Pancreatic neoplasms

Pancreatic neoplasms by Dr. Sreenath

1. Pancreatic Neoplasms Dr K Sreenath Junior Resident, Dept of Surgery RIMS Imphal

2. Pancreas Weighs between 75 and 125 g and measures 10 to 20 cm. Lies in the retroperitoneum just anterior to the first lumbar vertebrae Divided into four portions, the head, neck, body and tail.

3. Pancreas anatomy

4. Arterial supply Multiple arcades in the head and body of the pancreas provide a rich blood supply. The head of the pancreas cannot be resected without devascularizing the duodenum unless a rim of pancreas containing the pancreaticoduodenal arcade is preserved

5. Venous drainage Follows a pattern similar to the arterial supply Veins usually superficial to the arteries

6. Lymphatic drainage The lymphatic drainage from the pancreas is diffuse and widespread , which explains the high incidence of lymph node metastases and local recurrence of pancreatic cancer. The pancreatic lymphatics also communicate with lymph nodes in the transverse mesocolon and mesentery of the proximal jejunum. Tumors in the body and tail of the pancreas are often unresectable because they metastasize to these lymph nodes

7. Innervation The pancreas has a rich supply of afferent sensory fibers that travel superiorly to the celiac ganglia . Interruption of these somatic fibers with a celiac plexus block can interfere with transmission of pancreatic pain

8. Types of Pancreatic Neoplasms Neoplasms of exocrine pancreas Cystic neoplasms account for <1% of pancreatic cancers Ductal adenocarcinoma >90% of pancreatic cancers Neoplasms of endocrine pancreas Neuroendocrine tumors or islet-cell tumors, rare

9. Carcinoma Exocrine Pancreas

10. MC – Ductal adenocarcinoma Ninth most common cancer diagnosis Fourth in cancer deaths Men> women (1.3 : 1) African Americans have a slightly higher risk Mean age at diagnosis is 72 years Incidence lowest in Middle East and in India

11. Risk factors-Environmental Smoking C/C Pancreatitis Occuopational exposure Diabetes Obesity Diet ( Rich in protein and fat) Infectious - H pylori or HBV ? Genetic Alcohol , coffee and Radiation ..No Risk ( Maingot’s 12 th edn p. 1188)

12. Risk factors-Hereditary

13. Pathogenesis Most cases are sporadic. Sequential pathway has been observed in the development of PDAC from pancreatic intraepithelial neoplasia ( PanIN ) to invasive cancer. Genes identified- PDX1, KRAS2, CDKN2A/p16, P53, and DPC4 (SMAD4). KRAS2 oncogene is activated (by point mutation ) 95% of pancreatic cancers Earliest event in tumorigenesis .

14. PanIN : Progressive abnormality of the ductal epithelium from columnar metaplasia (PanIN-1A) through carcinoma in situ (PanIN-3). PanIN-1A : Presence of columnar, mucin -producing ductal epithelium PanIN-1B : The development of papillary architecture PanIN-2 : Evidence of nuclear atypia PanIN-3 (carcinoma in situ): marked cytologic atypia , complete loss of polarity

15. Molecular genetic progression from  PanIN  to invasive  ductal   adenocarcinoma .

16. Periampullary carcinoma Adenocarcinomas of the Head of the pancreas Ampulla of Vater , Distal bile duct ( cholangiocarcinoma ), Duodenum . Less commonly, acinar cell carcinomas or pancreatic endocrine neoplasms occur in the periampullary region of the pancreas

17. Clinical Presentation

18. Carcinoma Body and tail Late presentation Pain and weight loss are more common Rare Poor prognosis

19. Signs A palpable distended gallbladder (Courvoisier’s law) Left supraclavicular node (Virchow’s node & Troisier’s sign ) Periumbilical lymphadenopathy may be palpable (Sister Mary Joseph’s node). Peritoneal dissemination and perirectal tumor involvement may be palpable via digital rectal examination ( Blumer’s shelf) Migratory suprficial thrombophlebitis (Trousseau ‘s sign)

20. Laboratory Evaluation Hepatic function evaluation Coagulation profile Nutritional assessment. Tumor markers : CEA, CA19-9 CA19-9 Most sensitive most reliable tumor marker for pretreatment evaluation and post- treatment surveillance

