GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS

3. GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS Sima Patel, MD February 29th 2008

4. BACKGROUND Incidence 1-2 in 100,000 (true incidence is underestimated due to vague presentations and misdiagnosis) Account for <2% of GI malignancies Neuroendocrine tumors of the lung, GI tract and mediastinum have a higher incidence in patients >50 (exception: carcinoid of the appendix have a higher incidence in patients age <30)

5. NEUROENDOCRINE CELLS 1969 (Pearse) described APUD cells (amine precursor uptake and decarboxylation) cells that make polypeptides and biogenic amines These cells have dense core secretory granules which store and release hormones in response to external stimuli Do not have axons/synapses Are part of the diffuse endocrine system (DES) Endocrine tumors of the gut and pancreas originate from DES cells

6. CLASSIFICATION WHO CLASSIFICATION Well differentiated NET (non-invasive, benign behaving or uncertain malignant potential) Well-differentiated NE carcinomas (low grade malignant and has invasion or muscularis propria or metastasis) Poorly differentiated endocrine carcinomas (high grade, malignant)

7. CLASSIFICATION GENERAL CLASSIFICATION of Neuroendocrine gastroenteropancreatic tumors Carcinoid tumors 25% foregut (lung, thymus, gastric mucosa, duodenum) 40-60% midgut (distal ileum and jejunum) (includes carcinoid syndrome) Hindgut (colon, rectum) Endocrine Pancreatic Tumors 60% Functioning (Zollinger Ellison, hyperglycemic, verner-morrison, glucagonomas, VIPomas, etc) Non-functioning (usually large and metastatic at the time of diagnosis

8. INSULINOMAS Islet cell tumors Secrete excess of predominantly insulin Usually present at age 40-50 More common in women Clinical symptoms include sweating, tremors, tachycardia, confusion, weakness 10% of patients develop metastasis Complete resection cures most patients

9. GASTRINOMAS Over secretion of gastrin Zollinger-Ellison Syndrome: atypical peptic ulcer disease, gastric hyperacidity and hypersecretion, associated with islet cell pancreatic tumors Age at diagnosis ~50 More common in males (~60%) Metastasis in 60% of patients Complete resection results in 10 year survival of 90%; less likely if large primary

10. GLUCAGONOMAS Presents with mild DM and severe dermatitis (necrolytic migratory erythema), stomatitis, diarrhea ~70% are malignant Metastasis in >60% patients

11. VIPOMAS Over secretion of VIP Causes watery diarrhea, marked hypokalemia 80% are associated with the pancreas Metastasis occurs in ~70% of patients Complete resection results in 5 year survival of 95%

12. SOMATOSTATINOMAS Cholelithiasis, DM, diarrhea, weight loss, steatorrhea Metastasis in ~50% patients Complete resection with 5 year survival of 95% and if has metastasis the 5 year survival decreases to 60%

13. CARCINOID 1.5 per 100,000 Symptoms depend on location and size of tumor and presence of metastasis Can secrete a number of hormonal, growth, and other factors Symptoms include flushing of the face, severe diarrhea, and can have �asthma� symptoms

14. DIAGNOSTIC PROCEDURE Biopsy ? Immunohistochemistry Antibodies to chromogranin A Neuron specific endolase Synapthophysis Stain for serotonin if suspect carcinoid Stain for gastrin if suspect Zollinger � Ellison

15. LABORATORY EVALUATION Carcinoid: 24 hour urinary 5-HIAA raised in carcinoid tumors of the foregut and midgut but not generally raised in tumors of the hindgut Gastrinoma: raised basal serum gastrin, high gastric acid secretion Insulinoma: raised fasting insulin/glucose ratio, proinsulin or C-peptide

16. LABORATORY EVALUATION Glucagonoma: raised serum pancreatic glucagon and enteroglucagon VIPoma: raised fasting vasoactive intestinal peptide Ppoma: elevated fasting pancreatic polypeptide Somatostatinoma: elevated fasting somatostatin All NETs: elevated chromagranin A

17. RADIOLOGIC DIAGNOSIS CT MRI US Somatostatin Receptor Scintigraphy (SRS) � based on presence of somatostatin receptors in 80-90% of NET PET to evaluate tumor metastasis Endoscopic ultrasound � sensitivity/specificity appx 80% for tumors in pancreas and duodenum and can allow for FNA

18. THERAPY Surgery For localized disease Only way to cure Can include debulking or laser procedures however not applicable to all cases as many pts present with metastatic disease Medical therapy: Somatostatin analogs Interferon alpha Cytotoxic drugs

20. SOMATOSTATIN ANALOGS Used since 1980�s Hormone blocking agents that are synthetic somatostatin derivatives (ex: octreotide and lanreotide) First line for neuroendocrine gastroenteropancreatic tumors 2nd -3rd line for insulinomas and gastrinomas Side effects: development of gallstones secondary to inhibition of cholecystokinin release, pain at site, hypo or hyperglycemia, rash, alopecia, fluid retention

22. Interferon Alpha For mid-gut carcinoids Work by direct effect on tumor cells by blocking cell cycle in G1/S phase and inhibiting protein/hormone synthesis and inhibition of angiogenic function Can by used with or without somatostatin analogs SE: flu-like symptoms, fever, anemia, thrombocytopenia, leukopenia

23. CHEMOTHERAPY Cytotoxic treatment is generally a palliative option for metastasizing neuroendocrine carcinomas Streptozotocin, + 5-FU and doxorubicin (response rate >50% in malignant NET) Cisplatium/paraplatin + etoposide (for poorly differentiated NET in fore-gut

24. REFERENCES Irvin Modlin et al,. Gastroenteropancreatic Neuroendocrine Tumours. Lancet Oncology. Volume 9: pages 61-72, 2008. Oberg, Kjell. Neuroendocrine Gastroenteropancreatic Tumors: Recent Update on Diagnosis and Treatment. US Oncology Review. 1-6, 2006 JK Ramage et al,. Guidelines for the Management of Gastroenteropancreatic Neuroendocrine (including Carcinoid) Tumours. Gut. Volume 54: pages 1-16, 2004 Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Management of Advanced Neuroendocrine Tumors. Endocrine Reviews. 25(3): 458-511, 2004 Kasper, Dennis, and Eugene Braunwald, 16th edition, eds. Harrison�s Principles of Internal Medicine. New York: McGraw-Hill, 2005. Tierney Jr, Lawrence, and Stephen McPhee, 45th edition, eds. Current Medical Diagnosis and Treatment. New York: McGraw-Hill, 2006. Uptodate: Management of Metastatic Gastroenteropancreatic Neuroendocrine Tumors Uptodate: Localization of Pancreatic Endocrine Tumors (Islet-Cell tumors) Uptodate: Neuroendocrine Carcinoma of Unknown Primary Site