Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Neoplasms of the Endocrine Pancreas Clinical Presentation

  • Author: Evan S Ong, MD, MS; Chief Editor: Jules E Harris, MD, FACP, FRCPC  more...
 
Updated: Apr 14, 2015
 

History

The presentation in patients with neoplasms of the endocrine pancreas reflects the hormone secreted by the tumor. Thus, signs and symptoms vary with the different syndromes.

Insulinoma

Insulinomas are insulin-secreting tumors associated with the Whipple triad. The triad includes the following[27] :

  1. Symptoms of fasting hypoglycemia
  2. Documented fasting hypoglycemia with a serum glucose level less than 50 mg/dL
  3. Relief of hypoglycemic symptoms after glucose administration

Autonomous insulin secretion from insulinomas produces symptoms classified into two broad categories. Virtually all patients with an insulinoma who seek medical attention present with a subset of at least one of these two groups of symptoms, and more than half present with symptoms from both groups.[28]

First, the direct physiologic effect of hypoglycemia is neuroglycopenia, which results in the following symptoms[15] :

  • Headache
  • Light-headedness
  • Confusion
  • Visual disturbances
  • Seizures
  • Personality changes
  • Obtundation, or even coma

Second, in response to neuroglycopenic stress, the body generates a compensatory state of catecholamine excess, which can lead to the following[10] :

  • Palpitations
  • Weakness
  • Trembling
  • Diaphoresis
  • Tachycardia
  • Irritability

Because insulinoma syndrome is rare and because the associated symptoms are relatively nonspecific, the physician with clinical acumen who encounters a patient with the symptoms of neuroglycopenic stress and/or catecholamine excess may think of insulinoma; however, the patient should be examined first for other more common conditions in the differential diagnosis of hypoglycemia (see Other Problems to be Considered).

Reactive hypoglycemia is the most common form of noniatrogenic hypoglycemia. Reactive hypoglycemia can be differentiated from insulinoma syndrome by a history of symptom onset 3-4 hours after meals, rather than after extended periods of fasting.[29]

Gastrinoma

The classic triad of Zollinger-Ellison syndrome includes the following[1] :

  1. Severe gastrointestinal ulcerative disease
  2. Gastric acid hypersecretion
  3. Nonbeta islet cell tumors of the pancreas

Zollinger and Ellison rightly proposed that these pancreatic tumors released a stimulatory secretagogue into the circulation that induced gastric acid hypersecretion, resulting in ulcer disease. This substance is the polypeptide hormone now called gastrin. Currently, one patient in 1000 with primary duodenal ulcer disease and two patients in 100 with recurrent ulcers after ulcer surgery are estimated to have a gastrinoma.[30]

The clinical symptoms of patients with gastrinoma are a direct result of excessive levels of circulating gastrin. Abdominal pain and peptic ulceration of the upper gastrointestinal tract are the most common symptoms and are observed in 90-95% of patients with Zollinger-Ellison syndrome.[31, 32]

Peptic ulcer symptoms in patients found to have gastrinomas are similar to those of patients with a common peptic ulcer. The symptoms may be more protracted than those of a common peptic ulcer, and they are frequently refractory to standard medical and surgical therapies.

Although the symptoms of gastroesophageal reflux disease are rarely the only symptoms, they occur in approximately one third of the patients with Zollinger-Ellison syndrome. As many as 60% of patients with Zollinger-Ellison syndrome report dysphagia or odynophagia or have endoscopic findings consistent with reflux esophagitis.[33, 34]

Diarrhea occurs in more than a third of patients with gastrinoma; it is secondary to both the high volume of hydrochloric acid in the upper gastrointestinal tract and the direct effects of circulating gastrin on the secretory and absorptive properties of the small intestine. Occasionally, diarrhea may be the only presenting symptom of a gastrinoma.[35, 36]

Steatorrhea occurs in some people with gastrinoma syndrome secondarily; acid in the duodenum and proximal jejunum irreversibly denatures the pancreatic lipase, inactivating it. The denatured lipase is unable to hydrolyze intraluminal triglycerides to their respective diglycerides, monoglycerides, and fatty acids for absorption.[37]

Because the clinical history of patients with Zollinger-Ellison syndrome is often indistinguishable from that of patients with ordinary peptic ulcers, certain clinical conditions should alert clinicians to the possibility of gastrinoma syndrome. Many consider the following conditions to be indications for the initial measurement of a serum gastrin level[10] :

  • Postbulbar ulcers
  • Multiple ulcers
  • Ulcers refractory to standard medical therapy
  • Ulcer recurrence after antiulcer surgery
  • Ulcer and diarrhea
  • Prolonged unexplained diarrhea
  • Family history of peptic ulcer
  • Family history suggestive of MEN 1 syndrome
  • Ulcers in patients who are negative for Helicobacter pylori infection and have no history of nonsteroidal anti-inflammatory drug (NSAID) use
  • Nongastrinoma pancreatic endocrine tumor (ie, because of the high association of secondary elevations in hormone levels) [38, 39]
  • Prominent gastric rugal folds on images from upper endoscopy or a gastrointestinal series (reflecting the trophic effect of gastrin on the gastric fundus)

VIPoma

Symptoms of Verner-Morrison or WDHA syndrome (ie, watery diarrhea, hypokalemia, achlorhydria, acidosis) are the result of the physiologic effects of overproduction of VIP by pancreatic endocrine neoplasms.

