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INTRODUCTIONNeoplasms of the endocrine pancreas are rare, with an annual clinically recognized incidence approximating five cases per one million person-years.
Neoplasms of the endocrine pancreas are best divided into functional and nonfunctional varieties. The majority of pancreatic endocrine neoplasms discovered clinically are functional, indicating that they elaborate one or more hormonal products into the blood, leading to a recognizable clinical syndrome. By convention, functional tumors are named according to their predominant clinical syndrome and hormonal product. Patients with endocrine tumors of the pancreas with no recognizable clinical syndrome and normal serum hormone levels (excluding pancreatic polypeptide) are considered to have nonfunctional pancreatic endocrine tumors.
All neoplasms of the endocrine pancreas have a similar light microscopic appearance. Routine histologic examination does not predict the biologic behavior or the endocrine manifestations of these neoplasms. Immunofluorescence techniques and the peroxidase-antiperoxidase procedure allow demonstration of specific hormones within neoplastic cells. Malignancy is typically determined by the presence of local invasion, spread to regional lymph nodes, or the existence of hepatic or distant metastases.
Three general principles are applicable to the management of patients with suspected functional neoplasms of the endocrine pancreas. First, the recognition of the abnormal physiology or characteristic syndrome. Characteristic clinical syndromes are well described for insulinoma, gastrinoma, VIPoma and glucagonoma. The somatostatinoma syndrome is nonspecific, much more difficult to recognize, and exceedingly rare. Second, the detection of hormone elevations in serum by radioimmunoassay (RIA). RIAs are widely available for the measurement of insulin, gastrin, VIP and glucagon. Assays for somatostatin, pancreatic polypeptide, prostaglandins and other hormonal markers are not widely available, but can be obtained from selected laboratories or investigators. The third step in patient evaluation involves localization and staging of the tumor in preparation for possible operative intervention.
LOCALIZATION AND STAGINGAt present, the initial imaging technique recommended for localization of a pancreatic endocrine neoplasm is a dynamic abdominal CT scan with intravenous and oral contrast (22-25). The accuracy of CT in detecting the primary islet cell tumor varies widely, ranging from approximately 35 to 85%, being largely dependent upon the technique of scanning, and the size and location of the primary tumor. The accuracy of the CT scan in tumor localization is improved by the use of both oral and intravenous contrast, as well as with focused dynamic scanning through the pancreas at 5 mm intervals. The CT scan is also used to assess for peripancreatic lymph node enlargement and for the presence of hepatic metastases.
Should the CT scan fail to detect the primary tumor, the next step in radiograpic assessment may be visceral angiography, focusing upon selective visualization of the arterial supply to the pancreas and peripancreatic regions (26). The accuracy of angiography in detecting the primary islet cell tumor varies from 45 to 85%, being related to radiographic technique and expertise, selectivity of the contrast injection, and size and neovascularity of the primary tumor.
A newer technique that has shown clear promise for improving the results of preoperative localization of pancreatic endocrine neoplasms is endoscopic ultrasonography (27-29). Rosch and colleagues were able to correctly localize 32 of 39 tumors (82%) using endoscopic ultrasound, after a prior CT scan had failed to locate the tumor. In their experience, endoscopic ultrasonography was more sensitive than the combination of CT and visceral angiography. As further experience is gained with endoscopic ultrasound, it may offer distinct advantages in the evaluation of patients with pancreatic endocrine neoplasms.
Another technique that holds promise for the imaging of pancreatic endocrine tumors is somatostatin receptor imaging. These techniques rely upon the presence of somatostatin receptors on many islet cell tumors (33), and have the potential for identifying both primary tumors as well as hepatic and extrahepatic metastases.
In a minority of patients with pancreatic endocrine neoplasms, the primary tumor will not be localized following initial imaging studies such as CT, visceral angiography or endoscopic ultrasound. Most commonly this situation arises in patients with insulinoma or gastrinoma. In these cases, localization of the occult neoplasm may be assisted by the performance of selective transhepatic portal venous hormone sampling (37-41). This invasive technique is designed to demonstrate a step-up in hormone concentration at the site where the tumor drains its hormonal product into the portal venous system. The results of portal venous hormone sampling are used to define a region of the pancreas (or duodenum in the case of gastrinoma) harboring the occult tumor. The overall accuracy of this test ranges from 70 to over 95%, and the accuracy is dependent upon such factors as the number of portal venous samples obtained, the persistent autonomous production of the hormone by the tumor, and the careful handling and assaying of all specimens obtained.
