eMedicine Specialties > Oncology > Carcinomas of Endocrine Organs

Neoplasms of the Endocrine Pancreas: Differential Diagnoses & Workup

Author: Eric J Hanly, MD, Resident, Department of Surgery, The Johns Hopkins University School of Medicine; Fellow, Department of Surgery, The Johns Hopkins University School of Medicine
Coauthor(s): Ozanan R Meireles, MD, Research Fellow in Minimally Invasive Surgery, Department of Surgery, Johns Hopkins University School of Medicine; Michael R Marohn, DO, Associate Professor, Department of Surgery and Surgical Sciences, John Hopkins University School of Medicine; Charles J Yeo, MD, Samuel D Gross Professor and Chair of Surgery at Jefferson Medical College of Thomas Jefferson University and at Thomas Jefferson University Hospital; Keith D Lillemoe, MD, Professor and Chairman, Department of Surgery, Indiana University School of Medicine; Lisa H McGrail, MD, Associate Chief, Department of Hematology/Oncology, Malcolm Grow Medical Center
Contributor Information and Disclosures

Updated: Jun 29, 2006

Differential Diagnoses

Gastrinoma
Somatostatinomas
Glucagonoma
VIPomas
Insulinoma
WDHA Syndrome
Neoplasms of the Endocrine Pancreas
Zollinger-Ellison Syndrome

Other Problems to Be Considered

The DDX of hypoglycemia includes reactive hypoglycemia, functional hypoglycemia associated with gastrectomy or gastroenterostomy, nonpancreatic tumors, pleural mesothelioma, sarcoma, adrenal carcinoma, hepatocellular carcinoma, carcinoid, hypopituitarism, chronic adrenal insufficiency, extensive hepatic insufficiency, and surreptitious self-administration of insulin or ingestion of oral hypoglycemic agents (Yeo, 2001). See the review article by Service for an exhaustive list.

The DDX of peptic ulcer includes Helicobacter pylori infection, NSAID use, gastric cancer, duodenal cancer, pancreatic cancer, ischemic gastric injury, and postoperative marginal ulcer.

The DDX of hypergastrinemia due to nonulcerogenic causes (ie, with normal-to-low acid secretion) includes atrophic gastritis, pernicious anemia, previous vagotomy, renal failure, and short-gut syndrome (Yeo, 2001).

The DDX of hypergastrinemia due to ulcerogenic causes (ie, with excessive acid secretion) includes antral G cell hyperplasia or hyperfunction, gastric outlet obstruction, retained excluded antrum, and Zollinger-Ellison syndrome (Yeo, 2001).

The DDX of watery diarrhea includes villous adenoma, laxative abuse, celiac disease, parasitic and infectious diseases, inflammatory bowel disease, carcinoid syndrome, and gastrinoma (Yeo, 2001).

