Gastrinoma
Insulinoma
Glucagonoma
Miscellaneous

There is no detailed or generally accepted staging system for islet cell cancer; however, a logical division of these tumors 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.

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. (For more information on diarrhea, refer to the Gastrointestinal Complications ¹ summary.) 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. Although 32% of the patients died during the course of the study, only 50% of the 67 deaths were attributable to ZES-related causes that were mainly liver metastases with progressive anorexia and cachexia (67%) or secondary endocrine tumors consequent to MEN-1 syndrome. The development of bone or liver metastases (especially diffuse liver disease) or of ectopic Cushing syndrome during the study period predicted for significantly decreased survival times.[1]

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.[2-4] One large retrospective series has suggested that extensive preoperative radiologic studies are neither clinically effective nor cost effective because intraoperative ultrasound and visual inspection of the pancreas at surgery localize most occult insulinomas.[5]

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.

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.

References

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]