The Sol Goldman Pancreatic Cancer Research Center

Islet Cell Tumors of the Pancreas / Endocrine Neoplasms of the Pancreas

While the bulk of this web site is dedicated to the more common adenocarcinomas of the pancreas, the research team at Johns Hopkins also extensively studies islet cell tumors (also known as well-differentiated pancreatic endocrine neoplasms). In addition, all of the surgeons and all of the oncologists listed in this web site also treat patients with islet cell tumors / endocrine neoplasms of the pancreas. These tumors differ from pancreatic cancer (by that we mean adenocarcinoma of the pancreas) in three important ways. First, islet cell tumors / endocrine neoplasms grow much slower than does pancreatic cancer. As a result, patients with an islet cell tumor / endocrine neoplasm have a much better prognosis than do patients with pancreatic cancer. In fact, some patients with small islet cell tumors / pancreatic endocrine neoplasms are cured if their tumor is treated early enough. Second, some islet cell tumors / endocrine neoplasms produce large amounts of specific hormones, and the release of these hormones can result in dramatic clinical symptoms. For example, some islet cell tumors / endocrine neoplasms produce large quantities of insulin that is released into the bloodstream causing a dramatic lowering of blood sugar levels (called hypoglycemia). These tumors are called insulinomas. Third, some islet cell tumors / endocrine neoplasms arise in patients with a familial genetic syndrome. For example, Multiple Endocrine Neoplasia type 1 (MEN 1) is caused by an inherited mutation in the gene called menin, and patients with MEN 1 develop pituitary tumors, tumors of their parathyroid gland, and multiple islet cell tumors / endocrine neoplasms of their pancreas. An understanding of the familial risk is important for family counseling and for early detection efforts in affected individuals.

This section of our web site reviews the basics of islet cell tumors / pancreatic endocrine neoplasms with emphasis on the classification, diagnosis and treatment of these tumors. We also review the ongoing research accomplishments in this area by the Hopkins team. Although slightly technical, it is hoped that the information provided below will be useful for those physicians treating patients with endocrine tumors of the pancreas and for those patients suffering from endocrine tumors of the pancreas.

INTRODUCTION

The pancreas is really two organs in one. Most of the pancreas produces enzymes that help with the digestion of food. This portion of the pancreas is called the "exocrine" pancreas, and it is thought to give rise to the most common type of pancreatic cancer called ductal adenocarcinoma (also commonly simply referred to as pancreatic cancer). The pancreas also contains numerous islands of endocrine cells called the "islets of Langerhans." These islands contain small round cells (the endocrine cells) that produce the hormones that control blood sugar levels. These cells make insulin, glucagon and somatostatin. Insulin lowers blood sugar levels and glucagon generally raises blood sugar levels. Neoplasms (tumors) of the endocrine pancreas do occur, but are relatively rare, with an annual clinically recognized incidence approximating five cases per one million person-years. By contrast, pancreatic cancer (and again by this we mean ductal adenocarcinoma) strikes about 9 or 10 per 100,000 people each year. Neoplasms (tumors) of the endocrine pancreas are known by two broad names; "islet cell tumor," and "well-differentiated pancreatic endocrine neoplasm."

Islet cell tumors / pancreatic endocrine neoplasms are best divided into those that produce symptoms because they release hormones into the bloodstream ("functional") and those that form a mass but do not cause symptoms by releasing hormones into the blood stream ("nonfunctional). It used to be that the majority of islet cell tumors / pancreatic endocrine neoplasms that were discovered clinically were functional, indicating that they elaborate one or more hormonal products into the blood, leading to a recognizable clinical syndrome. As more and more people are getting CT scans for a wide variety of reasons, more and more islet cell tumors / pancreatic endocrine neoplasms are non-functional. These nonfunctional islet cell tumors / pancreatic endocrine neoplasms are seen as masses in the pancreas on imaging. By convention, functional islet cell tumors / endocrine neoplasms are named according to their predominant clinical syndrome and hormonal product. For example, insulinomas are islet cell tumors / pancreatic endocrine neoplasms that produce insulin and which thereby cause low blood sugar levels. Patients with islet cell tumors / pancreatic endocrine neoplasms of the pancreas with no recognizable clinical syndrome and normal serum hormone levels are considered to have nonfunctional pancreatic endocrine tumors.

CAUSES

Many of the risk factors that have been identified for pancreatic cancer (ductal adenocarcinomas of the pancreas) are not risk factors for islet cell tumors / pancreatic neuroendocrine neoplasms. For example, cigarette smoking doubles the risk of pancreatic cancer, but it does not appear to be a factor in the development of islet cell tumors / pancreatic endocrine neoplasms.