21. Imaging Studies Ultrasound abdomen Initial ivestigation Multiphase Multidetector CT - The imaging study of choice - Three-phase ( noncontrast , arterial, and portal venous) CT scan with 3- mm slices and coronal and 3 D reconstruction - Extension to SMA, Celiac axis, SMV-PV complex and contiguous structures can be determined - Metastasis can be asessed - Resectability can be predicted

22. US is often the initial test in symptomatic patients. US is used for diagnosis rather than staging, although liver metastasis and ascites may be seen. Ultrasound normal anatomy

23. CT Findings Axial CT image shows stage T1 pancreatic ductal adenocarcinoma Drawing shows T1 tumor, which is defined as being equal to or smaller than 2 cm in maximum diameter and confined to pancreas, and T2 tumor, larger than 2 cm and confined to pancreas

24. CT Findings Drawing shows T3 tumor, defined as tumor that may extend beyond pancreas but without involvement of celiac axis or superior mesenteric artery. Contrast-enhanced axial CT image shows T3 tumor that has involved common bile duct, requiring a stent, and that extends medially beyond confines of pancreatic head. Tumor is separated from superior mesenteric vein ( long arrow ) and superior mesenteric artery ( short arrow ) by fat plane (type A relationship). Note that tumor involves duodenum ( arrowhead ).

25. CT Findings Drawing shows T4 tumor, defined as primary tumor involving either superior mesenteric artery or celiac axis. Contrast-enhanced axial CT image shows pancreatic tumor ( white arrows ) engulfing celiac axis. Short black arrow = splenic artery, long black arrow = common hepatic artery.

26. E ndoscopic US To provide tissue diagnosis of suspected tumors through FNA prior to initiating systemic therapy. Beneficial for identifying small tumors smaller than 2 cm A 2.5cm round, hypoechoic tumor is identified in the the region of the genu. The superior mesenteric vein can be seen separate from the tumor. Invasion of the dilated CBD by a large irregular hypoechoic tumor located in the head of pancreas. A large hypoechoic tumor is seen to invade the portal vein (arrow), with loss of tumor-vessel interface and tumor extension into vessel lumen. The dilated CBD contains echogenic sludge.

27. MRI Findings The role of MRI in pancreatic cancer has been less well studied than the role of CT scanning. It does not appear to be superior to spiral CT scanning. The ability of MRI to demonstrate pancreatic adenocarcinoma largely depends on the demonstration of deformity of the gland , as reflected in its size, shape, contour, and signal intensity characteristics. Thin-section helical CT image obtained during pancreatic phase reveals large pancreatic tumor with tumor surrounding celiac trunk and hepatic artery. E xtent of vascular encasement is better depicted by CT scan than by MR images. T1 cont T1

28. MRI Findings Transverse T1-weighted fat-suppressed image shows verified adenocarcinoma of the pancreatic head Adenocarcinoma was visible as a low-signal-intensity tumor . The normal pancreas is of low signal intensity on T1-weighted images and of intermediate signal on T2-weighted images, with a variable amount of fat in the gland parenchyma.

29. MRCP Assessment of luminal pancreatobiliary anatomy Usefull for cystic lesions of the pancreas ERCP - To perform a biopsy and palliate jaundice ( biliary stenting ) Signs Abrupt block PD encasement Dubble duct sign Scrambled egg appearance

30. ERCP has a sensitivity of 95% and a specificity of 85% for pancreatic malignancy. Most pancreatic carcinomas arise from the ductal epithelium and produce complete or partial ductal obstruction. ERCP image shows dilated biliary tree and obstruction of common bile duct associated with tumor in pancreatic head. Endoscopic retrograde cholangiopancreatography (ERCP)

31. ERCP image shows slight narrowing of pancreatic duct and ductal dilatation. Sphincterotomy was performed, and pancreatic stent was placed. Contrast-enhanced CT scan fails to depict tumor ( arrow ) around stent in dilated common bile duct. Unenhanced T1-weighted MR image shows inhomogeneity of pancreatic head, but does not show tumor. Compared with other modalities, MRI appears to be more valuable for staging the extent and spread of pancreatic carcinoma than for tumor detection of lesions smaller than 2 cm.

32. Magnetic resonance cholangiopancreatography (MRCP ) MRCP is as sensitive as ERCP and may prevent inappropriate explorations of the pancreatic and bile ducts in patients with suspected pancreatic carcinoma in whom interventional endoscopic therapy is unlikely Coronal image from MR CP shows double-duct sign caused by obstruction by tumor. Dilated common bile duct and dilated pancreatic duct are seen proximal to abrupt cutof f.

