonal therapy, and chemotherapy can prolong and improve the quality of life [26,39,51,52]. Even large tumors can be debulked with the expectation that adjunctive treatment will be used to control unresectable residual disease. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)

•For patients with high-volume metastatic disease with a high growth rate or high-grade histology (ie, PanNEN G3 or PanNEC G3), best medical therapy may include hormone therapy, long-acting somatostatin analogues, or chemotherapy [53-55]. However, even in the presence of metastatic disease, palliative debulking may be indicated for relief of systemic or local symptoms related to hormone production. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion" and "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'Role of surgery'.)

•Whether there is a benefit to resection of a primary, nonfunctional PNET in patients with unresectable metastatic disease is debated. In some (but not all) series, this approach is associated with a modest survival benefit, but it is likely that this is the result of selection bias (ie, patients selected for this approach likely had a significantly lower tumor burden). (See 'Nonfunctional' below.)

In the absence of symptoms, there is little role for pancreatic resection for treating nonfunctioning tumors in the presence of extensive unresectable extrapancreatic disease. However, there may be a role for resection of the primary tumor in a patient with low-volume extrapancreatic metastatic disease, particularly with a primary involving the pancreatic head. Given the potentially long natural history of PNET, even when metastatic, tumors of the pancreatic head are more likely to result in symptoms (in contrast to those of the distal pancreas) by eroding into the duodenum, resulting in gastrointestinal hemorrhage, or may cause biliary or gastric outlet obstruction. Furthermore, as liver-directed therapies improve for treatment of liver-isolated metastatic disease, resection of the primary in the setting of unresectable liver-"only" disease should be strongly considered. (See 'Nonfunctional' below and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)

Contraindications — The conventional anatomic contraindications for the resection of pancreatic exocrine tumors, such as portal/superior mesenteric vein invasion and nodal or distant metastases, may not apply to patients with advanced PNETs. Perhaps one of the few relative contraindications based on anatomy is wide invasion of the celiac and superior mesenteric arterial axis. At times, surgery of the primary tumor site is beneficial to relieve symptoms. However, as discussed below, for patients with high-grade histology and rapidly progressive metastatic disease, best medical therapy is advised. (See 'Candidates for resection' above.)

Although surgery is the treatment for functional and nonfunctional PNETs, PNET associated with multiple endocrine neoplasia type 1 (MEN1) and Zollinger-Ellison syndrome (ZE syndrome) is typically managed medically, either initially or long-term, due to multifocality and perhaps due to the more indolent nature of these tumors in this setting. Indications for surgery in patients with PNETs associated with MEN1 and other syndromes are discussed separately. (See "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)" and "Multiple endocrine neoplasia type 1: Management" and "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Tuberous sclerosis complex: Management and prognosis" and "Neurofibromatosis type 1 (NF1): Management and prognosis".)

PANCREATIC RESECTION — The goal of surgery for sporadic pancreatic neuroendocrine tumors (PNETs) is to resect the tumor for cure or, in appropriate cases, to debulk the tumor (algorithm 1) [7,56]. Cure is effected by resecting the primary tumor and associated lymph nodes while preserving the maximal amount of pancreatic mass [7,56]. Preoperative selection and extent of surgery are based upon preoperative and/or intraoperative localization of the tumor to reduce the risk of recurrence. The improved sensitivity of gallium Ga-68 DOTATATE positron emission tomography (PET) scans has decreased the frequency of surgery without localization. (See 'Preoperative evaluation' above and 'Intraoperative localization' below.)

Intraoperative localization — If the PNET is not successfully localized preoperatively, complete evaluation of the pancreas and peripancreatic region is necessary intraoperatively. Exploration is aided by visual, manual, and ultrasonographic inspection. Intraoperative ultrasound (IOUS) has become indispensable in localizing occult PNETs and for defining anatomic relationships. For enucleation procedures, intraoperative ultrasound is vital to ensuring a safe resection during enucleation and should be used to ascertain the relative location of the pancreatic duct and how much intervening pancreatic parenchyma lies between the tumor and duct. (See 'Enucleation' below.)

The Kocher maneuver is used to elevate the second portion of the duodenum out of the retroperitoneum (figure 1) to allow circumferential exploration of the pancreatic head and uncinate process. The neck, body, and tail of the pancreas can be explored by dividing the gastrocolic ligament to enter the lesser sac. The pancreas is elevated out of the retroperitoneum by dividing the inferior retroperitoneal attachments.