Several genetic (familial) syndromes predispose to pancreatic neuroendocrine neoplasms. These are important to recognize for three reasons. First, because these genetic syndromes are caused by genetic changes that can be inherited, other family members may be at risk. Second, these genetic syndromes predispose to (increase the risk of) more than one tumor type. Individuals with one of these syndromes therefore have an increased risk of developing pancreatic and extra-pancreatic neuroendocrine tumors. Finally, these syndromes are important because they provide insight into the biology of pancreatic neuroendocrine neoplasms. Because the genes that cause these genetic syndromes are known, scientists can understand the cellular pathways which lead to the development of pancreatic neuroendocrine neoplasms. The hope is that a better understanding of these pathways will lead to better treatments.

Multiple Endocrine Neoplasia Type 1, abbreviated MEN-1, is a familial syndrome caused by inherited mutations in the MEN1 gene on chromosome 11. The MEN-1 gene codes for the menin protein, and patients with an inherited mutation in the MEN1 are predisposed to develop tumors of the pituitary (the small "master" gland at the base of the brain), the parathyroids (four small glands in neck which help control blood calcium levels), and the pancreas.

von Hippel-Lindau Syndrome, abbreviated VHL, is a familial syndrome caused by inherited mutations in the VHL gene on chromosome3. Patients with von Hippel-Lindau are predisposed to developing tumors in a number of organs including the the brain (hemagioblastoma), the eye (hemagioblastoma), the kidney (renal cell carcinoma), and the adrenals (pheochromocytoma). Pancreatic disease may be the first manifestation of VHL, and most patients with VHL eventually develop a pancreatic tumor. The pancreatic tumors in patients with VHL are interesting because they can have unique appearances. Some have a "clear" appearance under the microscope, and others are mixed tumors.

Tuberous Sclerosis Complex (TSC) is a third genetic syndrome which predisposes to pancreatic neuroendocrine neoplasms (http://www.tsalliance.org/index.aspx). Tuberous sclerosis complex is caused by inherited mutations in one of two genes- TSC1 or TSC2. The TSC1 gene is on chromosome 9 and it codes for the protein hamartin. The TSC2 gene is on chromosome 16 and it codes for the protein tuberin. Patients with tuberous sclerosis complex can suffer from developmental delay, mental retardation and even autism, and they are predisposed to develop a number of different tumors. They are predisposed to develop three different brain lesions- "tubers," subependymal giant cell astrocytomas and subependymal nodules. In fact, the name tuberous sclerosis comes from the brain lesions that these patients develop- Tuber in Latin means swelling and skleros in Greek means hard. They also can develop distinctive lesions of the skin (hypomelanotic macules and facial angiofibromas), kidney (angiomyolipomas), lungs (lymphangioleiomatosis), heart (rhabdomyomas), and eye tumors ( hamartomas). Most of these are entirely benign growths, but they can cause symptoms depending on their location. Although less common than the other manifestations of tuberous sclerosis, several patients with tuberous sclerosis complex have been reported who developed pancreatic neuroendocrine neoplasms.

Neurofibromatosis type 1, also known as von Recklinghausen disease, is a familial syndrome caused by inherited mutations in the NF1 gene on chromosome 17 (http://ghr.nlm.nih.gov/condition/neurofibromatosis-type-1). The NF1 gene codes for the protein neurofibromin. Patients with neurofibromatosis develop dark patches of skin (café-au-lait spots), and benign (non-cancerous) and malignant (cancerous) tumors of the nervous system. The benign nerous system tumors include neurofibromas, and the malignant the "malignant peripheral nerve sheath tumor." They can also develop distinctive eye lesions called Lisch nodules, and a small percentage develop somatostatinomas of the pancreas/duodenum.

Clinical genetic testing is now available for these syndromes, but such testing is best done with the help of a trained genetic counselor. Individuals found to have one of these genetic syndromes may benefit from increased screening for early tumors, and, it is our hope, that a better understanding of the genetics of these syndromes will lead to novel gene-specific therapies in the future.