33. Magnetic resonance cholangiopancreatography (MRCP) MR pancreatogram reveals a dilated pancreatic duct proximal to the obstructing pancreatic head mass. ERCP helps confirm the dilatation of the pancreatic duct in the body and the distal stricture .

34. MRI Findings Coronal oblique MRCP demonstrates pancreatic duct obstruction in the head with proximal dilatation of both pancreatic duct (PD) and common bile duct (CBD) , which is referred to as the double duct sign. Coronal MR angiogram in the venous phase shows vascular infiltration of the portal vein and venous confluens. Note the consecutive mesenteric collateral formatio n.

35. >The medial margin of the descending duodenum may be pulled medially at the level of the ampulla , forming a reversed-3 appearance. This is known as Frostberg 3 sign . >Rose thorn appearance Duodenal invasion at the level of papilla major demonstrated by upper GI endoscopy

36. Upper GI barium studies may reveal an extrinsic impression of the mass on the posteroinferior aspect of the antrum of the stomach, widened C loop of duodenum This is known as antral pad sign ” .

37. Percutaneous transhepatic cholangiogram (PTC ) > Percutaneous transhepatic cholangiogram showing a catheter in a dilated common bile duct with an abrupt, irregular stricture at the lower end, indicative of a pancreatic cancer >Not used routinely due to other less invasive imaging modalities

38. Staging

39. Following CT imaging, patients are classified into resectable , borderline resectable , or unresectable . Resectable tumors - Localized to the pancreas, with no evidence of SMV or portal vein involvement and a preserved fat plane Borderline resectable (1) severe unilateral or bilateral SMV-portal impingement; (2) less than 180-degree tumor abutment on the SMA (3) abutment or encasement of hepatic artery, if reconstructible (4) SMV occlusion, if of a short segment, and reconstructible . Unresectable tumors - Those that exhibit metastasis, including lymph node metastasis outside the field of resection, ascites , or vascular involvement

40. Staging laproscopy Indications Large tumors (>3 cm) Significantly elevated CA19-9 level (>100 U/ mL ) Uncertain findings on CT Body or tail tumors

41. Preoperative preparation Correction of anemia Replenishment of glycogen store Correction of dehydration Injection of vitamin K Adequate IV fluids and mannitol to ensure adequate diuresis Broad spctrum antibiotics 1-2 days prior Enteral or parenteral nutrition Pulmonary physiotherapy Preoperative biliary drainage – contraversial

42. Treatment Head of the pancreas > Pancreaticoduodenectomy is the procedure of choice. (Either Wipple’s or Traverso and Longmire) > Laparoscopic Pancreaticoduodenectomy Body and Tail of the Pancreas Distal pancreatectomy and en bloc splenectomy

43. Pancreaticoduodenectomy – 6 steps 1. A Cattell-Braasch maneuver 2. Extended Kocher maneuver 3. Portal dissection 4. Transect stomech 5. Transect jejunum 6. Transect pancreas and complete retroperitoneal dissection

44. Pancreaticoduodenectomy - reconstructions 1. End to side PJ 2. End to side HJ 3. End to side GJ ( antecolic )

45. Structures removed Distal stomach Gall bladder CBD Head of Pancreas Duodenum Proximal jejunum Regional lymphatics

46. Adjuvant Therapy

47. Palliative Therapy Biliary Obstruction ERCP with metal stent placement Surgical biliary -enteric bypass (Roux-en-Y hepaticojejunostomy )

48. Gastric Outlet Obstruction Endoscopic luminal stenting Double bypass consisting of a Roux-en-Y hepaticojejunostomy and gastrojejunostomy Pain Relief NSAIDS or long acting opioids Celiac nerve block Neurolysis

49. Recent advances Immunotherapy Allogenic tumor cell vaccine under phase 2 trial Angiogenesis inhibitors Becacizumab (anti VEGF) with gemcitabine under phase 3 trial K ras inhibitors Tipifarnib ( farnesyl transferase inhibitor)- studied and showed no improvement in outcome EGFR inhibitors EKB 569 and erlotinib Erlotinib approved for treatment of unresectable cancer( study by NCI of Canada)

50. Cystic neoplasms of the pancreas

51. Cystic neoplasms of the pancreas Second most common exocrine pancreatic neoplasm next to adenocarcinoma . Types Mucinous Serous IPMN