The ideal intraoperative probe for assessing the pancreas and its ductal system is a 12 MHz hockey stick probe (ie, pancreatic probe). Since the cord on the hockey stick probe comes off at a right angle to the active surface (unlike most probes where the cord comes off in line with the active surface), this configuration allows for a more ergonomic interrogation of the pancreas. For laparoscopic operations, a low-profile linear laparoscopic probe may be used. Saline may be instilled in the area to create a standoff (ie, increasing the distance between the probe and the pancreas to enhance the near field). Extrapancreatic sites including the duodenum, splenic hilum, small bowel, mesentery, and peripancreatic lymph nodes also must be explored. Through the meticulous combination of visual inspection, manual palpation, and IOUS, PNETs can be localized and defined, and the appropriate operation can be executed.

Extent of resection — A complete surgical resection involves removing the primary tumor as well as any lymph node metastases that may be present while preserving the maximal amount of pancreatic mass [7,56]. A variety of pancreatic resections, including traditional resections and pancreas-sparing resections, are used to treat PNETs. These are described below, and technical aspects of these procedures are discussed in more detail in the provided links. (See 'Traditional resections' below and 'Pancreas-sparing resections' below.)

PNETs that require traditional resection are usually larger, locally advanced, involve the common bile or pancreatic duct, and/or have evidence of lymph node or liver metastases. Nonfunctioning tumors typically present later in the disease course and are typically larger than functional tumors at the time of discovery and thus are not as often amenable to parenchyma-sparing operations. Traditional resection with appropriate lymphadenectomy is recommended for most patients with a nonfunctional PNET who have no evidence of metastatic disease [26,52].

Preoperative or intraoperative localization of the tumor determines the type of resection needed. (See 'Localization and malignant potential' above and 'Intraoperative localization' above.)

●For lesions located in the head, uncinate, or neck of the pancreas, pancreaticoduodenectomy is preferred for most lesions. Some lesions may be amenable to enucleation. (See 'Pancreaticoduodenectomy' below and 'Enucleation' below.)

●For lesions located in the body or tail of the pancreas, distal pancreatectomy can be performed. If the lesion is thought to be benign, splenic preservation may be attempted. When malignancy is suspected, distal pancreatectomy with splenectomy and peripancreatic lymphadenectomy should be performed. Some small lesions may be amenable to central pancreatectomy or enucleation. (See 'Central pancreatectomy' below and 'Distal pancreatectomy' below and 'Enucleation' below.)

●For multifocal disease, which is rare, total pancreatectomy is required because disease is present throughout the entire pancreas. (See 'Total pancreatectomy' below.)

Traditional resections — Traditional resections include pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy.

Pancreaticoduodenectomy — For PNETs in the head of the pancreas that are not amenable to enucleation, pancreaticoduodenectomy is the operation of choice. Conventional pancreaticoduodenectomy involves removal of the pancreatic head, duodenum, first 5 to 10 cm of the jejunum, common bile duct, gallbladder (figure 2), and a portion of the stomach. When oncologically appropriate, a pylorus-preserving pancreaticoduodenectomy can be performed. (See "Surgical resection of lesions of the head of the pancreas", section on 'Pancreaticoduodenectomy'.)

Distal pancreatectomy — Distal pancreatectomy involves removal of the body and tail of the pancreas (to the left of the superior mesenteric artery and vein). The traditional procedure includes splenectomy; however, a spleen-preserving technique reduces the risk of postsplenectomy sepsis and related infections [57,58]. For PNETs with a low risk of malignancy, a spleen-preserving technique is preferred. The spleen typically is preserved on a splenic vein and artery pedicle, but some authors advocate using a short gastric pedicle [59,60]. (See "Surgical resection of lesions of the body and tail of the pancreas", section on 'Distal pancreatectomy'.)

Total pancreatectomy — Total pancreatectomy removes nearly all or the entire pancreas. (See "Total pancreatectomy".)

Pancreas-sparing resections — With advances in surgical technique and the advent of laparoscopy, parenchyma-sparing operations, which include enucleation and central pancreatectomy, are gaining wider acceptance in the management of sporadic PNETs. Parenchyma-sparing operations have the benefit of tumor removal with minimal loss of pancreatic parenchyma [16]. Pancreas preservation may help to avoid pancreatic endocrine and exocrine insufficiency and, for tumors of the body/tail of the pancreas, spare the spleen. Parenchyma-sparing operations decrease postoperative insulin requirements when compared with more traditional resections [57,58]. Parenchyma-sparing operations are generally safe and effective for the management of small (<3 cm), nonfunctional PNETs without overt malignant features; however, even small PNETs may have lymph node disease, so when suspected, a traditional resection (pancreatic head resection, pancreatic tail resection) is indicated [61].

Central pancreatectomy — Central pancreatectomy (figure 3) is a parenchyma-sparing technique that removes the neck and proximal body of the pancreas while preserving the head and tail of the pancreas. Central pancreatectomy offers better preservation of pancreatic function with acceptable morbidity and mortality [60,62-67]. Central pancreatectomy can be used for selected patients with small, benign, or low-grade PNETs of the neck or proximal body of the pancreas that cannot be enucleated [60,62-69]. (See "Surgical resection of lesions of the body and tail of the pancreas", section on 'Central pancreatectomy'.)

