AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

In 1977, Larsson et al and Ganda et al independently reported the first 2 cases of somatostatinoma. Ganda and colleagues' case was that of a 46-year-old woman with an 8-year history of diabetes mellitus. During a cholecystectomy for cholelithiasis, a pancreatic mass was visualized. She was initially thought to have a nonfunctional islet cell tumor. Histologically, however, the tumor cells resembled D cells, and they contained large quantities of somatostatin. Complete resection of the tumor resulted in euglycemia for the patient.

A full description of somatostatinoma syndrome followed in 1979 when Krejs and colleagues described the morphologic and biochemical properties of a tumor of the ampulla of Vater in a 52-year-old man with distinct clinical symptoms and excessive somatostatin levels. Somatostatinomas are associated with excessive production of somatostatin by tumor cells of D-cell origin, and they are frequently associated with a classic clinical pentad of diabetes mellitus, cholelithiasis, weight loss, steatorrhea and diarrhea, and hypochlorhydria and achlorhydria.

Somatostatinomas are the most rare of the commonly accepted functional APUD (amine precursor uptake and decarboxylation) cell neuroendocrine tumors of the gastrointestinal tract, and they are found with almost equal frequency in the pancreas and duodenum. Such tumors very rarely arise in other locations (eg, lungs, liver, kidneys). Larger tumors are usually found in the pancreas (5 cm vs 2.5 cm in the duodenum), although malignancy is of equal incidence for primary tumors of the pancreas and duodenum (65%). Metastases are present in most patients at the time of clinical presentation. Pancreatic and duodenal somatostatinomas can sometimes be distinguished by their clinical presentations.

Pathophysiology

Somatostatin is a cyclic peptide present in both 14-amino acid and 28-amino acid forms. It acts in both an endocrine and a paracrine manner to inhibit secretion of many hormones, including insulin, glucagon, growth hormone, gastrin, cholecystokinin (CCK), secretin, and vasoactive intestinal peptide (VIP). This inhibitory action is thought to be responsible for the clinical manifestations that mark the disease. The generalized inhibition of gastrointestinal hormones results in restriction of gallbladder contractility, pancreatic exocrine function, and intestinal secretion and motility.

Somatostatin's reduction of insulin secretion results in diminished glucose use and hepatic glucose overproduction. Thus, the associated inhibitory syndrome leads to development of diabetes mellitus in 95% of patients. The clinical severity of diabetes can range from mild glucose intolerance to frank ketoacidosis. Cholelithiasis and biliary tract disease occur in 25-68% of patients with somatostatinoma; the conditions are secondary to suppression of CCK, inhibition of biliary motility, and altered fat metabolism. Diarrhea and steatorrhea are common symptoms of pancreatic somatostatin tumors and contribute to weight loss. In most patients, hypochlorhydria or achlorhydria occurs because of inhibited gastric acid secretion.

Somatostatinomas often simultaneously produce other hormone products, including insulin, gastrin, VIP, glucagon, corticotropin (previously adrenocorticotropic hormone [ACTH]), calcitonin, pancreatic polypeptide, and others. If these products are secreted into the bloodstream in significant quantities, they affect clinical presentation and diagnosis.

Duodenal somatostatinomas may be associated with neurofibromatosis, which is an autosomal dominant disorder characterized by abnormalities of growth and differentiation of the nervous system. Features of neurofibromatosis include multiple café-au-lait spots, neurofibromas, and congenital abnormalities (eg, abnormal bone and joint formation, mental retardation). Malignant tumors such as pheochromocytoma, Wilms tumor, and sarcoma may also occur in association with this syndrome.

Frequency

United States

Somatostatinomas occur with an annual incidence of 1 case per 40 million population. Somatostatinomas occur sporadically in 93% of cases, and 7% of cases are seen in conjunction with multiple endocrine neoplasia type 1 (MEN 1) syndrome. MEN 1 involves parathyroid, pancreatic, and pituitary neoplasms. Neurofibromatosis and pheochromocytoma are associated with the duodenal form of somatostatinoma.