SURGICAL EXPLORATIONAt the time of surgical exploration for pancreatic endocrine neoplasm, a complete evaluation of the pancreas and peripancreatic regions is performed. The liver is carefully assessed for evidence of metastatic disease. Potential extrapancreatic sites of tumor are evaluated in all cases, with particular attention being paid to the duodenum, splenic hilum, small bowel and its mesentery, peripancreatic lymph nodes and the reproductive tract in women. One technique that provides additional information in the intraoperative setting is real time ultrasonography, which can assist in tumor identification (47, 48). The goals of surgical therapy for pancreatic endocrine neoplasms include control of symptoms from hormone excess, safe resection of maximal tumor mass and preservation of maximal pancreatic parenchyma. Management strategies, including preoperative, intraoperative and postoperative considerations, vary for the different types of endocrine neoplasms of the pancreas.
INSULINOMAInsulinoma is the most common neoplasm of the endocrine pancreas. The insulinoma syndrome is associated with Whipple's triad: 1) symptoms of hypoglycemia during fasting, 2) documentation of hypoglycemia with serum glucose less than 50 mg/dl and 3) relief of hypoglycemic symptoms following administration of exogenous glucose (6). Autonomous insulin secretion from insulinomas leads to spontaneous hypoglycemia, with symptoms that can be characterized into two groups : neuroglycopenic symptoms (confusion, seizure, obtundation, personality change and coma) and hypoglycemia-induced catecholamine-surge symptoms (palpitations, tremulousness, diaphoresis and tachycardia). In most cases, patients consume carbohydrate-rich meals and snacks to relieve or prevent these symptoms.
Insulinoma is most reliably diagnosed using the technique of a monitored fast. During a monitored fast, blood for glucose and insulin determinations is sampled every four to six hours, and at the time of symptom occurrence. Additional support for the diagnosis of insulinoma comes from the calculation of the insulin to glucose ratio (I:G ratio) at different time points during the monitored fast. Normal individuals will have I:G ratios less than 0.3, while patients with insulinoma typically demonstrate I:G ratios greater than 0.4 after a prolonged fast.
After confirmation of the diagnosis of insulinoma by biochemical analyses, the appropriate localization and staging studies as described above are performed. For insulinoma the standard imaging studies include abdominal CT, endoscopic ultrasound and visceral angiography. The treatment of insulinoma is surgical in nearly all cases. Insulinomas are found evenly distributed within the pancreas, with approximately one-third being located in the head and uncinate process, one-third in the body of the gland, and one-third in the tail of the gland (51). Ninety percent of patients will be found to have benign solitary adenomas amenable to surgical cure. Less than 10% of patients with insulinoma will be found to have some form of the multiple endocrine neoplasia-1 (MEN-1) syndrome.
In approximately 10% of all cases insulinoma will be found metastatic to peripancreatic lymph nodes or to the liver, justifying a diagnosis of malignant insulinoma. Under these circumstances, cautious and safe resection of the primary tumor and accessible metastases should be considered (56-58). Such tumor debulking can be helpful in reducing problematic hypoglycemic symptoms which can threaten long-term survival. The average patient survives several years following diagnosis and treatment of malignant islet cell tumors, indicating that the natural history of these malignant tumors typically follows an indolent course (25, 59).
Chemotherapeutic agents with some efficacy against malignant insulinoma include streptozocin, dacarbazine (DTIC), doxorubicin and 5-fluorouracil (60-62). The highest response rates to chemotherapy have been observed using combination therapy.
Small benign insulinomas not in close proximity to the main pancreatic duct may be removed by enucleation (53), independent of their location within the gland (Figure 6). In the body and tail of the pancreas, insulinomas greater than 2 cm in diameter, and those in close proximity to the pancreatic duct are most commonly excised by distal pancreatectomy. Large insulinomas deep in the head or uncinate process of the pancreas may not be amenable to local excision, and may require pancreaticoduodenectomy (54).
GASTRINOMA (ZOLLINGER-ELLISON SYNDROME)In 1955 Zollinger and Ellison described two patients with severe peptic ulcer disease and pancreatic endocrine tumors, postulating that an ulcerogenic agent originated from the pancreatic tumor (9, 63). At present it is estimated that one in 1,000 patients with primary duodenal ulcer disease and two in 100 patients with recurrent ulcer following ulcer surgery harbor a gastrinoma (64). Seventy-five percent of gastrinomas occur sporadically, whereas 25% are associated with the MEN-1 syndrome. In the past, the majority of gastrinomas were found to be malignant, based on the findings of metastatic disease at the time of work-up or exploration. More recently, with increased awareness and earlier screening for hypergastrinemia, the diagnosis of gastrinoma is being made earlier, leading to the discovery of a higher percentage of benign curable neoplasms (65, 66).
Peptic ulceration of the upper GI tract and abdominal pain are seen in up to 90% of patients. Fifty percent of patients have some degree of diarrhea, while about 10% of patients present with diarrhea as the solitary symptom.