PATHOLOGY

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Figure 5

Islet cell tumors / pancreatic endocrine neoplasms of the pancreas have a distinct appearance. These tumors tend to form round well-demarcated masses (figure 1). This appearance contrasts to the appearance of pancreatic cancer (ductal adenocarcinomas) which forms much more poorly-defined masses. As they enlarge islet cell tumors / pancreatic endocrine neoplasms can grow into blood vessels, out of the pancreas and even into adjacent organs such as the spleen (figure 2). Islet cell tumors / endocrine neoplasms can also spread (metastasize) to lymph nodes and even to other organs such as the liver. Because they have the ability to spread, islet cell tumors / pancreatic endocrine neoplasms are generally considered "malignant" tumors.

All islet cell tumors / pancreatic endocrine neoplasms of the pancreas have a similar light microscopic appearance. These tumors are composed of round uniform cells with round uniform nuclei (figure 3). Special stains, called immunohistochemical stains, can be used to demonstrate the production of endocrine hormones, such as insulin and glucagon, in tissue sections made from biopsies or resected tumors (figure 4). Routine histologic examination does not predict the clinical behavior or the endocrine manifestations of these neoplasms. Prognosis is typically determined by the presence of local invasion, spread to regional lymph nodes, or the existence of hepatic or distant metastases.

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BLOOD TESTS

Elevated levels of the hormones produced by islet cell tumors / endocrine neoplasms can be detected in the blood by special tests that can be run on blood samples taken from a patient. These tests are measured using immunoassays, including radioimmunoassay. Tests for insulin, gastrin, VIP, glucagon, somatostatin, pancreatic polypeptide, prostaglandins and other hormonal markers are typically performed at selected large medical center or reference laboratories.

LOCALIZATION AND STAGING

At present, the initial imaging technique recommended for localization of an islet cell tumors / pancreatic endocrine neoplasms is a CT scan with intravenous and oral contrast (22-25). The accuracy of the CT scan in tumor localization is improved by the use of both oral and intravenous contrast. The CT scan is also used to assess for peripancreatic lymph node enlargement and for the presence of hepatic metastases. Islet cell tumors / pancreatic endocrine neoplasms typically produce solid masses on CT scanning and, importantly, these tumors usually "enhance" in the arterial phase (figure 5). This latter feature is believed to be a manifestation of the rich blood supply that these tumors have, and it is a helpful diagnostic feature.

Should the CT scan fail to detect the primary tumor, the next step in radiographic assessment may be visceral angiography, focusing upon selective visualization of the arterial supply to the pancreas and peripancreatic regions (26).

Endoscopic ultrasonography can also be used to visualize islet cell tumors / pancreatic endocrine neoplasms and this technique has the advantage that a biopsy can be taken at the same time (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 islet cell tumors / 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 / pancreatic endocrine neoplasms (33), and have the potential for identifying both primary tumors as well as liver and other metastases. These scans are called "octreotide scans". Basically, a radioactive form of octreotide, a drug similar to somatostatin, is injected into the blood stream. It travels in the bloodstream and binds to (attaches to) islet cell tumors / pancreatic endocrine neoplasms that have the receptor for somatostatin on their surface. A radiation-measuring device can then detect the radioactive octreotide localized to the tumor.

In a minority of patients with islet cell tumors / 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 very small 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 involves the insertion of a catheter in the blood stream. It is designed to demonstrate a step-up in hormone concentration at the site where the tumor drains its hormonal product into the blood vessels leading into the liver. 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.

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SURGICAL EXPLORATION

Surgical resection remains the best hope for a cure for patients with islet cell tumors / pancreatic endocrine neoplasms.

At 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, the area of the spleen (splenic hilum), small bowel and its blood vessels (mesentery), the lymph nodes around the pancreas 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). In general surgeons can perform a Whipple resection for tumors of the head of the pancreas and a distal pancreatectomy for tumors of the tail of the pancreas. 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.

Because islet cell tumors / pancreatic endocrine neoplasms grow relatively slowly, some patients with metastases may still benefit from surgical resection. If for instance, a patient has an islet cell tumor / pancreatic endocrine neoplasm in the tail of the pancreas and an isolated metastasis in the liver, that patient may benefit from having both lesions removed. This contrasts greatly with pancreatic cancer (ductal adenocarcinoma). Patients with ductal adenocarcinoma that has spread to the liver are generally not surgical candidates.

If you have an islet cell tumor / pancreatic endocrine neoplasm and would like to be treated at Johns Hopkins, please contact Dr. Barish Edil, Dr. Rich Schulick or Dr. Christopher Wolfgang directly at 410-933-PANC (410-933-7262). They specialize in the surgical treatment of these tumors.