52. Mucinous Cystic Neoplasm Most common cystic neoplasms of the pancreas. Young women, Men are rarely affected. Fifth decade. Typically found in the body and tail of the pancreas

53. Contain mucin -producing epithelium Presence of mucin -rich cells and ovarian-like stroma CT scan – solitary , fine septations , surrounded by a rim of calcification Predictors of malignancy Eggshell calcification, larger tumor size mural nodule on cross-sectional imaging

54. EUS and cyst fluid analyses demonstrate mucin -rich aspirate and high CEA levels (>192 ng / mL ) low levels of amylase Standard treatment - Pancreatic resection

55. Serous Cystic Neoplasm Predilection for the head of the pancreas Vague abdominal pain and less frequently with weight loss and obstructive jaundice Large , wellcircumscribed masses. Microscopy - multiloculated , glycogen-rich small cysts.

56. CT Scan- Central calcification, with radiating septa giving the sunburst appearance (10-20%) Large (>4 cm) or rapidly growing, symptomatic lesion Treatment is Resection Small (<4 cm) , asyptomatic can be observed.

57. Intraductal Papillary Mucinous Neoplasm First described by Ohashi Several names— Mucin secreting carcinoma Villous adenoma of the duct of Wirsung Diffuse intraductal papillary adenocarcinoma Intraductal cystadenoma Mucinous duct ectasia , and Intraductal papillary mucinous tumor.

58. Sixth to seventh decade of life. Commonly in head region. Wide spectrum ranging from benign adenoma, borderline, carcinoma in situ, and invasive adenocarcinoma . Types- Side branch or branch duct IPMN, Main duct IPMNs, Mixed -type IPMNs

59. Side Branch IPMN Involves dilation of the pancreatic duct side branches that communicate with but do not involve the main pancreatic duct. Focal (involving a single side branch) or multifocal Risk of malignant transformation directly related to the size of the cystic dilation Others - mural nodules or general thickening of the cyst wall symptoms like jaundice, pain, and diabetes

60. Small (<1 cm) IPMNs:- Surveillance with CT or MRI in 1 year Asymptomatic cysts ,1 -3 cm:- Imaging at 6 months followed by annual evaluation if no change in size. Cysts larger than 3 cm:- Surgical resection (Partial pancreatectomy ) Risk of invasive malignancy- 10% to 15%

61. Main Duct IPMN Abnormal cystic dilation of the main pancreatic duct with columnar metaplasia Endoscopy – thick mucinous secretions oozing from patulous papilla May be focal or diffuse 30% to 50% risk of harboring invasive pancreatic cancer at the time of presentation.

62. Treatment- Surgical resection (Risk of malignant transforamtion ) Predictors of malignancy- Jaundice, Elevated serum alkaline phosphatase Mural nodules, Diabetes Main pancreatic duct diameter of 7 mm Elevation of the CEA level is not predictive of invasive malignancy

63. CT scans – dilated main pancreatic duct, cysts of varying sizes, and possibly mural nodules. MRCP- localization of mural nodules and pretreatment classification of suspected side branch or main duct types of IPMN Aspirated fluid is typically viscous and clear, contains mucin and columnar mucinous cells with variable atypia Elevated CEA level (>192 ng / mL ; log scale)

64. Mixed-Type IPMN Side branch IPMN that has extended to involve the main pancreatic duct Risk of invasive malignancy at the time of presentation (30% to 50%) Surgical resection is indicated for the treatment

65. Neoplasms of Endocrine Pancreas

66. Paul Langerhans medical student, in 1869 pale staining cells within the pancreas Alpha (A) – G lucagon Beta (B) – I nsulin and amylin Delta (D) – S omatostatin and vasoactive intestinal peptide (VIP) F cells – P ancreatic polypeptide (PP) Gastrin -producing cells are normally present in the fetal pancreas only.

67. ISLET CELL TUMORS Very rare Most are benign and nonfunctional. The incidence of malignancy varies from 10% in insulinomas to almost 100% in glucagonomas . Insulinomas , glucagonomas , and VIPomas arise from the pancreas, whereas most gastrinomas occur in the duodenum.

68. Molecular genetics Distinct from that of pancreatic adenocarcinoma . Transcriptional silencing is believed to play a role in islet cell tumorigenesis . Loss of heterozygosity (LOH) 11q is common in functional pancreatic endocrine tumors LOH 6q is associated with the development of nonfunctional tumors.

