Surgical resection of sporadic pancreatic neuroendocrine neoplasms

INTRODUCTION — 

Pancreatic neuroendocrine neoplasms (PNENs) are rare, accounting for less than 3 percent of all pancreatic tumors [1,2]. PNENs encompass a diverse set of tumors arising in the pancreas that share a common progenitor cell [3]:

●Well-differentiated PNENs are referred to as pancreatic neuroendocrine tumors (PNETs). (See 'Tumor classification' below.)

●Poorly differentiated PNENs are high-grade lesions that are referred to as pancreatic neuroendocrine carcinomas (PNECs). (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)

PNENs were previously referred to as pancreatic "islet cell" tumors or pancreatic "carcinoids," but these terms are no longer used. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Classification'.)

The surgical management of sporadic PNENs is presented here. While most PNENs are sporadic, others can be associated with hereditary genetic syndromes (table 1). The management of PNENs associated with a hereditary genetic syndrome may differ from that of sporadic PNENs, since hereditary PNENs may be multifocal or have a more indolent clinical course. The surgical management of patients with PNENs associated with a hereditary genetic syndrome is discussed separately.

●(See "Management and prognosis of gastrinoma (Zollinger-Ellison syndrome)".)

●(See "Multiple endocrine neoplasia type 1: Management".)

●(See "Tuberous sclerosis complex: Management and prognosis".)

●(See "Neurofibromatosis type 1 (NF1): Management and prognosis".)

●(See "Surveillance and management of von Hippel-Lindau disease".)

PREOPERATIVE EVALUATION — 

The preoperative evaluation of PNENs must include tumor characteristics as well as the patient's overall health. It is also essential to obtain an accurate history and physical examination and review all pertinent laboratory and imaging studies.

Sporadic versus hereditary disease — It is important to distinguish sporadic PNENs from those associated with a genetic syndrome because such association greatly impacts surgical decision-making [4,5]. In general, hereditary PNENs are more likely to be multifocal and may have a more indolent clinical course.

The patient's history and genetic testing help determine whether the tumor is sporadic or associated with a genetic syndrome, such as multiple endocrine neoplasia type 1 (MEN1), Zollinger-Ellison syndrome, tuberous sclerosis, neurofibromatosis type 1, and von Hippel-Lindau disease (table 1).

●Previously, genetic syndromes were suspected and diagnosed based on family/personal history (eg, for neurofibromatosis type 1 or tuberous sclerosis). As an example, patients suspected of MEN1-associated gastrinoma should be asked whether they have a duodenal ulcer, diarrhea, or abdominal pain. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Zollinger-Ellison syndrome'.)

●More and more patients without classic symptoms of a genetic syndrome are also being identified with germline alterations (up to 17 percent). For example, around 20 to 30 percent of gastrinomas are associated with MEN1 [6]. Because MEN1-associated gastrinoma has a more indolent clinical course and, therefore, requires surgery later than sporadic gastrinoma, some practices offer MEN1 biochemical screening or genetic testing at the beginning of surgical evaluation for all "sporadic" PNEN.

●In practice, any patient with multiple (ie, >1) PNEN should be considered to have MEN1, regardless of biochemical or genetic screening results or lack of family history.

The management of PNENs associated with genetic syndromes is discussed separately. (See "Multiple endocrine neoplasia type 1: Management" and "Management and prognosis of gastrinoma (Zollinger-Ellison syndrome)" and "Tuberous sclerosis complex: Management and prognosis" and "Neurofibromatosis type 1 (NF1): Management and prognosis" and "Surveillance and management of von Hippel-Lindau disease".)

Tumor characteristics — For patients with a sporadic PNEN, specific tumor characteristics are important to determine optimal surgical management. Such characteristics include tumor functional status, differentiation (ie, well versus poorly differentiated), grade, and stage (ie, the extent of tumor invasion into contiguous structures, and the presence or absence of metastatic disease).

Although all PNENs are potentially malignant, it is extremely difficult to predict the course of disease based on the usual parameters. As an example, a small tumor size does not necessarily mean that it is indolent [7]. Similarly, a diagnosis of an aggressive PNEN cannot always be confirmed or excluded simply based on histology. The natural history of metastatic PNENs 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 and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Histopathology and immunohistochemistry'.)

Functionality — Sporadic PNENs can be divided into tumors that are functional (ie, hormone secreting) and nonfunctional (ie, biochemically inert). The tumor's functional status is determined by clinical symptoms and biochemical evidence of hormone excess and not by histologic appearance or the results of immunohistochemical staining. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Functionality'.)

