NeuroEndocrineTumours PANCREAS full.pptx

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1. Neuroendocrine tumors of Pancreas

2. Objectives Neuroendocrine tumors Insulinoma Gastrinoma Non functioning NET Other tumors

3. Introduction Prevalence is 1 to 6 per million population. Age : 60 to 80 years Male = female Neuroendocrine tumors include: Nonfunctional tumors Gastrinoma Insulinoma Somatostatinoma Glucagonoma Pancreatic peptide, VIP ,GHRF, ACTH, PTH – producing tumors Chromogranin A – tumor marker

4. Introduction Cell of origin – undifferentiated Pancreatic NET stem cell Microscopically: Sheets of small , round cells with uniform nuclei and cytoplasm, mitotic figures are rare Determination of malignancy cannot be made by histological appearance.

5. Introduction

6. Introduction Divided into: Aggressive Nonaggressive Factors predicting aggressive growth: Liver metastasis LN metastasis Local invasion Large tumor size Nonfunctional tumor Incomplete tumor resection

7. Introduction Genetics: Alterations in DPC 4 gene located on 18q21 C-MET gene expression suggests a more aggressive behaviour of PNET Familial - MEN 1 Von Recklinghausen disease – duodenal somatostatinoma and gastrinomas Von Hippel – Lindau disease – adenomas and carcinomas Tuberous sclerosis – insulinomas and nonfunctional PNETs.

8. Insulinoma

9. Insulinomas Tumor of pancreatic beta cells. Incidence is 1 in million people per year More common in females Usually benign. Uniformly distributed Can be : Sporadic (80%) Familial (20%)

10. Insulinomas – Clinical Features Weight gain Diagnosed with other disorder 1 month to 30 years Associated features of MEN-1

11. Insulinomas - DD Factitious hypoglycemia Urine sulfonyl urea concentration Proinsulin , c-peptide levels - ↑ in insulinomas

12. Insulinomas - Diagnosis Diagnostic 72 hour fast. Every 6 hours – glucose and insulin levels On symptoms – glucose, insulin, C-peptide and proinsulin Diagnosis: Neuroglycopenic symptoms Serum glucose levels - < 45mg/dl Serum Insulin levels - > 5micro/L Relief of symptoms with glucose administartion

13. Imaging modalities USG – 20% of insulinomas CECT – Investigation of choice

14. Imaging modalities

15. Imaging modalities Somatostatin Receptor Scintigraphy 68Ga-DOTATATE PET and 111In-octreotide Sensitivity of these tests is 90%.

16. EUS Tumors < 2cms – difficult to localise EUS – 2 to 3 mm EUS-FNAC Sensitivity - 70 – 90% Specificity - 100% Reliable in head of panacreas Limitations – accessory spleens, intrapancreatic LNs

17. Invasive test for localisation Arterial stimulation venous sampling Right and Left hepatic veins cannulated for sampling Calcium administration into Gastroduodenal, Proximal splenic, SMA, PHA Venous sampling for insulin levels at 30 , 60 , 120 seconds 2 fold increase in insulin levels is diagnostic.

18. Treatment Medical treatment – to prevent hypoglycemia IV Glucose Frequent carbohydrate diet with night meal Corn starch – to delay absorption of glucose Diazoxide – 400 to 600mg/day Long term medical management – unlocalised , unresectable and metastatic tumors Implantable glucose pumps

19. Treatment Surgical management is treatment of choice. Goal – localise and resect the tumor

20. Treatment Resection : Functional , symptomatic tumors G1 and G2 tumors with size > 2cms Resectable metastatic disease Surgery depends on location – Distal Pancreatectomy, Enucleation , PD Splenectomy Hepatic debulking

21. NCCN Guidelines

22. Gastrinoma

23. Introduction Gastrinomas are tumors arising from gastrin producing G cells . Also called Zollinger – Ellison syndrome. Sporadic or familial Solitary – Multiple in MEN 1 Majority are malignant Associated with LN metastasis and liver metastasis

24. Clinical Features Abdominal pain and diarrhoea Heart burn Nausea and vomiting Weight loss Metastatic disease Bleeding and perforation of peptic ulcer

25. Diagnosis Fasting levels of Serum Gastrin Other causes of hypergastrinemia include: Pernicious anemia Atrophic gastritis Pharmacologic acid suppression Antral G cell hyperplasia Retained gastric antrum Short bowel syndrome Renal failure Gastrin stimulation testing

