Pancreatic Endocrine Tumors
Pancreatic endocrine tumors (PETs) or pancreatic neuroendocrine tumors (PNETs) cover a spectrum of neoplasms. These tumors may produce clinical syndromes based on excessive hormone production (see below), or produce symptoms (abdominal pain, jaundice, etc) by mass effect in tumors that do not secrete hormones (nonfunctional tumors). With the increased use of CT scanning, there are a greater number of identified nonfunctioning neuroendocrine tumors of the pancreas.
PETs are not rare. Autopsy studies have documented an incidence of 1.5%. Most of these lesions are clinically silent.
Approximately 20% of patients with Zollinger-Ellison syndrome (ZES) develop PETs in the setting of multiple endocrine neoplasia type 1 (MEN-1). MEN-1 is inherited as an autosomal-dominant trait and is characterized by tumors of multiple endocrine organs, including the pituitary, pancreas, and parathyroid. The gene for MEN-1, which has been localized to the long arm of chromosome 11, has been identified and named MENIN.
The normal islet contains α, β, and γ cells, and enterochromaffin cells, which primarily secrete glucagon(Drug information on glucagon), insulin, somatostatin(Drug information on somatostatin), and serotonin, respectively. All of these hormones may be secreted in excess by PETs. Other hormones that may be secreted by these tumors include vasoactive intestinal peptide (VIP), gastrin, pancreatic polypeptide (PP), and calcitonin. The aggressiveness of a PET in terms of its metastatic potential appears to be a factor of the cell of origin.
The natural history of PETs is highly variable. As noted, many remain asymptomatic and undiagnosed. Others, with poorly differentiated histology, may be quite malignant and spread to distant organs. The behavior and treatment of these tumors are similar to small-cell lung cancer.
These are beta-cell tumors of the pancreatic islets that produce insulin. Four-fifths of insulinomas occur as a solitary lesion, and < 10% of these tumors demonstrate malignant potential (in terms of invasiveness or the development of metastases). In patients with the MEN-1 syndrome, insulinomas are multicentric (10% of patients). A small group of insulinomas is associated with diffuse islet-cell hyperplasia or nesidioblastosis.
These tumors are gastrin-secreting tumors associated with the ZES. They can be either sporadic or familial. Sporadic gastrinomas do not have associated endocrinopathies, whereas hereditary gastrinomas occur in patients with MEN-1 syndrome. Patients with the sporadic form of ZES may have single or multiple gastrinomas. This contrasts with the finding for patients with hereditary MEN-1 PETs, who generally have a more diffuse tumor process within the pancreas.
It is known that 80% to 90% of gastrinomas are located within the "gastrinoma triangle," defined as the junction of (1) the cystic and common duct, (2) the second and third portions of the duodenum, and (3) the neck and body of the pancreas.
More than 90% of gastrinomas are malignant. The spectrum of clinical disease progression includes localized tumors, regional lymph node metastases, and widespread metastatic disease.
Approximately 75% of VIPomas and approximately 50% of all glucagonomas and somatostatinomas are malignant.
Although many PETs cause considerable morbidity due to the inappropriately elevated levels of the hormones that they secrete, even "nonfunctional" PETs, such as those without an associated demonstrable hormone-related syndrome (ie, as PPomas, neurotensinomas, and nonsecretory PETs), may be aggressive. Nonfunctional tumors account for up to 30% of all PETs. Two-thirds of these nonfunctional tumors will demonstrate metastatic lesions at some point during the patient's lifetime.
The symptom complex that is observed depends on which hormone or hormones are secreted in excess.
These are associated with symptoms of recurrent hypoglycemia. Diagnosis of these tumors is made by the demonstration of inappropriately elevated levels of insulin, proinsulin, and C peptide at the time of hypoglycemia and an elevated insulin-glucose ratio of > 0.3).
Symptoms of gastrinoma-ZES are due to the effect of elevated levels of circulating gastrin. Ulceration of the upper GI tract is seen in > 90% of patients. Diarrhea is the second most common symptom. Approximately 25% of gastrinomas occur in the context of MEN-1 and are associated with parathyroid hyperplasia and hypercalcemia.
The diagnosis of ZES is established by the demonstration of hypergastrinemia (fasting serum gastrin concentration > 1,000 pg/mL) and gastric acid hypersecretion in a patient with ulcerative disease. Medications used for acid suppression could falsely elevate gastrin levels and should be discontinued before testing.