The primary and ubiquitous symptom of patients with a VIPoma is watery diarrhea, the occurrence of which may be constant, episodic, or intermittent.[21] Because diarrhea production in persons with Verner-Morrison syndrome is due to cyclic adenosine monophosphate–mediated prosecretory gastrointestinal stimulation by VIP, the term pancreatic cholera has been used to emphasize the physiologic mechanism of this disease.[15]

Abdominal cramps are common among patients with VIPoma syndrome, and flushing episodes occur in a small percentage of patients.[40]

The remaining symptoms associated with VIPomas are secondary to hypokalemia, which occurs because of fecal potassium losses that can reach 400 mEq/d. These symptoms may include muscular weakness, lethargy, and nausea.[10]

Glucagonoma

Glucagonomas secrete excessive amounts of glucagon and cause a syndrome characterized by the following[41] :

  • Dermatitis
  • Stomatitis
  • Weight loss
  • Anemia

The dermatitis associated with glucagonoma syndrome is termed necrolytic migratory erythema. This dermatitis is characterized by the cyclic migration of erythematous patches that spread serpiginously and then reveal central points of healing.[42]

Hyperglucagonemia in patients with glucagonomas results in glucose intolerance (ie, diabetes) and cachexia (secondary to anorexia and the catabolic effects of glucagon) that can be significant, even when the tumors are small and not metastatic.[43]

In addition, as many as a third of patients with glucagonoma syndrome have secondary thromboembolic phenomena; therefore, they may have a history consistent with deep venous thrombosis and/or pulmonary embolism.[44] This feature of glucagonomas is unique among the different neoplasms of the endocrine pancreas.

Normochromic normocytic anemia occurs in approximately half the patients with glucagonoma, and may manifest as fatigue.[45]

Somatostatinoma

The symptoms of somatostatinoma syndrome reflect the general inhibitory action of somatostatin on global gastroenteropancreatic function, as follows:

  • Patients with somatostatinomas often have history findings consistent with diabetes mellitus, which is probably secondary to the inhibitory action of somatostatin on insulin and glucagon release [46]
  • Inhibition of the action of cholecystokinin by somatostatin [47] likely causes relative biliary stasis and the formation of gallbladder calculi; this inhibition may be responsible for the symptoms of biliary colic that often occur in patients with somatostatinomas [48]
  • Patients with somatostatinoma syndrome may also have diarrhea and/or steatorrhea, both of which are likely to be caused by the inhibition of pancreatic enzyme and bicarbonate secretion [21]

When examining patients who present with the aforementioned features, the astute clinician should keep in mind that the triad of hyperglycemia, gallstones, and steatorrhea is not specific for somatostatinoma syndrome. Therefore, patients with these findings should be examined for more common disease entities prior to a comprehensive workup for somatostatinoma.

Carcinoid tumor

The signs and symptoms of carcinoid tumor are related to hypersecretion of serotonin (5-HT) and include the following:

  • Flushing
  • Diarrhea
  • Heart valvular lesions
  • Cramping
  • Telangiectasia
  • Peripheral edema
  • Wheezing
  • Cyanosis
  • Arthritis

Miscellaneous

Additional functional tumors of the endocrine pancreas have been reported, with secretion of growth hormone–releasing factor (GRF), neurotensin, parathyroid hormone-related peptide, pancreatic polypeptide (PP), adrenocorticotropin hormone (ACTH), and melanocyte-stimulating hormone (MSH), as follows:.

  • ACTHomas cause Cushing syndrome, with manifestations that include facial and torso obesity, high blood pressure, stretch marks on the abdomen, generalized weakness, osteoporosis, and facial hair growth in females
  • MSHomas cause skin hyperpigmentation
  • GRFomas primarily result in acromegaly but can also present as other symptoms; they are frequently associated with MEN 1 syndrome and can be accompanied by Zollinger-Ellison syndrome and/or Cushing syndrome in 40% of the cases
  • Neurotensinomas can cause hypotension, hypokalemia, weight loss, flushing, and diabetes; these tumors are usually malignant
  • PPomas have no characteristic symptoms and are associated with high circulating PP levels, although high PP levels can also be seen with other islet cell tumor syndromes
Next

Physical

Physical examination in patients with pancreatic endocrine tumors generally reveals nonspecific findings. However, visual identification of glucagonoma-associated necrolytic migratory erythema, stomatitis, angular chelitis, and VIPoma-associated flushing are important diagnostic clues.

Patients with functional neoplasms of the endocrine pancreas usually present when their tumors are small; however, a mass may be found on abdominal palpation if the patient has a large, nonfunctional tumor.

Large, nonfunctional neoplasms in the head of the pancreas may occasionally cause biliary obstruction, which can lead to jaundice.

