CHAPTER 19

!
THE PANCREAS

!!
Congenital anomalies
• Agenesis
• Pancreas divisum
• Annular pancreas
• Ectopic pancreas – stomach, duodenum, jejunum, Meckel, ileum
!
Classification of Pancreatitis
• Acute
• EtOH, gallstones, idiopathic
• Metabolic – EtOH, hyperlipidemia, hypercalcemia, drugs
• Genetic – PRSS1 (cleavage site on trypsin), SPINK (enzyme that inhibits trypsin activity)
• Mechanical – stones, trauma, iatrogenic
• Vascular – shock, embolism, vasculitis
• Infectious – mumps
• Less common causes:
• other causes of obstruction (tumors, pancreas divisum, biliary sludge, parasites)
• Chronic – repeated bouts of acute pancreatitis
• Chronic EtOH abuse
• Chronic obstruction – pseudocysts, calculi, neoplasms, trauma, pancreas divisum
• Tropical pancreatitis
• Hereditary pancreatitis – SPINK, PRSS1
• CFTR gene mutations
• Autoimmune pancreatitis – type 1 and type 2
!!
Etiology of acute pancreatitis
• Duct obstruction
• Acinar cell injury
• Defective intracellular transport → all ultimately lead to acinar cell injury which results in:
• interstitial inflammation and edema
• proteolysis (proteases)
• fat necrosis (lipases, phospholipases)
• hemorrhage (elastase)
!
Mimics of carcinoma in the pancreas
• Autoimmune pancreatitis
• Groove pancreatitis
• Adenomyomatous hyperplasia of the ampulla of Vater
• Accessory spleen
• Lipomatous hypertrophy of the pancreas
• Hyperplastic lymphoid tissue
• Lymphoepithelial cysts
• Hamartomas
• Granulomas
• Foreign bodies
!
Classification of cystic lesions of the pancreas
• Congenital
• Polycystic disease (AD PCKD and VHL syndrome)
• Inflammatory
• Pseudocysts – amylase rich
• Neoplastic
• Benign
• Serous cystadenomas (micro versus macro – VHL)
• Mucinous cystic neoplasms
• IPMN
• PanIN
• Lymphoepithelial cysts
• Malignant
• High grade mucinous cystic neoplasm
• IPMN with dysplasia
• PanIN with CIS
• Solid pseudopapillary neoplasm (low grade malignant)
• Serous cystadenocarcinoma
!
Solid Pseudopapillary Neoplasm (SPPN)
• arise in tail of pancreas in women
• characterized by poorly cohesive cells
• most are cured buy surgery, but 10% metastasize
• show mutations in CTNNB1 (ie: β-catenin - nuclear positivity)
!
Serous Cystadenoma
• genes often mutated: VHL (pt mutation) and TBCID3

Pancreatic Carcinoma
• PanIN is thought to be the precursor lesion (applies to small caliber ducts <5 mm)
• Risk factors:
• Older age (6—80 yrs)
• Smoking - strongest environmental influence - doubles risk
• Diet rich in fats
• Chronic pancreatitis
• Diabetes
• Molecular alterations in pancreatic cancer:
• PanIN-1A to PanIN-1B: telomere shortening and KRAS - 80-90% (chrom 12p) mutations
• PanIN-2: inactivation of p16 - 95% (chrom 9p)
• PanIN-3: inact’n of p53 - 50-70% (chrom 17p), SMAD4 - 55% (chrom 18q) and BRCA2
• leading to invasive carcinoma
!
Pancreatic Intraepithelial Neoplasia (PanIN):
• Normal: nonmucinous flattened or cuboidal epithelium w/o dysplasia
• PanIN-1A: flat mucinous epithelium w/o dysplasia
• PanIN-1B: papillary mucinous epithelium w/o dysplasia
• PanIN-2: flat or papillary mucinous epithelium with mild to moderate dysplasia (mild to mod nuclear
irregularity, hyperchromasia, and loss of polarity)
• PanIN-3: flat or papillary mucinous epithelium with severe dysplasia (marked nuclear irregularity,
hyerpchromasia, and loss of polarity) often with cribriforming and intraluminal blabbing (budding off
of noncohesive cells)
!
Other precursor lesions of ductal adenocarcinoma:
 • IPMN: intraductal grossly visible (1 cm or more) epithelial neoplasm of mucin producing cells,
arising in main pancreatic duct or its branches; neoplastic epithelium usually papillary, variable
mucin secretion, duct dilatation (cyst formation), and dysplasia
• Associated gene mutations: KRAS, GNAS (these reliably distinguish IPMN from Serous
cystadenoma, via cyst fluid FNA)
• another associated gene: RNF43 (LOH) - encoding intrinsic E3 ubiquitin ligase activity
!!
Features of Chronic Pancreatitis vs Invasive Adenocarcinoma
Chronic Pancreatitis Invasive Ductal Adenocarcinoma
Preserved lobular architecture Haphazard infiltrative pattern
Tubular or oval shaped ducts Irregularly shaped ducts
Ductal epithelial lining intact Partial/incomplete ducts may be seen
Ducts accompanied by islets and/or thick fibrous Bare ducts in fat with only thin rim of fibromuscular
tissue tissue
Acini or stroma b/w ducts and muscular vessels Ducts adjacent to muscular vessels
PNI very rare Perineural invasion may be p[resetn
Little variation in uclear size Nucelar size variation >4:1 may be seen
Nucleoli may be moderately enlarged Nucleoli may exceed 1/4 of nuclear diameter