Mortality/Morbidity

Postoperative 5-year survival rates of patients with metastatic somatostatinoma is 30-60%, but patients without metastases have a 5-year survival rate approaching 100%. Tanaka and associates reviewed 32 cases of duodenal somatostatinomas and found that primary tumors of patients with metastases were significantly larger (>2 cm) than tumors of patients without metastases. Extremely elevated somatostatin levels that persist suggest large malignant tumors with metastases. Some of the clinical symptoms of unresectable metastatic somatostatinoma can be controlled medically.

Race

No racial predilection has been identified.

Sex

Both males and females are equally affected.

Age

Most patients are in their fourth, fifth, or sixth decade of life.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

• Most patients with somatostatinomas are symptomatic. Because tumors are slow growing and symptoms are often present for several years before diagnosis, the disease is often quite advanced by the time patients seek appropriate medical attention.
• Two different symptomatic presentations can be distinguished. The inhibitory syndrome is common in pancreatic somatostatinomas, whereas tumors arising from the duodenal wall are more likely to manifest in association with mechanical enteric obstructive symptoms. Duodenal somatostatinomas may secrete reduced amounts of hormone that are insufficient to produce a systemic effect.
• The classic clinical pentad of somatostatinoma syndrome is as follows:
• • Diabetes mellitus: Symptoms range from mild glucose intolerance to frank hyperglycemic ketoacidosis.
  • Cholelithiasis: Patients typically present with symptoms of biliary colic or other complications of gallstones.
  • Weight loss: Patients may lose 18-45 lb. This symptom is more common with pancreatic tumors.
  • Steatorrhea and diarrhea: Patients characteristically report 3-10 exceptionally malodorous stools per day.
  • Hypochlorhydria and achlorhydria: This is generally an asymptomatic condition resulting from somatostatin-mediated inhibition of gastric acid secretion.
• Hypoglycemia, abdominal pain, anorexia, nausea, and vomiting are also relatively common complaints. Patients with duodenal somatostatinomas can present with obstructive jaundice, duodenal obstruction, abdominal pain, or gastrointestinal bleeding.
• Mixed clinical syndromes can occur if multiple functional hormone products are secreted in sufficient amounts. Patients with such tumors do not present with a predictable clinical pattern; instead, they exhibit a range of clinical and biochemical features of different types of pancreatic endocrine neoplasms.

Physical

Physical examination findings help identify patients with neurofibromatosis in association with somatostatinoma. As previously discussed, patients with somatostatinoma usually have weight loss and may develop jaundice if biliary tract obstruction is present. Physical findings are otherwise nonspecific.

Causes

Somatostatinoma is associated with MEN 1 syndrome in 7% of cases. Duodenal somatostatinomas are occasionally associated with neurofibromatosis and pheochromocytoma.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Obtain a fasting serum somatostatin level. The reference range is less than 100 pg/mL, but patients with somatostatinoma syndrome may have elevated levels measurable in nanograms per milliliter (this means increases of 1000-fold or greater). Somatostatinomas are very rare; hence, this test is only available in select centers.

Imaging Studies

• High-resolution spiral CT scanning enhanced with oral and intravenous contrast is the initial imaging technique used to localize and stage somatostatinomas. Even with thin cuts (3-5 mm) through the pancreas, this inexpensive and noninvasive modality has failed to identify up to 70% of pancreatic endocrine tumors. Many patients require more invasive and expensive localization techniques. Although no specific data exist regarding the sensitivity of CT scanning in localizing somatostatinomas, failure is probably less frequent because these tumors are relatively large at presentation compared with other pancreatic endocrine neoplasms. CT scanning is used to image the whole body and is therefore useful in the detection of metastatic disease.
• Improvements in MRI techniques are making this noninvasive modality useful in the localization of somatostatinomas. Recent studies have demonstrated the usefulness of contrast-enhanced (eg, gadolinium), T1-weighted MRI when evaluating small primary and metastatic pancreatic endocrine tumors.
• Somatostatin receptor scintigraphy (SRS) is a novel nuclear medicine imaging modality that takes advantage of the fact that many pancreatic endocrine tumors express large numbers of somatostatin receptors on their cell surfaces. Radiolabeled octreotide (an octapeptide somatostatin analogue) administered intravenously preferentially identifies such tumors by binding to somatostatin receptors. While the limited resolution of this technique does not afford the kind of detail necessary to determine the exact location of a primary tumor, SRS is particularly helpful in diagnosing small extrapancreatic metastases. While SRS was originally thought to be a poor tool for localization of somatostatinomas, recent data suggest that many somatostatinomas exhibit radiopharmaceutical uptake of the tracer.
• Endoscopic ultrasound (EUS) through the duodenum can be very helpful when localizing pancreatic endocrine tumors and assessing for lymph node metastases. This technique is particularly helpful in identifying small submucosal duodenal tumors and small pancreatic tumors. It cannot be used to detect hepatic or distant metastases.
• Because of the improved techniques of CT scanning, MRI, and EUS, visceral angiography does not have an essential role in the evaluation of patients with somatostatinomas and other neoplasms of the endocrine pancreas.