Previous
Next

Causes

Fundamental understanding of pancreatic endocrine tumors has increased greatly because of recent observations in the fields of classic and molecular genetics, as follows:

  • In one small series of malignant pancreatic endocrine tumors analyzed by genetic karyotyping, clonal chromosomal abnormalities were identified in more than half the specimens. [49]
  • Amplification of the HER-2/neu proto-oncogene has been demonstrated in gastrinomas (Evers, 1994), and a high level of mRNA expression for the alpha subunit of the cell cycle protein Gs is observed in insulinomas. [50]
  • Loss of heterozygosity at band 11q13 that results in the inactivation of a tumor suppressor gene in this region has been demonstrated in sporadic pancreatic endocrine tumors and in tumors of patients with MEN 1 syndrome or of those with von Hippel-Lindau syndrome. [51]
  • Recent genetic studies of endocrine tumors of the pancreas have suggested novel loci for tumor suppressor genes 3p25, 3p27, and 11p13, and others. Loss of alleles in these regions may serve as markers for malignant endocrine tumors of the pancreas. Also recently demonstrated is the fact that cyclin-dependent kinase inhibitor, p27kip1, is abundantly present in well-differentiated tumors but scant or absent in more aggressive tumors.

Multiple endocrine neoplasia type 1 (MEN 1) syndrome

MEN 1 syndrome, Wermer syndrome, is a genetic disorder with an autosomal dominant pattern of inheritance. The syndrome is characterized by hyperparathyroidism, adenomas of the pituitary, and neoplasms of the endocrine pancreas.[52]

As many as 97% of patients with MEN 1 syndrome have hyperparathyroidism. Between one third and one half of patients with MEN 1 syndrome have pituitary adenomas; prolactin-secreting tumors are the most common type.

Approximately 80% of patients with MEN 1 syndrome have pancreatic endocrine neoplasms. The pancreatic tumors in these patients tend to be multiple and usually secrete multiple hormonally active products.

Nearly all patients with pancreatic endocrine tumors associated with MEN 1 syndrome have one or more nonfunctional lesions, and the majority also have functional neoplasms, including gastrinomas (54%), insulinomas (21%), glucagonomas (3%), and VIPomas (1%).[21]

Environmental factors

No well-established environmental factors are known to be associated with the development of neoplasms of the endocrine pancreas. This lack is in stark contrast to knowledge about the development of neoplasms in the exocrine pancreas, for which cigarette smoking, specific diets, and exposure to industrial toxins are known risk factors.[53]

Previous
 
 
Contributor Information and Disclosures
Author

Evan S Ong, MD, MS Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona College of Medicine

Evan S Ong, MD, MS is a member of the following medical societies: Society of Surgical Oncology, Americas Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Benjamin Movsas, MD 

Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, American Society for Radiation Oncology

Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, FACP, FRCPC Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Jules E Harris, MD, FACP, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Society of Hematology, Central Society for Clinical and Translational Research, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Acknowledgements

Eric J Hanly, MD, Ozanan R Meireles, MD, Michael R Marohn, DO, Charles J Yeo, MD, Keith D Lillemoe, MD, and Lisa H McGrail, MD, are gratefully acknowledged for their contributions to this topic.

References
  1. Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg. 1955. 142:709.

  2. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958. 25:374.

  3. Ganda OP, Weir GC, Soeldner JS, et al. "Somatostatinoma": a somatostatin-containing tumor of the endocrine pancreas. N Engl J Med. 1977 Apr 28. 296(17):963-7. [Medline].

  4. Larsson LI, Hirsch MA, Holst JJ, et al. Pancreatic somatostatinoma. Clinical features and physiological implications. Lancet. 1977 Mar 26. 1(8013):666-8. [Medline].

  5. Howard JM, Gohara AF, Cardwell RJ. Malignant islet cell tumor of the pancreas associated with high plasma calcitonin and somatostatin levels. Surgery. 1989 Feb. 105(2 Pt 1):227-9. [Medline].

  6. McLeod MK, Vinik AI. Calcitonin immunoreactivity and hypercalcitoninemia in two patients with sporadic, nonfamilial, gastroenteropancreatic neuroendocrine tumors. Surgery. 1992 May. 111(5):484-8. [Medline].

  7. Mao C, Carter P, Schaefer P, et al. Malignant islet cell tumor associated with hypercalcemia. Surgery. 1995 Jan. 117(1):37-40. [Medline].

  8. Meko JB, Norton JA. Endocrine tumors of the pancreas. Curr Opin Gen Surg. 1994. 186-94. [Medline].

  9. Langstein HN, Norton JA, Chiang V, et al. The utility of circulating levels of human pancreatic polypeptide as a marker for islet cell tumors. Surgery. 1990 Dec. 108(6):1109-15; discussion 1115-6. [Medline].

  10. Yeo CJ. Neoplasms of the endocrine pancreas. In: Greenfield LJ, Mulholland MW, Oldham KT, eds. Surgery: Scientific Principles and Practice, 3rd ed. Philadelphia, Pa: Lippincott. 2001: 899-913.

  11. Pearse AG. Common cytochemical and ultrastructural characteristics of cells producing polypeptide hormones (the APUD series) and their relevance to thyroid and ultimobranchial C cells and calcitonin. Proc R Soc Lond B Biol Sci. 1968 May 14. 170(18):71-80. [Medline].

  12. Andrew A, Kramer B, Rawdon BB. The origin of gut and pancreatic neuroendocrine (APUD) cells--the last word?. J Pathol. 1998 Oct. 186(2):117-8. [Medline].

  13. Kloppel G, Heitz PU. Pancreatic endocrine tumors. Pathol Res Pract. 1988 Apr. 183(2):155-68. [Medline].

  14. Heitz PU, Kasper M, Polak JM, Kloppel G. Pancreatic endocrine tumors. Hum Pathol. 1982 Mar. 13(3):263-71. [Medline].

  15. Metz DC. Diagnosis and treatment of pancreatic neuroendocrine tumors. Semin Gastrointest Dis. 1995 Apr. 6(2):67-78. [Medline].