Workup

Laboratory Studies

  • Insulinoma
    • Monitored fasting test: Blood is sampled to determine glucose and insulin levels every 4-6 hours and when symptoms appear. Hypoglycemic symptoms typically occur when glucose levels are less than 50 mg/dL; concurrent serum insulin levels often exceed 25 mU/mL. The diagnosis of insulinoma is additionally supported by insulin-to-glucose ratios, which are calculated at different times during the monitored fast. After a prolonged fast, healthy persons have insulin-to-glucose ratios less than 0.3, whereas patients with insulinomas typically have ratios much higher than 0.4 (Yeo, 2001).
    • Proinsulin and C peptide test: The physiologically active form of insulin is produced in vivo when C peptide is cleaved from proinsulin in the beta cells of the pancreas. Therefore, insulin and C peptide are secreted in equimolar amounts, and the levels of all 3 proteins, namely, proinsulin, C peptide, and insulin, are increased in patients with insulinoma. The surreptitious administration of insulin should be considered when elevated insulin levels are present in a background of normal proinsulin and C peptide levels.
    • Anti-insulin antibody test: The presence of serum antibodies against insulin is strongly suggestive of the surreptitious administration of insulin and not insulinoma.
  • Gastrinoma
    • Fasting serum gastrin test: Levels greater than 200 pg/mL are suggestive of gastrinoma, and levels greater than 1000 pg/mL are virtually diagnostic of gastrinoma. Serum gastrin levels are also elevated in patients with pernicious anemia because of a lack of negative feedback from parietal cell secretion of hydrochloric acid; thus, hypergastrinemia in the absence of hyperchlorhydria and peptic ulcer is not attributable to a gastrinoma.
    • Gastric acid analysis: Basal acid secretion at a rate higher than 15 mEq/h or a basal-to-maximal acid output ratio that exceeds 0.6 supports the diagnosis of gastrinoma (Yeo, 2001).
    • Secretin stimulation test: A baseline fasting serum sample is drawn, after which secretin at 2 U/kg is administered as an intravenous bolus. Blood is drawn every 5 minutes for 30 minutes, and the serum gastrin level is determined in each sample. An increase in the gastrin level of more than 200 pg/mL above the basal level supports the diagnosis of gastrinoma (Wolfe, 1987).
  • VIPoma
    • Serum VIP test: Determined during periods of ongoing diarrhea, the level of serum VIP in patients with Verner-Morrison syndrome ranges from 225-1850 pg/mL. The normal serum VIP level is less than 170 pg/mL (Mekhjian, 1987).
    • Serum electrolyte analysis: Patients with WDHA syndrome generally have low serum potassium and bicarbonate levels secondary to fecal loss.
    • Gastric acid analysis: Patients with WDHA syndrome have low basal gastric acid output.
    • Stool analysis: VIPoma-associated diarrhea is secretory diarrhea; therefore, it has a low fecal fat content and a normal stool osmolar gap (Krejs, 1987).
  • Glucagonoma: Serum glucagon test levels greater than 1000 pg/mL are diagnostic of glucagonoma, levels less than 150 pg/mL are normal, and levels of 150-1000 pg/mL are equivocal (Guillausseau, 1982). Most patients with serum glucagon levels that are marginally elevated above 150 pg/mL do not have glucagonoma.
  • Somatostatinoma: With a fasting serum somatostatin evaluation, the normal level is below 100 pg/mL but patients with somatostatinoma syndrome have elevated levels on the order of nanograms per milliliter (Ganda, 1977; Krejs 1979). This test in available only in select centers.

Imaging Studies

  • Computed tomography
    • High-resolution contrast-enhanced spiral CT scanning with thin sections (ie, 3- to 5-mm section) through the pancreas is the initial imaging technique used to localize and stage most neoplasms of the endocrine pancreas.
    • CT scan is noninvasive; however, it fails to help identify as many as 70% of these lesions; therefore, most patients must be examined with additional, more expensive, or more invasive localization techniques (Pelley, 1997).
  • Magnetic resonance imaging
    • Significant technical advances have recently brought MRI to the forefront as a useful technique for the localization of neoplasms of the endocrine pancreas.
    • Because of the marked edema of the stromal tissue separating nests of endocrine cells, islet cell tumors present with exceptionally high relaxation times, resulting in greater enhancement on T1- and T2-weighted images than most pancreatic adenocarcinomas. Also, findings from 3 recent studies have demonstrated the usefulness of contrast-enhanced T1-weighted MRI studies in the evaluation of small primary and metastatic pancreatic endocrine tumors (Moore, 1995; Berger, 1996; Gibril, 1996). With the advent of hybrid fast-spin echo T2 sequences, small lesions that depend on minimization of motion-induced artifacts and maximization of resolution can be more accurately visualized (Mitchell, 1998).
  • Somatostatin receptor scintigraphy
    • This novel nuclear medicine imaging modality takes advantage of the fact that pancreatic endocrine tumors, with the notable exception of somatostatinomas, express large numbers of somatostatin receptors on their cell surfaces.
    • Radiolabeled octreotide is a somatostatin analogue that preferentially binds to somatostatin receptors; the intravenous administration of octreotide can be used to identify such tumors (Krausz, 1998).
    • Although the limited resolution of the images from this technique does not provide the detail necessary to determine the exact location of a primary tumor, somatostatin receptor scintigraphy is particularly helpful in diagnosing small extrapancreatic metastases (Frilling, 1998).
  • Endoscopic ultrasonography
    • In experienced hands, transduodenal endoscopic ultrasonography (EUS) can be helpful in localizing pancreatic endocrine tumors and in assessing lymph node metastases (Glover, 1992; Rosch, 1992).
    • The major disadvantage of this imaging modality is that it cannot be used to evaluate hepatic and distant spread. EUS is most useful in identifying small intraduodenal and pancreatic tumors.
  • Angiography
    • Because of improvements in the techniques of CT, MRI, and EUS, visceral angiography currently has no role in the selective visualization of the arterial supply to the pancreas and peripancreatic regions (Yeo, 2001).
    • Provocative angiography is a localization technique that takes advantage of the responsiveness of certain pancreatic endocrine tumors to specific biochemical stimulants and knowledge of the arterial supply of the pancreas and peripancreatic regions to map the location of occult gastrinomas and insulinomas.
      • In the selective arterial secretin stimulation test, secretin is selectively injected into the splenic, gastroduodenal, and inferior pancreaticoduodenal arteries (the last is a branch of the superior mesenteric artery) with concomitant and subsequent hepatic venous sampling for gastrin (Imamura, 1987; Thom, 1992). Based on the level of gastrin in each hepatic venous sample, the location of the gastrinoma is arterially mapped.
      • An analogous method is used in the selective arterial calcium stimulation test to determine the location of occult insulinomas, which respond to calcium stimulation by secreting insulin (Pereira, 1998).