Although central pancreatectomy has been performed laparoscopically, most series describe an open approach. Central pancreatectomy is technically challenging, and some studies report longer operative times and higher surgical morbidity [70-73]. Higher morbidity is attributed to the need to transect the pancreas in two locations, which, in the setting of benign or low-grade disease, is most often through pancreas with a soft texture and associated with higher rates of postoperative pancreatic fistula.

A single-institution study reviewed 73 central pancreatectomies and performed a matched-pair analysis to distal pancreatectomy [58]. The overall incidence of complications was 41 percent, with pancreatic fistula occurring in 21 percent. There were no deaths. These findings are consistent with those of other large series. There were no differences in fistula, morbidity, and mortality rates between central pancreatectomy and distal pancreatectomy groups. Patients undergoing central pancreatectomy had a lower incidence of new-onset or worsened diabetes than those undergoing distal pancreatectomy. Significantly fewer patients require insulin after central pancreatectomy, offering properly selected patients a better chance for a long-term, insulin-free lifestyle.

Enucleation — Enucleation allows for maximal preservation of pancreatic tissue while avoiding the complications associated with pancreatic and bowel anastomoses, division of the pancreatic duct, and postgastrectomy complications. (See "Surgical resection of lesions of the head of the pancreas", section on 'Enucleation procedures' and "Surgical resection of lesions of the body and tail of the pancreas", section on 'Enucleation procedures'.)

Enucleation is safe and is not detrimental to long-term survival for appropriately selected patients (eg, small, functional PNET in the pancreatic head, or possibly small, nonfunctional PanNEN G1 tumor if active surveillance is considered inappropriate). (See 'Staging and tumor classification' above.)

Enucleation may be attempted for insulinoma and gastrinoma <2 cm that are not abutting the pancreatic duct, as these are likely to be benign [26-28,74]. Enucleation is not appropriate for duodenal wall gastrinoma and is contraindicated for other types of functional tumors (often malignant), and for large tumors (ie, >3 cm; judgment call for tumors ≥2 to 3 cm), in the presence of nodal or metastatic disease or when lesions are in close proximity to the common bile or pancreatic duct. However, for some patients who do not wish to have a traditional resection, or patients with significant comorbidities who may not withstand traditional resection, enucleation may also be appropriate.

Enucleation has a lower mortality rate but similar morbidity compared with traditional resections. In particular, the rate of pancreatic fistula was roughly equivalent, but the severity was of lower grade using the International Study Group on Pancreatic Fistulas (ISGPF) criteria after enucleation [30]. Prior to enucleation, some advocate preoperative placement of pancreatic duct stents to more easily identify a major ductal disruption if it happens. Due to the relatively high leak rate of this operation, a drain is often placed in the area of resection.

A multicenter review compared outcomes of enucleation procedures (n = 36) with traditional resection (n = 86) in patients with small (≤3 cm) pancreatic, ampullary, and duodenal neuroendocrine tumors without evidence of metastatic disease [30]. Enucleation procedures included surgical pancreatic enucleation, transduodenal ampullary excision, and duodenal wall excision. Traditional resections included central pancreatectomy, distal pancreatectomy, pancreaticoduodenectomy, and total pancreatectomy. Tumors that were enucleated were more likely to be functional tumors located in the head of the pancreas and less likely to result in splenectomy. The estimated overall morbidity and five-year survival were similar between the enucleation and resection groups. Although the rate of pancreatic fistula was significantly higher in the enucleation group, the fistulas tended to be less severe after enucleation than after resection. For patients with pancreatic head tumors, enucleation was associated with decreased blood loss, operative time, and length of hospital stay compared with pancreaticoduodenectomy.

Enucleation is more controversial for nonfunctional PNETs smaller than 2 to 3 cm. Although traditional resection is preferred over enucleation for nonfunctional PNETs smaller than 2 to 3 cm in size, enucleation is an option for a PanNEN G1 tumor. In one large multi-institutional review comparing enucleation with traditional resection, patients had a similar five-year survival, and although patients undergoing enucleation had a significantly increased rate of pancreatic fistula, the severity of pancreatic fistula had tended toward a lower severity [30]. For this reason, the authors concluded that enucleation and traditional resection had equivalent outcomes for the management of small, nonfunctional PNETs. By contrast, another study found that even PNETs smaller than 3 cm carried a risk of lymph node metastases [9]. In a single-institution review of 318 patients with sporadic, nonfunctional PNETs, lymph node metastases were present in 14 percent of tumors <1 cm, 9 percent of tumors between 1 and 1.9 cm, and 37 percent of tumors between 2 and 2.9 cm. The presence of positive lymph nodes was a predictor of poorer survival on multivariate analysis.

