Pancreatic neuroendocrine tumors are a very heterogeneous group of tumors, and patient management must often be highly individualized. As other chapters within this textbook will cover specific management principles in greater detail, the remainder of this chapter will focus on the following basic concepts:
Surgical management of locoregional disease
Surgical approach to PNETs occurring as part of an inherited syndrome
Local treatment options for management of liver metastasis
Goals of systemic treatment
Surgical Management of Locoregional Disease
Surgical resection offers the only opportunity for cure and is considered the mainstay of therapy for patients with PNETs limited to locoregional disease (Table 145-2). Although nonfunctioning PNETs typically present at an advanced stage at the time of diagnosis, patients still have a much better prognosis than patients with pancreatic adenocarcinoma, and a median survival of 7 to 10 years is reported for patients undergoing surgery for locoregional disease.60-64 Formal pancreatectomy and regional lymphadenectomy are considered the standard of care for PNETs, as the majority of these tumors are malignant and have a high propensity for metastasis.19,65,66 Depending on the exact tumor location, pancreaticoduodenectomy, distal pancreatectomy, or (rarely) total pancreatectomy is indicated. Central pancreatectomy has occasionally been performed for modest-sized pancreatic neck tumors. Some centers recommend enucleation with regional lymphadenectomy for selected nonfunctioning PNETs less than 2 cm in diameter.67 Given the high propensity for metastasis despite surgical resection, close postoperative oncologic surveillance is routine. Postsurgical follow-up typically consists of biannual to annual physical examination, pertinent laboratory tests and imaging studies.68
For patients with functioning PNETs, surgical resection may provide immediate relief of the symptoms of hormone overproduction. Because functioning PNETs vary widely in terms of their size at presentation, their location within the pancreas, and their malignant potential, an understanding of the specific syndrome is critical to successful surgical intervention. Insulinomas and gastrinomas may be very small at presentation, and localization may be challenging. Preoperative localization is usually not as difficult for glucagonomas, VIPomas, or somatostatinomas, as they are usually larger at the time of presentation.
The vast majority of insulinomas are sporadic, solitary and benign, and are curable by simple surgical enucleation in most cases. However, large tumors (> 2cm) and tumors located close to the main pancreatic duct should be managed with a formal pancreatic resection (pancreaticoduodenectomy or distal pancreatectomy). As insulinomas that are clinically and radiographically localized at presentation almost always follow a benign course, there is little role for lymph node dissection.
Surgical resection of sporadic gastrinomas results in postoperative cure in 60%, with 10-year cure rates of approximately 30%.69,70 The goal is to perform complete tumor resection of the disease while preserving the maximal amount of pancreas. Depending upon the location of the tumor within the pancreas, resection may involve distal pancreatectomy (tumor in the body or tail of pancreas), enucleation (small tumor in the head of pancreas), pancreaticoduodenectomy (large tumor in the head of the pancreas), or full-thickness resection of the duodenal wall (duodenal tumor). Duodenotomy with careful palpation of the duodenum or endoscopic transillumination should be performed routinely, even for patients who do not have a diagnosed duodenal primary, as duodenal tumors in patients with gastrinoma are extremely common; they can be multiple and very small. Routine peripancreatic lymph node dissection is typically performed due to the high incidence of lymph node metastasis at the time of diagnosis.43,69-71
Glucagonomas, VIPomas, and somatostatinomas are usually large at the time of diagnosis, and are malignant in more than half of cases. Thus, formal pancreas resection with lymph node dissection is the mainstay of therapy and may be curative if performed at an early stage or palliative in advanced cases. A more individualized approach should be used for patients with locally-advanced unresectable disease. There exist insufficient data to unequivocally support debulking surgery. However, operative intervention may provide benefit for palliative reasons, e.g., biliary or gastric bypass to relieve biliary or gastric outlet obstruction, or debulking for the relief of symptoms of hormone overproduction refractory to medical management.
Surgical Approach to PNETs Occurring as Part of an Inherited Syndrome
The fundamental difference between patients with sporadic PNETs and patients with an inherited syndrome that predisposes them to PNETs is that sporadic PNETs are almost always solitary tumors that occur in the setting of a normal surrounding pancreas, whereas all pancreatic tissue is genetically abnormal and at risk of developing tumors in patients with MEN1 or VHL. The remainder of this section will focus on patients with MEN1, as PNETs in the setting of MEN1 are considerably more common than are PNETs in the setting of any other inherited tumor syndrome, including VHL.