  16. Norton JA, Levin B, Jensen RT. Cancer of the endocrine system. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 4th ed. Philadelphia, Pa:. Lippincott-Raven. 1993:1333-435.

  17. Helmrath MA. Miscellaneous endocrine disorders. In: Berry SM, Bass RC, Heaton KM, eds. The Mont Reid Surgical Handbook. 4th ed. St Louis, Mo:. Mosby. 1997: 355-67.

  18. Buchanan KD, Johnston CF, O''Hare MM, et al. Neuroendocrine tumors. A European view. Am J Med. 1986 Dec 22. 81(6B):14-22. [Medline].

  19. Eriksson B, Oberg K, Skogseid B. Neuroendocrine pancreatic tumors. Clinical findings in a prospective study of 84 patients. Acta Oncol. 1989. 28(3):373-7. [Medline].

  20. Weil C. Gastroenteropancreatic endocrine tumors. Klin Wochenschr. 1985 May 15. 63(10):433-59. [Medline].

  21. Jensen RT, Norton JA. Endocrine tumors of the pancreas. In: Feldman M, Scharschmidt BF, Sleisenger M, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia, Pa:. WB Saunders. 1998: 871-94.

  22. Eriksson B, Oberg K. PPomas and nonfunctioning endocrine pancreatic tumors: clinical presentation, diagnosis, and advances in management. In: Mignon M, Jensen RT, eds. Endocrine Tumors of the Pancreas. Frontiers of Gastrointestinal Research. Vol 23. Basel, Switzerland:. Karger. 1995: 208.

  23. Phan GQ, Yeo CJ, Hruban RH, et al. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. J Gastrointest Surg. 1998 Sep-Oct. 2(5):472-82. [Medline].

  24. Menegaux F, Schmitt G, Mercadier M, Chigot JP. Pancreatic insulinomas. Am J Surg. 1993 Feb. 165(2):243-8. [Medline].

  25. Thompson GB, Service FJ, van Heerden JA, et al. Reoperative insulinomas, 1927 to 1992: an institutional experience. Surgery. 1993 Dec. 114(6):1196-204; discussion 1205-6. [Medline].

  26. Metz DC, Jensen RT. Endocrine tumors of the pancreas. In: Haubrich WB, Berk F, Schaffner JE, eds. Bockus Gastroenterology. 5th ed. Philadelphia, Pa:. WB Saunders. 1994: 3002-34.

  27. Whipple AO, Frantz VK. Adenoma of islet cells with hyperinsulinism: a review. Ann Surg. 1935. 101:1299.

  28. Fajans SS, Vinik AI. Insulin-producing islet cell tumors. Endocrinol Metab Clin North Am. 1989 Mar. 18(1):45-74. [Medline].

  29. Service FJ. Hypoglycemic disorders. N Engl J Med. 1995 Apr 27. 332(17):1144-52. [Medline].

  30. Wolfe MM, Jensen RT. Zollinger-Ellison syndrome. Current concepts in diagnosis and management. N Engl J Med. 1987 Nov 5. 317(19):1200-9. [Medline].

  31. Way L, Goldman L, Dunphy JE. Zollinger-Ellison syndrome. An analysis of twenty-five cases. Am J Surg. 1968 Aug. 116(2):293-304. [Medline].

  32. Orloff SL, Debas HT. Advances in the management of patients with Zollinger-Ellison syndrome. Surg Clin North Am. 1995 Jun. 75(3):511-24. [Medline].

  33. Miller LS, Vinayek R, Frucht H, et al. Reflux esophagitis in patients with Zollinger-Ellison syndrome. Gastroenterology. 1990 Feb. 98(2):341-6. [Medline].

  34. Bieligk S, Jaffe BM. Islet cell tumors of the pancreas. Surg Clin North Am. 1995 Oct. 75(5):1025-40. [Medline].

  35. Stabile BE, Passaro E Jr. Recurrent peptic ulcer. Gastroenterology. 1976 Jan. 70(1):124-35. [Medline].

  36. Vinik AI, Thompson NW, Averbuch SD. Neoplasms of the gastroenteropancreatic endocrine system. In: Holland JF, Frei E, Bast RC, eds. Cancer Medicine. Philadelphia, Pa: Lea & Febiger. 1993: 1180-209.

  37. Shimoda SS, Saunders DR, Rubin CE. The Zollinger-Ellison syndrome with steatorrhea. II. The mechanism of fat and vitamin B 12 malabsorption. Gastroenterology. 1968 Dec. 55(6):705-23. [Medline].

  38. Wynick D, Williams SJ, Bloom SR. Symptomatic secondary hormone syndromes in patients with established malignant pancreatic endocrine tumors. N Engl J Med. 1988 Sep 8. 319(10):605-7. [Medline].

  39. Chiang HC, O''Dorisio TM, Huang SC, et al. Multiple hormone elevations in Zollinger-Ellison syndrome. Prospective study of clinical significance and of the development of a second symptomatic pancreatic endocrine tumor syndrome. Gastroenterology. 1990 Dec. 99(6):1565-75. [Medline].

  40. O''Dorisio TM, Mekhjian HS, Gaginella TS. Medical therapy of VIPomas. Endocrinol Metab Clin North Am. 1989 Jun. 18(2):545-56. [Medline].