Minimally invasive resection — With advances in surgical technique and the advent of laparoscopy, minimally invasive operations are gaining wider acceptance in the management of PNETs. There are descriptions and small series of minimally invasive approaches to most of the types of traditional pancreatic resections. These include laparoscopic and robotic techniques for everything from enucleation to pancreaticoduodenectomy. The location of the port sites or incision is based upon the location of the tumor. (See "Abdominal access techniques used in laparoscopic surgery".)

The most commonly performed minimally invasive pancreatic operations are laparoscopic enucleations and laparoscopic distal pancreatectomy. Laparoscopic distal pancreatectomy with spleen preservation is an option for benign, small PNETs located in the body or tail of the pancreas. Laparoscopic distal pancreatectomy can be performed with or without preservation of the spleen. Although central pancreatectomy has been performed laparoscopically, most reports describe an open approach. (See 'Enucleation' above and 'Central pancreatectomy' above and 'Distal pancreatectomy' above.)

The benefits of laparoscopic resection for PNETs include reduced postoperative pain, reduced hospital stay, faster recovery, and better cosmesis [75]. (See "Surgical resection of lesions of the body and tail of the pancreas", section on 'Open surgical versus minimally invasive distal pancreatectomy'.)

A review of 130 resections for PNETs noted that minimally invasive and parenchyma-sparing operations for these tumors were safe, feasible, and associated with shorter hospital stays [76]. A single-institution review evaluated 49 consecutive patients who underwent laparoscopic pancreatic surgery for PNETs, including 33 functional tumors and 16 nonfunctional tumors [16]. Laparoscopic resections included 22 enucleations, 15 spleen-preserving distal pancreatectomies, and 8 distal pancreatectomies with splenectomy. The estimated blood loss and operating times were lower in the laparoscopic enucleation group compared with the other laparoscopic groups, though overall complications, including pancreatic fistula, were higher in the laparoscopic enucleation group. The severity of fistula also was higher in the laparoscopic enucleation group. Overall morbidity was higher in the splenic preservation laparoscopic distal pancreatectomy group compared with laparoscopic distal pancreatectomy with splenectomy. There were no differences in length of hospital stay between all the laparoscopic approaches.

Robotic surgery has also been used in the treatment of PNETs. In a propensity score matched retrospective study of 120 patients with small (<2 cm) PNETs, robotic enucleation was associated with less blood loss (33 versus 80 mL), a shorter duration of surgery (117 versus 150 minutes), and a shorter length of hospital stay (12 versus 13.5 days) compared with open surgery [77]. The two groups had similar complication rates, including those of postoperative pancreatic fistula. The three-dimensional view and ability to articulate instruments using the robotic platform have extended the benefits of minimally invasive pancreatic surgery to a larger population of patients.

TECHNIQUES FOR SPECIFIC PNETS

Nonfunctional — For most patients with nonfunctional pancreatic neuroendocrine tumors (PNETs) who have no evidence of metastatic disease, traditional resection with appropriate lymphadenectomy is recommended [26,52]. (See 'Pancreatic resection' above.)

●Parenchyma-sparing operations (eg, enucleation, central pancreatectomy) are generally safe and effective for the management of small (2 to 3 cm), nonfunctional PNETs without overt malignant features; however, even small PNETs may have lymph node disease [9,30,61]. In a single-institution review of 318 patients with nonfunctional tumors, lymph node metastases were present in 14 percent of tumors <1 cm, 9 percent of tumors between 1 and 1.9 cm, and 37 percent of tumors between 2 and 2.9 cm [9]. The presence of positive lymph nodes was a predictor of poorer survival on multivariate analysis. As a result, traditional resection remains preferred rather than enucleation for nonfunctional PNETs smaller than 2 to 3 cm in size. Nevertheless, enucleation can be an appropriate choice in certain clinical circumstances, such as in those with a small PanNEN G1 tumor. In one multi-institutional review comparing enucleation versus traditional resection, patients had a similar five-year survival [30].

●Large (>3 cm), nonfunctional tumors with malignant features with indications for surgery require traditional oncological resection to achieve negative margins. Large tumors are debulked with intent to cure with the expectation that adjunctive treatment will be used for metastatic disease. In the appropriate clinical situation, a parenchyma-sparing resection may be appropriate for patients with larger nonfunctional tumors and significant comorbidities and/or who do not wish to have a traditional resection.

Surgical resection may also be pursued in patients with metastatic disease. As noted above, the main considerations in determining whether a patient with a nonfunctional PNET is a candidate for surgery is whether the extrapancreatic disease is potentially resectable, whether it is high volume or low volume, the histology, and the growth rate. (See 'Tumor characteristics' above and 'Candidates for resection' above.)