●Nonfunctional – Most PNENs have no defined clinical syndrome and no elevated hormone levels. 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 [4,8]. As such, the presentation of nonfunctional PNENs was often delayed. As the threshold for abdominal imaging steadily decreases, nonfunctional tumors are more frequently identified as incidental findings. (See "Classification, clinical presentation, diagnosis, 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, vasoactive intestinal peptide, glucagon, or somatostatin) (table 2) [9]. Although functionality may impact prognosis (eg, insulinomas are generally localized tumors), the biologic behavior of most functional neuroendocrine tumors is defined by the grade and stage of the tumor. In other words, the aggressiveness of PNENs (grade based on histologic features) does not correlate with the presence or type of hormone production. (See 'Functional PNET' below.)

Localization — Tumors can be localized using preoperative diagnostic imaging studies. Examples of such diagnostic imaging studies include cross-sectional imaging, such as contrast-enhanced computed tomography (CT) or gadolinium-enhanced magnetic resonance imaging (MRI), as well as functional somatostatin receptor-based imaging, such as gallium Ga-68 dotatate or gallium Ga-68 dotatoc (where available) and cu64 positron emission tomography CT or MRI. These studies can also determine whether the tumor has a more indolent or aggressive nature by determining the degree of local invasion, lymph node involvement, and distant metastases (to the liver or elsewhere). (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Somatostatin receptor-based imaging studies'.)

For pancreatic tumors, endoscopic ultrasound has a sensitivity ranging from 86 to 93 percent. When combined with spiral CT, the sensitivity approaches 100 percent [10]. Endoscopic fine needle aspiration 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 system' below.)

Two-thirds of sporadic gastrinomas reside in the duodenal wall, and these are particularly difficult to localize by preoperative imaging; intraoperative ultrasound and duodenotomy may be required to guide resection [11]. (See 'Localization of gastrinoma' below.)

Staging system — PNENs are staged using the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system, which is based on definitions proposed by the European Neuroendocrine Tumor Society (ENETS). Well-differentiated pancreatic neuroendocrine tumors (PNETs) are staged using the ninth version of the AJCC/UICC tumor, node, metastasis (TNM) staging system (table 3). Importantly, high-grade, poorly differentiated pancreatic neuroendocrine carcinomas (PNECs) are staged according to the AJCC/UICC staging system for exocrine pancreatic tumors (table 4). (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Staging system'.)

Tumor classification — PNENs are classified based on tumor differentiation (well differentiated or poorly differentiated) and tumor grade based on criteria from the World Health Organization (WHO) (table 5). In this topic, we use the terms "PNET G1," "PNET G2," and "PNET G3" to designate a well-differentiated PNET of histologic grade 1, 2, or 3, respectively, and "PNEC" to designate a poorly differentiated, high-grade neuroendocrine carcinoma. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Classification'.)

●Most sporadic PNETs are G1 or G2. These tumors have a relatively indolent clinical course and prolonged natural history, even when metastatic. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors", section on 'Classification and biologic behavior'.)

●PNET G3 tumors have a clinical course and natural history that is in between that of PNET G2 and PNEC G3. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Definition'.)

●PNEC are aggressive tumors that have a rapidly progressive clinical course and often present with metastatic disease. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Symptoms of metastatic disease'.)

Medical risk assessment — Although sporadic PNENs can present at any age, they generally occur in older individuals. The peak incidence is between the fourth and sixth decades, and thus, a 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".)

LOCALIZED DISEASE — 

Surgery is the only known curative therapy for sporadic, localized PNENs, whether functional or nonfunctional [12-14]. Surgery is indicated to alleviate systemic symptoms due to hormone overproduction, to treat compressive symptoms due to local mass effect, and to prevent metastasis or dissemination [15,16]. Tumor functionality, size, and location are important factors in choosing patients for surgical treatment and selecting the operative approach (algorithm 1).

Pancreatic neuroendocrine tumors

Nonfunctional PNET — For localized, sporadic, nonfunctional pancreatic neuroendocrine tumors (PNETs), treatment options include either surveillance or immediate surgical resection, depending on tumor size (algorithm 1).

PNET <1 cm — For localized, nonfunctional sporadic PNETs that are <1 cm, we suggest surveillance rather than immediate surgical resection. Surveillance allows the deferral of therapy and its associated toxicity until more compelling disease progression is documented. We suggest that such patients be surveilled according to the same schedule as the posttreatment patients. (See 'Posttreatment surveillance and re-resection' below.)