  41. Higgins GA, Recant L, Fischman AB. The glucagonoma syndrome: surgically curable diabetes. Am J Surg. 1979 Jan. 137(1):142-8. [Medline].

  42. Wilkinson DS. Necrolytic migratory erythema with carcinoma of the pancreas. Trans St Johns Hosp Dermatol Soc. 1973. 59(2):244-50. [Medline].

  43. Stacpoole PW. The glucagonoma syndrome: clinical features, diagnosis, and treatment. Endocr Rev. 1981 Summer. 2(3):347-61. [Medline].

  44. Leichter SB. Clinical and metabolic aspects of glucagonoma. Medicine (Baltimore). 1980 Mar. 59(2):100-13. [Medline].

  45. Guillausseau PJ, Guillausseau C, Villet R, et al. [Glucagonomas. Clinical, biological, anatomopathological and therapeutic aspects (general review of 130 cases]. Gastroenterol Clin Biol. 1982 Dec. 6(12):1029-41. [Medline].

  46. Vinik AI, Strodel WE, Eckhauser FE, et al. Somatostatinomas, PPomas, neurotensinomas. Semin Oncol. 1987 Sep. 14(3):263-81. [Medline].

  47. Brodish RJ, Kuvshinoff BW, McFadden DW, Fink AS. Somatostatin inhibits cholecystokinin-induced pancreatic protein secretion via cholinergic pathways. Pancreas. 1995 May. 10(4):401-6. [Medline].

  48. Boden G, Shimoyama R. Somatostatinoma. In: Cohen S, Soloway RD, eds. Hormone-Producing Tumors of the Gastrointestinal Tract. New York, NY: Churchill Livingstone. 1985: 85.

  49. Long PP, Hruban RH, Lo R, et al. Chromosome analysis of nine endocrine neoplasms of the pancreas. Cancer Genet Cytogenet. 1994 Oct. 77(1):55-9. [Medline].

  50. Zeiger MA, Norton JA. Gs alpha--identification of a gene highly expressed by insulinoma and other endocrine tumors. Surgery. 1993 Aug. 114(2):458-62; discussion 462-3. [Medline].

  51. Eubanks PJ, Sawicki MP, Samara GJ, et al. Pancreatic endocrine tumors with loss of heterozygosity at the multiple endocrine neoplasia type I locus. Am J Surg. 1997 Jun. 173(6):518-20. [Medline].

  52. Miller JA, Norton JA. Multiple endocrine neoplasia. Cancer Treat Res. 1997. 90:213-25. [Medline].

  53. Nakeeb A, Lillemoe KD, Yeo CJ. Neoplasms of the exocrine pancreas. In: Greenfield LJ, Mulholland MW, Oldham KT, eds. Surgery: Scientific Principles and Practice. 3rd ed. Philadelphia, Pa:. Lippincott-Raven. 2001:885-99.

  54. [Guideline] NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine Tumors Version 1.2015. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed: December 21, 2014.

  55. Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res. 2008 Dec 1. 14(23):7798-803. [Medline]. [Full Text].

  56. Warner RR, Curran T, Shafir MK, et al. Serum and ascites chromogranin-A in patients with metastatic neuroendocrine tumors. Pancreas. 2011 May. 40(4):622-6. [Medline].

  57. Mekhjian HS, O''Dorisio TM. VIPoma syndrome. Semin Oncol. 1987 Sep. 14(3):282-91. [Medline].

  58. Krejs GJ. VIPoma syndrome. Am J Med. 1987 May 29. 82(5B):37-48. [Medline].

  59. Krejs GJ, Orci L, Conlon JM, et al. Somatostatinoma syndrome. Biochemical, morphologic and clinical features. N Engl J Med. 1979 Aug 9. 301(6):285-92. [Medline].

  60. Naswa N, Sharma P, Kumar A, et al. Gallium-68-DOTA-NOC PET/CT of patients with gastroenteropancreatic neuroendocrine tumors: a prospective single-center study. AJR Am J Roentgenol. 2011 Nov. 197(5):1221-8. [Medline].

  61. Pelley RJ, Bukowski RM. Recent advances in diagnosis and therapy of neuroendocrine tumors of the gastrointestinal tract. Curr Opin Oncol. 1997 Jan. 9(1):68-74. [Medline].

  62. Moore NR, Rogers CE, Britton BJ. Magnetic resonance imaging of endocrine tumours of the pancreas. Br J Radiol. 1995 Apr. 68(808):341-7. [Medline].

  63. Berger JF, Laissy JP, Limot O, et al. Differentiation between multiple liver hemangiomas and liver metastases of gastrinomas: value of enhanced MRI. J Comput Assist Tomogr. 1996 May-Jun. 20(3):349-55. [Medline].

  64. Gibril F, Reynolds JC, Doppman JL, et al. Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study. Ann Intern Med. 1996 Jul 1. 125(1):26-34. [Medline].

  65. Mitchell DG. Diagnosis and staging of pancreatic tumors by magnetic resonance imaging. Neoplasms of the Digestive System. 1998. Lippincott Raven:

  66. Krausz Y, Bar-Ziv J, de Jong RB, et al. Somatostatin-receptor scintigraphy in the management of gastroenteropancreatic tumors. Am J Gastroenterol. 1998 Jan. 93(1):66-70. [Medline].