An excess of VIP causes a profuse, watery diarrhea, hypokalemia, hypophosphatemia, and hypochlorhydria, referred to as WDHA syndrome.
These tumors are associated with a rash (described as a necrotizing migratory erythema), glossitis, cheilosis, constipation and ileus, venous thrombosis, and diabetes.
These tumors are rare and are associated with elevated blood glucose levels, achlorhydria, cholelithiasis, and diarrhea.
Ultrasonography, CT, MRI, and selective arteriography with portal vein sampling have been utilized for the preoperative localization of insulinomas. The sensitivity of these preoperative imaging tests ranges from approximately 30% to 60%. This is because 40% of insulinomas measure ≤ 1 cm and two-thirds of these tumors are < 1.5 cm.
Because of the limited success of preoperative localization tests, and because 90% of these tumors will be found and successfully resected by an experienced endocrine surgeon, there is a general trend toward performing fewer tests. Some centers utilize preoperative ultrasonography if the patient has not undergone prior pancreatic surgery. Other centers still routinely employ portal vein catheterization and angiography. Most centers with EUS availability use the modality as a standard diagnostic tool for these tumors.
More recently, intraoperative sonography has been shown to aid the surgeon. In one series, 84% of tumors not localized preoperatively were correctly located by surgical exploration and intraoperative sonography. Many lesions not discovered by surgical palpation may be found by this technique. At present, there is much less reliance on blind distal resection than was previously advocated. Obviously, the technique of intraoperative ultrasonography may not be as helpful for the MEN-1 syndrome, in which multiple small insulinomas are involved.
CT, ultrasonography, selective abdominal angiography, selective venous sampling of gastrin, intraoperative ultrasonography, EUS, and intraoperative endoscopy have all been reported to be useful in localizing gastrinomas. More recently, somatostatin receptor scintigraphy (SRS) has become a valuable tool for PET localization; several studies have suggested greater sensitivity and specificity with SRS than with other diagnostic tests.
Surgery for insulinomas
For larger insulinomas in the body or tail of the pancreas, a distal pancreatectomy may be preferable to enucleation. For tumors in the head of the pancreas, enucleation of the tumor is usually possible. Patients with MEN-1 or islet-cell hyperplasia may benefit from an 80% distal pancreatectomy. If the insulinoma is not found at surgery, a blind pancreatectomy is not warranted. Further imaging and venous sampling studies may reveal the exact location of the tumor.
A surgical cure results in normal values on subsequent provocative testing, during which blood insulin and glucose concentrations are measured simultaneously. Some insulinoma recurrences actually represent persistent disease after incomplete tumor excisions or overlooked multiple secondary tumors.
Surgery for gastrinoma-ZES
The ideal treatment for gastrinoma-ZES is surgical excision of the gastrinoma. However, this approach is possible in only 20% of patients, most of whom have a sporadic tumor. With the development of effective antisecretory agents and preoperative localization with octreotide(Drug information on octreotide) scanning, the majority of patients demonstrating widespread metastatic disease can be identified and spared surgical exploration. In addition, some series report that patients with nonmetastatic sporadic gastrinoma may have a higher incidence of extrapancreatic sites than was previously thought. One series has reported that two-thirds of gastrinomas are extrapancreatic.
Patients with sporadic gastrinoma. All patients with sporadic gastrinoma should undergo localization studies and be considered for exploratory laparotomy, with the goal of potential cure of ZES. Recent evidence suggests that resection of primary gastrinoma decreases the incidence of liver metastases and ZES. Overall, surgery produces complete remission in approximately 60% of patients with sporadic ZES, and subsequent survival is excellent.
Patients with ZES and MEN-1. Some experts believe that surgery should not be used in the management of patients with MEN-1 and ZES. Instead, they recommend treatment with antisecretory medications. This approach is somewhat controversial, because some authors believe that all patients without demonstrated liver metastases should undergo surgery to remove duodenal and pancreatic gastrinomas.
Moreover, since many patients with ZES and MEN-1 die of metastatic gastrinoma at a young age, a surgical approach may be warranted. Surgery should be performed only if imaging studies localize the tumor. Although radical surgery may not provide a cure, removal of large tumors may decrease metastatic potential and increase survival.
Surgical procedure. Surgical resection of liver metastases is controversial; even more controversial is orthotopic liver transplantation. However, several authors have demonstrated meaningful survival in patients with small, isolated lesions. The use of ablative procedures, with open, laparoscopic, or percutaneous techniques, can reduce the neurohormonal tumor burden, protect hepatic function, and provide palliation in patients with hormonal production.