PNET 1 to 2 cm — For localized, nonfunctional sporadic PNETs that are between 1 and 2 cm, there is no consensus on which patient population is safe to observe, and treatment should be individualized based on age and comorbidities, tumor growth over time, estimated risk of symptom development, details of imaging, grade, the extent of surgical resection required, the patient's wishes, and access to long-term follow-up [17]. The goal is to balance the desire to achieve a cure with the considerable morbidity and mortality of major pancreatic resections. Endoscopic-guided radiofrequency ablation is an emerging technology that may play a role in the management of small, low-grade PNETs [18].

●The 2023 European Neuroendocrine Tumor Society (ENETS) guidelines recommend active surveillance for PanNENs <1 cm, whereas the management of tumors between 1 and 2 cm (without dilation of the main pancreatic duct) should be personalized based on patient characteristics [19].

●The National Comprehensive Cancer Network (NCCN) consensus-based clinical guidelines include the options of both observation and resection for nonfunctional PanNENs <2 cm [20].

●The North American Neuroendocrine Tumor Society (NANETS) guidelines recommend observation for PanNENs <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 [17].

For small, nonfunctional sporadic PNETs, the safety and efficacy of nonoperative management has been demonstrated in retrospective, observational studies [21]; however, prospective data may be forthcoming:

●An ongoing multicenter prospective observational study from the Netherlands (PANDORA study) aims to evaluate the feasibility of a surveillance protocol for nonfunctional PNETs ≤2 cm. Among 76 patients who have been followed for a median of 17 months, tumor growth of more than 0.5 cm per year was observed in 11 percent. Overall, surgery was performed in 6 percent of patients during the follow-up period, and only one patient developed metastatic disease [22].

●A multicenter international observational study (ASPEN) plans to enroll a total of 1000 patients with nonfunctional PNENs ≤2 cm. This study includes both surgery and surveillance. In an interim analysis, the vast majority of patients (81 percent) underwent a "watchful waiting" strategy [23].

PNET >2 cm — For most medically fit patients with localized, nonfunctional PNET >2 cm and no evidence of MEN1 or distant metastatic spread of disease, we suggest surgical resection with curative intent [19].

For most patients requiring resection of a nonfunctional PNET, we suggest traditional resection (pancreaticoduodenectomy, distal pancreatectomy, or total pancreatectomy) with appropriate lymphadenectomy rather than less extensive surgical approaches [12,24].

Parenchyma-sparing approaches, such as enucleation and central pancreatectomy, may reduce the risk of certain complications (eg, postoperative pancreatic insufficiency) but risks an inadequate lymphadenectomy [25]. Given that the risk of lymph node metastasis cannot be predicted by imaging features other than tumor size, consensus guidelines have endorsed parenchymal-sparing resections for PNETs that are <2 cm (NCCN [20]) or <3 cm (ENETS [19]). Whether to perform a traditional or parenchymal-sparing resection for small, nonfunctional PNET remains controversial mostly because of concerns for missed lymph node metastasis. (See 'Parenchyma-sparing resections' below.)

Regional lymph node involvement does not preclude traditional resection, although it does adversely affect overall survival [26,27]. For patients with locally advanced tumors, vascular resection/reconstruction and extended resections of adjacent organs can be performed with acceptable morbidity and mortality in specialized centers [26,28]. 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 because of good long-term oncologic outcomes [29]. Neoadjuvant peptide receptor radionucleotide therapy has been recommended [30]. Wide invasion of the celiac and superior mesenteric arterial axis is perhaps one of the few relative contraindications to surgery based on anatomy.

Patients who are not surgical candidates may either be observed or receive systemic therapy using the same approach for patients with unresectable or metastatic disease. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors", section on 'General approach to the patient' and "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Management of metastatic disease'.)

Functional PNET — Sporadic, functional PNETs of any size should be resected to relieve symptoms whenever possible and clinically appropriate [17,19,20].

Traditional resection with appropriate lymphadenectomy, rather than a more limited resection or enucleation, is recommended for patients with functional PNET >2 cm, which has a higher risk of malignancy and potential for nodal disease, and/or those abutting the pancreatic duct [12-14,24,31]. Parenchymal-sparing resection may be an appropriate alternative for small (<2 cm) insulinomas at favorable anatomical locations. (See 'Parenchyma-sparing resections' below.)

Insulinoma — Insulinoma is the most common functional neoplasm of the endocrine pancreas. For patients with a clinical syndrome consistent with insulinoma (90 percent of which are localized) who appear to have an isolated pancreatic lesion, surgical resection is the treatment of choice.

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".)