Other Tests

• Selective transhepatic portal venous sampling is another test to consider. For this invasive test, blood is sampled from different locations within the portal venous drainage of the pancreas and pancreatic bed. Serum levels of somatostatin are determined from the blood samples to help localize the tumor based on anatomic venous drainage. The sample with the highest serum hormone level is presumed to have been drawn from the main venous drainage of the tumor.

Procedures

• Endoscopic evaluation of the upper gastrointestinal tract is useful for excluding other conditions that can produce similar constellations of symptoms. Gastric pH should be measured at the time of endoscopy to evaluate for hypochlorhydria. Intraoperative endoscopic transduodenal illumination may help localize small endocrine tumors that reside within the wall of the duodenum or within the pancreatic parenchyma.
• Real-time intraoperative ultrasonography (IOUS) can provide additional information about the location and number of pancreatic endocrine tumors. It also can be used to detect small lymph node and hepatic metastases. This technique should always be used in patients who undergo exploration for tumors that could not be definitively localized preoperatively.

Histologic Findings

When visualized via light microscopy, somatostatinomas appear similar to other types of Apudomas (including other pancreatic endocrine tumors and carcinoid tumors). Routine histologic examination does not predict the biologic behavior of these neoplasms, and malignancy is typically determined by the presence of tumor spread to regional lymph nodes or by the existence of hepatic or distant metastases.

Immunofluorescence techniques and the peroxidase-antiperoxidase procedure allow the demonstration of somatostatin within neoplastic cells, but positive findings on immunohistochemical staining only confirm that a particular tumor can synthesize somatostatin. Such a finding, however, does not provide information about whether the synthesized hormone is released into the bloodstream. Thus, an important distinction must be made between true somatostatinomas (ie, tumors that are associated with documented elevation of somatostatin levels) and tumors that merely stain positively for somatostatin.

Staging

Prognosis is primarily based on the presence or absence of liver metastases. The presence of regional lymph node spread does not necessarily connote decreased patient survival. The standard TNM classification scheme is not used to stage somatostatinomas.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

• Chemotherapeutic treatment of metastatic somatostatinoma usually consists of combination treatment with intravenous 5-fluorouracil (5-FU) and streptozotocin. Somatostatinomas are very rare; therefore, assessing the efficacy of chemotherapy is difficult, although up to 50% of patients have had an objective humoral and clinical response to this treatment. Doxorubicin and 5-FU have also been used and may be a more effective combination. Palliative hepatic embolization or chemoembolization is another treatment option for patients with unresectable hepatic metastatic disease.
• Patients with metastatic and unresectable somatostatinomas also require specific symptomatic treatments. Associated diabetes can usually be controlled with oral agents and rarely requires the use of insulin. Pancreatic enzyme supplementation is useful to reduce diarrhea and steatorrhea.

