1. Clinicopathological Conference CPC #6 Todd T. Brown, MD, PhD Division of Endocrinology and Metabolism 45 y/o male with intermittent abdominal pain, nausea, and diarrhea

2. Questions Prior to surgery, what additional tests would help determine the cause of the patient’s symptoms? What are the most likely causes of the patient’s symptoms? What neoplasms can produce diarrhea as a symptom? By what mechanism(s) do they cause diarrhea?

3. Salient Features 45 year old, male Chronic, episodic abdominal pain, diarrhea Diarrhea watery and profuse Weight loss 1.3 cm mass in head of pancreas (Symptoms resolved after surgical resection)

4. abdominal pain, nausea, diarrhea Diagnosis

5. abdominal pain, nausea, diarrhea Diagnosis Clinical Course? Chronic, Intermittent Diarrhea Characteristics?

6. Chronic Diarrhea Fatty Inflammatory (RBCs/WBCs) Watery

7. abdominal pain, nausea, diarrhea Diagnosis Clinical Course? Chronic, Intermittent Diarrhea Characteristics ? Watery

8. Work-up of Secretory Diarrhea r/o infection (stool culture, ova & parasites, giardia antigen in stool) Evaluate for structural disease –Endoscopy with biopsy –Imaging AGA Guidelines, 1999

9. abdominal pain, nausea, diarrhea Diagnosis Clinical Course? Chronic, Intermittent Diarrhea Characteristics ? Watery Secretory Diarrhea with Pancreatic Mass

10. Functional Neuroendocrine Tumors of the Pancreas TumorDiarrhea? InsulinomaNo GlucagonomaNo Pancreatic CarcinoidYes SomatostatinomaYes Calcitonin-ProducingYes GastrinomaYes VIPomaYes

11. Recommended Work-up Calcitonin Gastrin VIP Urinary 5-HIAA (serotonin metabolite) Somatostatin Other hormonal work-up for secretory diarrhea TSH ACTH stimulation test

12. Glucagonoma Presentation: 4Ds –Diabetes –Dermatitis –Deep Vein Thrombosis –Depression Dermatitis –Necrolytic Migratory Erythema –Resolves with amino acid supplementation Large at Presentation

13. Carcinoid Arise anywhere in the GI tract (75-80% in small bowel, rare in pancreas) Many secretory products (histamine, serotonin most common) Flushing- histamine Diarrhea- serotonin –Stimulation of intestinal secretion and motility

14. Somatostatinoma Inhibits secretion of glucagon, growth hormone, insulin, gastrin Inhibits CCK-mediated secretion of pancreatic enzymes Clinical Syndrome: Diabetes Mellitus, Cholelithiasis, Diarrhea Steatorrhea and resulting diarrhea from decreased secretion of pancreatic lipase

15. Calcitonin Produced by C-cells in thyroid Elevations in calcitonin seen most often in medullary thyroid cancer Ectopic tumors can also produce calcitonin High calcitonin cause secretory diarrhea and flushing

16. Gastrinoma 60% in pancreas, 30% in duodenum Presents as PUD (pain, GI bleed)- 90% Diarrhea also a prominent symptom –Large volume of gastric acid –Acid damages gut mucosa –Pancreatic enzymes inactive at low pH

17. VIP-Secreting Tumors 90% in pancreas 70% have metastatic disease at presentation Classic Presentation: watery diarrhea, hypokalemia, acidosis (WDHA syndrome) Other names: pancreatic cholera syndrome, endocrine cholera, Verner- Morrison syndrome (1958)

18. Vasointestinal Polypeptide 28-amino acid polypeptide Close structural homology with secretin Acts as a neurotransmitter Stimulates enteric smooth muscle and intestinal/pancreatic secretion, inhibits gastric acid secretion G-protein coupled receptors

19. Mechanism of VIP-Associated Diarrhea Effect of Cholera Toxin on Enterocytes

20. Other Systemic Effects of VIP Decreased gastric acid secretion  hypochlorhydria Bone resorption  Hypercalcemia Glycogenolysis  Hyperglycemia Vasodilation  Flushing

21. Hormonal Co-secretion in VIPoma Pancreatic Polypeptide Calcitonin Gastrin Neurotensin Gastric Inhibitory Peptide Serotonin Glucagon Insulin Somatostatin Growth Hormone Releasing Hormone

22. MEN I and Neuroendocrine Tumors Autosomal dominant disease Parathyroid, Pituitary, Pancreas (3 Ps) Duodeno-pancreatic tumors –Gastrin (Zollinger-Ellison Syndrome)(50-70%) –Insulin (20-40%) –Glucagonoma (1-2%) –VIPoma (<1%) –Somatostatinoma (<1%) Family History, Serum Calcium, Prolactin important

23. abdominal pain, nausea, diarrhea Diagnosis Secretory Diarrhea with Pancreatic Mass Additional Features: Weight loss Diabetes Mellitus Family History of Narcissism Pertinent Negatives: No infectious causes No anemia No PUD, nl EGD No flushing K+ 3.8, Ca++ 9.6

24. abdominal pain, nausea, diarrhea VIP-producing Neuroendocrine Tumor of the Pancreas Secretory Diarrhea with Pancreatic Mass