Localization of insulinoma — Sporadic insulinomas are found with equal frequency in each of the sections of the pancreas [32]. Although sporadic insulinomas are most often solitary, they can be multiple in 10 percent of patients [2]. Thus, it is necessary to confirm the lesion's location and rule out the presence of other tumors preoperatively by molecular imaging [33] or intraoperatively with palpation and intraoperative ultrasound. It may be 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. Most insulinomas are located along the edges of the body or tail. 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. (See 'Intraoperative localization' below.)

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 [34]. This test involves drawing hepatic venous samples after selective calcium infusion into the splenic, gastroduodenal, and superior mesenteric arteries [35].

Resection of insulinoma — Because most insulinomas are localized, a parenchyma-sparing resection using a minimally invasive approach may be used as a first-line strategy for patients with localized insulinomas [36]. Since the risk of lymph node metastasis is low, a formal lymphadenectomy is not routinely required. However, the criteria for considering enucleation for insulinoma vary across consensus guidelines:

●The NCCN guidelines suggest enucleation of exophytic or peripheral insulinomas without any size criteria [20]. By contrast, deeper or invasive tumors and those in proximity to the main pancreatic duct should undergo transitional resection.

●The ENETS guidelines suggest enucleation of insulinomas <2 to 3 cm and located at ≥3 mm from the main pancreatic duct [19]. Central pancreatectomy is an option for patients with insulinomas located in the pancreatic neck, when enucleation is not feasible, and the remaining parenchyma is enough to guarantee a relevant pancreatic function.

●The NANETS guidelines suggest enucleation of insulinomas <2 cm and located >2 to 3 mm from the main pancreatic duct [17].

Alternatively, endoscopic ultrasound-guided radiofrequency ablation might be considered as a treatment option for insulinomas <2 cm [19].

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 differ [37].

Surgery for gastrinoma associated with MEN1 is generally delayed compared with surgery for sporadic gastrinoma. The former is reviewed separately. (See "Multiple endocrine neoplasia type 1: Management" and "Management and prognosis of gastrinoma (Zollinger-Ellison syndrome)", section on 'Gastrinoma due to MEN1'.)

Localization of gastrinoma — 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 the duodenum, and the junction of the body and neck of the pancreas [32]. 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 the detection of gastrinoma in the majority of patients who are explored [38]. Multiple lymph node biopsies should be taken to obtain a tissue diagnosis.

Resection of gastrinoma — Although gastrinomas can have histologic features that appear localized and tend to be indolent in nature, most have malignant potential and can grow and metastasize. Early surgical treatment, even with incomplete resection of gastrinoma tissue, appears to favorably affect the natural history. In general, the cure rate for sporadic, non-metastatic gastrinoma at one and five years is 60 percent and 30 to 40 percent, respectively [31,37,39,40].

Laparotomy is recommended for most patients with sporadic gastrinomas to define the extent of the disease and to achieve curative resection when possible. The role of laparoscopy in the surgical management of gastrinomas is controversial. Open operations are still more commonly performed for gastrinomas 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 [10].

Ideally, all gastrinoma tissue is resected. The type and extent of resection is controversial:

●The NCCN guidelines suggest enucleation of exophytic or peripheral gastrinomas without any size criteria; deeper or invasive tumors and those in proximity to the main pancreatic duct should undergo transitional resection [20]. However, both NANETS and ENETS suggest traditional resection of all pancreatic gastrinomas [17,36].

●As for sporadic, non-MEN1 gastrinomas in the duodenal wall, it remains unclear whether local excision via a duodenotomy is sufficient or a partial pancreaticoduodenectomy is required to provide a long-term cure [36].

Regardless of the type of procedure, it is always mandatory to perform a systematic peripancreatic lymphadenectomy during every operation for gastrinoma since it has been demonstrated that nodal dissection reduces the rate of Zollinger-Ellison syndrome persistence and improves survival [41,42].

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 — The majority of VIPomas, glucagonomas, and somatostatinomas are malignant and, therefore, require traditional resection with lymphadenectomy.

●VIPoma – VIPomas produce the hormone vasoactive intestinal peptide (VIP). The consequences of excess VIP secretion include large-volume secretory diarrhea and electrolyte abnormalities. Most VIPomas are located in the body or tail of the pancreas and can be managed with a distal pancreatectomy [43]. 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 [44-46]. 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. (See "Clinical presentation, diagnosis, and management of VIPoma", section on 'Pancreatic resection'.)

●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. Glucagonomas are usually located in the body or tail of the pancreas and can be managed with a distal pancreatectomy [43]. (See "Glucagonoma and the glucagonoma syndrome", section on 'Treatment'.)