Surgical Care

• Surgical resection is the only option that offers the hope of cure. The goals of surgical therapy are the same as for any pancreatic endocrine neoplasm, as follows:
• • To control symptoms of hormone excess
  • To safely resect maximal tumor mass
  • To preserve maximal pancreatic parenchyma
• Though most somatostatinomas are localized preoperatively, surgical exploration begins with a complete evaluation of the pancreas and peripancreatic regions. Dividing the gastrocolic ligament exposes the body and tail of the pancreas. This portion of the pancreas can be partially elevated out of the retroperitoneum by dividing the inferior retroperitoneal attachments to the gland. After the second portion of the duodenum has been elevated out of the retroperitoneum using the Kocher maneuver, the pancreatic head and uncinate process are palpated bimanually. The liver is carefully assessed for evidence of metastatic disease. Though somatostatinomas are less likely to originate from extrapancreatic locations than gastrinomas, evaluate potential extrapancreatic tumor sites. Evaluation includes inspection, palpation, and ultrasonographic examination of the duodenum, splenic hilum, small intestine (and its mesentery), peripancreatic lymph nodes, and, in women, the reproductive tract.
• Small (<2 cm) benign lesions that are remote from the main pancreatic duct may be enucleated. Regional pancreatectomy is usually necessary for tumors that are deep in the substance of the pancreatic gland (and therefore near the main duct), have ill-defined capsules, or are large (>2 cm). Tumors in the body or tail of the pancreas can be managed with distal pancreatectomy, whereas lesions in the head or uncinate process of the gland can be resected via pancreaticoduodenectomy. Tumors in the neck of the pancreas can be managed with middle segment pancreatectomy (oversewing the proximal pancreatic stump and draining the distal pancreatic duct via pancreaticogastrostomy or pancreaticojejunostomy).
• Debulking cytoreductive surgical resection of liver metastases can be performed in patients with limited hepatic spread. Unique among surgical treatment of pancreatic endocrine tumors, perform cholecystectomies during the first exploration of patients with somatostatinomas, so that if recurrence develops, cholelithiasis will not add to patient morbidity.

Consultations

• Endocrinologists
• Gastroenterologists
• Pancreatic or oncologic surgeons
• Medical oncologists

Diet

Fluid, electrolyte, and nutritional deficits are common complications of somatostatinoma syndrome. Patients in hormone-excess states may require parenteral supplementation.

Activity

Encourage patients to engage in activity as tolerated. No specific activity requirements or restrictions exist.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Streptozocin, 5-FU, and doxorubicin are the agents most commonly used in the treatment of somatostatin-secreting pancreatic neoplasms. Although 50% of patients may sustain a partial humoral and tumor response, the reported numbers are too small to reliably judge efficacy.

Drug Category: Antineoplastic agents

Inhibit cell growth and proliferation.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

• General measures to relieve symptoms are of paramount importance in patients with metastatic disease who have persistent symptoms despite surgical and chemotherapeutic treatment. Implement supportive medications such as antidiabetic agents and pancreatic extract.

Further Outpatient Care

• Provide surgical, oncological, and endocrinological follow-up care to assess tumor size, response to therapy, and the need for hormone replacement. Nutritional needs must be met, including supplementation with minerals and vitamins (especially vitamin B-12).

In/Out Patient Meds

• Administer hypoglycemic medication as needed.
• Chemotherapeutic agents are generally administered in a monitored setting.

Transfer

• Because somatostatinomas are so rare, require a well-coordinated multidisciplinary approach, and usually necessitate complex pancreatic surgery, transfer patients to tertiary referral centers with experience in treating neoplasms of the endocrine pancreas.

Prognosis

• Prognosis primarily depends on the presence or absence of metastatic disease at the time of presentation and initial treatment. Most somatostatinomas (84%) are metastatic at the time of presentation, but a number of 5-year survivors following combination surgery and chemotherapy have been reported among patients with metastatic disease. If treated with appropriate resection, virtually all patients with nonmetastatic somatostatinoma enjoy a cure.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Because somatostatinomas are rare, and heralding signs and symptoms are often nonspecific, delays in diagnosis can occur. These tumors can be cured if identified early; therefore, such errors in clinical judgment can be devastating for patients.
• In some cases, patients develop somatostatinomas as part of occult MEN 1 syndrome. If unrecognized, the hypercalcemia that results from hyperparathyroidism can lead to disastrous surgical complications. All patients who undergo surgical exploration for pancreatic endocrine tumors should be screened for MEN 1 during the preoperative period.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor, Michael G House, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Jul 12, 2006