Pancreatic Pathology Janak A. Parikh, MD, MSHS, FACS Clinical Teaching Faculty St. John Providence Hospital
Determination of resectability A 68 year old female presents with a biopsy proven adenoca of the pancreas. A staging CT scan demonstrates a 3 cm hypodense mass in the head of the pancreas with no evidence of extrapancreatic disease. There is evidence of abutment (< 30 O involvement) along the superior mesenteric vein-portal vein confluence. The celiac axis, superior mesenteric artery, and common hepatic artery are uninvolved.
Question The most appropriate management for this patient is: A. Endoscopic placement of a metal biliary stent B. Referral for neoadjuvant chemotherapy C. Surgical exploration with palliative biliary and gastric bypass D. Surgical exploration with pancreaticoduodenectomy E. Surgical exploration with total pancreatectomy
Answer The most appropriate management for this patient is: A. Endoscopic placement of a metal biliary stent B. Referral for neoadjuvant chemotherapy C. Surgical exploration with palliative biliary and gastric bypass D. Surgical exploration with pancreaticoduodenectomy E. Surgical exploration with total pancreatectomy
Pancreatic Cancer 45,000 new cases in 2013 Fourth leading cause of cancer death in the United States Only 10-15% of patients resectable Five year survival 20% for resected patients Five year survival 3% for all stages
CT Resectability-Classification Metastatic evidence of metastatic spread (typically to the liver, peritoneum or lung) Resectable no evidence of extra-pancreatic disease patent SMV/PV Normal tissue plane between tumor and the celiac, CHA, or the SMA. Borderline resectable patent SMV/PV, or short segment occlusion if reconstructable evidence of tumor abutment (< 180 degree or 50% vessel circumference) against celiac, CHA, or SMA Locally advanced SMV/PV occlusion with no option for reconstruction arterial encasement (> 180 degree or 50% vessel circumference) of celiac, CHA, or SMA
Management of severe gallstone pancreatitis 47 year old female presents with epigastric abdominal pain, vomiting and fevers Serum amylase is 4000 IU/ml, Tbili 2.6 mg/dl, AST 400 IU/L, ALT 450 U/L, and Alk Phos 720 U/L On admission she has four Ranson s criteria Ultrasound reveals multiple small gallstones and an 11 mm common bile duct.
Question The most appropriate management for this patient is: A. Endoscopic retrograde cholangiography and endoscopic sphincterotomy within 48 hours of admission B. Endoscopic retrograde cholangiography and endoscopic sphincterotomy prior to discharge C. Laparoscopic cholecystectomy and intraoperative cholangiography within 48 hours of admission D. Laparoscopic cholecystectomy and intraoperative cholangiography before discharge E. Open cholecystectomy and common bile duct exploration before discharge
Answer The most appropriate management for this patient is: A. Endoscopic retrograde cholangiography and endoscopic sphincterotomy within 48 hours of admission B. Endoscopic retrograde cholangiography and endoscopic sphincterotomy prior to discharge C. Laparoscopic cholecystectomy and intraoperative cholangiography within 48 hours of admission D. Laparoscopic cholecystectomy and intraoperative cholangiography before discharge E. Open cholecystectomy and common bile duct exploration before discharge
Gallstone Pancreatitis Acute pancreatitis 240,000/yr (40 cases/100,000) Necrotizing pancreatitis 15-20% (mortality: 15 20%) GSP responsible for 40-50%% of all cases of acute pancreatitis Pathogenesis related to transient obstruction of pancreatic duct Gallstones recovered in stool of 85% of patients with GSP vs. 10% of patients with symptomatic cholelithiasis Jemal, et al. CA 2007; 57: 47
2 Phases: Pathogenesis of Acute Pancreatitis Day 0-14 = SIRS cytokine mediated organ dysfunction Day 15 on = resolution vs. infection of pancreatic necrosis Zymogen activation Generation of inflammatory mediators Ischemia Systemic inflammatory response Multi-organ failure Insult Inflammation Ischemia Necrosis Apoptosis Werner et al. Gut 2005; 54:426-36