The appropriate management of PNETs in MEN1 is controversial, both with regard to the timing of surgery and the extent of surgery. With regard to the timing of surgery, an aggressive approach is to operate as soon as any PNET is detected.72-75 A less aggressive approach is based on the fact that tumors less than 2.5 to 3 cm in diameter rarely metastasize; thus, operation often can be safely deferred until tumors reach that size.76,77 With regard to the extent of surgery, total pancreatectomy would be curative/preventive in patients with MEN1 who are diagnosed early, but complete absence of exocrine and endocrine pancreatic function is an exceedingly difficult consequence to manage clinically with significant associated health risks of its own. Thus, this approach is only rarely utilized. An approach that attempts to balance oncologic principles with the desire to preserve as much pancreas as possible is the Thompson procedure: distal pancreatectomy, enucleation of any lesions in the pancreatic head and uncinate process that are palpable or visible with intraoperative ultrasonography, regional lymphadenectomy, and (for patients with tumors that produce gastrin) duodenotomy with careful palpation and local resection of any tumors found in the duodenum. Careful evaluation of the duodenum along with formal lymph node dissection may result in eugastrinemia in up to 60% of patients with gastrinoma in the setting of MEN1.78
It is generally accepted that functioning tumors should be resected at the time of diagnosis. In MEN1, insulinomas and gastrinomas are by far the most common functioning tumors. MEN1-associated insulinomas often require a more aggressive approach than the simple enucleation that is appropriate for a sporadic insulinoma, as these tumors are frequently multifocal, and have a higher recurrence rate and malignant potential than their sporadic counterparts.
The management of MEN1-associated gastrinomas differs considerably from the management of sporadic gastrinomas. MEN1-associated gastrinomas are often tiny and multifocal; surgical resection has not been shown to reliably result in normalization of gastrin levels or improved survival.43,79,80 Thus, these patients are often medically treated with proton pump inhibitors with the goal of controlling the symptoms of hypergastrinemia. However, although medical treatment can often provide reasonable symptom control for a period of time, it does not address the malignant potential of the tumors. Another complicating factor in patients with gastrinoma in the setting of MEN1 is that hypergastrinemia and the resulting symptoms of gastric acid hypersecretion are further exacerbated by the primary hyperparathyroidism and hypercalcemia that develops in nearly 100% of patients with MEN1. Surgical management of their parathyroid disease can often result in substantial alleviation of the symptoms of hypergastrinemia in these patients.
Local Treatment Options for Management of Liver Metastasis
The liver is by far the most common site of metastasis of PNETs, and hepatic metastasis is an important determinant of survival. Analysis of the Surveillance, Epidemiology, and End Results (SEER) database by Yao et al demonstrated that over 50% of patients with PNETs develop liver metastasis during the course of their disease.32,60,81 Hence, several modalities have been developed to treat liver metastasis and improved outcomes have been reported with more aggressive approaches. A multidisciplinary team consisting of surgeons, endocrinologists, oncologists and radiologists is needed to formulate an individualized treatment plan for each patient based on hepatic tumor distribution, presence of extrahepatic metastasis, clinical scenario and overall performance status.
Surgical resection of liver metastases from PNETs is the preferred method for management of a limited number of isolated metastases to the liver. Complete resection is the goal of surgery and offers the only potential for cure; however, there is evidence in the literature for symptom control and longer overall survival if at least 90% of the tumor burden is resected (cytoreductive surgery).82-84
LOCAL ABLATIVE TECHNIQUES
Liver metastases that are not surgically resectable may be treatable with local ablative techniques. Radiofrequency ablation (RFA) is the most commonly-used local ablative technique. RFA utilizes high-frequency radio waves to destroy the tumor by thermal energy.85-87 RFA can be performed percutaneously under image guidance or during laparoscopic or open surgery using intraoperative ultrasound. Other local ablative techniques that may be used to treat liver metastases include percutaneous ethanol injection, cryoablation, and microwave ablation.85-88
HEPATIC ARTERY CHEMOEMBOLIZATION
Hepatic artery chemoembolization is possible because of the dual blood supply to the liver: tumors in the liver derive most of their blood supply from the hepatic artery, whereas the normal liver parenchyma is mainly supplied by the portal vein. Hepatic artery chemoembolization is most commonly utilized for patients with diffuse, unresectable liver metastases.89,90 This procedure involves the intra-arterial delivery of high concentrations of chemotherapeutic agents directly to the tumor in the liver to limit systemic toxicity, followed by embolization of the arterial blood supply. Liver-directed intra-arterial therapies are discussed in more detail in Chapter 146 and in the Hepatobiliary Section.90-92
Ultimately, orthotopic liver transplantation may be offered to patients who are refractory to all other treatment options. Although cure rates are very low and long-term survival is plagued by frequent disease recurrences, liver transplantation may provide symptom relief in patients with severe symptoms of hormone overproduction, and may have curative potential in carefully selected patients with metastases confined to the liver.93
Goals of Systemic Treatment
Because more than half of patients with PNETs will eventually develop distant metastasis, systemic therapy has an important role in the management of these patients. Although cure is not possible in this situation, long-term survival is still common, because PNETs are often indolent tumors. Patients with functioning tumors may be plagued by the symptoms of hormone overproduction. Thus, the goals of systemic therapy typically focus more on the alleviation of symptoms, and less on the prolongation of survival time for patients with PNETs. Cytotoxic chemotherapy has had limited success, with substantial side effects. Targeted therapies carry some promise, although somatostatin analogues have demonstrated the greatest success in the treatment of symptoms.