!
• MCN: benign or potentially LG malignant cystic epithelial neoplasm c/o cells that contain
intracytoplasmic mucin
• much note common in woman, and in the tail (vs head) of pancreas
• can progress to invasive adenocarcinoma
• genes involved: RNF43, KRAS and p53

Inherited predisposition to pancreatic cancer

• Cancer syndromes
• Hereditary breast and ovarian cancer – BRCA2 (4-10 fold risk)
• FAMMM – p16 (20-35 fold risk)
• Peutz-Jeghers syndrome – STK11 (csm 19) (130 fold risk)
• Hereditary
• Family history - unknown genes involved (14-32 fold risk)
• Hereditary pancreatitis – PRSS1 and SPINK (50-80 fold risk)
!
• NB: the mutational profile of cystic fluid can be obtained to get a sense if the tumor is potentially
malignant and should be resected
!
Acinar Cell Carcinoma
• shows prominent acinar cell differentiation
• 15% if those with acinar cell carcinoma develop syndrome of metastatic fat necrosis due due lipase
release into circulation
!
Pancreatocoblastoma
• rare, mainly in kids 1-15 years old
• distinct micro appearance: squamous islands mixed with acinar cells
• malignant, but better px than pancreatic ductal adenocarcinomas
!!
!
REPORTING OF EXOCRINE PANCREATIC CARCINOMA
 • Specimen, Procedure
• Tumor site
• Tumor size
• independent px factor
• Histologic type
• includes ductal adenoma (and subtypes), HG NEC, serous cystadenocarcinoma, mucinous
cystadenocarcinoma, IPMC, acinar cell ca, pancreaticoblastoma, SPPC, others
• Histologic grade
• grade 1 (>95% glands), grade 2 (50-95% glands), grade 3 (≤49% glands), grade 4 (no diff’n or
minimal diff’n in rare, tiny foci)
• for ductal ca, grade has px significance (ie, grade 3 and 4 unfavorable)
• Microscopic tumor extension
• Margins
• NB: 5 margins of Whipple specimen (CBD, stomach, small bowel, pancreatic, uncinate process
(vascular bed) margin
• Treatment effect (if applicable)
• 0 = complete response, 1 = moderate response, 2 = minimal response, 3 = poor response
• LVI and PNI
• both are adverse px factors
• LN mets
• an independent px factor (min of 15 nodes suggested for optimal staging)
• pTNM Staging
• NB: m (multiple primary tumors), r (recurrent), y (post-treatment) descriptors
• pT stage
• pTis = PanIN-3
• pT1: ≤2 cm, limited to pancreas
• pT2: >2 cm, limited to pancreas
• pT3: extends beyond pancreas but w/o involvement of celiac axis or SMA
• pT4: involves celiac axis or SMA
• pN stage
• pN0: no nodes vs pN1: regional nodes involved
• pM stage:
• pM1: distant mets (includes peritoneal seeding or ascitic fluid positivity)
• Additional findings (PanIN, pancreatitis, others)
• Ancillary studies
• Clinical hx (neoadjuvant therapy, familial pancreatitis or syndromes, others)
!!
The Endocrine Pancreas
Classification of DM (11 categories):
• Type 1 DM
• Type 2 DM
• Genetic defects of beta cell function
• MODY (Maturity Onset Diabetes of the Young)– defects in multiple proteins affecting beta cells
and insulin
• Genetic defects in insulin action
• Type A insulin resistance
• Exocrine pancreatic defects
• Chronic pancreatitis
• Iatrogenic
• Neoplasia
• Trauma
• CF
• Infiltrative disease (hemochromatosis)
 • Endocrinopathies
• Acromegaly
• Cushings
• Hyperthyroidism
• Pheo
• Neoplasia
• Glucagonoma
• Adrenal cortical adenoma
• Paraneoplastic syndromes
• Infections
• Drugs – glucocorticoids
• Genetic syndromes
• Down syndrome
• Klinefelter
• Turner
• Prader-Willi
• Gestational diabetes
!
Insulin action and signalling
• Principle action is to increase the rate of glucose transport into striated muscle and adipocytes
• Glucose uptake into other tissues is independent of insulin
• Insulin signalling facilitates the transport of GLUT-4 to the plasma membrane
!
Type 1 DM
Genetic susceptibility
• HLA haplotype
• Variable tandem repeats in the insulin gene – may influence the level of expression of insulin in the
thymus
• Polymorphisms in CTLA-4 (thought to inhibit T-cell response)
!
Environmental factors
• Viral infection:
• Bystander damage leads to activation of autoreactive T cells
• Molecular mimicry
• Viral deja vu – an early viral infection remains latent in the islets and reinfection with a related
virus leads to an immune response in the infected islet cells
!
Mechanisms of beta cell destruction
• Failure of self tolerance in T cells
• Autoantibodies against islet cells are identified but it is not clear if they are involved in causing injury
!
Type 2 DM
• Insulin resistance
• Beta cell dysfunction
!
Complications of DM
• Macrovascular
• Microvascular
• Retinopathy, nephropathy, neuropathy
!
Etiology of complications
• Formation of advance glycosylation end (AGE) products
• AGE bind to a receptor on T cells, endothelium, and vascular sm and lead to a pro-
inflammatory state with release of growth factors
 • AGE can directly cross link ECM proteins and collagen IV – enhances protein deposition and
accelerates atherosclerosis – results in characteristic BM thickening in DM
• Activation of PKC
• Activated VEGF and is pro-inflammatory
• Intracellular hyperglycemia
• Constant influx of glucose in tissues that do not rely on insulin for glucose entry depletes
antioxidant mechanisms – major cause of diabetic neuropathy