●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. Most somatostatinomas are solitary and located in the head of the pancreas or duodenum and can be managed with pancreaticoduodenectomy. (See "Somatostatinoma: Clinical manifestations, diagnosis, and management", section on 'Treatment'.)

Pancreatic neuroendocrine carcinoma — For patients with localized pancreatic neuroendocrine carcinomas (PNECs), surgery alone is rarely curative. Given the aggressive biologic behavior these tumors exhibit, the extremely poor prognosis does not appear to be impacted by surgical resection [17]. Surgical resection, if offered, should be combined with chemotherapy and/or radiation therapy using a multimodality approach. Further details are discussed separately. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Treatment of locoregional disease'.)

METASTATIC DISEASE — 

With metastatic PNEN, the primary considerations in determining surgical treatment are whether the patient has distant metastatic disease, whether or not the extrapancreatic disease is potentially resectable (eg, liver) and whether it is high volume or low volume, histology, functionality, tumor differentiation, and grade of the primary tumor (algorithm 2). (See 'Tumor characteristics' above.)

Pancreatic neuroendocrine tumor grade 1 and 2 (PNET G1 and G2)

Potentially resectable metastatic disease — For patients with pancreatic neuroendocrine tumors (PNETs) G1 or G2 and potentially resectable metastatic disease (typically isolated hepatic metastases), we suggest surgical resection of both the primary and all metastatic sites, as this approach has acceptable morbidity and mortality and can offer the potential for long-term survival [26,47,48]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

Combining resection of the pancreas (primary lesion) and liver (metastasis) during one operation is a reasonable approach as long as intraoperative factors (blood loss, hypotension) and patient comorbidities do not contraindicate doing both, especially for distal lesions or in cases suitable for enucleation [49]. If the primary lesion and liver metastasis need to be resected separately, liver resection should generally be performed before a pancreaticoduodenectomy (Whipple), as the presence of a biliary-enteric anastomosis increases the risk of liver abscess in patients having liver-directed therapy [50].

Unresectable metastatic disease — For patients with PNET G1 or G2 and unresectable metastatic disease, we offer systemic therapy. Systemic treatment options include somatostatin analogues, chemotherapy, targeted agents, and peptide receptor radionuclide therapy. Liver-directed therapies such as ablation and hepatic arterial embolization of liver metastases also have a role in those with hepatic-predominant disease. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

Debulking metastases — Debulking surgery may have a role in treating symptomatic tumors that are refractory to systemic therapy. In such cases, palliative debulking of metastatic disease, usually in the liver, may be pursued even if complete resection cannot be accomplished. Retrospective studies suggest that cytoreduction of PNET liver metastasis may lead to both improvement in symptoms [51,52] and survival [52,53]. However, the benefit of cytoreducing PNET metastasis is not universally accepted since retrospective series are at risk for selection bias. Nevertheless, it is generally accepted that surgical resection can lead to an immediate tumor response that no other therapy can match. This has the potential to benefit patients through rapid decreases in hormone levels and improvement of symptoms, as well as "resetting the clock" and delaying liver failure due to hepatic replacement, which is the leading cause of death in patients with metastatic PNETs. Despite that, it is important to point out that these patients are rarely cured by hepatic resection or grossly complete cytoreduction; recurrence rates are 84 to 95 percent within five years [52,53]. This is because patients with metastatic PNET likely have many microscopic metastases throughout the liver, which are not appreciated even by the most sensitive imaging modalities [54]. Therefore, recurrence is the rule rather than the exception.

Patients with favorable or limited disease are more likely to be offered cytoreduction, while those with more extensive disease, unfavorable tumor biology, or significant comorbidity are more likely to be offered systemic or other nonsurgical therapies (eg, ablation, hepatic arterial embolization). Historical studies have shown survival benefits of cytoreduction versus historical controls when >90 percent of liver metastases can be resected [55,56]. Newer studies specifically evaluating the extent of cytoreduction have broadened that criterion to >70 percent cytoreduction [57-59].

Should the primary tumor be resected? — In the presence of unresectable metastatic disease, it is controversial whether there is a benefit to the resection of a primary, nonfunctional PNET. There are advocates of resecting the primary in the setting of metastatic disease [12,14,24,31], and those who disagree [60].

●In most series, removal of the primary tumor has been associated with longer survival, even in cases of unresectable metastatic disease [61-64]. 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 [65].

●In at least one series, resecting the primary PNET in the presence of extrapancreatic metastasis did not improve survival [60]. More importantly, since all studies were retrospective observation studies, 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) [15,61,63,66,67].