The diagnosis of gastrinoma should be suspected in several clinical settings, and the liberal use of serum gastrin measurement for screening is encouraged.
Gastric acid analysis is an important test in the evaluation of patients with suspected gastrinoma, as it can differentiate between ulcerogenic (high gastric acid) causes of hypergastrinemia and nonulcerogenic (low gastric acid) causes of hypergastrinemia.
Following the biochemical confirmation of the diagnosis of gastrinoma, two steps are important in patient management. First, gastric acid hypersecretion is pharmacologically controlled. Omeprazole in doses of 20 to 200 mg/day is now considered the drug of choice for antisecretory therapy in patients with gastrinoma (70, 71). The dose of omeprazole is adjusted to achieve a nonacidic gastric pH during the hour immediately prior to the next dose of the drug. Second, after the initiation of omeprazole therapy, all gastrinoma patients should undergo imaging studies in an effort to localize the primary tumor and to assess for metastatic disease. The modalities appropriate for localization and staging of gastrinoma patients have already been discussed and include dynamic abdominal CT scanning with intravenous and oral contrast, selective visceral angiography, endoscopic ultrasonography, somatostatin receptor imaging, percutaneous transhepatic portal venous sampling for gastrin, and the selective arterial secretin stimulation test.
Gastrinoma patients whose localization and staging studies are indicative of unresectable hepatic metastases should undergo percutaneous or laparoscopically-directed liver biopsy for absolute histologic verification. If unresectable gastrinoma is confirmed, then open surgical exploration is not performed and the patient is maintained on long-term omeprazole therapy.
The majority of patients should be offered surgical exploration with curative intent. At the time of exploration the entire abdomen is carefully assessed for areas of extrapancreatic and extraduodenal gastrinoma (72). The majority of gastrinomas have been identified to the right of the superior mesenteric vessels within the head of the pancreas or the duodenum: the so-called gastrinoma triangle (51, 73).
Primary tumors located within the substance of the pancreas that are small (< 2 cm) and well encapsulated may be carefully enucleated. Pancreatic tumors without defined capsules or situated deep in the pancreatic parenchyma may require partial pancreatic resection, via either distal pancreatectomy or pancreaticoduodenectomy (54, 76).
Primary gastrinomas identified within the duodenal wall are resected locally, with primary closure of the duodenal defect (78, 79). In a small percentage of patients gastrinoma may be found only in peripancreatic lymph nodes, with these lymph nodes harboring the primary tumor. Resection of these apparent lymph node primary gastrinomas has been associated with long-term eugastrinemia and biochemical cure in up to 50% of cases (80).
The overall results in patients with gastrinoma have improved markedly since the initial description of the syndrome.
Up to 35% of patients explored for gastrinoma with curative intent have been rendered eugastrinemic at followup, and considering only those patients explored and thought to be successfully resected, the cure rates approach 60 to 70%. These recent results represent a major improvement in the management of gastrinoma patients over the past decades, and support the practice of initial pharmacologic control of gastric hypersecretion using omeprazole, followed by tumor localization and staging, in hopes of curative resection.
Most patients with incurable metastatic gastrinoma succumb to eventual tumor growth and dissemination. Multiple modalities have been utilized in an effort to treat patients with such metastatic gastrinoma. The overall objective response rate to chemotherapy appears to be less than 50%.
Hepatic transplantation, hepatic artery embolization, and interferon therapy have all been used in small numbers of patients with gastrinoma metastatic to the liver (89-91). None of these therapies appears to be associated with reproducible improvements in survival.
VIPoma (VERNER-MORRISON SYNDROME)Synonyms for this syndrome include the WDHA syndrome (watery diarrhea, hypokalemia, and either achlorhydria or hypochlorhydria) and the pancreatic cholera syndrome. Patients characteristically present with intermittent severe diarrhea, typically of a watery nature, averaging 5 liters/day.
Hypokalemia results from the fecal loss of large amounts of potassium (up to 400 meq/day), and low serum potassium levels may be associated with muscular weakness, lethargy, and nausea.
The diagnosis of VIPoma is typically made after excluding other more common causes of diarrhea (Table 7). The active agent in the VIPoma syndrome is usually vasoactive intestinal polypeptide (VIP) (93), with a minority of patients having elevations of other candidate mediators such as peptide histidine-isoleucine (PHI) or prostaglandins (94).
After biochemical documentation of elevated VIP levels, tumor localization and staging begins with dynamic abdominal CT scan with intravenous and oral contrast.
A thoracic CT scan is indicated if the abdominal CT scan fails to identify a tumor.
