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Islet Cell Carcinoma (Endocrine Pancreas)

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of islet cell carcinoma (endocrine pancreas).


Islet Cell Carcinoma (Endocrine Pancreas)

General Information

Cancer of the endocrine pancreas includes a highly treatable and often curable collection of tumors. They are uncommon cancers with 200 to 1,000 new cases per year and occur in only 1.5% of detailed autopsy series. Islet tumors may either be functional (produce one or more hormones) or nonfunctional. The majority of functioning tumors that produce insulin are benign; however, 90% of nonfunctioning tumors are malignant. Many islet cell cancers are nonfunctional and produce symptoms from tumor bulk or metastatic dissemination. Because of the presence of several cell types in the pancreatic islet cells (alpha, beta, delta, A, B, C, D, E), the term islet cell carcinoma refers to at least five distinct cancers, which when functional, produce unique metabolic and clinical characteristics. Since the clinical manifestations in functional tumors may result from the metabolic effects of polypeptide(s) secreted by the cancer cells rather than from tumor bulk or metastatic disease, each tumor type must be considered separately, both diagnostically and therapeutically.1,2,3 Functional tumors may be too small in size to be detected by conventional imaging techniques.

The frequent long delays between initial symptoms and diagnosis and the varied effects of the polypeptides secreted often necessitate involvement of multiple surgical and medical subspecialties. Surgery is the only curative modality.4,5 Even in those cases not resectable for cure, effective palliation may be achieved because of the slow-growing nature of the majority of these tumors and the potential use of antihormonal pharmacologic therapy (for example, cimetidine in the ulcer-producing Zollinger-Ellison syndrome). Combination chemotherapy may provide effective palliation as well as increased survival in selected patients. In patients with indolent, slow-growing metastatic islet cell carcinoma, the best therapy may be careful observation and no treatment until palliation is required. Patients with multiple endocrine neoplasia syndrome type 1, an autosomal dominant condition in which 85% have pancreatic islet cell tumors, 90% have hyperparathyroidism, and 65% have pituitary tumors, are less likely to be cured by pancreatic resection than are patients with sporadic islet cell tumors. With the exception of pain relief from bone metastases, radiation therapy has a limited role in this disease.



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

2 Modlin IM, Lewis JJ, Ahlman H, et al.: Management of unresectable malignant endocrine tumors of the pancreas. Surg Gynecol Obstet 176 (5): 507-18, 1993.

3 Delcore R, Friesen SR: Gastrointestinal neuroendocrine tumors. J Am Coll Surg 178 (2): 187-211, 1994.

4 Danforth DN Jr, Gorden P, Brennan MF: Metastatic insulin-secreting carcinoma of the pancreas: clinical course and the role of surgery. Surgery 96 (6): 1027-37, 1984.

5 Evans DB, Skibber JM, Lee JE, et al.: Nonfunctioning islet cell carcinoma of the pancreas. Surgery 114 (6): 1175-81; discussion 1181-2, 1993.

Cellular Classification

Endocrine Tumors of the Pancreas

Islet cellsSecreted active agentTumor and syndromeAlphaGlucagonGlucagonoma (diabetes, dermatitis) BetaInsulinInsulinoma (hypoglycemia)DeltaSomatostatinSomatostatinoma (mild diabetes)D Gastrin Gastrinoma (peptic ulcer disease) A -> DVasoactive Intestinal Peptide (VIP) and/or other undefined mediatorsWDHA (watery diarrhea, hypokalemia, achlorhydria)serotonin (5-HT) Carcinoid ACTH Cushing’s diseaseMSHHyperpigmentationInteracinar cells Secreted active agent Tumor and syndrome F Pancreatic polypeptideMultiple hormonal syndromesEC 5-HT Carcinoid

Stage Information

There is no detailed or generally accepted staging system for islet cell cancer, although one can logically divide these tumors as follows:

  • Islet cell cancers occurring in one site.
  • Islet cell cancers occurring in several sites.
  • Islet cell cancers metastatic to regional lymph nodes or distant sites.