In our view, these situations must be individualized in the context of a long-term strategy for disease control. Factors to be considered include tumor functionality, location, local symptoms or complications, patient age/comorbidities, and planned peptide receptor radionuclide therapy [17]. Several clinical scenarios deserve special mention:

●For patients with PNET in the head of the pancreas that is relatively low grade and the metastatic tumor burden is not large, quality of life will be improved by resection of the primary. Otherwise, given the potentially long natural history of PNET, even when metastatic, bulky 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.

●For patients with metastatic disease that 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. Furthermore, resection of the primary tumor may be an option in some patients with hepatic-isolated metastases who experience complete responses with liver therapies, particularly as the efficacy of such therapies improves. Again, liver-directed therapies should generally be performed prior to or at the same time as pancreaticoduodenectomy to avoid potential liver abscesses due to bacterial translocations through biliary-enteric anastomosis. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)

Patients who undergo primary tumor resection are still at high risk for recurrence and require postoperative surveillance for the detection of disease progression. (See 'Posttreatment surveillance and re-resection' below.)

Pancreatic neuroendocrine tumor grade 3 (PNET G3) — Patients with metastatic PNET G3 are typically treated with systemic therapy. In very select cases (eg, limited, liver-only metastases), hepatic metastasectomy may be used to relieve systemic or local symptoms related to hormone production. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Management of metastatic disease' and "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Limited liver-isolated metastases'.)

Pancreatic neuroendocrine carcinoma — Patients with metastatic pancreatic neuroendocrine carcinoma (PNEC) are treated with systemic therapy. PNEC is an aggressive cancer characterized by rapid disease progression and early widespread metastases. As such, surgical resection is not indicated due to high relapse rates and poor overall survival [17]. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Initial treatment of metastatic disease'.)

SURGICAL TECHNIQUES — 

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 while preserving the maximal amount of pancreatic mass.

Intraoperative localization — Preoperative selection and extent of surgery are based on preoperative and/or intraoperative localization of the tumor to reduce the risk of recurrence. The improved sensitivity of gallium Ga-68 dotatoc positron emission tomography scans has decreased the frequency of surgery without localization. (See 'Localization' above.)

If the PNET is not successfully localized preoperatively, a complete evaluation of the pancreas and peripancreatic region is necessary intraoperatively. 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.

Depending on the clinical context, extrapancreatic sites including the duodenum, splenic hilum, small bowel, mesentery, and peripancreatic lymph nodes must also be considered and palpated or visualized for lymphadenopathy. Through the meticulous combination of visual inspection, manual palpation, and intraoperative ultrasound, PNETs can be localized and defined, and the appropriate operation can be executed.

Intraoperative ultrasound 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 ideal intraoperative ultrasound 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).

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 [4,68]. A variety of pancreatic resections, including traditional resections and parenchymal-sparing resections, are used to treat PNETs.

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

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; thus, they 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 [12,24]. (See 'Nonfunctional PNET' above.)

The type of traditional resection selected depending on tumor location:

●Pancreaticoduodenectomy – For lesions located in the head, uncinate, or neck of the pancreas, pancreaticoduodenectomy is preferred for most lesions. (See "Surgical resection of lesions of the head of the pancreas", section on 'Pancreaticoduodenectomy'.)

●Distal pancreatectomy – For lesions located in the body or tail of the pancreas, distal pancreatectomy can be performed. If the lesion is thought to be localized, splenic preservation may be attempted [69,70]. When malignancy is suspected, distal pancreatectomy with splenectomy and peripancreatic lymphadenectomy should be performed. (See "Surgical resection of lesions of the body and tail of the pancreas", section on 'Distal pancreatectomy'.)

●Total pancreatectomy – For multifocal disease, which is rare, total pancreatectomy is required because the disease is present throughout the entire pancreas. Total pancreatectomy may also be required for centrally located tumors that extend into the head of the gland. (See "Total pancreatectomy".)

Parenchyma-sparing resections — Parenchyma-sparing operations (central pancreatectomy or enucleation) may be safe for the management of small (eg, <2 cm) nonfunctional PNETs or insulinomas (and perhaps gastrinomas according to some guidelines) at favorable anatomical locations. This is controversial, however, because even small PNETs may have lymph node disease [7,16,71]. Thus, when lymph node metastasis or other malignant features are suspected, a traditional resection is indicated [71]. The controversy is evident in the lack of consensus on the precise criteria appropriate for enucleation. (See 'PNET >2 cm' above and 'Resection of insulinoma' above and 'Resection of gastrinoma' above.)