Comparison of Type 1 versus Type 2 DM

Type 1 DM Type 2 DM
Clinical Usually children Usually adults
Weight loss Most obese
Islet autoantibodies No autoantibodies
DKA HONK (hyperosmotic, nonketotic
coma)
Genetics HLA, polymorphisms on CTLA4, Linkage to obesity and diabetogenic
VNTR insulin gene genes
Pathogenesis Dysfunction in reg T cells Peripheral insulin resistance
Loss of tolerance Failure of beta cell compensation
Islet autoantigens
Pathology Insulitis Amyoid in islets
Beta cell depletion Mild beta cell depletion
Islet atrophy

!
Histologic findings in DM
• Pancreas
• Reduced islets (type 1)
• Insulitis – lymphocytic infiltrate in the islet (type 1)
• Amyloid within the islets – type 2
• Vascular
• Atherosclerosis
• Myocardial infarction – leading cause of death from DM
• Gangrene
• Hyaline arteriolosclerosis
• Diffuse thickening of BM
• Renal – second leading cause of death from DM, leading cause of ESRD
• Glomerular
• Thickening of the GBM
• Diffuse mesangial sclerosis
• Nodular glomerulosclerosis
• Efferent and afferent arteriolosclerosis and renal atherosclerosis
• Vascular – atherosclerosis and arteriolosclerosis
• Pyelonephritis – papillary necrosis
• Ocular and CNS
!!
Pancreatic endocrine lesions
o Nesidioblastosis – islet hyperplasia
o Infants born to diabetic mothers
o Beckwith-Weidemann syndrome
o Tumors
o May secrete hormone – insulinoma, gastrinoma
 o Tumors associated with syndromes are more likely to be multifocal
▪ MEN1
▪ VHL
▪ NF1
o Insulinomas are generally benign
o Other functional tumors are generally malignant
!!
REPORTING OF PANCREATIC ENDOCRINE NEOPLASMS
• Specimen and Procedure
• Tumor Site
• Tumor Size
• Tumors < 0.5 cm = NE microadenomas
• large tumor size (≥ 3.0 cm - associated with aggressive biologic behaviour)
• an independent px factor
• Tumor Focality
• are often multifocal in MEN1 cases and in up to 30% of gastrinomas and 13% of insulinomas
• Histologic type and grade
• WD NET (G1): < 2 mits/10 hpf; Ki-67 ≤2%
• WD NET (G2): 2 - 20 mits/10 hpf; Ki-67 3-20%
• PD NEC (G3): >20 mits/10 hpf; Ki-67 >20-% ***use checklist for carcinoma of pancreas
• Functional type
• functional of produce clinical syndrome based on secretory product:
• EC cell, serotonin producing (carcinoid syndrome, flushing, diarrhea), rare in pancreas
• Gastrin secreting (gastrinoma) (abdo pain, ulcer disease, diarrhea, GI bleeding)
• Glucagon secreting (glucagonoma) (diabetes, skin rash (necrolytic migratory erythema,