% Mortality Severity Scoring Systems in Acute Pancreatitis 20% will have severe disease Clinical scoring systems to predict severity Ranson s criteria Glasgow criteria APACHE-II Balthazar CT Grade A-E A: Normal B: Enlargement (edema) C: Abnl gland + peripanc inflam D: Fluid collection in 1 loc On admission or diagnosis Age White blood cell count Blood glucose LDH SGOT During initial 48 h Hematocrit decrease Blood urea nitrogen increase Serum calcium level Arterial po 2 Base deficit Fluid sequestration 100 20 E: 2 or more fluid collections/gas adjacent to pancreas 0 80 60 40 Acute pancreatitis Alcohol-induced Biliary > 55 years > 16000/mm 3 > 200 mg/dl > 350 U/I > 250 U/I > 10 % > 5 mg/dl > 8 mg/dl > 60 mm Hg > 4 meq/i > 6 I > 70 years > 18000/mm 3 > 220 mg/dl > 400 U/I > 250 U/I > 10 % > 2 mg/dl > 8 mg/dl > 5 meq/i > 4 I 0 to 2 3 to 5 6 to 8 9 to 11 Score
Randomized trials of early ERCP for gallstone pancreatitis Author Yr N ERCP Comp Mortality Timing ERCP Control ERCP Controls Neoptolemos Fan 1988 146 <72 hrs 24* 61 2 8 1993 127 < 24 hrs 0* 12 5 9 Nowak 1995 280 < 24 hrs 17* 36 2* 13 Folsch 1997 121 <72 hrs 46 51 8 4 Acosta 2006 61 < 48 hrs 29* 7 0 0 Oria 2007 102 <72 hrs 21 18 6 2 * Significantly different vs controls
Management of Gallstone Pancreatitis Patients with severe gallstone pancreatitis who fail to improve substantially during the initial 24 hour period should be considered for urgent endoscopic ERCP and endoscopic biliary sphincterotomy Patients with mild GSP should undergo cholecystectomy during the initial hospitalization If the gallbladder not removed risk of recurrent pancreatitis - 90% 3 months recurrence - 50%
Pancreatic Pseudocyst 50 year old male with diabetes and a past history of heavy alcohol use (none in the past year) presents with a 6 week history of left upper quadrant abdominal pain and fullness CT shows calcifications throughout the pancreas, a non dilated pancreatic duct in the head In the tail of the pancreas there is a 8 cm pseudocyst bulging against the transverse mesocolon associated with a dilated pancreatic duct (8 mm)
Question The most appropriate management for this patient is: A. Percutaneous cyst drainage B. Endoscopic cyst gastrostomy C. Surgical cyst gastrostomy D. Surgical Roux en Y pancreatic cyst jejunostomy E. Distal pancreatectomy and splenectomy
Answer The most appropriate management for this patient is: A. Percutaneous cyst drainage B. Endoscopic cyst gastrostomy C. Surgical cyst gastrostomy D. Surgical Roux en Y pancreatic cyst jejunostomy E. Distal pancreatectomy and splenectomy
Pancreatic Pseudocyst A fluid collection contained within a well-defined capsule of fibrous or granulation tissue or a combination of both Does not possess an epithelial lining Persists > 4 weeks Etiology Acute Pancreatitis Chronic pancreatitis Pancreatic trauma Pancreatic neoplasm
Natural History of Pseudocyst ~50% resolve spontaneously Size Nearly all <4cm resolve spontaneously >6cm 60-80% persist, necessitate intervention Cause Traumatic, chronic pancreatitis <10% resolve Duration - Less likely to resolve if persist > 6-8 weeks
Complications Infection GI obstruction Perforation Hemorrhage Recent hemorrhage Pseudoaneurysm Thrombosis Pseudoaneurysm
Pancreatic Pseudocyst Indications for drainage Presence of symptoms (> 6 wks) Enlargement of pseudocyst ( > 6 cm) Complications Suspicion of malignancy Intervention Percutaneous drainage Endoscopic drainage Surgical drainage
Operative Therapy Cystgastrostomy for cysts adhered to posterior wall of stomach Cystduodenostomy cysts in head and uncinate process of pancreas Cystjejunostomy via Roux-en Y limb, for cysts adhered elsewhere i.e. to transverse mesocolon
Management of IPMN A 67 year old male with acute onset right lower quadrant abdominal pain undergoes a CT scan for presumed appendicitis. An incidental 2 cm cyst is identified in the tail of the pancreas. Endoscopic ultrasound reveals a unilocular cyst, no evidence of mural nodularity, and a non dilated main pancreatic duct. Cyst aspiration reveals a cyst fluid amylase of 200,000 U/L and a cyst fluid CEA level of 400 ng/ml.