Parenchyma-sparing operations have the benefit of tumor removal with minimal loss of pancreatic parenchyma [10]. 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 [69,70].

Central pancreatectomy — Central pancreatectomy (figure 2) 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 can be used for selected patients with small, localized, or low-grade PNETs of the neck or proximal body of the pancreas that cannot be enucleated because of proximity to the pancreatic duct, and there is a left pancreatic remnant >5 cm [17,72-80]. (See "Surgical resection of lesions of the body and tail of the pancreas", section on 'Central pancreatectomy'.)

Central pancreatectomy offers better preservation of pancreatic function with acceptable morbidity and mortality [72-78].

●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.

●In theory, higher morbidity can be expected due to the need to transect the pancreas in two locations, which, in the setting of localized low-grade disease, is most often through pancreas with a soft texture and is associated with higher rates of postoperative pancreatic fistula [81-84]. However, in a single-institution study of 73 central pancreatectomies compared with matched distal pancreatectomies, there were no differences in fistula, morbidity, and mortality rates between central pancreatectomy and distal pancreatectomy groups [70].

Although most series describe an open approach, central pancreatectomy is increasingly being performed using minimally invasive techniques. (See 'Minimally invasive resection' below.)

Enucleation — This type of localized resection carries fewer risks and is the desired approach for single insulinoma when anatomically feasible. It also may be performed for other small pancreatic PNENs.

Enucleation is safe and is not detrimental to long-term survival for appropriately selected patients. 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.

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 [16]. 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 usually placed in the area of resection.

Resection of duodenal wall gastrinoma — For sporadic, non-multiple endocrine neoplasia type 1 (non-MEN1) gastrinomas in the duodenal wall, it remains unclear whether local excision via a duodenotomy is sufficient or a partial pancreaticoduodenectomy is required to provide long-term cure [36]. Retrospective studies on non-metastatic sporadic gastrinomas favored duodenotomy with lymphadenectomy compared with partial pancreaticoduodenectomy since there was no significant difference in survival outcomes but a lower complication rate after duodenotomy [41,85].

Lymphadenectomy — The extent of lymphadenectomy in the management of PNETs remains controversial since the relationship between nodal metastases and survival has been inconsistent [86-89]. Some studies have concluded that nodal metastases significantly decrease survival [90-94], while others have shown no association [66,95-101]. Hence, there is no universally accepted or established threshold for the minimum number of nodes that are required for accurate prognostication of PNETs [102].

If formal surgical resection is planned for PNET, oncologic resection with removal of 11 to 15 lymph nodes should be performed for accurate nodal staging. If pancreas-sparing surgery is planned for smaller PNETs (<2 cm), removal of suspicious nodes seen on preoperative imaging is warranted, and lymph node sampling may be considered if imaging is negative.

Usual practices of lymphadenectomy for specific PNETs (eg, insulinoma or gastrinoma) are discussed above. (See 'Resection of insulinoma' above and 'Resection of gastrinoma' above.)

Minimally invasive resection — With advances in surgical technique and the advent of robotics, minimally invasive operations are gaining wider acceptance in the management of PNETs. There are descriptions and an increasingly larger 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 [100,103].

The most commonly performed minimally invasive pancreatic operations are enucleations and distal pancreatectomy with or without splenic preservation. Central pancreatectomy and pancreaticoduodenectomy are increasingly being performed at specialized high-volume centers using a robotic platform.

The benefits of minimally invasive resection for PNETs include reduced postoperative pain, reduced hospital stay, faster recovery, and better cosmesis [104]. (See "Minimally invasive pancreatectomy (MIP)", section on 'Outcomes'.)

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 the highest risk [105-109]. Postoperative surveillance typically includes periodic cross-sectional imaging and functional hormonal levels as appropriate, followed by somatostatin receptor-based imaging (eg, gallium Ga-68 dotatoc positron emission tomography CT) if a new lesion is identified. However, there is no consensus as to the optimal follow-up strategy, including the frequency of surveillance.

For patients who are treated with surgery, guidelines from the National Comprehensive Cancer Network (NCCN) suggest that the initial assessment occurs within 4 to 12 months after resection, followed by repeat assessment every 6 to 12 months to a maximum of ten years [20]. (See "Clinical presentation, imaging and biomarker monitoring, and prognosis of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors".)

European Neuroendocrine Tumor Society (ENETS) guidelines recommend initial assessment within three to six months after surgery, then every 6 to 12 months for five years, then every 12 to 24 months for 10 years, and then every five years for nonfunctional pancreatic neuroendocrine tumors (PNETs) and functional PNETs that are not insulinoma [19,36]. Completely resected insulinomas only require a single follow-up in three to six months after resection.