  67. Frilling A, Malago M, Martin H, Broelsch CE. Use of somatostatin receptor scintigraphy to image extrahepatic metastases of neuroendocrine tumors. Surgery. 1998 Dec. 124(6):1000-4. [Medline].

  68. Glover JR, Shorvon PJ, Lees WR. Endoscopic ultrasound for localisation of islet cell tumours. Gut. 1992 Jan. 33(1):108-10. [Medline].

  69. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. 1992 Jun 25. 326(26):1721-6. [Medline].

  70. Imamura M, Takahashi K, Adachi H, et al. Usefulness of selective arterial secretin injection test for localization of gastrinoma in the Zollinger-Ellison syndrome. Ann Surg. 1987 Mar. 205(3):230-9. [Medline].

  71. Thom AK, Norton JA, Doppman JL, et al. Prospective study of the use of intraarterial secretin injection and portal venous sampling to localize duodenal gastrinomas. Surgery. 1992 Dec. 112(6):1002-8; discussion 1008-9. [Medline].

  72. Pereira PL, Roche AJ, Maier GW, et al. Insulinoma and islet cell hyperplasia: value of the calcium intraarterial stimulation test when findings of other preoperative studies are negative. Radiology. 1998 Mar. 206(3):703-9. [Medline].

  73. Vinik AI, Delbridge L, Moattari R, et al. Transhepatic portal vein catheterization for localization of insulinomas: a ten-year experience. Surgery. 1991 Jan. 109(1):1-11; discussion 111. [Medline].

  74. Fraker DL, Alexander HR. The surgical approach to endocrine tumors of the pancreas. Semin Gastrointest Dis. 1995 Apr. 6(2):102-13. [Medline].

  75. Gooding GA. Adrenal, pancreatic, and scrotal ultrasound in endocrine disease. Radiol Clin North Am. 1993 Sep. 31(5):1069-83. [Medline].

  76. Norton JA, Sigel B, Baker AR, et al. Localization of an occult insulinoma by intraoperative ultrasonography. Surgery. 1985 Mar. 97(3):381-4. [Medline].

  77. Grant CS, van Heerden J, Charboneau JW, et al. Insulinoma. The value of intraoperative ultrasonography. Arch Surg. 1988 Jul. 123(7):843-8. [Medline].

  78. Nasir A, Helm J, Turner L, et al. RUNX1T1: a novel predictor of liver metastasis in primary pancreatic endocrine neoplasms. Pancreas. 2011 May. 40(4):627-33. [Medline].

  79. Somogyi L, Mishra G. Diagnosis and staging of islet cell tumors of the pancreas. Curr Gastroenterol Rep. 2000 Apr. 2(2):159-64. [Medline].

  80. Macdonald JS, Haller D, McDougall IR. Endocrine system: pancreatic islet cell tumors. In: Abeloff MD, Armitage JO, Lichter AS, eds. Clinical Oncology. 2nd ed. New York, NY:. Churchill-Livingstone. 2000: 1384-97.

  81. Modlin IM, Kidd M, Drozdov I, Siddique ZL, Gustafsson BI. Pharmacotherapy of neuroendocrine cancers. Expert Opin Pharmacother. 2008 Oct. 9(15):2617-26. [Medline].

  82. Vinik AI, Moattari AR. Treatment of endocrine tumors of the pancreas. Endocrinol Metab Clin North Am. 1989 Jun. 18(2):483-518. [Medline].

  83. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10. 364(6):514-23. [Medline].

  84. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10. 364(6):501-13. [Medline].

  85. Anthony L, Vinik AI. Evaluating the characteristics and the management of patients with neuroendocrine tumors receiving octreotide LAR during a 6-year period. Pancreas. 2011 Oct. 40(7):987-94. [Medline].

  86. Hobday TJ, Qin R, Reidy-Lagunes D, Moore MJ, Strosberg J, Kaubisch A, et al. Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors. J Clin Oncol. 2014 Dec 8. [Medline].

  87. Ducreux M, Dahan L, Smith D, O'Toole D, Lepère C, Dromain C, et al. Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial) - A phase II non-randomised trial. Eur J Cancer. 2014 Dec. 50(18):3098-106. [Medline].

  88. Boden G. Glucagonomas and insulinomas. Gastroenterol Clin North Am. 1989 Dec. 18(4):831-45. [Medline].

  89. Moertel CG, Johnson CM, McKusick MA, et al. The management of patients with advanced carcinoid tumors and islet cell carcinomas. Ann Intern Med. 1994 Feb 15. 120(4):302-9. [Medline].

  90. Bilchik AJ, Sarantou T, Foshag LJ, et al. Cryosurgical palliation of metastatic neuroendocrine tumors resistant to conventional therapy. Surgery. 1997 Dec. 122(6):1040-7; discussion 1047-8. [Medline].

  91. Mazzaglia PJ, Berber E, Milas M, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery. 2007 Jul. 142(1):10-9. [Medline].

  92. Lillemoe KD, Kaushal S, Cameron JL, et al. Distal pancreatectomy: indications and outcomes in 235 patients. Ann Surg. 1999 May. 229(5):693-8; discussion 698-700. [Medline].

  93. Phan GQ, Yeo CJ, Cameron JL, et al. Pancreaticoduodenectomy for selected periampullary neuroendocrine tumors: fifty patients. Surgery. 1997 Dec. 122(6):989-96; discussion, 996-7. [Medline].