26. Diagnosis CECT – hypervascular MRI SRS EUS Ga DOTATATE

27. Diagnosis

28. Treatment Majority localised preoperatively. 20 – 30 % tumors not localised  exploration During surgery: Wide kocherisation Mobilisation of body and tail of pancreas IOUS Duodenotomy LN removal in gastrinoma triangle

29. Treatment Duodenal disease: enucleate Pancreatic disease: Head: <2 cm: enucleate >2 cm or duct involved: PD Body/Tail: Distal pancreatectomy & splenectomy

30. Prognosis Biochemical cure – 30 to 50% Recurrence R0/R1 – 85% 10 year survival R2 – 40% No excision – 25 %

31. MEN 1 disease

32. Metastatic disease Debulking of metastatic disease One lobe of liver involved : Hepatectomy Both lobes involved : TACE, TARE, RFA, MWA

33. Somatostatinoma

34. Introduction Arise from D cells of pancreas Produce somatostatin – inhibitory harmone Sixth decade of life Male = Female Duodenum or pancreas Pancreatic - aggressive Duodenal – NF1 disease

35. Clinical Features Diabetes (60%) Cholelithiasis (70%) Diarrhoea (30 -68%) Steatorrhoea Weight loss Hypochlorhydria (80%)

36. Diagnosis Incidental findings At diagnosis – metastatic and > 5cms Fasting plasma somatostatin levels > 14pmol/L CECT, MRI, SRS

37. Treatment Located in head of pancreas and duodenum – resection Metastatic disease – debulking 5 year survival rate : Duodenal – 30% Pancreatic – 15%

38. VIPomas

39. Introduction Located in pancreas Verner – Morrison syndrome Diarrhoea Hypokalemia Hypochlorhydria Hypercalcemia 50% are benign

40. Clinical Features Diarrhoea (70%) Hypokalemia Hypochlorhydria (75%) Flushing Hyperglycemia Hypercalcemia

41. Management Fasting plasma levels of VIP Localisation Correction of metabolic abnormalities Resection Debulking Long acting somatostatin analogues

42. Glucagonoma

43. Glucagonoma Excessive levels of glucagon 50 to 60 years of age Located in body and tail Malignant Liver metastasis at presentation

44. Clinical features Necrolytic Migratory Erythema (NME) TYPE 2 DM Weight loss Anaemia Stomatitis & Glossitis Pulmonary and Venous thromboembolism

45. Clinical Features

46. Management Plasma Glucagon concentration - greater than 1000 pg /mL Resection – subtotal pancreatectomy with splenectomy Debulking

47. GRFomas

48. GRFomas Secrete Growth Harmone Releasing Factor Common in lung, pancreas, jejunum, adrenal and retroperitoneum Associated with Zollinger syndrome and MEN 1 Large > 6cms and metastatic Acromegaly and pancreatic tumor Resection and debulking Octreotide therapy to relieve symptoms of acromegaly

49. Other tumors

50. Other tumors ACTH producing tumors PTHrP producing tumors Ghrelinomas

51. Non- functioning tumors

52. Introduction Not associated with syndromes Most common NET of pancreas. Large tumors Malignant and metastatic

53. Clinical features Abdominal pain Jaundice weight loss abdominal mass Nausea & vomiting Back pain Pancreatitis Incidental presentation

54. Prognosis 5 year survival rate: Benign – 89 % Indeterminate – 93% Malignant – 50% Produce substances – not sensitive and specific Chromgranin -A

55. Treatment Resection – PD Metastatic- debulking, hepatic embolization Everolimus based chemotherapy PRRT

56. NCCN Guidelines

57. Adjuvant therapy

58. Somatostatin analogues Most tumors express somatostatin receptors Somatostatin analogues – cytostatic activity PROMID trial

59. PROMID trial

60. CLARINET trail

61. Somatostatin analogues Side effects: Flatulence Diarrhoea Steatorrhoea Nausea Cholelithiasis Glucose intolerance

62. Everolimus Inhibits mTOR pathway RADIANT -3 trial

63. Sunitinib Inhibits VEGF, PDGF & C-kit 5 year overall survival difference of 9.5 months. Chemotherapy Alkylating agents : Streptozocin , Dacarbazine , Temozolamide Temozolamide alone vs CAPETEM (Capecitabine + Temozolamide ) Platinum compounds: FOLFOX / CAPEOX + Bevacizumab

64. Peptide Receptor Radionuclide Therapy (PPRT) SSA linked to beta rays emitting radioisotopes Lutetium -177 is used now a days NETTER -1 trial – 177 Lu DOTATATE + Octreotide vs Octreotide alone

65. Summary

66. Summary

67. THANK YOU