Question The most appropriate management for this patient is: A. Distal pancreatectomy and splenectomy B. Pancreatic cyst enucleation C. Endoscopic alcohol cyst ablation D. Endoscopic retrograde cholangiopancreatography E. Surveillance with MRI/MRCP in six months
Answer The most appropriate management for this patient is: A. Distal pancreatectomy and splenectomy B. Pancreatic cyst enucleation C. Endoscopic alcohol cyst ablation D. Endoscopic retrograde cholangiopancreatography E. Surveillance with MRI/MRCP in six months
Cystic Pancreatic Neoplasms TYPES OF CYSTIC NEOPLASMS Benign Premalignant Malignant Pseudocyst Serous Cystadenoma (SCN) Solid Pseudopapillary Neoplasm (SPN) Main Duct IPMN (MD-IPMN) Mucinous Cystic Neoplasm (MCN) Branch-Duct IPMN (BD-IPMN) Main Duct IPMN (MD-IPMN) Mucinous Cystic Neoplasm (MCN) Branch-Duct IPMN (BD-IPMN) Cystic Neuroendocrine (PNET)
Cystic Pancreatic Neoplasms SEROUS CYSTADENOMA
Cystic Pancreatic Neoplasms SOLID PSEUDOPAPILLARY NEOPLASM
Cystic Pancreatic Neoplasms MUCINOUS CYSTIC NEOPLASM
Cystic Pancreatic Neoplasms NEUROENDOCRINE TUMOR
Cystic Pancreatic Neoplasms INTRADUCTAL PAPILLARY MUCINOUS NEOPLAMS CT Head CT Body Gross Pathology Microscopic Path
MAKING A DIAGNOSIS
Cystic Pancreatic Neoplasms OBTAIN A THOROUGH HISTORY Symptoms Pain Pancreatic insufficiency New onset diabetes History of pancreatitis Family history of pancreatic cancer
Cystic Pancreatic Neoplasms IS THEIR PANCREATIC DUCTAL COMMUNICATION? Dilated main duct or side-branch on CT/MR MRI/MRCP* EUS Cyst fluid aspirate for amylase ERCP Yes DDx=Pseudocyst, IPMN No DDX=SCN, MCN
Cystic Pancreatic Neoplasms DISTINGUISH BETWEEN MUCINOUS VS. NON-MUCINOUS EUS-guided FNA for: Mucin CEA (>200) ERCP: mucin extruding from ampulla Yes DDx=MCN, IPMN No DDx=Pseudocyst, SCN
Cystic Pancreatic Neoplasms WHO NEEDS AN EUS? All cysts >=1cm to look for high-risk stigmata or worrisome features High-risk stigmata : MPD>=10mm or enhancing solid component Worrisome features : Cyst>=3cm, MPD5-9mm, non-enhancing solid component, thickened or enhancing cyst wall, abrupt change in MPD caliber with distal atrophy, lymphadenopathy
Cystic Pancreatic Neoplasms WHO NEEDS AN EUS? Diagnostic uncertainty Cyst fluid analysis for mucin, CEA, amylase Characterizing risk of malignancy Cyst fluid analysis for molecular markers (investigational)
WHAT TO DO NOW? WHEN TO OPERATE
% Patients Symptomatic SYMPTOMS & CYST PATHOLOGY 100 80 60 40 20 *p<0.05 vs Benign * * 0 Benign Premalignant Malignant
AGE & CYST PATHOLOGY % Patients >70yrs 70 60 50 40 30 20 10 0 *p<0.02 vs Benign & Premalignant Benign Premalignant Malignant *
Cystic Pancreatic Neoplasms PSEUDOCYSTS, SCN, SPN Pseudocysts: Treat if symptomatic (pain, mass effect, infected) Operation: Internal drainage SCN: Treat if symptomatic (pain, mass effect) in good risk patient Operation: Can enucleate if away from MPD; otherwise resection based on location