  94. Udelsman R, Yeo CJ, Hruban RH, et al. Pancreaticoduodenectomy for selected pancreatic endocrine tumors. Surg Gynecol Obstet. 1993 Sep. 177(3):269-78. [Medline].

  95. Sugg SL, Norton JA, Fraker DL, et al. A prospective study of intraoperative methods to diagnose and resect duodenal gastrinomas. Ann Surg. 1993 Aug. 218(2):138-44. [Medline].

  96. Farley DR, van Heerden JA, Grant CS, Thompson GB. Extrapancreatic gastrinomas. Surgical experience. Arch Surg. 1994 May. 129(5):506-11; discussion 511-2. [Medline].

  97. Gibril F, Doppman JL, Jensen RT. Recent advances in the treatment of metastatic pancreatic endocrine tumors. Semin Gastrointest Dis. 1995 Apr. 6(2):114-21. [Medline].

  98. Stefanini P, Carboni M, Patrassi N, Basoli A. Beta-islet cell tumors of the pancreas: results of a study on 1,067 cases. Surgery. 1974 Apr. 75(4):597-609. [Medline].

  99. Fjallskog ML, Sundin A, Westlin JE. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002. 19(1):35-42.

  100. Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1980 Nov 20. 303(21):1189-94. [Medline].

  101. Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20. 326(8):519-23. [Medline].

  102. Fjallskog ML, Janson ET, Falkmer UG, Vatn MH, Oberg KE, Eriksson BK. Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors. Neuroendocrinology. 2008. 88(1):53-8. [Medline].

  103. Rivera E, Ajani JA. Doxorubicin, streptozocin, and 5-fluorouracil chemotherapy for patients with metastatic islet-cell carcinoma. Am J Clin Oncol. 1998 Feb. 21(1):36-8. [Medline].

  104. Arvold ND, Willett CG, Fernandez-Del Castillo C, Ryan DP, Ferrone CR, Clark JW, et al. Pancreatic Neuroendocrine Tumors With Involved Surgical Margins: Prognostic Factors and the Role of Adjuvant Radiotherapy. Int J Radiat Oncol Biol Phys. 2012 Mar 11. [Medline].

  105. Welbourne RB, Wood SM, Polak JM. Pancreatic endocrine tumors. In: Bloom SR, Polak JM, eds. Gut Hormones. 2nd ed. New York, NY: Churchill-Livingstone. 1981: 547-54.

  106. Rothmund M, Angelini L, Brunt LM, et al. Surgery for benign insulinoma: an international review. World J Surg. 1990 May-Jun. 14(3):393-8; discussion 398-9. [Medline].

  107. McGuigan JE. Zollinger-Ellison syndrome and other hypersecretory states. In: Feldman M, Scharschmidt BF, Sleisenger M, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia, Pa:. WB Saunders. 1998:679-95.

  108. Stabile BE, Passaro E Jr. Benign and malignant gastrinoma. Am J Surg. 1985 Jan. 149(1):144-50. [Medline].

  109. Fraker DL, Norton JA, Alexander HR, et al. Surgery in Zollinger-Ellison syndrome alters the natural history of gastrinoma. Ann Surg. 1994 Sep. 220(3):320-8; discussion 328-30. [Medline].

  110. Weber HC, Venzon DJ, Lin JT, et al. Determinants of metastatic rate and survival in patients with Zollinger- Ellison syndrome: a prospective long-term study. Gastroenterology. 1995 Jun. 108(6):1637-49. [Medline].

  111. Jensen RT, Fraker DL. Zollinger-Ellison syndrome. Advances in treatment of gastric hypersecretion and the gastrinoma. JAMA. 1994 May 11. 271(18):1429-35. [Medline].

  112. Holst JJ. Glucagon-producing tumors. In: Cohen S, Soloway RD, eds. Hormone-Producing Tumors of the Gastrointestinal Tract. New York, NY: Churchill-Livingstone. 1985: 57.

  113. Verner JV, Morrison AB. Endocrine pancreatic islet disease with diarrhea. Report of a case due to diffuse hyperplasia of nonbeta islet tissue with a review of 54 additional cases. Arch Intern Med. 1974 Mar. 133(3):492-9. [Medline].

  114. Long RG, Bryant MG, Mitchell SJ, et al. Clinicopathological study of pancreatic and ganglioneuroblastoma tumours secreting vasoactive intestinal polypeptide (vipomas). Br Med J (Clin Res Ed). 1981 May 30. 282(6278):1767-71. [Medline].

  115. Kent RB 3rd, van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors. Ann Surg. 1981 Feb. 193(2):185-90. [Medline].

  116. Tomassetti P, Campana D, Piscitelli L. Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol. 2005 Nov. 16(11):1806-10.

  117. Abood GJ, Go A, Malhotra D, Shoup M. The surgical and systemic management of neuroendocrine tumors of the pancreas. Surg Clin North Am. 2009 Feb. 89(1):249-66, x. [Medline].

  118. Becker M, Aron DC. Ectopic ACTH syndrome and CRH-mediated Cushing''s syndrome. Endocrinol Metab Clin North Am. 1994 Sep. 23(3):585-606. [Medline].

  119. Canavese G, Azzoni C, Pizzi S. p27: a potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior. Hum Pathol. 2001 Oct. 32(10):1094-101. [Medline].