A nomogram, based on pathologic features of the resected specimen, is available to predict the likelihood of recurrence [110]. This likelihood can help determine the intensity and frequency of surveillance. Re-resection 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: Neuroendocrine neoplasms".)

SUMMARY AND RECOMMENDATIONS

●Tumor classification – The term "pancreatic neuroendocrine neoplasm" (PNEN) encompasses a diverse set of tumors arising in the pancreas that share a common progenitor cell. We use the terms "pancreatic neuroendocrine tumor (PNET) G1," "PNET G2," and "PNET G3" to designate a well-differentiated PNET of histologic grade grades 1, 2, or 3, respectively, and "PNEC" to designate a poorly differentiated, high-grade neuroendocrine carcinoma (table 5). (See 'Tumor classification' above.)

●Localized disease – Surgery is the only known curative therapy for sporadic, localized PNENs, regardless of functionality (algorithm 1).

•Functional PNET – For patients with localized PNETs (table 2) that are functional and of any size, we suggest surgical resection rather than medical therapy to relieve symptoms (Grade 2C). (See 'Functional PNET' above.)

•Nonfunctional PNET – For localized PNETs that are nonfunctional, the approach to treatment (excision versus surveillance) depends on tumor grade and size:

-PNET <1 cm – For patients with localized, nonfunctional PNET <1 cm, we suggest surveillance rather than immediate surgical resection (Grade 2C). (See 'PNET <1 cm' above.)

-PNET 1 to 2 cm – For patients with localized, nonfunctional PNET between 1 and 2 cm, there is no consensus on the optimal management strategy, and treatment should be individualized. (See 'PNET 1 to 2 cm' above.)

-PNET >2 cm – For medically fit patients with nonfunctional PNET >2 cm, we suggest surgical resection rather than medical therapy (Grade 2C). (See 'PNET >2 cm' above.)

•PNEC – For patients with localized PNEC, surgery alone is rarely curative. If offered, surgical resection should be combined with chemotherapy and/or radiation therapy using a multimodality approach. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Treatment of locoregional disease'.)

●Metastatic disease – For patients with sporadic PNEN and distant metastasis, surgical resection of the primary tumor or metastasis may be helpful depending on whether the extrapancreatic disease is resectable, tumor biology, patient symptoms, and response to systemic therapy (algorithm 2). (See 'Metastatic disease' above.)

•PNET G1 or G2

-Potentially resectable metastases – For patients with PNET G1 or G2 and potentially resectable metastatic disease, we suggest surgical resection of the primary along with all metastatic disease (Grade 2C). Aggressive resection has acceptable morbidity and can offer the potential for long-term survival. (See 'Potentially resectable metastatic disease' above.)

-Unresectable metastatic disease – For patients with PNET G1 or G2 and unresectable, metastatic disease, we offer systemic therapy. Systemic treatment options include somatostatin analogues, chemotherapy, targeted agents, and peptide receptor radionuclide therapy. Ablation and hepatic arterial embolization of liver metastases also have a role in those with hepatic predominant disease. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

In some cases, debulking of the metastatic diseases with or without resecting the primary tumor may be pursued even if complete resection cannot be accomplished, especially in those with functional PNET/neuroendocrine syndrome and/or those who are refractory to medical therapy. The decision to pursue surgery is a complex one and needs to take into account tumor biology, the volume of metastatic disease, the severity of any local or systemic symptoms, and the response to systemic therapy. (See 'Unresectable metastatic disease' above.)

•PNET G3 – Patients with metastatic PNET G3 are typically treated with systemic therapy. In very select cases (eg, limited, liver-only metastases), hepatic metastasectomy may be used to relieve systemic or local symptoms related to hormone production. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Management of metastatic disease' and "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Limited liver-isolated metastases'.)

•PNEC – Patients with metastatic PNEC are typically treated with systemic therapy. In these aggressive tumors, surgery is generally not indicated. (See 'Pancreatic neuroendocrine tumor grade 3 (PNET G3)' above.)

●Surgical techniques – For most PNENs, we suggest traditional types of resection with appropriate lymphadenectomy rather than less extensive surgical approaches (Grade 2C). Parenchyma-sparing approaches may be an appropriate alternative for small (eg, <2 cm) either nonfunctional PNET or insulinoma of favorable anatomic locations. However, parenchymal-sparing resection of PNENs is controversial because of concerns for lymph node metastasis, which could occur even with small tumors. (See 'Surgical techniques' 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 A Lee, MD, who contributed to an earlier version of this topic review.