International Consensus Guidelines Worrisome Features MPD 5-9mm Cyst >3cm Thickened-enhanced cyst wall High-Risk Stigmata MPD>=10mm Enhancing solid component Non-enhancing mural nodule Abrupt change in MPD caliber w/ distal atrophy LAD
Cystic Pancreatic Neoplasms MCN, IPMN 2012 Consensus guidelines MCN and MD-IPMN: Should all be formally resected in appropriate surgical candidates BD-IPMN: Resect if high-risk stigmata present Consider resection for worrisome features
% Invasive or Malignant IPMN INCIDENCE OF MALIGNANCY/ INVASION BY DUCT INVOLVEMENT 60% * 50% 40% Malignant, *P<0.001 Invasive, **P=0.02 57% 30% 20% 19% ** 28% 10% 14% 0% Branch DUCT INVOLVEMENT Main
% Invasive or Malignant IPMN INCIDENCE OF MALIGNANT/ INVASIVE 60% BRANCH DUCT BY SIZE 50% 40% Malignant, P= NS Invasive, P= NS 30% 20% 10% 17% 17% 20% 13% 19% 14% 0% <10mm 10mm-30mm >30mm Size (ICG Category)
% Incidence Mural Nodules 60% MURAL NODULE INCIDENCE : BRANCH DUCT IPMN 50% 40% 30% Mural Nodule * 33% * P= 0.008 * 28% 20% 10% 7% 7% 0% Adenoma Borderline CIS Invasive Grade of Dysplasia
PREDICTORS OF MALIGNANCY MULTIVARIATE ANALYSIS MALIGNANT OR P Main Duct IPMN 6.4 0.009 RADIOGRAPHIC Mural nodule 4.3 <0.01 INVASIVE Main Duct IPMN 5.4 0.02 MALIGNANT OR P Mural nodule 6.2 0.009 OVERALL Cytopathology 5.9 0.0009 INVASIVE Mural nodule 4.3 <0.04 Male Gender 3.6 <0.002 Cytopathology 4.3 <0.04
Cystic Pancreatic Neoplasms IPMN SUMMARY IPMNs occur in elderly pts, M>F Progression to invasive cancer 5-10 yrs Surgery can be performed safely 50-70% noninvasive, 80-100% survival 30-50% invasive, 40-60% survival 10-20% of noninvasive tumors recur 45-65% of invasive tumors recur
Cystic Pancreatic Neoplasms IPMN CONCLUSIONS IPMNs offer a unique opportunity to prevent or treat a less virulent form of pancreatic cancer Surgical resection should be recommended even in fit elderly patients Total pancreatectomy is not routinely recommended Careful follow-up is necessary after resection
Cystic Pancreatic Neoplasms WHEN TO OPERATE Older fit patients malignancy Symptomatic pts premalig or malig Increasing in size premalig or malig Younger asymptomatic cost effective
Cystic Pancreatic Neoplasms WHAT OPERATION Benign and premalignant Enucleation Segmental resection Laparoscopic resection Splenic preservation Main duct IPMN and malignant Resection - negative margins Palliative bypasses
Preoperative localization of insulinoma 45 year old male with acute onset of mental status changes Labs reveal a serum glucose of 30 mg/dl Fasting Proinsulin and C-peptide are elevated CT scan of the abdomen demonstrates no lesions in the pancreas
Question The most appropriate management for this patient is: A. magnetic resonance pancreatography B. octreotide scan C. ERCP D. EUS E. Arteriography with selective venous sampling
Answer The most appropriate management for this patient is: A. magnetic resonance pancreatography B. octreotide scan C. ERCP D. EUS E. Arteriography with selective venous sampling