Other Tests

  • Selective transhepatic portal venous sampling: In this invasive test, blood samples are obtained from different locations within the portion of the portal venous system into which the pancreas and pancreatic bed drain (Vinik, 1991). Serum levels of the tumor hormone product in question are determined from the blood samples to help localize the tumor based on anatomic venous drainage. The presumption is that the sample with the highest serum hormone level was drawn closest to the venous drainage point of the tumor.

Procedures

  • Endoscopy: Endoscopic evaluation of the upper gastrointestinal tract in patients with possible gastrinoma can be used to identify the location and number of peptic ulcers. The examination may reveal evidence of reflux esophagitis. Intraoperative endoscopic transduodenal illumination may be helpful in the localization of small pancreatic endocrine tumors located within the wall of the duodenum (Fraker, 1995).
  • Intraoperative ultrasonography (IOUS): It is the study of choice for localization of insulinomas and is more effective than any other preoperative diagnostic imaging study, with a sensitivity of 90% (Gooding, 1993). Real-time IOUS images can provide additional information about the location and number of pancreatic endocrine tumors, and IOUS can be used to detect small lymph node and hepatic metastases (Norton, 1985; Grant, 1988). This technique should always be used in patients who undergo exploration for tumors that could not be definitively localized before surgery.

Histologic Findings

When visualized with light microscopy, all pancreatic endocrine tumors appear similar and resemble carcinoid tumors, the most common type of APUDomas (Norton, 1993). Routine histologic examination cannot be used to predict the biologic behavior of these neoplasms. Malignancy is typically determined by the presence of tumor spread to regional lymph nodes or by the existence of hepatic or distant metastases (Yeo, 2001).

Immunofluorescence techniques and the peroxidase-antiperoxidase procedure allow the demonstration of specific hormones within neoplastic cells, but positive findings with immunohistochemical staining for neuroendocrine products (eg, insulin, gastrin, pancreatic polypeptide) only confirm that a particular tumor can synthesize these products; such findings provide no information about whether the synthesized products are actually released into the blood stream (Heitz, 1982).

Staging

  • The staging system for islet cell cancer is still being developed. These tumors are most often divided into 1 of 3 groups:
    • Islet cell cancers occurring in 1 site within the pancreas
    • Islet cell cancers occurring in several sites within the pancreas
    • Islet cell cancers that have spread to lymph nodes near the pancreas or to distant sites
  • Unlike pancreatic adenocarcinoma, in which the tumoral stage, resectability, and prognosis are determined by using the tumor, nodes, and metastasis classification, the prognosis of patients with pancreatic endocrine tumors is predicted with the presence or absence of liver metastases. The prognosis of patients with regional lymph node metastases is similar to that of patients with only a primary tumor (Somogyi, 2000).

