Neuroendocrine Tumors of the Pancreas

1. Neuroendocrine Tumors of the Pancreas Joshua M.V. Mammen MD PhD FACS

2. Overview of Talk • Non-functional Pancreatic Endocrine Tumors • Functional Pancreatic Endocrine Tumors

3. Nonfunctional Pancreatic endocrine tumors

4. Background • 58-85% of PET’s are non-functional • Most common location is the pancreatic head • Due to lack of symptoms, tend to present with a large size • Median survival: 3.2 years (7.1 years if potentially resectable) • Presentation: • Abdominal pain • Weight loss • Obstructive jaudice • Bowel obstruction

5. Diagnosis • Usually diagnosed by CT scan or MRI • Endoscopic ultrasound is more sensitive for smaller lesions • Octreotide imaging may help find additional lesions • 75% are secreting hormones in an occult fashion (chromogranin A, pancreatic polypeptitide)

6. Treatment • Only potentially curative strategy is surgical resection with regional lymphadenectomy • Imaging studies should be performed to assess for resectability • Incomplete resection or debulking is not recommended • Consider chemo or radio or bland embolization of hepatic metastases in setting of unresectable disease • May consider observation for low grade/slow growing disease

7. Treatment • Systemic treatment • Streptozocin based chemotherapy (up to 39% response in combination) • Octreotide

8. Functional Pancreatic Endocrine Tumors

9. Insulinoma • First described in 1935 by Whipple and Frantz • Most common functional PNET • Triad of symptoms (Whipple’s triad): • Hypoglcemic symptoms when fasting • Blood glucose level of less than 50 • Symptom relief with glucose

10. Insulnoma • 10% Malignant • 10% Multiple • 10% associated with MEN1

11. Insulinoma: Diagnosis • 72 hour monitored fast • Draw plasma glucose, C-peptide, proinsulin, and insulin every 6 hours • Continue test until plasma glucose is less than 45 and patient has symptoms • Criteria for diagnosis: • Insulin concentration greater than 6 uU/mL • Insulin to glucose ratio greater than 0.3 • C-peptide level greater than 0.2 nmol/L • Proinsulin level greater than 5pmol/L • Lack of plasma sulfonylurea

12. Insulinoma: Diagnosis • Exogenous insulin • Low C-peptide levels • Low proinsulinlevels • Oral hypoglycemic agents • Elevated C-peptide levels • Elevated proinsulin levels • Plasma sulfonylurea

13. Insulinoma: Treatment • Surgical resection is the main treatment • Prior to surgery, control glucose with small meals and diazoxide • Use intraoperative ultrasound to identify additional lesions at the time of surgery • Does not require anatomic resection, merely enucleation • If there is evidence of malignancy, should attempt formal resection (median disease free survival is 5 years)

14. Gastrinoma • First described by Zollinger and Ellison in 1955 • Secretes gastrin that leads to hyperchlorhydria and parietal cell hyperplasia • Triad • Atypical peptide ulcerations • Gastric hypersecretion with hyperacidity • Noninsulin producing islet tumor of the pancreas

15. Gastrinoma • Sporadic gastrinomas (75%) usually present at 45 years old • Majority (60%-90%) are malignant • Location • 63% are in the pancreatic head • Presentation • Abdominal pain (75%-100% • Diarrhea (35%-73%) • Heartburn (44%-64%) • Duodenal and Prepyloric ulcers (71%-91%)

16. Gastrinoma: Diagnosis • Carefully should withdraw PPI use • Fasting gastrin level of greater than 1000 pg/mL and pH less than 2.5 • Diagnosis requires: • Basal acid output greater than 15 mEq/hour • Positive secretin stimulation test • Adminster 2 units/kg intravenous secretin after overnight fast • Draw gastrin levels prior to secretin and at 0, 2, 5, 10, and 20 minutes • Positive is increase in serum gastrin over 200 pg/mL

17. Gastrinoma: Diagnosis • CT and MRI can localize larger lesions • Endoscopic ultrasound for smaller lesions • Octreotide Imaging • Selective angiography and selective arterial secretin injection

18. Diagnosis: Treatment • Initial treatment is PPI or H2 blocker • Perform enuclation or resection with associated lymph nodes if can be identified • If cannot identify preoperatively, surgical exploration with intraoperative ultrasound • Isolated liver metastases should be resected

19. Vasoactive Intestinal Polypeptidoma • Tumors secrete vasoactive intestinal polypeptide (also known as Vener-Morrison syndrome or watery diarrhea hypokalemia-achlorhydria syndrome- WDHA) • Presentation: • Large volume secretary diarrhea • Electrolyte imbalances (hypocholorhydria) • Flushing

20. Vasoactive Intestinal Polypeptidoma • 60-80% are malignant at presentation • 5- year survival is 69% • 80% are isolated to the pancreas • Diagnosis: • Fasting plasma vasoactive intestinal polypeptide levels greater than 500 pg/mL • High volume diarrhea • Imaging studies

21. Vasoactive Intestinal Polypeptidoma • Treatment is surgical resection with lymphadenectomy • Need to hydrate and correct electrolytes prior to surgery • Streptozocin based chemotherapy if unresectable

22. Glucagonoma • Arise pancreatic alpha cells • Cause increased glucagon secretion with glucose intolerance, weight loss, neuropsychiatric disturbances, venous thrombosis, and necrolytic migratory erythema

23. Glucagonoma • Diagnosis • Inappropriately elevated fasting glucagon grweater than 500 pg/mL • Biopsy of necrolytic migratory erythema • Imaging to identify location

24. Somatostatinoma • Arise from delta cells of the pancreas • Majority are sporadic (90%) • Most likely to be located in the pancreas • Presentation: • Diabetes mellitus • Cholelithiasis • Steatorrhea • Weight loss • Anemia • Diarrhea

25. Somatostatinoma • Somatostatin level greater than 100 pg/mL • Localize with imaging • Typically present late • Treatment is surgical resection with lymphadenectomy • Tumor debulking for palliation • Always perform cholecystectomy due to cholestasis

26. Summary • Generally, treatment is surgical resection for sporadic cases • Functional tumors have specific tests that help in diagnosis