The preparation for surgical exploration in patients with VIPoma must include correction of fluid and electrolyte losses involving vigorous intravenous fluid administration and appropriate electrolyte replacement. Therapy with parenterally-administered octreotide can be an important adjunct in the preoperative setting, as octreotide leads to a reduction in circulating VIP levels with a resultant decrease in the volume of diarrhea.
Surgical excision of the VIPoma is appropriate in all patients with the Verner-Morrison syndrome. The majority of VIPomas have been located in the distal pancreas, where they are amenable to resection via distal pancreatectomy.
Metastatic disease to lymph nodes and the liver have been reported in half of all cases. In the presence of metastatic disease, safe palliative debulking of metastatic tumor is indicated (95).
In patients with recurrent or unresectable VIPoma, octreotide therapy is used to reduce circulating VIP levels and control diarrhea. Chemotherapy specific for VIPoma patients has not been studied prospectively, although small numbers of patients have appeared to show partial responses to streptozocin, combination chemotherapy or interferon.
GLUCAGONOMAThe most common findings in the glucagonoma syndrome include severe dermatitis, mild diabetes, stomatitis, anemia, and weight loss (96). The dermatitis is manifested by a characteristic skin rash termed necrolytic migratory erythema. This rash exhibits cyclic migrations with erythematous patches that spread serpiginously, with central healing points of resolution.
The diagnosis of glucagonoma may be suggested by the clinical presentation and biopsy of the skin lesions, but is secured by the documentation of elevated levels of fasting serum glucagon.
Patients with biochemical documentation of hyperglucagonemia in the appropriate clinical setting should undergo radiographic localization and staging with dynamic contrast-enhanced abdominal CT scan. Because these tumors are usually large and solitary, the CT scan localizes the tumor in the majority of patients.
Most glucagonomas have been located in the body and tail of the pancreas. These tumors are typically large and bulky, and surgical resection has required distal pancreatectomy. Metastases have been found in the majority of patients, and safe debulking of these metastatic lesions should be considered.
Glucagonoma patients with incurable or recurrent disease appear to have low response rates to standard chemotherapeutic agents such as streptozocin and dacarbazine (97). Octreotide can be successful in reducing elevated glucagon levels, and in controlling the hyperglycemia and dermatitis associated with incurable glucagonoma (98, 99).
SOMATOSTATINOMAThe somatostatinoma syndrome is the least common of the five generally accepted functional pancreatic endocrine neoplasia syndromes, with an estimated annual incidence of less than one in forty million people. The clinical features of the somatostatinoma syndrome are nonspecific and include steatorrhea, diabetes, hypochlorhydria, and cholelithiasis. A fasting plasma somatostatin level can be used to confirm the diagnosis of a somatostatinoma.
The majority of somatostatinomas have been located in the head of the pancreas and the periampullary region. The most useful test for localization and staging has been the abdominal CT scan, which has been used to identify and stage these typically large tumors.
At surgery resection for cure has been uncommon, because of the presence of metastatic disease in most cases. Safe resection of the primary tumor and careful debulking of hepatic metastases appear indicated. At the time of exploration, cholecystectomy is indicated even in the absence of documented gallstones, because of the concern about the development of cholelithiasis with persistently elevated somatostatin levels.
NONFUNCTIONAL ISLET CELL TUMORSIn approximately one-third of patients with neoplasms of the endocrine pancreas there will be an absence of a defined clinical syndrome and a lack of elevated serum insulin, gastrin, VIP, glucagon and somatostatin levels. These patients are considered to have nonfunctional endocrine neoplasms.
These nonfunctional endocrine neoplasms present with clinical manifestations such as abdominal pain, weight loss and jaundice (105, 106), resulting from space-occupying lesions in the pancreas.
Nonfunctional tumors are most commonly located in the head, neck or unicinate process of the pancreas (107). The malignancy rate for these tumors ranges from 50 to 90%. However, in contrast to the poor prognosis associated with ductal adenocarcinoma of the pancreas, these nonfunctional tumors tend to grow in a more indolent fashion and to be associated with a longer survival.
Localization and staging studies are performed in similar fashion to patients with the more common diagnosis of ductal adenocarcinoma of the exocrine pancreas. The abdominal CT scan is used for evaluation of the primary tumor and to assess for hepatic metastases.
At surgery most of these nonfunctional neoplasms are larger than 2 cm, and are not safely excised by local techniques. Tumors in the head, neck or uncinate process of the pancreas typically require pancreaticoduodenectomy for safe resection, while tumors arising in the body or tail of the pancreas are treated by distal pancreatectomy.
The overall 5-year survival rate in all patients with resected nonfunctional pancreatic neoplasms approaches 50% (108).
In patients with unresectable disease, partial responses to combination chemotherapy have been reported.