Pancreatic Endocrine Tumors Incidence = 1 in 100,000; 2500 new cases each year in US Adeno:PEN 125:1 Second most common source of isolated liver metastases after colorectal cancer Secrete biologically active substances resulting in disabling symptoms Sporadic or association with MEN1
PNET: Insulinoma Sx: hypoglycemia (fasting <45), neuroglycopenic symptoms, relief of symptoms with glucose (Whipple s triad); obesity (wt gain) Weakness Diaphoresis Shaking Blurry vision Speech disturbances Confusion
PNET: Insulinoma Diagnosis Elevated serum insulin glucose ratio (ratio>0.3) Elevated C-peptide >1.7 72 hour fasting test Admission and glucose monitoring every 2 hours Insulin levels when glucose<50mg/dl Sensitivity: 75% at 24hrs, 90% at 48hrs, 98% at 72hrs Insulin >5 in setting of hypoglycemia highly suggestive WU: NO octreotide scan; CT/MRI/EUS Even distribution in pancreas (head/body/tail) Can hide in duodenum, splenic hilum, gastrocolic ligament 10% malignant, 10% multiple tumors, 10% MEN 1
PNET: Insulinoma Tend to be small tumors (<2 cm) Usually are solitarysolitary Benign (>90%) Uniformly distributed throughout pancreas Pre-operative localization difficult CT, US, and MRI have a <50% sensitivity Don t light up with (octreotide) scanning EUS - 85%sensitivity EUS especially useful for detection of small NETs (< 2.5 cm) missed by other imaging studies Arteriography with selective venous sampling has sensitivity in the 80%-90% range but is an invasive
PNET: Gastrinoma Sx: Diarrhea (improved with NGT), refractory ulcers or ulcers in unusual locations Dx: Serum gastrin >1000, Secretin stimulation test (gastrin increase >200) WU: Octreotide scan is best, CT/MR/EUS Tx: Resection, most in gastrinoma triangle (CD, panc neck/body, D2/D3) Located in duodenum in up to 60% 25% associated with MEN I (usually duodenum and multiple)
PNET: Gastrinoma Causes of hypergastrinemia High acid ZES (gastrinoma) GOO G-cell hyperplasia Retained antrum Low acid H2 blocker/ppi Atrophic gastritis Pernicious anemia Vitiligo Achlorhydria ESRD Vagotomy
PNET: Somatostatinoma Sx: Steatorrhea, Cl, gallstones, DM Dx: Somatostatin level 100-400pg/dL (14mol/L fasting) WU: Octreotide, CT/MR/EUS Tx: Resection Nearly all are malignant NOT associated with MEN1, but associated with pheochromocytoma and von Recklinghausen s (NF1)
Can be associated with MEN1 (10%) PNET: VIPoma Sx: watery diarrhea (persists despite fasting or NGT), K Cl (WDHA) Dx: elevated serum VIP (225-2000) WU: Octrotide scan, CT/MR, 10% can be extrapancreatic Tx: Resection 75% found in body/tail pancreas 50% malignant
PNET: Glucagonoma Sx: Necrolytic migratory erythema (dematitis), DM, anemia Dx: Glucagon 200-2000, glucagonoma syndrome: 4Ds (DM, dermatits, DVT, depression) WU: Octreotide scan, CT/MR/EUS Tx: Resection Most found in body/tail of pancreas Nearly all are malignant