Surgical resection for nonfunctioning tumors is indicated and should be performed wth a goal of negative soft tissue and pancreatic margins. Due to the variable aggressive patterns of these tumors, there has been an interest in maximal debulking.
Radiation therapy for PETs
Adjuvant therapy. There is no established role for adjuvant therapy after tumor resection of PETs. Anecdotal reports indicate that PETs may respond to palliative doses of irradiation. Long-term control of unresectable disease has been reported.
Chemotherapy for PETs
PETs are more sensitive to chemotherapy than are carcinoid tumors.
Single agents. Agents that have demonstrated antitumor activity include recombinant human interferon alfa-2a(Drug information on interferon alfa-2a) and alfa-2b (Roferon-A, Intron A, respectively), 5-FU, doxorubicin(Drug information on doxorubicin), dacarbazine(Drug information on dacarbazine), and streptozocin.
Two randomized placebo-controlled phase III trials for patients with advanced, lower-grade pancreatic neuroendocrine tumors have been reported. Everolimus (Afinitor) compared to placebo (Yao JC et al: N Engl J Med 2011) demonstrated superior progression-free survival (11 months vs 4.6 months, P < .001). Simarily, another randomized (Raymond E et al: N Engl J Med 2011), phase III trial of sunitinib (Sutent) compared with placebo for advanced pancreatic neuroendocrine tumors reported a significant improvement in progression-free survival favoring sunitinib (11.4 months vs 5.5 months, respectively; P < .0001).
Combination regimens. Combination chemotherapy is often more effective than monotherapy. For example, in an ECOG study involving the treatment of patients with PETs, the combination of 5-FU and streptozocin demonstrated a higher response rate than did streptozocin alone (63% vs 36%), as well as a better complete response rate (33% vs 12%) and median survival duration (26 vs 16.5 months). Therapy with doxorubicin plus streptozocin was superior to therapy with both 5-FU plus streptozocin and single-agent chlorozotocin in terms of response and survival and is the combination most widely used in the United States in PETs. Etoposide combined with cisplatin is active in poorly differentiated neuroendocrine malignancies but is marginally effective in well-differentiated lesions.
New agents. Antiangiogenic approaches and the recognition of other potential biologic targets have contributed to the development of a number of early-phase clinical trials incorporating bevacizumab with temozolomide (Temodar) and with 5-FU, leucovorin, and oxaliplatin(Drug information on oxaliplatin) (FOLFOX) chemotherapy, temozolomide with capecitabine(Drug information on capecitabine), sorafenib (Nexavar), vatalanib, imatinib(Drug information on imatinib) (Gleevec), thalidomide(Drug information on thalidomide) (Thalomid), and the mTOR inhibitors everolimus (Afinitor) and temsirolimus (Torisel). Sunitinib and everolimus have been approved by the US Food and Drug Administration for the treatment of pNETs.
Treatment of symptoms
Octreotide. As discussed more fully in the section on carcinoid tumors, a promising experimental approach for patients whose tumors express somatostatin receptors is the use of octreotide conjugated to a therapeutic radioisotope.
Other agents. Omeprazole(Drug information on omeprazole) (Prilosec), an inhibitor of the function of the parietal cell hydrogen pump, is more effective than histamine type 2 (H2)-receptor antagonists in blocking gastric acid production and is useful in the symptomatic management of gastrinomas.
Other agents available for symptomatic treatment of insulinomas include injectable diazoxide(Drug information on diazoxide) (Hyperstat), an insulin-release inhibitor, and, more recently, glucagon delivered by continuous infusion through a portable pump. Both of these agents are used in conjunction with frequent high-carbohydrate meals.
Patients with the glucagonoma syndrome are treated symptomatically with insulin, high-protein meals, supplemental zinc, amino acid infusions, and anticoagulants.
Bisphosphonate therapy should be considered for patients with bone metastases.
Hepatic arterial embolization. Hepatic arterial embolization, given with chemotherapy (chemoembolization) or without, is an alternative palliative therapy for patients with either carcinoid tumors or a PET who have predominant liver metastases or symptoms. Embolization is best reserved for patients with < 75% tumor involvement of the liver, bilirubin level < 2 mg/dL, and an ECOG performance status of ≤ 2. In addition, a patent main portal vein is required for this procedure.
Other liver-directed therapeutic strategies include radiofrequency ablation (RFA) for select patients and 90yttrium microspheres.