There are advocates of resecting the primary in the setting of metastatic disease [26,28,52,74] and those who disagree [78]. In our view, these situations must be individualized and considered in the context of a long-term strategy for disease control. Bulky disease in the pancreatic head will likely produce significant symptoms. In general, if the tumor is relatively low-grade and the metastatic tumor burden is not large, quality of life will be improved by resection of the primary. In addition, if the metastatic disease is isolated to the liver, resection of the primary combined with local liver-directed therapy may allow the patient to avoid long-term systemic therapy and its side effects.

In most (but not all [78]) series, removal of the primary tumor has been associated with longer survival, even in cases of unresectable metastatic disease [35,37,38,79]. As an example, in an analysis of 2158 patients with metastatic nonfunctioning PNETs, removal of the primary tumor was associated with a median survival of 4.8 years compared with one year in patients whose primary tumor was not resected [42]. In another review of 163 patients with malignant nonfunctional PNETs, patients able to undergo complete resection of localized disease had prolonged median survival (7.1 versus 5.2 years) [80]. However, it remains possible that this apparent survival benefit is the result of selection bias (ie, patients selected for this approach likely had a significantly lower tumor burden) [29,35,38,43,80]. For this reason, resection of the primary tumor in patients with unresectable metastatic disease remains controversial.

An important point is that these patients are at high risk for recurrence and require postoperative surveillance for the detection of disease progression. (See 'Posttreatment surveillance and re-resection' below.)

Functional — There is general consensus that sporadic, functional PNETs should be resected to relieve symptoms whenever possible and clinically appropriate [26-28,74]. The main consideration in determining the best treatment for functional PNETs is whether the patient has potentially resectable metastatic disease, the histology, growth rate, and whether symptoms from hormone secretion are refractory to medical therapy [26]. (See 'Candidates for resection' above.)

Traditional resection with appropriate lymphadenectomy, rather than a more limited resection or enucleation, is recommended for patients with functional PNETs >2 cm, which have a higher risk of malignancy and potential for nodal disease, and/or those that are abutting the pancreatic duct and have no evidence of metastatic disease [26-28,52,74].

Insulinoma — Insulinoma, which is the most common functioning neoplasm of the endocrine pancreas, is typically benign. Insulinoma can be sporadic or associated with multiple endocrine neoplasia type 1 (MEN1) syndrome, which requires a different surgical approach. Sporadic insulinomas tend to be solitary lesions that respond well to limited resection, whereas MEN1-associated tumors are often multifocal and may require more extensive resections. (See "Insulinoma", section on 'Treatment' and "Multiple endocrine neoplasia type 1: Management".)

Sporadic insulinomas are found with equal frequency in each of the sections of the pancreas [81]. Although sporadic insulinomas are most often solitary, they can be multiple in 10 percent of patients [2], and thus, it is necessary to confirm the lesion's location and rule out the presence of other tumors preoperatively or intraoperatively with palpation and intraoperative ultrasound. It is often necessary to perform an extended Kocher maneuver (figure 1) of the duodenum to the level of the superior mesenteric vein to allow bimanual palpation or intraoperative ultrasound of the entire head and uncinate process to plan either an anterior or posterior approach to the lesion. The size of the tumor and its location in relation to the common bile and/or pancreatic duct determines whether the tumor can be enucleated or should be removed using a more traditional resection. Most insulinomas are located along the edges of the body or tail. (See 'Intraoperative localization' above.)

If the tumor cannot be localized, blind distal pancreatectomy is no longer advocated. In the case of a nonlocalized tumor, postoperative selective arterial calcium stimulation with hepatic venous sampling should be performed [82]. This test involves drawing hepatic venous samples after selective calcium infusion into the splenic, gastroduodenal, and superior mesenteric arteries [83].

Enucleation can be attempted for small insulinomas (<2 cm) that are not abutting the pancreatic duct [16,26-28,30,74]. Insulinomas located on the anterior or posterior surfaces of the neck, body, or tail with a tissue plane between the tumor and the pancreatic duct can usually be enucleated. However, insulinoma >2 cm and/or abutting the pancreatic duct, and those without a clear plane between the tumor capsule and pancreatic parenchyma, should be removed via a traditional resection. When the lesion is larger (>2 cm) and/or involves the common bile or pancreatic duct or does not have a clear plane between the tumor capsule and pancreatic duct, a more traditional resection should be performed. Ten percent of insulinomas are malignant and demonstrate local infiltration of lymph nodes or liver metastases. Peripancreatic lymph node dissection should be performed in the rare patient with malignant insulinoma. In the presence of liver metastases, resection of the primary tumor and accessible metastases is advocated if it can be done safely. Tumor debulking helps reduce hypoglycemic symptoms and improves long-term survival. If a tumor is deemed unresectable, medications can be employed to minimize hypoglycemia and the progression of disease [84-86]. Following these guidelines, the cure rate for insulinoma is close to 100 percent [74,87,88].