Gastrinoma

Diagnosis is dependent on elevated serum gastrin and elevated gastric acid levels. Provocative testing with calcium and secretin shows considerable overlap, and the value of these tests is limited. Zollinger-Ellison syndrome (ZES) is a syndrome of unrelenting peptic ulcer disease, diarrhea, and gastric hyperacidity, associated with a gastrin-producing tumor. It accounts for less than 1% of all peptic ulcer disease. Sixty percent to 75% of gastrinomas associated with multiple endocrine neoplasia syndrome type 1 (MEN-1) are malignant with metastasis at diagnosis. Sporadic gastrinomas are less often malignant; 70% are multicentric.

    Diagnostic tests:
  1. BAO:MAO >/= 0.6 (Basal Acid Output:Maximal Acid Output).
  2. Overnight AO >/= 100 mmols.
  3. BAO >/= 10 mmols/hr.
  4. Serum gastrin 10 times normal, or greater than 500 pg/mL (Note: the accuracy of gastrin assays may vary widely).
  5. Secretin test: 1 unit/kg IV rapid injection: Positive = 100% increase in gastrin within 10 minutes; 2 units/kg: Positive = 100% increase over baseline.
  6. Elevated human chorionic gonadotropin levels.

In the era of proton pump inhibitors and H2 blocking agents, the potentially lethal hyperacidity and hypersecretory states induced by excessive gastrin production can be controlled. In a series of 212 patients with ZES, no patients died of causes related to acid hypersecretion despite the fact that only 2.3% of patients had been subjected to total gastrectomy and that the cohort upon which the report was based had a long median follow-up period of 13.8 years. While 32% of patients died over the course of the study, only 50% of these 67 deaths were attributable to ZES-related causes, mainly liver metastases with progressive anorexia and cachexia (67%) or secondary endocrine tumors consequent to multiple endocrine neoplasia type I (MEN-1) syndrome. The development of bone or liver metastases (especially diffuse liver disease) or of ectopic Cushing’s syndrome during the study period predicted for significantly decreased survival times.1,

Insulinoma

Insulinomas are far more likely to be benign than malignant. Only 10% are multiple and only 10% are malignant; 10% are associated with MEN-1. The clinical manifestations are those of hypoglycemia, which is produced by inappropriate secretion of insulin by the tumor. These tumors may occur alone or as part of a MEN syndrome. Fasting hypoglycemia (<40 mg/dL) associated with an elevated insulin level (in the absence of exogenous administration of insulin) is pathognomonic. Measurement of plasma proinsulin may be helpful for diagnosing insulin-secreting carcinoma. These are usually slow-growing tumors and, when localized to the pancreas or regional lymph nodes, can be cured with pancreatic resection. The approach to management depends on carefully performed preoperative localization studies and the findings at exploratory laparotomy.2,3,4 However, one large retrospective series has suggested that extensive preoperative radiologic studies are neither clinically effective nor cost-effective, since intraoperative ultrasound and visual inspection of the pancreas at surgery localize most occult insulinomas.5,

Glucagonoma

Glucagonoma is the third most common endocrine-secreting islet cell tumor and 70% of glucagonomas are malignant. Necrolytic migratory erythema, hyperglycemia, and venous thrombosis comprise a virtually diagnostic triad. The measurement of serum glucagon confirms the diagnosis.

Miscellaneous

    The following classifications are considered under miscellaneous:
  • VIPoma (Verner-Morrison Syndrome) - characterized by watery diarrhea, hypokalemia, achlorhydria (WDHA).
  • Somatostatinoma - 90% malignant, adult onset diabetes.
  • Pancreatic polypeptide.

These are rare but defined clinical syndromes associated with specific polypeptide hormone production by islet cell tumors. Because of their rarity and similar approaches to management, they are grouped in this section.



1 Yu F, Venzon DJ, Serrano J, et al.: Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome. J Clin Oncol 17 (2): 615-30, 1999.

2 Danforth DN Jr, Gorden P, Brennan MF: Metastatic insulin-secreting carcinoma of the pancreas: clinical course and the role of surgery. Surgery 96 (6): 1027-37, 1984.

3 Kahn CR, Rosen SW, Weintraub BD, et al.: Ectopic production of chorionic gonadotropin and its subunits by islet-cell tumors. A specific marker for malignancy. N Engl J Med 297 (11): 565-9, 1977.