  120. Evers BM, Rady PL, Sandoval K, et al. Gastrinomas demonstrate amplification of the HER-2/neu proto-oncogene. Ann Surg. 1994 Jun. 219(6):596-601; discussion 602-4. [Medline].

  121. Fedorak IJ, Ko TC, Gordon D, et al. Localization of islet cell tumors of the pancreas: a review of current techniques. Surgery. 1993 Mar. 113(3):242-9. [Medline].

  122. Mallinson CN, Bloom SR, Warin AP, et al. A glucagonoma syndrome. Lancet. 1974 Jul 6. 2(7871):1-5. [Medline].

  123. Maton PN. The use of the long-acting somatostatin analogue, octreotide acetate, in patients with islet cell tumors. Gastroenterol Clin North Am. 1989 Dec. 18(4):897-922. [Medline].

  124. Mazzaglia PJ, Berber E, Milas M, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery. 2007 Jul. 142(1):10-9. [Medline].

  125. Oberg K, Eriksson B. Medical treatment of neuroendocrine gut and pancreatic tumors. Acta Oncol. 1989. 28(3):425-31. [Medline].

  126. Pless J, Bauer W, Briner U, et al. Chemistry and pharmacology of SMS 201-995, a long-acting octapeptide analogue of somatostatin. Scand J Gastroenterol Suppl. 1986. 119:54-64. [Medline].

  127. Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature. 1982 Nov 18. 300(5889):276-8. [Medline].

  128. Schein P, Kahn R, Gorden P, et al. Streptozotocin for malignant insulinomas and carcinoid tumor. Report of eight cases and review of the literature. Arch Intern Med. 1973 Oct. 132(4):555-61. [Medline].

  129. Thorner MO, Perryman RL, Cronin MJ, et al. Somatotroph hyperplasia. Successful treatment of acromegaly by removal of a pancreatic islet tumor secreting a growth hormone-releasing factor. J Clin Invest. 1982 Nov. 70(5):965-77. [Medline].

  130. Wilder RM, Allan FN, Power WH. Carcinoma of the islands of the pancreas: Hyperinsulinism and hypoglycemia. JAMA. 1927. 89:348.

  131. Yeo CJ. Islet cell tumors of the pancreas. In: Niederhuber JE, ed. Current Therapy in Oncology. St. Louis, Mo: Mosby-Year Book; 1993:. 272.

 
Previous
Next
 
Neoplasms of the endocrine pancreas. CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (Yeo, 1993).
Celiac axis angiography illustrating neoplasms of the endocrine pancreas. Contrast is seen opacifying the common hepatic artery (CHA) and splenic artery (SA). The superior pancreatic artery (arrow) is seen as an early U-shaped branch of the splenic artery.
Highly selective distal angiography illustrating neoplasms of the endocrine pancreas. With the arterial catheter now advanced into the superior pancreatic artery, the contrast blush of this vascular tumor is easily seen (arrows).
Neoplasms of the endocrine pancreas. Intravenous and oral contrast-enhanced CT scan image in a patient with chronic diarrhea and elevated levels of serum vasoactive intestinal peptide. In the venous phase of this scan, the splenic vein (SV) is clearly seen draining the 5-cm tumor (T) located anteromedial to the spleen (S) in the tail of the pancreas.
Neoplasms of the endocrine pancreas. Schematic diagram of provocative angiography. Access to the central venous and arterial systems is obtained through cannulation of a femoral vein and a femoral artery. In the selective arterial secretin stimulation test, secretin is injected selectively into the splenic, gastroduodenal (a branch of the common hepatic), and inferior pancreaticoduodenal (a branch of the superior mesenteric) arteries with concomitant and subsequent hepatic venous sampling for gastrin. Based on the level of gastrin in each hepatic venous sample, the location of the gastrinoma is arterially mapped. An analogous method can be used in the selective arterial calcium stimulation test to determine the location of occult insulinomas that respond to calcium stimulation by secreting insulin.
Neoplasms of the endocrine pancreas. Graphic depiction of the results of a selective arterial secretin stimulation test in a patient with an occult gastrinoma. The gastrin gradient (the rise in hepatic vein gastrin concentration divided by the basal value) is plotted over time. An increase in gastrin gradient from 0 to 2 thus represents a 200% rise compared to the basal level. A significant rise in hepatic vein gastrin concentration is observed both after the injection of secretin into the superior mesenteric artery (SMA) and after secretin injection into the gastroduodenal artery (GDA), but no such increase occurs following secretin injection into the splenic artery (SPL). This patient's neoplasm is thus localized to the head of the pancreas or the duodenum
Neoplasms of the endocrine pancreas. Octreotide scan (anterior view) in a patient with a pancreatic endocrine tumor. The large pancreatic-tail neoplasm is seen retaining tracer in the patient's left upper quadrant. Several tracer-enhancing hepatic metastases are seen in the patient's right upper quadrant and epigastrium. Tracer is also seen in the bladder following renal excretion (round density in the hypogastrium) (Yeo, 2001).
Neoplasms of the endocrine pancreas. CT scan with oral and intravenous contrast in a patient with a glucagon-secreting neoplasm. This 10-cm contrast-enhancing tumor (T) is seen obliterating the normal appearance of the tail of the pancreas (Yeo, 2001).
Neoplasms of the endocrine pancreas. Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.