Gastrinoma — Gastrinomas produce the hormone gastrin. The consequences of hypergastrinemia are gastric acid hypersecretion and its related complications. Patients with gastrinoma are classified as having either sporadic or familial gastrinoma. This distinction is important because the pathophysiology, natural history, and medical management differs [12]. The management of gastrinoma associated with MEN1 is reviewed elsewhere. (See "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)" and "Multiple endocrine neoplasia type 1: Management".)

Laparotomy is recommended for most patients with a sporadic gastrinoma to define the extent of disease and to achieve curative resection when possible. Although gastrinomas can have histologic features that appear benign and tend to be indolent in nature, most have malignant potential and can grow and metastasize. Early laparotomy and resection, even with incomplete resection of gastrinoma tissue, appears to favorably affect the natural history. In general, the cure rate for sporadic, nonmetastatic gastrinoma is 60 percent and 30 to 40 percent, respectively, at one and five years [12,74,89,90].

Gastrinomas may be single or multiple and are often duodenal (approximately two-thirds arise in the duodenal wall) or extrapancreatic in location. These tumors are typically found in the so-called "gastrinoma triangle," which is delineated by the junction of the cystic and common bile duct, the junction of the second and third portion of duodenum, and the junction of the body and neck of the pancreas [81]. At surgery, a thorough exploration of the abdomen, including the liver, is required. The lesser sac should be opened, and bimanual palpation of the body and tail of the pancreas should be performed. A Kocher maneuver with inspection and palpation of the head of the pancreas and lymph nodes behind the uncinate process should also be performed. The surgeon should look and feel for small duodenal wall and submucosal tumors by performing a duodenotomy if necessary. The routine use of duodenotomy and intraoperative ultrasound has resulted in detection of gastrinoma in the majority of patients who are explored [91]. Multiple lymph node biopsies should be taken to obtain a tissue diagnosis.

The type and extent of resection depends on the location of the gastrinoma. Ideally, all gastrinoma tissue is resected. Regional lymphadenectomy should also be performed as required. Small gastrinomas (<2 cm) in the head of the pancreas can be enucleated as these are likely to be benign, though larger tumors may require pancreaticoduodenectomy [8,92]. Enucleation may be attempted for small pancreatic gastrinomas that are not abutting the pancreatic duct [26-28,74]. Small tumors in the duodenal wall may be amenable to full-thickness excision and primary closure. With gastrinoma >2 cm, there is a higher risk of malignancy and potential for nodal disease, and these should be removed via a traditional resection. Gastrinomas in the body or tail of the pancreas are best managed with a distal pancreatectomy. Although enucleation has been described for pancreatic tail lesions, traditional resection is preferred because of the more aggressive nature of gastrinoma to the left of the superior mesenteric vein [93].

The role of laparoscopy in the surgical management of gastrinomas is controversial. Open operations are still more commonly performed for gastrinoma because they commonly are not localized preoperatively, are often located in the duodenum, and are commonly associated with lymph node metastases. Indeed, accessing the "gastrinoma triangle" where most gastrinomas are located can be difficult laparoscopically [16]. In the past, if the tumor was not able to be localized, a parietal cell vagotomy or total gastrectomy was performed. With the advent of proton pump inhibitors, these procedures are no longer advocated.

Others

●VIPoma – Before resection, all patients with VIPoma require correction of dehydration, hypokalemia, and other metabolic abnormalities. Preoperative octreotide administration can reduce the levels of circulating VIP. (See "VIPoma: Clinical manifestations, diagnosis, and management", section on 'Treatment'.)

Preoperative localization of the VIPoma is essential because 10 percent of patients have extrapancreatic tumors in the retroperitoneum or chest. All patients with localized tumors on preoperative imaging should undergo surgical exploration.

Most VIPomas are located in the body or tail of the pancreas and can be managed with a distal pancreatectomy [94]. More than 60 percent of VIPomas are malignant, with up to 60 percent having metastasized to lymph nodes, liver, kidneys, or bone [16]. In one study, only 44 percent of VIPomas were resectable, and of those, only 28 percent were resectable for cure [95]. Thus, careful evaluation of the lymph nodes and liver must be performed preoperatively and intraoperatively. In the case of liver metastases, debulking surgery may be indicated for symptomatic management of diarrhea. (See "Overview of hepatic resection".)

●Glucagonoma – (See "Glucagonoma and the glucagonoma syndrome", section on 'Treatment'.)