stomatitis)
• Insulin secreting (insulinoma) (hypoglycemia, neurophysch disturbances)
• Somatostatinoma secreting (somatostatinoma) (diabetes, steatorrhea, achlorydia); rarely
encountered
• VIP secreting (VIPoma) (watery diarrhea, hypokalemia, achlorydia)
• Mitotic Rate
• high mitotic rate, marked pleomorphism and tumor necrosis - all correlate with malignant
potential
• count based in 50 hpf (40X objective) and in area of highest mitotic rate and report average per
10 hpf
• Ki-67 index reported as % positive cells in area of highest nuclear labelling
• recommended that 500 to 2000 tumor cells be counted
• Tumor Necrosis
• Microscopic Tumor Extension
• Margins
• LVI and PNI
• Pathologic Staging
• NB: m (multiple primary tumors), r (recurrent), y (post-treatment) descriptors
• pT stage:
• pT1: ≤2 cm, limited to pancreas
• pT2: >2 cm, limited to pancreas
• pT3: extends beyond pancreas but w/o involvement of celiac axis or SMA
• pT4: involves celiac axis or SMA
• pN stage
• pN0: no nodes vs pN1: regional nodes involved
• LN mets are independent px factor
• min nodes for NET has not been established
• pM stage:
 • pM1: distant mets (includes peritoneal seeding or ascitic fluid positivity)
• most common site of mets is liver (can also occur w/o associated regional LN mets)
• Additional Findings (pancreatitis, adenomatosis, others)
• Ancillary studies (Ki-67, others)
• Clinical Hx (syndromes, familial background, clinical findings)
!
Pancreatic Neuroendocrine Tumors
• >50% have liver mets at time of dx
• 5 year survival rate is 65%
• Genetics: 3 primary gene mutations known so far:
• MEN1 - 44%
• DAXX (death-domain associated protein) and ATRX (alpha thalassemia/mental retardation
syndrome X-linked ) - both are req’d for incorporation of H3.3 into telomeres
• there correlated with alternative telomere lengthening (a new cancer pathway)
• TSC2, PTEN, and PIK3CA - 16% mTOR pathway genes (a target for tx)
• can therefore compare the above genes with the main 4 in adenoma for dx certainty
!!

IHC in various pancreatic neoplasms (Odze, 2008)

Acinar Cell Mixed Acinar- Pancreatoblastoma Pancreatic Endocrine Solid Pseudopapillary
Ca Endocrine Ca Neoplasm Neoplasm
Keratin ++ ++ ++ ++ -/+
Vimentin - - - - ++
Trypsin ++ ++ ++ - -
Chromogranin - ++ + ++ -
Synaptophysin - ++ + ++ +
CD56 - ++ + ++ ++
?-antitrypsin + + + -/+ ++
CEA - - + + -
-, usually negative; -/+, usually negative, may be positive; +, often positive; ++, consistently positive