4 Pasieka JL, McLeod MK, Thompson NW, et al.: Surgical approach to insulinomas. Assessing the need for preoperative localization. Arch Surg 127 (4): 442-7, 1992.

5 van Heerden JA, Grant CS, Czako PF, et al.: Occult functioning insulinomas: which localizing studies are indicated? Surgery 112 (6): 1010-4; discussion 1014-5, 1992.

Treatment Option Overview

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Gastrinoma

The approach to treatment often depends on the results of preoperative localization studies and findings at exploratory laparotomy. At exploration, 85% of these tumors are found in the gastrinoma triangle with 40% on the surface of the pancreas and 40% outside of the pancreas. Only 15% are found within the substance of the pancreas. Percutaneous transhepatic venous sampling may occasionally provide accurate localization of single sporadic gastrinomas. Total gastrectomy is no longer considered the immediate treatment of choice and is selectively used depending on effectiveness of other treatment programs.1,

Standard treatment options:

  1. Single lesion in head of the pancreas:
    • Enucleation.
    • Parietal cell vagotomy and cimetidine.
    • Total gastrectomy (in very unusual circumstances).
  2. Single or multiple lesions in the duodenum:
    • Pancreatoduodenectomy.
  3. Single lesion in body/tail of the pancreas:
    • Resection of body/tail.
  4. Multiple lesions in pancreas:
    • Resection of body/tail and, if residual disease is present,
    • Parietal cell vagotomy and cimetidine, or
    • Total gastrectomy.
  5. No tumor found:
    • Parietal cell vagotomy and cimetidine.
    • Total gastrectomy.
  6. Liver metastases:
    • Liver resection where possible; radiofrequency ablation and cryosurgical ablation are options.
    • Chemoembolization of liver.
  7. Metastatic disease or disease refractory to surgery and cimetidine:
    • Combination chemotherapy: doxorubicin + streptozocin or fluorouracil + streptozocin in patients when doxorubicin is contraindicated.2,
    • Somatostatin analogue therapy (SMS 201-995).3,

Patients with hepatic-dominant disease and substantial symptoms caused by tumor bulk or hormone-release syndromes may benefit from procedures that reduce hepatic arterial blood flow to metastases (hepatic arterial occlusion with embolization or with chemoembolization). Such treatment may also be combined with systemic chemotherapy in selected patients.4 Treatment with proton pump inhibitors or H2 blocking agents may aid in control of peptic symptoms.



1 Glowniak JV, Shapiro B, Vinik AI, et al.: Percutaneous transhepatic venous sampling of gastrin: value in sporadic and familial islet-cell tumors and G-cell hyperfunction. N Engl J Med 307 (5): 293-7, 1982.

2 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 326 (8): 519-23, 1992.

3 Kvols LK, Buck M, Moertel CG, et al.: Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Ann Intern Med 107 (2): 162-8, 1987.

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

Insulinoma

Standard treatment options:

  1. Single lesion in head of pancreas or single lesion less than 1.0 cm in tail of pancreas:
    • Enucleation, if feasible.
  2. Single lesion in body/tail greater than 1.0 cm:
    • Distal pancreatectomy.
  3. Multiple lesions: occur in 10%, suspect multiple endocrine neoplasia syndrome type 1 (MEN-1):
    • Resect body and tail.
  4. Metastatic lesions-lymph nodes or distant sites:
    • Resect when possible. Consider radiofrequency or cryosurgical ablation if not resectable.
  5. Unresectable:
    • Combination chemotherapy: doxorubicin + streptozocin or fluorouracil + streptozocin in patients when doxorubicin is contraindicated.1,2,
    • Pharmacologic palliation: diazoxide 300 to 500 mg/day
    • Somatostatin analogue therapy (SMS 201-995).3 Necrotizing erythema of glucagonoma is relieved in 24 hours with somatostatin analogue, with nearly complete disappearance within 1 week.

Patients with hepatic-dominant disease and substantial symptoms caused by tumor bulk or hormone-release syndromes may benefit from procedures that reduce hepatic arterial blood flow to metastases (hepatic arterial occlusion with embolization or with chemoembolization). Such treatment may also be combined with systemic chemotherapy in selected patients.4,



1 Danforth DN Jr, Gorden P, Brennan MF: Metastatic insulin-secreting carcinoma of the pancreas: clinical course and the role of surgery. Surgery 96 (6): 1027-37, 1984.