Glucagonomas are usually located in the body or tail of the pancreas and can be managed with a distal pancreatectomy [94]. These tumors are typically large and most often metastatic. Careful evaluation of the liver is necessary. Surgical resection should aim to remove all tumors for potential cure or debulk as much tumor mass as possible for symptomatic relief [96].

●Somatostatinoma – (See "Somatostatinoma: Clinical manifestations, diagnosis, and management", section on 'Treatment'.)

Most somatostatinomas are solitary and located in the head of the pancreas or duodenum and can be managed with pancreaticoduodenectomy. Resection of the primary tumor with debulking of metastatic disease has been recommended [97]. (See 'Pancreaticoduodenectomy' above and "Somatostatinoma: Clinical manifestations, diagnosis, and management", section on 'Pancreatic resection' and "Somatostatinoma: Clinical manifestations, diagnosis, and management", section on 'Liver-directed therapy for metastatic disease'.)

POSTTREATMENT SURVEILLANCE AND RE-RESECTION — Fewer than 20 percent of patients will recur after surgical therapy, but it is not established which patients are at highest risk [98-102]. Postoperative surveillance typically includes periodic cross-sectional imaging and functional hormonal levels as appropriate, followed by somatostatin receptor-based imaging (eg, 68-Gallium DOTATATE scanning) if a new lesion is identified. However, there is no consensus as to the optimal follow-up strategy, including the frequency of surveillance. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest that the initial assessment occur within 4 to 12 months after resection, followed by repeat assessment every 6 to 12 months to a maximum of ten years [32]. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring".)

A nomogram, based on pathological features of the resected specimen, is available to predict likelihood of recurrence [103]. This likelihood can help determine the intensity and frequency of surveillance.

Reresection should be considered in patients who have evidence of tumor recurrence on postoperative surveillance.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

SUMMARY AND RECOMMENDATIONS

●Definitions – The term "pancreatic neuroendocrine neoplasm (PNEN)" encompasses a diverse set of tumors arising in the pancreas that share a common progenitor cell. PNENs are rare overall and exhibit a wide spectrum of clinical behavior that has made classification and staging difficult. The well-differentiated forms are referred to as "pancreatic neuroendocrine tumors (PNETs)," while high-grade poorly differentiated PNENs are referred to as "pancreatic neuroendocrine carcinomas (PNECs)." (See 'Introduction' above.)

While most PNETs are sporadic, PNETs can also be associated with genetic syndromes. The recommendations below refer to sporadic PNETs. The management of PNETs associated with genetic syndromes is discussed separately. (See "Multiple endocrine neoplasia type 1: Management" and "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Tuberous sclerosis complex: Management and prognosis" and "Neurofibromatosis type 1 (NF1): Management and prognosis".)

●Tumor classification – Terminology is evolving. The current World Health Organization (WHO) classification recognizes three grades of well-differentiated PNETs: low (PanNET G1), intermediate (PanNET G2), or high-grade (PanNET G3); poorly differentiated, high-grade neuroendocrine neoplasms are all referred to as PanNEC G3 tumors (table 3). We prefer the terms "PNET G1," "PNET G2," and "PNET G3" to designate well-differentiated PNETs of varying grades and "PNEC" to designate a high-grade, poorly differentiated neuroendocrine neoplasm. (See 'Staging and tumor classification' above.)

For patients with PNEC, surgery alone is rarely curative, even for patients with apparently localized disease. Nevertheless, resection may benefit selected patients when used in conjunction with chemotherapy and/or radiation therapy in a multimodality approach. Management of gastroenteropancreatic NECs is discussed elsewhere. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'Localized disease'.)

●Goals of surgery – Surgery is the only curative modality for sporadic PNETs, and resection of the primary tumor in localized, regional, and even metastatic disease can improve patient survival. The goal of surgical resection of primary, sporadic PNETs is to completely remove the tumor for cure or, in appropriate cases, to debulk the tumor (algorithm 1).

●Surgical indications – There is some (though decreasing) disagreement among expert groups as to how to manage small (<2 cm) nonfunctioning, well-differentiated PNETs. While the 2016 European Neuroendocrine Tumor Society (ENETS) guidelines and consensus-based guidelines form the National Comprehensive Cancer Network (NCCN) both endorse observation for nonfunctional, well-differentiated, incidentally discovered PNETS <2 cm [32,33], current guidelines from the North American Neuroendocrine Tumor Society have recommended observing PNETS <1 cm and individualizing management of 1 to 2 cm lesions based on age, comorbidities, growth, grade, extent of surgery needed, and patient preference [34]. Until more conclusive data become available, the decision to pursue nonoperative management for small nonfunctional PNETs should be made individually after weighing risks against benefits, with the recognition that the morbidity of any pancreatic resection is considerable. (See 'Candidates for resection' above.)