More on Neoplasms of the Endocrine Pancreas

Overview: Neoplasms of the Endocrine Pancreas
Differential Diagnoses & Workup: Neoplasms of the Endocrine Pancreas
Treatment & Medication: Neoplasms of the Endocrine Pancreas
Follow-up: Neoplasms of the Endocrine Pancreas
Multimedia: Neoplasms of the Endocrine Pancreas
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

pancreatic cancer, pancreas cancer, pancreatic neoplasm, pancreas neoplasm, pancreatic islet cell tumor, pancreatic islet cell adenoma, pancreatic endocrine tumor, pancreatic neuroendocrine tumor, insulinoma syndrome, insulinoma, Zollinger-Ellison syndrome, ZES, gastrinoma syndrome, gastrinoma, Verner-Morrison syndrome, WDHA syndrome, watery diarrhea, hypokalemia, achlorhydria, pancreatic cholera, vasoactive intestinal peptide-releasing tumor, VIPoma, glucagonoma syndrome, somatostatinoma syndrome, calcitoninoma, parathyrinoma, growth hormone releasing facto-secreting tumor, GRFoma, adrenocorticotropin hormone-secreting tumor, ACTHoma, neurotensinoma, pancreatic endocrine neoplasm, pancreatic polypeptidomas, PPomas, islet cell tumor, pancreatic cholera, MEN 1 syndrome, MEN-I syndrome, MEN-1 syndrome, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type I, MEN syndrome, APUDomas

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Contributor Information and Disclosures

Author

Eric J Hanly, MD, Resident, Department of Surgery, The Johns Hopkins University School of Medicine; Fellow, Department of Surgery, The Johns Hopkins University School of Medicine
Eric J Hanly, MD is a member of the following medical societies: American Medical Association, Association of Military Surgeons of the US, MedChi, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Coauthor(s)

Ozanan R Meireles, MD, Research Fellow in Minimally Invasive Surgery, Department of Surgery, Johns Hopkins University School of Medicine
Ozanan R Meireles, MD is a member of the following medical societies: American College of Surgeons and Society of American Gastrointestinal and Endoscopic Surgeons
Disclosure: Nothing to disclose.

Michael R Marohn, DO, Associate Professor, Department of Surgery and Surgical Sciences, John Hopkins University School of Medicine
Disclosure: Nothing to disclose.

Charles J Yeo, MD, Samuel D Gross Professor and Chair of Surgery at Jefferson Medical College of Thomas Jefferson University and at Thomas Jefferson University Hospital
Charles J Yeo, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Endocrine Surgeons, American College of Surgeons, American Gastroenterological Association, American Hepato-Pancreato-Biliary Association, American Surgical Association, Association for Academic Surgery, Johns Hopkins Medical and Surgical Association, Pancreas Club, Phi Beta Kappa, Sigma Xi, Society for Surgery of the Alimentary Tract, and Society of University Surgeons
Disclosure: Nothing to disclose.

Keith D Lillemoe, MD, Professor and Chairman, Department of Surgery, Indiana University School of Medicine
Disclosure: Nothing to disclose.

Lisa H McGrail, MD, Associate Chief, Department of Hematology/Oncology, Malcolm Grow Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Michael C Perry, MD, Professor, Department of Internal Medicine, Nellie B Smith Chair of Oncology, Director, Division of Hematology and Oncology, University of Missouri at Columbia/Ellis Fischel Cancer Center
Michael C Perry, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Missouri State Medical Association, Southern Association for Oncology, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, American Society for Therapeutic Radiology and Oncology, and American Society of Clinical Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

John S Macdonald, MD, Professor of Medicine, New York Medical College; Chief, Division of Medical Oncology, St Vincent's Hospital and Medical Center; Medical Director, Saint Vincent's Comprehensive Cancer Center
Disclosure: Nothing to disclose.

 
 
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