2 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 326 (8): 519-23, 1992.

3 Kvols LK, Buck M, Moertel CG, et al.: Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Ann Intern Med 107 (2): 162-8, 1987.

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

Glucagonoma

Standard treatment options:

  1. Single lesion in head of pancreas or single lesion less than 1.0 cm in tail of pancreas:
    • Enucleation, if feasible.
  2. Single lesion in body/tail greater than 1.0 cm:
    • Distal pancreatectomy.
  3. Multiple lesions:
    • Resect body and tail.
  4. Metastatic disease-lymph nodes or distant sites:
    • Resect when possible. Consider radiofrequency or cryosurgical ablation if not resectable.
  5. Unresectable disease:
    • Combination chemotherapy: doxorubicin + streptozocin or fluorouracil + streptozocin in patients for whom doxorubicin is contraindicated.1,
    • Somatostatin analogue therapy (SMS 201-995).2 Necrotizing erythema of glucagonoma is relieved in 24 hours with somatostatin analogue, with nearly complete disappearance within 1 week.

Patients with hepatic-dominant disease and substantial symptoms caused by tumor bulk or hormone-release syndromes may benefit from procedures that reduce hepatic arterial blood flow to metastases (hepatic arterial occlusion with embolization or with chemoembolization). Such treatment may also be combined with systemic chemotherapy in selected patients.3,



1 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 326 (8): 519-23, 1992.

2 Kvols LK, Buck M, Moertel CG, et al.: Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Ann Intern Med 107 (2): 162-8, 1987.

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

Miscellaneous Islet Cell Carcinoma

Standard treatment options:

For watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome, somatostatinoma, and pancreatic polypeptide:

  1. Single lesion in head of pancreas or single lesion less than 1.0 cm in tail of pancreas:
    • Enucleation, if feasible.
  2. Single lesion in body/tail greater than 1.0 cm:
    • Distal pancreatectomy.
  3. Multiple lesions:
    • Resect body and tail.
  4. Metastatic disease-lymph nodes or distant sites:
    • Resect when possible. Consider radiofrequency or cryosurgical ablation if not resectable.
  5. Unresectable disease:
    • Combination chemotherapy: doxorubicin + streptozocin or fluorouracil + streptozocin in patients for whom doxorubicin is contraindicated.1,
    • Somatostatin analogue therapy (SMS 201-995) for WDHA syndrome and pancreatic polypeptide.2, Necrotizing erythema of glucagonoma is relieved in 24 hours with somatostatin analogue, with nearly complete disappearance within 1 week.

Patients with hepatic-dominant disease and substantial symptoms caused by tumor bulk or hormone-release syndromes may benefit from procedures that reduce hepatic arterial blood flow to metastases (hepatic arterial occlusion with embolization or with chemoembolization). Such treatment may also be combined with systemic chemotherapy in selected patients.3,



1 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 326 (8): 519-23, 1992.

2 Kvols LK, Buck M, Moertel CG, et al.: Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Ann Intern Med 107 (2): 162-8, 1987.

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

Recurrent Islet Cell Carcinoma

Deciding on further treatment depends on many factors, including the specific cancer, prior treatment, and site of recurrence, as well as individual patient considerations. Clinical trials are appropriate and should be considered when possible. Information about ongoing clinical trials is available at the NCI Cancer.gov Web site. Attempts at re-resection are worthwhile for patients with gastrinomas, insulinomas, and glucagonomas. Somatostatin analogues will aid in control of syndromes of some of these tumors. Intra-arterial chemotherapy has been useful for a number of patients with liver metastases. Patients with hepatic-dominant disease and substantial symptoms caused by tumor bulk or hormone-release syndromes may benefit from continuous-infusion intra-arterial chemotherapy or procedures that reduce hepatic arterial blood flow to metastases (hepatic arterial occlusion with embolization or with chemoembolization). Such treatment may also be combined with systemic chemotherapy in selected patients.1,



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

Changes to This Summary (06/05/2003)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

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2003-06-05







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