Important factors to consider when selecting the surgical approach to sporadic PNETs include functional status, benign or malignant nature, involvement with contiguous structures, presence of metastatic disease, and proliferative index. (See 'Staging and tumor classification' above and 'Preoperative evaluation' above.)

•Clinical symptoms and biochemical evidence of hormone excess determine the tumor's functional status, classifying sporadic PNET as nonfunctional or functional (ie, insulinoma, gastrinoma, VIPoma, glucagonoma, or somatostatinoma). Up to one-half of sporadic PNETs have no defined clinical syndrome and no elevated hormone levels.

•Preoperative imaging by cross-sectional and functional imaging with or without endoscopic ultrasound can help localize the tumor and also determine the tumor's benign or malignant nature by determining the degree of local invasion, lymph node involvement, and metastases to the liver or elsewhere. The only reliable indicators of malignant potential are the presence of invasion, metastases, or tumor recurrence. The majority of glucagonomas, VIPomas, somatostatinomas, and gastrinomas are malignant. Most large, nonfunctional, well-differentiated PNETs are also malignant. (See 'Localization and malignant potential' above and 'Staging and tumor classification' above.)

●Surgical approaches – Surgery is indicated in patients with PNETs to alleviate systemic symptoms due to hormone overproduction or compression due to local mass effect and to prevent malignant transformation or dissemination. With malignant tumors, the primary consideration in determining surgical treatment is whether the patient has distant metastatic disease, whether the extrapancreatic disease is potentially resectable, whether metastatic disease is high volume or low volume, and the histology and growth rate. (See 'Candidates for resection' above.)

•For patients with malignant, sporadic PNET and no evidence of distant metastatic spread of disease, exploratory laparotomy and resection with curative intent can be offered. The goal of curative resection is removal of the primary tumor and associated lymph nodes while preserving the maximal amount of pancreatic mass. Surgery for high-grade, poorly differentiated PNETs is rarely beneficial and should only be done in conjunction with chemotherapy and radiation therapy in a multimodality approach.

•For patients with malignant, sporadic PNET and potentially resectable metastatic disease, an aggressive resection of the primary and metastatic sites can offer the potential for long-term survival.

•For patients with unresectable, metastatic disease, best medical therapy including long-acting somatostatin analogues is the usual first-line approach. In some cases, surgery may be pursued even if complete resection cannot be accomplished. The decision to pursue surgery is a complex one and needs to take into account tumor histology, the volume of metastatic disease, and the growth rate:

-For patients with low-volume metastatic well-differentiated low-grade tumors (ie, PanNEN G1), resection of metastatic sites in conjunction with adjuvant therapies such as ablation, embolization, or long-acting somatostatin analogues can prolong and improve the quality of life. Even large tumors can be debulked with the expectation that adjunctive treatment will be used to control unresectable residual disease. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)

-For patients with well-differentiated tumors with high-volume metastatic disease and a rapid growth rate, initial systemic therapy is an appropriate option. However, palliative debulking may still be indicated for relief of systemic or local symptoms related to hormone production. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)

•Whether there is a benefit to resection of a primary, nonfunctional PNET in patients with unresectable metastatic disease is debated. In some (but not all) series, this approach is associated with a modest survival benefit, but it is likely that this is the result of selection bias (ie, patients selected for this approach likely had a significantly lower tumor burden). In our view, this decision must be individualized. (See 'Candidates for resection' above and 'Nonfunctional' above.)

●Surgical techniques – Traditional pancreatic resection (eg, pancreaticoduodenectomy, pancreatic tail resection) and pancreas-sparing resections (enucleation, central pancreatectomy) are used to treat PNETs, depending on the location of the tumor. Parenchyma-sparing operations are generally safe and effective for the management of small PNETs; however, even small PNETs may have lymph node disease and require traditional resection. Enucleation may be attempted for insulinoma and gastrinoma <2 cm that are not abutting the pancreatic duct, as these are likely to be benign. For some patients with significant comorbidities who may not withstand traditional resection, enucleation may also be appropriate. (See 'Pancreatic resection' above.)

If the PNET is not successfully localized on preoperative imaging, intraoperative localization includes visual and manual inspection of the pancreas and intraoperative ultrasound (IOUS), which can also be used during the course of the procedure to ensure a safe resection. Extrapancreatic sites should also be explored. (See 'Intraoperative localization' above.)

●Postsurgical surveillance – Postoperative surveillance typically includes periodic cross-sectional imaging and functional hormone levels, as appropriate, followed by somatostatin receptor-based imaging if a new lesion is identified. Re-resection should be considered in patients with evidence of tumor recurrence. (See 'Posttreatment surveillance and re-resection' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James Lee, MD, who contributed to an earlier version of this topic review.