MEDICAL TREATMENT

Because these tumors are so slow growing they often do not respond to conventional chemotherapy (which usually targets fast growing cells). However, the U.S. Food and Drug Administration (FDA) recently approved the drugs Sutent (sunitinib) and Afinitor (Everolimus) for the treatment of advanced pancreatic endocrine tumors (also known as islet cell tumors or pancreatic neuroendocrine tumors [PanNETs]). Sutent is manufactured by Pfizer, and Afinitor by Novartis. It is exciting to see that the options available for patients with pancreatic neuoendocrine tumors is growing.

Afinitor was approved for the treatment of patients with progressive pancreatic neuroendocrine tumors that are not resectable surgically, that are locally advanced or metastatic. This approval by the FDA was based on a phase III clinical trial of Afinitor, in which the drug was shown to prolong progression free survival in patients with advanced PanNETs. This phase III trial was reported in the New England Journal of Medicine (N Engl J Med. 2011 Feb 10;364(6):514-23.). The research team at Johns Hopkins has played a role in understanding the likely mechanism by which Afinitor works. The team sequenced all of the known human genes in a series of pancreatic neuroendocrine tumors and found that one in six of these tumors harbors an activating mutation (DNA change) in the mTOR pathway. (Jiao, Shi, Edil, de Wilde, Klimstra, Maitra, Schulick, Tang, Wolfgang, Choti, Velculescu, Diaz, Jr., Vogelstein, Hruban & Papadopoulos, Science, 2011). This is the very pathway that Afinitor targets, and it is likely that Afinitor will be most effective in patients with a tumor with an mTOR pathway gene mutation.

Sunitinib belongs to the class of drugs called "tyrosine kinase inhibitors," and it has both effects against blood vessels in tumors (antiangiogenic) and effects against the tumor itself (antitumor properties). In a phase III clinical trial treatment with Sunitinib has been shown to significantly improve progression free survival in patients with metastatic pancreatic neuroendocrine tumors (PNETs) (Reviewed in: Cancer Metastasis Rev, 2011, Suppl 1:19-26).

In some instance metastases to the liver can be treated by destroying their blood supply using techniques such as hepatic artery embolisation and chemoembolisation. These approaches involve the selective cannulation of the blood vessels leading to the liver. The vessels feeding the metastases are identified and then destroyed (embolized). In some instances drugs can be used to block the symptoms causes by the release of hormones from the tumor. For example, proton pump inhibitors can be used to counteract the high levels of stomach acid produced in patients with gastrinomas. Finally, in selected patients response rates as high as 70% have been reported following the treatment of islet cell tumors / pancreatic endocrine neoplasms with the drug streptozocin. If you have an islet cell tumor / pancreatic endocrine neoplasm, and would like to be treated by a medical oncologist at Johns Hopkins please contact Dr. Ross Donehower, Dr. Daniel Laheru, or Dr. Dung Li directly at 410-933-PANC (410-933-7262). They specialize in the medical treatment of islet cell tumors.

PROGNOSIS

The most important prognostic factor is whether or not the tumor can be removed surgically. Other significant prognostic for patients with an islet cell tumor / pancreatic endocrine neoplasm include the size of the tumor, the presence or absence of blood vessel invasion, the presence or absence of metastases to lymph nodes or other organs, The 5-year survival rate ranges between 50 and 70% in most series.

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INSULINOMA

Insulinoma is the most common syndromic islet cell tumor / pancreatic endocrine neoplasm. The insulinoma syndrome is associated with the "Whipple's triad:" 1) symptoms of hypoglycemia (low blood sugar levels) during fasting, 2) documentation of hypoglycemia with blood glucose (sugar) less than 50 mg/dl and 3) relief of symptoms following administration of exogenous glucose (6). Symptoms include confusion, seizure, obtundation, personality change and coma, as well as palpitations, tremulousness, diaphoresis (sweating) and tachycardia (fast heart rate). 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 is sampled every four to six hours for glucose and insulin determinations, 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 the diagnosis of insulinoma is confirmed 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 of the pancreas, 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 small solitary tumors 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 (see below).

In approximately 10% of all cases insulinoma will be found to have spread (metastasized) 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.

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GASTRINOMA (ZOLLINGER-ELLISON SYNDROME)

Gastrinomas are islet cell tumors / pancreatic endocrine neoplasms that release large quantities of the hormone gastrin into the blood stream leading to stomach/duodenal ulcers. 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 (see below). In the past, the majority of gastrinomas had already metastasized at the time of diagnosis. More recently, with increased awareness and earlier screening, the diagnosis of gastrinoma is being made earlier, leading to the discovery of a higher percentage of 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. So called "proton pump inhibitors" (lansoprazole, pantoprazole esomeprasole, etc) in high doses can be used to control acid production in the stomach in patients with gastrinoma (70, 71). Second, after the initiation of proton pump 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, endoscopic ultrasonography, somatostatin receptor imaging, percutaneous transhepatic portal venous sampling for gastrin, and the selective arterial secretin stimulation test. The majority of patients should be offered surgical exploration with curative intent. At the time of exploration the entire abdomen is carefully assessed for tumors within the pancreas and outside of the pancreas (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).