69. Insulinoma Most common functioning tumor Equal distribution in the head, body, and tail. 97% are located in the pancreas, remaining 3% are located in the duodenum, splenic hilum , or gastrocolic ligament Whipple’s triad fasting-induced neuroglyopenic symptoms of hypoglycemia low blood glucose levels (40 to 50 mg/ dL ), relief of symptoms after the administration of glucose.

70. 72 hour fast test High level of serum insulin (>5 µU/ mL ) Insulin-to-glucose ratio higher than 0.3 C peptide levels higher than 1.2 µg/ mL CECT or MRI Hyperattenuating because of their rich vascular supply

71. Gastrinoma Second most common functional pancreatic endocrine tumor Cell of origin is not clear, because the normal adult pancreas has no gastrin -producing cells. More common in men Produce Zollinger -Ellison syndrome (ZES) Hypergastrinemia , subsequent severe peptic ulceration, severe diarrhea.

72. Abdominal pain (75%) Diarrhea releived by nasogastric aspiration Symptoms of GERD Gastrinoma triangle (90%) The cystic duct CBD junction The jn between the second and third portions of the duodenum Junction between the neck and body of the pancreas

73. Presence of hypergastrinemia in the presence of increased secretion of gastric acid. An elevated serum gastrin level coupled with a pH lower than 2 in the gastric aspirate Fasting levels of gastrin . higher than 1000 pg/ mL (upper limit of normal of 100 pg/ mL ) An increase of more than 200 pg/ mL in the gastrin value after administration of secretin

74. VIpomas Release high levels of VIP Verner -Morrison syndrome Also known as WDHA syndrome (watery diarrhea, hypokalemia , achlorhydria ) or pancreatic cholera. Solitory , larger than 3 cm ; 75% body and tail Hypokalemia , hypomagnesemia , hypo or achlorhydria , hypercalcemia .

75. Glucagonomas Very rare Tend to be larger, averaging 5 to 10 cm in size Most are malignant Almost always arise in the pancreas and 65% to 75% are found in the body or tail. A fasting glucagon level higher than 50 pmol /L is considered diagnostic. The glucagonoma syndrome: 4Ds: diabetes, dermatitis, deep vein thrombosis, and depression

76. Somatostatinomas   Usually solitary and 85% are larger than 2 cm. Mostly at head of pancreas Ninety percent are malignant Steatorrhea , diabetes mellitus, hypochlorhydria, and gallstones Fasting somatostatin level higher than 14 mol/liter Associated with von Recklinghausen’s disease and pheochromocytomas

77. Nonfunctional Neuroendocrine Tumors Defined as a pancreatic tumor of endocrine origin, with no definable hormonal syndrome. Late in seeking help hence most tumors are malignant and metastasized at the time of presentation Identified by positive immunostaining for chromogranin A or synaptophysin .

78. Localization Cross -sectional imaging with CT or MRI first step in localization. sensitivity is 71% to 82% and is directly related to the size of the tumor. vascular blush in the arterial phase is critical lesions smaller than 1cm cannot be identified. Endoscopic ultrasound (EUS) Overall sensitivity of 93% Greater sensitivity when compared with CT and MRI for detecting tumors < 3 cm Allows for fine-needle aspiration (FNA) of tumors

79. Somatostatin receptor scintigraphy (SRS) Not useful for insulinoma The sensitivity for SRS is over 80% for all pancreatic endocrine tumors excluding insulinomas It has an overall sensitivity of 80% to 100% and specificity higher than 90% for gastrinomas . SRS may not show the exact location of a tumor indicates its vicinity within a few centimeters Angiographic techniques and portal venous sampling (sensitivity higher than 90%) Blind exploration with intraoperative ultrasound

80. treatment The treatment of endocrine tumors is surgical. (pancreatic head resection, distal pancreatic resection, or enucleation .) Performed by open or laparoscopic approaches Insulinoma – Enucleation Metastatic _ Streptozotocin , with or without 5-fluorouracil Gastrinoma Small well encapsulated _ Enucleation Large unencapsulated _ Require segmental resection, including distal pancreatectomy or pancreaticoduodenectomy . Radiation therapy and chemotherapy are ineffective.

81. VIPomas , glucagonomas , somatostatinomas , and nonfunctional pancreatic endocrine tumors- Resection is the treatment of choice for and remains the only curative option. Dacarbazine is uniquely effective against glucagonoma .

82. Thank you