Gastrinomas within the pancreas are usually surgically resected either by distal pancreatectomy or pancreaticoduodenectomy (54, 76). Gastrinomas may also arise within the duodenum and they often can be surgically resected 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 (normal gastrin levels) and biochemical cure in up to 50% of cases (80).

Patients with gastrinomas that cannot be removed surgically can be treated long-term omeprazole therapy to alleviate their symptoms.

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 follow-up, 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.

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VIPoma (VERNER-MORRISON SYNDROME)

VIPomas are islet cell tumors / pancreatic endocrine neoplasms that cause symptoms by releasing large amounts of the hormone VIP into the blood stream. Synonyms for this syndrome include the WDHA syndrome (watery diarrhea, hypokalemia (low potassium levels in the blood), and either achlorhydria or hypochlorhydria (low chloride)) and the pancreatic cholera syndrome. Patients characteristically present with intermittent severe diarrhea, typically of a watery nature, averaging 5 liters/day (that is an awful lot of diarrhea!).

Hypokalemia (low blood potassium) results from the fecal loss of large amounts of potassium (up to 400 meq/day), and low blood 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. The active agent in the VIPoma syndrome is the hormone 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 abdominal CT scan with intravenous and oral contrast.

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 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 tail of the 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 surgical 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.

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GLUCAGONOMA

Glucagonomas are islet cell tumors / pancreatic endocrine neoplasms that cause symptoms by releasing large quantities of the hormone glucagon into the blood stream. The most common findings in the glucagonoma syndrome include severe dermatitis (skin rash), mild diabetes, stomatitis (mouth sores), anemia (low red blood cell count), and weight loss (96). The dermatitis is manifested by a characteristic skin rash termed "necrolytic migratory erythema." This rash exhibits cyclic migrations with erythematous (red) patches that spread 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 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 surgical 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).

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SOMATOSTATINOMA

Somatostainomas are islet cell tumors / pancreatic endocrine neoplasms that cause symptoms by releasing large quantities of the hormone somatostatin into the blood stream. The somatostatinoma syndrome is the least common of the five functional pancreatic endocrine neoplasia syndromes (listed above), 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 (oily stools), diabetes, hypochlorhydria (low blood chloride levels), and cholelithiasis (stones in the gallbladder). A fasting blood 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. 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 liver metastases appear indicated. At the time of exploration, cholecystectomy (removal of the gallbladder) is indicated even in the absence of documented gallstones, because of the concern about the development of gallstones with persistently elevated somatostatin levels.

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NONFUNCTIONAL ISLET CELL TUMORS / PANCREATIC ENDOCRINE NEOPLASMS

A growing number of patients with islet cell tumors / pancreatic endocrine neoplasms do not have a clinical syndrome caused by hormone production from the tumor. These patients are considered to have nonfunctional islet cell tumors / pancreatic endocrine neoplasms.

These nonfunctional islet cell tumors / pancreatic endocrine neoplasms present with clinical manifestations such as abdominal pain, weight loss and jaundice (105, 106), resulting from space-occupying lesions in the pancreas. In some patients the islet cell tumors / pancreatic endocrine neoplasms is detected by chance when the patient has a CT scan for another indication.

Nonfunctional islet cell tumors / pancreatic endocrine neoplasms are most commonly located in the head, neck or unicinate process of the pancreas (107). The majority of these behave in a malignant fashion. However, in contrast to the poor prognosis associated with ductal adenocarcinoma of the pancreas (commonly known as pancreatic cancer), these nonfunctional islet cell tumors / pancreatic endocrine neoplasms tend to grow in a more indolent fashion and are 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 (the Whipple resection) 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. The highest response rate of 69% was seen in patients receiving streptozocin plus doxorubicin.

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* This text was, in part, abstracted from a book chapter written by former Hopkins surgeon Dr. Charles Yeo, ("Neoplasms of the Endocrine Pancreas" from Greenfield et al, Surgery: Scientific Principles in Practice, Second Edition published by Lippincott-Raven Publishers, abstracted with permission).

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